FC RECEPTOR-HOMOLOG 5 (FCRH5) SPECIFIC BINDING MOLECULES AND BISPECIFIC T-CELL ENGAGING ANTIBODIES INCLUDING SAME AND RELATED METHODS

Cross-Reference to Related Applications

[0001] This application claims priority from U.S. provisional application No. 63/424,843, filed November 11, 2022, entitled “FC RECEPTOR-HOMOLOG 5 (FCRH5) SPECIFIC BINDING MOLECULES AND BISPECIFIC T-CELL ENGAGING ANTIBODIES INCLUDING SAME AND RELATED METHODS”, the contents of which are incorporated by reference in their entirety.

Incorperation by Reference of Sequence Listing

[0002] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled 21737-20002.4O.xml created November 9, 2023, which is 231,332 bytes in size. The information in the electronic format of the Sequence Listing is incorporated by reference in its entirety.

Field

[0003] The present disclosure relates in some aspects to molecules that bind to Fc Receptor homolog 5 (FcRH5), in particular, to human antibodies specific for FcRH5, including antibody fragments and related binding molecules and recombinant receptors that include the same. In some aspects, among the binding molecules of the present disclosure are bispecific antibodies directed to FcRH5 and CD3. The disclosure further relates to polynucleotides that encode the binding molecules, including the antibodies or bispecific antibodies. The present disclosure further relates to pharmaceutical compositions and methods and uses of such binding molecules for treatment of diseases in which specific targeting, and in some aspects T-cell-mediated killing, of cells that express FcRH5 is desired.

Background

[0004] Fc receptor-like (FcRL) proteins, also known as Fc receptor homolog (FcRH) proteins, are a family of cellular receptors homologous to FcyRI and are predominantly expressed by B cells. FcRH5, also known as FcRL5, is expressed on both mature B cells and plasma cells. FcRH5 has been implicated in human diseases, including cancer and autoimmune conditions. In particular, FcRH5 has been shown to be overexpressed on malignant B cells of hairy cell leukemia, chronic lymphocytic leukemia, mantle cell lymphoma and multiple myeloma patients. Therapeutics targeting FcRH5 and for killing malignant cells expressing FcRH5 are needed. Provided are embodiments that meet such needs. Brief Description of Drawings

[0005] FIG. l.depicts an exemplary IgGl 2+1 bispecific antibody format.

[0006] FIG. 2A and 2B depicts tumor cell killing and INFy cytokine release T cell activation assays, respectively, in vitro of two exemplary bi-specific antibody formats (TCE_A and TCE_B) and 1+1 antibody controls (TCE_E and TCE-F) against the exemplary tumor cell line Mino cells.

[0007] FIG. 2C depicts results of T cell binding for the two exemplary bi-specific antibody formats (TCE_A and TCE_B) and 1+1 antibody controls (TCE_E and TCE-F).

[0008] FIGS. 3A-3D depict tumor cell killing and IFN y cytokine production for the exemplary bispecific construct TCE_A using various cell types, including Rec-1 cells in FIG. 3A, Mino cells in FIG. 3B, Jeko-1 cells in FIG. 3C, and the FcRH5 negative cell line Karpas 422 cells in FIG. 3D.

[0009] FIGS. 4A-4C depict antitumor activity, IFN-y cytokine release, and T cell activation (as assessed by CD69 positive cells) after incubation with exemplary 2+1 TCE-A construct, 1+1 antibody comparator and HEExCD3 control (2+1) in co-cultures of T cells and tumor cell lines, either Rec-1 cells (FIG. 4A), Mino cells (FIG. 4B) or Karpas 422 (FIG. 4C).

[0010] FIG. 5 depicts binding of the exemplary 2+1 TCE-A construct, 1+1 antibody comparator and HEExCD3 control (2+1) to T cells.

[0011] FIG. 6A- J depicts measures of cytokine release by bi-specific TCE constructs or controls when incubated with human PBMC samples in the absence of target cells, including cytokines INF-y (FIG. 6A), IL-ip (FIG. 6B), TNF-a (FIG. 6C), IE-2 (FIG. 6D), IE-4 (FIG. 6E), IL-6 (FIG. 6F), IL-8 (FIG. 6G), IL-10 (FIG. 6H), IL-12p70 (FIG. 61), and IL-13 (FIG. 6J).

[0012] FIG. 7 and FIG. 8A depict tumor volume reduction in hNSG MINO xenograft mouse model when administered varying doses of the exemplary TCE-A 2+1 bispecific construct or controls in two different donors, donor 1 shown in FIG. 7 and donor 2 shown in FIG. 8A.

[0013] FIG. 8B depicts immunohistochemistry (IHC) for CD4 and CD8 T cell infiltration in tumors collected from hNSG MINO xenograft mice administered the TCE-A 2+1 bispecific construct or control.

[0014] FIG. 9A and FIG. 9B depict inflammatory cytokine levels in hNSG MINO xenograft mice treated with the exemplary TCE-A 2+1 bispecific construct or controls as seen in the tumors (FIG. 9A) and in plasma (FIG. 9B).

Summary

[0015] Provided herein is a bispecific antibody comprising two anti- Fc receptor-like protein 5 (FcRH5) binding region, one anti-CD3 binding region and a heterodimeric Fc, wherein: each anti- FcRH5 binding region is a Fab comprising a first heavy chain variable region (VH1) and a heavy chain constant region 1 (CHI), and a light chain (LC) comprising a light chain variable region (VL) and a light chain constant region (CL); the anti-CD3 binding region is a Fab comprising a second heavy chain variable region (VH2) and a CHI, and the LC comprising the VL and the CL; the LC is a common light chain, wherein the LC of each binding region has the same sequence and is associated with each VH1-CH1 and with the VH2-CH1; the VH1-CH1 of one anti-FcRH5 binding region is comprised in a first heavy chain (HC1); the VH1-CH1 of the other anti-FcRH5 binding region and the VH2-CH2 of the anti-CD3 binding region is comprised in a second heavy chain (HC2); and the heterodimeric Fc comprises a first and second polypeptide each comprising a hinge-CH2-CH3, wherein the first polypeptide of the heterodimeric Fc is linked to the VH-CH1 of the HC1 and the second polypeptide of the heterodimeric Fc is linked to the VH2-CH1 of HC2.

[0016] In some of any of the provided embodiments, the bispecific antibody comprises: (a) a first polypeptide that is the HC1 comprising a first amino acid sequence having the formula: VH1-CH1 and a second amino acid sequence having the formula: hinge-CH2-CH3; (b) a second polypeptide that is the HC2 comprising a first amino acid sequence having the formula: VH1-CH1, a second amino acid sequence having the formula: VH2-CH1 and a third amino acid sequence having the formula: hinge-CH2-CH3; and (c) a third, fourth and fifth polypeptide that is the common light chain (LC) comprising an amino acid sequence having the formula: VL-CL.

[0017] In some of any of the provided embodiments, the LC comprises a VL comprising a complementarity determining region 1 (CDRL1) set forth in SEQ ID NO: 81, a CDRL2 set forth in SEQ ID NO: 82 and a CDRL3 set forth in SEQ ID NO: 83; or the LC comprises a VL comprising a CDRL1 set forth in SEQ ID NO:81, a CDRL2 set forth in SEQ ID NO:82 and a CDRL3 set forth in SEQ ID NO: 100.

[0018] In some of any of the provided embodiments, the VL comprises a sequence of amino acids that exhibits at least 85%, at least 90% or at least 95% sequence identity to SEQ ID NO:31. In some of any of the provided embodiments, the VL comprises the sequence of amino acids set forth in SEQ ID NO: 31. In some of any of the provided embodiments, the VL comprises a sequence of amino acids that exhibits at least 85%, at least 90% or at least 95% sequence identity to SEQ ID NO:99. In some of any of the provided embodiments, the VL comprises the sequence of amino acids set forth in SEQ ID NO:99. In some of any of the provided embodiments, the LC comprises a sequence of amino acids that exhibits at least 85%, at least 90% or at least 95% sequence identity to SEQ ID NO: 102. In some of any of the provided embodiments, the LC comprises the sequence of amino acids set forth in SEQ ID NO: 102.

[0019] In some of any of the provided embodiments, one of the anti-FcRH5 binding region is fused to the anti-CD3 binding region. In some of any of the provided embodiments, the regions are fused indirectly via a linker. In some of any of the provided embodiments, the linker is a peptide linker. In some of any of the provided embodiments, the linker is a GS linker of 5-20 amino acids. In some of any of the provided embodiments, the linker comprises GGGGSGGGGS (SEQ ID NO:91). In some of any of the provided embodiments, the linker further comprises a partial hinge sequence at the N-terminus of the peptide linker to allow the anti-FcRH5 binding region to associate with the LC. In some of any of the provided embodiments, the partial hinge sequence is EPKSCD (SEQ ID NO: 85).

[0020] Also provided herein is a bispecific antibody comprising a first binding region that binds to Fc receptor-like protein 5 (FcRH5), a second binding region that binds to FcRH5 and a third binding region that binds to CD3, wherein the bispecific antibody comprises: (a) a first heavy chain (HC1) comprising a first amino acid sequence having the formula: VH1-CH1 and a second amino acid sequence having the formula: hinge-CH2-CH3; (b) a second heavy chain (HC2) comprising a first amino acid sequence having the formula: VH1-CH1, a second amino acid sequence having the formula: VH2-CH1 and a third amino acid sequence having the following formula: hinge-CH2-CH3; (c) a first light chain (LC1) comprising an amino acid sequence having the following formula: VL- CL; (d) a second light chain (LC2) comprising an amino acid sequence having the following formula: VL-CL; and (e) a third light chain (LC3) comprising an amino acid sequence having the following formula: VL-CL wherein: VH1 is a first heavy chain variable region; VH2 is a second heavy chain variable region; CHI is a heavy chain constant region 1; CH2 is a heavy chain constant region 2 and CH3 is a heavy chain constant region 3; VL is a light chain variable region and CL is a light chain constant region; VH1-CH1 of HC1 associates with LC1 to form the first binding region; VH1-CH1 of HC2 associates with LC2 to form the second binding region; and VH2-CH1 of HC2 associates with LC3 to form the third binding region.

[0021] In some of any of the provided embodiments, the hinge-CH2-CH3 of HC1 is a first polypeptide chain of a heterodimeric Fc and the hinge-CH2-CH3 of HC2 is a second polypeptide chain of the heterodimeric Fc. In some of any of the provided embodiments, each of LC1, LC2 and LC3 is a common light chain that has the same amino acid sequence. In some of any of the provided embodiments, each of the LC1, LC2 and LC2 comprises: a VL comprising a complementarity determining region 1 (CDRL1) set forth in SEQ ID NO:81, a CDRL2 set forth in SEQ ID NO:82 and a CDRL3 set forth in SEQ ID NO:83; or a VL comprising a CDRL1 set forth in SEQ ID NO:81, a CDRL2 set forth in SEQ ID NO:82 and a CDRL3 set forth in SEQ ID NO: 100. In some of any of the provided embodiments, the VL of each of the LC1, LC2 and LC2 comprises a sequence of amino acids that exhibits at least 85%, at least 90% or at least 95% sequence identity to SEQ ID NO:31. In some of any of the provided embodiments, the VL of each of the LC1, LC2 and LC2 comprises the sequence of amino acids set forth in SEQ ID NO:31. In some of any of the provided embodiments, the VL of each of the LC1, LC2 and LC2 comprises a sequence of amino acids that exhibits at least 85%, at least 90% or at least 95% sequence identity to SEQ ID NO:99. In some of any of the provided embodiments, the VL of each of the LC1, LC2 and LC2 comprises the sequence of amino acids set forth in SEQ ID NO:99. In some of any of the provided embodiments, each of the LC1, LC2 and LC2 comprises a sequence of amino acids that exhibits at least 85%, at least 90% or at least 95% sequence identity to SEQ ID NO:102. In some of any of the provided embodiments, each of the LC1, LC2 and LC2 comprises the sequence of amino acids set forth in SEQ ID NO: 102. In some of any of the provided embodiments, the first amino acid sequence VH1-CH1 of HC2 is linked to a partial hinge sequence at its C-terminus to allow the HC2 to associate with the LC2. In some of any of the provided embodiments, the partial hinge sequence is EPKSCD (SEQ ID NO: 85).

[0022] In some of any of the provided embodiments, the first amino acid sequence of HC2 is fused to the second amino acid sequence of HC2 indirectly via a linker, optionally wherein the linker is linked at the C-terminus of the partial hinge sequence. In some of any of the provided embodiments, the linker is a peptide linker. In some of any of the provided embodiments, the linker is a GS linker of 5-20 amino acids. In some of any of the provided embodiments, the linker comprises GGGGSGGGGS (SEQ ID NO:91).

[0023] In some of any of the provided embodiments, the VH1 is selected from the group consisting of: (a) a VH1 comprising a heavy chain complementarity determining region 1 (CDR-H1), a heavy chain complementarity determining region 2 (CDR-H2) and a heavy chain complementarity determining region 3 (CDR-H3) contained within SEQ ID NO:1, (b) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:2; (c) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NOG; (d) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:4; (e) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NOG; (f) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NOG; (g) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:7; (h) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NOG; (i) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:9; (j) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO: 10; (k) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:11; (1) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO: 12; (m) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:13; (n) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO: 14; (o) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:15; (p) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:16; (q) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO: 17; (r) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:18; (s) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO: 19; (t) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:20; (u) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:21; (v) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:22; (w) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:23; (x) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:24; (y) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:25; (z) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:26; (aa) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:27; (bb) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:28; (cc) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO: 29; and(dd) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:30.

[0024] In some of any of the provided embodiments, the VH1 comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:29. In some of any of the provided embodiments, the VH1 is selected from the group consisting of: (a) a VH1 region comprising a heavy chain complementarity determining region 1 (CDR-H1), a heavy chain complementarity determining region 2 (CDR-H2) and a heavy chain complementarity determining region 3 (CDR-H3) comprising the sequence set forth in SEQ ID NOS:32, 33, 34, respectively; (b) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:35, 36, and 37, respectively; (c) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:38, 39, 40, respectively; (d) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:41, 42, 43, respectively, (e) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:41, 44, 45, respectively; (f) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:46, 47, 34, respectively; (g) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:48, 49, 34, respectively; (h) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:46, 50, 34, respectively; (i) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 46, 50, 51, respectively; (j) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:48, 49, 51, respectively; (k) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:46, 52, 51, respectively; (1) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 46, 47, 51, respectively; (m) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 46, 52, 51, respectively; (n) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 46, 47, 51, respectively; (o) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:54, 55, 37, respectively; (p) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:56, 57, 58, respectively; (q) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:56, 57, 59, respectively; (r) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:60, 61, 62, respectively; (s) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:63, 64, 40, respectively; (t) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:65, 66, 40, respectively; (u) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:65, 66, 67, respectively; (v) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:63, 64, 68, respectively; (w) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:65, 66, 69, respectively; (x) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 65, 66, 70, respectively; (y) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 65, 66, 71, respectively; (z) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 72, 73, 74, respectively; (aa) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 65, 66, 75, respectively; (bb) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 65, 76, 77, respectively; (cc) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:78, 76, 79, respectively; (dd) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 63, 76, 67, respectively.

[0025] In some of any of the provided embodiments, the VH1 region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:78, 76, 79, respectively. In some of any of the provided embodiments, (a) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:1, (b) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:2; (c) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:3; (d) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:4; (e) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:5; (f) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:6; (g) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:7; (h) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:8; (i) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:9; (j) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO 10; (k) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:11; (1) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 12; (m) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 13; (n) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 14; (o) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 15; (p) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 16; (q) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 17; (r) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:18; (s) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 19; (t) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:20; (u) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:21; (v) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:22; (w) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:23; (x) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:24; (y) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:25; (z) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:26; (aa) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:27; (bb) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:28; (cc) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:29; or (dd) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:30.

[0026] In some of any of the provided embodiments, the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:29. In some of any of the provided embodiments, (a) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO:1, (b) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO:2; (c) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO:3; (d) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO:4; (e) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO:5; (f) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO: 6; (g) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO:7; (h) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO:8; (i) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO:9; (j) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO 10; (k) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO:11; (1) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO: 12; (m) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO: 13; (n) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO: 14; (o) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO: 15; (p) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO: 16; (q) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO:17; (r) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO:18; (s) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO: 19; (t) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO: 20; (u) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO:21; (v) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO:22; (w) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO:23; (x) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO:24; (y) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO:25; (z) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO:26; (aa) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO:27; (bb) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO:28; (cc) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO:29; or (dd) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO:30. [0027] In some of any of the provided embodiments, the VH1 region comprises the amino acid sequence set forth in SEQ ID NO:29. In some of any of the provided embodiments, the CHI of the VH1-CH1 comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:84. In some of any of the provided embodiments, the CHI of the VH1-CH1 comprises the amino acid sequence set forth in SEQ ID NO:84. In some of any of the provided embodiments, the VH1-CH1 comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:87. In some of any of the provided embodiments, the VH1-CH1 comprises the amino acid sequence set forth in SEQ ID NO:87. In some of any of the provided embodiments, the VH1-CH1 of the HC2 is linked to a partial hinge sequence at its C-terminus to allow the HC2 to associate with the LC2. In some of any of the provided embodiments, the partial hinge sequence is EPKSCD (SEQ ID NO: 85). In some of any of the provided embodiments, the VH1-CH1 of the HC2 linked to the partial hinge sequence comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:90. In some of any of the provided embodiments, the VH1-CH1 of the HC2 linked to the partial hinge sequence comprises the amino acid sequence set forth in SEQ ID NO:90.

[0028] In some of any of the provided embodiments, the VH2 comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:92. In some of any of the provided embodiments, the VH2 comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:93, 94, 95, respectively. In some of any of the provided embodiments, the VH2 comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:92. In some of any of the provided embodiments, the VH2 comprises the sequence set forth in SEQ ID NO: 92. In some of any of the provided embodiments, the VH2 comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO: 103. In some of any of the provided embodiments, the VH2 comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:93, 104, 95, respectively. In some of any of the provided embodiments, the VH2 comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 103. In some of any of the provided embodiments, the VH2 comprises the sequence set forth in SEQ ID NO: 103.

[0029] In some of any of the provided embodiments, the CHI of the VH2-CH1 comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:84. In some of any of the provided embodiments, the CHI of the VH2-CH1 comprises the amino acid sequence set forth in SEQ ID NO:84. In some of any of the provided embodiments, the VH2-CH1 comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:96. In some of any of the provided embodiments, the VH2-CH1 comprises the amino acid sequence set forth in SEQ ID NO:96. In some of any of the provided embodiments, the VH2-CH1 comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 106. In some of any of the provided embodiments, the VH2-CH1 comprises the amino acid sequence set forth in SEQ ID NO: 106.

[0030] Provided herein is a bispecific antibody comprising: a) a first heavy chain comprising in order: a first binding region that binds to FcRH5 comprising the amino acid sequence set forth in SEQ ID NO: 87 and a first polypeptide chain of a heterodimeric Fc; b) a second heavy chain comprising in order: a second binding region that binds to FcRH5 comprising the amino acid sequence set forth in SEQ ID NO:90, a linker, a third binding region that binds to CD3 comprising the amino acid sequence set forth in SEQ ID NO:96, and a second polypeptide chain of the heterodimeric Fc; and c) three copies of a common light chain comprising the amino acid sequence set forth in SEQ ID NO: 102, wherein each common light chain is associated with one of the first binding region, the second binding region and the third binding region.

[0031] Also provided herein is a bispecific antibody comprising: a) a first heavy chain comprising in order: a first binding region that binds to FcRH5 comprising the amino acid sequence set forth in SEQ ID NO:87 and a first polypeptide chain of a heterodimeric Fc; b) a second heavy chain comprising in order: a second binding region that binds to FcRH5 comprising the amino acid sequence set forth in SEQ ID NO:90, a linker, a third binding region that binds to CD3 comprising the amino acid sequence set forth in SEQ ID NO: 106, and a second polypeptide chain of the heterodimeric Fc; and c) three copies of a common light chain comprising the amino acid sequence set forth in SEQ ID NO: 102, wherein each common light chain is associated with one of the first binding region, the second binding region and the third binding region.

[0032] In some of any of the provided embodiments, each of the first and second polypeptide of the heterodimeric Fc comprises one or more amino acid substitutions in a wild-type Fc polypeptide region to effect heterodimer formation between the first polypeptide and the second polypeptide. In some of any of the provided embodiments, the wild-type Fc region is an IgGl Fc region. In some of any of the provided embodiments, the wild-type Fc region comprises the sequence set forth in SEQ ID NO: 122.

[0033] In some of any of the provided embodiments, the one more amino acid substitutions are a knob-into-hole modification or a charge mutation to reduce or prevent self-association due to charge repulsion. In some of any of the provided embodiments, the one or more substitutions are a knob-into- hole modification. In some of any of the provided embodiments, the one or more amino acid substitutions of the first Fc polypeptide comprise Thr366Ser, Leu368Ala and Tyr407Val and the one or more amino acid substitutions of the second Fc polypeptide of the heterodimeric Fc comprises the Thr366Trp. In some of any of the provided embodiments, the one or more amino acid substitutions of the first Fc polypeptide or the second Fc polypeptide comprise T350V, L351Y, F405A and Y407V and the other of the one or more amino acid substitutions of the first Fc polypeptide or the second Fc polypeptide of the heterodimeric Fc comprises T350V, T366L, K392L and T394W. In some of any of the provided embodiments, the amino acid substitution is a charge mutation to increase electrostatic complementarity of the polypeptides. In some of any of the provided embodiments, the heterodimeric Fc region comprises one or more amino acid substitutions to reduce binding affinity to an Fc receptor and/or to reduce effector function, optionally as compared to a wild-type IgGl Fc domain. In some of any of the provided embodiments, the one or more amino acid substitutions are selected from L234A, L234V, L235A, L235E, G237A, D265S, S267K, R292C, N297G, V302C, and P329G by EU numbering. In some of any of the provided embodiments, the one or more amino acid substitution comprises L234A and L235A. In some of any of the provided embodiments, the one or more amino acid substitution comprises L234A, L235A, and D265S. In some of any of the provided embodiments, the one or more amino acid substitution comprises L234A, L235A, and P329G. In some of any of the provided embodiments, one or both polypeptides of the heterodimeric Fc lacks Lys447.

[0034] In some of any of the provided embodiments, one of the first polypeptide and the second polypeptide of the heterodimeric Fc region comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity SEQ ID NOS: 124, 126 or 128; and the other of the first polypeptide and second polypeptide of the heterodimeric Fc region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity SEQ ID NOS: 125, 127 or 129. In some of any of the provided embodiments, one of the first polypeptide and the second polypeptide of the heterodimeric Fc region comprise the amino acid sequence set forth in any one of SEQ ID NOS: 124, 126 or 128; and the other of the first polypeptide and the second polypeptide of the heterodimeric Fc region comprises the amino acid sequence set forth in any one of SEQ ID NOS: 125, 127 or 129. In some of any of the provided embodiments, the first polypeptide of the heterodimeric Fc region comprise the amino acid sequence set forth in SEQ ID NO: 126 and the second polypeptide of the heterodimeric Fc region comprises the amino acid sequence set forth in SEQ ID NO: 127. In some of any of the provided embodiments, the first polypeptide of the heterodimeric Fc region comprise the amino acid sequence set forth in SEQ ID NO: 128 and the second polypeptide of the heterodimeric Fc region comprises the amino acid sequence set forth in SEQ ID NO: 129.

[0035] Provided herein is a bispecific antibody comprising: a) a first heavy chain comprising a first binding region that binds to FcRH5, wherein the first heavy chain comprises the amino acid sequence set forth in SEQ ID NO:89; b) a second heavy chain comprising a second binding region that binds to FcRH5 and a third binding region that binds to CD3, wherein the second heavy chain comprises the amino acid sequence set forth in SEQ ID NO:98; and c) three copies of a common light chain comprising the amino acid sequence set forth in SEQ ID NO: 102, wherein each common light chain is associated with one of the first binding region, the second binding region or the third binding region.

[0036] Provided herein is a bispecific antibody comprising: a) a first heavy chain comprising a first binding region that binds to FcRH5, wherein the first heavy chain comprises the amino acid sequence set forth in SEQ ID NO:89; b) a second heavy chain comprising a second binding region that binds to FcRH5 and a third binding region that binds to CD3, wherein the second heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 107; and c) three copies of a common light chain comprising the amino acid sequence set forth in SEQ ID NO: 102, wherein each common light chain is associated with one of the first binding region, the second binding region or the third binding region.

[0037] In some of any of the provided embodiments, the FcRH5 is human FcRH5, optionally wherein the FcRH5 has the amino acid sequence set forth in SEQ ID NO: 130. In some of any of the provided embodiments, the first and second binding region bind FcRH5 within the membrane proximal domain 9. In some of any of the provided embodiments, the first and second binding region bind to cell-surface expressed FcRH5. In some of any of the provided embodiments, the first and second binding regions do not bind to soluble FcRH5.

[0038] In some of any of the provided embodiments, the first and second binding regions exhibit no binding or weak binding to FcRHl, FcRH2, FcRH3 and/or FcRH4, optionally wherein the weak binding is a dissociation constant (KD) of 100 nM or more, more optionally wherein binding is as determined by surface plasmon resonance (SPR), e.g. Example 3. In some of any of the provided embodiments, the first and second binding regions exhibit no or weak binding to FcRHl, FcRH2, FcRH3 and FcRH4, optionally wherein the weak binding is a dissociation constant (KD) of 100 nM or more, more optionally wherein binding is as determined by surface plasmon resonance (SPR), e.g. Example 3.

[0039] In some of any of the provided embodiments, the first and second binding regions have a dissociation constant (KD) for binding FcRH5 of less than about 5 nM. In some of any of the provided embodiments, the first and second binding regions have a KD for binding FcRH5 of about 0.05 and about 2 nM, optionally as determined by surface plasmon resonance (SPR), e.g. Example 3. In some of any of the provided embodiments, the CD3 is CD3epsilon (CD3a). In some of any of the provided embodiments, the CD3 is human CD3epsilon. In some of any of the provided embodiments, the bispecific antibody does not induce T cell activation in the absence of tumor antigen, optionally as determined by assessing cytokine release after incubation of the bispecific antibody with normal healthy donor PBMCs for about 24 hours, e.g. Example 5. In some of any of the provided embodiments, the bispecific antibody binds to an FcRH5-expressing target cell and a CD3-expressing T cell. In some of any of the provided embodiments, the bispecific antibody mediates cytolysis of the target cell by the CD3-expressing T cell. [0040] Provided herein is a polynucleotide encoding a heavy chain or a light chain of any of the provided bispecific antibodies. Provided herein is a set of polynucleotides encoding the heavy(s) and the light chains(s) of any of the provided bispecific antibodies.

[0041] Provided herein is a set of polynucleotides comprising: a) a first polynucleotide encoding a first heavy chain comprising a first binding region that binds to FcRH5, wherein the first polynucleotides comprises the nucleotide sequence set forth in SEQ ID NO:111; b) a second polynucleotide encoding a second heavy chain comprising a second binding region that binds to FcRH5 and a third binding region that binds to CD3, wherein the second polynucleotide comprises the nucleotide sequence set forth in SEQ ID NO: 112; and c) a third polynucleotide encoding a common light chain comprising the nucleotide sequence set forth in SEQ ID NO: 110.

[0042] Provided herein is a set of polynucleotides comprising: a) a first polynucleotide encoding a first heavy chain comprising a first binding region that binds to FcRH5, wherein the first polynucleotides comprises the nucleotide sequence set forth in SEQ ID NO:111; b) a second polynucleotide encoding a second heavy chain comprising a second binding region that binds to FcRH5 and a third binding region that binds to CD3, wherein the second polynucleotide comprises the nucleotide sequence set forth in SEQ ID NO: 113; and c) a third polynucleotide encoding a common light chain comprising the nucleotide sequence set forth in SEQ ID NO: 110.

[0043] Provided herein is a vector comprising the any of the provided polynucleotides. Provided herein is a set of vectors, wherein each vector of the set comprises a polynucleotide of any of the provided set of polynucleotides.

[0044] In some of any of the provided embodiments, the vector is an expression vector. In some of any of the provided embodiments, the vector is a viral vector or a eukaryotic vector, optionally wherein the eukaryotic vector is a mammalian vector.

[0045] Provided herein is a cell, comprising any of the provided polynucleotide or the set for polynucleotides, or any of the provided vector or set of vectors. In some of any of the provided embodiments, the cell is recombinant or isolated. In some of any of the provided embodiments, the cell is a mammalian cell. In some of any of the provided embodiments, the cell is a HEK293 or CHO cell.

[0046] Provided herein is a method of producing a bispecific antibody, the method comprising introducing into a cell any of the provided polynucleotide or set of polynucleotides or any of the provided vector or set of vectors and culturing the cell under conditions to produce the bispecific antibody.

[0047] Provided herein is a method of producing a bispecific antibody, the method comprising culturing any of the provided cells under conditions in which the bispecific antibody is produced by the cell. Provided herein is a bispecific antibody produced by any of the provided methods. [0048] Provided herein is a pharmaceutical composition comprising any of the provided bispecific antibodies and a pharmaceutically acceptable carrier. In some of any of the provided embodiments, the composition is sterile.

[0049] Provided herein is an anti- Fc receptor-like protein 5 (FcRH5) antibody comprising: a heavy chain variable (VH) region and a light chain variable (VL) region, wherein: the VL region comprises a light chain complementarity determining region 1 (CDR-L1), a light chain complementarity determining region 2 (CDR-L2) and a light chain complementarity determining region 3 (CDR-L3) contained within SEQ ID NO:31 or 99, and wherein: (a) the VH region comprises a heavy chain complementarity determining region 1 (CDR-H1), a heavy chain complementarity determining region 2 (CDR-H2) and a heavy chain complementarity determining region 3 (CDR-H3) contained within SEQ ID NO:1, (b) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:2; (c) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:3; (d) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:4; (e) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:5; (f) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:6; (g) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:7; (h) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:8; (i) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:9; (j) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO: 10; (k) the VH region comprises a CDR-H1, a CDR-H2 and a CDR- H3 contained within SEQ ID NO:11; (1) the VH region comprises a CDR-H1, a CDR-H2 and a CDR- H3 contained within SEQ ID NO: 12; (m) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:13; (n) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO: 14; (o) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:15; (p) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:16; (q) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO: 17; (r) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:18; (s) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:19; (t) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:20; (u) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:21; (v) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:22; (w) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:23; (x) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:24; (y) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:25; (z) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:26; (aa) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:27; (bb) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:28; (cc) the VH region comprises a CDR-H1, a CDR- H2 and a CDR-H3 contained within SEQ ID NO:29; and (dd) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:30.

[0050] In some of any of the provided embodiments, the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 set forth in SEQ ID NO:99 and the VH region comprises a CDR-H1, a CDR- H2 and a CDR-H3 contained within SEQ ID NO: 29. In some of any of the provided embodiments, the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 set forth in SEQ ID NO:31 and the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:29.

[0051] Provided herein is an anti- Fc receptor-like protein 5 (FcRH5) antibody comprising: a heavy chain variable (VH) region and a light chain variable (VL) region, wherein: the VL comprises a CDRL1 set forth in SEQ ID NO:81, a CDRL2 set forth in SEQ ID NO:82 and a CDRL3 set forth in SEQ ID NO:83; or the VL comprises a CDRL1 set forth in SEQ ID NO:81, a CDRL2 set forth in SEQ ID NO:82 and a CDRL3 set forth in SEQ ID NO: 100; and wherein: a) the VH comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:32, 33, 34, respectively; (b) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:35, 36, and 37, respectively; (c) the VH region comprises a CDR- Hl, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:38, 39, 40, respectively; (d) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:41, 42, 43, respectively, (e) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:41, 44, 45, respectively; (f) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:46, 47, 34, respectively; (g) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:48, 49, 34, respectively; (h) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:46, 50, 34, respectively; (i) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 46, 50, 51, respectively; (j) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:48, 49, 51, respectively; (k) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:46, 52, 51, respectively; (1) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:46, 47, 51, respectively; (m) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 46, 52, 51, respectively; (n) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:46, 47, 51, respectively; (o) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:54, 55, 37, respectively; (p) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:56, 57, 58, respectively; (q) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:56, 57, 59, respectively; (r) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:60, 61, 62, respectively; (s) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:63, 64, 40, respectively; (t) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:65, 66, 40, respectively; (u) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:65, 66, 67, respectively; (v) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:63, 64, 68, respectively; (w) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:65, 66, 69, respectively; (x) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 65, 66, 70, respectively; (y) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 65, 66, 71, respectively; (z) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 72, 73, 74, respectively; (aa) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 65, 66, 75, respectively; (bb) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 65, 76, 77, respectively; (cc) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:78, 76, 79, respectively; or (dd) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 63, 76, 67, respectively.

[0052] In some of any of the provided embodiments, the VL comprises a CDRL1 set forth in SEQ ID NO: 81, a CDRL2 set forth in SEQ ID NO: 82 and a CDRL3 set forth in SEQ ID NO: 83; and the VH1 region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:78, 76, 79, respectively. In some of any of the provided embodiments, the VL comprises a CDRL1 set forth in SEQ ID NO:81, a CDRL2 set forth in SEQ ID NO:82 and a CDRL3 set forth in SEQ ID NO: 100; and the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:78, 76, 79, respectively.

[0053] In some of any of the provided embodiments, the VL comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:31 or 99; and a) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:1, (b) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:2; (c) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:3; (d) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:4; (e) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:5; (f) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:6; (g) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:7; (h) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:8; (i) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:9; (j) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO 10; (k) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:11; (1) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 12; (m) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 13; (n) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 14; (o) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 15; (p) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 16; (q) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:17; (r) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:18; (s) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 19; (t) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:20; (u) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:21; (v) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:22; (w) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:23; (x) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:24; (y) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:25; (z) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:26; (aa) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:27; (bb) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:28; (cc) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:29; or (dd) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:30.

[0054] In some of any of the provided embodiments, the VL comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:31 or 99; and the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:29. In some of any of the provided embodiments, the VL comprises the sequence of amino acids set forth in SEQ ID NO:31 or 99; and a) the VH region comprises the amino acid sequence set forth in SEQ ID NO:1, (b) the VH region comprises the amino acid sequence set forth in SEQ ID NO:2; (c) the VH region comprises the amino acid sequence set forth in SEQ ID NO:3; (d) the VH region comprises the amino acid sequence set forth in SEQ ID NO:4; (e) the VH region comprises the amino acid sequence set forth in SEQ ID NO:5; (f) the VH region comprises the amino acid sequence set forth in SEQ ID NO:6; (g) the VH region comprises the amino acid sequence set forth in SEQ ID NO:7; (h) the VH region comprises the amino acid sequence set forth in SEQ ID NO: 8; (i) the VH region comprises the amino acid sequence set forth in SEQ ID NO:9; (j) the VH region comprises the amino acid sequence set forth in SEQ ID NO 10; (k) the VH region comprises the amino acid sequence set forth in SEQ ID NO:11; (1) the VH region comprises the amino acid sequence set forth in SEQ ID NO: 12; (m) the VH region comprises the amino acid sequence set forth in SEQ ID NO: 13; (n) the VH region comprises the amino acid sequence set forth in SEQ ID NO: 14; (o) the VH region comprises the amino acid sequence set forth in SEQ ID NO: 15; (p) the VH region comprises the amino acid sequence set forth in SEQ ID NO: 16; (q) the VH region comprises the amino acid sequence set forth in SEQ ID NO: 17; (r) the VH region comprises the amino acid sequence set forth in SEQ ID NO: 18; (s) the VH region comprises the amino acid sequence set forth in SEQ ID NO: 19; (t) the VH region comprises the amino acid sequence set forth in SEQ ID NO:20; (u) the VH region comprises the amino acid sequence set forth in SEQ ID NO:21; (v) the VH region comprises the amino acid sequence set forth in SEQ ID NO:22; (w) the VH region comprises the amino acid sequence set forth in SEQ ID NO:23; (x) the VH region comprises the amino acid sequence set forth in SEQ ID NO:24; (y) the VH region comprises the amino acid sequence set forth in SEQ ID NO:25; (z) the VH region comprises the amino acid sequence set forth in SEQ ID NO:26; (aa) the VH region comprises the amino acid sequence set forth in SEQ ID NO:27; (bb) the VH region comprises the amino acid sequence set forth in SEQ ID NO:28; (cc) the VH region comprises the amino acid sequence set forth in SEQ ID NO:29; or (dd) the VH region comprises the amino acid sequence set forth in SEQ ID NO:30.

[0055] In some of any of the provided embodiments, the VL comprises the amino acid sequence set forth in SEQ ID NO:99; and the VH region comprises the amino acid sequence set forth in SEQ ID NO:29. In some of any of the provided embodiments, the VL comprises the amino acid sequence set forth in SEQ ID NO:31; and the VH region comprises the amino acid sequence set forth in SEQ ID NO:29.

[0056] In some of any of the provided embodiments, said antibody is recombinant. In some of any of the provided embodiments, the VH region and the VL region is human. In some of any of the provided embodiments, the antibody is a full length antibody. In some of any of the provided embodiments, the antibody is an antigen-binding fragment. In some of any of the provided embodiments, the antigen-binding fragment thereof comprises a fragment antigen-binding region (Fab). In some of any of the provided embodiments, the antigen-binding fragment thereof comprises a single chain Fv (scFv).

[0057] In some of any of the provided embodiments, the VH region and the VL region are joined by a flexible linker. In some of any of the provided embodiments, the flexible linker comprises the sequence set forth in any one of SEQ ID NOs:131-136. In some of any of the provided embodiments, the antibody specifically binds to a human Fc receptor-like protein 5 (FcRH5) protein. In some of any of the provided embodiments, the FcRH5 is a human FcRH5, optionally comprising the amino acid sequence set forth in SEQ ID NO: 130. In some of any of the provided embodiments, the antibody binds FcRH5 within the membrane proximal domain 9. In some of any of the provided embodiments, the antibody binds to cell-surface expressed FcRH5. In some of any of the provided embodiments, the antibody does not bind to soluble FcRH5.

[0058] In some of any of the provided embodiments, the antibody exhibits no or weak binding to FcRHl, FcRH2, FcRH3 and/or FcRH4, optionally wherein the weak binding is a dissociation constant (KD) of about 100 nM or more, more optionally wherein binding is as determined by surface plasmon resonance (SPR), e.g. Example 3. In some of any of the provided embodiments, the first and second binding regions exhibit no or weak binding to FcRHl, FcRH2, FcRH3 and FcRH4, optionally wherein the weak binding is a dissociation constant (KD) of about 100 nM or more, more optionally wherein binding is as determined by surface plasmon resonance (SPR), e.g. Example 3. In some of any of the provided embodiments, the antibody has a dissociation constant (KD) for binding FcRH5 of about or less than 5 nM, optionally as determined by surface plasmon resonance (SPR), e.g. Example 3. In some of any of the provided embodiments, the antibody has a KD for binding FcRH5 of about 0.05 and about 2 nM, optionally as determined by surface plasmon resonance (SPR), e.g. Example 3.

[0059] Provided herein is a single chain cell-surface protein, comprising any of the provided antibodies. Provided herein is a conjugate, comprising any of the provided antibodies, and a heterologous molecule or moiety. In some of any of the provided embodiments, the heterologous molecule or moiety is a therapeutic moiety. In some of any of the provided embodiments, the heterologous molecule or moiety is a toxin.

[0060] Provided herein is a bispecific antibody, comprising any of the provided anti-FcRH5 antibodies and a second antibody that binds to a molecule on a T cell

[0061] In some of any of the provided embodiments, the second antibody is a Fab, optionally wherein the anti-FcRH5 antibody is a Fab and the second antibody is a Fab. In some of any of the provided embodiments, the molecule on a T cell is CD3. In some of any of the provided embodiments, the antibody is an anti-CD3 antibody, optionally an anti-CD3 Fab.

[0062] In some of any of the provided embodiments, the anti-CD3 antibody comprises a variable light chain (VE) and a variable heavy chain (VH), wherein: the VL comprises a CDR-E1, a CDR-E2 and a CDR-E3 contained within SEQ ID NO: 99 and the VH comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:92; or the VL comprises a CDR-L1, a CDR-L2 and a CDR-L3 contained within SEQ ID NO: 99 and the VH comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO: 103. In some of any of the provided embodiments, the VL comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:81, 82, 100, respectively, and the VH comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:93, 94, 95, respectively; or the VL comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:81, 82, 100, respectively, and the VH comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:93, 104, 95, respectively.

[0063] In some of any of the provided embodiments, the VL comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 99, and the VH comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:92; or the VL comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:99, and the VH comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 103. In some of any of the provided embodiments, the VL comprises the amino acid sequence set forth in SEQ ID NO:99, and the VH comprises the amino acid sequence set forth in SEQ ID NO:92; or the VL comprises the amino acid sequence set forth in SEQ ID NO:99, and the VH comprises the amino acid sequence set forth in SEQ ID NO: 103.

[0064] In some of any of the provided embodiments, the anti-CD3 antibody comprises: a light chain comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:102; and a heavy chain comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NOs:96; or a light chain comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:102; and a heavy chain comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NOs:106. In some of any of the provided embodiments, the anti-CD3 antibody comprises: a light chain comprising the amino acid sequence set forth in SEQ ID NO: 102; and a heavy chain comprising the amino acid sequence set forth in SEQ ID NOs:96; or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 102; and a heavy chain comprising the amino acid sequence set forth in SEQ ID NOs:106.

[0065] In some of any of the provided embodiments, a heterodimeric Fc region comprising a first and second polypeptide each comprising a hinge-CH2-CH3, wherein the first polypeptide of the heterodimeric Fc is linked to the C-terminus of the anti-FcRH5 antibody and the second polypeptide of the heterodimeric Fc is linked to the C-terminus of the second antibody. In some of any of the provided embodiments, each of the first and second polypeptide of the heterodimeric Fc comprises one or more amino acid substitutions in a wild-type Fc polypeptide region to effect heterodimer formation between the first polypeptide and the second polypeptide. In some of any of the provided embodiments, the wild-type Fc region is an IgGl Fc region. In some of any of the provided embodiments, the wild-type Fc region comprises the sequence set forth in SEQ ID NO: 122.

[0066] In some of any of the provided embodiments, the one more amino acid substitutions are a knob-into-hole modification or a charge mutation to reduce or prevent self-association due to charge repulsion. In some of any of the provided embodiments, the one or more substitutions are a knob-into- hole modification. In some of any of the provided embodiments, the one or more amino acid substitutions of the first Fc polypeptide comprise Thr366Ser, Leu368Ala and Tyr407Val and the one or more amino acid substitutions of the second Fc polypeptide of the heterodimeric Fc comprises the Thr366Trp. In some of any of the provided embodiments, the one or more amino acid substitutions of the first Fc polypeptide or the second Fc polypeptide comprise T350V, L351Y, F405A and Y407V and the other of the one or more amino acid substitutions of the first Fc polypeptide or the second Fc polypeptide of the heterodimeric Fc comprises T350V, T366L, K392L and T394W.

[0067] In some of any of the provided embodiments, the amino acid substitution is a charge mutation to increase electrostatic complementarity of the polypeptides. In some of any of the provided embodiments, the heterodimeric Fc region comprises one or more amino acid substitutions to reduce binding affinity to an Fc receptor and/or to reduce effector function, optionally as compared to a wildtype IgGl Fc domain. In some of any of the provided embodiments, the one or more amino acid substitutions are selected from L234A, L234V, L235A, L235E, G237A, D265S, S267K, R292C, N297G, V302C, and P329G by EU numbering. In some of any of the provided embodiments, the one or more amino acid substitution comprises L234A and L235A. In some of any of the provided embodiments, the one or more amino acid substitution comprises L234A, L235A, and D265S. In some of any of the provided embodiments, the one or more amino acid substitution comprises L234A, L235A, and P329G. In some of any of the provided embodiments, one or both polypeptides of the heterodimeric Fc lacks Lys447.

[0068] In some of any of the provided embodiments, one of the first polypeptide and the second polypeptide of the heterodimeric Fc region comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity SEQ ID NOS: 124, 126 or 128; and the other of the first polypeptide and second polypeptide of the heterodimeric Fc region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity SEQ ID NOS: 125, 127 or 129. In some of any of the provided embodiments, one of the first polypeptide and the second polypeptide of the heterodimeric Fc region comprise the amino acid sequence set forth in any one of SEQ ID NOS: 124, 126 or 128; and the other of the first polypeptide and the second polypeptide of the heterodimeric Fc region comprises the amino acid sequence set forth in any one of SEQ ID NOS: 125, 127 or 129. In some of any of the provided embodiments, the first polypeptide of the heterodimeric Fc region comprise the amino acid sequence set forth in SEQ ID NO: 126 and the second polypeptide of the heterodimeric Fc region comprises the amino acid sequence set forth in SEQ ID NO: 127. In some of any of the provided embodiments, the first polypeptide of the heterodimeric Fc region comprise the amino acid sequence set forth in SEQ ID NO: 128 and the second polypeptide of the heterodimeric Fc region comprises the amino acid sequence set forth in SEQ ID NO: 129.

[0069] Provided herein is a chimeric antigen receptor (CAR) comprising an extracellular antigen-binding domain comprising any of the provided antibody or antigen-binding fragment thereof, a transmembrane region and an intracellular signaling region. In some of any of the provided embodiments, comprising a spacer between the extracellular antigen-binding domain and the transmembrane domain. In some of any of the provided embodiments, the spacer comprises at least a portion of an immunoglobulin or a variant thereof. In some of any of the provided embodiments, the spacer comprises at least a portion of a hinge region of an immunoglobulin or a variant thereof. In some of any of the provided embodiments, the spacer is less than at or about 15 amino acids in length. In some of any of the provided embodiments, the at least a portion of a hinge region comprises all or a portion of an IgG4 hinge region, optionally a human IgG4 hinge region, or a variant thereof. In some of any of the provided embodiments, the at least a portion of a hinge region comprises all or a portion of an IgG2 hinge region, optionally a human IgG2 hinge region, or a variant thereof. In some of any of the provided embodiments, the spacer comprises at least a portion of a hinge region and at least a portion of a CH3 region of an immunoglobulin or a variant thereof. In some of any of the provided embodiments, the at least a portion of a CH3 region comprises all or a portion of an IgG4 CH3 and/or an IgG2 CH3, wherein the IgG4 CH3 is optionally a human IgG4 CH3 and the IgG2 CH3 is optionally a human IgG2 CH3.

[0070] In some of any of the provided embodiments, the transmembrane region is or comprises a transmembrane domain from CD4, CD28, or CD8. In some of any of the provided embodiments, the transmembrane region is or comprises a transmembrane domain from CD28, optionally a human CD28. In some of any of the provided embodiments, the intracellular signaling region comprises an intracellular signaling domain capable of inducing a primary activation signal in a T cell, is a T cell receptor (TCR) component and/or comprises an immunoreceptor tyrosine-based activation motif (IT AM). In some of any of the provided embodiments, the intracellular signaling region is an intracellular signaling domain that is or comprises a cytoplasmic signaling domain of a CD3-zeta (CD3Q chain, optionally a human CD3^ chain. In some of any of the provided embodiments, the intracellular signaling region further comprises a costimulatory signaling region. In some of any of the provided embodiments, the costimulatory signaling region is between the transmembrane region and the intracellular signaling domain. In some of any of the provided embodiments, the costimulatory signaling region comprises an intracellular signaling domain of a T cell costimulatory molecule or a signaling portion thereof. In some of any of the provided embodiments, the costimulatory signaling region comprises an intracellular signaling domain of CD28, 4-1BB, or ICOS. In some of any of the provided embodiments, the costimulatory signaling region comprises an intracellular signaling domain of CD28, optionally a human CD28. In some of any of the provided embodiments, the costimulatory signaling region comprises an intracellular signaling domain of 4- IBB, optionally a human 4- IBB. In some of any of the provided embodiments, the encoded chimeric antigen receptor comprises from its N to C terminus in order: the extracellular antigen-binding domain, the spacer, the transmembrane region and the intracellular signaling region.

[0071] Provided herein is a polynucleotide comprising a nucleic acid encoding any of the provided anti-FcRH5 antibody or antigen-binding domain thereof. Provided herein is a polynucleotide comprising a nucleic acid encoding any of the provided single chain cell surface proteins. Also provided herein is a polynucleotide comprising a nucleic acid encoding any of the provided conjugates. Provided herein is a polynucleotide comprising a nucleic acid encoding any of the provided anti-FcRH5 chimeric antigen receptors. In some of any of the provided embodiments, the polynucleotide is optimized by splice site elimination. In some of any of the provided embodiments, the polynucleotide is codon-optimized for expression in a human cell.

[0072] Provided herein is a vector, comprising any of the provided polynucleotides. In some of any of the provided embodiments, the vector is a viral vector. In some of any of the provided embodiments, the viral vector is a retroviral vector or a lentiviral vector.

[0073] Provided herein is a cell comprising any of the provided anti-FcRHL5 antibody or antigen-binding fragment thereof, any of the provided single chain cell surface proteins or any of the provided conjugates. Provided herein is a cell comprising any of the provided chimeric antigen receptors. Provided herein is a cell comprising any of the provided polynucleotides or any of the provided vectors.

[0074] In some of any of the provided embodiments, the cell is a lymphocyte. In some of any of the provided embodiments, the cell is an NK cell or a T cell. In some of any of the provided embodiments, the cell is a T cell and the T cell is a CD4+ T cell or a CD8+ T cell. In some of any of the provided embodiments, the cell is a primary cell obtained from a subject. In some of any of the provided embodiments, less than at or about 10%, at or about 9%, at or about 8%, at or about 7%, at or about 5%, at or about 4%, at or about 3%, at or about 2% or at or about 1% of the cells in the plurality comprise an anti-FcRH5 chimeric antigen receptor that exhibits tonic signaling and/or antigen independent activity or signaling.

[0075] Provided herein is a composition comprising any of the provided cells. Also provided herein is a composition comprising any of the provided anti-FcRH5 antibody or antigen-binding fragment thereof, any of the provided single chain cell surface protein, any of the provided conjugates, or any of the provided chimeric antigen receptors.

[0076] In some of any of the provided embodiments, the composition further comprises a pharmaceutically acceptable excipient. In some of any of the provided embodiments, the composition comprises CD4+ and CD8+ T cells and the ratio of CD4+ to CD8+ T cells is from at or about 1:3 to 3:1, optionally at or about 1:2 to 2:1, optionally at or about 1:1. In some of any of the provided embodiments, less than at or about 10%, at or about 9%, at or about 8%, at or about 7%, at or about 5%, at or about 4%, at or about 3%, at or about 2% or at or about 1% of the cells in the plurality comprise an anti-FcRH5 chimeric antigen receptor that exhibits tonic signaling and/or antigen independent activity or signaling.

[0077] Provided herein is a method of treatment comprising administering any of the provided cells or any of the provided compositions to a subject having a disease or disorder associated with FcRH5.

[0078] Provided herein is any of the provided cells or any of the provided compositions for use in treating a disease or disorder associated with FcRH5. Provided herein is the use of any of the provided cells or any of the provided compositions for the treatment of a disease or disorder associated with FcRH5.

[0079] Provided herein is a method of treatment, comprising administering any of the provided anti-FcRH5 antibody or antigen-binding fragment thereof, any of the provided single chain cell surface proteins, any of the provided conjugates, any of the provided anti-FcRH5 chimeric antigen receptor, any of the provided polynucleotides, or any of the provided vectors, to a subject having a disease or disorder associated with FcRH5. Provided herein is any of the provided anti-FcRH5 antibody or antigen-binding fragment thereof, any of the provided single chain cell surface proteins, any of the provided conjugates, any of the provided anti-FcRH5 chimeric antigen receptor, any of the provided polynucleotides, or any of the provided vectors, for use in treating a disease or disorder associated with FcRH5.

[0080] Provided herein is the use of any of the provided anti-FcRH5 antibody or antigen-binding fragment thereof, any of the provided single chain cell surface proteins, any of the provided conjugates, any of the provided anti-FcRH5 chimeric antigen receptor, any of the provided polynucleotides, or any of the provided vectors, for the manufacture of a medicament for treating a disease or disorder associated with FcRH5. Provided herein is the use of any of the provided anti- FcRH5 antibody or antigen-binding fragment thereof, any of the provided single chain cell surface proteins, any of the provided conjugates, any of the provided anti-FcRH5 chimeric antigen receptor, any of the provided polynucleotides, or any of the provided vectors, for the treatment of a disease or disorder associated with FcRH5.

[0081] In some of any of the provided embodiments, the disease or disorder associated with FcRH5 is a cancer. In some of any of the provided embodiments, the cancer is a FcRH5-expressing cancer. In some of any of the provided embodiments, the cancer is associated with a FcRH5- expressing solid tumor or a FcRHL5-expressing hematologic malignancy.

Detailed Description

[0082] Provided in some aspects are FcRH5-binding molecules, such as anti-FcRH5 antibodies including antigen-binding antibody fragments that specifically bind to FcRH5 proteins, such as a human FcRH5 protein. The binding molecules also include proteins that include any of the provided anti-FcRH5 antibodies, including chimeric antigen receptors (CARs), conjugates and bispecific antibodies. In particular embodiments, provided are bispecific anti-FcRH5 and anti-CD3 T cell engaging antibodies that mediate specific targeting and T cell-mediated killing of cells that express FcRH5. Also provided are polynucleotides containing nucleic acids sequences encoding all or a portion of such binding molecules, including polynucleotides that encode polypeptide chains of the bispecific antibodies. Among the provided embodiments are approaches for targeting cells expressing FcRH5 useful in the treatment of diseases and conditions, including cancers. [0083] FcRH5 is expressed only in the B-cell lineage, starting as early as pre-B-cells, but does not attain full expression until the mature B-cell stage, and continues to be expressed in plasma cells, whereas certain other B-cell-specific markers are downregulated (Polson et al. Int. Immunol. 18:1363- 73, 2006). FcRH5 has been implicated in human diseases, including cancer and autoimmune conditions (Kochi et al. Nat. Genet. 37:478-485 (2005); Li et al. Blood. 112(1): 179-87 (2008)). In particular, FcRH5 has been shown to be overexpressed on malignant B cells of hairy cell leukemia, chronic lymphocytic leukemia, mantle cell lymphoma and multiple myeloma patients (Poison et al. (2006); Li et al. (2008)). In addition, FcRH5 mRNA is overexpressed in multiple myeloma cell lines with lq21 abnormalities as detected by oligonucleotide arrays (Inoue Am. J. Pathol. 165:71-81, 2004). Moreover, FcRH5 expression has been observed in all multiple myeloma patient samples and in 95% of lymphoma patient samples tested. Normal tissue expression is limited to mature B cell lineage including plasma cells.

[0084] FcRH5 is a low affinity receptor for both IgA and IgG. Cell-expressed FcRH5 (set forth in SEQ ID NO: 130; UniProt No. Q96RD9) is a 977-amino acid type I transmembrane glycoprotein with nine extracellular Ig-type domains harboring eight potential N-linked glycosylation sites, a 23- amino acid transmembrane domain, and a 104-amino acid cytoplasmic domain with IT AM and ITIM- sequences that regulate BCR-signaling. FcRH5 also has a soluble version, which lacks the membrane proximal Ig-type domain 9. In particular, the Ig-type domain 9 is the unique extracellular region that differentiates from the other major isoforms of FcRH5. For instance, FcRH5a represents a 759-amino acid secreted glycoprotein with eight Ig-like domains followed by 13 unique, predominantly polar amino acids at its C-terminus. FcRH5b diverges from FcRH5a at amino acid residue 560 and extends for a short stretch of 32 additional residues, whose hydrophobicity is compatible with its docking to the plasma membrane via a GPI anchor.

[0085] FcRH5 belongs to a family of six (6) IgSF superfamily (IgSF) genes including FcRHl (also called IRTA5), FcRH2 (also called IRTA4), FcRH3 (also called IRTA3), FcRH4 (also called IRTA1), FcRH5 (also called FcRL5 or IRTA2) and FcRH6 (Polson AG et al., Int. Immunol. (2006) 18 (9): 1363-1373). All FcRHs are type I transmembrane glycoproteins with multiple extracellular Ig-type domains and cytoplasmic domains that contain activating and/or inhibitory signaling motifs based on consensus immunoreceptor tyrosine. The FcRH genes are structurally related, and their protein products share 28-60% extracellular identity with each other. They also share 15-31% identity with their closest FcR relatives. There is a high degree of homology between the different FcRHs. For instance, the last Ig-like domain 9 is highly conserved among FcRHl, FcRH2, FcRH3 and FcRH5.

[0086] Therapies targeting FcRH5 are known but many exhibit cross-reactivity to other isoforms, such as cross-reactivity to FcRHl and FcRH3. There is a need for improved therapies targeting FcRH5 that have minimal cross-reactivity with other FcRHs to avoid nonspecific adverse effects. For instance, cross-reactivity to FcRH3, which is expressed in normal NK cells, could lead to undesired killing of normal NK cells. In some aspects, the provided embodiments related to antibodies and binding molecules that exhibit minimal to no cross-reactivity to other FcRH isoforms. For instance, as exemplified in Example 3, exemplary anti-FcRH5 binding molecules provided herein bind to an epitope within Ig-like domain 9 of FcRH5 yet exhibit no to very weak binding for FcRHl, 2, 3 and 4 and very high sub-nanomolar binding affinity to FcRH5. Notably, provided FcRH5 -directed binding molecules exhibit very little binding to FcRH3, which is expressed on NK cells. The ability of provided antibodies to bind within the membrane proximal domain of FcRH5 also reduces binding to the soluble FcRH5 form to reduce a sink effect. Further, it has been demonstrated that T cell engagers that target the membrane proximal domain of an antigen has better tumor cell killing activity compared to T cell engagers that target membrane distal domains.

[0087] Moreover, therapies targeting FcRH5 that specifically kill FcRH5-expressing cells are needed. Among therapies for targeted killing of antigen-expression cells are therapies that direct T cells to tumors, such as CAR-T cell therapies and T cell-engager bispecific antibody therapies that selectively recruit T cells to tumor cells. In this approach, targeted antibody therapy delivers cytotoxic cells specifically to the antigen-expressing cancer cells.

[0088] Although certain of such therapies exist they are not always entirely satisfactory. In many instances, current therapies may exhibit the aforementioned problem of cross-reactivity to other FcRH proteins. Further, in some instances, current therapies may exhibit undesired tonic signaling either in the absence of FcRH5 antigen or due to high affinity binding to CD3 on T cells. This risk of tonic signaling may exacerbate the chance of toxicities, such as cytokine release syndrome (CRS), to the FcRH5 -directed therapy. CRS is a concern for T cell modality therapies including T cell engagers. While on target T cell killing of tumor cells results in cytokine release, tonic signaling and cytokine release of T cells through CD3 binding independent of tumor associated antigen binding is not desired. Improved strategies are needed for optimal responses to antibody or T cell-mediated therapies. Provided are embodiments that meet such needs.

[0089] Among the provided embodiments are T cell engager bispecific antibodies directed against FcRH5 and CD3 (anti-FcRH5 and anti-CD3). Among the T cell engager bispecific antibodies provided herein are those that are formatted in a unique 2+1 format thereby providing bivalent and high affinity binding to FcRH5. In some aspects, provided binding molecules contain a detuned anti- CD3 arm that has reduced affinity to CD3 compared to other T cell engagers, thereby minimizing risks of tonic signaling and CRS. Further, provided binding molecules are formatted with a common light chain sequence that is shared by the FcRH5 and CD3 binding arms, which, in some aspects, may improve ease and manufacturability of the T cell engager molecules. Moreover, the provided bispecific antibodies are selective for FcRH5 compared to other FcRH family members and exhibit highly potent target cell killing. Due to the highly selective and potent activity, and low tonic signaling, the provided bispecific antibodies are promising candidates for treatment of FcRH5 positive malignancies, such as for treating lymphoma and multiple myeloma tumor cells, including relapsed/refractory disease. [0090] All publications, including patent documents, scientific articles and databases, referred to in this application are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication were individually incorporated by reference. If a definition set forth herein is contrary to or otherwise inconsistent with a definition set forth in the patents, applications, published applications and other publications that are herein incorporated by reference, the definition set forth herein prevails over the definition that is incorporated herein by reference.

[0091] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

I. FCRH5 BINDING MOLECULES

[0092] Provided are FcRH5-binding molecules, such as FcRH5-targeted antibodies (also called anti-FcRH5 antibodies) and chimeric or bispecific molecules containing the same. Such binding molecules, including antibodies, specifically bind to FcRH5 proteins, such as a human FcRH5 protein. Among the FcRH5 -binding polypeptides are antibodies (including antigen-binding fragments). In some embodiments, the antibodies or antigen-binding fragments include a heavy chain variable region (VH) and a light chain variable region (VL), including full-length antibodies as well as functional antigen-binding fragments such as Fabs or single chain Fv fragments (scFvs). The antibodies include antibodies that specifically bind to FcRH5, e.g., human FcRH5. Among the provided anti- FcRH5 antibodies are human antibodies, or antibodies that are modified from or variant of human antibodies. The antibodies include isolated antibodies.

[0093] Also among the binding molecules are polypeptides containing such antibodies, including bispecific antibodies and recombinant receptors such as chimeric antigen receptors (CARs) containing such antibodies. The FcRH5-binding molecules that incorporate the provided antibodies (e.g., antigen-binding antibody fragments) specifically bind to FcRH5, such as human FcRH5 protein. Among the provided bispecific molecules are T cell engagers (TCEs) that incorporate an anti-FcRH5 antibody or antigen-binding fragment and antibody for specific targeting of T cells, such as an anti- CD3 antibody or antigen-binding fragment.

[0094] In some aspects, the FcRH5-binding molecules include isolated molecules.

[0095] Also provided are polynucleotides containing nucleic acids sequences encoding all or a portion of any of the provided binding molecules, including any of the provided antibodies or antigenbinding fragments or other binding molecules incorporating the same. The provided polynucleotides can be incorporated into constructs, such as deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) constructs, such as those that can be introduced into cells for expression thereof. A. FcRH5-Targeted Antibodies

[0096] Provided are anti-FcRH5 antibodies, including full-length antibodies and functional antigen-binding fragments. Exemplary antibodies are described below. In some embodiments, the antibody, e.g., the anti-FcRH5 antibody, such as a full-length antibody or antigen-binding antibody fragment, contains a heavy chain variable region (VH) sequence and a light chain variable region (VL) sequence as described, or a sufficient antigen-binding portion thereof. In some embodiments, the anti-FcRH5 antibody is an antigen-binding antibody fragment that is a single chain fragment, such as a single chain Fv (scFv) fragment. In some aspects, the scFv comprises a VH region and a VL region. In some embodiments, the anti-FcRH5 antibody is an antigen-binding antibody fragment that is a Fab. In some embodiments, the antibodies include antibodies that specifically bind to FcRH5, e.g., human FcRH5. In some embodiments, the antibodies provided herein bind to human FcRH5 set forth in SEQ ID NO: 130 (UniProt No. Q96RD).

[0097] The term “antibody” herein is used in the broadest sense and includes polyclonal and monoclonal antibodies, including intact antibodies and functional (antigen-binding) antibody fragments, including fragment antigen binding (Fab) fragments, F(ab’)2 fragments, Fab’ fragments, Fv fragments, recombinant IgG (rlgG) fragments, heavy chain variable (VH) regions capable of specifically binding the antigen, single chain antibody fragments, including single chain variable fragments (scFv), and single domain antibodies (e.g., sdAb, sdFv, nanobody) fragments. The term encompasses genetically engineered and/or otherwise modified forms of immunoglobulins, such as intrabodies, peptibodies, chimeric antibodies, fully human antibodies, humanized antibodies, and heteroconjugate antibodies, multispecific, e.g., bispecific or trispecific, antibodies, diabodies, triabodies, and tetrabodies, tandem di-scFv, tandem tri-scFv. Unless otherwise stated, the term “antibody” should be understood to encompass functional antibody fragments thereof also referred to herein as “antigen-binding fragments.” The term also encompasses intact or full-length antibodies, including antibodies of any class or sub-class, including IgG and sub-classes thereof, IgM, IgE, IgA, and IgD.

[0098] An antigen-binding site of an antibody provided herein contains six complementarity determining regions (CDRs) which contribute in varying degrees to the affinity of the binding site for antigen. There are three heavy chain variable domain CDRs (CDR-H1, CDR-H2 and CDR-H3) and three light chain variable domain CDRs (CDR-E1, CDR-E2 and CDR-E3). A skilled artisan is familiar with CDR and framework regions (FRs) of antibodies, and can determine the boundaries of such regions using various known schemes.

[0099] The terms “complementarity determining region,” and “CDR,” synonymous with “hypervariable region” or “HVR,” are known to refer to non-contiguous sequences of amino acids within antibody variable regions, which confer antigen specificity and/or binding affinity. In general, there are three CDRs in each heavy chain variable region (CDR-H1, CDR-H2, CDR-H3) and three CDRs in each light chain variable region (CDR-L1, CDR-L2, CDR-L3). “Framework regions” and “FR” are known to refer to the non-CDR portions of the variable regions of the heavy and light chains. In general, there are four FRs in each full-length heavy chain variable region (FR-H1, FR-H2, FR-H3, and FR-H4), and four FRs in each full-length light chain variable region (FR-L1, FR-L2, FR- L3, and FR-L4).

[0100] The precise amino acid sequence boundaries of a given CDR or FR can be readily determined using any of a number of well-known schemes, including those described by Kabat et al. (1991), “Sequences of Proteins of Immunological Interest,” 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (“Kabat” numbering scheme); Al-Lazikani et al., J Mol Biol, 1997; 273(4):927-48 (“Chothia” numbering scheme); MacCallum et al. , J. Mol. Biol, 1996; 262:732- 745.” (“Contact” numbering scheme); Lefranc MP et al., Dev Comp Immunol, 2003; 27(l):55-77 (“IMGT” numbering scheme); Honegger A and Pliickthun A, J Mol Biol, 2001; 309(3):657-70, (“Aho” numbering scheme); Martin et al., PNAS, 1989; 86(23):9268-9272, (“AbM” numbering scheme); and Ye et al., Nucleic Acids Res. 2013; 41(Web Server issue) :W34-40, (“IgBLAST numbering scheme). Details regarding various numbering schemes are also described in, for example, Jarasch et al., Proteins, 2017; 85(1):65-71; Martin et al., Bioinformatics tools for antibody engineering. In: Diibel, S. (editor) Handbook of Therapeutic Antibodies, Vol. 1. Wiley-VCH, Weinheim, Germany; Martin, A.C.R. (2010). Protein Sequence and Structure Analysis of Antibody Variable Domains. In: Kontermann, R., Diibel, S. (eds) Antibody Engineering. Springer Protocols Handbooks. Springer, Berlin, Heidelberg, and Martin, ACR, Antibody Information: How to identify the CDRs by looking at a sequence [online] <http://www.bioinf.org.uk/abs/info.html>, all of which are incorporated by reference in their entireties. Various prediction algorithm tools are available and known for numbering antibody residues and CDRs (e.g., AbYsis, Abnum, AbYmod, AbRSA, IgBLAST, IMGT, or ANARCI).

[0101] The boundaries of a given CDR or FR may vary depending on the scheme used for identification. For example, the Kabat scheme is based on structural alignments, while the Chothia scheme is based on structural information. Numbering for both the Kabat and Chothia schemes is based upon the most common antibody region sequence lengths, in some cases with insertions. Insertions in the sequence relative to the standard numbering scheme are indicated using insertion letter codes. For example, residues that are inserted between residues L30 and L31 are indicated as L31A, L31B, etc. Deletions in the sequence relative to the standard scheme are accommodated by skipping numbers. The two schemes place certain insertions and deletions (“indels”) at different positions, resulting in differential numbering. For instance, the Chothia numbering scheme is nearly identical to the Kabat numbering scheme, except that insertions are placed at structural positions and topologically equivalents residues do get assigned the same numbers. The Contact scheme is based on analysis of complex crystal structures and is similar in many respects to the Chothia numbering scheme. The AbM scheme is a compromise between Kabat and Chothia definitions based on that used by Oxford Molecular’s AbM antibody modeling software. The IgBLAST scheme is based on matching to germline V, D and J genes, and can be determined using National Center for Biotechnology Information (NCBI)’s IgBLAST tool.

[0102] In some embodiments, reference to CDRs herein is by Kabat numbering. In some embodiments, Kabat numbering can be determined by known sequence rules as described in, for example, Kabat et al. (1991), “Sequences of Proteins of Immunological Interest,” 5th Ed. Public Health Svice, National Institutes of Health, Bethesda, MD. In some embodiments, the Kabat numbering scheme in some aspects can include any of the following rules to designate CDRs: CDR- L1 starts at approximately residue 24 of the light chain, always has a preceding C residue, and always has a following W residue; the end of CDR-L1 is defined by a stretch of 3 residues, where the W residue can be followed by Y, L, or F, followed by Q or L; CDR-1 has a length of 10 to 17 residues; CDR-L2 always starts 16 residues after the end of CDR-L1; the two residues before CDR-L2 are I and Y but can also be V and Y, I and K, or I and F; CDR-L2 is always 7 residues long; CDR-L3 always starts 33 residues after the end of CDR-L2, always has a preceding C residue, and is strictly followed by a F-G-X-G sequence motif, where X is any amino acid; CDR-L3 has a length of 7 to 11 residues; CDR-H1 starts at approximately position 26 of the heavy chain; the first amino acid in CDR-H1 is always 9 residues after a conserved C residue; CDR-H1 is followed by an invariant W residue followed by V, I, or A; CDR-H1 has a length of 5 to 7 residues; CDR-H2 always starts at 15 residues after the end of CDR-H1; the first residue in CDR-H2 is usually preceded by the sequence motif L-E-W-I-G but a number of variations exist; the end of CDR-H2 is defined by a motif of 3 residues - the first residue of the motif of 3 residues can be either K or R, the second residue of the motif of 3 residues can be L, I, V, F, T, or A, the third residue of the motif of 3 residues can be T, S, I, or A; CDR-H2 has a length of 16 to 19 residues; CDR-H3 always starts 33 residues after the end of CDR-H2 and is always 3 residues after a C residue - the first residue of CDR-H3 is preceded by the conserved C residue followed by two residues, which are usually A-R; the residues following CDR- H3 is strictly followed by a W-G-X-G sequence motif, where the X is any amino acid; CDR-H3 typically has a length of 3 to 25 residues; CDR-H3 can be much longer than 25 residues.

[0103] In some embodiments, reference to CDRs herein is by Chothia numbering. In some cases, according to the Chothia numbering scheme, exact boundary positions of certain CDRs can differ based on different definitions for the CDRs (See e.g., Martin, ACR, Antibody Information: How to identify the CDRs by looking at a sequence [online] <http://www.bioinf.org.uk/abs/info.html>). For example, in some instances, the boundary positions for CDR-L1 according to Chothia numbering can be L26— L32 (Chothia et al., Science, 1986; 233(4765):755-8 and Chothia C. and Lesk A.M. J Mol Biol, 1987; 196(4):901-17). In some instances, the boundary positions for CDR-L1 can be L25— L32 (Al-Lazikani et al., J Mol Biol, 1997; 273(4):927-48). In some instances, the boundary positions for CDR-L2 can be L50— L52 and for CDR-L3 can be L91— L96 (Chothia et al., Science, 1986; 233(4765):755-8; Chothia C. and Lesk A.M. J Mol Biol, 1987; 196(4):901-17; Al-Lazikani et al., J Mol Biol, 1997; 273(4):927-48). In some instances, the boundary positions for CDR-H1 according to Chothia numbering can be H26— H32 (Chothia et al., Science, 1986; 233(4765):755-8; Chothia C. and Lesk A.M. J Mol Biol, 1987; 196(4):901-17; Al-Lazikani et al., J Mol Biol, 1997; 273(4):927-48). In some instances, the boundary positions for CDR-H2 can be H53— H55 (Chothia et al., Science, 1986; 233(4765):755-8 and Chothia C. and Lesk A.M. J Mol Biol, 1987, 196(4):901-17); H52a-H55 (Tramontane et al., J Mol Biol, 1990, 215(1): 175-82). In some instances, the boundary positions for CDR-H2 can be H52— H56 (Al-Lazikani et al., J Mol Biol., 1997; 273(4):927-48). In some instances, the boundary positions for CDR-H3 can be H96— H101 (Chothia et al., Science, 1986; 233(4765):755- 8 and Chothia C. and Lesk A.M. J Mol Biol., 1987; 196(4):901-17). In some instances, the boundary positions for CDR-H3 can be H92— H104 (Morea et al., Biophys Chem, 1997; 68(1-3): 9-16 and Morea et al., J Mol Biol., 1998; 275(2): 269-94).

[0104] Table 1, below, lists exemplary position boundaries of CDR-L1, CDR-L2, CDR-L3 and CDR-H1, CDR-H2, CDR-H3 as identified by Kabat, Chothia, AbM, and Contact schemes, respectively. For CDR-H1, residue numbering is listed using both the Kabat and Chothia numbering schemes. FRs are located between CDRs, for example, with FR-L1 located before CDR-L1, FR-L2 located between CDR-L1 and CDR-L2, FR-L3 located between CDR-L2 and CDR-L3 and so forth. It is noted that because the shown Kabat numbering scheme places insertions at H35A and H35B, the end of the Chothia CDR-H1 loop when numbered using the shown Kabat numbering convention varies between H32 and H34, depending on the length of the loop.

1 - Kabat et al. (1991), “Sequences of Proteins of Immunological Interest,” 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD

2 - Al-Lazikani et al., (1997) JMB 273,927-948

[0105] Thus, unless otherwise specified, a “CDR” or “complementary determining region,” or individual specified CDRs (e.g., CDR-H1, CDR-H2, CDR-H3), of a given antibody or region thereof, such as a variable region thereof, should be understood to encompass a (or the specific) complementary determining region as defined by any of the aforementioned schemes, or other known schemes. For example, where it is stated that a particular CDR (e.g., a CDR-H3) contains the amino acid sequence of a corresponding CDR in a given VH or VL region amino acid sequence, it is understood that such a CDR has a sequence of the corresponding CDR (e.g., CDR-H3) within the variable region, as defined by any of the aforementioned schemes, or other known schemes. In some embodiments, the provided binding molecule, e.g., an anti-FcRH5 antibody or antigen-binding fragment thereof comprises a CDR-H1, a CDR-H2, and a CDR-H3 as contained within a given VH region amino acid sequence and defined by any of the aforementioned schemes, such as Kabat, Chothia, AbM, IgBLAST, IMGT, or Contact method, or other known schemes, and a CDR-L1, a CDR-L2, and a CDR-L3 as contained within a given VL region amino acid sequence and defined by any of the aforementioned schemes, such as Kabat, Chothia, AbM, IgBLAST, IMGT, or Contact method, or other known schemes. In some embodiments, specific CDR sequences are specified. In some embodiments, specific CDR sequences are specified. Exemplary CDR sequences of provided antibodies are described using various numbering schemes (see e.g. Table 1), although it is understood that a provided antibody can include CDRs as described according to any of the other aforementioned numbering schemes or other known numbering schemes.

[0106] Likewise, unless otherwise specified, a FR or individual specified FR(s) (e.g., FR-H1, FR-H2, FR-H3, FR-H4), of a given antibody or region thereof, such as a variable region thereof, should be understood to encompass a (or the specific) framework region as defined by any of the known schemes. In some instances, the scheme for identification of a particular CDR, FR, or FRs or CDRs is specified, such as the CDR as defined by the Kabat, Chothia, AbM, IgBLAST, IMGT, or Contact method, or other known schemes. In other cases, the particular amino acid sequence of a CDR or FR is given.

[0107] The term “variable region” or “variable domain” refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to antigen. The variable regions of the heavy chain and light chain (VH and VL, respectively) of a native antibody generally have similar structures, with each domain comprising four conserved framework regions (FRs) and three CDRs. (See, e.g., Kindt et al. Kuby Immunology, 6th ed., W.H. Freeman and Co., page 91 (2007). A single VH or VL domain may be sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind a particular antigen may be isolated using a VH or VL domain from an antibody that binds the antigen to screen a library of complementary VL or VH domains, respectively. See, e.g., Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991).

[0108] Among the provided antibodies are antibody fragments. An “antibody fragment” or “antigen-binding fragment” refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds the antigen to which the intact antibody binds. Examples of antibody fragments include but are not limited to Fv, Fab, Fab’, Fab’-SH, F(ab’)2; diabodies; linear antibodies; heavy chain variable (VH) regions, single-chain antibody molecules such as scFvs and single-domain antibodies comprising only the VH region; and multispecific antibodies formed from antibody fragments. In some embodiments, the antibody is or comprises an antibody fragment comprising a variable heavy chain (VH) and a variable light chain (VL) region. In some embodiments, the antibodies are single-chain antibody fragments comprising a heavy chain variable (VH) region and/or a light chain variable (VL) region, such as scFvs. In some embodiments, the antibodies are Fab composed of an entire light chain (i.e. light chain variable (VL) region and a constant light chain (CL)) and the heavy chain variable (VH) region and the first constant domain of one heavy chain (CHI).

[0109] Antibody fragments can be made by various techniques, including but not limited to proteolytic digestion of an intact antibody as well as production by recombinant host cells. For instance, papain digestion of full-length antibodies produces two identical antigen-binding fragments, called "Fab" fragments, and a residual "Fc" fragment, a designation reflecting the ability to crystallize readily. Pepsin treatment of an antibody yields a single large F(ab')2 fragment which roughly corresponds to two disulfide linked Fab fragments having different antigen-binding activity and is still capable of cross-linking antigen. Fab' fragments differ from Fab fragments by having a few additional residues at the carboxy terminus of the CHI domain including one or more cysteines from the antibody hinge region. Fab'-SH is the designation herein for Fab' in which the cysteine residue(s) of the constant domains bear a free thiol group. F(ab')2 antibody fragments originally were produced as pairs of Fab' fragments which have hinge cysteines between them. Other chemical couplings of antibody fragments are also known. In some embodiments, the antibodies are recombinantly- produced fragments. For instance, the chains of an antibody or antigen-binding fragment can be incorporated into an expression vector and expressed from a host cell to produce the antibody. In some instances, a recombinantly-produced antibody fragments also can include fragments comprising arrangements that do not occur naturally, such as those with two or more antibody regions or chains joined by synthetic linkers, e.g., peptide linkers, and/or that are may not be produced by enzyme digestion of a naturally-occurring intact antibody. In some aspects, the antibody fragments are scFvs.

[0110] A “humanized” antibody is an antibody in which all or substantially all CDR amino acid residues are derived from non-human CDRs and all or substantially all FR amino acid residues are derived from human FRs. A humanized antibody optionally may include at least a portion of an antibody constant region derived from a human antibody. A “humanized form” of a non-human antibody, refers to a variant of the non-human antibody that has undergone humanization, typically to reduce immunogenicity to humans, while retaining the specificity and affinity of the parental non- human antibody. In some embodiments, some FR residues in a humanized antibody are substituted with corresponding residues from a non-human antibody (e.g., the antibody from which the CDR residues are derived), e.g., to restore or improve antibody specificity or affinity.

[0111] Among the provided anti-FcRH5 antibodies are human antibodies. A “human antibody” is an antibody with an amino acid sequence corresponding to that of an antibody produced by a human or a human cell, or non-human source that utilizes human antibody repertoires or other human antibody-encoding sequences, including human antibody libraries. The term excludes humanized forms of non-human antibodies comprising non-human antigen-binding regions, such as those in which all or substantially all CDRs are non-human. The term includes antigen-binding fragments of human antibodies. Human antibodies can be produced using various techniques known in the art, including phage-display libraries. Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991). Also available for the preparation of human monoclonal antibodies are methods described in Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); Boerner et al., J. Immunol. 147(l):86-95 (1991). See also van Dijk and van de Winkel, Curr. Opin. Pharmacol., 5: 368-74 (2001).

[0112] Human antibodies may be prepared by administering an immunogen to a transgenic animal that has been modified to produce intact human antibodies or intact antibodies with human variable regions in response to antigenic challenge. Such animals typically contain all or a portion of the human immunoglobulin loci, which replace the endogenous immunoglobulin loci, or which are present extrachromosomally or integrated randomly into the animal’s chromosomes. In such transgenic animals, the endogenous immunoglobulin loci have generally been inactivated. Examples of such transgeneic animals include immunized xenomice (see, e.g., U.S. Pat. Nos. 6,075, 181 and 6, 150,584 regarding XENOMOUSE technology). See also, for example, Li et al., Proc. Natl. Acad. Sci. USA, 103 :3557-3562 (2006) regarding human antibodies generated via a human B-cell hybridoma technology. Human antibodies also may be derived from human antibody libraries, including phage display and cell-free libraries, containing antibody-encoding sequences derived from a human repertoire.

[0113] Among the provided antibodies, e.g., antigen-binding fragments, are human antibodies. In some embodiments of a provided human anti-FcRH5 antibody, e.g., antigen-binding fragments, the human antibody contains a VH region that comprises a portion having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence encoded by a germline nucleotide human heavy chain V segment, a portion having at least 95%, 96%, 97%, 98%, 99%, or 100 % sequence identity to an amino acid sequence encoded by a germline nucleotide human heavy chain D segment, and/or a portion having at least 95%, 96%, 97%, 98%, 99%, or 100 % sequence identity to an amino acid sequence encoded by a germline nucleotide human heavy chain J segment; and/or contains a VL region that comprises a portion having at least 95%, 96%, 97%, 98%, 99%, or 100 % sequence identity to an amino acid sequence encoded by a germline nucleotide human kappa or lambda chain V segment, and/or a portion having at least 95%, 96%, 97%, 98%, 99%, or 100 % sequence identity to an amino acid sequence encoded by a germline nucleotide human kappa or lambda chain J segment.

[0114] Among the provided antibodies, e.g., antigen-binding fragments, are human antibodies. In some embodiments of a provided human anti- FcRH5 antibody, e.g., antigen-binding fragments, the human antibody contains a VH region that comprises a portion having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence encoded by a germline nucleotide human heavy chain V segment, a portion having at least 95%, 96%, 97%, 98%, 99%, or 100 % sequence identity to an amino acid sequence encoded by a germline nucleotide human heavy chain D segment, and/or a portion having at least 95%, 96%, 97%, 98%, 99%, or 100 % sequence identity to an amino acid sequence encoded by a germline nucleotide human heavy chain J segment; and contains a VL region that comprises a portion having at least 95%, 96%, 97%, 98%, 99%, or 100 % sequence identity to an amino acid sequence encoded by a germline nucleotide human kappa or lambda chain V segment, and/or a portion having at least 95%, 96%, 97%, 98%, 99%, or 100 % sequence identity to an amino acid sequence encoded by a germline nucleotide human kappa or lambda chain J segment. In some embodiments, the portion of the VH region corresponds to the CDR-H1, the CDR-H2 and/or the CDR-H3. In some embodiments, the portion of the VH region corresponds to the CDR-H1, the CDR-H2 and the CDR-H3. In some embodiments, the portion of the VL region corresponds to the CDR-L1, the CDR-L2 and/or the CDR-L3. In some embodiments, the portion of the VL region corresponds to the CDR-L1, the CDR-L2 and the CDR-L3.

[0115] In some embodiments, the human antibody or antigen-binding fragment thereof, contains a CDR-H1 having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence of the corresponding CDR-H1 region within a sequence encoded by a germline nucleotide human heavy chain V segment. For example, the human antibody in some embodiments contains a CDR-H1 having a sequence that is 100% identical or with no more than one, two or three amino acid differences as compared to the corresponding CDR-H1 region within a sequence encoded by a germline nucleotide human heavy chain V segment.

[0116] In some embodiments, the human antibody or antigen-binding fragment thereof, contains a CDR-H2 having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence of the corresponding CDR-H2 region within a sequence encoded by a germline nucleotide human heavy chain V segment. For example, the human antibody in some embodiments contains a CDR-H2 having a sequence that is 100% identical or with no more than one, two or three amino acid difference as compared to the corresponding CDR-H2 region within a sequence encoded by a germline nucleotide human heavy chain V segment.

[0117] In some embodiments, the human antibody or antigen-binding fragment thereof, contains a CDR-H3 having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence of the corresponding CDR-H3 region within a sequence encoded by a germline nucleotide human heavy chain V segment, D segment and J segment. For example, the human antibody in some embodiments contains a CDR-H3 having a sequence that is 100% identical or with no more than one, two or three amino acid differences as compared to the corresponding CDR-H3 region within a sequence encoded by a germline nucleotide human heavy chain V segment, D segment and J segment.

[0118] In some embodiments, the human antibody or antigen-binding fragment thereof, contains a CDR-L1 having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence of the corresponding CDR-L1 region within a sequence encoded by a germline nucleotide human light chain V segment. For example, the human antibody in some embodiments contains a CDR-L1 having a sequence that is 100% identical or with no more than one, two or three amino acid differences as compared to the corresponding CDR-L1 region within a sequence encoded by a germline nucleotide human light chain V segment. [0119] In some embodiments, the human antibody or antigen-binding fragment thereof, contains a CDR-L2 having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence of the corresponding CDR-L2 region within a sequence encoded by a germline nucleotide human light chain V segment. For example, the human antibody in some embodiments contains a CDR-L2 having a sequence that is 100% identical or with no more than one, two or three amino acid difference as compared to the corresponding CDR-L2 region within a sequence encoded by a germline nucleotide human light chain V segment.

[0120] In some embodiments, the human antibody or antigen-binding fragment thereof, contains a CDR-L3 having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence of the corresponding CDR-L3 region within a sequence encoded by a germline nucleotide human light chain V segment and J segment. For example, the human antibody in some embodiments contains a CDR-L3 having a sequence that is 100% identical or with no more than one, two or three amino acid differences as compared to the corresponding CDR-L3 region within a sequence encoded by a germline nucleotide human light chain V segment and J segment.

[0121] Among the provided antibodies are monoclonal antibodies, including monoclonal antibody fragments. The term “monoclonal antibody” as used herein refers to an antibody obtained from or within a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical, except for possible variants containing naturally occurring mutations or arising during production of a monoclonal antibody preparation, such variants generally being present in minor amounts. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different epitopes, each monoclonal antibody of a monoclonal antibody preparation is directed against a single epitope on an antigen. The term is not to be construed as requiring production of the antibody by any particular method. A monoclonal antibody may be made by a variety of techniques, including but not limited to generation from a hybridoma, recombinant DNA methods, phage-display and other antibody display methods.

[0122] In some embodiments, the anti- FcRH5 antibody, e.g., antigen-binding antibody fragment, contains a VH region sequence that contains a heavy chain complementarity determining region 1 (CDR-H1), a CDR-H2 and a CDR-H3 as described and contains a VL region sequence that contains a CDR-L1, a CDR-L2 and/or a CDR-L3 as described. Also among the provided antibodies and fragment thereof are those having sequences at least at or about 85%, at or about 86%, at or about 87%, at or about 88%, at or about 89%, at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identical to such a sequence, e.g., any of the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, CDR-L3 sequences of the antibodies described herein. Also among the provided antibodies and fragment thereof are those having sequences at least at or about 85%, at or about 86%, at or about 87%, at or about 88%, at or about 89%, at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identical to such a sequence, e.g., any of the VH and VL sequences, respectively, of the antibodies described herein. In some aspects, among the provided antibodies, including fragment thereof, are those having sequences at least at or about 85% sequence identity to any such sequences. In some aspects, among the provided antibodies, including fragment thereof, are those having sequences at least at or about 86% sequence identity to any such sequences. In some aspects, among the provided antibodies and fragment thereof are those having sequences at least at or about 87% sequence identity to any such sequences. In some aspects, among the provided antibodies, including fragment thereof, are those having sequences at least at or about 88% sequence identity to any such sequences. In some aspects, among the provided antibodies, including fragment thereof, are those having sequences at least at or about 89% sequence identity to any such sequences. In some aspects, among the provided antibodies, including fragment thereof, are those having sequences at least at or about 90% sequence identity to any such sequences. In some aspects, among the provided antibodies, including fragment thereof, are those having sequences at least at or about 91% sequence identity to any such sequences. In some aspects, among the provided antibodies, including fragment thereof, are those having sequences at least at or about 92% sequence identity to any such sequences. In some aspects, among the provided antibodies, including fragment thereof, are those having sequences at least at or about 93% sequence identity to any such sequences. In some aspects, among the provided antibodies, including fragment thereof, are those having sequences at least at or about 94% sequence identity to any such sequences. In some aspects, among the provided antibodies, including fragment thereof, are those having sequences at least at or about 95% sequence identity to any such sequences. In some aspects, among the provided antibodies, including fragment thereof, are those having sequences at least at or about 96% sequence identity to any such sequences. In some aspects, among the provided antibodies, including fragment thereof, are those having sequences at least at or about 97% sequence identity to any such sequences. In some aspects, among the provided antibodies, including fragment thereof, are those having sequences at least at or about 98% sequence identity to any such sequences. In some aspects, among the provided antibodies, including fragment thereof, are those having sequences at least at or about 99% sequence identity to any such sequences.

[0123] In some embodiments, provided are anti-FcRH5 antibodies, including antibody fragments, that have a heavy chain variable (VH) region having an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VH region amino acid sequence set forth in SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30, and a light chain variable sequence (VL) region that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VL region amino acid sequence set forth in SEQ ID NO:31 or 99. In some embodiments, provided anti-FcRH5 antibodies, including antibody fragments, contain a CDR-H1, a CDR-H2 and a CDR-H3 present in a VH sequence set forth in any one of SEQ ID NOS: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30, and a CDR-L1, a CDR-L2, and a CDR-L3 present in a VL sequence set forth in SEQ ID NO:31 or 99.

[0124] In some embodiments, the light chain sequence contains a VL region that comprises a CDR-L1, a CDR-L2, and a CDR-L3 present in the VL region sequence set forth in SEQ ID NO:31. In some embodiments, the VL region of an antibody or antigen-binding fragment thereof comprises a CDR-L1, a CDR-L2 and a CDR-L3 according to Kabat numbering. In some embodiments, the VL region of an antibody or antigen-binding fragment thereof comprises a CDR-L1, a CDR-L2 and a CDR-L3 according to Chothia numbering. In some embodiments, the VL region of an antibody or antigen-binding fragment thereof comprises a CDR-L1, a CDR-L2 and a CDR-L3 according to AbM numbering. In some embodiments, the VL region of an antibody or antigen-binding fragment thereof comprises a CDR-L1, a CDR-L2 and a CDR-L3 according to IMGT numbering.

[0125] In some embodiments, the VL comprises a CDRL1 set forth in SEQ ID NO:81, a CDRL2 set forth in SEQ ID NO:82 and a CDRL3 set forth in SEQ ID NO:83.

[0126] In some embodiments, the light chain sequence contains a VL region that comprises a CDR-L1, a CDR-L2, and a CDR-L3 present in the VL region sequence set forth in SEQ ID NO: 99. In some embodiments, the VL region of an antibody or antigen-binding fragment thereof comprises a CDR-L1, a CDR-L2 and a CDR-L3 according to Kabat numbering. In some embodiments, the VL region of an antibody or antigen-binding fragment thereof comprises a CDR-L1, a CDR-L2 and a CDR-L3 according to Chothia numbering. In some embodiments, the VL region of an antibody or antigen-binding fragment thereof comprises a CDR-L1, a CDR-L2 and a CDR-L3 according to AbM numbering. In some embodiments, the VL region of an antibody or antigen-binding fragment thereof comprises a CDR-L1, a CDR-L2 and a CDR-L3 according to IMGT numbering.

[0127] In some embodiments, the VL comprises a CDRL1 set forth in SEQ ID NO:81, a CDRL2 set forth in SEQ ID NO:82 and a CDRL3 set forth in SEQ ID NO: 100.

[0128] In some embodiments, the VH region contains a CDR-H1, a CDR-H2, and a CDR-H3 present in the VH region sequence set forth in SEQ ID NO: 1. In some embodiments, the VH region contains a CDR-H1, a CDR-H2, and a CDR-H3 present in the VH region sequence set forth in SEQ ID NO: 2. In some embodiments, the VH region contains a CDR-H1, a CDR-H2, and a CDR-H3 present in the VH region sequence set forth in SEQ ID NO: 3. In some embodiments, the VH region contains a CDR-H1, a CDR-H2, and a CDR-H3 present in the VH region sequence set forth in SEQ ID NO: 4. In some embodiments, the VH region contains a CDR-H1, a CDR-H2, and a CDR-H3 present in the VH region sequence set forth in SEQ ID NO: 5. In some embodiments, the VH region contains a CDR- Hl, a CDR-H2, and a CDR-H3 present in the VH region sequence set forth in SEQ ID NO: 6. In some embodiments, the VH region contains a CDR-H1, a CDR-H2, and a CDR-H3 present in the VH region sequence set forth in SEQ ID NO: 7. In some embodiments, the VH region contains a CDR-H1, a CDR-H2, and a CDR-H3 present in the VH region sequence set forth in SEQ ID NO: 8. In some embodiments, the VH region contains a CDR-H1, a CDR-H2, and a CDR-H3 present in the VH region sequence set forth in SEQ ID NO: 9. In some embodiments, the VH region contains a CDR-H1, a CDR-H2, and a CDR-H3 present in the VH region sequence set forth in SEQ ID NO: 10. In some embodiments, the VH region contains a CDR-H1, a CDR-H2, and a CDR-H3 present in the VH region sequence set forth in SEQ ID NO: 11. In some embodiments, the VH region contains a CDR-H1, a CDR-H2, and a CDR-H3 present in the VH region sequence set forth in SEQ ID NO: 12. In some embodiments, the VH region contains a CDR-H1, a CDR-H2, and a CDR-H3 present in the VH region sequence set forth in SEQ ID NO: 13. In some embodiments, the VH region contains a CDR-H1, a CDR-H2, and a CDR-H3 present in the VH region sequence set forth in SEQ ID NO: 14. In some embodiments, the VH region contains a CDR-H1, a CDR-H2, and a CDR-H3 present in the VH region sequence set forth in SEQ ID NO: 15. In some embodiments, the VH region contains a CDR-H1, a CDR-H2, and a CDR-H3 present in the VH region sequence set forth in SEQ ID NO: 16. In some embodiments, the VH region contains a CDR-H1, a CDR-H2, and a CDR-H3 present in the VH region sequence set forth in SEQ ID NO: 17. In some embodiments, the VH region contains a CDR-H1, a CDR-H2, and a CDR-H3 present in the VH region sequence set forth in SEQ ID NO: 18. In some embodiments, the VH region contains a CDR-H1, a CDR-H2, and a CDR-H3 present in the VH region sequence set forth in SEQ ID NO: 19. In some embodiments, the VH region contains a CDR-H1, a CDR-H2, and a CDR-H3 present in the VH region sequence set forth in SEQ ID NO: 20. In some embodiments, the VH region contains a CDR-H1, a CDR-H2, and a CDR-H3 present in the VH region sequence set forth in SEQ ID NO: 21. In some embodiments, the VH region contains a CDR-H1, a CDR-H2, and a CDR-H3 present in the VH region sequence set forth in SEQ ID NO: 22. In some embodiments, the VH region contains a CDR-H1, a CDR-H2, and a CDR-H3 present in the VH region sequence set forth in SEQ ID NO: 23. In some embodiments, the VH region contains a CDR-H1, a CDR-H2, and a CDR-H3 present in the VH region sequence set forth in SEQ ID NO: 24. In some embodiments, the VH region contains a CDR-H1, a CDR-H2, and a CDR-H3 present in the VH region sequence set forth in SEQ ID NO: 25. In some embodiments, the VH region contains a CDR-H1, a CDR-H2, and a CDR-H3 present in the VH region sequence set forth in SEQ ID NO: 26. In some embodiments, the VH region contains a CDR-H1, a CDR-H2, and a CDR-H3 present in the VH region sequence set forth in SEQ ID NO: 27. In some embodiments, the VH region contains a CDR-H1, a CDR-H2, and a CDR-H3 present in the VH region sequence set forth in SEQ ID NO: 28. In some embodiments, the VH region contains a CDR-H1, a CDR-H2, and a CDR-H3 present in the VH region sequence set forth in SEQ ID NO: 29. In some embodiments, the VH region contains a CDR-H1, a CDR-H2, and a CDR-H3 present in the VH region sequence set forth in SEQ ID NO: 30. In some of the above embodiments, the VH region of an antibody or antigen-binding fragment thereof comprises a CDR-H1, a CDR-H2, and a CDR-H3 according to Kabat numbering. In some of the above embodiments, the VH region of an antibody or antigen-binding fragment thereof comprises a CDR- Hl, a CDR-H2 and a CDR-H3 according to Chothia numbering. In some of the above embodiments, the VH region of an antibody or antigen-binding fragment thereof comprises a CDR-H1, a CDR-H2 and a CDR-H3 according to AbM numbering. In some of the above embodiments, the VH region of an antibody or antigen-binding fragment thereof comprises a CDR-H1, a CDR-H2 and a CDR-H3 according to IMGT numbering.

[0129] In some embodiments, the VH region of an antibody or antigen-binding fragment thereof comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:32, 33, 34, respectively. In some embodiments, the VH region of an antibody or antigen-binding fragment thereof comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:35, 36, and 37, respectively. In some embodiments, the VH region of an antibody or antigen-binding fragment thereof comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:38, 39, 40, respectively. In some embodiments, the VH region of an antibody or antigen-binding fragment thereof comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:41, 42, 43, respectively. In some embodiments, the VH region of an antibody or antigen-binding fragment thereof comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:41, 44, 45, respectively. In some embodiments, the VH region of an antibody or antigen-binding fragment thereof comprises a CDR- Hl, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:46, 47, 34, respectively. In some embodiments, the VH region of an antibody or antigen-binding fragment thereof comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:48, 49, 34, respectively. In some embodiments, the VH region of an antibody or antigen-binding fragment thereof comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:46, 50, 34, respectively. In some embodiments, the VH region of an antibody or antigen-binding fragment thereof comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 46, 50, 51, respectively. In some embodiments, the VH region of an antibody or antigen-binding fragment thereof comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:48, 49, 51, respectively. In some embodiments, the VH region of an antibody or antigen-binding fragment thereof comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:46, 52, 51, respectively. In some embodiments, the VH region of an antibody or antigen-binding fragment thereof comprises a CDR- Hl, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 46, 47, 51, respectively. In some embodiments, the VH region of an antibody or antigen-binding fragment thereof comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 46, 52, 51, respectively. In some embodiments, the VH region of an antibody or antigen-binding fragment thereof comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:46, 47, 51, respectively. In some embodiments, the VH region of an antibody or antigen-binding fragment thereof comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:54, 55, 37, respectively. In some embodiments, the VH region of an antibody or antigen-binding fragment thereof comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:56, 57, 58, respectively. In some embodiments, the VH region of an antibody or antigen-binding fragment thereof comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:56, 57, 59, respectively. In some embodiments, the VH region of an antibody or antigen-binding fragment thereof comprises a CDR- Hl, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:60, 61, 62, respectively. In some embodiments, the VH region of an antibody or antigen-binding fragment thereof comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:63, 64, 40, respectively. In some embodiments, the VH region of an antibody or antigen-binding fragment thereof comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:65, 66, 40, respectively. In some embodiments, the VH region of an antibody or antigen-binding fragment thereof comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:65, 66, 67, respectively. In some embodiments, the VH region of an antibody or antigen-binding fragment thereof comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:63, 64, 68, respectively. In some embodiments, the VH region of an antibody or antigen-binding fragment thereof comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:65, 66, 69, respectively. In some embodiments, the VH region of an antibody or antigen-binding fragment thereof comprises a CDR- Hl, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 65, 66, 70, respectively. In some embodiments, the VH region of an antibody or antigen-binding fragment thereof comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 65, 66, 71, respectively. In some embodiments, the VH region of an antibody or antigen-binding fragment thereof comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 72, 73, 74, respectively. In some embodiments, the VH region of an antibody or antigen-binding fragment thereof comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 65, 66, 75, respectively. In some embodiments, the VH region of an antibody or antigen-binding fragment thereof comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 65, 76, 77, respectively. In some embodiments, the VH region of an antibody or antigen-binding fragment thereof comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:78, 76, 79, respectively. In some embodiments, the VH region of an antibody or antigen-binding fragment thereof comprises a CDR- Hl, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 63, 76, 67, respectively.

[0130] In some embodiments, the VL region comprises a CDRL1 set forth in SEQ ID NO:81, a CDRL2 set forth in SEQ ID NO:82 and a CDRL3 set forth in SEQ ID NO:83; and the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:78, 76, 79, respectively. [0131] In some embodiments, the VL region comprises a CDRL1 set forth in SEQ ID NO:81, a CDRL2 set forth in SEQ ID NO:82 and a CDRL3 set forth in SEQ ID NO: 100; and the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:78, 76, 79, respectively.

[0132] In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 31 or 99, and the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:1. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:31. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:99. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:31 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO:1. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:99 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO:1.

[0133] In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 31 or 99, and the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:2. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:31. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:99. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:31 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO:2. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:99 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO:2.

[0134] In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 31 or 99, and the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:3. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:31. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:99. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:31 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO:3. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:99 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO:3.

[0135] In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 31 or 99, and the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:4. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:31. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:99. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:31 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO:4. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:99 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO:4.

[0136] In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 31 or 99, and the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:5. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:31. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:99. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:31 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO:5. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:99 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO:5.

[0137] In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 31 or 99, and the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:6. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:31. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:99. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:31 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO:6. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:99 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO:6.

[0138] In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 31 or 99, and the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:7. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:31. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:99. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:31 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO:7. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:99 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO:7.

[0139] In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 31 or 99, and the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:8. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:31. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:99. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:31 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO:8. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:99 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO:8.

[0140] In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 31 or 99, and the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:9. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:31. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:99. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:31 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO:9. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:99 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO:9.

[0141] In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 31 or 99, and the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 10. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:31. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:99. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:31 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO: 10. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:99 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO: 10.

[0142] In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 31 or 99, and the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 11. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:31. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:99. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:31 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO: 11. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:99 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO: 11. [0143] In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 31 or 99, and the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 12. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:31. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:99. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:31 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO: 12. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:99 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO: 12.

[0144] In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 31 or 99, and the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 13. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:31. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:99. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:31 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO: 13. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:99 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO: 13.

[0145] In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 31 or 99, and the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 14. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:31. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:99. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:31 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO: 14. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:99 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO: 14.

[0146] In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 31 or 99, and the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 15. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:31. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:99. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:31 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO: 15. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:99 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO: 15.

[0147] In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 31 or 99, and the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 16. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:31. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:99. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:31 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO: 16. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:99 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO: 16.

[0148] In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 31 or 99, and the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 17. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:31. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:99. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:31 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO: 17. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:99 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO: 17.

[0149] In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 31 or 99, and the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 18. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:31. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:99. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:31 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO: 18. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:99 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO: 18.

[0150] In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 31 or 99, and the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 19. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:31. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:99. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:31 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO: 19. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:99 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO: 19.

[0151] In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 31 or 99, and the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:20. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:31. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:99. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:31 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO:20. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:99 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO:20.

[0152] In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 31 or 99, and the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:21. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:31. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:99. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:31 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO:21. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:99 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO:21.

[0153] In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 31 or 99, and the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:22. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:31. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:99. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:31 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO:22. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:99 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO:22.

[0154] In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 31 or 99, and the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:23. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:31. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:99. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:31 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO:23. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:99 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO:23.

[0155] In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 31 or 99, and the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:24. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:31. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:99. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:31 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO:24. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:99 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO:24.

[0156] In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 31 or 99, and the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:25. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:31. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:99. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:31 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO:25. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:99 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO:25.

[0157] In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 31 or 99, and the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:26. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:31. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:99. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:31 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO:26. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:99 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO:26.

[0158] In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 31 or 99, and the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:27. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:31. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:99. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:31 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO:27. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:99 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO:27.

[0159] In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 31 or 99, and the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:28. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:31. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:99. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:31 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO:28. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:99 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO:28. [0160] In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 31 or 99, and the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:29. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:31. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:99. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:31 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO:29. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:99 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO:29.

[0161] In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 31 or 99, and the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:30. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:31. In some embodiments, the VL region comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:99. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:31 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO:30. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:99 and the VH region comprises the sequence of amino acids set forth in SEQ ID NO:30.

[0162] In some embodiments, the antibody is an antigen-binding fragment containing any of the above VH and VL regions. In some embodiments, the anti-FcRH5 antibody is an scFv containing any of the above VH and VL regions. In some embodiments, the scFv includes a linker joining the two antibody VH and VL region. The linker typically is a peptide linker, e.g., a flexible and/or soluble peptide linker, such as one rich in glycine and serine. In some aspects, the linker rich in glycine and serine (and/or threonine) includes at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% glycine, serine, and/or threonine amino acid(s). In some embodiments, the linker includes at least at or about 50%, 55%, 60%, 70%, or 75%, glycine, serine, and/or threonine. In some embodiments, the linker is comprised substantially entirely of glycine, serine, and/or threonine. The linkers generally are between about 5 and about 50 amino acids in length, typically between at or about 10 and at or about 30, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30, and in some examples between 10 and 25 amino acids in length. Exemplary linkers include linkers having various numbers of repeats of the sequence GGGGS (4GS; SEQ ID NO: 131) or GGGS (3GS; SEQ ID NO: 132), such as between 2, 3, 4 and 5 repeats of such a sequence. Exemplary linkers include those having the sequence set forth in SEQ ID NO: 133 (GGGGSGGGGSGGGGS). Exemplary linkers further include those having the sequence set forth in SEQ ID NO: 134 (GSTSGSGKPGSGEGSTKG). Exemplary linkers further include those having or consisting of the sequence set forth in SEQ ID NO: 135 (SRGGGGSGGGGSGGGGSLEMA). An exemplary linker includes those having or consisting of the sequence set forth in SEQ ID NO: 136 (GSRGGGGSGGGGSGGGGSLEMA). In some embodiments, the VH region may be amino terminal to the VL region. In some embodiments, the VH region may be carboxy terminal to the VL region. In particular embodiments, the fragment, e.g., scFv, may include a VH region or portion thereof, followed by the linker, followed by a VL region or portion thereof. In other embodiments, the fragment, e.g., the scFv, may include the VL region or portion thereof, followed by the linker, followed by the VH region or portion thereof.

[0163] In some embodiments, the antibody is an antigen-binding fragment that further comprises at least a portion of an immunoglobulin constant region of the heavy chain and at least a portion of an immunoglobulin constant region of the light chain. In some embodiments, the anti-FcRH5 antibody is a Fab containing any of the above VH and VL regions. In some embodiments, the constant regions include a light chain constant region and/or a heavy chain constant region 1 (CHI). In some embodiments, the Fab contains a heavy chain comprising any of the above VH regions and an immunoglobulin constant heavy chain domain 1 (CHI domain) and a light chain comprising any of the above VL regions and an immunoglobulin constant light chain (CL).

[0164] In some such embodiments, the antibody is a full-length antibody that also contains a heavy chain and light chain constant region. In some embodiments, the antibody includes at least a portion of a hinge region or a variant thereof. In some embodiments, the antibody includes a CH2 and/or CH3 domain, such as an Fc region. In some embodiments, the Fc region is an Fc region of a human IgG, such as an IgGl or IgG4. In some embodiments, the heavy chain constant portion is derived from an IgGl immunoglobulin constant chain. In some embodiments, the light chain CL is from a kappa or lambda light chain sequence.

[0165] In some embodiments, the light chain is a I (lambda) light chain. In some embodiments, the light chain is a K (kappa) light chain. In some embodiments, the light chain (VL-CL) has the sequence set forth in SEQ ID NO: 102 or a sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:102. In some embodiments, the light chain (VL-CL) has a sequence having at least at or about 95% identity to SEQ ID NO: 102. In some embodiments, the light chain (VL-CL) has a sequence having at least at or about 98% identity to SEQ ID NO: 102. In some embodiments, the light chain (VL-CL) has a sequence having at least at or about 99% identity to SEQ ID NO: 102. In some embodiments, the light chain (VL-CL) has the sequence set forth in SEQ ID NO: 102. In some embodiments, the light chain (VL- CL) has the sequence set forth in SEQ ID NO: 109 or a sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 109. In some embodiments, the light chain (VL-CL) has the sequence set forth in SEQ ID NO: 109. In some embodiments, the light chain (VL-CL) has a sequence having at least at or about 95% identity to SEQ ID NO: 109. In some embodiments, the light chain (VL-CL) has a sequence having at least at or about 98% identity to SEQ ID NO: 109. In some embodiments, the light chain (VL-CL) has a sequence having at least at or about 99% identity to SEQ ID NO: 109. In some embodiments, the light chain (VL-CL) has the sequence set forth in SEQ ID NO: 119 or a sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 119. In some embodiments, the light chain (VL-CL) has a sequence having at least at or about 95% identity to SEQ ID NO: 119. In some embodiments, the light chain (VL-CL) has a sequence having at least at or about 98% identity to SEQ ID NO: 119. In some embodiments, the light chain (VL-CL) has a sequence having at least at or about 99% identity to SEQ ID NO: 119. In some embodiments, the light chain (VL-CL) has the sequence set forth in SEQ ID NO: 119.

[0166] Also provided are polynucleotides (or nucleic acid molecules) encoding the binding molecules, such as anti-FcRH5 antibodies or antigen-binding fragments thereof or any of the provided binding molecules incorporating such antibodies or antigen-binding fragments. The polynucleotides may include those encompassing natural and/or non-naturally occurring nucleotides and bases, e.g., including those with backbone modifications. Among the provided polynucleotides include those encoding a chain or chains of an anti-FcRH5 antibody or antigen-binding domain thereof described herein. In some embodiments, the antibody or antigen-binding fragment thereof contain multiple domains or chains (e.g., heavy chain and a light chain), and all of the antibody or antigen-binding fragment thereof is encoded in one polynucleotide. In some embodiments, the antibody or antigenbinding fragment thereof contain multiple domains or chains (e.g., heavy chain and a light chain), and the antibody or antigen-binding fragment thereof is encoded in multiple polynucleotides. Also provided are polynucleotides that contain a nucleic acid encoding any of the single chain cell surface proteins described herein.

[0167] Also provided are polynucleotides that have been optimized for codon usage and/or to eliminate splice sites, such as cryptic splice sites. In some embodiments, the polynucleotides are modified to optimize codon usage. In some embodiments, the polynucleotides are codon optimized for expression in a mammalian cell, such as a CHO cell, or a human cell.

[0168] In some embodiments, the polynucleotides are comprised in a vector. The vectors can include viral vectors or eukaryotic expression vectors. In some embodiments, the viral vector is a vector derived from simian virus 40 (SV40), adenoviruses, adeno-associated virus (AAV), or retroviral or lenti viral vectors. [0169] In a further embodiment, a host cell comprising such polynucleotides is provided. In one such embodiment, a host cell comprises (e.g., has been transformed with) a vector or vectors that comprise one or more polynucleotides that encodes an amino acid sequence comprising the binding molecule or a chain thereof. In some embodiments, a host cell comprises (e.g., has been transformed with) one or more vectors comprising one or more polynucleotide that encodes one or more an amino acid sequence comprising one or more antibodies and/or portions thereof, e.g., antigen-binding fragments thereof. In some embodiments, a host cell comprises (e.g., has been transformed with) (1) a vector comprising a polynucleotide that encodes an amino acid sequence comprising the VL region of the antibody and an amino acid sequence comprising the VH region of the antibody, or (2) a first vector comprising a polynucleotide that encodes an amino acid sequence comprising the VL region of the antibody and a second vector comprising a polynucleotide that encodes an amino acid sequence comprising the VH region of the antibody. In some embodiments, one or more such host cells are provided. In some embodiments, a composition containing one or more such host cells are provided.

[0170] Also provided are methods of making the FcRH5 binding molecules, including anti- FcRH5 antibodies (including antigen-binding fragments) or a binding molecule incorporating such antibodies or fragments. For recombinant production of the binding molecule, such as an anti-FcRH5 antibody, a polynucleotide sequence or a polynucleotide encoding an antibody, e.g., as described above, may be isolated and inserted into one or more vectors for further cloning and/or expression in a host cell. Such polynucleotide sequences may be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of the antibody). In some embodiments, a method of making the FcRH5 binding molecules, such as anti-FcRH5 antibody, is provided, wherein the method comprises culturing a host cell comprising a polynucleotide sequence encoding the binding molecule, as provided above, under conditions suitable for expression of the binding molecule, and optionally recovering the binding molecule from the host cell (or host cell culture medium).

[0171] Exemplary eukaryotic cells that may be used to express polypeptides include, but are not limited to, COS cells, including COS 7 cells; 293 cells, including 293-6E cells; CHO cells, including CHO-S, DG44. Lecl3 CHO cells, and FUT8 CHO cells; PER.C6® cells; and NSO cells. In some embodiments, the antibody heavy chains and/or light chains (e.g., VH region and/or VL region) may be expressed in yeast. See, e.g., U.S. Publication No. US 2006/0270045 Al. In some embodiments, a particular eukaryotic host cell is selected based on its ability to make desired post-translational modifications to the heavy chains and/or light chains (e.g., VH region and/or VL region). For example, in some embodiments, CHO cells produce polypeptides that have a higher level of sialylation than the same polypeptide produced in 293 cells.

[0172] In some embodiments, the antibody or antigen-binding fragment provided herein is produced in a cell-free system. Exemplary cell-free systems are described, e.g., in Sitaraman et al., Methods Mol. Biol. 498: 229-44 (2009); Spirin, Trends Biotechnol. 22: 538-45 (2004); Endo et al., Biotechnol. Adv. 21: 695-713 (2003).

[0173] In some aspects, any of the exemplary provided antibodies, including antibody fragments, described above can be comprised in a FcRH5-binding molecule. In some embodiments, any of the exemplary provided antibodies, including antibody fragments, is comprised as part of the extracellular domain in a recombinant receptor, such as anti-FcRH5 chimeric antigen receptor (CAR). In some embodiments, any of the exemplary provided antibodies, including antibody fragments, is comprised in a conjugate. In some embodiments, any of the exemplary provided antibodies, including antibody fragments, is comprised in a multispecific antibody composed of at least one anti-FcRH5 antibody that is formatted with at least one additional antibody directed against a different target antigen. In some embodiments, the multispecific antibody is a bispecific T cell engager specific for FcRH5 and CD3 and composed of at least one anti-FcRH5 antibody or antigen-binding fragment (e.g. anti-FcRH5 Fab) and an anti-CD3 antibody or antigen-binding fragment (e.g. anti-CD3 Fab). Exemplary binding molecules are described herein.

Exemplary Features

[0174] In some aspects, the provided antibodies, and binding molecules incorporating the same, have one or more specified functional features, such as binding properties, including binding to particular epitopes or exhibiting lower or reduced binding to a related but different antigen.

[0175] In some embodiments, the provided antibodies or antigen-binding fragment thereof specifically bind to a Fc receptor-homolog 5 (FcRH5) protein. In some of the embodiments provided herein, FcRH5 refers to human FcRH5. A molecule is said to exhibit "specific binding" or "preferential binding" (used interchangeably herein) if it reacts or associates more frequently, more rapidly, with greater duration and/or with greater affinity with a particular cell or molecule than it does with alternative cells or molecules. An antibody specifically binds or preferentially binds to a target cell or molecule if it binds with greater affinity, avidity, more readily, and/or with greater duration than it binds to other cells or molecules. For example, an antibody that specifically or preferentially binds to human FcRH5 is an antibody that binds human FcRH5, such as to a cell that expresses human FcRH5, with greater affinity, avidity, more readily, and/or with greater duration than it binds to other FcRH5 molecules or non-FcRH5 molecules or epitopes. It is also understood by reading this definition that specific binding or preferential binding does not necessarily require (although it can include) exclusive binding. Methods to determine such specific or preferential binding are also well known in the art, e.g., an immunoassay. In certain embodiments described herein, the anti-FcRH5 antibodies, and binding molecules incorporating the same, specifically or preferentially bind to human FcRH5 with greater affinity/avidity than to other FcRH molecules, such as human FcRHl, human FcRH2, human FcRH3 and/or human FcRH4. [0176] The observation that an antibody or other binding molecule binds to FcRH5 or specifically binds to FcRH5 does not necessarily mean that it binds to FcRH5 from every species. For example, in some embodiments, features of binding to FcRH5, such as the ability to specifically bind thereto and/or to compete for binding thereto with a reference antibody, and/or to bind with a particular affinity or compete to a particular degree, in some embodiments, refers to the ability with respect to a human FcRH5 protein and the antibody may not have this feature with respect to a FcRH5 of another species such as mouse. In some embodiments, the antibody binds to human FcRH5 and binds to FcRH5 of another species, such as Rhesus macaque or cynomolgus macaque. In some embodiments, the antibody or an antigen-binding fragment thereof binds to human FcRH5 and does not bind to FcRH5 of another species, such as mouse.

[0177] In some embodiments, the anti-FcRH5 antibodies specifically bind to a particular epitope or region of FcRH5, such as generally an extracellular epitope or region of human FcRH5. In some embodiments, the antibodies or antigen-binding fragment thereof bind, such as specifically bind, to an extracellular epitope or region of human FcRH5 set forth in SEQ ID NO: 130, or an allelic variant or splice variant thereof. In some embodiments, the provided anti-FcRH5 antibodies bind to the membrane proximal domain of the extracellular domain of FcRH5. In some embodiments, the provided anti-FcRH5 antibodies bind to an epitope within Ig-like domain 9 of human FcRH5, such as an epitope within the sequence of amino acids 743-850 of SEQ ID NO: 130.

[0178] In some of the provided embodiments, the antibody or antigen-binding fragment thereof does not bind to, is not cross-reactive to, or binds at a lower extent, level or degree or affinity to a non-FcRH5 protein. In some embodiments, the extent of binding of an anti-FcRH5 antibody to an unrelated, non-FcRH5 protein is less than at or about 50%, 40%, 30%, 20% or 10% of the binding of the antibody to human FcRH5 as measured in the same assay. In some embodiments, the antibody or antigen-binding fragment does not specifically bind to FcRHl, FcRH2, FcRH3 and/or FcRH4.

[0179] In some of the provided embodiments, the antibody or antigen-binding fragment thereof does not bind to, is not cross-reactive to, or binds at a lower extent, level or degree or affinity to a Fc receptor homolog 1 (FcRHl) protein, optionally a human FcRHl protein. In some embodiments, the extent of binding of some of the provided anti-FcRH5 antibodies or fragments thereof to a non- FcRH5 protein, such as a FcRHlprotein, is at least at or about 75%, 80%, 90%, 95% or 99% less than the binding of the antibody to human FcRH5. In some embodiments, among provided antibodies are antibodies of which binding to a FcRHl, such as a human FcRHl, is less than or at or about 30%, 20% or 10%, such as less than at or about 10%, of the binding of the antibody to human FcRH5.

[0180] In some of the provided embodiments, the antibody or antigen-binding fragment thereof does not bind to, is not cross-reactive to, or binds at a lower extent, level or degree or affinity to a Fc receptor homolog 2 (FcRH2) protein, optionally a human FcRH2 protein. In some embodiments, the extent of binding of some of the provided anti- FcRH5 antibodies or fragments thereof to a non-

FcRH5 protein, such as a FcRH2 protein, is at least at or about 75%, 80%, 90%, 95% or 99% less than the binding of the antibody to human FcRH5. In some embodiments, among provided antibodies are antibodies of which binding to a FcRH2, such as a human FcRH2, is less than or at or about 30%, 20% or 10%, such as less than at or about 10%, of the binding of the antibody to human FcRH5.

[0181] In some of the provided embodiments, the antibody or antigen-binding fragment thereof does not bind to, is not cross-reactive to, or binds at a lower extent, level or degree or affinity to a Fc receptor homolog 3 (FcRH3) protein, optionally a human FcRH3 protein. In some embodiments, the extent of binding of some of the provided anti- FcRH5 antibodies or fragments thereof to a non- FcRH5 protein, such as a FcRH3 protein, is at least at or about 75%, 80%, 90%, 95% or 99% less than the binding of the antibody to human FcRH5. In some embodiments, among provided antibodies are antibodies of which binding to a FcRH3, such as a human FcRH3, is less than or at or about 30%, 20% or 10%, such as less than at or about 10%, of the binding of the antibody to human FcRH5.

[0182] In some of the provided embodiments, the antibody or antigen-binding fragment thereof does not bind to, is not cross-reactive to, or binds at a lower extent, level or degree or affinity to a Fc receptor homolog 4 (FcRH4) protein, optionally a human FcRH4 protein. In some embodiments, the extent of binding of some of the provided anti- FcRH5 antibodies or fragments thereof to a non- FcRH5 protein, such as a FcRH4 protein, is at least at or about 75%, 80%, 90%, 95% or 99% less than the binding of the antibody to human FcRH5. In some embodiments, among provided antibodies are antibodies of which binding to a FcRH4, such as a human FcRH4, is less than or at or about 30%, 20% or 10%, such as less than at or about 10%, of the binding of the antibody to human FcRH5.

[0183] In some embodiments, the provided antibodies are capable of binding to FcRH5, such as human FcRH5, with at least a certain affinity, as measured by any of a number of known methods. In some embodiments, the affinity is represented by an equilibrium dissociation constant (KD). In some embodiments, the affinity is represented by ECso-

[0184] A variety of assays are known for assessing binding affinity, equilibrium dissociation constant (KD), equilibrium association constant (KA), ECSO, on-rate (association rate constant; k _on or k _a ; units of 1/Ms or M 's ¹ ) and the off-rate (dissociation rate constant; k _o ff or k ; units of 1/s or s ') and/or determining whether a binding molecule (e.g., an antibody or fragment thereof) specifically binds to a particular ligand (e.g., an antigen, such as a FcRH5 protein). One can determine the binding affinity of a binding molecule, e.g., an antibody or an antigen-binding fragment thereof, for an antigen, e.g., FcRH5, such as human FcRH5, such as by using any of a number of binding assays that are well known. For example, in some embodiments, a BIAcore® instrument can be used to determine the binding kinetics and constants of a complex between two proteins (e.g., an antibody or fragment thereof, and an antigen, such as a FcRH5protein), using surface plasmon resonance (SPR) analysis (see, e.g., Scatchard et al., Ann. N.Y. Acad. Sci. 51:660, 1949; Wilson, Science 295:2103, 2002; Wolff et al., Cancer Res. 53:2560, 1993; and U.S. Patent Nos. 5,283,173, 5,468,614, or the equivalent). [0185] SPR measures changes in the concentration of molecules at a sensor surface as molecules bind to or dissociate from the surface. The change in the SPR signal is directly proportional to the change in mass concentration close to the surface, thereby allowing measurement of binding kinetics between two molecules. The dissociation rate constant (k _o ffor ka), the association rate constant (k _on or k _a ) and/or equilibrium dissociation constant (KD) and/or equilibrium association constant (KA) for the complex can be determined by monitoring changes in the refractive index with respect to time as buffer is passed over the chip. Other suitable assays for measuring the binding of one protein to another include, for example, immunoassays such as enzyme linked immunosorbent assays (ELISA) and radioimmunoassays (RIA), or determination of binding by monitoring the change in the spectroscopic or optical properties of the proteins through fluorescence, UV absorption, circular dichroism, or nuclear magnetic resonance (NMR). Other exemplary assays include, but are not limited to, Western blot, ELISA, analytical ultracentrifugation, spectroscopy, flow cytometry, sequencing, genetic reporter assays, flow cytometry, and other methods for detection of expressed nucleic acids or binding of proteins.

[0186] In some embodiments, the binding molecule, e.g., antibody or fragment thereof, binds, such as specifically binds, to an antigen, e.g., a FcRH5 protein or an epitope therein, with an affinity or KA (i.e., an equilibrium association constant of a particular binding interaction with units of 1/M or M ¹ ; equal to the ratio of the on-rate [k _on or k _a ] to the off-rate [k _o ff or kd] for this association reaction, assuming bimolecular interaction) equal to or greater than 10 ⁵ M In some embodiments, the binding molecule binds, such as specifically binds, to an epitope of an antigen, e.g., human FcRH5, with an affinity or KA (i.e., an equilibrium association constant of a particular binding interaction with units of 1/M or M ') equal to or greater than 10 ⁵ M ¹ (which equals the ratio of the on-rate [k _on ] to the off-rate [k _o ff] for this association reaction). In some embodiments, the binding molecule, e.g., antibody or antigen-binding fragment thereof, exhibits a binding affinity for a T cell epitope of the target polypeptide with an affinity or KA ranging from at or about 10 ⁶ M ¹ to at or about IO ¹⁰ M ¹ , such as from at or about 10 ⁶ M ¹ to at or about 10 ⁹ M ¹ , or from at or about 10 ⁶ M ¹ to at or about 10 ⁸ M In some embodiments, binding affinity may be classified as high affinity or as low affinity. For example, in some cases, a binding molecule, e.g., antibody or antigen-binding fragment thereof, that exhibits high affinity binding to a particular epitope interacts with such epitope with a KA of at least at or about 10 ⁷ M ¹ , at least at or about 10 ⁸ M ¹ , at least at or about 10 ⁹ M ¹ , at least at or about IO ¹⁰ M ¹ , at least at or about 10 ¹¹ M ¹ , at least at or about 10 ¹² M ¹ , or at least at or about 10 ¹³ M ¹ . In some cases, a binding molecule, e.g., antibody or antigen-binding fragment thereof, that exhibits low affinity binding exhibits a KA of up to 10 ⁷ M ¹ , up to 10 ⁶ M ¹ , up to 10 ⁵ M

[0187] Alternatively, affinity can be defined as an equilibrium dissociation constant (KD) of a particular binding interaction with units of M (e.g., 10 ⁵ M to 10 ¹³ M). In some embodiments, the antibody or fragment thereof exhibits a binding affinity for the epitope with a KD (i.e., an equilibrium dissociation constant of a particular binding interaction with units of M; equal to the ratio of the off- rate [k _o ff or kd] to the on-rate [k _on or k _a ] for this association reaction, assuming bimolecular interaction) of equal to or less than 10 ⁵ M. For example, the equilibrium dissociation constant Ki>can range from 10 ⁵ M to 10 ¹³ M, such as 10 ⁷ M to 10 ¹¹ M, 10 ⁷ M to 10 ¹⁰ M, 10 ⁷ M to 10 ⁹ M, 10 ⁸ M to 10 ¹⁰ M, or 10 ⁹ M to 10 ¹⁰ M.

[0188] The on-rate (association rate constant; k _on or k _a ; units of 1/Ms or M 's ¹ ) and the off-rate (dissociation rate constant; koff or k ; units of 1/s or s ¹ ) can be determined using any of the known assay methods, for example, surface plasmon resonance (SPR), or other methods described herein for measuring the binding of one protein to another.

[0189] In some embodiments, the binding affinity (EC50) and/or the equilibrium dissociation constant (KD) of the antibody to FcRH5, such as human FcRH5, is from at or about 0.1 nM to at or about 500 nM, from at or about 0.1 nM to at or about 100 nM, from at or about 0.1 nM to at or about 50 nM, from at or about 0.1 nM to at or about 10 nM, from at or about 0.1 nM to at or about 1 nM, from at or about 1 nM to at or about 500 nM, from at or about 1 nM to at or about 100 nM, from at or about 1 nM to at or about 50 nM, from at or about 1 nM to at or about 10 nM, from at or about 10 nM to at or about 500 nM, from at or about 10 nM to at or about 100 nM, from at or about 10 nM to at or about 50 nM, from at or about 50 nM to at or about 500 nM, from at or about 50 nM to at or about 100 nM or from at or about 100 nM to at or about 500 nM. In certain embodiments, the binding affinity (EC50) and/or the equilibrium dissociation constant (KD) of the antibody to FcRH5, such as human FcRH5, is at or about or less than at or about 100 nM, 50 nM, 40 nM, 30 nM, 25 nM, 20 nM, 19 nM, 18 nM, 17 nM, 16 nM, 15 nM, 14 nM, 13 nM, 12 nM, 11 nM, 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, or 1 nM, or a range defined by any of the foregoing. In some embodiments, the antibodies bind to FcRH5, such as human FcRH5, with a sub-nanomolar binding affinity, for example, with a binding affinity less than at or about 1 nM, such as less than at or about 0.9 nM, 0.8 nM, 0.7 nM, 0.6 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM or 0.1 nM. In some embodiments, the binding affinity (EC50) and/or the equilibrium dissociation constant, KD, of the binding molecule, e.g., anti- FcRH5 antibody or fragment thereof, to a FcRH5 protein, such as a human FcRH5 protein, is from at or about 0.01 nM to about 1 pM, 0.1 nM to 1 pM, 1 nM to 1 pM, 1 nM to 500 nM, 1 nM to 100 nM, 1 nM to 50 nM, 1 nM to 10 nM, 10 nM to 500 nM, 10 nM to 100 nM, 10 nM to 50 nM, 50 nM to 500 nM, 50 nM to 100 nM or 100 nM to 500 nM. In certain embodiments, the binding affinity (EC50) and/or the equilibrium dissociation constant, KD, of the binding molecule, e.g., anti-FcRH5 antibody or fragment thereof, to a FcRH5 protein, such as a human FcRH5 protein, is at or about or less than at or about 1 pM, 500 nM, 100 nM, 50 nM, 40 nM, 30 nM, 25 nM, 20 nM, 19 nM, 18 nM, 17 nM, 16 nM, 15 nM, 14 nM, 13 nM, 12 nM, 11 nM, 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, or 1 nM or less, or a range defined by any of the foregoing.

[0190] In some embodiments, the EC50 and/or the KD of the binding molecule, e.g., anti- FcRH5 antibody or fragment thereof, to a FcRH5 protein, is between at or about 10 nM and at or about 90 nM, between at or about 20 nM and at or about 80 nM, between at or about 30 nM and at or about 70 nM, between at or about 40 nM and at or about 60 nM, or between at or about 40 nM and at or about 50 nM. In certain embodiments, the EC50 and/or the KD of the binding molecule, e.g., anti- FcRH5 antibody or fragment thereof, to a FcRH5 protein, such as a human FcRH5 protein, is at or about 10 nM, 20 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM or 100 nM, or a range defined by any of the foregoing. In certain embodiments, the EC50 and/or the KD of the binding molecule, e.g., anti- FcRH5 antibody or fragment thereof, to a FcRH5 protein, such as a human FcRH5 protein, is at or about 1 nM, 2 nM, 3 nM, 4 nM, 5 nM, 6 nM, 7 nM, 8 nM, 9 nM or 10 nM, or a range defined by any of the foregoing. In certain embodiments, the EC50 and/or the KD of the binding molecule, e.g., anti-FcRH5 antibody or fragment thereof, to a FcRH5 protein, such as a human FcRH5 protein, is at or about 0.1 nM, 0.2 nM, 0.3 nM, 0.4 nM, 0.5 nM, 0.6 nM, 0.7 nM, 0.8 nM, 0.9 nM, or 1.0 nM, or a range defined by any of the foregoing. In some embodiments, the EC50 and/or the KD of the binding molecule, e.g., anti-FcRH5 antibody or fragment thereof, to a FcRH5 protein, such as a human FcRH5 protein, is at or about 0.01 nM, 0.02 nM, 0.03 nM, 0.04 nM, 0.05 nM, 0.06 nM, 0.07 nM, 0.08 nM, 0.09 nM, or 0.1 nM, or a range defined by any of the foregoing.

[0191] In some embodiments, the provided binding molecule, e.g., anti- FcRH5 antibody or antigen-binding fragment thereof, has a fast off-rate (dissociation rate constant; k _o ff or kd; units of 1/s or s' ¹ ). In some embodiments, the off-rate (k _o ff or kd) of the provided binding molecules is between at or about 1 x 10 ⁵ s ¹ and at or about 1 x 10 ² s' ¹ , such as at or about 5 x 10 ⁵ s ¹ and at or about 9 x 10 ³ s' ¹ , at or about 1 x 10 ⁴ s ¹ and at or about 8 x 10 ³ s' ¹ , at or about 5 x 10 ⁴ s ¹ and at or about 7 x 10 ³ s' ¹ , at or about 1 x 10 ³ s ¹ and at or about 6 x 10 ³ s' ¹ , and at or about 4 x 10 ³ s ¹ and at or about 6 x 10 ³ s' '. In some embodiments, the off-rate (koff or kd) of the provided binding molecules is at least at or about 1 x 10 ⁵ s' ¹ , 5 x 10 ⁵ s' ¹ , 1 x 10 ⁴ s' ¹ , 5 x 10 ⁴ s' ¹ , 1 x 10 ³ s' ¹ , 5 x 10 ³ s' ¹ , or 1 x 10 ² s' ¹ . In some embodiments, the off-rate (k _o ff or kd) of the provided binding molecules is at least at or about 6 x 10 ⁴ s 7 x 10 ⁴ s 8 x 10 ⁴ s 9 x 10 ⁴ s' ¹ , 1 x 10 ³ s' ¹ , 2 x 10 ³ s' ¹ , 3 x 10 ³ s' ¹ , 4 x 10 ³ s' ¹ , 5 x 10 ³ s' ¹ , 6 x 10 ³ s' ¹ , 7 x 10 ³ s' ¹ , 8 x 10 ³ s' ¹ , 9 x 10 ³ s ¹ or 1 x 10 ² s' ¹ . In some embodiments, the off-rate (k _o ffor kd) of the provided binding molecules is at least at or about 4 x 10 ³ s 5 x 10 ³ s ¹ or 6 x 10 ³ s ^L or a range defined by any of the foregoing. In some embodiments, the provided binding molecule, e.g., anti- FcRH5 antibody or antigen-binding fragment thereof, has an off-rate that is at least at or about 2- fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold or 10-fold faster than the off-rate of a reference anti- FcRH5 antibody or an antigen-binding fragment thereof, for example, anti-FcRH5.

[0192] In some embodiments, the antibodies display a binding preference for FcRH5-expressing cells as compared to FcRH5 -negative cells, such as particular cells known and/or described herein to express FcRH5 and known not to express FcRH5, or expressing a related but different antigen, e.g., FcRHl, FcRH2, FcRH3 and/or FcRH4. In some embodiments, the binding preference is observed where a significantly greater degree of binding is measured to the FcRH5-expressing, as compared to the non-expressing, cells or cells expressing a related but different antigen. In some embodiments, the fold change in degree of binding detected, for example, as measured by mean fluorescence intensity in a flow cytometry-based assay and/or dissociation constant or EC50, to the FcRH5-expressing cells as compared to the non- FcRH5-expressing cells or cells expressing a related but different antigen, is at least at or about 1.5, 2, 3, 4, 5, 6, or more, and/or is about as great, about the same, at least as great or at least about as great, or greater, than the fold change observed for the corresponding form of the reference antibody. In some cases, the total degree of observed binding to FcRH5 or to the FcRH5- expressing cells is approximately the same, at least as great, or greater than that observed for the corresponding form of the reference antibody.

[0193] Anti-FcRH5 antibodies provided herein may be identified, screened for, or characterized for their physical/chemical properties and/or biological activities by various known assays. In one aspect, the antibody is tested for its antigen binding activity, e.g., by known methods such as EFISA, Western blotting, and/or flow cytometric assays, including cell-based binding assays, for example, assessing binding of the antibody (e.g., conjugated to a fluorescent marker or tagged) to a cell expressing the target antigen, e.g., FcRH5, in some cases compared to results using cells that do not express the target antigen, e.g., FcRH5, or cells that express a different antigen, e.g., FcRHl. Binding affinity may be measured as KD, KA or EC50.

B. Chimeric Antigen Receptor

[0194] Among the provided FcRH5 binding molecules are cell surface proteins, such as recombinant antigen receptors, such as those that include one of the provided antibodies or antigenbinding fragments. Also provided are polynucleotides that encode all or a portion of such cell surface proteins, e.g., receptors. Among the recombinant antigen receptors are functional non-TCR antigen receptors, such as chimeric antigen receptors (CARs). The FcRH5-binding receptors generally contain antibodies (e.g., antigen-binding fragments) that specifically bind to FcRH5 proteins, such as to human FcRH5. Also provided are polynucleotides that encode a provided recombinant antigen receptors. Also provided are cells expressing the recombinant antigen receptors, compositions containing such cells and uses thereof in adoptive cell therapy, such as treatment of diseases and disorders associated with FcRH5 expression, compositions and articles of manufacture and uses of the same.

[0195] The chimeric receptors, such as CARs, generally include an extracellular antigen-binding domain that includes, is, or is comprises an anti-FcRH5 antibody, such as an anti-FcRH5 antibody or fragment thereof described herein. In some embodiments, the chimeric receptors, e.g., CARs, include an intracellular signaling domain. In some embodiments, the chimeric receptors also include a spacer and/or a transmembrane domain. In some embodiments, the spacer is located between the extracellular antigen-binding domain and the transmembrane domain. In some embodiments, the CAR comprises an extracellular antigen-binding domain, a spacer, a transmembrane domain and an intracellular signaling region. [0196] In some embodiments, the extracellular antigen-binding domain of the CAR includes one or more of any of the FcRH5 -binding antibodies or antigen-binding fragments thereof described herein, e.g., in Section I. A. In some embodiments, the extracellular antigen-binding domain of the CAR includes an antigen-binding fragment of an anti-FcRH5 antibody molecule, such as containing a variable heavy (Vu) chain region and a variable light (VL) chain region of the antibody. In some embodiments, the antigen-binding fragment may include fragment antigen-binding (Fab) fragments, F(ab’)2 fragments, Fab’ fragments, Fv fragments, and single chain antibody fragments, including single chain variable fragments (scFv). In some embodiments, the extracellular antigen-binding domain of the CAR includes an anti-FcRH5 scFv. In some embodiments, the scFv includes a linker that links the VH and the VL domains of the scFv. In some embodiments, the linker is a Whitlow linker having the amino acid sequence set forth in SEQ ID NO: 155. In some embodiments, the linker is a GS linker, such as a linker having the amino acid sequence set forth in SEQ ID NO: 156.

[0197] In some embodiments, the recombinant receptor such as the CAR further includes a spacer (in some cases also called a spacer region) between the antigen-binding domain, e.g., scFv, and transmembrane domain. In some embodiments, the length of the spacer is adjusted to optimize the biophysical synapse distance between the CAR-expressing cell, such as a CAR-expressing cell, and the target of the CAR, such as a FcRH5-expressing tumor cell. In some embodiments, the CAR is expressed by a T cell, and the length of the spacer is adjusted to a length that is compatible for T cell activation or to optimize CAR T-cell performance. Various lengths of spacers can be employed.

[0198] Exemplary spacers include those having at least at or about 7 to at or about 300 amino acids, at or about 7 to at or about 229 amino acids, at or about 7 to at or about 200 amino acids, at or about 7 to at or about 175 amino acids, at or about 7 to at or about 150 amino acids, at or about 7 to at or about 125 amino acids, at or about 7 to at or about 100 amino acids, at or about 7 to at or about 75 amino acids, at or about 10 to at or about 50 amino acids, at or about 10 to at or about 40 amino acids, at or about 10 to at or about 30 amino acids, at or about 10 to at or about 20 amino acids, or at or about 10 to at or about 15 amino acids in length, and including any integer between the endpoints of any of the listed ranges. Exemplary spacers include those having at least at or about at or about 50 to at or about 175 amino acids, at or about 50 to at or about 150 amino acids, at or about 10 to at or about 125 amino acids, at or about 50 to at or about 100 amino acids, at or about 100 to at or about 300 amino acids, at or about 100 to at or about 250 amino acids, at or about 125 to at or about 250 amino acids, or at or about 200 to at or about 250 amino acids, and including any integer between the endpoints of any of the listed ranges. In some embodiments, a spacer is at least at or about 12 amino acids, to at least at or about 119 amino acids, at least at or about 125 amino acids, at least at or about 200 amino acids, or at least at or about 220 amino acids, or at least at or about 225 amino acids in length. In some embodiments, a spacer is at least at or about 13 amino acids, to at least at or about 120 amino acids, at least at or about 125 amino acids, at least at or about 200 amino acids, or at least at or about 220 amino acids, or at least at or about 229 amino acids in length. In some embodiments, a spacer is at or about 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 amino acids in length. In some embodiments, the spacer is at least at or about 100 amino acids in length, such as at least at or about 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 130, 135, 140, 145, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, or 250 amino acids in length.

[0199] In some embodiments, the spacer may be or include at least a portion of an immunoglobulin constant region or variant or modified version thereof, that includes a IgG hinge region, and optionally a CHI, CH2 and/or CH3 region of an IgG. In some embodiments, the IgG is a human IgG, such as IgG4, IgG2 or IgGl. Exemplary spacers include an IgG hinge alone, an IgG hinge linked to one or more of a CH2 and CH3 domain, or IgG hinge linked to the CH3 domain.

[0200] In some embodiments, the spacer includes a hinge sequence that has the formula X1PPX2P (SEQ ID NO: 144), where Xi is glycine, cysteine or arginine and X2 is cysteine or threonine.

[0201] Non-limiting examples of spacers include CD8a hinge domain (SEQ ID NO: 138), CD28 hinge domain (SEQ ID NO: 139 or 140), IgG4 hinge domain (SEQ ID NO: 141 or 142), IgG4 hinge - CH2-CH3 domain (SEQ ID NO: 143), hinge-CH3 (SEQ ID NO: 145), and variants thereof,

[0202] Additional exemplary spacers include, but are not limited to, those described in Hudecek et al. (2013) Clin. Cancer Res., 19:3153, Hudecek et al. (2015) Cancer Immunol. Res., 3(2):125-50, or WO2014031687. In some embodiments, the nucleotide sequence of the spacer is optimized to reduce RNA heterogeneity upon expression. In some embodiments, the nucleotide sequence of the spacer is optimized to reduce cryptic splice sites or reduce the likelihood of a splice event at a splice site.

[0203] In some embodiments, the transmembrane domain is derived either from a natural or from a synthetic source. Where the source is natural, the domain in some aspects is derived from any membrane-bound or transmembrane protein. Transmembrane domains include those derived from (i.e. comprise at least the transmembrane domain(s) of) the alpha, beta or zeta chain of the T-cell receptor, CD3 epsilon, CD4, CD5, CD8, CD9, CD16, CD22, CD28, CD33, CD37, CD45, CD64, CD80, CD86, CD134, CD137, and/or CD154. In one embodiment, a transmembrane domain that naturally is associated with one of the domains in the receptor, e.g., CAR, is used.

[0204] In some embodiments, the transmembrane domain of the receptor, e.g., the CAR is a transmembrane domain of human CD28 (Accession No.: P10747.1) or variant thereof. In some embodiments, the transmembrane domain is a 27-amino acid or 28-amino acid transmembrane domain of a human CD28 (Accession No.: P10747.1). In some embodiments, the transmembrane domain is set forth in SEQ ID NO: 146. In some embodiments, the transmembrane domain is set forth in SEQ ID NO: 147.

[0205] In some embodiments, the transmembrane domain of the receptor, e.g. the CAR, is a transmembrane domain of human CD 8 or variant thereof. In some embodiments, the transmembrane domain is set forth in SEQ ID NO: 148. [0206] In some embodiments, the receptor, e.g., the CAR, generally includes an intracellular signaling region comprising at least one intracellular signaling component or components. Among the intracellular signaling domains are those that mimic or approximate a signal through a natural antigen receptor, a signal through such a receptor in combination with a costimulatory receptor, and/or a signal through a costimulatory receptor alone. T cell activation is in some aspects described as being mediated by two classes of cytoplasmic signaling sequences: those that initiate antigendependent primary activation through the TCR (primary cytoplasmic signaling sequences), and those that act in an antigen-independent manner to provide a secondary or co-stimulatory signal (secondary cytoplasmic signaling sequences). In some aspects, the CAR includes one or both of such classes of cytoplasmic signaling sequences. In some embodiments, upon ligation of the CAR, the cytoplasmic domain or intracellular signaling region of the CAR stimulates and/or activates at least one of the normal effector functions or responses of the immune cell, e.g., T cell engineered to express the CAR. For example, in some contexts, the CAR induces a function of a T cell such as cytolytic activity or T- helper activity, such as secretion of cytokines or other factors. In some embodiments, the intracellular signaling domain or domains include the cytoplasmic sequences of the T cell receptor (TCR), and in some aspects also those of co-receptors that in the natural context act in concert with such receptor to initiate signal transduction following antigen receptor engagement, and/or any derivative or variant of such molecules, and/or any synthetic sequence that has the same functional capability.

[0207] In some aspects, the CAR includes a primary cytoplasmic signaling sequence that regulates primary stimulation and/or activation of the TCR complex. Primary cytoplasmic signaling sequences that act in a stimulatory manner may contain signaling motifs which are known as immunoreceptor tyrosine-based activation motifs or IT AMs. Examples of IT AM containing primary cytoplasmic signaling sequences include those derived from TCR or CD3 zeta, FcR gamma, CD3 gamma, CD3 delta and CD3 epsilon. In some embodiments, the intracellular signaling region in the CAR contains a cytoplasmic signaling domain, portion thereof, or sequence derived from CD3 zeta.

[0208] In some embodiments, the intracellular signaling domain comprises a human CD3 zeta (also referred to as CD3^ or CD3z) stimulatory signaling domain or functional variant thereof, such as an 112 AA cytoplasmic domain of isoform 3 of human CD3^ (Accession No.: P20963.2) or a CD3 zeta signaling domain as described in U.S. Patent No.: 7,446,190 or U.S. Patent No. 8,911,993.

[0209] In some embodiments, the human CD3^ signaling domain of the intracellular signaling domain comprises or consists of the sequence set forth in SEQ ID NO: 149, or a variant thereof having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to a human CD3 signaling domain set forth in SEQ ID NO: 149. In some embodiments, the human CD3^ signaling domain of the intracellular signaling domain comprises or consists of the sequence set forth in SEQ ID NO: 149. In some embodiments, the human CD3^ signaling domain of the intracellular signaling domain comprises the sequence set forth in SEQ ID NO: 149. In some embodiments, the human CD3^ signaling domain of the intracellular signaling domain consists of the sequence set forth in SEQ ID NO: 149.

[0210] In some embodiments, the human CD3z signaling domain of the intracellular signaling domain comprises or consists of the sequence set forth in SEQ ID NO: 150, or a variant thereof having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO: 150. In some embodiments, the human CD3z signaling domain of the intracellular signaling domain comprises or consists of the sequence set forth in SEQ ID NO: 150. In some embodiments, the human CD3z signaling domain of the intracellular signaling domain comprises the sequence set forth in SEQ ID NO: 150. In some embodiments, the human CD3z signaling domain of the intracellular signaling domain consists of the sequence set forth in SEQ ID NO: 150.

[0211] In some embodiments, the human CD3z signaling domain of the intracellular signaling domain comprises or consists of the sequence set forth in SEQ ID NO: 151, or a variant thereof having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO: 151. In some embodiments, the human CD3z signaling domain of the intracellular signaling domain comprises or consists of the sequence set forth in SEQ ID NO: 151. In some embodiments, the human CD3z signaling domain of the intracellular signaling domain comprises the sequence set forth in SEQ ID NO: 151. In some embodiments, the human CD3z signaling domain of the intracellular signaling domain consists of the sequence set forth in SEQ ID NO:151.

[0212] In the context of a natural TCR, full activation generally requires not only signaling through the TCR, but also a costimulatory signal. Thus, in some embodiments, to promote full activation, a component for generating secondary or co-stimulatory signal is also included in the CAR. Exemplary costimulatory molecules include CD28, 4-1BB, 0X40, DAP10, and ICOS.

[0213] In some embodiments, the intracellular domain comprises an intracellular costimulatory signaling domain of 4-1BB or functional variant or portion thereof, such as a 42-amino acid cytoplasmic domain of a human 4-1BB (Accession No. Q07011.1) or functional variant or portion thereof. In certain embodiments, the intracellular signaling region comprises a 4- IBB signaling domain linked to a CD3 (e.g., CD3-zeta) intracellular domain. In some embodiments, the costimulatory domain of the intracellular signaling domain is an intracellular domain sequence of 4- 1BB set forth in SEQ ID NO: 152 or a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO: 152. In some embodiments, the 4-1BB signaling domain comprises or consists of the sequence set forth in SEQ ID NO: 152. In some embodiments, the 4-1BB signaling domain comprises the sequence set forth in SEQ ID NO: 152. In some embodiments, the 4-1BB signaling domain consists of the sequence set forth in SEQ ID NO: 152. [0214] In some embodiments, the intracellular domain comprises an intracellular costimulatory signaling domain of CD28 or functional variant or portion thereof. In certain embodiments, the intracellular signaling region comprises a CD28 signaling domain linked to a CD3 (e.g., CD3-zeta) intracellular domain. In some embodiments, the costimulatory domain of the intracellular signaling domain comprises an intracellular signaling domain of human CD28 or functional variant or portion thereof, such as a 41 amino acid domain thereof and/or such a domain with an LL to GG substitution at positions 186-187 of a native CD28 protein. In some embodiments, the costimulatory domain of the intracellular signaling domain is an intracellular domain sequence of CD28 set forth in SEQ ID NO: 153 or 154 or a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO:153 or 154. In some embodiments, the CD28 signaling domain comprises or consists of the sequence set forth in SEQ ID NO: 153. In some embodiments, the CD28 signaling domain comprises the sequence set forth in SEQ ID NO: 153. In some embodiments, the CD28 signaling domain consists of the sequence set forth in SEQ ID NO: 153. In some embodiments, the CD28 signaling domain comprises or consists of the sequence set forth in SEQ ID NO: 154. In some embodiments, the CD28 signaling domain comprises the sequence set forth in SEQ ID NO: 154. In some embodiments, the CD28 signaling domain consists of the sequence set forth in SEQ ID NO: 154.

[0215] In other embodiments, the CAR does not include a component for generating a costimulatory signal. In some aspects, an additional CAR is expressed in the same cell and provides the component for generating the secondary or costimulatory signal. In some embodiments, the stimulatory or activating components are included within one CAR, whereas the costimulatory component is provided by another CAR recognizing another antigen. In some embodiments, the CARs include activating or stimulatory CARs, and costimulatory CARs, both expressed on the same cell (see WO 2014/055668). In some embodiments, the cells further include inhibitory CARs (iCARs, see Fedorov et al., Sci. Transl. Medicine, 5(215) (December, 2013), such as a CAR recognizing an antigen other than FcHR5, whereby a stimulatory or an activating signal delivered through the FcHR5 -targeting CAR is diminished or inhibited by binding of the inhibitory CAR to its ligand, e.g., to reduce off-target effects.

[0216] In some embodiments, engineered cells expressing the provided anti-FcRH5 CARs exhibit biological activity or functional activity, such as anti-tumor activity, tumor growth inhibition, tumor volume reduction, persistence, expansion, or prolonged survival of the subject, when administered to a subject for adoptive cell therapy. In some embodiments, biological activity or functional activity of a chimeric receptor, such as cytotoxic activity, can be measured using any of a number of known methods. The activity can be assessed or determined either in vitro or in vivo. In some embodiments, activity can be assessed once the cells are administered to the subject (e.g., human). Parameters to assess include specific binding of an engineered or natural T cell or other immune cell to antigen, e.g., in vivo, e.g., by imaging, or ex vivo, e.g., by ELISA or flow cytometry. In certain embodiments, the ability of the engineered cells to destroy target cells can be measured using any suitable known methods, such as cytotoxicity assays described in, for example, Kochenderfer et al., J. Immunotherapy, 32(7): 689-702 (2009), and Herman et al. J. Immunological Methods, 285(1): 25-40 (2004). In certain embodiments, the biological activity of the cells also can be measured by assaying expression and/or secretion of certain cytokines, such as interlekukin-2 (IL-2), interferon-gamma (IFNy), interleukin-4 (IL-4), TNF-alpha (TNFa), interleukin-6 (IL-6), interleukin- 10 (IL-10), interleukin- 12 (IL-12), granulocyte-macrophage colony-stimulating factor (GM-CSF), CD 107a, and/or TGF-beta (TGFP). Assays to measure cytokines are well known, and include but are not limited to, ELISA, intracellular cytokine staining, cytometric bead array, RT-PCR, ELISPOT, flow cytometry and bio-assays in which cells responsive to the relevant cytokine are tested for responsiveness (e.g. proliferation) in the presence of a test sample. In some aspects the biological activity can be measured using an animal model of the disease or condition, such as a tumor xenograft model, and assessing the reduction in tumor burden or load and/or survival. In some aspects the biological activity is measured by assessing clinical outcome, such as reduction in tumor burden or load.

[0217] Also provided are polynucleotides (or nucleic acid molecules) encoding the chimeric antigen receptor. The polynucleotides may include those encompassing natural and/or non-naturally occurring nucleotides and bases, e.g., including those with backbone modifications. Also provided are polynucleotides that have been optimized for codon usage and/or to eliminate splice sites, such as cryptic splice sites. In some embodiments, the polynucleotides are modified to optimize codon usage. In some embodiments, the polynucleotides are codon optimized for expression in a mammalian cell, such as a human cell.

[0218] In some embodiments, the polynucleotides are comprised in a vector. The vectors can include viral vectors or mammalian expression vectors. In some embodiments, the viral vector is a vector derived from simian virus 40 (SV40), adenoviruses, adeno-associated virus (AAV), or retroviral or lenti viral vectors.

[0219] Also provided are cells such as engineered cells that comprise or express any of the provided recombinant receptor (e.g., a chimeric antigen receptor) such as one that comprises an extracellular domain including an anti-FcRH5 antibody or fragment as described herein. Also provided are cells such as engineered cells that comprise any of the provided polynucleotides encoding any of the provided recombinant receptors (e.g., CAR).

[0220] The cells generally are eukaryotic cells, such as mammalian cells, and typically are human cells. In some embodiments, the cells are derived from the blood, bone marrow, lymph, or lymphoid organs, are cells of the immune system, such as cells of the innate or adaptive immunity, e.g., myeloid or lymphoid cells, including lymphocytes, typically T cells and/or NK cells. Other exemplary cells include stem cells, such as multipotent and pluripotent stem cells, including induced pluripotent stem cells (iPSCs). The cells typically are primary cells, such as those isolated directly from a subject and/or isolated from a subject and frozen. In some embodiments, the cells include one or more subsets of T cells or other cell types, such as whole T cell populations, CD4+ cells, CD8+ cells, and subpopulations thereof, such as those defined by function, activation state, maturity, potential for differentiation, expansion, recirculation, localization, and/or persistence capacities, antigen-specificity, type of antigen receptor, presence in a particular organ or compartment, marker or cytokine secretion profile, and/or degree of differentiation. With reference to the subject to be treated, the cells may be allogeneic and/or autologous. Among the methods include off-the-shelf methods. In some aspects, such as for off-the-shelf technologies, the cells are pluripotent and/or multipotent, such as stem cells, such as induced pluripotent stem cells (iPSCs). In some embodiments, the methods include isolating cells from the subject, preparing, processing, culturing, and/or engineering them, as described herein, and re-introducing them into the same patient, before or after cryopreservation.

[0221] Among the sub-types and subpopulations of T cells and/or of CD4+ and/or of CD8+ T cells are naive T (TN) cells, effector T cells (TEFF), memory T cells and sub-types thereof, such as stem cell memory T (TSCM), central memory T (TCM), effector memory T (TEM), or terminally differentiated effector memory T cells, tumor-infiltrating lymphocytes (TIL), immature T cells, mature T cells, helper T cells, cytotoxic T cells, mucosa-associated invariant T (MAIT) cells, naturally occurring and adaptive regulatory T (Treg) cells, helper T cells, such as TH1 cells, TH2 cells, TH3 cells, TH17 cells, TH9 cells, TH22 cells, follicular helper T cells, alpha/beta T cells, and delta/gamma T cells. In some embodiments, the cells are T cells. In some embodiments, the engineered cells include CD4+ and CD8+ T cells engineered with the recombinant receptor (e.g. CAR).

[0222] In some embodiments, the cells are natural killer (NK) cells. In some embodiments, the cells are monocytes or granulocytes, e.g., myeloid cells, macrophages, neutrophils, dendritic cells, mast cells, eosinophils, and/or basophils.

C. Immunoconjugates

[0223] In some embodiments, the FcRH5 binding molecule, e.g. anti-FcRH5 antibody or antigen-binding fragment, is or is part of an immunoconjugate, in which the antibody is conjugated to one or more heterologous molecule(s), such as, but not limited to, a cytotoxic or an imaging agent. Cytotoxic agents include, but are not limited to, radioactive isotopes (e.g., At ²¹¹ , 1 ¹³¹ , 1 ¹²⁵ , Y ⁹⁰ , Re ¹⁸⁶ , Re ¹⁸⁸ , Sm ¹⁵³ , Bi ²¹² , P ³² , Pb ²¹² and radioactive isotopes of Lu); chemotherapeutic agents (e.g., methotrexate, adriamicin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin or other intercalating agents); growth inhibitory agents; enzymes and fragments thereof such as nucleolytic enzymes; antibiotics; toxins such as small molecule toxins or enzymatically active toxins. In some embodiments, the antibody is conjugated to one or more cytotoxic agents, such as chemotherapeutic agents or drugs, growth inhibitory agents, toxins (e.g., protein toxins, enzymatically active toxins of bacterial, fungal, plant, or animal origin, or fragments thereof), or radioactive isotopes.

[0224] Among the immunoconjugates are antibody-drug conjugates (ADCs), in which an antibody is conjugated to one or more drugs, including but not limited to a maytansinoid (see U.S. Patent Nos. 5,208,020, 5,416,064 and European Patent EP 0 425 235 Bl); an auristatin such as monomethylauristatin drug moieties DE and DF (MMAE and MMAF) (see U.S. Patent Nos. 5,635,483 and 5,780,588, and 7,498,298); a dolastatin; a calicheamicin or derivative thereof (see U.S. Patent Nos. 5,712,374, 5,714,586, 5,739,116, 5,767,285, 5,770,701, 5,770,710, 5,773,001, and 5,877,296; Hinman et al., Cancer Res. 53:3336-3342 (1993); and Lode et al., Cancer Res. 58:2925- 2928 (1998)); an anthracycline such as daunomycin or doxorubicin (see Kratz et al., Current Med. Chem. 13:477-523 (2006); Jeffrey et al., Bioorganic & Med. Chem. Letters 16:358-362 (2006); Torgov et al., Bioconj. Chem. 16:717-721 (2005); Nagy et al., Proc. Natl. Acad. Sci. USA 97:829-834 (2000); Dubowchik et al., Bioorg. & Med. Chem. Letters 12:1529-1532 (2002); King et al., J. Med. Chem. 45:4336-4343 (2002); and U.S. Patent No. 6,630,579); methotrexate; vindesine; a taxane such as docetaxel, paclitaxel, larotaxel, tesetaxel, and ortataxel; a trichothecene; and CC1065.

[0225] Also among the immunoconjugates are those in which the antibody is conjugated to an enzymatically active toxin or fragment thereof, including but not limited to diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, Shiga-like toxin, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes.

[0226] Also among the immunoconjugates are those in which the antibody is conjugated to a radioactive atom to form a radioconjugate. Exemplary radioactive isotopes include At ²¹¹ , 1 ¹³¹ , 1 ¹²⁵ , Y ⁹⁰ , Re ¹⁸⁶ , Re ¹⁸⁸ , Sm ¹⁵³ , Bi ²¹² , P ³² , Pb ²¹² and radioactive isotopes of Lu.

[0227] Conjugates of an antibody and cytotoxic agent may be made using any of a number of known protein coupling agents, e.g., linkers, (see Vitetta et al., Science 238:1098 (1987)), WO94/11026. The linker may be a “cleavable linker” facilitating release of a cytotoxic drug in the cell, such as acid-labile linkers, peptidase-sensitive linkers, photolabile linkers, dimethyl linkers, and disulfide-containing linkers (Chari et al., Cancer Res. 52:127-131 (1992); U.S. Patent No. 5,208,020).

[0228] In some embodiments, the provided antibodies, including antigen-binding fragments, may be cysteine engineered in which one or more residues of an antibody are substituted with cysteine residues,. Cysteine-engineered antibodies, such as “thioMAbs” and other cysteine engineered variants, can be used in order to generate reactive thiol groups at accessible sites, e.g., for use in conjugation of agents and linker-agents, to produce immunoconjugates. Cysteine engineered antibodies are described, e.g., in U.S. Patent Nos. 7,855,275 and 7,521,541. D. Multispecific Antibodies

[0229] In certain embodiments, the FcRH5-binding molecules, e.g., antibodies or antigenbinding fragment thereof, or fusion proteins, such as recombinant receptors (e.g. CARs) containing the same, are multispecific. In some embodiments, the FcRH5-binding molecules, e.g. antibodies or antigen-binding fragments, is incorporated into essentially any antibody format, including multispecific (including bispecific( formats). In certain embodiments, the multispecific antibodies incorporate any of the provided anti-FcRH5 antibodies, including antigen-binding fragments. In some embodiments, the multispecific antibody is a bispecific antibody. Multispecific antibodies have binding specificities for at least two different sites, which may be in the same or different antigens. In certain embodiments, one of the binding specificities is for FcRH5 and the other is for another antigen. In certain embodiments, bispecific antibodies may bind to two different epitopes of FcRH5. Bispecific antibodies may also be used to localize cytotoxic agents to cells which express FcRH5. Bispecific antibodies can be prepared as full length antibodies or antibody fragments. Among the multispecific antibodies are multispecific single-chain antibodies, e.g., diabodies, triabodies, and tetrabodies, tandem di-scFvs, and tandem tri-scFvs.

[0230] Exemplary additional antigens include B cell specific antigens, other tumor-specific antigens, such as antigens expressed specifically on or associated with B cell leukemia, lymphoma, B cell chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), Burkitt's Lymphoma, mantle cell lymphoma (MCL), non-small cell lung cancer (NSCLC), neuroblastoma, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, epithelial squamous cell cancer, melanoma, myeloma, stomach cancer, brain cancer, lung cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, prostate cancer, testicular cancer, thyroid cancer, uterine cancer, adrenal cancer and/or head and neck cancer, and antigens expressed on T cells. Exemplary antigens include CD3, CD4, CD5, CD8, CD14, CD15, CD19, CD20, CD21, CD22, CD23, CD25, CD33, CD37, CD38, CD40, CD40L, CD46, CD52, CD54, CD74, CD80, CD126, CD138, B7, MUC-1, la, HM1.24, HLA-DR, tenascin, an angiogenesis factor, VEGF, PIGF, ED-B fibronectin, an oncogene, an oncogene product, CD66a-d, necrosis antigens, li, IL-2, T101, TAC, IL-6, TRAIL-R1 (DR4) and TRAIL-R2 (DR5).

[0231] In some embodiments, the multispecific antibody is a T cell-engaging therapy that is or comprises at least one FcRH5-directed antibody as described and an anti-T cell binding domain that is a binding molecule capable of binding to a surface molecule expressed on a T cell. In some embodiments, the surface molecule is an activating component of a T cell, such as a component of the T cell receptor complex. In some embodiments, the activating component of the T cell is a surface molecule. In some embodiments, the surface molecule is or comprises a T-cell antigen. Exemplary T- cell antigens include but are not limited to CD2, CD3, CD4, CD5, CD6, CD8, CD25, CD28, CD30, CD40, CD44, CD45, CD69 and CD90. In some aspects, the binding of the bispecific T cell engaging molecule with the T cell antigen stimulates and/or activates the T cell. In some aspects, an activating component of the T cell is a T cell surface molecule, such as CD3 or CD2. Any T cell-engager formats can be generated with a provided anti-FcRH5 antibody.

[0232] In some embodiments, the anti-T cell binding domain of the T cell-engaging therapy is or comprises an antibody or antigen-binding fragment. In some embodiments, the T cell-engaging therapy is a bispecific antibody containing at least one antigen-binding domain binding to an activating component of the T cell (e.g. a T cell surface molecule, e.g. CD3 or CD2) and at least one antigen-binding domain binding to FcRH5 as described. In some embodiments, the simultaneous or near simultaneous binding of such an antibody to both of its targets can result in a temporary interaction between the target cell and T cell, thereby resulting in activation, e.g. cytotoxic activity, of the T cell and subsequent lysis of the target cell.

[0233] In some embodiments, each antigen-binding domains, including the anti-T cell binding domain and the at least one anti-FcRH5 binding domain, comprise an antibody or an antigen-binding fragment. In some embodiments, the multispecific antibody contains one anti-FcRH5 binding domain and one anti-T cell binding domain. In some embodiments, the multispecific antibody is a bispecific trivalent antibody (also called TriFabs) that exhibits bivalent binding for FcRH5 and monovalent binding to the T cell activation component. In some embodiments, the multispecific antibody contains two FcRH5 binding domains (e.g. Fab) and one anti-T cell binding domain (e.g. Fab).

[0234] In some embodiments, the anti-T cell binding domain includes an antibody or an antigenbinding fragment thereof selected from the group consisting of a Fab fragment, a F(ab')2 fragment, an Fv fragment, an scFv, a scAb, a dAb, a single domain heavy chain antibody, and a single domain light chain antibody. In some embodiments, the anti-T cell binding domain is a Fab.

[0235] In some embodiments, each of the at least one anti-FcRH5 domain includes an antibody or an antigen-binding fragment thereof selected from the group consisting of a Fab fragment, a F(ab')2 fragment, an Fv fragment, an scFv, a scAb, a dAb, a single domain heavy chain antibody, and a single domain light chain antibody. In some embodiments, the anti-FcRH5 domain can include any of the antibodies or antigen-binding fragments as described in Section I. A. In some embodiments, the anti- FcRH5 antibody that binds to FcRH5 includes (i) any of the provided VH domains as described in Section I. A and (ii) any of the provided VL domains described in Section I. A. In some embodiments, each of the anti-FcRH5 domains is a Fab.

[0236] Methods of producing bi-specific T cell engagers are known, including fusion of two different hybridomas (Milstein and Cuello, Nature 1983;305:537-540), chemical tethering though heterobifunctional cross linkers (Staerz et al. Nature 1985; 314:628-631), manufacturing of scFv- based agents of multivalency and multispecificity by varying the linker length (e.g. U.S. Pat. No. 5,844,094, U.S. Pat. No. 5,837,242 and WO 98/44001), diabodies including Dual-Affinity Re-

Targeting (DART®) (see, e.g., Moore et al., 2011, Blood 117:4542-51; Veri et al, 2010, Arthritis

Rheum 62: 1933-43), and tetravalent and bispecific antibody-like proteins known as DVD-Igs which are engineered from two monoclonal antibodies (Wu, C. et al., Nature Biotechnology, 25, p 1290- 1297, 2007). Exemplary bispecific formats are known, see e.g. Brinkmann et al. MAbs 2017, 9:182- 212.

[0237] For instance, among such exemplary bispecific antibodies are bispecific T cell engager (BiTE) molecules, which contain tandem scFv molecules fused by a flexible linker (see e.g. Nagorsen and Bauerle, Exp Cell Res 317, 1255-1260 (2011); tandem scFv molecules fused to each other via, e.g. a flexible linker, and that further contain an Fc domain composed of a first and a second subunit capable of stable association (WO2013026837); diabodies and derivatives thereof, including tandem diabodies (Holliger et al, Prot Eng 9, 299-305 (1996); Kipriyanov et al, J Mol Biol 293, 41-66 (1999)); dual affinity retargeting (DART) molecules that can include the diabody format with a C- terminal disulfide bridge; or triomabs that include whole hybrid mouse/rat IgG molecules (Seimetz et al, Cancer Treat Rev 36, 458-467 (2010); and trivalent bispecific antibodies (e.g. Mayer et al. 2015 Int. J Mol Sci, 16:27497-27507 and U.S. patent publication No. US20200062826).

[0238] Examples of bispecific antibody molecules formats which may be used include (i) a single antibody that has two arms comprising different antigen-binding regions; (ii) a single chain antibody that has specificity to two different epitopes, e.g., via two scFvs linked in tandem by an extra peptide linker; (iii) a dual-variable-domain antibody (DVD-Ig), where each light chain and heavy chain contains two variable domains in tandem through a short peptide linkage (Wu et al., Generation and Characterization of a Dual Variable Domain Immunoglobulin (DVD-Ig™) Molecule, In: Antibody Engineering, Springer Berlin Heidelberg (2010)); (iv) a chemically-linked bispecific (Fab')2 fragment; (v) a Tandab, which is a fusion of two single chain diabodies resulting in a tetravalent bispecific antibody that has two binding sites for each of the target antigens; (vi) a flexibody, which is a combination of scFvs with a diabody resulting in a multivalent molecule; (vii) a so-called “dock and lock” molecule, based on the “dimerization and docking domain” in Protein Kinase A, which, when applied to Fabs, can yield a trivalent bispecific binding protein consisting of two identical Fab fragments linked to a different Fab fragment; (viii) a so-called Scorpion molecule, comprising, e.g., two scFvs fused to both termini of a human Fab-arm; and (ix) a diabody.

[0239] Particular exemplary anti-CD3/anti-FcRH5 bispecific antibodies are described in Section II.

II. BISPECIFIC T-CELL ENGAGER

[0240] Provided herein are bispecific antibodies directed to FcRH5 and CD3 (also referred to as FcRH5xCD3 bispecific antibodies). The provided bispecific antibodies provide a targeted antibody therapy for delivering cytotoxic T cells specifically to the FcRH5 antigen-expressing cancer cells. Hence, in some aspects the provided bispecific antibodies may also be called T cell engagers (TCE) or FcRH5 -targeted TCE. In particular embodiments, the provided bispecific antibodies can be used in therapeutic settings in which specific targeting and T cell-mediated killing of cells that express FcRH5 is desired.

[0241] In some embodiments, the TCE structures described herein are highly potent in inducing killing/lysis of all cell types which exhibit the selected target, FcRH5. Species described herein bind simultaneously to (a) FcRH5-expressing cells, e.g., tumor cells or B-cells; and, (b) T cells, which results in T cell activation and subsequent target-cell lysis.

[0242] A bispecific antibody provided herein is not limited to any particular bispecific format or method of producing it. Depending on the desired functional properties for a particular use, particular antigen binding regions can be selected from the set of antibodies or antigen-binding regions provided herein. Examples of bispecific antibody formats include those described in Section I.D above. Exemplary bispecific formats are provided below. In some embodiments, the bispecific antibody is formatted as a bivalent antibody. In some embodiments, the bispecific antibody is formatted as a trivalent antibody.

[0243] In some embodiments of the provided FcRH5xCD3 bispecific antibodies, the antibody contains at least one FcRH5 binding region. The FcRH5 binding region can include any of the antibody or antigen-binding fragment as described in Section I.A. In some embodiments, the FcRH5 binding region is a Fab.

[0244] In embodiments of the provided bispecific antibodies, the antibody contains an anti-CD3 binding region. The anti-CD3 binding region of the disclosure agonize, stimulate, activate, and/or otherwise augment CD3-mediated T cell activation. Biological activities of CD3 include, for example, T cell activation and other signaling through interaction between CD3 and the antigen-binding subunits of the T-Cell Receptor (TCR). For example, the anti-CD3 binding domains of the disclosure completely or partially activate T cells via engagement of CD3 (e.g. CD3E) on T cells by partially or completely modulating, e.g., agonizing, stimulating, activating or otherwise augmenting CD3- mediated T cell activation.

[0245] The anti-CD3 binding regions of the disclosure include monoclonal antibodies, such as, for example, mammalian monoclonal antibodies, primate monoclonal antibodies, fully human monoclonal antibodies, as well as humanized monoclonal antibodies and chimeric antibodies, as well as antigen-binding fragments thereof. In some embodiments, the anti-CD3 binding region includes one or more copies of an antibody or an antigen-binding fragment thereof.

[0246] In some embodiments, the anti-CD3 binding region includes one or more copies of an antibody or an antigen-binding fragment thereof selected from the group consisting of a Fab fragment, a F(ab')2 fragment, an Fv fragment, a scFv, a scAb, a dAb, a single domain heavy chain antibody, and a single domain light chain antibody. In some embodiments, the anti-CD3 binding region is monovalent for binding CD3. In some embodiments, the anti-CD3 binding region is a Fab. [0247] Antibodies raised against CD3 or the T-cell Receptor Complex, which CD3 is part of, are known. Any of such antibodies or monovalent fragments thereof can be incorporated as part of a provided bispecific antibody with an anti-FcRH5 antibody. Anti-CD3 antibodies include, but are not limited to, those described in International PCT publication Nos. W02008119567, WO2012162067, W02015001085, WO2018208864, WO2020219978; and US Patent No. 10544220.

[0248] In some embodiments, the antibody directed against CD3 can be against any chain of the T cell co-receptor protein complex. In mammals, the complex contains a CD3y (gamma) chain (human CD3y chain UniProtKB/Swiss-Prot No P09693, or cynomolgus monkey CD3y UniProtKB/Swiss-Prot No Q95LI7), a CD35 (delta) chain (human CD35 UniProtKB/Swiss-Prot No P04234, or cynomolgus monkey CD35 UniProtKB/Swiss-Prot No Q95LI8), two CD3s (epsilon) chains (human CD3s UniProtKB/Swiss-Prot No P07766; cynomolgus CD3s UniProtKB/Swiss-Prot No Q95LI5; or rhesus CD3s UniProtKB/Swiss-Prot No G7NCB9), and a CD3^-chain (zeta) chain (human CD3^ UniProtKB/Swiss-Prot No P20963, cynomolgus monkey CD3 UniProtKB/Swiss-Prot No Q09TKO). These chains associate with a molecule known as the T-cell receptor (TCR) and generate an activation signal in T lymphocytes. The TCR and CD3 molecules together comprise the TCR complex.

[0249] In some embodiments, the anti-CD3 antibody is specific for CD3 epsilon (CD3e). In particular embodiments, the CD3 targeted is human CD3e (e.g. UniProt P07766; A8K997; SEQ ID NO: 137).

[0250] In some embodiments, the anti-CD3 antibody can be chosen as having a particular or desired binding affinity. In some embodiments, the anti-CD3 antibody has a CD3 dissociation constant (Kd) of < 1 pM, < 100 nM, <10 nM, < 1 nM, <0.1 nM, <0.01 nM, or <0.001 nM (e.g., 10 ⁸ M or less, e.g., from 10 ⁸ M to 10 ¹³ M, e.g., from 10 ⁹ M to 10 ¹³ M). In some embodiments, the provided bispecific antibodies incorporate anti-CD3 antibodies that exhibit a medium binding affinity for binding to CD3. In some embodiments, an anti-CD3 antibody incorporated in bispecific antibodies herein exhibits a binding affinity (Kd) that is greater than 5 nM. In some embodiments, an anti-CD3 antibody incorporated in bispecific antibodies herein exhibits a binding affinity (Kd) that is greater than 10 nM. In some embodiments, the Kd of an anti-CD3 antibody is at or about 5 nM, 7.5 nM, 10 nM, 15 nM, 20 nM, 25 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM, or any value between any of the foregoing.

[0251] In some embodiments, the anti-CD3 antibody is able to activate T cells via engagement of CD3, such as CD3e, on the T cells. The anti-CD3 antibody exhibits activity to agonize, stimulate, activate, and/or otherwise augment CD3-mediated T cell activation. Biological activities of CD3 include, for example, T cell activation and other signaling through interaction between CD3 and the antigen-binding subunits of the T-Cell Receptor (TCR). Any of a variety of methods are known for measuring T cell activation. In some embodiments, T cell activation can be assessed by determining the ability of a provided bispecific antibody to stimulate cytokine production, proliferation or cytotoxic activity in T cell cultures. In some embodiments, the activity is present in co-cultures of T cells with FcRH5-expressing target cells but not present in the absence of FcRH5-expressing cells. In some embodiments, the FcRH5xCD3 bispecific antibodies elicit potent T cell activation or T cell killing when also engaged by or bound to FcRH5, such as FcRH5-expressing target cells (e.g. FcRH5- expresssing tumor cells).

[0252] In some embodiments, biological activity or functional activity of a provided bispecific antibody, such as cytotoxic activity, can be measured using any of a number of known methods. The activity can be assessed or determined either in vitro or in vivo. In some embodiments, activity can be assessed once the bispecific antibody is administered to the subject (e.g., human). Parameters to assess include specific binding of the bispecific antibody to a T cell (e.g. natural T cell) or FcRH5- expressing cell, e.g., in vivo, e.g., by imaging, or ex vivo, e.g., by ELISA or flow cytometry. In certain embodiments, the ability of the bispecific antibody to destroy target cells can be measured using any suitable known methods, such as cytotoxicity assays described in, for example, Kochenderfer et al., J. Immunotherapy, 32(7): 689-702 (2009), and Herman et al. J. Immunological Methods, 285(1): 25-40 (2004). In certain embodiments, the biological activity of the bispecific antibody also can be measured by assaying expression and/or secretion of certain cytokines, such as interlekukin-2 (IL-2), interferon-gamma (IFNy), interleukin- 1 beta (IL-1 ), interleukin-4 (IL-4), TNF- alpha (TNFa), interleukin-6 (IL-6), interleukin- 10 (IL-10), interleukin- 12 (IL-12), interleukin- 13 (IL- 13), granulocyte-macrophage colony-stimulating factor (GM-CSF), CD107a, and/or TGF-beta (TGF ). Assays to measure cytokines are well known, and include but are not limited to, ELISA, intracellular cytokine staining, cytometric bead array, RT-PCR, ELISPOT, flow cytometry and bioassays in which cells responsive to the relevant cytokine are tested for responsiveness (e.g. proliferation) in the presence of a test sample. In some aspects the biological activity can be measured using an animal model of the disease or condition, such as a tumor xenograft model, and assessing the reduction in tumor burden or load and/or survival. In some aspects the biological activity is measured by assessing clinical outcome, such as reduction in tumor burden or load.

[0253] In some embodiments, the anti- CD3 antibody, e.g., antigen-binding antibody fragment, contains a VH region sequence that contains a heavy chain complementarity determining region 1 (CDR-H1), a CDR-H2 and a CDR-H3 as described and contains a VL region sequence that contains a CDR-L1, a CDR-L2 and a CDR-L3 as described.

[0254] In some embodiments, bispecific antibodies provided herein include functional variants of the VL regions, VH regions, or one or more CDRs of the bispecific antibodies of the examples as provided herein. A functional variant of a VL, VH, or CDR used in the context of a bispecific antibody still allows each arm of the bispecific antibody to retain at least a substantial proportion (at least about 50%, 60%, 70%, 80%, 90%, 95% or more) of the affinity and/or the specificity/selectivity of the parent bispecific antibody and in some cases such a bispecific antibody may be associated with greater affinity, selectivity and/or specificity than the parent bispecific antibody. [0255] Such functional variants typically retain high sequence identity to the parent bispecific antibody. The percent identity between two sequences is a function of the number of identical positions shared by the sequences (i.e., % homology=# of identical positions/total # of positionsxlOO), taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences. The percent identity between two nucleotide or amino acid sequences may e.g. be determined using the algorithm of E. Meyers and W. Miller, Comput. Appl. Biosci 4, 11-17 (1988) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. In addition, the percent identity between two amino acid sequences may be determined using the Needleman and Wunsch, J. Mol. Biol. 48, 444-453 (1970) algorithm.

[0256] Exemplary variants include those which differ from VH and/or VL and/or CDR regions of the parent bispecific antibody sequences mainly by conservative substitutions; for instance 10, such as 9, 8, 7, 6, 5, 4, 3, 2 or 1 of the substitutions in the variant are conservative amino acid residue replacements.

[0257] Among the provided antibodies and fragment thereof are those having sequences at least at or about 85%, at or about 86%, at or about 87%, at or about 88%, at or about 89%, at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identical to such a sequence, e.g., any of the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, CDR-L3 sequences of the antibodies described herein. Also among the provided antibodies and fragment thereof are those having sequences at least at or about 85%, at or about 86%, at or about 87%, at or about 88%, at or about 89%, at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identical to such a sequence, e.g., any of the VH and VL sequences, respectively, of the antibodies described herein. In some aspects, among the provided antibodies, including fragment thereof, are those having sequences at least at or about 85% sequence identity to any such sequences. In some aspects, among the provided antibodies, including fragment thereof, are those having sequences at least at or about 86% sequence identity to any such sequences. In some aspects, among the provided antibodies and fragment thereof are those having sequences at least at or about 87% sequence identity to any such sequences. In some aspects, among the provided antibodies, including fragment thereof, are those having sequences at least at or about 88% sequence identity to any such sequences. In some aspects, among the provided antibodies, including fragment thereof, are those having sequences at least at or about 89% sequence identity to any such sequences. In some aspects, among the provided antibodies, including fragment thereof, are those having sequences at least at or about 90% sequence identity to any such sequences. In some aspects, among the provided antibodies, including fragment thereof, are those having sequences at least at or about 91% sequence identity to any such sequences. In some aspects, among the provided antibodies, including fragment thereof, are those having sequences at least at or about 92% sequence identity to any such sequences. In some aspects, among the provided antibodies, including fragment thereof, are those having sequences at least at or about 93% sequence identity to any such sequences. In some aspects, among the provided antibodies, including fragment thereof, are those having sequences at least at or about 94% sequence identity to any such sequences. In some aspects, among the provided antibodies, including fragment thereof, are those having sequences at least at or about 95% sequence identity to any such sequences. In some aspects, among the provided antibodies, including fragment thereof, are those having sequences at least at or about 96% sequence identity to any such sequences. In some aspects, among the provided antibodies, including fragment thereof, are those having sequences at least at or about 97% sequence identity to any such sequences. In some aspects, among the provided antibodies, including fragment thereof, are those having sequences at least at or about 98% sequence identity to any such sequences. In some aspects, among the provided antibodies, including fragment thereof, are those having sequences at least at or about 99% sequence identity to any such sequences.

[0258] In some embodiments, the at least one FcRH5 binding region and the CD3 binding region are connected by a linker. In some embodiments, the linker is a peptide linker. In some embodiments, the linker can be of various lengths, for example 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 amino acids in length. In some embodiments, the linker is composed predominately or entirely of the amino acids Glycine and Serine, denoted as GS-linkers herein. In some embodiments, the peptide linker is a flexible linker that is or comprises GS, GGS, GGGGS (SEQ ID NO: 155), GGGGGS (SEQ ID NO: 156) or combinations thereof. In some of any embodiments, the peptide linker is or comprises (GGS)n, wherein n is 1 to 10. In some of any embodiments, the peptide linker is or comprises (GGGGS)n (SEQ ID NO: 157), wherein n is 1 to 10. In some of any embodiments, the peptide linker is or comprises (GGGGGS)n (SEQ ID NO: 158), wherein n is 1 to 6, such as 1, 2, 3, 4, 5 or 6. In some embodiments, the GS-linker comprises an amino acid sequence selected from the group consisting of GGSGGS, i.e., (GGS) ₂ (SEQ ID NO: 159); GGSGGSGGS, i.e., (GGS) ₃ (SEQ ID NO: 160); GGSGGSGGSGGS, i.e., (GGS) ₄ (SEQ ID NO: 161); and GGSGGSGGSGGSGGS, i.e., (GGS)s (SEQ ID NO: 162). In some embodiments, the linker is or comprises GGS. In some embodiments, the linker is or comprises GGGGS (SEQ ID NO: 155). In some embodiments, the linker is GGGGSGGGGS (SEQ ID NO: 91). In some embodiments, the linker is GGGGSGGGGSGGGGS (SEQ ID NO: 163). In some embodiments, the linker is or comprises GGGGGS (SEQ ID NO: 164). In some embodiments, the linker is or comprises GGGGGSGGGGGSGGGGGS (SEQ ID NO: 165). In some embodiments, the linker is or comprises GGSGGGGSGGGGSGGGGS (SEQ ID NO: 166). In some embodiments, the linker is or comprises GGGGSGGGGSGGGGS (SEQ ID NO: 167). In some embodiments, the linker is or comprises GGGGG (SEQ ID NO: 168).

[0259] Exemplary FcRH5xCD3 bispecific antibodies are described in the following subsections. A. Bivalent Bispecific Antibodies (1+1)

[0260] In some embodiments, the provided FcRH5xCD3 bispecific antibodies are bivalent bispecific antibodies. In some embodiments, the provided FcRH5xCD3 bivalent bispecific antibody include two antigen binding sites, namely one antigen binding sites for FcRH5 and one antigen binding site for CD3. In some embodiments, the provided FcRH5xCD3 bivalent bispecific antibody is monovalent for binding to FcRH5 and monovalent for binding to CD3.

[0261] In some embodiments, there is provided a bispecific antibody comprising a first binding region that binds to FcRH5 and a second binding region that binds to CD3. In some embodiments, the bispecific antibody provided herein is composed of one Fab fragment of an antibody specifically binding to CD3 (further named also as “CD3-Fab”), and one Fab fragment of an antibody specifically binding to FcRH5 (further named also as “FcRH5-Fab(s)”) and a Fc part. In some embodiments, the first FcRH5-Fab and the CD3-Fab are linked via their C-termini to the hinge region of said Fc part. In some embodiments, each of the CD3-Fab and FcRH5-Fabs are associated with a light chain (LC) In some embodiments, the bispecific antibody is composed of (a) a first heavy chain (HC1) comprising a first amino acid sequence having the formula: VH1-CH1 and a second amino acid sequence having the formula: hinge-CH2-CH3; and (b) a second heavy chain (HC2) comprising a first amino acid sequence having the formula: VH2-CH1 and a second amino acid sequence having the following formula: hinge-CH2-CH3. In some embodiments, the bispecific antibody is further composed of two light chains (VL-CL), namely a first light chain (LC1) and a second light chain (LC2). In some embodiments, the VH1-CH1 of HC1 associates with LC1 to form the first binding region and the VH2-CH1 of HC2 associates with LC2 to form the second binding region. In some embodiments, the light chain sequences can be the same of different. In some embodiments, each of the two light chain sequences are the same and are a common light chain sequence. In some embodiments, each of the two light chain sequence are different.

[0262] In some embodiments, the light chain contains a VL region that comprises a CDR-L1, a CDR-L2, and a CDR-L3 present in the light chain sequence set forth in SEQ ID NO:31. In some embodiments, the VL comprises a CDRL1 set forth in SEQ ID NO:81, a CDRL2 set forth in SEQ ID NO:82 and a CDRL3 set forth in SEQ ID NO:83. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:31.

[0263] In some embodiments, the light chain sequence contains a CDR-L1, a CDR-L2, and a CDR-L3 present in the light chain sequence set forth in SEQ ID NO: 99. In some embodiments, the VL comprises a CDRL1 set forth in SEQ ID NO:81, a CDRL2 set forth in SEQ ID NO:82 and a CDRL3 set forth in SEQ ID NO: 100. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:99.

[0264] In some embodiments, the light chain is a I (lambda) light chain. In some embodiments, the light chain is a K (kappa) light chain. In some embodiments, the light chain (VL-CL) has the sequence set forth in SEQ ID NO: 102 or a sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:102. In some embodiments, the light chain (VL-CL) has the sequence set forth in SEQ ID NO: 102. In some embodiments, the light chain (VL-CL) has the sequence set forth in SEQ ID NO: 109 or a sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 109. In some embodiments, the light chain (VL-CL) has the sequence set forth in SEQ ID NO: 109. In some embodiments, the light chain (VL-CL) has the sequence set forth in SEQ ID NO: 119 or a sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:119. In some embodiments, the light chain (VL-CL) has the sequence set forth in SEQ ID NO: 119.

[0265] In some embodiments, the FcRH5-Fabs can include a Fab heavy chain antigen-binding fragment of any of the antibodies as described in Section LA. In some embodiments, the FcRH5-Fab heavy chain fragment is composed of any VH chain as described in Section LA and a CHI. In some embodiments, the bispecific antibody has an IgGl isotype, IgG2 isotype, IgG3 isotype or IgG4 isotype, and the CHI of the FcRH5-Fab is the CHI of the immunoglobulin isotype. In some embodiments, the CHI is of the IgGl isotype, IgG2 isotype, or IgG4 isotype. In some embodiments, the CHI is of the IgGl isotype. In some embodiments, the CHI of each FcRH5-Fab has the sequence of amino acids set forth in SEQ ID NO: 116 or a sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:116. In some embodiments, the CHI has the sequence set forth in SEQ ID NO: 116.

[0266] In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:32, 33, 34, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:35, 36, and 37, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:38, 39, 40, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:41, 42, 43, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:41, 44, 45, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:46, 47, 34, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:48, 49, 34, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:46, 50, 34, respectively. In some embodiments, the VH region of the FcRH5- Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 46, 50, 51, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:48, 49, 51, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:46, 52, 51, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:46, 47, 51, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 46, 52, 51, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:46, 47, 51, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab)comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:54, 55, 37, respectively. In some embodiments, the VH region of the FcRH5- Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:56, 57, 58, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:56, 57, 59, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:60, 61, 62, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:63, 64, 40, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:65, 66, 40, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:65, 66, 67, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:63, 64, 68, respectively. In some embodiments, the VH region of the FcRH5- Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:65, 66, 69, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 65, 66, 70, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 65, 66, 71, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 72, 73, 74, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 65, 66, 75, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 65, 76, 77, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:78, 76, 79, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 63, 76, 67, respectively.

[0267] In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:1. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:2. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:3. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:4. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:5. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:6. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:7. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:8. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:9. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 10. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 11. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:12. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 13. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 14. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:15. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 16. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 17. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:18. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 19. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:20. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:21. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:22. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:23. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:24. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:25. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:26. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:27. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:28. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:29. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:30.

[0268] In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO:1. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO:2. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO: 3. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO:4. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO:5. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO:6. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO:7. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO:8. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO:9. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO: 10. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO: 11. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO: 12. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO: 13. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO: 14. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO: 15. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO: 16. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO: 17. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO: 18. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO: 19. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO:20. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO: 21. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO:22. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO:23. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO:24. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO: 25. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO:26. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO: 27. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO:28. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO: 29. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO:30.

[0269] In some embodiments, the VH region of the FcRH5-Fab comprises a CDR-H1, a CDR- H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:78, 76, 79, respectively. In some embodiments, the VH region of the FcRH5-Fab comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:29. In some embodiments, the VH region of the FcRH5-Fab comprises the amino acid sequence set forth in SEQ ID NO:29.

[0270] In some embodiments, the FcRH5-Fab heavy chain fragment is composed of any VH chain as described and a CHI. In some embodiments, the bispecific antibody has an IgGl isotype, IgG2 isotype, IgG3 isotype or IgG4 isotype, and the CHI of the FcRH5-Fab is the CHI of the immunoglobulin isotype. In some embodiments, the CHI is of the IgGl isotype, IgG2 isotype, or

IgG4 isotype. In some embodiments, the CHI is of the IgGl isotype. In some embodiments, the CHI of each FcRH5-Fab has the sequence of amino acids set forth in SEQ ID NO: 116 or a sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 116. In some embodiments, the CHI has the sequence set forth in SEQ ID NO: 116.

[0271] In some embodiments, the heavy chain sequence (VH-CH1) of the FcRH5-Fab comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 117. In some embodiments, the heavy chain sequence (VH-CH1) of the FcRH5-Fab comprises the amino acid sequence set forth in SEQ ID NO: 117.

[0272] In some embodiments, the CD3-Fab can include a Fab heavy chain antigen-binding fragment. The antibody can be an anti-CD3 Fab incorporating sequences of any anti-CD3-Fab as described above or herein. In some embodiments, the CD3-Fab is an antibody as described in International PCT publ. No. WO2018208864, which is incorporated by reference herein. In some embodiments, the FcRH5-Fab heavy chain fragment is composed of a VH chain sequence and a CHI.

[0273] In some embodiments, among the CD3-Fabs that are incorporated in the bispecific antibodies, have a heavy chain variable (VH) region having an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VH region amino acid sequence set forth in SEQ ID NO: 92 or 103, and a light chain variable sequence (VL) region that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VL region amino acid sequence set forth in SEQ ID NO:31 or 99.

[0274] In some embodiments, the CD3-Fabs have a VH region that contains a CDR-H1, a CDR- H2 and a CDR-H3 present in a VH sequence set forth in SEQ ID NO: 92 or 103, and a VL region that contains a CDR-L1, a CDR-L2, and a CDR-L3 present in a VL sequence set forth in SEQ ID NO:31 or 99. In some embodiments, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 according to Kabat numbering. In some embodiments, the VH region comprises a CDR-H1, a CDR- H2 and a CDR-H3 according to Chothia numbering. In some embodiments, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 according to AbM numbering. In some embodiments, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 according to IMGT numbering. In some embodiments, the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 according to Kabat numbering. In some embodiments, the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 according to Chothia numbering. In some embodiments, the VL region comprises a CDR-L1, a CDR- L2 and a CDR-L3 according to AbM numbering. In some embodiments, the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 according to IMGT numbering.

[0275] In some embodiments, the light chain sequence of the CD3-Fab contains a VL region that comprises a CDR-L1, a CDR-L2, and a CDR-L3 present in the light chain sequence set forth in SEQ ID NO:31 or 99. In some embodiments, the VL region of the CD3-Fab comprises a CDRL1 set forth in SEQ ID N0:81, a CDRL2 set forth in SEQ ID NO:82 and a CDRL3 set forth in SEQ ID NO:83. In some embodiments, the light chain sequence of the CD3-Fab contains a VL region that comprises a CDR-L1, a CDR-L2, and a CDR-L3 present in the light chain sequence set forth in SEQ ID NO: 99. In some embodiments, the VL of the CD3-Fab comprises a CDRL1 set forth in SEQ ID NO:81, a CDRL2 set forth in SEQ ID NO:82 and a CDRL3 set forth in SEQ ID NO: 100. In some embodiments, the light chain sequence of the CD3-Fab contains a VL region that comprises a CDR- Ll, a CDR-L2, and a CDR-L3 present in the light chain sequence set forth in SEQ ID NO: 31.

[0276] In some embodiments, the heavy chain of the CD3-Fab contains a VH region that comprises a CDR-H1, a CDR-H2, and a CDR-H3 present in the VH region sequence set forth in SEQ ID NO: 92. In some embodiments, the VH region of the CD3-Fab comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:93, 94 and 95, respectively.

[0277] In some embodiments, the light chain of the CD3-Fab has a VL region that comprises a CDRL1 set forth in SEQ ID NO:81, a CDRL2 set forth in SEQ ID NO:82 and a CDRL3 set forth in SEQ ID NO:83; and the heavy chain of the CD3-Fab has a VH region that comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 93, 94 and 95, respectively.

[0278] In some embodiments, the light chain of the CD3-Fab has a VL region that comprises a CDRL1 set forth in SEQ ID NO:81, a CDRL2 set forth in SEQ ID NO:82 and a CDRL3 set forth in SEQ ID NO: 100; and the heavy chain of the CD3-Fab has a VH region that comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 93, 94 and 95, respectively.

[0279] In some embodiments, the heavy chain of the CD3-Fab contains a VH region that comprises a CDR-H1, a CDR-H2, and a CDR-H3 present in the VH region sequence set forth in SEQ ID NO: 103. In some embodiments, the VH region of the CD3-Fab comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:93, 104 and 95, respectively.

[0280] In some embodiments, the light chain of the CD3-Fab has a VL region that comprises a CDRL1 set forth in SEQ ID NO:81, a CDRL2 set forth in SEQ ID NO:82 and a CDRL3 set forth in SEQ ID NO:83; and the heavy chain of the CD3-Fab has a VH region that comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 93, 104 and 95, respectively.

[0281] In some embodiments, the light chain of the CD3-Fab has a VL region that comprises a CDRL1 set forth in SEQ ID NO:81, a CDRL2 set forth in SEQ ID NO:82 and a CDRL3 set forth in SEQ ID NO: 100; and the heavy chain of the CD3-Fab has a VH region that comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 93, 104 and 95, respectively.

[0282] In some embodiments, the light chain of the CD3-Fab has a VL region that comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:31 or 99, and a the heavy chain of the CD3-Fab has a VH region that comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:92 or 103. In some embodiments, the light chain of the CD3-Fab has a VL region that comprises the sequence of amino acids set forth in SEQ ID NO:31 and a the heavy chain of the CD3- Fab has a VH region that comprises the sequence of amino acids set forth in SEQ ID NO: 92. In some embodiments, the light chain of the CD3-Fab has a VL region that comprises the sequence of amino acids set forth in SEQ ID NO:99 and the heavy chain of the CD3-Fab has a VH region that comprises the sequence of amino acids set forth in SEQ ID NO:92. In some embodiments, the light chain of the CD3-Fab has a VL region that comprises the sequence of amino acids set forth in SEQ ID NO:31 and the heavy chain of the CD3-Fab has a VH region that comprises the sequence of amino acids set forth in SEQ ID NO: 103. In some embodiments, the light chain of the CD3-Fab has a VL region that comprises the sequence of amino acids set forth in SEQ ID NO:99 and the heavy chain of the CD3- Fab has a VH region that comprises the sequence of amino acids set forth in SEQ ID NO: 103.

[0283] In some embodiments, the CD3-Fab contains any of the above VH and VL regions. In some embodiments, the constant regions include a light chain constant region and/or a heavy chain constant region 1 (CHI). In some embodiments, the Fab contains a heavy chain comprising any of the above VH regions and an immunoglobulin constant heavy chain domain 1 (CHI domain) and a light chain comprising any of the above VL regions and an immunoglobulin constant light chain (CL).

[0284] In some embodiments, the CD3-Fab has a light chain sequence that comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 109, and a heavy chain sequence that comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 114. In some embodiments, the light chain sequence comprises the sequence of amino acids set forth in SEQ ID NO: 109 and the heavy chain sequence comprises the sequence of amino acids set forth in SEQ ID NO: 114.

[0285] In some embodiments, the CD3-Fab has a light chain sequence that comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 109, and a heavy chain sequence that comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 120. In some embodiments, the light chain sequence comprises the sequence of amino acids set forth in SEQ ID NO: 109 and the heavy chain sequence comprises the sequence of amino acids set forth in SEQ ID NO: 120.

[0286] In some embodiments, the Fc is a heterodimeric Fc composed of a different first and second Fc polypeptide each comprising a hinge-CH2-CH3, in which the interface of one of the CH3 domains is modified or altered to promote the formation of the trivalent bispecific antibody. In some embodiments, the CH3 domain or domains is altered by “knob-into-holes” technology which is described in detail with several examples in e.g. WO 96/027011, Ridgway, J. B., et al., Protein Eng 9 (1996) 617-621; and. Merchant, A. M., et al., Nat Biotechnol 16 (1998) 677-681. Exemplary heterodimeric Fc molecules for use in the provided bispecific antibodies, and methods for promoting heterodimerization between chains, is further described in Section II.C.

B. Trivalent Bispecific Antibodies (2+1)

[0287] In some embodiments, the provided FcRH5xCD3 bispecific antibodies are trivalent bispecific antibodies. In some embodiments, the provided FcRH5xCD3 trivalent bispecific antibody includes three antigen binding sites, namely two antigen binding sites for FcRH5 and one antigen binding site for CD3. In some embodiments, the provided FcRH5xCD3 trivalent bispecific antibody is bivalent for binding to FcRH5 and monovalent for binding to CD3.

[0288] In some embodiments, there is provided a bispecific antibody comprising a first binding region that binds to FcRH5, a second binding region that binds to FcRH5 and a third binding region that binds to CD3. In some embodiments, the trivalent bispecific antibody provided herein is composed of one Fab fragment of an antibody specifically binding to CD3 (further named also as “CD3-Fab”), and two Fab fragments of an antibody specifically binding to FcRH5 (further named also as “FcRH5-Fab(s)”) and a Fc part. In some embodiments, the first FcRH5-Fab and the CD3-Fab are linked via their C-termini to the hinge region of said Fc part and said second FcRH5-Fab is linked with its C-terminus to the N-terminus of said CD3-Fab. In some embodiments, each of the CD3-Fab and FcRH5-Fabs are associated with a light chain (EC). In some embodiments, the bispecific antibody is composed of (a) a first heavy chain (HC1) comprising a first amino acid sequence having the formula: VH1-CH1 and a second amino acid sequence having the formula: hinge-CH2-CH3; and (b) a second heavy chain (HC2) comprising a first amino acid sequence having the formula: VH1- CH1, a second amino acid sequence having the formula: VH2-CH1 and a third amino acid sequence having the following formula: hinge-CH2-CH3. In some embodiments, the bispecific antibody is further composed of three light chains (VE-CE), namely a first light chain (LC1), a second light chain (LC2) and a third light chain (LC3). In some embodiments, the VH1-CH1 of HC1 associates with LC1 to form the first binding region; the VH1-CH1 of HC2 associates with LC2 to form the second binding region; and the VH2-CH1 of HC2 associates with LC3 to form the third binding region. In some embodiments, the light chain sequences can be the same or different. In some embodiments, at least two light chain sequences (at least two of LC1, LC2 and LC3) are the same and are a common light chain sequence. In some embodiments, each light chain sequence (LC1, LC2 and LC3) are the same and are a common light chain sequence.

[0289] In some embodiments, the trivalent bispecific antibody specifically binds to FcRH5 (e.g. human FcRH5) and CD3 (e.g. human CD3) and are characterized in containing a common light chain. In provided aspects, the use of a common light chain avoids mispairing of the light chain and thus allows for an antibody molecule that combines two binders that share one light chain but still have separate specificities.

[0290] In some embodiments, the common light chain sequence incorporated in provided bispecific antibodies contains a VL region that comprises a CDR-L1, a CDR-L2, and a CDR-L3 present in the light chain sequence set forth in SEQ ID NO:31 or SEQ ID NO: 99. In some embodiments, the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 according to Kabat numbering. In some embodiments, the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 according to Chothia numbering. In some embodiments, the VL region comprises a CDR-L1, a CDR- L2 and a CDR-L3 according to AbM numbering. In some embodiments, the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 according to IMGT numbering.

[0291] In some embodiments, the common light chain contains a VL region that comprises a CDR-L1, a CDR-L2, and a CDR-L3 present in the light chain sequence set forth in SEQ ID NO:31. In some embodiments, the VL comprises a CDRL1 set forth in SEQ ID NO:81, a CDRL2 set forth in SEQ ID NO:82 and a CDRL3 set forth in SEQ ID NO:83. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:31.

[0292] In some embodiments, the common light chain sequence contains a VL region that comprises CDR-L1, a CDR-L2, and a CDR-L3 present in the light chain sequence set forth in SEQ ID NO: 99. In some embodiments, the VL comprises a CDRL1 set forth in SEQ ID NO: 81, a CDRL2 set forth in SEQ ID NO:82 and a CDRL3 set forth in SEQ ID NO: 100. In some embodiments, the VL region comprises the sequence of amino acids set forth in SEQ ID NO:99.

[0293] In some embodiments, the light chain is a X (lambda) light chain. In some embodiments, the light chain is a K (kappa) light chain. In some embodiments, the light chain (VL-CL) has the sequence set forth in SEQ ID NO: 102 or a sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:102. In some embodiments, the light chain (VL-CL) has a sequence having at least at or about 95% identity to SEQ ID NO: 102. In some embodiments, the light chain (VL-CL) has a sequence having at least at or about 96% identity to SEQ ID NO: 102. In some embodiments, the light chain (VL-CL) has a sequence having at least at or about 97% identity to SEQ ID NO: 102. In some embodiments, the light chain (VL-CL) has a sequence having at least at or about 98% identity to SEQ ID NO: 102. In some embodiments, the light chain (VL-CL) has a sequence having at least at or about 99% identity to SEQ ID NO: 102. In some embodiments, the light chain (VL-CL) has the sequence set forth in SEQ ID NO: 102.

[0294] In some embodiments, the trivalent bispecific antibody provided herein is composed of one Fab fragment of an antibody specifically binding to CD3 (further named also as “CD3-Fab”), and two Fab fragment of an antibody specifically binding to FcRH5 (further named also as “FcRH5- Fab(s)”) and a Fc part. In some embodiments, the first FcRH5-Fab and the CD3-Fab are linked via their C-termini to the hinge region of said Fc part and said second FcRH5-Fab is linked with its C- terminus to the N-terminus of said CD3-Fab. The CD3-Fab and FcRH5-Fab include the common light chains as described herein. FIG. 1 provides an exemplary depiction of provided trivalent bispecific (FcRH5xCD3) antibodies, in which is composed of a common light chain sequence.

[0295] In some embodiments, the Fc is a heterodimeric Fc composed of a different first and second Fc polypeptide each comprising a hinge-CH2-CH3, in which the interface of one of the CH3 domains is modified or altered to promote the formation of the trivalent bispecific antibody. In some embodiments, the CH3 domain or domains is altered by “knob-into-holes” technology which is described in detail with several examples in e.g. WO 96/027011, Ridgway, J. B., et al., Protein Eng 9 (1996) 617-621; and. Merchant, A. M., et al., Nat Biotechnol 16 (1998) 677-681. Exemplary heterodimeric Fc molecules for use in the provided bispecific antibodies, and methods for promoting heterodimerization between chains, is further described in Section II.C.

[0296] In some embodiments, there is provided herein a bispecific antibody comprising two anti- Fc receptor-like protein 5 (FcRH5) binding regions, one anti-CD3 binding region and a heterodimeric Fc. In some embodiments, each anti-FcRH5 binding region is a Fab comprising a first variable heavy chain (VH1) and a heavy chain constant region 1 (CHI), and a common light chain comprising a variable light chain (VL) and a light chain constant region (CL). In some embodiments, the anti-CD3 binding region is a Fab comprising a second variable heavy chain (VH2) and a CHI, and the common LC comprising the VL and the CL. In some embodiments, the common light chain of each binding region has the same sequence and is associated with each VH1-CH1 and with the VH2-CH1. In some embodiments, the first FcRH5-Fab (VH1-CH1) of one anti-FcRH5 binding region is comprised in a first heavy chain (HC1) of the bispecific antibody, and the second FcRH5-Fab (VH1-CH1) and the CD3-Fab (VH2-CH2) are comprised in a second heavy chain (HC2). In some embodiments, the first polypeptide of the heterodimeric Fc is linked to the FcRH5 Fab (VH-CH1) of the HC1 and the second polypeptide of the heterodimeric Fc is linked to the CD3-Fab (VH2-CH1) of HC2.

[0297] In some embodiments, the bispecific antibody is formed by two heavy chain sequences (HC1 and HC2). In some embodiments, the HC1 polypeptide includes a first amino acid sequence having the formula VH1-CH1 (first FcRH5-Fab) and a second amino acid sequence having the formula hinge-CH2-CH3 (first Fc polypeptide of the heterodimeric Fc). In some embodiments, the HC2 polypeptide includes a first amino acid sequence that has the formula: VH1-CH1 (second FcRH5-Fab), a second amino acid sequence having the formula: VH2-CH1 (CD3-Fab) and a third amino acid sequence having the formula: hinge-CH2-CH3 (second Fc polypeptide of the heterodimeric Fc). In some embodiments, the bispecific antibody is further formed by three polypeptides for the common light chains having the formula VL-CL, in which each common light chain sequence has the same sequence and is independently associated with each Fab, i.e., each VH1- CH1 and with the VH2-CH1.

[0298] In some embodiments, the FcRH5-Fabs can include a Fab heavy chain antigen-binding fragment of any of the antibodies as described in Section LA. In some embodiments, the FcRH5-Fab heavy chain fragment is composed of any VH chain as described in Section I. A and a CHI. In some embodiments, the VH sequence of each FcRH5-Fab is the same. In some embodiments, the VH sequence of each FcRH5-Fab is different. In some embodiments, the VH sequence of each FcRH5- Fab is different but binds to the same epitope of FcRH5. In some embodiments, each FcRH5-Fab is the same. In some embodiments, each FcRH5-Fab is different but binds to the same epitope of FcRH5.

[0299] In some embodiments, the bispecific antibody has an IgGl isotype, IgG2 isotype, IgG3 isotype or IgG4 isotype, and the CHI of the FcRH5-Fab is the CHI of the immunoglobulin isotype. In some embodiments, the CHI is of the IgGl isotype, IgG2 isotype, or IgG4 isotype. In some embodiments, the CHI is of the IgGl isotype. In some embodiments, the CHI of each FcRH5-Fab has the sequence of amino acids set forth in SEQ ID NO: 84 or a sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:84. In some embodiments, the CHI has the sequence set forth in SEQ ID NO: 84. In some embodiments, the FcRH5-Fab of the HC2 (i.e. the second FcRH5-Fab that is linked with its C- terminus to the N-terminus of said CD3-Fab) terminates with an amino acid sequence of a hinge region. In some embodiments, the hinge region is the native hinge region normally associated with the CHI domain of an antibody molecule. In some embodiments, the hinge region is a modified hinge region. In some embodiments, the hinge region has the amino acid sequence set forth as EPKSCD (SEQ ID NO: 85). In some embodiments, the first FcRH5-Fab is composed of any VH chain as described in Section I.A and the CHI set forth in SEQ ID NO:84. In some embodiments, the second FcRH5-Fab is composed of any VH chain as described in Section I.A, the CHI set forth in SEQ ID NO:84 and terminates with the hinge sequence set forth in SEQ ID NO:85. In some embodiments, the first FcRH5-Fab comprises any VH chain as described in Section I.A fused to the sequence set forth in SEQ ID NO:86.

[0300] In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:32, 33, 34, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:35, 36, and 37, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:38, 39, 40, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:41, 42, 43, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:41, 44, 45, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:46, 47, 34, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:48, 49, 34, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:46, 50, 34, respectively. In some embodiments, the VH region of the FcRH5- Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 46, 50, 51, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:48, 49, 51, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:46, 52, 51, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:46, 47, 51, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 46, 52, 51, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:46, 47, 51, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab)comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:54, 55, 37, respectively. In some embodiments, the VH region of the FcRH5- Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:56, 57, 58, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:56, 57, 59, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:60, 61, 62, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:63, 64, 40, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:65, 66, 40, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:65, 66, 67, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:63, 64, 68, respectively. In some embodiments, the VH region of the FcRH5- Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:65, 66, 69, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 65, 66, 70, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 65, 66, 71, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 72, 73, 74, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 65, 66, 75, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 65, 76, 77, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:78, 76, 79, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 63, 76, 67, respectively.

[0301] In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:1. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:2. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:3. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:4. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:5. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:6. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:7. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:8. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:9. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 10. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 11. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:12. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 13. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 14. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:15. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 16. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 17. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:18. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 19. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:20. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:21. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:22. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:23. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:24. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:25. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:26. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:27. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:28. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:29. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:30.

[0302] In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO:1. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO:2. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO: 3. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO:4. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO:5. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO:6. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO:7. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO:8. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO:9. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO: 10. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO: 11. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO: 12. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO: 13. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO: 14. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO: 15. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO: 16. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO: 17. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO: 18. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO: 19. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO:20. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO: 21. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO:22. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO:23. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO:24. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO: 25. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO:26. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO: 27. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO:28. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO: 29. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO:30.

[0303] In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:78, 76, 79, respectively. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:29. In some embodiments, the VH region of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO: 29. [0304] In some embodiments, the heavy chain sequence (VH-CH1) of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:87. In some embodiments, the heavy chain sequence (VH-CH1) of the FcRH5-Fab (first and second FcRH5- Fab) comprises an amino acid sequence having at least at or about 95% identity to SEQ ID NO: 87. In some embodiments, the heavy chain sequence (VH-CH1) of the FcRH5-Fab (first and second FcRH5- Fab) comprises an amino acid sequence having at least at or about 96% identity to SEQ ID NO: 87. In some embodiments, the heavy chain sequence (VH-CH1) of the FcRH5-Fab (first and second FcRH5- Fab) comprises an amino acid sequence having at least at or about 97% identity to SEQ ID NO:87. In some embodiments, the heavy chain sequence (VH-CH1) of the FcRH5-Fab (first and second FcRH5- Fab) comprises an amino acid sequence having at least at or about 98% identity to SEQ ID NO: 87. In some embodiments, the heavy chain sequence (VH-CH1) of the FcRH5-Fab (first and second FcRH5-Fab) comprises an amino acid sequence having at least at or about 99% identity to SEQ ID NO:87. In some embodiments, the heavy chain sequence (VH-CH1) of the FcRH5-Fab (first and second FcRH5-Fab) comprises the amino acid sequence set forth in SEQ ID NO: 87.

[0305] In some embodiments, the heavy chain sequence of at least one of the FcRH5-Fab further includes a hinge region of the immunoglobulin sequence. In some embodiments, the hinge region is the native hinge region normally associated with the CHI domain of an antibody molecule. In some embodiments, the hinge region is a modified hinge region. In some embodiments, the hinge region has the amino acid sequence set forth as EPKSCD (SEQ ID NO: 85). In some embodiments, the heavy chain sequence (VH-CH1) of at least one of the FcRH5-Fab comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:90. In some embodiments, the heavy chain sequence (VH-CH1) of at least one of the FcRH5-Fab comprises an amino acid sequence having at least at or about 95% identity to SEQ ID NO:90. In some embodiments, the heavy chain sequence (VH-CH1) of at least one of the FcRH5-Fab comprises an amino acid sequence having at least at or about 96% identity to SEQ ID NO:90. In some embodiments, the heavy chain sequence (VH-CH1) of at least one of the FcRH5-Fab comprises an amino acid sequence having at least at or about 97% identity to SEQ ID NO:90. In some embodiments, the heavy chain sequence (VH-CH1) of at least one of the FcRH5-Fab comprises an amino acid sequence having at least at or about 98% identity to SEQ ID NO:90. In some embodiments, the heavy chain sequence (VH-CH1) of at least one of the FcRH5-Fab comprises an amino acid sequence having at least at or about 99% identity to SEQ ID NO:90. In some embodiments, the heavy chain sequence (VH-CH1) of at least one of the FcRH5-Fab comprises the amino acid sequence set forth in SEQ ID NO:90.

[0306] In some embodiments, the heavy chain sequence of the first FcRH5-Fab is set forth in SEQ ID NO: 87 and the heavy chain sequence of the second FcRH5-Fab further includes a hinge sequence and is set forth in SEQ ID NO:90. In some embodiments, the CD3-Fab can include a Fab heavy chain antigen-binding fragment. The antibody can be an anti-CD3 Fab incorporating sequences of any anti-CD3-Fab as described above or herein that includes the common light chain sequence. In some embodiments, the CD3-Fab is an antibody as described in International PCT publ. No.

WO2018208864, which is incorporated by reference herein. In some embodiments, the CD3-Fab heavy chain fragment is composed of a VH chain sequence and a CHI.

[0307] In some embodiments, among the CD3-Fabs that are incorporated in the bispecific antibodies have a heavy chain variable (VH) region having an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VH region amino acid sequence set forth in SEQ ID NO: 92 or 103.

[0308] In some embodiments, the CD3-Fabs incorporated in provided bispecific antibodies contains a VH region that comprises a CDR-L1, a CDR-L2, and a CDR-L3 present in the VH region amino acid sequence set forth in SEQ ID NO: 92 or 103. In some embodiments, the VH region comprises a CDR-L1, a CDR-L2 and a CDR-L3 according to Kabat numbering. In some embodiments, the VH region comprises a CDR-L1, a CDR-L2 and a CDR-L3 according to Chothia numbering. In some embodiments, the VH region comprises a CDR-L1, a CDR-L2 and a CDR-L3 according to AbM numbering. In some embodiments, the Vh region comprises a CDR-L1, a CDR-L2 and a CDR-L3 according to IMGT numbering.

[0309] In some embodiments, the VH region of the CD3-Fab comprises a CDR-H1, a CDR-H2, and a CDR-H3 present in the VH region sequence set forth in SEQ ID NO: 92. In some embodiments, the VH region of the CD3-Fab comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:93, 94 and 95, respectively. In some embodiments, the VH region of the CD3-Fab comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:92. In some embodiments, the VH region of the CD3-Fab comprises an amino acid sequence having at least at or about 95% identity to SEQ ID NO:92. In some embodiments, the VH region of the CD3-Fab comprises an amino acid sequence having at least at or about 96% identity to SEQ ID NO:92. In some embodiments, the VH region of the CD3-Fab comprises an amino acid sequence having at least at or about 97% identity to SEQ ID NO:92. In some embodiments, the VH region of the CD3-Fab comprises an amino acid sequence having at least at or about 98% identity to SEQ ID NO: 92. In some embodiments, the VH region of the CD3-Fab comprises an amino acid sequence having at least at or about 99% identity to SEQ ID NO:92. In some embodiments, the VH region of the CD3-Fab has the sequence set forth in SEQ ID NO: 92.

[0310] In some embodiments, the VH region of the CD3-Fab comprises a CDR-H1, a CDR-H2, and a CDR-H3 present in the VH region sequence set forth in SEQ ID NO: 103. In some embodiments, the VH region of the CD3-Fab comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:93, 104 and 95, respectively. In some embodiments, the VH region of the CD3-Fab comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 103. In some embodiments, the VH region of the CD3-Fab comprises an amino acid sequence having at least at or about 95% identity to SEQ ID NO: 103. In some embodiments, the VH region of the CD3-Fab comprises an amino acid sequence having at least at or about 96% identity to SEQ ID NO: 103. In some embodiments, the VH region of the CD3-Fab comprises an amino acid sequence having at least at or about 97% identity to SEQ ID NO: 103. In some embodiments, the VH region of the CD3-Fab comprises an amino acid sequence having at least at or about 98% identity to SEQ ID NO: 103. In some embodiments, the VH region of the CD3-Fab comprises an amino acid sequence having at least at or about 99% identity to SEQ ID NO: 103. In some embodiments, the VH region of the CD3-Fab has the sequence set forth in SEQ ID NO: 103.

[0311] In some embodiments, the anti-CD3 antibody is a Fab containing any of the above VH regions and a CHI. In some embodiments, the bispecific antibody has an IgGl isotype, IgG2 isotype, IgG3 isotype or IgG4 isotype, and the CHI of the CD3-Fab is the CHI of the immunoglobulin isotype. In some embodiments, the CHI is of the IgGl isotype, IgG2 isotype, or IgG4 isotype. In some embodiments, the CHI is of the IgGl isotype. In some embodiments, the CHI of each CD3- Fab has the sequence of amino acids set forth in SEQ ID NO: 84 or a sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:84. In some embodiments, the CHI has the sequence set forth in SEQ ID NO: 84.

[0312] In some embodiments, the heavy chain sequence of the CD3-Fab comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:96. In some embodiments, the heavy chain sequence of the CD3-Fab comprises an amino acid sequence having at least at or about 95% identity to SEQ ID NO:96. In some embodiments, the heavy chain sequence of the CD3-Fab comprises an amino acid sequence having at least at or about 96% identity to SEQ ID NO:96. In some embodiments, the heavy chain sequence of the CD3-Fab comprises an amino acid sequence having at least at or about 97% identity to SEQ ID NO:96. In some embodiments, the heavy chain sequence of the CD3-Fab comprises an amino acid sequence having at least at or about 98% identity to SEQ ID NO:96. In some embodiments, the heavy chain sequence of the CD3-Fab comprises an amino acid sequence having at least at or about 99% identity to SEQ ID NO:96. In some embodiments, the heavy chain sequence of the CD3-Fab comprises the amino acid sequence set forth in SEQ ID NO:96.

[0313] In some embodiments, the heavy chain sequence of the CD3-Fab comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 106. In some embodiments, the heavy chain sequence of the CD3-Fab comprises an amino acid sequence having at least at or about 95% identity to SEQ ID NO: 106. In some embodiments, the heavy chain sequence of the CD3-Fab comprises an amino acid sequence having at least at or about 96% identity to SEQ ID NO: 106. In some embodiments, the heavy chain sequence of the CD3-Fab comprises an amino acid sequence having at least at or about 97% identity to SEQ ID NO: 106. In some embodiments, the heavy chain sequence of the CD3-Fab comprises an amino acid sequence having at least at or about 98% identity to SEQ ID NO: 106. In some embodiments, the heavy chain sequence of the CD3-Fab comprises an amino acid sequence having at least at or about 99% identity to SEQ ID NO: 106. In some embodiments, the heavy chain sequence of the CD3-Fab comprises the amino acid sequence set forth in SEQ ID NO: 106.

[0314] Provided herein is a bispecific antibody containing a first heavy chain containing the heavy chain of the first FcRH5-Fab and a second heavy chain containing the second FcRH5-Fab and the CD3-Fab. In some embodiments, the first heavy chain includes in order: the heavy chain of the first FcRH5-Fab comprising the amino acid sequence set forth in SEQ ID NO: 87 and a first polypeptide chain of a heterodimeric Fc. In some embodiments, the second heavy chain comprises in order: the heavy chain of the second FcRH5-Fab comprising the amino acid sequence set forth in SEQ ID NO:90, a linker, the heavy chain of the CD3-Fab comprising the amino acid sequence set forth in SEQ ID NO:96, and a second polypeptide chain of the heterodimeric Fc. In some embodiments, the bispecific antibody is also composed of three copies of a common light chain comprising the amino acid sequence set forth in SEQ ID NO: 102, wherein each common light chain is associated with one of the first FcRH5-Fab, the second FcRH5-Fab and the CD3-Fab. The heterodimeric Fc can be any as described below.

C. Fc region of Bispecific Antibody Formats

[0315] In some embodiments, the bispecific antibody is a full length antibody, such as a full length IgGl antibody. In some embodiments, the full-length IgGl antibody is a full length IgGl, X (lambda), K (kappa) antibody or IgGl, K (kappa), K (kappa) antibody. In some embodiments, the full- length antibody includes an Fc region, e.g. composed of at least a hinge region, a CH2 domain, and a CH3 domain.

[0316] In some embodiments, the bispecific antibody is a dimer formed by polypeptides, each containing an Fc region. In some embodiments, the Fc region is formed by Fc domains that are mutated or modified to promote heterodimerization in which different polypeptides can be dimerized to yield a heterodimer. Thus, in some embodiments, the dimer is a heterodimer in which two polypeptide chains of the multispecific polypeptide construct are different. Exemplary modifications to promote heterodimerization are known, including any as described below.

[0317] In one aspect, a bispecific antibody provided herein is composed of a heterodimeric Fc region that facilitates interactions of two different heavy chain polypeptides in which each heavy chain polypeptide contains at least one different binding arm of the bispecific antibody. In some embodiments, the bispecific antibody includes a first heavy chain containing at least one anti-FcRH5 antibody (e.g. Fab) and a first polypeptide chain of the heterodimeric Fc and a second heavy chain containing the anti-CD3 antibody (e.g. Fab) and the second polypeptide chain of the heterodimeric Fc. In some embodiments the first polypeptide chain of the heterodimeric Fc-region comprises a first CH3 region, and the second polypeptide chain of the heterodimeric Fc region comprises a second CH3 region, wherein the sequences of the first and second CH3 regions are different and are such that the heterodimeric interaction between said first and second CH3 regions is stronger than each of the homodimeric interactions of said first and second CH3 regions.

[0318] In some embodiments, each polypeptide of an immunoglobulin Fc region comprises a human IgGl polypeptide sequence that is at least 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 122. In some embodiments, each polypeptide of an immunoglobulin Fc region comprises a human IgGl polypeptide sequence that is at least 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 123.

[0319] In the context of the provided disclosure the following notations are, unless otherwise indicated, used to describe a mutation; i) substitution of an amino acid in a given position is written as e.g. T350V which means a substitution of a Threonine in position 350 with a Valine; and ii) for specific variants the specific three or one letter codes are used, including the codes Xaa and X to indicate any amino acid residue. Thus, the substitution of Threonine with Valine in position 350 is designated as: T350V.

[0320] In some embodiments, an IgGl Fc polypeptide or a variant thereof such as any described below can be made in a Gl ml or Gl m3 allotype. In some embodiments, the Fc region can contain amino acids of the human G1 ml allotype, such as residues containing Asp (D) and Leu (L) at positions 356 and 358, e.g. as set forth in SEQ ID NO: 123. In some cases, an Fc polypeptide can contain amino acid substitutions E356D and M358L to reconstitute residues of allotype G1 ml. In other embodiments, the Fc region can contain amino acids of the human G1 m3 allotype, such as residues Glu (E) and Met (M) at positions 356 and 358 by EU numbering, e.g. as set forth in SEQ ID NO: 122. In some cases, an Fc polypeptide can contain amino acid substitutions D356E and L358M to reconstitute residues of allotype G1 m3.

[0321] In some embodiments, a bispecific antibody is formatted with an Fc region that lacks a C- terminal Lys (K) residue. In some embodiments, the human IgGl Fc region lacks Lys447 (EU index of Kabat et al 1991 Sequences of Proteins of Immunological Interest).

[0322] In particular embodiments of bispecific antibodies provided herein, the human IgG Fc region is modified to induce heterodimerization. Various methods are known for promoting heterodimerization of complementary Fc polypeptides, see e.g. Ridgway et al, Protein Eng. 9:617-621 (1996); Merchant et al, Nat. Biotechnol. 16(7): 677-81 (1998); Moore et al. (2011) MAbs, 3:546-57; Von Kreudenstein et al. MAbs, (2013) 5:646-54; Gunasekaran et al. (2010) J. Biol. Chem., 285:19637-46; Leaver-Fay et al. (2016) Structure, 24:641-51; Ha et al. (2016) Frontiers in Immunology, 7:1; Davis et al. (2010) Protein Eng Des Sei, 23:195-202; published international PCT Appl. No. WO 1998/050431, WO 2009/089004, WO2011143545 WO 2014/067011, WO 2012/058768, W02018027025; published U.S. patent Appl. No. US20140363426, US20150307628, US20180016354, US20150239991; and U.S. patent Nos. US5731168, US7183076, US9701759, US9605084, and US9650446. Methods to promote heterodimerization of Fc chains include mutagenesis of the Fc region, such as by including a set of “knob-into-hole” mutations or including mutations to effect electrostatic steering of the Fc to favor attractive interactions among different polypeptide chains. For example, in some embodiments, the Fc polypeptides of a heterodimer includes a mutation to alter charge polarity across the Fc dimer interface such that coexpression of electrostatically matched Fc chains support favorable attractive interactions thereby promoting desired Fc heterodimer formation, whereas unfavorable repulsive charge interactions suppress unwanted Fc homodimer formation (Guneskaran et al. (2010) JBC, 285: 19637-19646). When co-expressed in a cell, association between the chains is possible but the chains do not substantially self-associate due to charge repulsion. Other strategies for generating a heterodimeric Fc include mixing human IgG and IgA CH3 domain segments to create a complementary CH3 heterodimer, which is referred to as a SEED Fc.

[0323] Methods and variants for heterodimerization also include those described in published international PCT App. WO2014/145806, including “knobs and holes” mutations (also called “skew” variants), mutations that relate to “electrostatic steering” or “charge pairs,” and pl variants. Heterodimeric variants also include any as described in U.S. published Appl. No. US2012/0149876 or US2018/011883.

[0324] In some embodiments, modifications include introduction of a protuberance (knob) into a first Fc polypeptide and a cavity (hole) into a second Fc polypeptide such that the protuberance is positionable in the cavity to promote complexing of the first and second Fc-containing polypeptides. Amino acids targeted for replacement and/or modification to create protuberances or cavities in a polypeptide are typically interface amino acids that interact or contact with one or more amino acids in the interface of a second polypeptide.

[0325] In some embodiments, a first Fc polypeptide that is modified to contain protuberance (hole) amino acids include replacement of a native or original amino acid with an amino acid that has at least one side chain which projects from the interface of the first Fc polypeptide and is therefore positionable in a compensatory cavity (hole) in an adjacent interface of a second polypeptide. Most often, the replacement amino acid is one which has a larger side chain volume than the original amino acid residue. One of skill in the art knows how to determine and/or assess the properties of amino acid residues to identify those that are ideal replacement amino acids to create a protuberance. In some embodiments, the replacement residues for the formation of a protuberance are naturally occurring amino acid residues and include, for example, arginine (R), phenylalanine (F), tyrosine (Y), or tryptophan (W). In some examples, the original residue identified for replacement is an amino acid residue that has a small side chain such as, for example, alanine, asparagine, aspartic acid, glycine, serine, threonine, or valine.

[0326] In some embodiments, a second Fc polypeptide that is modified to contain a cavity (hole) is one that includes replacement of a native or original amino acid with an amino acid that has at least one side chain that is recessed from the interface of the second polypeptide and thus is able to accommodate a corresponding protuberance from the interface of a first polypeptide. Most often, the replacement amino acid is one which has a smaller side chain volume than the original amino acid residue. One of skill in the art knows how to determine and/or assess the properties of amino acid residues to identify those that are ideal replacement residues for the formation of a cavity. Generally, the replacement residues for the formation of a cavity are naturally occurring amino acids and include, for example, alanine (A), serine (S), threonine (T) and valine (V). In some examples, the original amino acid identified for replacement is an amino acid that has a large side chain such as, for example, tyrosine, arginine, phenylalanine, or tryptophan.

[0327] The CH3 interface of human IgGl, for example, involves sixteen residues on each domain located on four anti-parallel P-strands which buries 1090 A2 from each surface (see e.g., Deisenhofer et al. (1981) Biochemistry, 20:2361-2370; Miller et al., (1990) J Mol. Biol., 216, 965- 973; Ridgway et al., (1996) Prot. Engin., 9: 617-621; U.S. Pat. No. 5,731,168). Modifications of a CH3 domain to create protuberances or cavities are described, for example, in U.S. Pat. No. 5,731,168; International Patent Applications WO98/50431 and WO 2005/063816; and Ridgway et al., (1996) Prot. Engin., 9: 617-621. In some examples, modifications of a CH3 domain to create protuberances or cavities are typically targeted to residues located on the two central anti-parallel P- strands. The aim is to minimize the risk that the protuberances which are created can be accommodated by protruding into the surrounding solvent rather than being accommodated by a compensatory cavity in the partner CH3 domain.

[0328] In some embodiments, to promote heterodimerization both polypeptides of the Fc heterodimer contain paired or complementary amino acid modifications. Exemplary paired amino acid modification of polypeptides of an Fc fusion are set forth in Table 2. [0329] In general, the Fc region is responsible for effector functions, such as complementdependent cytotoxicity (CDC) and antibody-dependent cell cytotoxicity (ADCC), in addition to the antigen-binding capacity, which is the main function of immunoglobulins. Additionally, the FcRn sequence present in the Fc region plays the role of regulating the IgG level in serum by increasing the in vivo half-life by conjugation to an in vivo FcRn receptor. In some embodiments, such functions can be altered, such as reduced or enhanced, in an Fc for use with the provided multispecific polypeptide constructs.

[0330] In some embodiments, the Fc region includes an Fc polypeptide that is mutated or modified to alter one or more effector functions. Various examples of mutations to Fc polypeptides to alter, such as reduce, effector function are known, including any as described below. In some embodiments, reference to amino acid substitutions in an Fc region is by EU numbering by Kabat (also called Kabat numbering) unless described with reference to a specific SEQ ID NO. EU numbering is known and is according to the most recently updated IMGT Scientific Chart (IMGT®, the international ImMunoGeneTics information system®, http://www.imgt.org/IMGTScientificChart/Numbering/Hu_IGHGnbe r.html (created: 17 May 2001, last updated: 10 Jan 2013) and the EU index as reported in Kabat, E.A. et al. Sequences of Proteins of Immunological interest. 5th ed. US Department of Health and Human Services, NIH publication No. 91-3242 (1991).

[0331] In some embodiments, the human IgGl Fc region is modified to alter antibodydependent cellular cytotoxicity (ADCC) and/or complement-dependent cytotoxicity (CDC), e.g., the amino acid modifications described in Natsume et al., 2008 Cancer Res, 68(10): 3863-72; Idusogie et al., 2001 J Immunol, 166(4): 2571-5; Moore et al., 2010 mAbs, 2(2): 181-189; Lazar et al., 2006 PNAS, 103(11): 4005-4010, Shields et al., 2001 JBC, 276(9): 6591-6604; Stavenhagen et al., 2007 Cancer Res, 67(18): 8882-8890; Stavenhagen et al., 2008 Advan. Enzyme Regul., 48: 152-164; Alegre et al, 1992 J Immunol, 148: 3461-3468; Reviewed in Kaneko and Niwa, 2011 Biodrugs, 25(1): 1-11 ; U.S. Patent No. 8101720; U.S. Patent No. 9475881; and U.S. Patent NO. 10851164, the contents of each of which are hereby incorporated by reference in their entireties.

[0332] In some embodiments, the Fc region, such as the human IgGl Fc region is modified to enhance ADCC activity or CDC activity. Examples of mutations that enhance ADCC include modification at Ser239 and Ile332, for example Ser239Asp and Ile332Glu (S239D, I332E). Examples of mutations that enhance CDC include modifications at Lys326 and Glu333. In some embodiments, the Fc region is modified at one or both of these positions, for example Lys326Ala and/or Glu333Ala (K326A and E333A) using the Kabat numbering system.

[0333] In some embodiments, the Fc region is altered to provide reduced Fc-mediated effector functions, such as via reduced Fc receptor binding, e.g. binding to FcyR binding but generally not FcRn binding. In some embodiments, the human IgGl Fc region fusion proteins of the present disclosure lack or have reduced Fucose attached to the N-linked glycan-chain at N297. There are numerous ways to prevent fucosylation, including but not limited to production in a FUT8 deficient cell line; addition inhibitors to the mammalian cell culture media, for example Castanospermine; and metabolic engineering of the production cell line. In some embodiments, the human IgGl Fc region is modified at amino acid Asn297 to prevent glycosylation of the fusion protein, e.g., Asn297Ala (N297A) or Asn297Asp (N297D).

[0334] In some embodiments, the Fc region of the fusion protein is altered at one or more of the following positions to reduce Fc receptor binding: Leu 234 (L234), Leu235 (L235), Asp265 (D265), Asp270 (D270), Ser298 (S298), Asn297 (N297), Asn325 (N325) orAla327 (A327). For example, Leu 234Ala (L234A), Leu235Ala (L235A), Asp265Asn (D265N), Asp270Asn (D270N), Ser298Asn (S298N), Asn297Ala (N297A), Asn325Glu (N325E) orAla327Ser (A327S). In some embodiments, the Fc region of the fusion protein is modified at amino acid Leu235 to alter Fc receptor interactions, e.g., Leu235Glu (L235E) or Leu235Ala (L235A). In some embodiments, the Fc region of the fusion protein is modified at amino acid Leu234 to alter Fc receptor interactions, e.g., Leu234Ala (L234A). In some embodiments, the Fc region of the fusion protein is altered at both amino acid 234 and 235, e.g., Leu234Ala and Leu235Ala (L234A/L235A) or Leu234Val and Leu235Ala (L234V/L235A). In particular embodiments, the Fc region contains LALA mutations Leu234Ala and Leu235Ala (L234A/L235A). In some embodiments, modifications within the Fc region reduce binding to Fc- receptor-gamma receptors while have minimal impact on binding to the neonatal Fc receptor (FcRn).

[0335] In some embodiments, the Fc comprises amino acid modification of at least one of L234, L235, or D265. In another embodiment, the Fc comprises amino acid modification of at least L234, L235 and D265. In another embodiment, the Fc comprises the amino acid modification L234A, L235A and D265S. In particular aspects, the IgGl has been modified to comprise or consist of an L234A, an L235A, and a D265S mutation as identified using Kabat numbering to render the Fc effector-less.

[0336] In some embodiments, the Fc comprises a P329G mutation in the Fc together with L234A-L235A (LALA) mutations. In particular aspects, the IgGl has been modified to comprise or consist of an L234A, an L235A, and a P329G mutation as identified using Kabat numbering to render the Fc effector-less. In some embodiments, P329G is able to disrupt the interaction between hlgG and hFcyR, which combined with the effectorless mutations L234A/L235A mutations create a triple mutant L234A/L235A/P329G with no detectable binding to Clq or FcyRs, resulting in abrogated ADCC. In some embodiments, such an Fc disrupts the interaction with Fcy-receptors (FcyRs) while maintaining the binding to neonatal Fc-receptor (nFcR) and therefore wildtype-antibody-like pharmacokinetics in subjects.

[0337] In some embodiments, the human IgG Fc region is modified to enhance FcRn binding. Examples of Fc mutations that enhance binding to FcRn are Met252Tyr, Ser254Thr, Thr256Glu (M252Y, S254T, T256E, respectively) (Kabat numbering, Dall’ Acqua et al 2006, J. Biol Chem Vol. 281(33) 23514-23524), Met428Leu and Asn434Ser (M428L, N434S) (Zalevsky et al 2010 Nature Biotech, Vol. 28(2) 157-159) (EU index of Kabat et al 1991 Sequences of Proteins of Immunological Interest). In some embodiments, the mutated or modified Fc polypeptide includes the following mutations: Met252Tyr and Met428Leu or Met252Tyr and Met428Val (M252Y, M428L, or M252Y, M428V) using the Kabat numbering system.

[0338] In some embodiments, the Fc region is mutated in one or more of the following positions to reduce Fc receptor binding: Glu233 (E233), Eeu234 (E234), or Eeu235 (E235). The one or more mutations can include E233P, E234V and/or E235A.

[0339] In some embodiments, the Fc region of the fusion protein is altered at Gly236 to reduce Fc receptor binding. For example, wherein Gly236 is deleted from the fusion protein. In some embodiments, the human IgGl Fc region is modified at amino acid Gly236 to enhance the interaction with CD32A, e.g., Gly236Ala (G236A).

[0340] In particular embodiments, the mutations of the Fc region to reduce Fc effector function, e.g. via reducing Fc receptor binding to FcyR, include mutations from among any of G236R/E328R, E233P/E234V/E235A/G236del/S239K, E233P/E234V/E235A/G236del/S267K, E233P/E234V/E235A/G236del/S239K/A327G, E233P/E234V/E235A/G236del/S267K/A327G or E233P/L234V/L235A/G236del.

[0341] In some embodiments, the bispecific antibody contains a first Fc polypeptide that has at least 85%, 90%, 95% or 98% sequence identity to the Fc polypeptide set forth in SEQ ID NO: 124 and contains the mutations T350V, E351Y, F405A and Y407V; and a second Fc polypeptide that has at least 85%, 90%, 95% or 98% sequence identity to the Fc polypeptide set forth in SEQ ID NO: 125 and contains the mutations T350V, T366E, K392E and T394W. In some embodiments, the bispecific antibody contains a first Fc polypeptide set forth in SEQ ID NO: 124 and a second Fc polypeptide set forth in SEQ ID NO: 125.

[0342] In some embodiments, the bispecific antibody contains a first Fc polypeptide that has at least 85%, 90%, 95% or 98% sequence identity to the Fc polypeptide set forth in SEQ ID NO: 126 and contains the mutations T350V, E351Y, F405A and Y407V and the mutations E234A, E235A and D265S; and a second Fc polypeptide that has at least 85%, 90%, 95% or 98% sequence identity to the Fc polypeptide set forth in SEQ ID NO: 127 and contains the mutations T350V, T366E, K392E and T394W and the mutations E234A, E235A and D265S. In some embodiments, the bispecific antibody contains a first Fc polypeptide set forth in SEQ ID NO: 126 and a second Fc polypeptide set forth in SEQ ID NO: 127.

[0343] In some embodiments, the bispecific antibody contains a first Fc polypeptide that has at least 85%, 90%, 95% or 98% sequence identity to the Fc polypeptide set forth in SEQ ID NO: 128 and contains the mutations T350V, E351Y, F405A and Y407V and the mutations E234A, E235A and P329G; and a second Fc polypeptide that has at least 85%, 90%, 95% or 98% sequence identity to the Fc polypeptide set forth in SEQ ID NO: 129 and contains the mutations T350V, T366E, K392E and T394W and the mutations E234A, E235A and P329G. In some embodiments, the bispecific antibody contains a first Fc polypeptide set forth in SEQ ID NO: 128 and a second Fc polypeptide set forth in SEQ ID NO: 129.

[0344] Provided herein is a bispecific antibody that is an asymmetric, two-arm, immunoglobulin (Ig)Gl -based monoclonal antibody (mAb) that binds bivalently to FcRH5 and monovalently to the cluster of differentiation 3 epsilon chain (CD3e). In some embodiments, the antibody is a FcRH5xCD3 trivalent bispecific antibody. In some embodiments, the bispecific antibody comprises a heavy chain (anti-FcRH5) A chain (HC1) comprising at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:89. In some embodiments, the bispecific antibody comprises a heavy chain (anti-FcRH5) A chain (HC1) comprising SEQ ID NO: 89. In some embodiments, the bispecific antibody comprises a heavy chain (anti-FcRH5 and anti-CD3) B chain (HC2) comprising at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity SEQ ID NO:98. In some embodiments, the bispecific antibody comprises a heavy chain (anti-FcRH5 and anti-CD3) B chain (HC2) comprising SEQ ID NO:98. In some embodiments, the bispecific antibody comprises a heavy chain (anti-FcRH5) A chain (HC1) comprising at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:89; a heavy chain (anti- FcRH5 and anti-CD3) B chain (HC2) comprising at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity SEQ ID NO:98; and a light chain (anti-CD3) (LC) comprising at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity SEQ ID NO: 102.

[0345] In some embodiments, the bispecific antibody comprises a heavy chain (anti-FcRH5) A chain (HC1) (SEQ ID NO:89); a heavy chain (anti-FcRH5 and anti-CD3) B chain (HC2) (SEQ ID NO:98); and a light chain (anti-CD3) (LC) (SEQ ID NO: 102). Methods of treatment and uses of the bispecific trivalent anti-FcRH5/anti-CD3 T cell engaging antibody (TCE), for the treatment of oncological conditions, hematological malignancies, and autoimmune disorders is described herein.

[0346] The provided anti-FcRH5/anti-CD3 T cell engaging antibody (TCE) confers high potency and selective FcRH5 targeting on the surface of FcRH5-expressing cells, including multiple myeloma (MM) cell lines and primary myeloma cells. No or minimal binding was observed against other FcRH family members. The avidity effect, along with a higher affinity of binding to FcRH5, permits preferential binding to FcRH5 expressed on target cells over CD3e on T cells. Further, nonspecific T cell activation is reduced in the absence of simultaneous binding to FcRH5-expressing cells, at least in part because the binding to CD3e is designed as monovalent, with lower affinity. No binding to cell lines lacking FcRH5 or CD3 expression is observed.

D. Methods of Preparing Bispecific Antibodies

[0347] In some embodiments, the bispecific antibodies provided herein can be obtained by coexpression of constructs encoding the polypeptides of the bispecific antibody in a single host cell. In some embodiments, the methods include co-expressing the first polypeptide comprising the first heavy chain, the second polypeptide comprising the second heavy chain, and the polypeptide(s) comprising the light chain. For instance, in the case of a common light chain sequence the provided methods for producing the bispecific antibodies include co-expressing the first polypeptide comprising the first heavy chain, the second polypeptide comprising the second heavy chain, and a third polypeptide comprising the light chain. In other embodiments in which the anti-FcRH5 binding molecule (e.g. Fab) and the anti-CD3 binding molecule (e.g. Fab) contain different light chains, the provided methods for producing bispecific antibodies include co-expressing the first polypeptide comprising the first heavy chain, the second polypeptide comprising the second heavy chain, a third polypeptide comprising a first light chain that associates with one of the anti-FcRH5 antibody or the anti-CD3 antibody, and a fourth polypeptide comprising a second light chain that associates with the other of the anti-FcRH5 antibody or the anti-CD3 antibody.

[0348] In some embodiments, nucleic acids encoding the polypeptide chains are incorporated into expression vectors for introducing into the host cell. In some embodiments, the produced heterodimeric protein, which is the bispecific antibody, can be obtained from the cell culture. In some embodiments, the host cell is a eukaryotic or prokaryotic host cell. Thus, also provided are expression vector containing polynucleotides encoding a polypeptide chain of the provided bispecific antibodies. Also provided herein is a recombinant eukaryotic or prokaryotic host cell containing the polynucleotides or vector, and which is able to produces a bispecific antibody provided herein.

[0349] Suitable expression vectors, including promoters, enhancers, etc., and suitable host cells for the production of antibodies are well-known in the art. Examples of host cells include yeast, bacterial and mammalian cells, such as CHO or HEK cells. In some embodiments, examples of host cells include yeast, bacterial, plant and mammalian cells, such as CHO, CHO-S, HEK, HEK293, HEK-293F, Expi293F, PER.C6 or NSO cells or lymphocytic cells.

[0350] An expression vector may be any suitable vector, including chromosomal, non- chromosomal, and synthetic nucleic acid vectors (a nucleic acid sequence comprising a suitable set of expression control elements). Examples of such vectors include derivatives of SV40, bacterial plasmids, phage DNA, baculovirus, yeast plasmids, vectors derived from combinations of plasmids and phage DNA, and viral nucleic acid (RNA or DNA) vectors. In one embodiment, nucleic acid is comprised in a naked DNA or RNA vector, including, for example, a linear expression element (as described in for instance Sykes and Johnston, Nat Biotech 17, 355-59 (1997)), a compacted nucleic acid vector (as described in for instance U.S. Pat. No. 6,077,835 and/or WO 00/70087), a plasmid vector such as pBR322, pUC 19/18, or pUC 118/119, a “midge” minimally-sized nucleic acid vector (as described in for instance Schakowski et al., Mol Ther 3, 793-800 (2001)), or as a precipitated nucleic acid vector construct, such as a CaP04-precipitated construct (as described in for instance W0200046147, Benvenisty and Reshef, PNAS USA 83, 9551-55 (1986), Wigler et al., Cell 14, 725

I l l (1978), and Coraro and Pearson, Somatic Cell Genetics 7, 603 (1981)). Such nucleic acid vectors and the usage thereof are well known in the art (see for instance U.S. Pat. Nos. 5,589,466 and 5,973,972).

[0351] In one embodiment, the vector is suitable for expression of the polypeptide chains in a bacterial cell. Examples of such vectors include expression vectors such as BlueScript (Stratagene), pIN vectors (Van Heeke & Schuster, J Biol Chem 264, 5503-5509 (1989), pET vectors (Novagen, Madison Wis.) and the like).

[0352] An expression vector may also or alternatively be a vector suitable for expression in a yeast system. Any vector suitable for expression in a yeast system may be employed. Suitable vectors include, for example, vectors comprising constitutive or inducible promoters such as alpha factor, alcohol oxidase and PGH (reviewed in: F. Ausubel et al., ed. Current Protocols in Molecular Biology, Greene Publishing and Wiley InterScience New York (1987), and Grant et al., Methods in Enzymol 153, 516-544 (1987)).

[0353] An expression vector may also or alternatively be a vector suitable for expression in mammalian cells, e.g. a vector comprising glutamine synthetase as a selectable marker, such as the vectors described in Bebbington (1992) Biotechnology (NY) 10:169-175.

[0354] A nucleic acid and/or vector may also comprises a nucleic acid sequence encoding a secretion/localization sequence, which can target a polypeptide, such as a nascent polypeptide chain, to the periplasmic space or into cell culture media. Such sequences are known in the art, and include secretion leader or signal peptides.

[0355] The expression vector may comprise or be associated with any suitable promoter, enhancer, and other expression-facilitating elements. Examples of such elements include strong expression promoters (e. g., human CMV IE promoter/enhancer as well as RSV, SV40, SL3-3, MMTV, and HIV LTR promoters), effective poly (A) termination sequences, an origin of replication for plasmid product in E. coli, an antibiotic resistance gene as selectable marker, and/or a convenient cloning site (e.g., a polylinker). Nucleic acids may also comprise an inducible promoter as opposed to a constitutive promoter such as CMV IE.

[0356] In some embodiments, the host cell may comprise the nucleic acid molecules encoding the polypeptides stably integrated into the cellular genome. In another embodiment, the cell is transformed to contain non-integrated nucleic acid, such as a plasmid, cosmid, phagemid, or linear expression element.

[0357] By virtue of the Fc region of the first heavy chain and second heavy chain being a different polypeptide chain of a heterodimeric Fc each containing different mutations in their CH3 region to promote heterodimeric interactions, the polypeptide chains of the first and second heavy chain will associate to form the bispecific antibody. Moreover, the light chain also will associate with the respective heavy chains.

[0358] The resulting bispecific antibodies can be purified by any suitable method such as, for example, by affinity chromatography over Protein A or Protein G columns. Where two nucleic acid molecules encoding different polypeptides are transformed into cells, formation of homo- and heterodimers will occur. Conditions for expression can be adjusted so that heterodimer formation is favored over homodimer formation.

[0359] Techniques for recovery of heterodimers from homodimers based on a differential affinity of the heterodimers for an affinity reagent are known. In some aspects, such techniques include designing a heterodimer so that one of the Fc polypeptide chains does not bind to the affinity reagent protein A. In some cases, one of the polypeptide chain can contain one or more amino acid substitution to abrogate or reduce affinity for the protein A reagent in one of the polypeptides of the Fc heterodimer, see e.g. WO2017134440, W02010151792, Jendeberg et al. (Jendeberg et al., (1997) J. Immunol. Methods, 201(1): 25-34. In some of these embodiments, the Fc region may be modified at the protein-A binding site on one member of the heterodimer so as to prevent protein-A binding and thereby enable more efficient purification of the heterodimeric fusion protein. An exemplary modification within this binding site is Ile253, for example Ile253Arg (I253R). In some embodiments, the modification may be H435R or H435R/Y436F. In some embodiments, an Fc polypeptide of an Fc heterodimer can contain a modification so that it is capable of binding protein A but not protein G (pA+/pG-). Exemplary pA+/pG- amino acid modifications include an Fc containing serine at position 428, serine at position 434 and optionally histidine at position 436, with reference to human IgGl or comprising these residues at the corresponding positions in human IgG 2, 3, or 4. In some aspects, such amino acid modifications in one IgG Fc polypeptide at positions 428, 434 and optionally 436 reduces or prevents the binding of protein G, enhancing the purification of the protein.

[0360] In some embodiments, separate plasmids encoding each chain of the bispecific antibody are transfected at an equimolar ratio into mammalian cells (such as HEK293 or CHO). Recombinant protein is secreted into the supernatant and can be collected, such as after 3-7 days. In some embodiments, the antibody is purified by protein A chromatography, followed by either preparative size exclusion chromatography (SEC) or flow-through hydrophobic interaction chromatography (HIC). In some embodiments, a second chromatography step may be carried out, such as on SEC (AKTA with Superdex-200 resin) or FT-HIC (AKTA with butyl/phenyl sepharose), to remove undesired cross-paired species.

[0361] In some embodiments, the bispecific antibody is a purified bispecific antibody.

III. POLYNUCLEOTIDES ENCODING BINDING MOLECULES

[0362] Also provided are polynucleotides encoding the binding molecules provided herein, such as antibodies or chains (e.g. heavy or light chains) thereof. Among the provided polynucleotides are those encoding the anti-FcRH5 antibodies (e.g., antigen-binding fragment) or chains thereof described herein. Also among the provided polynucleotides are those encoding the bispecific antibodies or chains thereof described herein. Also provided are polynucleotides that contain a nucleic acid encoding any of the single chain cell surface proteins described herein. Also provided are polynucleotides that contain a nucleic acid encoding any of the conjugate described herein.

[0363] In some embodiments, the antibody or antigen-binding fragment thereof contains multiple domains or chains (e.g., heavy chain and a light chain), and all of the antibody or antigenbinding fragment thereof is encoded in one polynucleotide. In some embodiments, the binding molecule, such as the antibody or antigen-binding fragment thereof, contains multiple domains or chains (e.g., a heavy chain and a light chain), and all of the binding molecule is encoded in more than one polynucleotide, such as two or more polynucleotides. In some embodiments, the polynucleotides are comprised in a vector.

[0364] The polynucleotides may include those encompassing natural and/or non-naturally occurring nucleotides and bases, e.g., including those with backbone modifications. The terms “nucleic acid molecule”, “nucleic acid”, “sequence of nucleotides”, and “polynucleotide” may be used interchangeably, and refer to a polymer of nucleotides. Such polymers of nucleotides may contain natural and/or non-natural nucleotides, and include, but are not limited to, DNA, RNA, and PNA. “Nucleic acid sequence” refers to the linear sequence of nucleotides that comprise the nucleic acid molecule or polynucleotide.

[0365] In some aspects, provided are polynucleotides that contain nucleic acid sequences encoding any of the binding molecules provided herein, for example, in any of Sections I or II. In some embodiments, provided are polynucleotides that contain nucleic acid sequences encoding a chain (e.g. heavy or light chain) of any of the binding molecules provided herein, for example, in Sections I or II.

[0366] In some cases, the polynucleotide encoding the binding molecule, such as an antibody or antigen-binding fragment thereof, contains a signal sequence that encodes a signal peptide. In some embodiments, the signal peptide is encoded upstream of the nucleic acid sequences encoding the binding molecules, such as an antibody or antigen-binding fragment thereof, or joined at the 5’ terminus of the nucleic acid sequences encoding the binding molecule. In some aspects, the signal sequence may encode a signal peptide derived from a native polypeptide.

[0367] In some cases, the polynucleotide encoding the binding molecules, such as an antibody or antigen-binding fragment thereof, can contain additional components, such as promoters, regulatory elements and/or multicistronic elements. In some embodiments, the nucleic acid sequence encoding the binding molecules (e.g. an antibody or antigen-binding fragment thereof), or chains thereof, can be operably linked to any of the additional components.

[0368] In some embodiments, provided are polynucleotides contain nucleic acid sequences encoding a variable heavy chain domain (Vu) of an antibody provided herein or an antigen-binding fragment thereof. In some embodiments, provided are polynucleotides contain nucleic acid sequences encoding a variable light chain domain (VL) of an antibody provided herein or an antigen-binding fragment thereof. In some embodiments, provided are polynucleotides that contain nucleic acid sequences encoding a variable heavy chain domain (VH) and a variable light chain domain (VL) of an antibody provided herein or an antigen-binding fragment thereof.

[0369] In some embodiments, provided are polynucleotides encoding a heavy or light chain of a bispecific antibody as provided herein.

[0370] In some embodiments, provided herein are polynucleotides encoding chains of a bispecific antibody containing a first heavy chain comprising the heavy chain of the first FcRH5-Fab, a second heavy chain comprising the second FcRH5-Fab and the CD3-Fab, and a common light chain. In some embodiments, the polynucleotide encoding the first heavy chain comprises a sequence of nucleotides that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:111. In some embodiments, the polynucleotide encoding the first heavy chain has the sequence of nucleotides set forth in SEQ ID NO: 111. In some embodiments, the polynucleotide encoding the second heavy chain comprises a sequence of nucleotides that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 112. In some embodiments, the polynucleotide encoding the second heavy chain has the sequence of nucleotides set forth in SEQ ID NO: 112. In some embodiments, the polynucleotide encoding the light chain comprises a sequence of nucleotides that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 110. In some embodiments, the polynucleotide encoding the light chain has the sequence of nucleotides set forth in SEQ ID NO: 110.

[0371] In some embodiments, provided herein are polynucleotides encoding chains of a bispecific antibody containing a first heavy chain comprising the heavy chain of the first FcRH5-Fab, a second heavy chain comprising the second FcRH5-Fab and the CD3-Fab, and a common light chain. In some embodiments, the polynucleotide encoding the first heavy chain comprises a sequence of nucleotides that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:111. In some embodiments, the polynucleotide encoding the first heavy chain has the sequence of nucleotides set forth in SEQ ID NO: 111. In some embodiments, the polynucleotide encoding the second heavy chain comprises a sequence of nucleotides that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 113. In some embodiments, the polynucleotide encoding the second heavy chain has the sequence of nucleotides set forth in SEQ ID NO: 113. In some embodiments, the polynucleotide encoding the light chain comprises a sequence of nucleotides that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 110. In some embodiments, the polynucleotide encoding the light chain has the sequence of nucleotides set forth in SEQ ID NO: 110.

[0372] Also provided are polynucleotides that have been optimized for codon usage and/or to eliminate splice sites, such as cryptic splice sites. In some embodiments, the polynucleotides are modified to optimize codon usage. In some embodiments, the polynucleotides are codon optimized for expression in a mammalian cell, such as a human cell. In some embodiments, the polynucleotides can be codon optimized for expression in human cells.

IV. PHARMACEUTICAL COMPOSITIONS

[0373] Also provided are compositions including any of the provided binding molecules, including antibodies such as bispecific antibodies. Also provided are compositions including any of the provided engineered cells incorporating or expressing a provided binding molecule, such as a CAR. The compositions may include pharmaceutical compositions and formulations.

[0374] The term “pharmaceutical formulation” refers to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered.

[0375] A “pharmaceutically acceptable carrier” refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to a subject. A pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative.

[0376] In some embodiments, the provided compositions include a pharmaceutically acceptable carrier. Suitable pharmaceutically acceptable carriers include, for example, one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof. Pharmaceutically acceptable carriers may further comprise minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life or effectiveness of the binding proteins.

[0377] In some aspects, the choice of carrier is determined in part by the particular active ingredient or by the method of administration. Accordingly, there are a variety of suitable formulations. For example, the pharmaceutical composition can contain preservatives. Suitable preservatives may include, for example, methylparaben, propylparaben, sodium benzoate, and benzalkonium chloride. In some aspects, a mixture of two or more preservatives is used. The preservative or mixtures thereof are typically present in an amount of about 0.0001% to about 2% by weight of the total composition. Carriers are described, e.g., by Remington’s Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980). Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed, and include, but are not limited to: buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m- cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g. Zn-protein complexes); and/or non-ionic surfactants such as polyethylene glycol (PEG).

[0378] Buffering agents in some aspects are included in the compositions. Suitable buffering agents include, for example, citric acid, sodium citrate, phosphoric acid, potassium phosphate, and various other acids and salts. In some aspects, a mixture of two or more buffering agents is used. The buffering agent or mixtures thereof are typically present in an amount of about 0.001% to about 4% by weight of the total composition. Methods for preparing administrable pharmaceutical compositions are known. Exemplary methods are described in more detail in, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins; 21st ed. (May 1, 2005).

[0379] Formulations of the antibodies described herein can include lyophilized formulations and aqueous solutions.

[0380] The pharmaceutical composition in some aspects can employ time-released, delayed release, and sustained release delivery systems such that the delivery of the composition occurs prior to, and with sufficient time to cause, sensitization of the site to be treated. Many types of release delivery systems are available and known. Such systems can avoid repeated administrations of the composition, thereby increasing convenience to the subject and the physician.

[0381] The provided compositions can be conveniently provided as sterile liquid preparations, e.g., isotonic aqueous solutions, suspensions, emulsions, dispersions, or viscous compositions, which may be buffered to a selected pH. Liquid preparations are normally easier to prepare than gels, other viscous compositions, and solid compositions. Additionally, liquid compositions are somewhat more convenient to administer, especially by injection. Viscous compositions, on the other hand, can be formulated within the appropriate viscosity range to provide longer contact periods with specific tissues. Liquid or viscous compositions can comprise carriers, which can be a solvent or dispersing medium containing, for example, water, saline, phosphate buffered saline, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like) and suitable mixtures thereof.

[0382] The formulations to be used for in vivo administration are generally sterile. Sterility may be readily accomplished, e.g., by filtration through sterile filtration membranes.

[0383] Sterile injectable solutions can be prepared by incorporating the active ingredient, such as the FcRH5 binding molecules including bispecific antibodies of the presently disclosed subject matter, in the required amount of the appropriate solvent with various amounts of the other ingredients, as desired. Such compositions may be in admixture with a suitable carrier, diluent, or excipient such as sterile water, physiological saline, glucose, dextrose, or the like. The compositions can also be lyophilized. The compositions can contain auxiliary substances such as wetting, dispersing, or emulsifying agents (e.g., methylcellulose), pH buffering agents, gelling or viscosity enhancing additives, preservatives, flavoring agents, colors, and the like, depending upon the route of administration and the preparation desired. Standard texts, such as “REMINGTON’S PHARMACEUTICAL SCIENCE,” 17th edition, 1985, incorporated herein by reference, may be consulted to prepare suitable preparations, without undue experimentation.

[0384] Various additives which enhance the stability and sterility of the compositions, including antimicrobial preservatives, antioxidants, chelating agents, and buffers, can be added. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, alum inurn monostearate and gelatin. As is understood to a skilled artisan, any vehicle, diluent, or additive used would have to be compatible with the active ingredient, such as the FcRH5 binding molecules including bispecific antibodies of the presently disclosed subject matter.

[0385] The compositions can be isotonic, i.e., they can have the same osmotic pressure as blood and lacrimal fluid. The desired isotonicity of the compositions of the presently disclosed subject matter may be accomplished using sodium chloride, or other pharmaceutically acceptable agents such as dextrose, boric acid, sodium tartrate, propylene glycol or other inorganic or organic solutes. Sodium chloride is preferred particularly for buffers containing sodium ions.

[0386] Viscosity of the compositions, if desired, can be maintained at the selected level using a pharmaceutically acceptable thickening agent. Methylcellulose can be used because it is readily and economically available and is easy to work with. Other suitable thickening agents include, for example, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, carbomer, and the like. The concentration of the thickener can depend upon the agent selected. The important point is to use an amount that will achieve the selected viscosity. Obviously, the choice of suitable carriers and other additives will depend on the exact route of administration and the nature of the particular dosage form, e.g., liquid dosage form (e.g., whether the composition is to be formulated into a solution, a suspension, gel or another liquid form, such as a time release form or liquid-filled form).

[0387] The pharmaceutical composition in some embodiments contains the active ingredient, e.g. FcRH5 binding molecules (including bispecific antibodies) or engineered cells, in amounts effective to treat or prevent the disease or condition, such as a therapeutically effective or prophylactically effective amount. Therapeutic or prophylactic efficacy in some embodiments is monitored by periodic assessment of treated subjects. For repeated administrations over several days or longer, depending on the condition, the treatment is repeated until a desired suppression of disease symptoms occurs. However, other dosage regimens may be useful and can be determined. The desired dosage can be delivered by a single bolus administration of the composition, by multiple bolus administrations of the composition, or by continuous infusion administration of the composition.

[0388] The skilled artisan can readily determine the amount of FcRH5 binding molecule, such as provided bispecific antibodies, and optional additives, vehicles, and/or carrier in compositions and to be administered in methods of the presently disclosed subject matter. Typically, any additives (in addition to the FcRH5 binding molecules) are present in an amount of from about 0.001% to about 50% by weight) solution in phosphate buffered saline, and the active ingredient is present in the order of micrograms to milligrams, such as from about 0.0001 wt% to about 5 wt %, from about 0.0001 wt% to about 1 wt %, from about 0.0001 wt% to about 0.05 wt%, from about 0.001 wt% to about 20 wt %, from about 0.01 wt% to about 10 wt %, or from about 0.05 wt% to about 5 wt %. For any composition to be administered to an animal or human, and for any particular method of administration, toxicity should be determined, such as by determining the lethal dose (LD) and LD50 in a suitable animal model e.g., rodent such as mouse; and, the dosage of the composition(s), concentration of components therein and timing of administering the composition(s), which elicit a suitable response. Such determinations do not require undue experimentation from the knowledge of the skilled artisan, this disclosure and the documents cited herein. And, the time for sequential administrations can be ascertained without undue experimentation.

V. METHODS OF USE AND TREATMENT

[0389] Also provided are methods of administering and uses of the provided FcRH5 binding molecules, including antibodies such as bispecific antibodies, or molecules incorporating the same. Also provided are methods of administering and uses of a provided engineered cells containing a FcRH5 binding molecule (e.g. CAR). Such methods and uses include therapeutic methods and uses, for example, involving administration of the molecules (e.g., FcRH5-binding molecules, including bispecific antibodies), cells (e.g., engineered cells), or compositions containing the same, to a subject having a disease, condition, or disorder associated with FcRH5 such as a disease, condition, or disorder associated with FcRH5 expression, or in which cells or tissues express FcRH5, e.g., specifically express FcRH5. In some embodiments, the molecules (e.g., FcRH5-binding molecules, including bispecific antibodies) or cells (e.g., engineered cells) are administered in an effective amount to effect treatment of the disease or disorder. Provided herein are uses of the binding molecules (e.g., anti-FcRH5 antibodies including bispecific antibodies) and cells incorporating the same (e.g., engineered cells) in such methods and treatments, and in the preparation of a medicament in order to carry out such therapeutic methods. Uses include uses of the binding molecules or engineered cells in such methods and treatments, and in the preparation of a medicament in order to carry out such therapeutic methods. In some embodiments, the methods are carried out by administering the binding molecules or cells, or compositions comprising the same, to the subject having, having had, or suspected of having the disease or condition. In some embodiments, the methods thereby treat the disease or condition or disorder in the subject. Also provided herein are of use of any of the compositions, such as pharmaceutical compositions provided herein, for the treatment of a disease or disorder associated with FcRH5, for example, a FcRH5-expressing cancer. [0390] The methods and uses can be for therapeutic treatments to a patient suffering from a cancer (e.g., multiple myeloma) and includes an amount sufficient to prevent, inhibit or reduce the progression of the cancer. Progression includes, e.g., the growth, invasiveness, metastases and/or recurrence of the cancer, e.g., tumor. In certain embodiments, the method can include administering to a subject an effective amount of an anti-FcRH5 antibody or antigen-binding fragment thereof (or a pharmaceutical composition thereof) to produce an anti-cancer effect in the subject. Amounts effective for this use will depend upon the severity of the disease and the general state of the patient's own immune system. Dosing schedules will also vary with the disease state and status of the patient, and will typically range from a single bolus dosage or continuous infusion to multiple administrations per day (e.g., every 4-6 hours), or as indicated by the treating physician and the patient’s condition.

[0391] As used herein, “treatment” (and grammatical variations thereof such as “treat” or “treating”) refers to complete or partial amelioration or reduction of a disease or condition or disorder, or a symptom, adverse effect or outcome, or phenotype associated therewith. Desirable effects of treatment include, but are not limited to, preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis. The terms do not imply complete curing of a disease or complete elimination of any symptom or effect(s) on all symptoms or outcomes.

[0392] As used herein, “delaying development of a disease" means to defer, hinder, slow, retard, stabilize, suppress and/or postpone development of the disease (such as cancer). This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease. For example, a late stage cancer, such as development of metastasis, may be delayed.

[0393] “Preventing,” as used herein, includes providing prophylaxis with respect to the occurrence or recurrence of a disease in a subject that may be predisposed to the disease but has not yet been diagnosed with the disease. In some embodiments, the provided molecules and compositions are used to delay development of a disease or to slow the progression of a disease.

[0394] As used herein, to “suppress” a function or activity is to reduce the function or activity when compared to otherwise same conditions except for a condition or parameter of interest, or alternatively, as compared to another condition. For example, an antibody or composition or cell which suppresses tumor growth reduces the rate of growth of the tumor compared to the rate of growth of the tumor in the absence of the antibody or composition or cell.

[0395] An “effective amount” of an agent, e.g., a pharmaceutical formulation, binding molecule, antibody, or cells, or composition, in the context of administration, refers to an amount effective, at dosages/amounts and for periods of time necessary, to achieve a desired result, such as a therapeutic or prophylactic result. [0396] A “therapeutically effective amount” of an agent, e.g., a pharmaceutical formulation, antibody, or cells, refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result, such as for treatment of a disease, condition, or disorder, and/or pharmacokinetic or pharmacodynamic effect of the treatment. The therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the subject, and the populations of cells administered. In some embodiments, the provided methods involve administering the molecules, cells, and/or compositions at effective amounts, e.g., therapeutically effective amounts.

[0397] A “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically but not necessarily, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.

[0398] As used herein, a “subject” is a mammal, such as a human or other animal, and typically is human.

[0399] An “anti-cancer effect” means one or more of: a reduction in aggregate cancer cell mass, a reduction in cancer cell growth rate, a reduction in cancer cell proliferation, a reduction in tumor mass, a reduction in tumor volume, a reduction in tumor cell proliferation, a reduction in tumor growth rate or a reduction in tumor metastasis. In certain embodiments, the anti-cancer effect is a reduction in the number of cancer cells. In certain embodiments, where the cancer is a solid tumor, an anti-cancer effect can be a reduction in tumor size and/or a reduction in the rate of tumor growth. In certain embodiments, the anti-cancer effect is a reduction in the aggregate cancer cell burden. In certain embodiments, the anti-cancer effect is a reduction in the rate of cell proliferation and/or an increase in the rate of cell death. In certain embodiments, the anti-cancer effect is a prolongation of survival. In certain embodiments, the anti-cancer effect is a prolongation in the interval until relapse.

[0400] Among the diseases to be treated are any FcRH5-associated disease or condition or disease or condition in which FcRH5 is specifically expressed. In certain diseases and conditions, FcRH5 is expressed on malignant cells and cancers. In some embodiments, the disease or condition is a FcRH5-expressing cancer. Cancers associated with FcRH5 expression include hematologic malignancies such as multiple myeloma.

[0401] The identification of medical conditions treatable by FcRH5 binding molecules of the presently disclosed subject matter, including antibodies such as bispecific antibodies or engineered cells containing the same, is well within the ability and knowledge of one skilled in the art. Examples of cancer include, but are not limited to, B cell proliferative disorders. Non-limiting examples of suitable cancers that can be treated with the disclosed antibodies or antigen-binding fragments thereof include multiple myeloma, Non-Hodgkin Lymphoma (e.g., Mantle Cell), Hodgkin Lymphoma, Chronic Lymphocytic Leukemia (CLL), Acute lymphocytic leukemia (ALL), Hairy Cell Leukemia, Burketts Lymphoma and Waldenstrom’s Macroglobulinemia. In certain embodiments, the cancer is multiple myeloma. In certain embodiments, the cancer is Non-Hodgkin Lymphoma. For example, human individuals who are either suffering from multiple myeloma or who are at risk of developing multiple myeloma are suitable for administration of the presently disclosed FcRH5 binding molecules. A clinician skilled in the art can readily determine, for example, by the use of clinical tests, physical examination and medical/family history, if an individual is a candidate for such treatment.

[0402] In some embodiments, the cancer is a multiple myeloma (MM), which may be relapsed or refractory MM. The MM may be, e.g., typical MM (e.g., immunoglobulin G (IgG) MM, IgA MM, IgD MM, IgE MM, or IgM MM), light chain MM (LCMM) (e.g., lambda light chain MM or kappa light chain MM), or non-secretory MM. The MM may have one or more cytogenetic features (e.g., high-risk cytogenic features), e.g., t(4; 14), t(l 1 ; 14), t(l 4; 16), and/or del( 17p), as described in the International Myeloma Working Group (IMWG) criteria provided in Sonneveld et al., Blood, 127(24): 2955-2962, 2016, and/or 1 q21 , as described in Chang et ah, Bone Marrow Transplantation, 45: 1 17-121 , 2010. Cytogenic features may be detected, e.g., using fluorescent in situ hybridization (FISH).

[0403] The subjects can have an advanced form of disease (e.g., multiple myeloma), in which case the treatment objective can include mitigation or reversal of disease progression, and /or amelioration of side effects. The subjects can have a history of the condition, for which they have already been treated, in which case the therapeutic objective will typically include a decrease or delay in the risk of recurrence.

[0404] In some aspects of any of the methods described herein, the MM is a relapsed or refractory (R/R) MM. In some aspects, the individual has received at least three prior lines of treatment for the MM. In some aspects, the individual has received at least four prior lines of treatment for the MM. In some aspects, the individual has been exposed to a prior treatment comprising a proteasome inhibitor, an IMiD, and/or an anti-CD38 therapeutic agent. In some aspects, the proteasome inhibitor is bortezomib, carfilzomib, or ixazomib. In some aspects, the IMiD is thalidomide, lenalidomide, or pomalidomide. In some aspects, the anti-CD38 therapeutic agent is an anti-CD38 antibody. In some aspects, the anti-CD38 antibody is daratumumab, MOR202, or isatuximab. In some aspects, the anti-CD38 antibody is daratumumab. In some aspects, the individual has been exposed to a prior treatment comprising an anti-SLAMF7 therapeutic agent, a nuclear export inhibitor, a histone deacetylase (HD AC) inhibitor, an autologous stem cell transplant (ASCT), a bispecific antibody, an antibody-drug conjugate (ADC), a CAR-T cell therapy, or a BCMA-directed therapy. In some aspects, the anti-SLAMF7 therapeutic agent is an anti-SLAMF7 antibody. In some aspects, the anti-SLAMF7 antibody is elotuzumab. In some aspects, the nuclear export inhibitor is selinexor. In some aspects, the HD AC inhibitor is panobinostat. In some aspects, the BCMA-directed therapy is an antibody-drug conjugate targeting BCMA, a T-cell engager targeting BCMA, or a CAR T therapy targeting BCMA.

[0405] Any suitable method or route can be used to administer a presently disclosed FcRH5 binding molecules. Routes of administration include, for example, oral, intravenous, intraperitoneal, subcutaneous, or intramuscular administration. It should be emphasized, however, that the presently disclosed subject matter is not limited to any particular method or route of administration.

[0406] In some embodiments, the binding molecule, such as an anti-FcRH5/anti-CD3 bispecific antibody that binds to FcRH5 and CD3, is administered to a subject in an effective amount from 0.01 mg and 200 mg. In some embodiments, the dose is from about 0.05 mg to about 180 mg, such as from about 0.1 mg to about 160 mg, from about 0.5 mg to about 140 mg, from about 1 mg to about 120 mg, from about 1 .5 mg to about 100 mg, from about 2.0 mg to about 80 mg, from about 2.5 mg to about 50 mg, from about 3.0 mg to about 25 mg, from about 3.0 mg to about 15 mg, from about 3.0 mg to about 10 mg, or from about 3.0 mg to about 5 mg. The dose can be administered one or more times in a dosing cycle. In some embodiments, the dosing cycle is two weeks or 14 days. In some embodiments, the dosing cycle is three weeks or 21 days. In some embodiments, the dosing cycle is four weeks or 28 days. In some embodiments, the dosing cycle is six weeks or 42 days. In some embodiments, the binding molecule, such as an anti-FcRH5/anti-CD3 bispecific antibody that binds to FcRH5 and CD3, is administered daily, two times a week, three times a week, or once a week. In some embodiments, binding molecule, such as an anti-FcRH5/anti-CD3 bispecific antibody that binds to FcRH5 and CD3, is administered once a week in a dosing cycle.

[0407] In some embodiments, administration of the molecules (e.g., FcRH5-binding molecules, including bispecific antibodies), cells (e.g., engineered cells), or compositions containing the same are administered until progressive disease is observed or until minimal residual disease (MRD) is observed.

A. Combination Therapies

[0408] In some embodiments, the provided molecules (e.g., FcRH5-binding molecules, including bispecific antibodies), cells (e.g., engineered cells), or compositions containing the same are administered to the subject in a combination therapy. For example, the bispecific anti-FcRH5/anti- CD3 antibody may be administered with one or more additional agents.

[0409] In certain embodiments, the presently disclosed subject matter provides a method of treating a cancer, e.g., a tumor, by administering a presently disclosed FcRH5 binding molecules and, optionally, in combination with one or more other agents. “In combination with” or “in conjunction with,” as used interchangeably herein, means that the FcRH5 binding molecule and the other agent are administered to a subject as part of a treatment regimen or plan. In certain embodiments, being used in combination does not require that the FcRH5 binding molecule and the other agent are physically combined prior to administration or that they be administered over the same time frame. For example, and not by way of limitation, the FcRH5 binding molecule and the other agent can be administered concurrently to the subject being treated, or can be administered at the same time or sequentially in any order or at different points in time. [0410] In some embodiments, provided molecules (e.g., FcRH5-binding molecules, including bispecific antibodies), cells (e.g., engineered cells), or compositions containing the same described herein are administered as part of a combination treatment or combination therapy, such as simultaneously with, sequentially with or intermittently with, in any order, one or more additional therapeutic intervention. In some embodiments, the one or more additional therapeutic interventions includes administering one or more agents, such as a cytotoxic agent or chemotherapeutic agent, immunomodulatory agent, immune checkpoint inhibitor, adenosine pathway or adenosine receptor antagonist or agonist or a kinase inhibitor. In some embodiments, the one or more additional therapeutic interventions include a surgical treatment, transplant or radiation therapy.

[0411] In some embodiments, the additional agent for combination treatment or combination therapy enhances, boosts and/or promotes the efficacy and/or safety of the therapeutic effect of the FcRH5-binding molecules, including bispecific antibodies, engineered cells (e.g., CAR-expressing cells) and/or compositions. In some embodiments, the additional agent is selected from among a protein phosphatase inhibitor, a kinase inhibitor, a cytokine, an immunomodulator, or an agent that decreases the level or activity of a regulatory T (Treg) cell. In some embodiments, the additional agent enhances safety, by virtue of reducing or ameliorating adverse effects of the administered FcRH5-binding molecules, including bispecific antibodies, engineered cells and/or compositions. In some embodiments, the additional agent can treat the same disease, condition or a comorbidity. In some embodiments, the additional agent can ameliorate, reduce or eliminate one or more toxicities, adverse effects or side effects that are associated with administration of the FcRH5 -binding molecules, including bispecific antibodies, engineered cells and/or compositions.

[0412] In some embodiments, the additional therapy, treatment or agent includes chemotherapy, radiation therapy, surgery, transplantation, adoptive cell therapy, antibodies, cytotoxic agents, chemotherapeutic agents, cytokines, growth inhibitory agents, anti-hormonal agents, kinase inhibitors, anti-angiogenic agents, cardioprotectants, immunostimulatory agents, immunosuppressive agents, immune checkpoint inhibitors, antibiotics, angiogenesis inhibitors, metabolic modulators or other therapeutic agents or any combination thereof. In some embodiments, the additional agent is a protein, a peptide, a nucleic acid, a small molecule agent, a cell, a toxin, a lipid, a carbohydrate or combinations thereof, or any other type of therapeutic agent, e.g. radiation. In some embodiments, the additional therapy, agent or treatment includes surgery, chemotherapy, radiation therapy, transplantation, administration of cells expressing a recombinant receptor, e.g., CAR, kinase inhibitor, immune checkpoint inhibitor, mTOR pathway inhibitor, immunosuppressive agents, immunomodulators, antibodies, immunoablative agents, antibodies and/or antigen binding fragments thereof, antibody conjugates, other antibody therapies, cytotoxins, steroids, cytokines, peptide vaccines, hormone therapy, antimetabolites, metabolic modulators, drugs that inhibit either the calcium dependent phosphatase calcineurin or the p70S6 kinase FK506) or inhibit the p70S6 kinase, alkylating agents, anthracyclines, vinca alkaloids, proteasome inhibitors, GITR agonists, protein tyrosine phosphatase inhibitors, protein kinase inhibitors, an oncolytic virus, and/or other types of immunotherapy. In some embodiments, the additional agent or treatment is bone marrow transplantation, T cell ablative therapy using chemotherapy agents such as, fludarabine, external-beam radiation therapy (XRT), cyclophosphamide, and/or antibody therapy.

[0413] In some embodiments, the additional agent is a structural or functional analog or derivative of thalidomide and/or an inhibitor of E3 ubiquitin ligase. In some embodiments, the immunomodulatory agent binds to cereblon (CRBN). In some embodiments, the immunomodulatory agent binds to the CRBN E3 ubiquitin-ligase complex. In some embodiments, the immunomodulatory agent binds to CRBN and the CRBN E3 ubiquitin-ligase complex. In some embodiments, the immunomodulatory agent up-regulates the protein or gene expression of CRBN. In some aspects, CRBN is the substrate adaptor for the CRL4 ^CRBN E3 ubiquitin ligase, and modulates the specificity of the enzyme. In some embodiments, binding to CRB or the CRBN E3 ubiquitin ligase complex inhibits E3 ubiquitin ligase activity. In some embodiments, the immunomodulatory agent induces the ubiquitination of KZF1 (Ikaros) and IKZF3 (Aiolos) and/or induces degradation of IKZF1 (Ikaros) and IKZF3 (Aiolos). In some embodiments, the immunomodulatory agent induces the ubiquitination of casein kinase 1A1 (CKla) by the CRL4 ^CRBN E3 ubiquitin ligase. In some embodiments, the ubiquitination of CKla results in CKla degradation.

[0414] In some embodiments, the additional agent is an inhibitor of the Ikaros (IKZF1) transcription factor. In some embodiments, the additional agent enhances ubiquitination of Ikaros. In some embodiments, the additional agent enhances the degradation of Ikaros. In some embodiments, the additional agent down-regulates the protein or gene expression of Ikaros. In some embodiments, administration of the additional agent causes a decrease in Ikaros protein levels.

[0415] In some embodiments, the additional agent is an inhibitor of the Aiolos (IKZF3) transcription factor. In some embodiments, the additional agent enhances ubiquitination of Aiolos. In some embodiments, the additional agent enhances the degradation of Aiolos. In some embodiments, the additional agent down-regulates the protein or gene expression of Aiolos. In some embodiments, administration of the additional agent causes a decrease in Aiolos protein levels.

[0416] In some embodiments, the additional agent is an inhibitor of both the Ikaros (IKZF1) and Aiolos (IKZF3) transcription factors. In some embodiments, the additional agent enhances ubiquitination of both Ikaros and Aiolos. In some embodiments, the additional agent enhances the degradation of both Ikaros and Aiolos. In some embodiments, the additional agent enhances ubiquitination and degradation of both Ikaros and Aiolos. In some embodiments, administration of the additional agent causes both Aiolos protein levels and Ikaros protein levels to decrease.

[0417] In some embodiments the additional agent is a thalidomide derivative. Thalidomide derivatives relate to 2-(2,6-dioxopiperidin-3-yl)-2,3 dihydro-IHisoindole-1, 3-dione and immunotherapeutic derivatives thereof such as, but not limited todenalidomide (3-(4-amino- 1-oxo- 2,3-dihydro- 1 H-isoindol-2-yl) piperidine-2, 6-dione; CAS Registry Number 191732-72-6); pomalidomide (4-amino-2-(2,6-dioxopiperidine-3-yl)isoindoline-l, 3-dione, CAS Registry Number 19171-19-8); iberdomide ((S)-3-(4-((4-20 (morpholinomethyl)benzyl)oxy)-l-oxotsoindolin-2- yl)piperidtne-2,6-dtone; CAS Registry Number 1323403-33-3); avadomide (3-(5-amino-2-methyl-4- oxo-3, 4-dihydroquinazolin-3-yl)piperidine-2, 6-dione; CAS Registry Number 1398053-45-6), and the respective salts (preferably HC1 salts 1:1). Thalidomide denvatives are IMiD or CeLMoD agents that modulate Cereblon. In some embodiments, the thalidomide derivative is pomalidomide, lenalidomide, iberdomide, avadomide, mezigdomide or a combination thereof.

[0418] In some embodiments, the immunomodulatory agent is lenalidomide (Revlimid®) (3-(4- amino-1 -oxo- l,3-dihydro-2H-isoindol-2-yl)piperidine-2, 6-dione; CAS Registry Number 191732-72- 6) or a pharmaceutically acceptable salt thereof. The structure of lenalidomide is as follows:

[0420] In some embodiments, the immunomodulatory agent is pomalidomide (Pomalyst® or Imnovid®) (4-amino-2-(2,6-dioxopiperidin-3-yl)isoindole- 1,3-dione; CAS Registry Number 19171- 19-8) or a pharmaceutically acceptable salt thereof. The structure of pomalidomide is as follows:

[0422] In some embodiments, the immunomodulatory agent is iberdomide ((S)-3-[4-(4- morpholin-4-ylmethyl-benzyloxy)-l-oxo-l,3-dihydro-isoindol-2 -yl]-piperidine-2, 6-dione; CAS Registry Number 1323403-33-3) or a pharmaceutically acceptable salt thereof. The structure of iberdomide is as follows:

[0424] In some embodiments, the immunomodulatory agent is mezigdomide (S)-4-(4-(4-(((2- (2,6-dioxopiperidin-3-yl)- 1 -oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin- 1 -yl)-3- fluorobenzonitrile CAS Registry Number 2259648-80-9) or a pharmaceutically acceptable salt thereof. Mezigdomide is a CELMoD agent, also referred to as CC-92480. The structure of mezgidomide is as follows: [0425]

[0426] In some embodiments, the additional agent is an immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor is a molecule that totally or partially reduces, inhibits, interferes with or modulates one or more checkpoint proteins. Checkpoint proteins regulate T-cell activation or function. These proteins are responsible for co-stimulatory or inhibitory interactions of T-cell responses. Immune checkpoint proteins regulate and maintain self-tolerance and the duration and amplitude of physiological immune responses. In some embodiments, the immune checkpoint inhibitor can enhance or boost the immune response in the subject.

[0427] Immune checkpoint inhibitors include any agent that blocks or inhibits the inhibitory pathways of the immune system. Such inhibitors may include small molecule inhibitors or may include antibodies, or antigen binding fragments thereof, that bind to and block or inhibit immune checkpoint receptors, ligands and/or receptor-ligand interaction. In some embodiments, modulation, enhancement and/or stimulation of particular receptors can overcome immune checkpoint pathway components. Illustrative immune checkpoint molecules that may be targeted for blocking, inhibition, modulation, enhancement and/or stimulation include, but are not limited to, PD-1 (CD279), PD-L1 (CD274, B7-H1), PDL2 (CD273, B7-DC), CTLA-4, LAG-3 (CD223), TIM-3, 4-1BB (CD137), 4- 1BBL (CD137L), GITR (TNFRSF18, AITR), CD40, 0X40 (CD134, TNFRSF4), CXCR2, tumor associated antigens (TAA), B7-H3, B7-H4, BTLA, HVEM, GAL9, B7H3, B7H4, VISTA, KIR, 2B4 (belongs to the CD2 family of molecules and is expressed on all NK, y5, and memory CD8+ (a ) T cells), CD160 (also referred to as BY55), CGEN-15049, CEACAM (e.g., CEACAM-1, CEACAM-3 and/or CEACAM-5), TIGIT, LAIR1, CD160, 2B4, CD80, CD86, B7-H3 (CD276), B7-H4 (VTCN1), HVEM (TNFRSF14 or CD270), KIR, A2aR, MHC class I, MHC class II, GAL9, adenosine, and a transforming growth factor receptor (TGFR; e.g., TGFR beta). Immune checkpoint inhibitors include antibodies, or antigen binding fragments thereof, or other binding proteins that bind to and block or inhibit and/or enhance or stimulate the activity of one or more of any of the said molecules.

[0428] Exemplary immune checkpoint inhibitors include Tremelimumab (CTLA-4 blocking antibody, also known as ticilimumab, CP-675,206), anti-OX40, PD-L1 monoclonal antibody (Anti- B7-H1; MEDI4736), MK-3475 (PD-1 blocker), nivolumab (anti-PD-1 antibody), CT-011 (anti-PD-1 antibody), BY55 monoclonal antibody, AMP224 (anti-PD-Ll antibody), BMS-936559 (anti-PD-Ll antibody), MPLDL3280A (anti-PD-Ll antibody), MSB0010718C (anti-PD-Ll antibody) and ipilimumab (anti-CTLA-4 antibody, also known as Yervoy®, MDX-010 and MDX-101). Exemplary of immunomodulatory antibodies include, but are not limited to, Daclizumab (Zenapax), Bevacizumab (Avastin ®), Basiliximab, Ipilimumab, Nivolumab, pembrolizumab, MPDL3280A, Pidilizumab (CT-011), MK-3475, BMS-936559, MPDL3280A (Atezolizumab), tremelimumab, IMP321, BMS-986016, LAG525, urelumab, PF-05082566, TRX518, MK-4166, dacetuzumab (SGN- 40), lucatumumab (HCD122), SEA-CD40, CP-870, CP-893, MEDI6469, MEDI6383, MOXR0916, AMP-224, MSB0010718C (Avelumab), MEDI4736, PDR001, rHIgM12B7, Ulocuplumab, BKT140, Varlilumab (CDX-1127), ARGX-110, MGA271, lirilumab (BMS-986015, IPH2101), IPH2201, ARGX-115, Emactuzumab, CC-90002 and MNRP1685A or an antibody-binding fragment thereof. Other exemplary immunomodulators include, e.g., afutuzumab (available from Roche®); pegfilgrastim (Neulasta®); lenalidomide (CC-5013, Revlimid®); thalidomide (Thalomid®), actimid (CC4047); and IRX-2 (mixture of human cytokines including interleukin 1, interleukin 2, and interferon .gamma., CAS 951209-71-5, available from IRX Therapeutics).

[0429] In some embodiments, the additional agent is a chemotherapeutic agent (sometimes referred to as a cytotoxic agent). In particular embodiments, the chemotherapeutic agent is any agent known to those of skill in the art to be effective for the treatment, prevention or amelioration of hyperproliferative disorders such as cancer. Chemotherapeutic agents include, but are not limited to, small molecules, synthetic drugs, peptides, polypeptides, proteins, nucleic acids (e.g., DNA and RNA polynucleotides including, but not limited to, antisense nucleotide sequences, triple helices and nucleotide sequences encoding biologically active proteins, polypeptides or peptides), antibodies, synthetic or natural inorganic molecules, mimetic agents, and synthetic or natural organic molecules. In particular embodiments, chemotherapeutic drugs include alkylating agents, anthracy clines, cytoskeletal disruptors (taxanes), epothilones, histone deacetylase inhibitors, topoisomerase inhibitors, topoisomerase II inhibitors, kinase inhibitors, nucleotide analogs and precursor analogs, peptide antibiotics, platinum-based agents, and vinca alkaloids and derivatives.

[0430] Chemotherapeutic agents may include, but are not limited to, abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, amifostine, anastrozole, arsenic trioxide, asparaginase, BCG live, bevaceizumab, bexarotene, bleomycin, bortezomib, busulfan, calusterone, camptothecin, capecitabine, carboplatin, carmustine, celecoxib, cetuximab, chlorambucil, cinacalcet, cisplatin, cladribine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, darbepoetin alfa, daunorubicin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolone, Elliott's B solution, epirubicin, epoetin alfa, estramustine, etoposide, exemestane, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gemcitabine, gemtuzumab ozogamicin, gefitinib, goserelin, hydroxyurea, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib, interferon alfa-2a, interferon alfa-2b, irinotecan, letrozole, leucovorin, levamisole, lomustine, meclorethamine, megestrol, melphalan, mercaptopurine, mesna, methotrexate, methoxsalen, methylprednisolone, mitomycin C, mitotane, mitoxantrone, nandrolone, nofetumomab, oblimersen, oprelvekin, oxaliplatin, paclitaxel, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed, pentostatin, pipobroman, plicamycin, polifeprosan, porfimer, procarbazine, quinacrine, rasburicase, rituximab, sargramostim, streptozocin, talc, tamoxifen, tarceva, temozolomide, teniposide, testolactone, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, and zoledronate.

[0431] In some examples, the one or more additional agents are administered subsequent to or prior to the administration of the FcRH5 -binding molecules, including bispecific antibodies, engineered cells (e.g., CAR-expressing cells) and/or compositions described herein, such as separated by a selected time period. In some examples, the time period is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, or 3 months. For example, in some embodiments, the additional agent is first administered prior to the administration of the FcRH5-binding molecules, including bispecific antibodies, engineered cells (e.g., CAR-expressing cells) and/or compositions described herein, e.g., two weeks, 12 days, 10 days, 8 days, one week, 6 days, 5 days, 4 days, 3 days, 2 days or 1 day before the administration. For example, in some embodiments, the additional agent is first administered after the administration of the FcRH5 -binding molecules, including bispecific antibodies, engineered cells (e.g., CAR-expressing cells) and/or compositions described herein, e.g., two weeks, 12 days, 10 days, 8 days, one week, 6 days, 5 days, 4 days, 3 days, 2 days or 1 day after the administration.

[0432] The dose of the additional agent can be any therapeutically effective amount. Therapeutically effective doses of any of the above described agents are known or can be empirically determined by a skilled artisan. The one or more additional agents can be administered to the patient at one time, repeated or administered over a series of treatments.

VI. ARTICLES OF MANUFACTURE OR KITS

[0433] Also provided are articles of manufacture or kits containing the provided binding molecules (e.g., antibodies including bispecific antibodies) or engineered cells incorporating a binding molecule containing the same (e.g., CARs). In some embodiments, the articles of manufacture or kits contain any of the provided compositions. The articles of manufacture may include a container and a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, test tubes, IV solution bags, etc. The containers may be formed from a variety of materials such as glass or plastic. In some embodiments, the container has a sterile access port. Exemplary containers include an intravenous solution bags, vials, including those with stoppers pierceable by a needle for injection. The article of manufacture or kit may further include a package insert indicating that the compositions can be used to treat a particular condition such as a condition described herein (e.g., FcRH5-expressing cancer). Alternatively, or additionally, the article of manufacture or kit may further include another or the same container comprising a pharmaceutically- acceptable buffer. It may further include other materials such as other buffers, diluents, filters, needles, and/or syringes.

[0434] The label or package insert may indicate that the composition is used for treating the FcRH5-expressing or FcRH5-associated disease, disorder or condition in an individual. The label or a package insert, which is on or associated with the container, may indicate directions for reconstitution and/or use of the formulation. The label or package insert may further indicate that the formulation is useful or intended for subcutaneous, intravenous, or other modes of administration for treating or preventing a FcRH5 -expressing or FcRH5-associated disease, disorder or condition in an individual. In some aspects, the label or package insert can include instructions for use, for example instructions for administering the antibody or antigen-binding fragment thereof, the single chain cell surface protein, the conjugate, the chimeric antigen receptor, the cell or the composition, in some aspects in accord with any of the methods or uses described herein.

[0435] The container in some embodiments holds a composition which is by itself or combined with another composition effective for treating, preventing and/or diagnosing the condition. The article of manufacture or kit may include (a) a first container with a composition contained therein first medicament), wherein the composition includes the binding molecule (e.g., anti-FcRH5 antibody including a bispecific antibody) or engineered cells incorporating a chimeric molecule including the same (e.g. CAR); and (b) a second container with a composition contained therein. In some aspects, the article or kit further comprises instructions on the label or package insert for treating the subject in an effective amount.

VII. DEFINITIONS

[0436] Unless defined otherwise, all terms of art, notations and other technical and scientific terms or terminology used herein are intended to have the same meaning as is commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and/or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art.

[0437] As used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly indicates otherwise.

[0438] The term “about” as used herein refers to the usual error range for the respective value readily known to the skilled person in this technical field. Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”.

[0439] As used herein, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. For example, “a” or “an” means “at least one” or “one or more.” It is understood that aspects, embodiments, and variations described herein include “comprising,” “consisting,” and/or “consisting essentially of’ aspects, embodiments and variations.

[0440] Throughout this disclosure, various aspects of the claimed subject matter are presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the claimed subject matter. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range. For example, where a range of values is provided, it is understood that each intervening value, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the claimed subject matter. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the claimed subject matter, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the claimed subject matter. This applies regardless of the breadth of the range.

[0441] As used herein, reference to a “corresponding form” of an antibody means that when comparing a property or activity of two antibodies, the property is compared using the same form of the antibody. For example, if it is stated that an antibody has greater activity compared to the activity of the corresponding form of a first antibody, that means that a particular form, such as a Fab of that antibody, has greater activity compared to the Fab form of the first antibody.

[0442] The term “bispecific antibody” refers to an antibody which has two different antigenbinding specificities. In some embodiments, a bispecific antibody has two different antigen-binding regions defined by different antibody sequences. Where an antibody has more than one specificity, the recognized epitopes may be associated with a single antigen or with more than one antigen.

[0443] The term “valent” denotes the presence of a specified number of binding sites in an antibody molecule. A natural antibody for example or a full length antibody according to the invention has two binding sites and is bivalent.

[0444] The term “monovalent antibody” means that an antibody molecule has a single binding site for binding a single molecule of the antigen. Typically a monovalent antibody is not capable of antigen crosslinking.

[0445] The term “trivalent” denotes the presence of three binding sites in an antibody molecule. The term “trivalent, bispecific” antibody as used herein denotes an antibody that has three antigenbinding sites of which two bind to the same antigen (or the same epitope of the antigen) and the third binds to a different antigen or a different epitope of the same antigen.

[0446] The term "Fc region" herein is used to define a C -terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. The term includes native sequence Fc regions and variant Fc regions. In one embodiment, a human IgG heavy chain Fc region extends from Cys226, or from Pro230, to the carboxyl-terminus of the heavy chain. However, the C -terminal lysine (Lys447) of the Fc region may or may not be present. Unless otherwise specified herein, numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also called the EU index, as described in Kabat et ah, Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health. Bethesda. Md., 1991. [0447] ‘ ‘Effector functions” refer to those biological activities attributable to the Fc region of an antibody, which vary with the antibody isotype. Examples of antibody effector functions include: Clq binding and complement dependent cytotoxicity (CDC); Fc receptor binding; antibodydependent cell-mediated cytotoxicity (ADCC); phagocytosis; down regulation of cell surface receptors (e.g. B cell receptor); and B cell activation.

[0448] The terms “full length antibody,” “intact antibody,” and “whole antibody” are used herein interchangeably to refer to an antibody having a structure substantially similar to a native antibody structure or having heavy chains that contain an Fc region as defined herein.

[0449] An “isolated” antibody is one which has been separated from a component of its natural environment. In some embodiments, an antibody is purified to greater than 95% or 99% purity as determined by, for example, electrophoretic e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatographic (e.g., ion exchange or reverse phase HPEC). For review of methods for assessment of antibody purity, see, e.g., Flatman et al., J. Chromatogr. B 848:79-87 (2007).

[0450] An “isolated” nucleic acid refers to a nucleic acid molecule that has been separated from a component of its natural environment. An isolated nucleic acid includes a nucleic acid molecule contained in cells that ordinarily contain the nucleic acid molecule, but the nucleic acid molecule is present extrachromosomally or at a chromosomal location that is different from its natural chromosomal location.

[0451] The terms “nucleic acid molecule”, “nucleic acid”, “sequence of nucleotides”, and “polynucleotide” may be used interchangeably, and refer to a polymer of nucleotides. Such polymers of nucleotides may contain natural and/or non-natural nucleotides, and include, but are not limited to, DNA, RNA, and PNA. “Nucleic acid sequence” refers to the linear sequence of nucleotides that comprise the nucleic acid molecule or polynucleotide.

[0452] The terms “polypeptide” and “protein” are used interchangeably to refer to a polymer of amino acid residues, and are not limited to a minimum length. Polypeptides, including the provided antibodies and antibody chains and other peptides, e.g., linkers and FcRH5-binding peptides, may include amino acid residues including natural and/or non-natural amino acid residues. The terms also include post-expression modifications of the polypeptide, for example, glycosylation, sialylation, acetylation, phosphorylation, and the like. In some aspects, the polypeptides may contain modifications with respect to a native or natural sequence, as long as the protein maintains the desired activity. These modifications may be deliberate, as through site-directed mutagenesis, or may be accidental, such as through mutations of hosts which produce the proteins or errors due to PCR amplification.

[0453] The terms “host cell,” “host cell line,” and “host cell culture” are used interchangeably and refer to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells. Host cells include “transformants” and “transformed cells,” which include the primary transformed cell and progeny derived therefrom without regard to the number of passages. Progeny may not be completely identical in nucleic acid content to a parent cell, but may contain mutations. Mutant progeny that have the same function or biological activity as screened or selected for in the originally transformed cell are included herein.

[0454] As used herein, “percent (%) amino acid sequence identity” and “percent identity” and “sequence identity” when used with respect to an amino acid sequence (reference polypeptide sequence) is defined as the percentage of amino acid residues in a candidate sequence (e.g., the subject antibody or fragment) that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Appropriate parameters for aligning sequences can be determined, including using any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.

[0455] In some aspects, corresponding positions of the one or more modifications, such as one or more substitutions, can be determined in reference to positions of a reference amino acid sequence or a reference nucleotide sequence. As used herein, recitation that nucleotides or amino acid positions “correspond to” nucleotides or amino acid positions in a disclosed sequence, such as set forth in the Sequence listing, refers to nucleotides or amino acid positions identified upon alignment with the disclosed sequence to maximize identity using a standard alignment algorithm, such as the GAP algorithm or other available algorithms. By aligning the sequences, corresponding residues can be identified, for example, using conserved and identical amino acid residues as guides. In general, to identify corresponding positions, the sequences of amino acids are aligned so that the highest order match is obtained (see, e.g., Computational Molecular Biology, Lesk, A.M., ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith, D.W., ed., Academic Press, New York, 1993; Computer Analysis of Sequence Data, Part I, Griffin, A.M., and Griffin, H.G., eds., Humana Press, New Jersey, 1994; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; and Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., M Stockton Press, New York, 1991; Carrillo et al. (1988) SIAM J Applied Math 48: 1073). Alignment for determining corresponding positions can be obtained in various ways, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Appropriate parameters for aligning sequences can be determined, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. For example, corresponding residues can be determined by alignment of a reference sequence that is a wild-type Cas protein by available alignment methods. By aligning the sequences, one skilled in the art can identify corresponding residues, for example, using conserved and/or identical amino acid residues as guides.

[0456] An amino acid substitution may include replacement of one amino acid in a polypeptide with another amino acid. The substitution may be a conservative amino acid substitution or a nonconservative amino acid substitution. Amino acid substitutions may be introduced into a binding molecule, e.g., antibody, of interest and the products screened for a desired activity, e.g., retained/improved antigen-binding, decreased immunogenicity, or improved ADCC or CDC.

[0457] Amino acids generally can be grouped according to the following common side-chain properties:

(1) hydrophobic: Norleucine, Met, Ala, Vai, Leu, He;

(2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gin;

(3) acidic: Asp, Glu;

(4) basic: His, Lys, Arg;

(5) residues that influence chain orientation: Gly, Pro;

(6) aromatic: Trp, Tyr, Phe.

[0458] In some embodiments, conservative substitutions can involve the exchange of a member of one of these classes for another member of the same class. In some embodiments, nonconservative amino acid substitutions can involve exchanging a member of one of these classes for another class.

[0459] The term “vector,” as used herein, refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. The term includes the vector as a selfreplicating nucleic acid structure as well as the vector incorporated into the genome of a host cell into which it has been introduced. Certain vectors are capable of directing the expression of nucleic acids to which they are operatively linked. Such vectors are referred to herein as “expression vectors.”

[0460] The term “package insert” is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, combination therapy, contraindications and/or warnings concerning the use of such therapeutic products.

[0461] A “pharmaceutically acceptable carrier” refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to a subject. A pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative.

[0462] As used herein, a “composition” refers to any mixture of two or more products, substances, or compounds, including cells. It may be a solution, a suspension, liquid, powder, a paste, aqueous, non-aqueous or any combination thereof.

[0463] As used herein, a statement that a cell or population of cells is “positive” for a particular marker refers to the detectable presence on or in the cell of a particular marker, typically a surface marker. When referring to a surface marker, the term refers to the presence of surface expression as detected by flow cytometry, for example, by staining with an antibody that specifically binds to the marker and detecting the antibody, wherein the staining is detectable by flow cytometry at a level substantially above the staining detected carrying out the same procedure with an isotype-matched control under otherwise identical conditions and/or at a level substantially similar to that for cell known to be positive for the marker, and/or at a level substantially higher than that for a cell known to be negative for the marker.

[0464] As used herein, a statement that a cell or population of cells is “negative” for a particular marker refers to the absence of substantial detectable presence on or in the cell of a particular marker, typically a surface marker. When referring to a surface marker, the term refers to the absence of surface expression as detected by flow cytometry, for example, by staining with an antibody that specifically binds to the marker and detecting the antibody, wherein the staining is not detected by flow cytometry at a level substantially above the staining detected carrying out the same procedure with an isotype-matched control under otherwise identical conditions, and/or at a level substantially lower than that for cell known to be positive for the marker, and/or at a level substantially similar as compared to that for a cell known to be negative for the marker.

VIII. EXEMPLARY EMBODIMENTS

[0465] Among the provided embodiments are:

[0466] 1. A bispecific antibody comprising two anti- Fc receptor-like protein 5 (FcRH5) binding region, one anti-CD3 binding region and a heterodimeric Fc, wherein: each anti-FcRH5 binding region is a Fab comprising a first heavy chain variable region (VH1) and a heavy chain constant region 1 (CHI), and a light chain (LC) comprising a light chain variable region (VL) and a light chain constant region (CL); the anti-CD3 binding region is a Fab comprising a second heavy chain variable region (VH2) and a CHI, and the LC comprising the VL and the CL; the LC is a common light chain, wherein the LC of each binding region has the same sequence and is associated with each VH1-CH1 and with the VH2-CH1; the VH1-CH1 of one anti-FcRH5 binding region is comprised in a first heavy chain (HCl);the VH1-CH1 of the other anti-FcRH5 binding region and the VH2-CH2 of the anti-CD3 binding region is comprised in a second heavy chain (HC2); and the heterodimeric Fc comprises a first and second polypeptide each comprising a hinge-CH2-CH3, wherein the first polypeptide of the heterodimeric Fc is linked to the VH-CH1 of the HC1 and the second polypeptide of the heterodimeric Fc is linked to the VH2-CH1 of HC2.

[0467] 2. The bispecific antibody of embodiment 1 , wherein the bispecific antibody comprises: (a) a first polypeptide that is the HC1 comprising a first amino acid sequence having the formula: VH1-CH1 and a second amino acid sequence having the formula: hinge-CH2-CH3; (b) a second polypeptide that is the HC2 comprising a first amino acid sequence having the formula: VH1- CH1, a second amino acid sequence having the formula: VH2-CH1 and a third amino acid sequence having the formula: hinge-CH2-CH3; and(c) a third, fourth and fifth polypeptide that is the common light chain (LC) comprising an amino acid sequence having the formula: VL-CL. [0468] 3. The bispecific antibody of embodiment 1 or embodiment 2, wherein: the LC comprises a VL comprising a complementarity determining region 1 (CDRL1) set forth in SEQ ID NO: 81, a CDRL2 set forth in SEQ ID NO: 82 and a CDRL3 set forth in SEQ ID NO: 83; or the LC comprises a VL comprising a CDRL1 set forth in SEQ ID NO: 81, a CDRL2 set forth in SEQ ID NO:82 and a CDRL3 set forth in SEQ ID NO: 100.

[0469] 4. The bispecific antibody of any of embodiments 1-3, wherein the VL comprises a sequence of amino acids that exhibits at least 85%, at least 90% or at least 95% sequence identity to SEQ ID NO:31.

[0470] 5. The bispecific antibody of any of embodiments 1-4, wherein the VL comprises the sequence of amino acids set forth in SEQ ID NO:31.

[0471] 6. The bispecific antibody of any of embodiments 1-3, wherein the VL comprises a sequence of amino acids that exhibits at least 85%, at least 90% or at least 95% sequence identity to SEQ ID NO:99.

[0472] 7. The bispecific antibody of any of embodiments 1-3 and 6, wherein the VL comprises the sequence of amino acids set forth in SEQ ID NO:99.

[0473] 8. The bispecific antibody of any of embodiments 1-7, wherein the LC comprises a sequence of amino acids that exhibits at least 85%, at least 90% or at least 95% sequence identity to SEQ ID NO: 102.

[0474] 9. The bispecific antibody of any of embodiments 1-3 and 6-8, wherein the LC comprises the sequence of amino acids set forth in SEQ ID NO: 102.

[0475] 10. The bispecific antibody of any of embodiments 1-9, wherein one of the anti-FcRH5 binding region is fused to the anti-CD3 binding region.

[0476] 11. The bispecific antibody of embodiment 10, wherein the regions are fused indirectly via a linker.

[0477] 12. The bispecific antibody of embodiment 11, wherein the linker is a peptide linker.

[0478] 13. The bispecific antibody of embodiment 11 or embodiment 12, wherein the linker is a GS linker of 5-20 amino acids.

[0479] 14. The bispecific antibody of any of embodiments 11-13, wherein the linker comprises GGGGSGGGGS (SEQ ID NO:91).

[0480] 15. The bispecific antibody of any of embodiments 11-14, wherein the linker further comprises a partial hinge sequence at the N-terminus of the peptide linker to allow the anti-FcRH5 binding region to associate with the LC.

[0481] 16. The bispecific antibody of embodiment 15, wherein the partial hinge sequence is EPKSCD (SEQ ID NO: 85).

[0482] 17. A bispecific antibody comprising a first binding region that binds to Fc receptor-like protein 5 (FcRH5), a second binding region that binds to FcRH5 and a third binding region that binds to CD3, wherein the bispecific antibody comprises: (a) a first heavy chain (HC1) comprising a first amino acid sequence having the formula: VH1-CH1 and a second amino acid sequence having the formula: hinge-CH2-CH3; (b) a second heavy chain (HC2) comprising a first amino acid sequence having the formula: VH1-CH1, a second amino acid sequence having the formula: VH2-CH1 and a third amino acid sequence having the following formula: hinge-CH2-CH3; (c) a first light chain (LC1) comprising an amino acid sequence having the following formula: VL-CL; (d) a second light chain (LC2) comprising an amino acid sequence having the following formula: VL-CL; and (e) a third light chain (LC3) comprising an amino acid sequence having the following formula: VL-CL wherein: VH1 is a first heavy chain variable region; VH2 is a second heavy chain variable region; CHI is a heavy chain constant region 1 ; CH2 is a heavy chain constant region 2 and CH3 is a heavy chain constant region 3; VL is a light chain variable region and CL is a light chain constant region; VH1- CH1 of HC1 associates with LC1 to form the first binding region; VH1-CH1 of HC2 associates with LC2 to form the second binding region; and VH2-CH1 of HC2 associates with LC3 to form the third binding region.

[0483] 18. The bispecific antibody of embodiment 17, wherein the hinge-CH2-CH3 of HC1 is a first polypeptide chain of a heterodimeric Fc and the hinge-CH2-CH3 of HC2 is a second polypeptide chain of the heterodimeric Fc.

[0484] 19. The bispecific antibody of embodiment 17 or embodiment 18, wherein each of LC1, LC2 and LC3 is a common light chain that has the same amino acid sequence.

[0485] 20. The bispecific antibody of any of embodiments 17-19, wherein each of the LC1, LC2 and LC2 comprises: a VL comprising a complementarity determining region 1 (CDRL1) set forth in SEQ ID NO: 81, a CDRL2 set forth in SEQ ID NO: 82 and a CDRL3 set forth in SEQ ID NO: 83; or a VL comprising a CDRL1 set forth in SEQ ID NO:81, a CDRL2 set forth in SEQ ID NO:82 and a CDRL3 set forth in SEQ ID NO: 100.

[0486] 21. The bispecific antibody of any of embodiments 17-20, wherein the VL of each of the LC1, LC2 and LC2 comprises a sequence of amino acids that exhibits at least 85%, at least 90% or at least 95% sequence identity to SEQ ID NO:31.

[0487] 22. The bispecific antibody of any of embodiments 17-21, wherein the VL of each of the LC1, LC2 and LC2 comprises the sequence of amino acids set forth in SEQ ID NO:31.

[0488] 23. The bispecific antibody of any of embodiments 17-20, wherein the VL of each of the LC1, LC2 and LC2 comprises a sequence of amino acids that exhibits at least 85%, at least 90% or at least 95% sequence identity to SEQ ID NO: 99.

[0489] 24. The bispecific antibody of any of embodiments 17-20 and 23, wherein the VL of each of the LC1, LC2 and LC2 comprises the sequence of amino acids set forth in SEQ ID NO: 99.

[0490] 25. The bispecific antibody of any of embodiments 17-24, wherein each of the LC1, LC2 and LC2 comprises a sequence of amino acids that exhibits at least 85%, at least 90% or at least 95% sequence identity to SEQ ID NO: 102. [0491] 26. The bispecific antibody of any of embodiments 17-20 and 13-25, wherein each of the LC1, LC2 and LC2 comprises the sequence of amino acids set forth in SEQ ID NO: 102.

[0492] 27. The bispecific antibody of any of embodiments 2-26, wherein the first amino acid sequence VH1-CH1 of HC2 is linked to a partial hinge sequence at its C-terminus to allow the HC2 to associate with the LC2.

[0493] 28. The bispecific antibody of embodiment 27, wherein the partial hinge sequence is EPKSCD (SEQ ID NO: 85).

[0494] 29. The bispecific antibody of embodiment 27 or embodiment 28, wherein the first amino acid sequence of HC2 is fused to the second amino acid sequence of HC2 indirectly via a linker, optionally wherein the linker is linked at the C-terminus of the partial hinge sequence.

[0495] 30. The bispecific antibody of embodiment 29, wherein the linker is a peptide linker.

[0496] 31. The bispecific antibody of embodiment 29 or embodiment 30, wherein the linker is a GS linker of 5-20 amino acids.

[0497] 32. The bispecific antibody of any of embodiments 29-31, wherein the linker comprises GGGGSGGGGS (SEQ ID NO:91).

[0498] 33. The bispecific antibody of any of embodiments 1-32, wherein the VH1 is selected from the group consisting of: (a) a VH1 comprising a heavy chain complementarity determining region 1 (CDR-H1), a heavy chain complementarity determining region 2 (CDR-H2) and a heavy chain complementarity determining region 3 (CDR-H3) contained within SEQ ID NO:1, (b) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:2; (c) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NOG; (d) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:4; (e) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NOG; (f) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NOG; (g) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NOG; (h) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NOG; (i) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:9; (j) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO: 10; (k) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:11; (1) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO: 12; (m) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:13; (n) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO: 14; (o) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:15; (p) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:16; (q) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO: 17; (r) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:18; (s) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO: 19; (t) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:20; (u) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:21; (v) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:22;

(w) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:23; (x) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:24; (y) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:25; (z) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:26; (aa) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO: 27; (bb) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:28; (cc) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:29; and(dd) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:30.

[0499] 34. The bispecific antibody of any of embodiments 1-33, wherein the VH1 comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO: 29.

[0500] 35. The bispecific antibody of any of embodiments 1-33, wherein the VH1 is selected from the group consisting of: (a) a VH1 region comprising a heavy chain complementarity determining region 1 (CDR-H1), a heavy chain complementarity determining region 2 (CDR-H2) and a heavy chain complementarity determining region 3 (CDR-H3) comprising the sequence set forth in SEQ ID NOS:32, 33, 34, respectively; (b) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:35, 36, and 37, respectively; (c) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:38, 39, 40, respectively; (d) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:41, 42, 43, respectively, (e) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:41, 44, 45, respectively; (f) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:46, 47, 34, respectively; (g) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:48, 49, 34, respectively; (h) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:46, 50, 34, respectively; (i) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 46, 50, 51, respectively; (j) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:48, 49, 51, respectively; (k) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:46, 52, 51, respectively; (1) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 46, 47, 51, respectively; (m) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 46, 52, 51, respectively; (n) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 46, 47, 51, respectively; (o) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:54, 55, 37, respectively; (p) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:56, 57, 58, respectively; (q) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:56, 57, 59, respectively; (r) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:60, 61, 62, respectively; (s) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:63, 64, 40, respectively; (t) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:65, 66, 40, respectively; (u) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:65, 66, 67, respectively; (v) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:63, 64, 68, respectively; (w) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:65, 66, 69, respectively; (x) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 65, 66, 70, respectively; (y) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 65, 66, 71, respectively; (z) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 72, 73, 74, respectively; (aa) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 65, 66, 75, respectively; (bb) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 65, 76, 77, respectively; (cc) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:78, 76, 79, respectively; (dd) a VH1 region comprising a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 63, 76, 67, respectively.

[0501] 36. The bispecific antibody of any of embodiments 1-35, wherein the VH1 region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:78, 76, 79, respectively.

[0502] 37. The bispecific antibody of any of embodiments 1-36, whereim(a) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:1, (b) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:2; (c) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:3; (d) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:4; (e) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:5; (f) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:6; (g) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:7; (h) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:8; (i) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:9; (j) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO 10; (k) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:11; (1) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 12; (m) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 13; (n) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 14; (o) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 15; (p) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 16; (q) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 17; (r) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:18; (s) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 19; (t) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:20; (u) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:21; (v) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:22; (w) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:23; (x) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:24; (y) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:25; (z) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:26; (aa) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:27; (bb) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:28; (cc) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:29; or (dd) the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:30.

[0503] 38. The bispecific antibody of any of embodiments 1-37, wherein the VH1 region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:29.

[0504] 39. The bispecific antibody of any of embodiments 1-38, wherein:(a) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO:1, (b) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO:2; (c) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO:3; (d) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO:4; (e) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO:5; (f) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO:6; (g) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO:7; (h) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO:8; (i) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO:9; (j) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO 10; (k) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO:11; (1) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO: 12; (m) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO: 13; (n) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO: 14; (o) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO: 15; (p) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO:16; (q) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO:17; (r) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO:18; (s) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO: 19; (t) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO:20; (u) the VH1 region comprises the amino acid sequence set forth in SEQ ID N0:21; (v) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO:22; (w) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO:23; (x) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO:24; (y) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO: 25; (z) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO:26; (aa) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO: 27; (bb) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO:28; (cc) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO:29; or(dd) the VH1 region comprises the amino acid sequence set forth in SEQ ID NO:30.

[0505] 40. The bispecific antibody of any of embodiments 1-39, wherein the VH1 region comprises the amino acid sequence set forth in SEQ ID NO: 29.

[0506] 41. The bispecific antibody of any of embodiments 1-39, wherein the CHI of the VH1- CH1 comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:84.

[0507] 42. The bispecific antibody of any of embodiments 1-41, wherein the CHI of the VH1- CH1 comprises the amino acid sequence set forth in SEQ ID NO:84.

[0508] 43. The bispecific antibody of any of embodiments 1-42, wherein the VH1-CH1 comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:87.

[0509] 44. The bispecific antibody of any of embodiments 1-43, wherein the VH1-CH1 comprises the amino acid sequence set forth in SEQ ID NO: 87.

[0510] 45. The bispecific antibody of any of embodiments 1-44, wherein the VH1-CH1 of the HC2 is linked to a partial hinge sequence at its C-terminus to allow the HC2 to associate with the LC2.

[0511] 46. The bispecific antibody of embodiment 45, wherein the partial hinge sequence is EPKSCD (SEQ ID NO: 85).

[0512] 47. The bispecific antibody of any of embodiments 33-46, wherein the VH1-CH1 of the HC2 linked to the partial hinge sequence comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:90.

[0513] 48. The bispecific antibody of any of embodiments 33-47, wherein the VH1-CH1 of the HC2 linked to the partial hinge sequence comprises the amino acid sequence set forth in SEQ ID NO:90.

[0514] 49. The bispecific antibody of any of embodiments 1-48, wherein the VH2 comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO: 92.

[0515] 50. The bispecific antibody of any of embodiments 1-49, wherein the VH2 comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:93, 94, 95, respectively. [0516] 51. The bispecific antibody of any of embodiments 1-50, wherein the VH2 comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:92.

[0517] 52. The bispecific antibody of any of embodiments 1-51, wherein the VH2 comprises the sequence set forth in SEQ ID NO:92.

[0518] 53. The bispecific antibody of any of embodiments 1-48, wherein the VH2 comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO: 103.

[0519] 54. The bispecific antibody of any of embodiments 1-49, wherein the VH2 comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:93, 104, 95, respectively.

[0520] 55. The bispecific antibody of any of embodiments 1-50, wherein the VH2 comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 103.

[0521] 56. The bispecific antibody of any of embodiments 1-51, wherein the VH2 comprises the sequence set forth in SEQ ID NO: 103.

[0522] 57. The bispecific antibody of any of embodiments 1-56, wherein the CHI of the VH2- CH1 comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:84.

[0523] 58. The bispecific antibody of any of embodiments 1-57, wherein the CHI of the VH2- CH1 comprises the amino acid sequence set forth in SEQ ID NO:84.

[0524] 59. The bispecific antibody of any of embodiments 1-58, wherein the VH2-CH1 comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:96.

[0525] 60. The bispecific antibody of any of embodiments 1-59, wherein the VH2-CH1 comprises the amino acid sequence set forth in SEQ ID NO:96.

[0526] 61. The bispecific antibody of any of embodiments 1-58, wherein the VH2-CH1 comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 106.

[0527] 62. The bispecific antibody of any of embodiments 1-59, wherein the VH2-CH1 comprises the amino acid sequence set forth in SEQ ID NO: 106.

[0528] 63. A bispecific antibody comprising: a) a first heavy chain comprising in order: a first binding region that binds to FcRH5 comprising the amino acid sequence set forth in SEQ ID NO: 87 and a first polypeptide chain of a heterodimeric Fc; b) a second heavy chain comprising in order: a second binding region that binds to FcRH5 comprising the amino acid sequence set forth in SEQ ID NO:90, a linker, a third binding region that binds to CD3 comprising the amino acid sequence set forth in SEQ ID NO:96, and a second polypeptide chain of the heterodimeric Fc; and c) three copies of a common light chain comprising the amino acid sequence set forth in SEQ ID NO: 102, wherein each common light chain is associated with one of the first binding region, the second binding region and the third binding region.

[0529] 64. A bispecific antibody comprising: a) a first heavy chain comprising in order: a first binding region that binds to FcRH5 comprising the amino acid sequence set forth in SEQ ID NO: 87 and a first polypeptide chain of a heterodimeric Fc; b) a second heavy chain comprising in order: a second binding region that binds to FcRH5 comprising the amino acid sequence set forth in SEQ ID NO:90, a linker, a third binding region that binds to CD3 comprising the amino acid sequence set forth in SEQ ID NO: 106, and a second polypeptide chain of the heterodimeric Fc; and c) three copies of a common light chain comprising the amino acid sequence set forth in SEQ ID NO: 102, wherein each common light chain is associated with one of the first binding region, the second binding region and the third binding region.

[0530] 65. The bispecific antibody of any of embodiments 1-64, wherein each of the first and second polypeptide of the heterodimeric Fc comprises one or more amino acid substitutions in a wildtype Fc polypeptide region to effect heterodimer formation between the first polypeptide and the second polypeptide.

[0531] 66. The bispecific antibody of embodiment 65, wherein the wild-type Fc region is an IgGl Fc region.

[0532] 67. The bispecific antibody of embodiment 65 or embodiment 66, wherein the wild-type Fc region comprises the sequence set forth in SEQ ID NO: 122.

[0533] 68. The bispecific antibody of any of embodiments 65-67, wherein the one more amino acid substitutions are a knob-into-hole modification or a charge mutation to reduce or prevent selfassociation due to charge repulsion.

[0534] 69. The bispecific antibody of any of embodiments 65-68, wherein the one or more substitutions are a knob-into-hole modification.

[0535] 70. The bispecific antibody of any of embodiments 65-69, wherein the one or more amino acid substitutions of the first Fc polypeptide comprise Thr366Ser, Eeu368Ala and Tyr407Val and the one or more amino acid substitutions of the second Fc polypeptide of the heterodimeric Fc comprises the Thr366Trp.

[0536] 71. The bispecific antibody of any of embodiments 65-69, wherein the one or more amino acid substitutions of the first Fc polypeptide or the second Fc polypeptide comprise T350V, E351Y, F405A and Y407V and the other of the one or more amino acid substitutions of the first Fc polypeptide or the second Fc polypeptide of the heterodimeric Fc comprises T350V, T366E, K392E and T394W.

[0537] 72. The bispecific antibody of any of embodiments 65-68, wherein the amino acid substitution is a charge mutation to increase electrostatic complementarity of the polypeptides. [0538] 73. The bispecific antibody of any of embodiments 1-72, wherein the heterodimeric Fc region comprises one or more amino acid substitutions to reduce binding affinity to an Fc receptor and/or to reduce effector function, optionally as compared to a wild-type IgGl Fc domain.

[0539] 74. The bispecific antibody of embodiment 73, wherein the one or more amino acid substitutions are selected from L234A, L234V, L235A, L235E, G237A, D265S, S267K, R292C, N297G, V302C, and P329G by EU numbering.

[0540] 75. The bispecific antibody of embodiment 73 or embodiment 74, wherein the one or more amino acid substitution comprises L234A and L235A.

[0541] 76. The bispecific antibody of any of embodiments 73-75, wherein the one or more amino acid substitution comprises L234A, L235A, and D265S.

[0542] 77. The bispecific antibody of any of embodiments 73-75, wherein the one or more amino acid substitution comprises L234A, L235A, and P329G.

[0543] 78. The bispecific antibody of any of embodiments 1-104, wherein one or both polypeptides of the heterodimeric Fc lacks Lys447.

[0544] 79. The bispecific antibody of any of embodiments 1-78, wherein: one of the first polypeptide and the second polypeptide of the heterodimeric Fc region comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity SEQ ID NOS: 124, 126 or 128; and the other of the first polypeptide and second polypeptide of the heterodimeric Fc region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity SEQ ID NOS: 125, 127 or 129.

[0545] 80. The bispecific antibody of any of embodiments 1-79, wherein: one of the first polypeptide and the second polypeptide of the heterodimeric Fc region comprise the amino acid sequence set forth in any one of SEQ ID NOS: 124, 126 or 128; and the other of the first polypeptide and the second polypeptide of the heterodimeric Fc region comprises the amino acid sequence set forth in any one of SEQ ID NOS: 125, 127 or 129.

[0546] 81. The bispecific antibody of any of embodiments 1-80, wherein the first polypeptide of the heterodimeric Fc region comprise the amino acid sequence set forth in SEQ ID NO: 126 and the second polypeptide of the heterodimeric Fc region comprises the amino acid sequence set forth in SEQ ID NO: 127.

[0547] 82. The bispecific antibody of any of embodiments 1-80, wherein the first polypeptide of the heterodimeric Fc region comprise the amino acid sequence set forth in SEQ ID NO: 128 and the second polypeptide of the heterodimeric Fc region comprises the amino acid sequence set forth in SEQ ID NO: 129.

[0548] 83. A bispecific antibody comprising: a) a first heavy chain comprising a first binding region that binds to FcRH5, wherein the first heavy chain comprises the amino acid sequence set forth in SEQ ID NO:89; b) a second heavy chain comprising a second binding region that binds to FcRH5 and a third binding region that binds to CD3, wherein the second heavy chain comprises the amino acid sequence set forth in SEQ ID NO:98; and c) three copies of a common light chain comprising the amino acid sequence set forth in SEQ ID NO: 102, wherein each common light chain is associated with one of the first binding region, the second binding region or the third binding region.

[0549] 84. A bispecific antibody comprising: a) a first heavy chain comprising a first binding region that binds to FcRH5, wherein the first heavy chain comprises the amino acid sequence set forth in SEQ ID NO:89; b) a second heavy chain comprising a second binding region that binds to FcRH5 and a third binding region that binds to CD3, wherein the second heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 107; and c) three copies of a common light chain comprising the amino acid sequence set forth in SEQ ID NO: 102, wherein each common light chain is associated with one of the first binding region, the second binding region or the third binding region.

[0550] 85. The bispecific antibody of any of embodiments 1-84, wherein the FcRH5 is human FcRH5, optionally wherein the FcRH5 has the amino acid sequence set forth in SEQ ID NO: 130.

[0551] 86. The bispecific antibody of any of embodiments 1-85, wherein the first and second binding region bind FcRH5 within the membrane proximal domain 9.

[0552] 87. The bispecific antibody of any of embodiments 1-86, wherein the first and second binding region bind to cell-surface expressed FcRH5.

[0553] 88. The bispecific antibody of any of embodiments 1-87, wherein the first and second binding regions do not bind to soluble FcRH5.

[0554] 89. The bispecific antibody of any of embodiments 1-88, wherein the first and second binding regions exhibit no binding or weak binding to FcRHl, FcRH2, FcRH3 and/or FcRH4, optionally wherein the weak binding is a dissociation constant (KD) of 100 nM or more, more optionally wherein binding is as determined by surface plasmon resonance (SPR), e.g. Example 3.

[0555] 90. The bispecific antibody of any of embodiments 1-88, wherein the first and second binding regions exhibit no or weak binding to FcRHl, FcRH2, FcRH3 and FcRH4, optionally wherein the weak binding is a dissociation constant (KD) of 100 nM or more, more optionally wherein binding is as determined by surface plasmon resonance (SPR), e.g. Example 3.

[0556] 91. The bispecific antibody of any of embodiments 1-90, wherein the first and second binding regions have a dissociation constant (KD) for binding FcRH5 of less than about 5 nM.

[0557] 92. The bispecific antibody of any of embodiments 1-90, wherein the first and second binding regions have a KD for binding FcRH5 of about 0.05 and about 2 nM, optionally as determined by surface plasmon resonance (SPR), e.g. Example 3.

[0558] 93. The bispecific antibody of any of embodiments 1-92, wherein the CD3 is CD3epsilon.

[0559] 94. The bispecific antibody of any of embodiments 1-93, wherein the CD3 is human CD3epsilon. [0560] 95. The bispecific antibody of any of embodiments 1-94, wherein the bispecific antibody does not induce T cell activation in the absence of tumor antigen, optionally as determined by assessing cytokine release after incubation of the bispecific antibody with normal healthy donor PBMCs for about 24 hours, e.g. Example 5.

[0561] 96. The bispecific antibody of any of embodiments 1-95, wherein the bispecific antibody binds to an FcRH5-expressing target cell and a CD3-expressing T cell.

[0562] 97. The bispecific antibody of any of embodiments 1-96, wherein the bispecific antibody mediates cytolysis of the target cell by the CD3-expressing T cell.

[0563] 98. A polynucleotide encoding a heavy chain or a light chain of the bispecific antibody of any of embodiments 1-97.

[0564] 99. A set of polynucleotides encoding the heavy(s) and the light chains(s) of the bispecific antibody of any of embodiments 1-97.

[0565] 100. A set of polynucleotides comprising: a) a first polynucleotide encoding a first heavy chain comprising a first binding region that binds to FcRH5, wherein the first polynucleotides comprises the nucleotide sequence set forth in SEQ ID NO:111; b) a second polynucleotide encoding a second heavy chain comprising a second binding region that binds to FcRH5 and a third binding region that binds to CD3, wherein the second polynucleotide comprises the nucleotide sequence set forth in SEQ ID NO: 112; and c) a third polynucleotide encoding a common light chain comprising the nucleotide sequence set forth in SEQ ID NO: 110.

[0566] 101. A set of polynucleotides comprising: a) a first polynucleotide encoding a first heavy chain comprising a first binding region that binds to FcRH5, wherein the first polynucleotides comprises the nucleotide sequence set forth in SEQ ID NO:111; b) a second polynucleotide encoding a second heavy chain comprising a second binding region that binds to FcRH5 and a third binding region that binds to CD3, wherein the second polynucleotide comprises the nucleotide sequence set forth in SEQ ID NO: 113; and c) a third polynucleotide encoding a common light chain comprising the nucleotide sequence set forth in SEQ ID NO: 110.

[0567] 102. A vector comprising the polynucleotide of embodiment 98.

[0568] 103. A set of vectors, wherein each vector of the set comprises a polynucleotide of the set of polynucleotides of any of embodiments 99-101.

[0569] 104. The vector of embodiment 102 or the set of vectors of embodiments 103, wherein the vector is an expression vector.

[0570] 105. The vector or set of vectors of any of embodiments 102-104, wherein the vector is a viral vector or a eukaryotic vector, optionally wherein the eukaryotic vector is a mammalian vector.

[0571] 106. A cell, comprising the polynucleotide or the set for polynucleotides of any of embodiments 98-101, or a vector or set of vectors of any of embodiments 103-105.

[0572] 107. The cell of embodiment 106, wherein the cell is recombinant or isolated.

[0573] 108. The cell of embodiment 107, wherein the cell is a mammalian cell. [0574] 109. The cell of any of embodiments 106-108, wherein the cell is a HEK293 or CHO cell.

[0575] 110. A method of producing a bispecific antibody, the method comprising introducing into a cell a polynucleotide or set of polynucleotides of any of embodiments 98-101 or a vector or set of vectors of any of embodiments 102-105 and culturing the cell under conditions to produce the bispecific antibody.

[0576] 111. A method of producing a bispecific antibody, the method comprising culturing the cell of any of embodiments 106-109 under conditions in which the bispecific antibody is produced by the cell.

[0577] 112. The method of embodiment 110 or embodiment 111, further comprising isolating or purifying the bispecific antibody construct from the cell or from the supernatant of the cell culture.

[0578] 113. A bispecific antibody produced by the method of any of embodiments 110-112.

[0579] 114. A pharmaceutical composition comprising the bispecific antibody of any of embodiments 1-97 or embodiment 113 and a pharmaceutically acceptable carrier.

[0580] 115. The pharmaceutical composition of embodiment 114 that is sterile.

[0581] 116. An anti- Fc receptor-like protein 5 (FcRH5) antibody comprising: a heavy chain variable (VH) region and a light chain variable (VL) region, wherein:

[0582] the VL region comprises a light chain complementarity determining region 1 (CDR-L1), a light chain complementarity determining region 2 (CDR-L2) and a light chain complementarity determining region 3 (CDR-L3) contained within SEQ ID NO:31 or 99, and wherein: (a) the VH region comprises a heavy chain complementarity determining region 1 (CDR-H1), a heavy chain complementarity determining region 2 (CDR-H2) and a heavy chain complementarity determining region 3 (CDR-H3) contained within SEQ ID NO:1, (b) the VH region comprises a CDR-H1, a CDR- H2 and a CDR-H3 contained within SEQ ID NO:2; (c) the VH region comprises a CDR-H1, a CDR- H2 and a CDR-H3 contained within SEQ ID NO:3; (d) the VH region comprises a CDR-H1, a CDR- H2 and a CDR-H3 contained within SEQ ID NO:4; (e) the VH region comprises a CDR-H1, a CDR- H2 and a CDR-H3 contained within SEQ ID NO:5; (f) the VH region comprises a CDR-H1, a CDR- H2 and a CDR-H3 contained within SEQ ID NO:6; (g) the VH region comprises a CDR-H1, a CDR- H2 and a CDR-H3 contained within SEQ ID NO:7; (h) the VH region comprises a CDR-H1, a CDR- H2 and a CDR-H3 contained within SEQ ID NO: 8; (i) the VH region comprises a CDR-H1, a CDR- H2 and a CDR-H3 contained within SEQ ID NO:9; (j) the VH region comprises a CDR-H1, a CDR- H2 and a CDR-H3 contained within SEQ ID NO: 10; (k) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:11; (1) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO: 12; (m) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:13; (n) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO: 14; (o) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:15; (p) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:16; (q) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO: 17; (r) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:18; (s) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO: 19; (t) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:20; (u) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:21; (v) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:22; (w) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:23; (x) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:24; (y) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:25; (z) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:26; (aa) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO: 27; (bb) the VH region comprises a CDR- Hl, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:28; (cc) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO: 29; and (dd) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:30.

[0583] 117. The anti-FcRH5 antibody of embodiment 116, wherein the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 set forth in SEQ ID NO:99 and the VH region comprises a CDR- Hl, a CDR-H2 and a CDR-H3 contained within SEQ ID NO: 29.

[0584] 118. The anti-FcRH5 antibody of embodiment 116, wherein the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 set forth in SEQ ID NO:31 and the VH region comprises a CDR- Hl, a CDR-H2 and a CDR-H3 contained within SEQ ID NO: 29.

[0585] 119. An anti- Fc receptor-like protein 5 (FcRH5) antibody comprising: a heavy chain variable (VH) region and a light chain variable (VL) region, wherein: the VL comprises a CDRL1 set forth in SEQ ID NO:81, a CDRL2 set forth in SEQ ID NO: 82 and a CDRL3 set forth in SEQ ID NO:83; or the VL comprises a CDRL1 set forth in SEQ ID NO:81, a CDRL2 set forth in SEQ ID NO:82 and a CDRL3 set forth in SEQ ID NO:100; and wherein: a) the VH comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:32, 33, 34, respectively; (b) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:35, 36, and 37, respectively;(c) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:38, 39, 40, respectively; (d) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:41, 42, 43, respectively, (e) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:41, 44, 45, respectively; (f) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:46, 47, 34, respectively; (g) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:48, 49, 34, respectively; (h) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:46, 50, 34, respectively; (i) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 46, 50, 51, respectively; (j) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:48, 49, 51, respectively; (k) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:46, 52, 51, respectively; (1) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:46, 47, 51, respectively; (m) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 46, 52, 51, respectively; (n) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 46, 47, 51, respectively; (o) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:54, 55, 37, respectively; (p) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:56, 57, 58, respectively; (q) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:56, 57, 59, respectively; (r) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:60, 61, 62, respectively; (s) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:63, 64, 40, respectively; (t) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:65, 66, 40, respectively; (u) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:65, 66, 67, respectively; (v) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:63, 64, 68, respectively; (w) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:65, 66, 69, respectively; (x) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 65, 66, 70, respectively; (y) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 65, 66, 71, respectively; (z) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 72, 73, 74, respectively; (aa) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 65, 66, 75, respectively; (bb) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 65, 76, 77, respectively; (cc) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:78, 76, 79, respectively; or (dd) the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 63, 76, 67, respectively.

[0586] 120. The anti-FcRH5 antibody of any of embodiments 116-119, wherein: the VL comprises a CDRL1 set forth in SEQ ID NO:81, a CDRL2 set forth in SEQ ID NO:82 and a CDRL3 set forth in SEQ ID NO:83; and the VH1 region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:78, 76, 79, respectively. [0587] 121. The anti-FcRH5 antibody of any of embodiments 116-120, wherein: the VL comprises a CDRL1 set forth in SEQ ID NO:81, a CDRL2 set forth in SEQ ID NO:82 and a CDRL3 set forth in SEQ ID NO: 100; and the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:78, 76, 79, respectively.

[0588] 122. The anti-FcRH5 antibody of any of embodiments 116-121, wherein:

[0589] the VL comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:31 or 99; and a) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:1, (b) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:2; (c) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:3; (d) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:4; (e) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:5; (f) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:6; (g) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:7; (h) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:8; (i) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:9; (j) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO 10; (k) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:11; (1) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:12; (m) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:13; (n) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:14; (o) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:15; (p) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:16; (q) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:17; (r) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:18; (s) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:19; (t) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:20; (u) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:21; (v) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:22;(w) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:23; (x) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:24; (y) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:25; (z) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:26; (aa) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:27; (bb) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:28; (cc) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:29; or (dd) the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:30.

[0590] 123. The anti-FcRH5 antibody of any of embodiments 116-122, wherein: the VL comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:31 or 99; and the VH region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:29.

[0591] 124. The anti-FcRH5 antibody of any of embodiments 116-123, wherein: the VL comprises the sequence of amino acids set forth in SEQ ID NO:31 or 99; and a) the VH region comprises the amino acid sequence set forth in SEQ ID NO:1, (b) the VH region comprises the amino acid sequence set forth in SEQ ID NO:2; (c) the VH region comprises the amino acid sequence set forth in SEQ ID NO:3; (d) the VH region comprises the amino acid sequence set forth in SEQ ID NO:4; (e) the VH region comprises the amino acid sequence set forth in SEQ ID NO:5; (f) the VH region comprises the amino acid sequence set forth in SEQ ID NO:6; (g) the VH region comprises the amino acid sequence set forth in SEQ ID NO:7; (h) the VH region comprises the amino acid sequence set forth in SEQ ID NO: 8; (i) the VH region comprises the amino acid sequence set forth in SEQ ID NO:9; (j) the VH region comprises the amino acid sequence set forth in SEQ ID NO 10; (k) the VH region comprises the amino acid sequence set forth in SEQ ID NO:11; (1) the VH region comprises the amino acid sequence set forth in SEQ ID NO: 12; (m) the VH region comprises the amino acid sequence set forth in SEQ ID NO: 13; (n) the VH region comprises the amino acid sequence set forth in SEQ ID NO: 14; (o) the VH region comprises the amino acid sequence set forth in SEQ ID NO: 15; (p) the VH region comprises the amino acid sequence set forth in SEQ ID NO: 16; (q) the VH region comprises the amino acid sequence set forth in SEQ ID NO: 17; (r) the VH region comprises the amino acid sequence set forth in SEQ ID NO: 18; (s) the VH region comprises the amino acid sequence set forth in SEQ ID NO: 19; (t) the VH region comprises the amino acid sequence set forth in SEQ ID NO:20; (u) the VH region comprises the amino acid sequence set forth in SEQ ID NO:21; (v) the VH region comprises the amino acid sequence set forth in SEQ ID NO:22; (w) the VH region comprises the amino acid sequence set forth in SEQ ID NO:23; (x) the VH region comprises the amino acid sequence set forth in SEQ ID NO:24; (y) the VH region comprises the amino acid sequence set forth in SEQ ID NO:25; (z) the VH region comprises the amino acid sequence set forth in SEQ ID NO:26; (aa) the VH region comprises the amino acid sequence set forth in SEQ ID NO:27; (bb) the VH region comprises the amino acid sequence set forth in SEQ ID NO:28; (cc) the VH region comprises the amino acid sequence set forth in SEQ ID NO:29; or (dd) the VH region comprises the amino acid sequence set forth in SEQ ID NO:30.

[0592] 125. The anti-FcRH5 antibody of any of embodiments 116-124, wherein: the VL comprises the amino acid sequence set forth in SEQ ID NO: 99; and the VH region comprises the amino acid sequence set forth in SEQ ID NO: 29.

[0593] 126. The anti-FcRH5 antibody of any of embodiments 116-124, wherein: the VL comprises the amino acid sequence set forth in SEQ ID NO:31; and the VH region comprises the amino acid sequence set forth in SEQ ID NO: 29.

[0594] 127. The anti-FcRH5 antibody of any of embodiments 116-126, wherein said antibody is recombinant.

[0595] 128. The anti-FcRH5 antibody of any of embodiments 116-127, wherein the VH region and the VL region is human.

[0596] 129. The anti-FcRH5antibody of any of embodiments 116-128, wherein the antibody is a full length antibody. [0597] 130. The anti-FcRH5 antibody of any of embodiments 116-129, wherein the antibody is an antigen-binding fragment.

[0598] 131. The anti-FcRH5 antibody of any of embodiments 116-130, wherein the antigenbinding fragment thereof comprises a fragment antigen-binding region (Fab).

[0599] 132. The anti-FcRH5 antibody of any of embodiments 116-131, wherein the antigenbinding fragment thereof comprises a single chain Fv (scFv).

[0600] 133. The anti-FcRH5 antibody of embodiment 132, wherein the VH region and the VL region are joined by a flexible linker.

[0601] 134. The anti-FcRH5 antibody of embodiment 133, wherein the flexible linker comprises the sequence set forth in any one of SEQ ID NOs:131-136.

[0602] 135. The anti-FcRH5 antibody of any of embodiments 116-134, wherein the antibody specifically binds to a human Fc receptor-like protein 5 (FcRH5) protein.

[0603] 136. The anti-FcRH5 of any of embodiments 116-135, wherein the FcRH5 is a human FcRH5, optionally comprising the amino acid sequence set forth in SEQ ID NO: 130.

[0604] 137. The anti-FCRH5 antibody of any of embodiments 116-136, wherein the antibody binds FcRH5 within the membrane proximal domain 9.

[0605] 138. The anti-FcRH5 of any of embodiments 116-137, wherein the antibody binds to cellsurface expressed FcRH5.

[0606] 139. The anti-FcRH5 antibody of any of embodiments 116-138, wherein the antibody does not bind to soluble FcRH5.

[0607] 140. The anti-FcRH5 antibody of any of embodiments 116-139, wherein the antibody exhibits no or weak binding to FcRHl, FcRH2, FcRH3 and/or FcRH4, optionally wherein the weak binding is a dissociation constant (KD) of about 100 nM or more, more optionally wherein binding is as determined by surface plasmon resonance (SPR), e.g. Example 3.

[0608] 141. The anti-FcRH5 antibody of any of embodiments 116-140, wherein the first and second binding regions exhibit no or weak binding to FcRHl, FcRH2, FcRH3 and FcRH4, optionally wherein the weak binding is a dissociation constant (KD) of about 100 nM or more, more optionally wherein binding is as determined by surface plasmon resonance (SPR), e.g. Example 3.

[0609] 142. The anti-FcRH5 antibody of any of embodiments 116-141, wherein the antibody has a dissociation constant (KD) for binding FcRH5 of about or less than 5 nM, optionally as determined by surface plasmon resonance (SPR), e.g. Example 3.

[0610] 143. The anti-FcRH5 antibody of any of embodiments 116-142, wherein the antibody has a KD for binding FcRH5 of about 0.05 and about 2 nM, optionally as determined by surface plasmon resonance (SPR), e.g. Example 3.

[0611] 144. A single chain cell-surface protein, comprising the antibody of any of embodiments

116-143. [0612] 145. A conjugate, comprising the antibody of any of embodiments 116-144, and a heterologous molecule or moiety.

[0613] 146. The conjugate of embodiment 145, wherein the heterologous molecule or moiety is a therapeutic moiety.

[0614] 147. The conjugate of embodiment 145, wherein the heterologous molecule or moiety is a toxin.

[0615] 148. A bispecific antibody, comprising the anti-FcRH5 antibody of any of embodiments 116-143 and a second antibody that binds to a molecule on a T cell.

[0616] 149. The bispecific antibody of embodiment 148, wherein the second antibody is a Fab, optionally wherein the anti-FcRH5 antibody is a Fab and the second antibody is a Fab.

[0617] 150. The bispecific antibody of embodiment 148 or embodiment 149, wherein the molecule on a T cell is CD3.

[0618] 151. The bispecific antibody of any of embodiments 148-150, wherein the antibody is an anti-CD3 antibody, optionally an anti-CD3 Fab.

[0619] 152. The bispecific antibody of embodiment 151, wherein the anti-CD3 antibody comprises a variable light chain (VL) and a variable heavy chain (VH), wherein: the VL comprises a CDR-L1, a CDR-L2 and a CDR-L3 contained within SEQ ID NO: 99 and the VH comprises a CDR- Hl, a CDR-H2 and a CDR-H3 contained within SEQ ID NO: 92; or the VL comprises a CDR-L1, a CDR-L2 and a CDR-L3 contained within SEQ ID NO: 99 and the VH comprises a CDR-H1, a CDR- H2 and a CDR-H3 contained within SEQ ID NO: 103.

[0620] 153. The bispecific antibody of embodiment 151 or embodiment 152, wherein:

[0621] the VL comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:81, 82, 100, respectively, and the VH comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:93, 94, 95, respectively; or the VL comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:81, 82, 100, respectively, and the VH comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:93, 104, 95, respectively.

[0622] 154. The bispecific antibody of any of embodiments 151-153, wherein: the VL comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:99, and the VH comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:92; or the VL comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:99, and the VH comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 103. [0623] 155. The bispecific antibody of any of embodiments 151-154, wherein: the VL comprises the amino acid sequence set forth in SEQ ID NO:99, and the VH comprises the amino acid sequence set forth in SEQ ID NO:92; or the VL comprises the amino acid sequence set forth in SEQ ID NO: 99, and the VH comprises the amino acid sequence set forth in SEQ ID NO: 103.

[0624] 156. The bispecific antibody of any of embodiments 151-155, wherein the anti-CD3 antibody comprises: a light chain comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 102; and a heavy chain comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NOs:96; or a light chain comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 102; and a heavy chain comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NOs:106.

[0625] 157. The bispecific antibody of any of embodiments 151-156, wherein the anti-CD3 antibody comprises: a light chain comprising the amino acid sequence set forth in SEQ ID NO: 102; and a heavy chain comprising the amino acid sequence set forth in SEQ ID NOs:96; or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 102; and a heavy chain comprising the amino acid sequence set forth in SEQ ID NOs:106.

[0626] 158. The bispecific antibody of any of embodiments 151-157, comprising a heterodimeric Fc region comprising a first and second polypeptide each comprising a hinge-CH2-CH3, wherein the first polypeptide of the heterodimeric Fc is linked to the C-terminus of the anti-FcRH5 antibody and the second polypeptide of the heterodimeric Fc is linked to the C-terminus of the second antibody.

[0627] 159. The bispecific antibody of embodiment 158, wherein each of the first and second polypeptide of the heterodimeric Fc comprises one or more amino acid substitutions in a wild-type Fc polypeptide region to effect heterodimer formation between the first polypeptide and the second polypeptide.

[0628] 160. The bispecific antibody of embodiment 159, wherein the wild-type Fc region is an IgGl Fc region.

[0629] 161. The bispecific antibody of embodiment 159 or embodiment 160, wherein the wildtype Fc region comprises the sequence set forth in SEQ ID NO: 122.

[0630] 162. The bispecific antibody of any of embodiments 159-161, wherein the one more amino acid substitutions are a knob-into-hole modification or a charge mutation to reduce or prevent self-association due to charge repulsion.

[0631] 163. The bispecific antibody of any of embodiments 159-162, wherein the one or more substitutions are a knob-into-hole modification. [0632] 164. The bispecific antibody of any of embodiments 159-163, wherein the one or more amino acid substitutions of the first Fc polypeptide comprise Thr366Ser, Leu368Ala and Tyr407Val and the one or more amino acid substitutions of the second Fc polypeptide of the heterodimeric Fc comprises the Thr366Trp.

[0633] 165. The bispecific antibody of any of embodiments 159-163, wherein the one or more amino acid substitutions of the first Fc polypeptide or the second Fc polypeptide comprise T350V, L351Y, F405A and Y407V and the other of the one or more amino acid substitutions of the first Fc polypeptide or the second Fc polypeptide of the heterodimeric Fc comprises T350V, T366L, K392L and T394W.

[0634] 166. The bispecific antibody of any of embodiments 159-162, wherein the amino acid substitution is a charge mutation to increase electrostatic complementarity of the polypeptides.

[0635] 167. The bispecific antibody of any of embodiments 148-166, wherein the heterodimeric

Fc region comprises one or more amino acid substitutions to reduce binding affinity to an Fc receptor and/or to reduce effector function, optionally as compared to a wild-type IgGl Fc domain.

[0636] 168. The bispecific antibody of embodiment 167, wherein the one or more amino acid substitutions are selected from L234A, L234V, L235A, L235E, G237A, D265S, S267K, R292C, N297G, V302C, and P329G by EU numbering.

[0637] 169. The bispecific antibody of embodiment 167 or embodiment 168, wherein the one or more amino acid substitution comprises L234A and L235A.

[0638] 170. The bispecific antibody of any of embodiments 167-169, wherein the one or more amino acid substitution comprises L234A, L235A, and D265S.

[0639] 171. The bispecific antibody of any of embodiments 167-169, wherein the one or more amino acid substitution comprises L234A, L235A, and P329G.

[0640] 172. The bispecific antibody of any of embodiments 148-171, wherein one or both polypeptides of the heterodimeric Fc lacks Lys447.

[0641] 173. The bispecific antibody of any of embodiments 148-172, wherein: one of the first polypeptide and the second polypeptide of the heterodimeric Fc region comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity SEQ ID NOS: 124, 126 or 128; and the other of the first polypeptide and second polypeptide of the heterodimeric Fc region comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity SEQ ID NOS: 125, 127 or 129.

[0642] 174. The bispecific antibody of any of embodiments 148-173, wherein: one of the first polypeptide and the second polypeptide of the heterodimeric Fc region comprise the amino acid sequence set forth in any one of SEQ ID NOS: 124, 126 or 128; and the other of the first polypeptide and the second polypeptide of the heterodimeric Fc region comprises the amino acid sequence set forth in any one of SEQ ID NOS: 125, 127 or 129. [0643] 175. The bispecific antibody of any of embodiments 148-174, wherein the first polypeptide of the heterodimeric Fc region comprise the amino acid sequence set forth in SEQ ID NO: 126 and the second polypeptide of the heterodimeric Fc region comprises the amino acid sequence set forth in SEQ ID NO: 127.

[0644] 176. The bispecific antibody of any of embodiments 148-174, wherein the first polypeptide of the heterodimeric Fc region comprise the amino acid sequence set forth in SEQ ID NO: 128 and the second polypeptide of the heterodimeric Fc region comprises the amino acid sequence set forth in SEQ ID NO: 129.

[0645] 177. A chimeric antigen receptor (CAR) comprising an extracellular antigen-binding domain comprising the antibody or antigen-binding fragment thereof of any of embodiments 116-143, a transmembrane region and an intracellular signaling region.

[0646] 178. The chimeric antigen receptor of embodiment 177, further comprising a spacer between the extracellular antigen-binding domain and the transmembrane domain.

[0647] 179. The chimeric antigen receptor of embodiment 178, wherein the spacer comprises at least a portion of an immunoglobulin or a variant thereof.

[0648] 180. The chimeric antigen receptor of embodiment 178 or embodiment 179, wherein the spacer comprises at least a portion of a hinge region of an immunoglobulin or a variant thereof.

[0649] 181. The chimeric antigen receptor of any of embodiments 177-180, wherein the spacer is less than at or about 15 amino acids in length.

[0650] 182. The chimeric antigen receptor of any of embodiments 180-181, wherein the at least a portion of a hinge region comprises all or a portion of an IgG4 hinge region, optionally a human IgG4 hinge region, or a variant thereof.

[0651] 183. The chimeric antigen receptor of any of embodiments 180-182, wherein the at least a portion of a hinge region comprises all or a portion of an IgG2 hinge region, optionally a human IgG2 hinge region, or a variant thereof.

[0652] 184. The chimeric antigen receptor of any of embodiments 178-183, wherein the spacer comprises at least a portion of a hinge region and at least a portion of a CH3 region of an immunoglobulin or a variant thereof.

[0653] 185. The chimeric antigen receptor of any of embodiments 177-184 wherein the at least a portion of a CH3 region comprises all or a portion of an IgG4 CH3 and/or an IgG2 CH3, wherein the IgG4 CH3 is optionally a human IgG4 CH3 and the IgG2 CH3 is optionally a human IgG2 CH3.

[0654] 186. The chimeric antigen receptor of any of embodiments 177-185, wherein the transmembrane region is or comprises a transmembrane domain from CD4, CD28, or CD8.

[0655] 187. The chimeric antigen receptor of any of embodiments 177-186, wherein the transmembrane region is or comprises a transmembrane domain from CD28, optionally a human CD28. [0656] 188. The chimeric antigen receptor of any of embodiments 177-187, wherein intracellular signaling region comprises an intracellular signaling domain capable of inducing a primary activation signal in a T cell, is a T cell receptor (TCR) component and/or comprises an immunoreceptor tyrosine-based activation motif (IT AM).

[0657] 189. The chimeric antigen receptor of any of embodiments 177-188, wherein the intracellular signaling region is an intracellular signaling domain that is or comprises a cytoplasmic signaling domain of a CD3-zeta (CD3Q chain, optionally a human CD3^ chain.

[0658] 190. The chimeric antigen receptor of any of embodiments 177-189, wherein the intracellular signaling region further comprises a costimulatory signaling region.

[0659] 191. The chimeric antigen receptor of embodiment 190, wherein the costimulatory signaling region is between the transmembrane region and the intracellular signaling domain.

[0660] 192. The chimeric antigen receptor of embodiment 190 or embodiment 191, wherein the costimulatory signaling region comprises an intracellular signaling domain of a T cell costimulatory molecule or a signaling portion thereof.

[0661] 193. The chimeric antigen receptor of any of embodiments 190-192, wherein the costimulatory signaling region comprises an intracellular signaling domain of CD28, 4-1BB, or ICOS.

[0662] 194. The chimeric antigen receptor of any of embodiments 190-193, wherein the costimulatory signaling region comprises an intracellular signaling domain of CD28, optionally a human CD28.

[0663] 195. The chimeric antigen receptor of any of embodiments 190-193, wherein the costimulatory signaling region comprises an intracellular signaling domain of 4- IBB, optionally a human 4- IBB.

[0664] 196. The chimeric antigen receptor of any of embodiments 177-195, wherein the encoded chimeric antigen receptor comprises from its N to C terminus in order: the extracellular antigenbinding domain, the spacer, the transmembrane region and the intracellular signaling region.

[0665] 197. A polynucleotide comprising a nucleic acid encoding the anti-FcRH5 antibody or antigen-binding domain thereof of any of embodiments 116-143.

[0666] 198. A polynucleotide comprising a nucleic acid encoding the single chain cell surface protein of embodiment 144.

[0667] 199. A polynucleotide comprising a nucleic acid encoding the conjugate of any of embodiments 145-147.

[0668] 200. A polynucleotide comprising a nucleic acid encoding the anti-FcRH5 chimeric antigen receptor of any of embodiments 177-196.

[0669] 201. The polynucleotide of any of embodiments 197-200, wherein the polynucleotide is optimized by splice site elimination.

[0670] 202. The polynucleotide of any of embodiments 197-201, wherein the polynucleotide is codon-optimized for expression in a human cell. [0671] 203. A vector, comprising the polynucleotide of any of embodiments 197-202.

[0672] 204. The vector of embodiment 203, wherein the vector is a viral vector.

[0673] 205. The vector of embodiment 204, wherein the viral vector is a retroviral vector or a lentiviral vector.

[0674] 206. A cell comprising the anti-FcRHL5 antibody or antigen-binding fragment thereof of any of embodiments 116-143, the single chain cell surface protein of embodiment 144 or the conjugate of any of embodiments 145-147.

[0675] 207. A cell comprising the anti-FcRHL5 chimeric antigen receptor of any of embodiments 177-196.

[0676] 208. A cell comprising the polynucleotide of any of embodiments 197-202, or the vector of any of 203-205.

[0677] 209. The cell of any of embodiments 206-208, that is a lymphocyte.

[0678] 210. The cell of any of embodiments 206-208, that is an NK cell or a T cell.

[0679] 211. The cell of any of embodiments 206-210, wherein the cell is a T cell and the T cell is a CD4+ T cell or a CD8+ T cell.

[0680] 212. The cell of any of embodiments 206-211, wherein the cell is a primary cell obtained from a subject.

[0681] 213. The cell of any of embodiments 206-212, wherein, among a plurality of the cells, less than at or about 10%, at or about 9%, at or about 8%, at or about 7%, at or about 5%, at or about 4%, at or about 3%, at or about 2% or at or about 1% of the cells in the plurality comprise an anti- FcRH5 chimeric antigen receptor that exhibits tonic signaling and/or antigen independent activity or signaling.

[0682] 214. A composition comprising the cell of any of embodiments 206-213.

[0683] 215. A composition comprising the anti-FcRH5 antibody or antigen-binding fragment thereof of any of embodiments 116-143, the single chain cell surface protein of embodiment 144, the conjugate of any of embodiments 145-147, or the anti-FcRH5 chimeric antigen receptor of any of embodiments 177-196.

[0684] 216. The composition of embodiment 214 or embodiment 215, further comprising a pharmaceutically acceptable excipient.

[0685] 217. The composition of embodiment 214 or embodiment 216, wherein the composition comprises CD4+ and CD8+ T cells and the ratio of CD4+ to CD8+ T cells is from at or about 1:3 to 3:1, optionally at or about 1:2 to 2:1, optionally at or about 1:1.

[0686] 218. The composition of any of embodiments 214, 216 and 217, wherein, among a plurality of the cells in the composition, less than at or about 10%, at or about 9%, at or about 8%, at or about 7%, at or about 5%, at or about 4%, at or about 3%, at or about 2% or at or about 1% of the cells in the plurality comprise an anti-FcRH5 chimeric antigen receptor that exhibits tonic signaling and/or antigen independent activity or signaling. [0687] 219. A method of treatment, comprising administering the cell of any of embodiments 206-213 or the composition of any of embodiments 214-218 to a subject having a disease or disorder associated with FcRH5.

[0688] 220. The cell of any of embodiments 206-213 or the composition of any of embodiments 214-218 for use in treating a disease or disorder associated with FcRH5.

[0689] 221. Use of the cell of any of embodiments 206-213 or the composition of any of embodiments 214-218 for the manufacture of a medicament for treating a disease or disorder associated with FcRH5.

[0690] 222. Use of the cell of any of embodiments 206-213 or the composition of any of embodiments 214-218 for the treatment of a disease or disorder associated with FcRH5.

[0691] 223. A method of treatment, comprising administering the anti-FcRH5 antibody or antigen-binding fragment thereof of any of embodiments 116-143, the single chain cell surface protein of embodiment 144, the conjugate of any of embodiments 145-147, the anti-FcRH5 chimeric antigen receptor of any of embodiments 177-196, the polynucleotide of any of embodiments 197-202, or the vector of any of 203-205 to a subject having a disease or disorder associated with FcRH5.

[0692] 224. The anti-FcRH5 antibody or antigen-binding fragment thereof of any of embodiments 116-143, the single chain cell surface protein of embodiment 144, the conjugate of any of embodiments 145-147, the anti-FcRH5 chimeric antigen receptor of any of embodiments 177-196, the polynucleotide of any of embodiments 197-202, or the vector of any of 203-205 for use in treating a disease or disorder associated with FcRH5.

[0693] 225. Use of the anti-FcRH5 antibody or antigen-binding fragment thereof of any of embodiments 116-143, the single chain cell surface protein of embodiment 144, the conjugate of any of embodiments 145-147, the anti-FcRH5 chimeric antigen receptor of any of embodiments 177-196, the polynucleotide of any of embodiments 197-202, or the vector of any of 203-205 for the manufacture of a medicament for treating a disease or disorder associated with FcRH5.

[0694] 226. Use of the anti-FcRH5 antibody or antigen-binding fragment thereof of any of embodiments 116-143, the single chain cell surface protein of embodiment 144, the conjugate of any of embodiments 145-147, the anti-FcRH5 chimeric antigen receptor of any of embodiments 177-196, the polynucleotide of any of embodiments 197-202, or the vector of any of 203-205 for the treatment of a disease or disorder associated with FcRH5.

[0695] 227. The method, the cell, composition, antibody or antigen-binding fragment thereof, single chain cell surface protein, conjugate, chimeric antigen receptor, polynucleotide or vector for use or the use of any of embodiments 219-226, wherein the disease or disorder associated with FcRH5 is a cancer.

[0696] 228. The method, the cell, composition, antibody or antigen-binding fragment thereof, single chain cell surface protein, conjugate, chimeric antigen receptor, polynucleotide or vector for use or the use of embodiment 227, wherein the cancer is a FcRH5-expressing cancer. [0697] 229. The method, the cell, composition, antibody or antigen-binding fragment thereof, single chain cell surface protein, conjugate, chimeric antigen receptor, polynucleotide or vector for use or the use of any of embodiments 219-228, wherein the cancer is associated with a FcRH5- expressing solid tumor or a FcRHL5-expressing hematologic malignancy.

[0698] 230. The method, the cell, composition, antibody, or antigen-binding fragment thereof, single chain cell surface protein, conjugate, chimeric antigen receptor, polynucleotide or vector for use, or the use of any of embodiments 219-229, wherein the cancer is Non-Hodgkin's lymphoma (NHL) or multiple myeloma (MM).

IX. EXAMPLES

[0699] The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention.

Example 1: Screen and Selection of FcRH5 Binders

[0700] Antibody clones were selected from Adimab LLC platform yeast display libraries and were selected as Fabs for binding to an epitope of human FcRH5 within the membrane proximal domain 9. Since soluble FcRH5 lacks the membrane proximal domain, it is expected that the antibodies would not bind soluble FcRH5 thereby reducing the sink effect by binding to the soluble form. Further, without wishing to be bound by theory, certain T cell engagers that target the membrane proximal domain of an antigen have better tumor cell killing activity compared to T cell engagers that target membrane distal domains.

[0701] Antigens were biotinylated using the EZ-Link Sulfo-NHS -Biotinylation Kit from Pierce. Goat F(ab’)2 anti-human kappa-FITC (LC-FITC), ExtrAvidin-PE (EA-PE) and Streptavidin-AF633 (SA-633) were obtained from Southern Biotech, Sigma, and Molecular Probes, respectively. Streptavidin MicroBeads and MACS LC separation columns were purchased from Miltenyi Biotec. Goat anti-human IgG-PE (Human-PE) was obtained from Southern Biotech.

[0702] Primary Discovery:

[0703] Eight naive human synthetic yeast libraries each of ~10 ⁹ diversity were propagated as previously described (see, e.g., Y. Xu et al, Addressing polyspecificity of antibodies selected from an in vitro yeast presentation system: a FACS-based, high-throughput selection and analytical tool.

PEDS 26.10, 663-70 (2013); WG2009036379; WG2010105256; and WG2012009568.). For the first two rounds of selection, a magnetic bead sorting technique utilizing the Miltenyi MACS system was performed, as previously described (see, e.g., Siegel et al, High efficiency recovery and epitopespecific sorting of an scFv yeast display library." J Immunol Methods 286(1-2), 141-153 (2004).) Briefly, yeast cells (~10 ¹⁰ cells/library) were incubated with 300 pL of 100 nM biotinylated monomeric human FCRH5 domain 7-9 protein-Fc or full-length human FCRH5 ECD epitope-tagged antigen for 30 min at 30°C in wash buffer (phosphate-buffered saline (PBS)/0.1% bovine serum albumin (BSA)). After washing once with 40 ml ice-cold wash buffer, the cell pellet was resuspended in 20 mL wash buffer, and Streptavidin MicroBeads (500 pL) were added to the yeast and incubated for 15 min at 4°C. Next, the yeast were pelleted, resuspended in 20 mL wash buffer, and loaded onto a Miltenyi LS column. After the 20 mL were loaded, the column was washed 3 times with 3 ml wash buffer. The column was then removed from the magnetic field, and the yeast were eluted with 5 mL of growth media and then grown overnight. The following rounds of selection were performed using flow cytometry. Approximately 2xl0 ⁷ yeast were pelleted, washed three times with wash buffer, and incubated at 30°C with either monomeric human FCRH5 domain 7-9 protein-Fc (100 nM), monomeric human FCRH5 domain 9 protein-Fc (100 nM), full-length cyno FCRH5 ECD epitopetagged antigen (100 nM), full-length human FCRH3 ECD epitope-tagged antigen (1 pM), with a poly-specificity depletion reagent (PSR) to remove non-specific antibodies from the selection, or a unrelated biotinylated protein to remove off-target binding antibodies from the selection. For the PSR depletion, the libraries were incubated with a 1:10 dilution of biotinylated PSR reagent as previously described (see, e.g., Y. Xu et al, Addressing polyspecificity of antibodies selected from an in vitro yeast presentation system: a FACS-based, high-throughput selection and analytical tool. PEDS 26.10, 663-70 (2013).) Yeast were then washed twice with wash buffer and stained with LC-FITC (diluted 1:100) and either SA-633 (diluted 1:500) or EAPE (diluted 1:50) or mAPC (diluted 1:500) secondary reagents for 15 min at 4°C. After washing twice with wash buffer, the cell pellets were resuspended in 0.3 mL wash buffer and transferred to strainer-capped sort tubes. Sorting was performed using a FACS ARIA sorter (BD Biosciences) and sort gates were determined to select for antibodies with desired characteristics. Selection rounds were repeated until a population with the desired characteristics was obtained. After the final round of sorting, yeast were plated and individual colonies were picked for characterization. i. Antibody Optimization:

[0704] Optimization of antibodies was performed by introducing diversities into the heavy chain variable regions as described below.

[0705] CDRH1 and CDRH2 selection: The CDRH3 of a single antibody was recombined into a premade library with CDRH1 and CDRH2 variants of a diversity of 1 x 10 ⁸ and selections were performed with one round of MACS and four rounds of FACS as described in the naive discovery.

[0706] CDRH3 selection: CDRH3 diversification was obtained by ordering oligos with variegation in the CDRH3. The variable regions (FR1-FR3) from the best IgGs of the CDRH1/CDRH2 maturation cycle were combined with the CDRH3 oligos and transformed into yeast containing the light chain plasmid of the parent.

[0707] For all optimization cycles in the different FACS rounds the libraries were looked at for PSR binding and affinity pressure. Affinity pressure was applied by titrating either monomeric human FCRH5 domain 7-9 protein-Fc (various concentrations), monomeric human FCRH5 domain 9 protein-Fc (various concentrations), full-length cyno FCRH5 ECD epitope-tagged antigen (various concentrations). Negative selections versus full-length human FCRH3 ECD epitope-tagged antigen (1 pM), with a poly-specificity depletion reagent (PSR) to remove non-specific antibodies from the selection, or a unrelated biotinylated protein to remove off-target binding antibodies from the selection were employed as needed.

[0708] Antibody production and purification:

[0709] Yeast clones were grown to saturation and then induced for 48 h at 30°C with shaking. After induction, yeast cells were pelleted and the supernatants were harvested for purification. IgGs were purified using a Protein A column and eluted with acetic acid, pH 2.0. Fab fragments were generated by papain digestion and purified over KappaSelect (GE Healthcare LifeSciences).

2. Affinity measurements:

[0710] Affinity measurements (KD) were performed via Bio-Layer Interferometry (BLI) on an Octet HTX generally as previously described (see, e.g., Estep et al, High throughput solution-based measurement of antibody-antigen affinity and epitope binning. Mabs 5(2), 270-278 (2013)). Briefly, affinity measurements were performed by loading IgGs on-line onto anti-human capture (AHC) sensors. Sensors were equilibrated off-line in assay buffer for 30 min and then monitored online for 60 seconds for baseline establishment. Sensors with loaded IgGs were exposed to various FCRH5 or FCRL3 protein antigens antigen for 3 minutes, and afterwards were transferred to assay buffer for 3 min for off-rate measurement. All kinetics were analyzed using the 1 : 1 binding model. For peptide binding biotinylated peptide was loaded onto SA sensors and the antibody was in solution.

2. Cell binding analy sis:

[0711] IgGs were screened for binding to various target expressing (Human FCRH5 (full-length ECD), Cyno FCRH5 (full-length ECD), Human FCRH5 (domain 9 (ECD)), and control cell (Human FCRH3 (full-length ECD) or non-transfected (parental) HEK293 lines). All cell lines were derived from the HEK293 cell line. Briefly, IgGs (100 pL at 100 nM) were incubated with 200,000 cells of the desired cell line. All IgGs were assayed separately in a designated well of a 96 microwell assay plate. Following incubation (15 min at 22-25 °C) with the indicated cell lines; the micro well plates were centrifuged at 500 x g for 5 minutes. Supernatants were then carefully decanted, and cells were washed in 100 pL of 4°C PBSF 3 times using centrifugation in between each wash to gather cells. Following the final wash cell pellets were incubated with Goat-anti-Human IgG RPE from Southern Biotech (Cat# 2040-09) and Propidium Iodide from Roche (Cat#l 1348639001) for 15 min at 4°C. Following incubation cells were collected by centrifugation and washed as described previously. After the final wash cell pellets were resuspended in 100 pL 4°C PBSF prior to measurement on a FACS CANTO analyzer (BD Biosciences). [0712] A common light chain technology was utilized to identify one light chain amino acid sequence that is shared by the selected anti-FcRH5 Fabs in this Example and the anti-CD3 Fabs in Example 3. A similar screening strategy was used as that described in WO2018208864, the contents of which are hereby incorporated in their entirety.

[0713] Table El sets forth the variable heavy chain, and respective CDR, sequences of VH chains of exemplary selected anti-FcRH5 antibodies. The common light chain of each selected antibody contained a VL with CDRL1: SEQ ID NO: 81, CDRL2: SEQ ID NO: 82, CDRL3; SEQ ID NO: 83, with full VL set forth in SEQ ID NO: 31. Example 2: FcRH5- and CD3-directed Bispecific Antibody Design

[0714] Bispecific antibodies directed against FcRH5 and CD3 (FcRH5xCD3) were designed in two different formats. In one format, the bispecific antibodies were composed of one Fab arm that binds to CD3 and two Fab arms that bind to FcRH5 (designated 2+1 format). In another format, the bispecific antibodies were composed of one Fab arm that binds CD3 and one Fab arm that binds FcRH5 (designated 1 +1 format).

[0715] The bispecific antibodies were generated based on exemplary anti-FcRH5 antibody sequences described in Example 1 along with an anti-CD3 Fab. The constructs differed in the anti- CD3 Fab sequence that was included in the construct. Table E2A and Table E2B set forth the heavy chain and light chain sequences, respectively, of the exemplary anti-CD3 Fabs, including respective CDR sequences. The CD3-2 anti-CD3 antibody was chosen as an exemplary high affinity (e.g about 5 nM or less) antibody and CD3-1 anti-CD3 antibody was chosen as an exemplary detuned anti- CD3antibody with a medium affinity (e.g. about 10 nM or higher binding affinity), when screened for binding to CD3 as a naked Fab. Example 3 further provides results of CD3 binding affinity of bispecific constructs incorporating the exemplary anti-CD3 binders.

A. 2+1 Format

[0716] The IgGl 2+1 bispecific antibody format is shown in FIG. 1. T cell engager, TCE, conducts were made containing two Fabs that bind to FcRH5, one FcRH5 Fab alone (short arm) and one FcRH5 Fab stacked with a third Fab that binds to CD3 (long arm) (Table E3). The Fabs (VH- CH1) were formatted on an effectorless Fc domain that also included mutations in the CH3 domain to allow for heterodimerization of the bispecific antibody.

[0717] In one format, exemplary Fab arms in the 2+1 format were designed with a common light chain sequence shared by the three Fabs of the construct, and which was formatted on the Fc backbone. The resulting 2+1 bispecific format is thus formed by only three polypeptide chains, in which the common light chain is one chain. The common light chain contained a VL with CDRL1 : SEQ ID NO: 81, CDRL2: SEQ ID NO: 82, CDRL3; SEQ ID NO: 100, with full VL set forth in SEQ ID NO: 99. The full common light chain sequence (VL-CL) amino acid (aa) sequence is set forth in SEQ ID NO: 102 and the nucleotide (nt) sequence is set forth in SEQ ID NO: 110. The FcRH5 Fab (VH-CH1) of heavy chain B was C-terminally fused with a partial hinge (EPKSCD; SEQ ID NO:85) to permit the formation of a disulfide bond between the heavy and light chain. The CHI of the heavy chain B containing the partial hinge sequence is set forth in SEQ ID NO: 86.

[0718] Table E3 summarizes the components and respective SEQ ID NOs of exemplary bispecific 2+1 TCE constructs with a common light chain.

B. 1+1 Format

[0719] In the format designated 1+1, the bispecific antibodies were composed of one Fab arm that binds CD3 and one Fab arm that binds FcRH5. The Fab arms were formatted on an effectorless Fc that included mutations in the CH3 domain to allow for heterodimerization of the bispecific antibody. The TCE constructs differed in the anti-CD3 Fab sequence that was included in the construct.

[0720] Table E4 summarizes the components and respective SEQ ID Nos of exemplary bispecific 1+1 TCE constructs in this format. The 1+1 format TCE_F contains the same FcRH5 and CD3 binders as TCE_A. The 1+1 format molecule TCE_E contains the same FcRH5 binder and a higher affinity CD3 binder as TCE_B.

Example 3: Binding Specificity and Affinity of Bispecific Antibodies

[0721] Binding kinetics of TCE_A, TCE_B, TCE_E, and TCE_F against recombinant human FcRH5 (sourced from R&D Biosystems, PN:2078-FC-050) was measured by Surface Plasmon Resonance (SPR) using a Biacore T200 instrument.

[0722] A Cytiva sourced Protein A chip was used to capture each antibody at a normalized concentration of 0.1 pg/mL at a flow rate 10 pL/min for 60 seconds. Recombinant human FcRH5 was serially diluted in HBS-EP+ running buffer (100 nM - 0.1 nM) in two-fold dilutions. TCE_E, TCE_F were run in a separate assay with different dilutions (lOOnM - 3.7nM, 3-fold dilutions). Recombinant human FcRH5 was injected at a flow rate of 30 pl/min over the captured antibodies. Association was monitored for 180 seconds, and dissociation was monitored for 600 seconds. Surfaces were regenerated between cycles with 10 mM glycine-HCl, pH 1.5 injected for 60 seconds at 30 pl/min. lx HBS-EP+ was used as running buffer throughout the experiment. Experiments were performed at 25 °C. Referenced subtracted data were fit to a 1 : 1 kinetic model using Biacore software (Cytiva) with global fit analysis in the 1 : 1 kinetic fit model. The goodness of the fit was expressed by the evaluation software as Chi2. Binding results are shown in Table E5.

[0723] Binding kinetics of TCE_A, TCE_B, TCE_E, and TCE_F against recombinant human FcRHl, FcRH2, FcRH3 and FcRH4 (all sourced from R&D Biosystems, PN:2049-FC (FcRHl), 2048-FC (FcRH2), 3126-FC (FcRH3), and 2426-FC (FcRH4)) was measured by SPR using a Biacore T200 instrument. As described above, a Cytiva sourced Protein A chip was used to capture each antibody at a normalized concentration of 0.1 pg/mL at a flow rate 10 pE/min for 60 seconds. Recombinant human FcRHs were serially diluted in HBS-EP+ running buffer (500 nM - 0.4 nM) in three-fold dilutions. Recombinant human FcRHs were injected at a flow rate of 30 pl/min over the captured antibodies. Association was monitored for 180 seconds, and dissociation was monitored for 300 seconds. Surfaces were regenerated between cycles with 10 mM glycine-HCl, pH 1.5 injected for 60 seconds at 30 pl/min. lx HBS-EP+ was used as running buffer throughout the experiment. Experiments were performed at 25 °C. Referenced subtracted data were fit to a 1:1 kinetic model using Biacore Evaluation software (Cytiva) with global fit analysis in the 1 : 1 kinetic fit model. The goodness of the fit was expressed by the evaluation software as Chi2.

[0724] Results are shown in Table E6 for TCE_A and TCE_B bispecific constructs. Steady-state affinity Kd was used due to the weak affinities of some exemplary binders to the other FcRH family members. As shown in Table E6, very little binding was observed against FcRH2 using any of the exemplary FcRH5 binder constructs. The remaining FcRH family members, FcRH 1, 3, and 4, each displayed weak binding.

[0725] Similar binding assays were carried out against cynomolgus FcRH5 and to human CD3 using similar binding assays. The commercially sourced biotinylated CD3 was captured at 0.05 pg/mL on the streptavidin sensor chip. TCE_A was diluted in HBS-EP+ running buffer to a concentration of 300nM and a dose response curve was generated using a 3 times serial dilution for 8 point curve (300nM-0.41nM). TCE_A was injected over the surface for 180 seconds (association time) followed by 300 seconds of buffer flow (dissociation time). The data was analyzed using the Cytiva Biacore Insight Evaluation Software. Table E7 summarizes binding characteristics for 2+1 bispecific constructs.

[0726] Together, these results indicate that the 2+1 bispecific constructs bind to FcRH5 and CD3. For the exemplary bispecific constructs TCE_A and TCE_B, the binding to FcRH5 was highly specific since only weak binding was observed to other FcRH proteins. In particular, the results show weak binding to FcRH3, which is desirable in order to avoid binding to FcRH3 expressed on NK cells.

Example 4: In Vitro Antitumor Activity and T cell Activation

[0727] To measure in vitro antitumor activity and T cell activation, lymphoma cell lines (Rec-1, Mino, Jeko-1, and Karpas 422 cell lines) were stained with CellTrace Violet (Thermo Fisher #C34557) to distinguish from pan T cells (Stemcell Technologies #70024) in co-culture. The tumor cell lines were mixed with pan T cells in an effector (T cell) to target cell (tumor cell) ratio of 2:1. The co-culture was incubated with bispecific antibody construct or control molecules in concentration ranges from 0.05 pM to 100 nM for 48 hours in CO2 incubator at 37°C. At the end of 48 hours, coculture assay supernatant was harvested for Meso Scale Discovery (MSD) INFy cytokine readout, and cells from the co-culture mixture were stained with LIVE/DEAD Fixable Far Red Dead Cell Stain (Thermo Fisher #E-34974) to determine cell killing and with FITC anti-human CD69 antibody (Biolegend #310904) to measure T cell activation. Cells were fixed in 1% paraformaldehyde

(Electron Microscopy Sciences # 15710) and analyzed on a BD FACS Canto flow cytometer. Percent of tumor cell killing was measured by gating on CellTrace Violet positive tumor population and measuring the LIVE/DEAD Fixable Far Red Dead Cell Stain signal gating and counting distinct live and dead tumor cell populations. CD69 T cell activation was measured by gating the CellTrace Violet negative population and measure FITC signal.

Z Comparison of Activity of Bispecific Constructs

[0728] Antitumor activity and T cell activation actvity of exemplary bispecific construct TCE_A, TCE_B, TCE_E and TCE_F were assessed. As described in Example 2, the 1+1 format TCE_F contains the same FcRH5 and CD3 binders as TCE_A. The 1+1 format molecule TCE_E contains the same FcRH5 binder and a higher affinity CD3 binder as TCE_B.

[0729] These molecules representing the two bispecific formats were compared in in vitro T cell antitumor cell killing assays, INFy cytokine release T cell activation assays, and T cell binding assays as described. Results are set forth in FIG. 2A (tumor cell killing), FIG. 2B (INFy cytokine) and FIG. 2C (T cell binding), wherein a secondary antibody only condition was also assessed as a control.

[0730] The 2+1 format molecules demonstrated 10-fold increased potency in the tumor cell killing assays over their 1+1 counterparts, with TCE_A yielding EC50 of 0.012 nM compared to 0.13 nM with TCE_E, and an EC50 of 0.006 nM for TCE_B compared to 0.05 nM with TCE_F as shown in FIG. 2A. INFy cytokine levels measured in the assay supernatant also demonstrated the same trends for T cell activation as depicted in FIG. 2B. In some aspects, it is considered that the improved potency of the 2+1 format compared to the 1+1 format may be due to avid binding of the two FcRH5 binding Fab arms providing a more stable interaction with the tumor cell surface. T cell binding through the CD3 Fab arm is decreased in the 2+1 format compared to the 1+1 format as shown in FIG. 2C. In some aspects, it is considered that this observation is likely due to the stacked Fab orientation with the CD3 Fab arm sandwiched between the FcRH5 Fab arm and the Fc region. Reduced T cell binding with enhanced tumor cell killing is desirable in a T cell engager (TCE) in that reduced T cell binding in the absence of target tumor cell may result in lower levels of tonic T cell activation and risk of cytokine release.

2. A ctivity against FcRHS- Expressing Ceiis

[0731] In vitro antitumor cell activity was measured against lymphoma cell lines (Rec-1, Mino, Jeko-1, and Karpas 422 cell lines) of differing FcRH5 expression levels. Antibody binding capacity (ABC) was calculated for these cell lines using flow cytometry along with quant calibration beads to determine relative expression for these cell lines. The REC-1 cell line with an ABC value of 30,000 was classified as a high FcRH5 expressor, the Mino cell line with an ABC value of 4,000 was classified as medium FcRH5 expressor, the Jeko-1 cell line with an ABC value of 1,000 was classified as a low FcRH5 expressor, and the Karpas 422 was identified as negative for FcRH5. The ABC expression values of these are in line with five dissociated patient lymphoma tumor samples with ABC values ranging from 2,000 to 24,000. A (HELxCD3) 2+1 format negative control wherein the FcRH5 Fabs are replaced with HEE Fabs was also assessed. In this negative control molecule, the CD3 Fab is left intact in the stacked Fab format on the long arm as described in Example 1 , and HEL refers to the Hen Egg-white Lysozyme.

[0732] Results for tumor cell killing and IFN y cytokine for the exemplary bispecific construct TCE_A are shown in FIG. 3A (Rec-1 cells), FIG. 3B (Mino cells), FIG. 3C (Jeko-1 cells) and FIG. 3D (Karpa 422 cells). TCE_A yielded potent killing of the FcRH5 positive cell lines tested with sub nM EC50 values of 0.004 nM for REC-1, 0.022 nM for Mino, 0.33 nM for Jeko-1 and greater than 100 nM for Karpas 422 cells. INFy cytokine levels measured in supernatant were observed to positively correlate with killing potency. No killing or INFy cytokine release was observed in the Karpas 422 FcRH5 negative cell line with TCE_A. The Karpas 422 cell line is positive for FcRHl and FcRH3 family members demonstrating the selectivity of TCE_A against these FcRH family members.

3. Comparison to Bispecific construct benchmark with FcBHJ and FcKff3 crossreactivity

[0733] The activity of TCE_A was compared to another exemplary 1+1 bispecific with an FcRH5 binder portion that exhibits cross-reactivity to FcRHl and FcRH3 and a high affinity CD3 binder (“Comparator TCE”). The constructs were tested for for tumor cell killing, IFN y cytokine levels and T cell activition in Rec-1, Mino and Karpas-422 cells lines. Results are shown in FIGS. 4A-4C.

[0734] The TCE_A bispecific construct was observed to be as potent or more potent than the 1+1 comparator in the FcRH5 positive cell lines tested. Antitumor activity for both antibodies was positively correlated with INFy cytokine release, and CD69 positive activated T cell numbers demonstrating the T cell dependency of the killing activity in the Rec-1 (FIG. 4A) and Mino cell lines (FIG. 4B).

[0735] Killing of the FcRH5 negative cell line Karpas 422 was observed with the comparator TCE while no killing of this cell line was observed with the TCE_A bispecific construct (FIG. 4C). As the Karpas 422 cell line is positive for FcRHl and FcRH3 family members, this result further supports greater selectivity of TCE_A against FcRH5 compared to other FcRH family members.

[0736] Binding to T cells also was assessed as shown in FIG. 5. As shown, the 1+1 anitbody benchmark comparator yielded much higher binding to T Cells. This result is consistent with the TCE_A bispecific construct incorporating a detuned anti_CD3 Fab binder, whereas the comparator 1+1 format contains a high affinity anti-CD3 Fab binder. Due to the lower binding to T cells of the TCE_A construct, there is potential for lower risk of tonic signaling/CRS with the lower affinity CD3 arm in TCE_A.

[0737] Table E8 sets forth a summary of the results.

Example 5: Evaluation of Tonic Signalling

[0738] Cytokine release syndrome (CRS) is a concern for T cell modality therapies including T cell engagers. While on target T cell killing of tumor cells results in cytokine release, tonic signaling and cytokine release of T cells through CD3 binding independent of tumor associated antigen binding is not desired. The T-cell immune response is defined by low affinity binding of the T-cell receptor (TCR) to its cognate antigen resulting in an intracellular phosphorylation signaling cascade. This signaling results in activation of transcription factors such as NF AT and NFKB that lead to an increase in cytokine and effector protein expression. T-cell cytolytic activity does not require the formation of a mature immune synapse, and CD3-based T cell engagers (TCEs) exploit this by forming a TCR- independent immune synapse between a tumor cell and T-cell.

[0739] To evaluate tonic signaling and cytokine release, TCE_A and TCE_B bispecific antibodies along with negative and positive control antibodies were incubated with normal healthy donor PBMCs for 24 hours. Specifically, levels of interleukin (IL)-l beta (P), IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, tumor necrosis factor-alpha (TNF-a), and interferon-gamma (IFN-y) were each evaluated at 24- and 48-hours post-treatment by a CRA (Meso Scale Discovery #K0081674) using soluble antibody at a concentration range of 0.001 nM to 100 nM (0.00015 pg/mL to 15 pg/mL). As a positive control, signaling with a 1+1 bispecific Comparator TCE described in Example 4 was assessed that binds to CD3 with high affinity. In addition, anti-hu.CD3 mAh (clone OKT-3, Absolute Antibody #00122-10.0) also was assessed as a positive control. Negative controls included HELxCD3 2+1 bsAbanti-hu.CD3 Fc silent mAh (clone OKT-3, Absolute Antibody #00122-10.3), and RSV hu. IgGl isotype control. Data was tested for significance versus the isotype control at 100 nM by RM One-way ANOVA, followed by Sidak’s multiple comparisons test (GraphPad Prism v8).

[0740] As shown in FIGs. 6A-6J, TCE_A and TCE_B bispecific antibodies did not induce tonic release of any of the ten tested cytokines over negative controls for all ten human PBMC samples tested. Despite donor variability being observed with several cytokines (notably IL-8, IL-10 and TNFa), the levels of cytokine released by binding of the 2+1 exemplary FcRH5 CD3 antibodies was not significantly different from that of the isotype control antibody.

[0741] In contrast, the comparator TCE bispecific antibody induced some low T cell activation in the absence of tumor antigen as evidenced by positive cytokine signal at the highest dose level tested, indicating the presence of tonic signaling. In addition, significant cytokine release in the absence of tumor antigen also was observed with monoclonal anti CD3 positive control antibodies OKT3 and SP34 in all PBMC samples tested.

[0742] The CD3 monoclonal positive control antibodies are bivalent, and thus are able to induce CD3 clustering on the T cell surface leading to tonic signaling and activation. These data support that exemplary 2+1 antibody format promotes monovalent binding to T cells due to its single CD3 arm. Overall, the FcRH5xCD3 TCE 2+1 bispecific antibodies induced nominal levels of cytokine, indicating minimal risk of cytokine release in humans.

Example 6: Antitumor activity in a MINO xenograft model.

[0743] The exemplary 2+1 FcRH5xCD3 bispecific antibody, TCE_A, was tested for antitumor activity in vivo in a hNSG MINO xenograft model. Briefly, female nonobese and diabetes-free (NOD) severe-combined immunodeficient (SCID) mice were inoculated with 3 x 10 ⁶ MINO cells in the right flank. When the tumors were approximately 100 mm ³ in size (e..g., Day 16), the mice were humanized (hNSG) by adoptive transfer of 10 ⁷ hPBMC cells/mouse of donor. The following day, hNSG mice bearing MINO tumors were dosed intravenously with (i) the 2+1 FcRH5xCD3 bispecific antibody, (ii) the CD3xHEL negative control, or (iii) a CD3xCD20 bispecific antibody positive control. Exemplary FcRH5xCD3 bispecific antibody, FcRH5A_CD3_2+l, was tested at 3 and 10 mg/kg with a once a week (QW) dosing for 3 weeks. A negative control, the CD3xHEL antibody, was dosed at 3 and 10 mg/kg. A positive control, the CD3xCD20 bispecific antibody, was dosed at 10 mg/kg.

[0744] Results from PBMCs from two different donors are described below.

Z hNSG MINO Nenograft Model with a Donor A

[0745] In this study, the final tumor volume reduction was determined on Day 35, when the mean tumor volumes in the non-humanized NSG and hNSG groups reached approximately 2400 mm ³ . Significant (p<0.0001) antitumor activity of exemplary 2+1 antibody TCE_A with a tumor volume reduction (TVR) of 95% was observed at both 3 and 10 mg/kg, QW (FIG. 7). In the same dosing regimen, the positive control showed an 88% TVR at 10 mg/kg. There was no significant body weight loss in the animals treated with any of the treatment groups.

[0746] In addition to the antitumor activity assayed above, plasma was collected 24h after the 3rd dose of either the exemplary 2+1 antibody TCE_A or any of the above described controls and analyzed by mesoscale for GM-CSF, IFN-y, IL-ip, IL-2, IL-6, IL-10, IL-17A and TNF-a. No significant changes were observed with treatment of the exemplary 2+1 antibody or positive control. Blood and spleens were also collected at the end of the study to confirm T cell engraftment. T cell engraftment was lost in the group treated with the positive control CD3xCD20 bispecific antibody most likely due to hyperactivation and exhaustion of T cells since this bispecific antibody is very potent.

[0747] Tumors were collected at the end of the study and stained by immunohistochemistry for CD4, CD8, CD25 and Granzyme B. T cell infiltration, CD25 and Granzyme B staining was observed in the groups treated with TCE_A at 3 and 10 mg/kg, but not in the groups treated with negative conrol, suggesting that the tumor killing activity is dependent upon T cells recruitment and activation.

2. hNSG M7NO Xenograft Mode/ with a Donor B

[0748] A second xenograft study was conducted to determine the antitumor activity of exemplary 2+1 anitbody TCE_A in a hNSG MINO xenograft model with a different hPBMC donor.

[0749] In this study, the final tumor volume reduction was determined on Day35 at the time of the termination of the study when the mean tumor volumes in the non-humanized NSG and hNSG groups reached approximately 2500 mm ³ . Significant (p<0.0001) antitumor activity of TCE_A with a tumor volume reduction of 95% (with 3 regressions) and 90% (with 2 regressions) was observed respectively at 3 and 10 mg/kg, QW, respectively (FIG. 8A). In the same dosing regimen, the postiive control showed a 71% TVR at 10 mg/kg. There was no significant body weight loss in the animals treated with any treatment group.

[0750] Plasma was collected 24h after the 3rd dose and analyzed by mesoscale for the same inflammatory cytokines as described above. Similarly to the results described in the study above, no significant changes were observed with treatment of the exemplary 2+1 TCE antibody or positive control. Blood and spleens were also collected at the end of the study to confirm T cell engraftment. T cell engraftment was lost in the group treated with the CD3xCD20 positive control as in the previously observed in the study described above.

[0751] Tumors were collected at the end of the study and stained by IHC for CD4 and CD8. T cell infiltration was only observed in the groups treated with TCE_A at 3 (FIG. 8B) and 10 mg/kg, but not with the negative control, further suggesting that the tumor killing activity is dependent upon T cells recruitment.

2. Summary

[0752] Taken together, the exemplary 2+1 antibody TCE_A significantly inhibited tumor growth in hNSG MINO xenograft models with weekly dosing. Further, the use of two different donors to humanize NSG mice produced similar results. The antitumor activity of TCE_A was also observed to be dependent upon recruitment of T cells in the tumor, T cell activation, and production of inflammatory cytokines and Granzyme B.

Example 7 : Phamacodynamics in a hNSG MINO Xenograft Model

[0753] A hNSG MINO xenograft model with hPBMC donor as described in Example 6 above was used to further characterize in vivo activity of the exemplary 2+1 bispecific antibody TCE_A. Briefly, female NOD-SCID mice were inoculated with MINO cells in the right flank. When the tumors were approximately 100 mm ³ , the mice were humanized (hNSG) by adoptive transfer of hPBMC, and the following day groups of hNSG mice bearing MINO tumors were dosed with the exemplary antibody and the negative control. Exemplary FcRH5xCD3 bispecific antibody, TCE_A and the negative control, CD3xHEL, were tested at 3 mg/kg with a once a week (QW) dosing for 3 weeks.

[0754] Blood and spleens were collected 24h post the 2nd and 3rd dose to confirm the engraftment of T cells. Tumors and plasma were also collected after the 2nd and 3rd dose and analyzed by mesoscale for GM-CSF, Granzyme B, IFN-y, IL-ip, IL-2, IL-2Ra (CD25), IL-6, IL-10, IL-17A and TNF-a.

[0755] Significant increase of most inflammatory cytokines and Granzyme B in the group treated with exemplary antibody TCE_A was seen 24h post the 2nd dose in tumors (FIG. 9A) and in plasma (FIG. 9B) but not 24h post the 3rd dose. A moderate increase of CD25 with TCE_A was seen intratumor ally 24h post the 3rd dose.

[0756] Exemplary samples of the tumors collected post the 2nd and 3rd dose were fixed and stained by multiplex immunofluorescence for DAPI, CD4, CD8, CD25, Granzyme B and CD3. Infiltration of CD4 and CD8 cells, and expression of CD25 and Granzyme B was only observed following treatment with exemplary antibody TCE_A and not was not observed following treatment with the negative control or without treatment.

[0757] These data support that exemplary antibody TCE_A has a mechanism of action that is dependent upon T cell recruitment in the tumor and T cell activation.

[0758] The present invention is not intended to be limited in scope to the particular disclosed embodiments, which are provided, for example, to illustrate various aspects of the invetion. Various modifications to the compositions and methods described will become apparent from the description and teachings herein. Such variations may be practiced without departing from the true scope and spirit of the disclosure and are intended to fall within the scope of the present disclosure. X. SEQUENCE TABLE