SCREENING ASSAYS, MODULATORS AND MODULATION OF INTRACELLULAR SIGNALLING MEDIATED BY IMMUNOGLOBULIN SUPERFAMILY CELL ADHESION MOLECULES

FIELD OF THE INVENTION

[0001 ] This invention relates generally to screening assays for identifying modulators of activation of molecules associated with certain diseases and/or conditions, to such modulators, and to methods of treatment comprising administration of such modulators. More specifically, the invention relates to modulators of activation of Immunoglobulin Superfamily Cell Adhesion Molecules (IgSF CAMs), including but not limited to Activated Leukocyte Cell Adhesion Molecule (ALCAM, also known as cluster of differentiation 166 [CD166]), Melanoma Cell Adhesion Molecule (MCAM, also known as CD146/MUC18), Basal Cell Adhesion Molecule (BCAM, also known as the Lutheran blood group glycoprotein), Epithelial Cell Adhesion Molecule (EpCAM, also known as TACSTD1 (tumor-associated calcium signal transducer 1 ), CD326 (cluster of differentiation 326), or the 17-1 A antigen), Cell Adhesion Molecule 4 (CADM4, also known as TSLL2, IGSF4C, SynCAM4, or Necl-4) via IgSF CAM ligand- independent mechanisms by certain co-located, activated G Protein-Coupled Receptors (GPCRs), including activated type 1 angiotensin receptor (AT1 R), with or without also modulating activation of IgSF CAMs by IgSF CAM ligands. This invention also relates to screening assays for identifying such modulators, and to methods of treatment of IgSF CAM- related disorders using said modulators. This invention also relates to modulators of activation of the Receptor for Advanced Glycation End-products (RAGE) via RAGE ligand-independent mechanisms by certain co-located, activated G Protein-Coupled Receptors (GPCRs), including activated type 1 angiotensin receptor (AT1 R) and activated complement receptor C5a receptor 1 , with or without also modulating activation of RAGE by RAGE ligands, where the modulators are analogues, fragments or derivatives of members of the IgSF CAM superfamily, including ALCAM559-580. This invention also relates to screening assays for identifying such modulators, and to methods of treatment of RAGE-related disorders using said modulators.

BACKGROUND OF THE INVENTION

[0002] Cell adhesion molecules (CAMs) facilitate interactions between cells and their external environment, and include cadherins, integrins, selectins, and IgSF CAMs. The Immunoglobulin Superfamily is characterised by an extracellular domain (which contains one or more Ig-like domains), a single transmembrane domain, and a cytoplasmic tail. IgSF CAMs are cell adhesion molecules (CAMs) that belong to the Immunoglobulin Superfamily (IgSF). They mediate adhesion through their N-terminal Ig-like ectodomains, which commonly bind other Ig-like domains of the same structure on an opposing cell surface (homophilic adhesion) but may also interact with integrins and carbohydrates (heterophilic adhesion).

[0003] Some IgSF CAMs can also act as pattern recognition receptors, and become activated by diverse ligands, triggering intracellular signalling pathways, mediated by the C- terminal intracellular domains of IgSF CAM members which interact with cytoskeletal or adaptor proteins involved in the propagation of signalling events mediated by ligand binding.

[0004] Activated Leukocyte Cell Adhesion Molecule (ALCAM) is a 105-kDa type I transmembrane protein and member of the IgSF CAM superfamily. ALCAM contains a multi ligand binding extracellular immunoglobulin-like ectodomain, comprising two N-terminal, membrane-distal variable-(V)-type and three membrane-proximal constant-(C2)-type Ig folds (VVC2C2C2) ectodomain, a single-span transmembrane domain and a short (32 amino acid) cytosolic domain.

[0005] ALCAM is primarily implicated in cell adhesion between adjacent cells, mediated by homophilic trans interactions (ALCAM-ALCAM) or heterophilic interaction (ALCAM-CD6) specifically via its NH ₂ -terminal V-type immunoglobulin folds (Patel et al., 1995, Swart, 2002, van Kempen et al., 2001 , Zimmerman et al., 2006) while the proximal C-type immunoglobulin folds mediate oligomerization in cis.

[0006] The ectodomain of ALCAM also functions as a pattern recognition multi-ligand receptor with diverse ligands including S100 proteins that trigger activation of NFKB dependent pathways (von Bauer, Oikonomou et al. 2013) accompanied by activation of the small GTPases RhoA, Rac1 and Cdc42.

[0007] ALCAM is shed upon activation by MMPs/ADAMs, releasing a soluble isoform (Hebron, Li et al. 2018). ALCAM is partly regulated by alternative splicing that modulates the rate of shedding. It is known that NFKB activation directly enhances ALCAM expression by binding to the ALCAM promoter (Wang, Gu et al. 201 1 ).

[0008] ALCAM is also a nerve-derived growth factor (NGF) and brain-derived neurotrophic factor (BDNF) co-receptor, and is involved in neurite outgrowth and neuron survival in cooperation with fibroblast growth factor signalling (Wade, Thomas et al. 2012). Notably the extracellular (ligand binding) ectodomain of ALCAM is required for potentiation of NGF-dependent neurite outgrowth and constructs without the intracellular cytoplasmic domain retain this function. [0009] ALCAM expression was first identified on leucocytes, but is broadly detectable in a wide variety of cell types, including epithelial cells, fibroblasts, neuronal cells, hepatocytes, podocytes and bone marrow cells, although typically restricted to subsets of cells involved in dynamic growth and migration.

[00010] ALCAM is involved in several important physiological processes such as maturation of hematopoietic stem cells in blood forming tissues, angiogenesis, neural development, axon fasciculation, the immune response, and osteogenesis.

[0001 1 ] Dynamic alteration of cell adhesion is an integral step to cancer progression and ALCAM has been associated with the progression of diverse types of cancer. ALCAM has been implicated in many aspects of tumour biology including growth, migration and invasion of tumour cells. ALCAM’s participation in malignant progression has been recognized in numerous studies for many common cancers including but not limited to: pancreatic cancer (Hong, Michalski et al. 2010), melanoma (Penna, Orso et al. 2013), prostate cancer (Hansen, Arnold et al. 2014) breast cancer (Piao, Jiang et al. 2012), liver cancer/hepatoma (Yu, Wang et al. 2014), mesothelioma (Inaguma, Lasota et al. 2018), gastric cancer (Ye, Du et al. 2015), bladder cancer (Arnold Egloff, Du et al. 2017), brain tumours (Atukeren, Turk et al. 2017) and colon cancer (Kozovska, Gabrisova et al. 2014), in which elevated ALCAM shedding directly relates to poor patient outcome and a more invasive tumour pattern. ALCAM is thought to be directly involved in cell migration, invasion, spread and metastasis. Soluble ALCAM (sALCAM) or ALCAM-lgG-Fc chimeras containing the ectodomain are able to inhibit cell-cell adhesion and modulate cell migration.

[00012] ALCAM has also been implicated in a range of immunological disorders including but not limited to asthma (Kim, Hong et al. 2018), delayed-type hypersensitivity (von Bauer, Oikonomou et al. 2013), and food allergy (Kim, Kim et al. 2018). ALCAM has been identified as an important costimulatory molecule on antigen-presenting cells (APCs) contributing to the antigen specific induction of T cell activation and proliferation relevant to immunological disorders, including allergy and autoimmunity.

[00013] ALCAM has also been implicated in a range of brain disorders, in particular those neuro-inflammatory disorders in which leukocyte migration across the blood-brain barrier is implicated including multiple sclerosis (Lecuyer, Saint-Laurent et al. 2017), encephalomyelitis (Lecuyer, Saint-Laurent et al. 2017) and retinal vascular disease (Smith, Chipps et al. 2012).

[00014] ALCAM has also been implicated in a range of chronic inflammatory diseases including but not limited to chronic kidney disease (Smith, Chipps et al. 2012) diabetic nephropathy (Sulaj, Kopf et al. 2017), atherosclerosis (Rauch, Rosenkranz et al. 201 1 ), stroke (Smedbakken, Jensen et al. 201 1 ), and aortic valve sclerosis (Guerraty, Grant et al. 201 1 ).

[00015] Although the ligand-binding actions of the ectodomain of ALCAM are well known, the functions of the short (32 amino acid) cytoplasmic domain of ALCAM are poorly understood. It is thought that the cytosolic tail of ALCAM possibly regulates adhesion through links with the cytoskeleton. The cytoplasmic tail of ALCAM contains a positive-charge-rich domain at the membrane proximal site and a KTEA peptide motif at the C-terminus, facilitating interactions with adaptor proteins, ezrin and syntenin-1 respectively (Weidle, Eggle et al. 2010, Te Riet, Helenius et al. 2014). ALCAM also binds IQ-GAP1 following homotypic interactions (ALCAM-ALCAM) of ectodomains. PKCa also plays a role in the modulation of ALCAM- dependent adhesion (Zimmerman, Nelissen et al. 2004). However, the cytoplasmic domain does not contain conserved PKC-phosphorylation motifs and despite there being two serines and two threonines present in the cytoplasmic domain of ALCAM, these are dispensable for ALCAM-mediated adhesion (Zimmerman, Nelissen et al. 2004).

[00016] Prior art teaches away from the cytoplasmic domain of ALCAM being significantly involved in ALCAM-mediated adhesion. Mutant ALCAM constructs in which the cytoplasmic domain has been deleted retain the actions of full-length ALCAM on cell proliferation, while constructs lacking the extracellular N-terminal V-domain are non-functional with respect to adhesion, ligand binding and proliferation.

[00017] Melanoma cell adhesion molecule (MCAM) (also known as M-CAM, CD146 or cell MUC18) is a 1 13kDa cell adhesion molecule of the immunoglobulin superfamily of cell adhesion molecules (IgSF CAM) with 22.7% identity and 41 .7% similarity to ALCAM. Like ALCAM, it contains a large multi-ligand binding extracellular immunoglobulin-like ectodomain, comprising two N-terminal, membrane-distal variable-(V)-type and three membrane-proximal constant-(C2)-type Ig folds (VVC2C2C2) ectodomain, a single-span transmembrane domain and a short (63 amino acid) cytosolic domain.

[00018] MCAM is primarily implicated in cell adhesion between adjacent cells, mediated by homophilic trans interactions (MCAM-MCAM) or heterophilic interaction (MCAM-laminin4) specifically via its NH2-terminal V-type immunoglobulin folds while the proximal C-type immunoglobulin folds mediate oligomerization in cis (Wang and Yan 2013).

[00019] MCAM also functions as a pattern recognition multi-ligand receptor with diverse ligands including S100 proteins that trigger activation of NFKB dependent pathways (Ruma, Putranto et al. 2016). [00020] The interaction of MCAM with VEGFR-2 on the endothelial cell surface has been shown to activate AKT and p38 signaling and increase cell migration (Jouve, Bachelier et al. 2015). Interaction with Laminin-4 facilitates Th17 cell entry into the central nervous system. Binding of Netrin-1 to CD146/MCAM was reported to activate an array of downstream signaling and increase endothelial cell proliferation, migration, and angiogenesis (Tu, Zhang et al. 2015). Recently, CD146 was reported to interact with galectin-1 and galectin-3 (Colomb, Wang et al. 2017). Notably, the extracellular (ligand binding) ectodomain of MCAM appears to be critical for these functions.

[00021 ] MCAM is actively involved in many normal cellular processes including vascular development, signal transduction, cell migration, mesenchymal stem cell differentiation, angiogenesis and immune response (Shih 1999).

[00022] MCAM is highly expressed by endothelial cells and has been used for the identification of endothelial progenitors in the circulation. MCAM is also expressed on other vascular cells including smooth muscle and pericytes. Soluble MCAM thought to be a marker of endothelial damage. MCAM is also a differentiation marker of intermediary placental trophoblast, and is expressed in mammary lobular and ductal epithelium (Guezguez et al. 2006).

[00023] MCAM is also known to be highly expressed by melanoma cells where it is associated with melanoma metastasis (Johnson 1999). CD146 is also overly expressed on a large variety of carcinomas in addition to melanoma (Wang and Yan 2013). It is thought that CD146 promotes tumor growth, angiogenesis, and metastasis, and CD146 is regarded as a promising target for tumor therapy (Wang and Yan 2013).

[00024] Although the ligand-binding actions of the ectodomain of MCAM are known, the functions of the cytoplasmic domain of MCAM are poorly understood. It is thought that the cytosolic tail of MCAM possibly regulates adhesion through links with the cytoskeleton. The cytosolic tail of MCAM contains two potential recognition sites for protein kinase C (PKC), an ERM (protein complex of ezrin, radixin and moesin) binding site, a motif with microvilli extension and a double leucine motif for baso-lateral targeting in epithelia. Although the cytosolic tail is not required for ligand binding and adhesion, the mutant MCAM in which the cytosolic tail has been deleted is unable to activate NFKB after activation with S100A8/A9 (Ruma, Putranto et al. 2016).

[00025] Basal cell adhesion molecule (BCAM), also known as the Lutheran blood group glycoprotein, is a 78-85 kDa cell adhesion molecule of the immunoglobulin superfamily of cell adhesion molecules (IgSF CAM) similar to ALCAM. Like ALCAM, BCAM contains a large multi-ligand binding extracellular immunoglobulin-like ectodomain, comprising two N-terminal, membrane-distal variable-(V)-type and three membrane-proximal constant-(C2)-type Ig folds (VVC2C2C2) ectodomain, a single-span transmembrane domain and a short cytosolic domain. The 78 kDa isoform exhibits the same N-terminal amino acid sequence as the 85 kDa but lacks the last 40 C-terminal amino acids of the cytoplasmic tail.

[00026] BCAM is primarily implicated in cell adhesion between adjacent cells, mediated by homophilic (trans) interactions (BCAM-BCAM) or heterophilic interaction (BCAM-laminina5 or BCAM-integrin a4b1 ) specifically via its NFMerminal V-type immunoglobulin folds while the proximal C-type immunoglobulin folds mediate oligomerization in cis. The extracellular domains of BCAM represent high affinity laminin receptors (El Nemer, Gane et al. 1998). Furthermore, the long-tail (85 kDa) or the short-tail (78 kDa) BCAM confer to transfected cells the same laminin binding capacity.

[00027] BCAM was originally identified in the Lutheran blood group system and is the major laminin-binding protein in sickle red cells (Zen, Batchvarova et al. 2004), myeloproliferative neoplasms (Novitzky-Basso, Spring et al. 2018), and polycythemia rubra vera (De Grandis, Cassinat et al. 2015), where it mediates endothelial cell adhesion.

[00028] BCAM may also have a role in leukocyte recruitment in inflamed tissue, including crescentic glomerulonephritis, where BCAM deficiency was sufficient to prevent severe glomerular damage and renal failure in mice (Fluang, Filipe et al. 2014).

[00029] BCAM is implicated in the development and progression of a range of cancers. BCAM has been shown to be upregulated in skin, brain, and endometrial-ovarian tumors, in hepatocellular carcinoma, and in breast cancer, where it represents an independent marker of response to neoadjuvant chemotherapy (Bartolini, Cardaci et al. 2016). Data suggest that BCAM-targeted agents might have broad application in different tumor types (Bartolini, Cardaci et al. 2016).

[00030] Although the ligand-binding actions of the ectodomain of BCAM are known, the functions of the cytoplasmic domain of BCAM are poorly understood. The predominant 78kDa isoform has a tail of only 20 amino acids, while the 85kDa isoform’s tail is 60 amino acids long. It is thought that the cytosolic tail of BCAM possibly regulates adhesion through links with the cytoskeleton. The Arg573Lys574 motif in the shared cytoplasmic tail of BCAM attaches to the spectrin cytoskeleton and regulates cell adhesive activity and actin organization in epithelial cells. The cytoplasmic tail carries an SFI3 binding motif, a di-leucine motif, and potential phosphorylation sites. Protein kinase A phosphorylates Ser621 in the cytoplasmic tail and stimulates adhesion of sickled red blood cells to laminin under flow conditions. A constitutively active JAK2 promotes Lu-mediated red cell adhesion through the Rap1/Akt pathway. The abnormal adhesion of red blood cells to laminin a5 is due to the Ser621 phosphorylation of Lu/BCAM by the JAK2/Rap1/Akt pathway (Kikkawa, Ogawa et al. 2013).

[00031 ] Epithelial cell adhesion molecule (EpCAM) is a 30- to 40-kDa type I membrane glycoprotein. EpCAM is known to play a role in cell adhesion through homotypic interactions as well as cell signaling, migration, proliferation, and differentiation. Like other IgSF CAMs it contains an immunoglobulin-like extracellular domain, a single transmembrane domain and a short (26 amino acids) intracellular domain, sometimes referred to as EpICD. The intracellular domain of EpCAM (EpICD) is required for EpCAM to mediate intercellular adhesion due to its ability to inteact with the intracellular actin cytoskeleton via alpha-actinin.

[00032] EpCAM is highly expressed in epithelial cancers, including colon carcinoma where it is thought to play a role in oncogenicity, tumorigenesis and metastasis. EpCAM expression has been considered to be a prognostic marker as well as a potential target for immunotherapeutic strategies.

[00033] EpCAM can be cleaved from the cell surface, releasing the extracellular domain into the area surrounding the cell, and EpICD is released into the cytoplasm, where it forms a complex with the proteins FHL2, b-catenin, and Lef that binds to DNA and promotes the transcription of genes that promote tumor growth. Nuclear localisation of EpICD is a poor prognostic feature of epithelial cancers.

[00034] Cell Adhesion Molecule 4 (CADM4) is a type I membrane glycoprotein known to play a role in cell adhesion through homotypic interactions as well as cell signaling, migration, proliferation, and differentiation. Like other IgSF CAMs it contains an immunoglobulin-like extracellular domain, a single transmembrane domain and a short (43 amino acid) intracellular domain. The loss of or reduced expression of CADM4 is associated with tumor progression in some cancers.

[00035] CADM4 is also a member of the nectin-like (Neel) adhesion proteins also known as SynCAMs, Necl-proteins play an important role in nerve myelination and neurodevelopment, partly through regulation of axon-glia interactions.

[00036] The renin-angiotensin aldosterone system (RAAS) is a key homeostatic pathway that is also implicated in the development and progression of many common diseases and disease processes. Inhibition of the renin-angiotensin aldosterone system (RAAS) with angiotensin-converting enzyme (ACE) inhibitors, or angiotensin II receptor type 1 (ATi R) blockers (inhibitors) is widely used for the management of many diseases and/or conditions including hypertension, cardiovascular disease (CVD), heart failure, chronic kidney disease (CKD), and diabetic complications. RAAS inhibition has also been shown to have benefits in preventing diabetes (Tikellis et ai, 2004), in neuroprotection (Thoene-Reineke et ai, 201 1 ), modifying the growth of certain cancers (Shen et ai, 2016) and even in ageing, with genetic deletion of ATi R conferring longevity in mice (Benigni et ai, 2009).

[00037] These actions of RAAS blockers are additional to and independent of blood pressure lowering conferred by RAAS blockers, as comparable lowering of the blood pressure with other agents does not confer the same benefits (Lee et ai., 1993). Specifically, activation of the ATi R by angiotensin II (Ang II) triggers induction of oxidative stress, activation of Nuclear Factor KB (NFKB) and inflammation through pathways that are distinct from those that cause vasoconstriction.

[00038] Activation of the renin-angiotensin aldosterone system (RAAS) is known to be an important mediator of atherosclerosis (Lee et a!., 1993; and Jacoby et a/., 2003). Atherogenesis is increased following an infusion of angiotensin (Ang) II and in experimental models is associated with physiological RAAS activation, including a low salt diet (Tikellis et a/., 2012), diabetes (Goldin et ai., 2006; and Soro-Paavonen et ai., 2008) and genetic deletion of angiotensin converting enzyme 2 ( Ace2 ) (Thomas et ai, 2010), independent of its effects on blood pressure homeostasis. Similarly, inhibition of the RAAS has anti-atherosclerotic actions that are additional to and independent of lowering systemic blood pressure (Candido et at., 2002; Candido et at., 2004; and Knowles et at., 2000). Ang II has a number of direct pro-atherosclerotic effects (Daugherty et ai, 2000; Ferrario et ai, 2006; and Ekholm et ai, 2009), including the induction of oxidative stress (Rajagopalan etai, 1996), vascular adhesion (Grafe et ai, 1997) and inflammation (Marvar et ai, 2010).

[00039] These pro-atherosclerotic actions are thought to be primarily mediated by activation of the type 1 angiotensin receptor (ATi R) and subsequent induction of reactive oxygen species (ROS) and activation of NFKB signalling (Li et ai, 2008). However, the signalling mechanisms that underlie these actions are poorly understood, including their relative independence from conventional vasoconstrictor signalling via the ATi R.

[00040] It is against this background that the inventors describe the selective interactions between certain activated GPCRs, such as ATi R, and the cytosolic tail of certain IgSF CAMs, independently of any IgSF CAM ligand, or the transmembrane domain or ectodomain of said IgSF CAMs, initiating downstream signalling leading to activation of NFKB, a key transcription factor implicated in inflammation, oxidative stress, fibrogenesis, cellular proliferation and cellular survival.

[00041] The inventors have shown that selective modulation, such as inhibition, of IgSF CAM ligand-independent activation (transactivation) of the cytosolic tail of certain IgSF CAMs by certain activated GPCRs, can be achieved by targeting this pathway using common signalling elements shared by these IgSF CAMs, and the inventors’ assays and modulators identified therefrom, act upon this transactivation (ligand-independent activation of an IgSF CAM) process.

[00042] The inventors show that an analogue, fragment or derivative of an IgSF CAM can modulate signalling mediated by the cytosolic tails of certain IgSF CAMs.

[00043] The inventors further show that an analogue, fragment or derivative of the Receptor for Advanced Glycation End-Products (RAGE) can also modulate signalling mediated by the cytosolic tails of certain IgSF CAMs.

[00044] The inventors further show that an analogue, fragment or derivative of certain IgSF CAMs can modulate RAGE ligand-independent activation of RAGE by certain activated co located GPCRs and resultant signalling mediated by the cytosolic tail of RAGE.

SUMMARY OF THE INVENTION

[00045] The inventors have shown that key elements in the cytosolic tail of RAGE can modulate activation of IgSF CAMs, specifically ALCAM, BCAM, EpCAM, CADM4 and MCAM.

[00046] The inventors have further shown that key elements in the cytosolic tail of RAGE can modulate IgSF CAM ligand-independent activation of IgSF CAMs, specifically ALCAM, BCAM, EpCAM, CADM4 and MCAM, by certain activated co-located GPCRs, specifically the AT 1 receptor by Angiotensin II.

[00047] The inventors have shown that following activation of certain co-located GPCRs, such as ATiR by Ang II, the cytosolic tail of IgSF CAMs, and specifically ALCAM, BCAM, EpCAM, CADM4 and MCAM, can be activated, independently of any cognate ligand or the ectodomain of said IgSF CAMs, initiating downstream signalling leading to activation of NFKB, a key transcription factor implicated in inflammation, oxidative stress, fibrogenesis, cellular proliferation and cellular survival.

[00048] In one form of the invention, the human ALCAM ectodomain (500 amino acids) corresponds to residues 28-527. [00049] In one form of the invention, the human MCAM ectodomain (536 amino acids) corresponds to residues 24-559.

[00050] In one form of the invention, the human BCAM ectodomain (516 amino acids) corresponds to residues 32-547.

[00051 ] In one form of the invention, the human EpCAM ectodomain (242 amino acids) corresponds to residues 24-265.

[00052] In one form of the invention, the human CADM4 ectodomain (304 amino acids) corresponds to residues 21 - 324.

[00053] In one form of the invention, the human ALCAM cytosolic tail (cytosolic domain; 34 amino acids) corresponds to residues 550-583.

[00054] In one form of the invention, the human ALCAM cytosolic tail (cytosolic domain; 33 amino acids) corresponds to residues 551 -583.

[00055] In one form of the invention, the human MCAM cytosolic tail (cytosolic domain; 63 amino acids) corresponds to residues 584-646.

[00056] In one form of the invention, the MCAM cytosolic tail (cytosolic domain; 54 amino acids) corresponds to residues 584-637.

[00057] In one form of the invention, the human BCAM cytosolic tail (cytosolic domain; 60 amino acids) corresponds to residues 569-628.

[00058] In one form of the invention, the human EpCAM cytosolic tail (cytosolic domain 26 amino acids) corresponds to residues 289-314.

[00059] In one form of the invention, the human CADM4 cytosolic tail (cytosolic domain 43 amino acids) corresponds to residues 346-388.

[00060] The inventors have further shown that key elements in the cytosolic tail of an IgSF CAM, specifically ALCAM, can also modulate RAGE ligand-independent activation of RAGE by certain activated co-located GPCRs, specifically activation of the AT1 receptor by Angiotensin II.

[00061 ] Prior art does not suggest or disclose any evidence for a functional interaction between the cytosolic tail of an IgSF CAM and a GPCR, such as an angiotensin receptor, such as AT 1 R. Nor does it anticipate that activation of a GPCR by that GPCR’s cognate ligand, such as an angiotensin receptor by Ang II, would directly result in activation of an IgSF CAM, in particular the cytosolic tail, nor the subsequent induction of signalling via an IgSF CAM, in the absence of any ligand for the IgSF CAM or indeed without requiring the presence of the ligand binding ectodomain of these proteins, which is considered necessary for signalling and teaches away from these findings. Consequently, it could not be anticipated that modulation of ligand-independent activation of the cytosolic tail of an IgSF CAM would involve modulation of signalling induced following activation of a certain co-located GPCR, such as by binding of Ang II to the ATi R.

[00062] In a preferred form of the present invention, the IgSF CAM is ALCAM.

[00063] In another preferred form of the present invention, the IgSF CAM is BCAM.

[00064] In another preferred form of the present invention, the IgSF CAM is MCAM.

[00065] In another preferred form of the present invention, the IgSF CAM is EpCAM.

[00066] In another preferred form of the present invention, the IgSF CAM is CADM4.

[00067] In a particularly preferred form of the present invention, the IgSF CAM is ALCAM or BCAM.

[00068] In another particularly preferred form of the present invention, the IgSF CAM is ALCAM or MCAM.

[00069] In another particularly preferred form of the present invention, the IgSF CAM is ALCAM or EpCAM.

[00070] In another particularly preferred form of the present invention, the IgSF CAM is ALCAM or CADM4.

[00071 ] In another particularly preferred form of the present invention, the IgSF CAM is BCAM or MCAM.

[00072] In another particularly preferred form of the present invention, the IgSF CAM is BCAM or EpCAM.

[00073] In another particularly preferred form of the present invention, the IgSF CAM is BCAM or CADM4. [00074] In another particularly preferred form of the present invention, the IgSF CAM is MCAM or EpCAM.

[00075] In another particularly preferred form of the present invention, the IgSF CAM is MCAM or CADM4.

[00076] In another particularly preferred form of the present invention, the IgSF CAM is EpCAM or CADM4.

[00077] In another particularly preferred form of the present invention, the IgSF CAM is ALCAM or BCAM or MCAM.

[00078] In another particularly preferred form of the present invention, the IgSF CAM is ALCAM or BCAM or EpCAM.

[00079] In another particularly preferred form of the present invention, the IgSF CAM is ALCAM or BCAM or CADM4.

[00080] In another particularly preferred form of the present invention, the IgSF CAM is ALCAM or MCAM or EpCAM.

[00081] In another particularly preferred form of the present invention, the IgSF CAM is ALCAM or MCAM or CADM4.

[00082] In another particularly preferred form of the present invention, the IgSF CAM is ALCAM or EpCAM or CADM4.

[00083] In another particularly preferred form of the present invention, the IgSF CAM is BCAM or MCAM or EpCAM.

[00084] In another particularly preferred form of the present invention, the IgSF CAM is BCAM or MCAM or CADM4.

[00085] In another particularly preferred form of the present invention, the IgSF CAM is MCAM or EpCAM or CADM4.

[00086] In another particularly preferred form of the present invention, the IgSF CAM is ALCAM or BCAM or MCAM or EpCAM.

[00087] In another particularly preferred form of the present invention, the IgSF CAM is ALCAM or BCAM or MCAM or CADM4. [00088] In another particularly preferred form of the present invention, the IgSF CAM is BCAM or MCAM or EpCAM or CADM4.

[00089] In another particularly preferred form of the present invention, the IgSF CAM is ALCAM or MCAM or EpCAM or CADM4.

[00090] In another particularly preferred form of the present invention, the IgSF CAM is ALCAM or BCAM or EpCAM or CADM4.

[00091 ] In another particularly preferred form of the present invention, the IgSF CAM is ALCAM or BCAM or MCAM or EpCAM or CADM4.

[00092] In one form of the present invention, the IgSF CAM superfamily (IgSF CAMs) comprises: ALCAM (also known as CD166 or MEMD), BCAM (also known as CD239), BOC (also known as CDON2), CADM1 (also known as NECL2, ST17, BL2, SYNCAM, IGSF4A, Necl-2, SYNCAM 1 or RA175), CADM2 (also known as NECL3, Necl-3 or SynCAM2), CADM3 (also known as BlgR, FLJ10698, TSLL1 , NECL1 , SynCAM3 or Necl-1 ), CADM4 (also known as TSLL2, Necl-4 or SynCAM4), CD2, CD244 (also known as 2B4, NAIL, NKR2B4, Nmrk or SLAMF4), CD28, CD47 (also known as IAP or OA3), CD58, CD84 (also known as SLAMF5, hCD84 or mCD84), CD96 (also known as TACTILE), CHL1 (also known as CALL, L1 CAM2, FLJ44930 or MGC132578), CNTN1 (also known as F3 or GP135), CNTN2 (also known as TAG-1 or TAXI ), CNTN3 (also known as BIG-1 ), CNTN4 (also known as BIG-2), CNTN5 (also known as NB-2 or hNB-2), CNTN6 (also known as NB-3), CRTAM (also known as CD355), DSCAM (also known as CHD2-42 or CHD2-52), DSCAML1 (also known as KIAA1 132), F1 1 R (also known as PAM-1 , JCAM, JAM-1 , JAM-A, JAMA or CD321 ), FGFRL1 , GP6 (also known as GPVI), HEPACAM (also known as FLJ25530, hepaCAM or GLIALCAM), ICAM1 (also known as BB2 or CD54), ICAM2 (also known as CD102), ICAM3 (also known as CDW50, ICAM-R or CD50), ICAM4 (also known as CD242), ICAM5 (also known as TLN), IGSF5 (also known as JAM4), IZUM01 (also known as IZUMO, MGC34799 or OBF), IZUM01 R (also known as Folbp3 or JUNO), JAM2 (also known as VE-JAM, JAM-B, JAMB or CD322), JAM3 (also known as JAM-C or JAMC), JAML (also known as Gm638 or AMICA), L1 CAM (also known as CD171 ), LILRB2 (also known as LIR-2, ILT4, MIR-10, LIR2, CD85d or MIR10), LRFN1 (also known as KIAA1484 or SALM2), LRFN2 (also known as FIGLER2), LRFN3 (also known as MGC2656, SALM4 or FIGLER1 ), LRFN4 (also known as MGC3103, SALM3. or FIGLER6), LRFN5 (also known as FIGLER8, SALM5), LRRC4 (also known as NAG 14), LRRC4B (also known as DKFZp761 A179 or HSM), LRRC4C (also known as KIAA1580 or NGL-1 ), MADCAM1 (also known as MACAM1 ), MCAM (also known as MUC18, CD146, MelCAM, METCAM or HEMCAM), MPZ (also known as HMSNIB, CMT2I or CMT2J), MPZL2 (also known as EVA), NCAM1 (also known as NCAM or CD56), NCAM2 (also known as NCAM21 or MGC51008), NECTIN1 (also known as PRR, PRR1 , PVRR1 , SK-12, HlgR, CLPED1 , CD1 1 1 or OFC7), NECTIN2 (also known as PVRR2, PRR2 or CD1 12), NECTIN3 (also known as nectin-3, PPR3, PVRR3, DKFZP566B0846, CDw1 13 or CD1 13), NECTIN4 (also known as nectin-4, PRR4 or LNIR), NE01 (also known as NGN, HsT17534, IGDCC2 or NTN1 R2), NFASC (also known as NRCAML, KIAA0756, FLJ46866 or NF), NRCAM (also known as KIAA0343 or Bravo), PECAM1 (also known as CD31 ), PTPRM (also known as RPTPU or hR-PTPu), PVR (also known as CD155, HVED, Necl-5, NECL5 or Tage4), R0B01 (also known as DUTT1 , FLJ21882 or SAX3), R0B02 (also known as KIAA1568), SDK1 (also known as FLJ31425), SIGLECL1 (also known as FLJ40235), SIRPA (also known as SHPS1 , SIRP, MYD-1 , BIT, P84, SHPS-1 , SIRPalpha, CD172a, SIRPalpha2, MFR or SIRP-ALPHA- 1 ), SIRPG (also known as bA77C3.1 , SIRP-B2, SIRPgamma or CD172g), SLAMF1 (also known as CD150), SLAMF6 (also known as KALI, NTBA, KALIb, Ly108, SF2000, NTB-A or CD352), THY1 (also known as CD90), UNC5A (also known as KIAA1976 or UNC5H1 ), UNC5B (also known as UNC5H2 or p53RDL1 ), UNC5D (also known as KIAA1777 or Unc5h4), VCAM1 (also known as CD106), CLMP (also known as ASAM, FLJ22415 or ACAM), CXADR (also known as CAR), ESAM (also known as W1 17m), GPA33 (also known as A33), IGSF1 1 (also known as BT-lgSF, MGC35227, Igsf13, VSIG3 or CT1 19), VSIG1 (also known as MGC44287), VSIG2 (also known as CTXL, CTH), VSIG8, OPCML (also known as OPCM, OBCAM or IGLON1 ), NTM (also known as FI NT, NTRI, IGLON2 or CEPU-1 ), LSAMP (also known as LAMP or IGLON3), NEGR1 (also known as KILON, MGC46680, Ntra or IGLON4), IGLON5 (also known as LOC402665), SIGLEC1 (also known as SIGLEC-1 , CD169, FLJ00051 , FLJ00055, FLJ00073, FLJ32150, dJ1009E24.1 or sialoadhesin), SIGLEC10 (also known as SIGLEC-10, SLG2, PRO940 or MGC126774), SIGLEC1 1 , SIGLEC12 (also known as SLG, S2V, Siglec-XII, Siglec-12 or Siglec-L1 ), SIGLEC14, SIGLEC15 (also known as HsT1361 ), SIGLEC16 (also known as Siglec-P16), SIGLEC17P, SIGLEC18P, CD22 (also known as SIGLEC-2 or SIGLEC2), SIGLEC20P, SIGLEC21 P, SIGLEC22P, SIGLEC24P, SIGLEC25P, SIGLEC26P, SIGLEC27P, SIGLEC28P, SIGLEC29P, CD33 (also known as SIGLEC3, SIGLEC-3, p67 or FLJ00391 ), SIGLEC30P, SIGLEC31 P, MAG (also known as SIGLEC4A, SIGLEC-4A or S-MAG), SIGLEC5 (also known as OB-BP2, SIGLEC-5 or CD170), SIGLEC6 (also known as OB-BP1 , SIGLEC-6 or CD327), SIGLEC7 (also known as SIGLEC- 7, p75/AIRM1 , QA79 or CD328), SIGLEC8 (also known as SIGLEC-8, SAF2, SIGLEC8L or MGC59785), and SIGLEC9 (also known as CD329).

[00093] In one form of the present invention, the IgSF CAM superfamily (IgSF CAMs) comprises: ALCAM (also known as CD166 or MEMD), BCAM (also known as CD239), BOC (also known as CDON2), CADM1 (also known as NECL2, ST17, BL2, SYNCAM, IGSF4A, Necl-2, SYNCAM1 or RA175), CADM2 (also known as NECL3, Necl-3 or SynCAM2), CADM3 (also known as BlgR, FLJ10698, TSLL1 , NECL1 , SynCAM3 or Necl-1 ), CADM4 (also known as TSLL2, Necl-4 or SynCAM4), CD2, CD244 (also known as 2B4, NAIL, NKR2B4, Nmrk or SLAMF4), CD28, CD47 (also known as IAP or OA3), CD58, CD84 (also known as SLAMF5, hCD84 or mCD84), CD96 (also known as TACTILE), CHL1 (also known as CALL, L1 CAM2, FLJ44930 or MGC132578), CNTN1 (also known as F3 or GP135), CNTN2 (also known as TAG-1 or TAXI ), CNTN3 (also known as BIG-1 ), CNTN4 (also known as BIG-2), CNTN5 (also known as NB-2 or hNB-2), CNTN6 (also known as NB-3), CRTAM (also known as CD355), DSCAM (also known as CHD2-42 or CHD2-52), DSCAML1 (also known as KIAA1 132), F1 1 R (also known as PAM-1 , JCAM, JAM-1 , JAM-A, JAMA or CD321 ), FGFRL1 , GP6 (also known as GPVI), HEPACAM (also known as FLJ25530, hepaCAM or GLIALCAM), ICAM1 (also known as BB2 or CD54), ICAM2 (also known as CD102), ICAM3 (also known as CDW50, ICAM-R or CD50), ICAM4 (also known as CD242), ICAM5 (also known as TLN), IGSF5 (also known as JAM4), IZUM01 (also known as IZUMO, MGC34799 or OBF), IZUM01 R (also known as Folbp3 or JUNO), JAM2 (also known as VE-JAM, JAM-B, JAMB or CD322), JAM3 (also known as JAM-C or JAMC), JAML (also known as Gm638 or AMICA), L1 CAM (also known as CD171 ), LILRB2 (also known as LIR-2, ILT4, MIR-10, LIR2, CD85d or MIR10), LRFN1 (also known as KIAA1484 or SALM2), LRFN2 (also known as FIGLER2), LRFN3 (also known as MGC2656, SALM4 or FIGLER1 ), LRFN4 (also known as MGC3103, SALM3. or FIGLER6), LRFN5 (also known as FIGLER8, SALM5), LRRC4 (also known as NAG 14), LRRC4B (also known as DKFZp761 A179 or HSM), LRRC4C (also known as KIAA1580 or NGL-1 ), MADCAM1 (also known as MACAM1 ), MCAM (also known as MUC18, CD146, MelCAM, METCAM or HEMCAM), MPZ (also known as HMSNIB, CMT2I or CMT2J), MPZL2 (also known as EVA), NCAM1 (also known as NCAM or CD56), NCAM2 (also known as NCAM21 or MGC51008), NECTIN1 (also known as PRR, PRR1 , PVRR1 , SK-12, HlgR, CLPED1 , CD1 1 1 or OFC7), NECTIN2 (also known as PVRR2, PRR2 or CD1 12), NECTIN3 (also known as nectin-3, PPR3, PVRR3, DKFZP566B0846, CDw1 13 or CD1 13), NECTIN4 (also known as nectin-4, PRR4 or LNIR), NE01 (also known as NGN, HsT17534, IGDCC2 or NTN1 R2), NFASC (also known as NRCAML, KIAA0756, FLJ46866 or NF), NRCAM (also known as KIAA0343 or Bravo), PECAM1 (also known as CD31 ), PTPRM (also known as RPTPU or hR-PTPu), PVR (also known as CD155, HVED, Necl-5, NECL5 or Tage4), R0B01 (also known as DUTT1 , FLJ21882 or SAX3), R0B02 (also known as KIAA1568), SDK1 (also known as FLJ31425), SIGLECL1 (also known as FLJ40235), SIRPA (also known as SHPS1 , SIRP, MYD-1 , BIT, P84, SHPS-1 , SIRPalpha, CD172a, SIRPalpha2, MFR or SIRP-ALPHA- 1 ), SIRPG (also known as bA77C3.1 , SIRP-B2, SIRPgamma or CD172g), SLAMF1 (also known as CD150), SLAMF6 (also known as KALI, NTBA, KALIb, Ly108, SF2000, NTB-A or CD352), THY1 (also known as CD90), UNC5A (also known as KIAA1976 or UNC5H1 ), UNC5B (also known as UNC5H2 or p53RDL1 ), UNC5D (also known as KIAA1777 or Unc5h4), VCAM1 (also known as CD106), CLMP (also known as ASAM, FLJ22415 or ACAM), CXADR (also known as CAR), ESAM (also known as W1 17m), GPA33 (also known as A33), IGSF1 1 (also known as BT-lgSF, MGC35227, Igsf13, VSIG3 or CT1 19), VSIG1 (also known as MGC44287), VSIG2 (also known as CTXL, CTH), VSIG8, OPCML (also known as OPCM, OBCAM or IGLON1 ), NTM (also known as HNT, NTRI, IGLON2 or CEPU-1 ), LSAMP (also known as LAMP or IGLON3), NEGR1 (also known as KILON, MGC46680, Ntra or IGLON4) and IGLON5 (also known as LOC402665).

[00094] In one form of the present invention, the IgSF CAM superfamily (IgSF CAMs) comprises: ALCAM (also known as CD166 or MEMD), BCAM (also known as CD239), BOC (also known as CDON2), CADM1 (also known as NECL2, ST17, BL2, SYNCAM, IGSF4A, Necl-2, SYNCAM 1 or RA175), CADM2 (also known as NECL3, Necl-3 or SynCAM2), CADM3 (also known as BlgR, FLJ10698, TSLL1 , NECL1 , SynCAM3 or Necl-1 ), CADM4 (also known as TSLL2, Necl-4 or SynCAM4), CD2, CD244 (also known as 2B4, NAIL, NKR2B4, Nmrk or SLAMF4), CD28, CD47 (also known as IAP or OA3), CD58, CD84 (also known as SLAMF5, hCD84 or mCD84), CD96 (also known as TACTILE), CHL1 (also known as CALL, L1 CAM2, FLJ44930 or MGC132578), CNTN1 (also known as F3 or GP135), CNTN2 (also known as TAG-1 or TAXI ), CNTN3 (also known as BIG-1 ), CNTN4 (also known as BIG-2), CNTN5 (also known as NB-2 or hNB-2), CNTN6 (also known as NB-3), CRTAM (also known as CD355), DSCAM (also known as CHD2-42 or CHD2-52), DSCAML1 (also known as KIAA1 132), F1 1 R (also known as PAM-1 , JCAM, JAM-1 , JAM-A, JAMA or CD321 ), FGFRL1 , GP6 (also known as GPVI), HEPACAM (also known as FLJ25530, hepaCAM or GLIALCAM), ICAM1 (also known as BB2 or CD54), ICAM2 (also known as CD102), ICAM3 (also known as CDW50, ICAM-R or CD50), ICAM4 (also known as CD242), ICAM5 (also known as TLN), IGSF5 (also known as JAM4), IZUM01 (also known as IZUMO, MGC34799 or OBF), IZUM01 R (also known as Folbp3 or JUNO), JAM2 (also known as VE-JAM, JAM-B, JAMB or CD322), JAM3 (also known as JAM-C or JAMC), JAML (also known as Gm638 or AMICA), L1 CAM (also known as CD171 ), LILRB2 (also known as LIR-2, ILT4, MIR-10, LIR2, CD85d or MIR10), LRFN1 (also known as KIAA1484 or SALM2), LRFN2 (also known as FIGLER2), LRFN3 (also known as MGC2656, SALM4 or FIGLER1 ), LRFN4 (also known as MGC3103, SALM3. or FIGLER6), LRFN5 (also known as FIGLER8, SALM5), LRRC4 (also known as NAG 14), LRRC4B (also known as DKFZp761 A179 or HSM), LRRC4C (also known as KIAA1580 or NGL-1 ), MADCAM1 (also known as MACAM1 ), MCAM (also known as MUC18, CD146, MelCAM, METCAM or HEMCAM), MPZ (also known as HMSNIB, CMT2I or CMT2J), MPZL2 (also known as EVA), NCAM1 (also known as NCAM or CD56), NCAM2 (also known as NCAM21 or MGC51008), NECTIN1 (also known as PRR, PRR1 , PVRR1 , SK-12, HlgR, CLPED1 , CD1 1 1 or OFC7), NECTIN2 (also known as PVRR2, PRR2 or CD1 12), NECTIN3 (also known as nectin-3, PPR3, PVRR3, DKFZP566B0846, CDw1 13 or CD1 13), NECTIN4 (also known as nectin-4, PRR4 or LNIR), NE01 (also known as NGN, HsT17534, IGDCC2 or NTN1 R2), NFASC (also known as NRCAML, KIAA0756, FLJ46866 or NF), NRCAM (also known as KIAA0343 or Bravo), PECAM1 (also known as CD31 ), PTPRM (also known as RPTPU or hR-PTPu), PVR (also known as CD155, HVED, Necl-5, NECL5 or Tage4), R0B01 (also known as DUTT1 , FLJ21882 or SAX3), R0B02 (also known as KIAA1568), SDK1 (also known as FLJ31425), SIGLECL1 (also known as FLJ40235), SIRPA (also known as SHPS1 , SIRP, MYD-1 , BIT, P84, SHPS-1 , SIRPalpha, CD172a, SIRPalpha2, MFR or SIRP-ALPHA- 1 ), SIRPG (also known as bA77C3.1 , SIRP-B2, SIRPgamma or CD172g), SLAMF1 (also known as CD150), SLAMF6 (also known as KALI, NTBA, KALIb, Ly108, SF2000, NTB-A or CD352), THY1 (also known as CD90), UNC5A (also known as KIAA1976 or UNC5H1 ), UNC5B (also known as UNC5H2 or p53RDL1 ), UNC5D (also known as KIAA1777 or Unc5h4), VCAM1 (also known as CD106), CLMP (also known as ASAM, FLJ22415 or ACAM), CXADR (also known as CAR), ESAM (also known as W1 17m), GPA33 (also known as A33), IGSF1 1 (also known as BT-lgSF, MGC35227, Igsf13, VSIG3 or CT1 19), VSIG1 (also known as MGC44287), VSIG2 (also known as CTXL, CTH), VSIG8, SIGLEC1 (also known as SIGLEC- 1 , CD169, FLJ00051 , FLJ00055, FLJ00073, FLJ32150, dJ1009E24.1 or sialoadhesin), SIGLEC10 (also known as SIGLEC-10, SLG2, PRO940 or MGC126774), SIGLEC1 1 , SIGLEC12 (also known as SLG, S2V, Siglec-XII, Siglec-12 or Siglec-L1 ), SIGLEC14, SIGLEC15 (also known as HsT1361 ), SIGLEC16 (also known as Siglec-P16), SIGLEC17P, SIGLEC18P, CD22 (also known as SIGLEC-2 or SIGLEC2), SIGLEC20P, SIGLEC21 P, SIGLEC22P, SIGLEC24P, SIGLEC25P, SIGLEC26P, SIGLEC27P, SIGLEC28P, SIGLEC29P, CD33 (also known as SIGLEC3, SIGLEC-3, p67 or FLJ00391 ), SIGLEC30P, SIGLEC31 P, MAG (also known as SIGLEC4A, SIGLEC-4A or S-MAG), SIGLEC5 (also known as OB-BP2, SIGLEC-5 or CD170), SIGLEC6 (also known as OB-BP1 , SIGLEC-6 or CD327), SIGLEC7 (also known as SIGLEC-7, p75/AIRM1 , QA79 or CD328), SIGLEC8 (also known as SIGLEC-8, SAF2, SIGLEC8L or MGC59785), and SIGLEC9 (also known as CD329).

[00095] In one form of the present invention, the IgSF CAM superfamily (IgSF CAMs) comprises: ALCAM (also known as CD166 or MEMD), BCAM (also known as CD239), BOC (also known as CDON2), CADM1 (also known as NECL2, ST17, BL2, SYNCAM, IGSF4A, Necl-2, SYNCAM 1 or RA175), CADM2 (also known as NECL3, Necl-3 or SynCAM2), CADM3 (also known as BlgR, FLJ10698, TSLL1 , NECL1 , SynCAM3 or Necl-1 ), CADM4 (also known as TSLL2, Necl-4 or SynCAM4), CD2, CD244 (also known as 2B4, NAIL, NKR2B4, Nmrk or SLAMF4), CD28, CD47 (also known as IAP or OA3), CD58, CD84 (also known as SLAMF5, hCD84 or mCD84), CD96 (also known as TACTILE), CHL1 (also known as CALL, L1 CAM2, FLJ44930 or MGC132578), CNTN1 (also known as F3 or GP135), CNTN2 (also known as TAG-1 or TAXI ), CNTN3 (also known as BIG-1 ), CNTN4 (also known as BIG-2), CNTN5 (also known as NB-2 or hNB-2), CNTN6 (also known as NB-3), CRTAM (also known as CD355), DSCAM (also known as CHD2-42 or CHD2-52), DSCAML1 (also known as KIAA1 132), F1 1 R (also known as PAM-1 , JCAM, JAM-1 , JAM-A, JAMA or CD321 ), FGFRL1 , GP6 (also known as GPVI), HEPACAM (also known as FLJ25530, hepaCAM or GLIALCAM), ICAM1 (also known as BB2 or CD54), ICAM2 (also known as CD102), ICAM3 (also known as CDW50, ICAM-R or CD50), ICAM4 (also known as CD242), ICAM5 (also known as TLN), IGSF5 (also known as JAM4), IZUM01 (also known as IZUMO, MGC34799 or OBF), IZUM01 R (also known as Folbp3 or JUNO), JAM2 (also known as VE-JAM, JAM-B, JAMB or CD322), JAM3 (also known as JAM-C or JAMC), JAML (also known as Gm638 or AMICA), L1 CAM (also known as CD171 ), LILRB2 (also known as LIR-2, ILT4, MIR-10, LIR2, CD85d or MIR10), LRFN1 (also known as KIAA1484 or SALM2), LRFN2 (also known as FIGLER2), LRFN3 (also known as MGC2656, SALM4 or FIGLER1 ), LRFN4 (also known as MGC3103, SALM3. or FIGLER6), LRFN5 (also known as FIGLER8, SALM5), LRRC4 (also known as NAG 14), LRRC4B (also known as DKFZp761 A179 or HSM), LRRC4C (also known as KIAA1580 or NGL-1 ), MADCAM1 (also known as MACAM1 ), MCAM (also known as MUC18, CD146, MelCAM, METCAM or HEMCAM), MPZ (also known as HMSNIB, CMT2I or CMT2J), MPZL2 (also known as EVA), NCAM1 (also known as NCAM or CD56), NCAM2 (also known as NCAM21 or MGC51008), NECTIN1 (also known as PRR, PRR1 , PVRR1 , SK-12, HlgR, CLPED1 , CD1 1 1 or OFC7), NECTIN2 (also known as PVRR2, PRR2 or CD1 12), NECTIN3 (also known as nectin-3, PPR3, PVRR3, DKFZP566B0846, CDw1 13 or CD1 13), NECTIN4 (also known as nectin-4, PRR4 or LNIR), NE01 (also known as NGN, HsT17534, IGDCC2 or NTN1 R2), NFASC (also known as NRCAML, KIAA0756, FLJ46866 or NF), NRCAM (also known as KIAA0343 or Bravo), PECAM1 (also known as CD31 ), PTPRM (also known as RPTPU or hR-PTPu), PVR (also known as CD155, HVED, Necl-5, NECL5 or Tage4), R0B01 (also known as DUTT1 , FLJ21882 or SAX3), R0B02 (also known as KIAA1568), SDK1 (also known as FLJ31425), SIGLECL1 (also known as FLJ40235), SIRPA (also known as SHPS1 , SIRP, MYD-1 , BIT, P84, SHPS-1 , SIRPalpha, CD172a, SIRPalpha2, MFR or SIRP-ALPHA- 1 ), SIRPG (also known as bA77C3.1 , SIRP-B2, SIRPgamma or CD172g), SLAMF1 (also known as CD150), SLAMF6 (also known as KALI, NTBA, KALIb, Ly108, SF2000, NTB-A or CD352), THY1 (also known as CD90), UNC5A (also known as KIAA1976 or UNC5H1 ), UNC5B (also known as UNC5H2 or p53RDL1 ), UNC5D (also known as KIAA1777 or Unc5h4), OPCML (also known as OPCM, OBCAM or IGLON1 ), NTM (also known as HNT, NTRI, IGLON2 or CEPU-1 ), LSAMP (also known as LAMP or IGLON3), NEGR1 (also known as KILON, MGC46680, Ntra or IGLON4), IGLON5 (also known as LOC402665), SIGLEC1 (also known as SIGLEC-1 , CD169, FLJ00051 , FLJ00055, FLJ00073, FLJ32150, dJ1009E24.1 or sialoadhesin), SIGLEC10 (also known as SIGLEC-10, SLG2, PRO940 or MGC126774), SIGLEC1 1 , SIGLEC12 (also known as SLG, S2V, Siglec-XII, Siglec-12 or Siglec-L1 ), SIGLEC14, SIGLEC15 (also known as HsT1361 ), SIGLEC16 (also known as Siglec-P16), SIGLEC17P, SIGLEC18P, CD22 (also known as SIGLEC-2 or SIGLEC2), SIGLEC20P, SIGLEC21 P, SIGLEC22P, SIGLEC24P, SIGLEC25P, SIGLEC26P, SIGLEC27P, SIGLEC28P, SIGLEC29P, CD33 (also known as SIGLEC3, SIGLEC-3, p67 or FLJ00391 ), SIGLEC30P, SIGLEC31 P, MAG (also known as SIGLEC4A, SIGLEC-4A or S-MAG), SIGLEC5 (also known as OB-BP2, SIGLEC-5 or CD170), SIGLEC6 (also known as OB-BP1 , SIGLEC-6 or CD327), SIGLEC7 (also known as SIGLEC-7, p75/AIRM1 , QA79 or CD328), SIGLEC8 (also known as SIGLEC-8, SAF2, SIGLEC8L or MGC59785), and SIGLEC9 (also known as CD329).

[00096] In one form of the present invention, the IgSF CAM superfamily (IgSF CAMs) comprises: ALCAM (also known as CD166 or MEMD), BCAM (also known as CD239), BOC (also known as CDON2), CADM1 (also known as NECL2, ST17, BL2, SYNCAM, IGSF4A, Necl-2, SYNCAM 1 or RA175), CADM2 (also known as NECL3, Necl-3 or SynCAM2), CADM3 (also known as BlgR, FLJ10698, TSLL1 , NECL1 , SynCAM3 or Necl-1 ), CADM4 (also known as TSLL2, Necl-4 or SynCAM4), CD2, CD244 (also known as 2B4, NAIL, NKR2B4, Nmrk or SLAMF4), CD28, CD47 (also known as IAP or OA3), CD58, CD84 (also known as SLAMF5, hCD84 or mCD84), CD96 (also known as TACTILE), CHL1 (also known as CALL, L1 CAM2, FLJ44930 or MGC132578), CNTN1 (also known as F3 or GP135), CNTN2 (also known as TAG-1 or TAXI ), CNTN3 (also known as BIG-1 ), CNTN4 (also known as BIG-2), CNTN5 (also known as NB-2 or hNB-2), CNTN6 (also known as NB-3), CRTAM (also known as CD355), DSCAM (also known as CHD2-42 or CHD2-52), DSCAML1 (also known as KIAA1 132), F1 1 R (also known as PAM-1 , JCAM, JAM-1 , JAM-A, JAMA or CD321 ), FGFRL1 , GP6 (also known as GPVI), HEPACAM (also known as FLJ25530, hepaCAM or GLIALCAM), ICAM1 (also known as BB2 or CD54), ICAM2 (also known as CD102), ICAM3 (also known as CDW50, ICAM-R or CD50), ICAM4 (also known as CD242), ICAM5 (also known as TLN), IGSF5 (also known as JAM4), IZUM01 (also known as IZUMO, MGC34799 or OBF), IZUM01 R (also known as Folbp3 or JUNO), JAM2 (also known as VE-JAM, JAM-B, JAMB or CD322), JAM3 (also known as JAM-C or JAMC), JAML (also known as Gm638 or AMICA), L1 CAM (also known as CD171 ), LILRB2 (also known as LIR-2, ILT4, MIR-10, LIR2, CD85d or MIR10), LRFN1 (also known as KIAA1484 or SALM2), LRFN2 (also known as FIGLER2), LRFN3 (also known as MGC2656, SALM4 or FIGLER1 ), LRFN4 (also known as MGC3103, SALM3. or FIGLER6), LRFN5 (also known as FIGLER8, SALM5), LRRC4 (also known as NAG 14), LRRC4B (also known as DKFZp761 A179 or HSM), LRRC4C (also known as KIAA1580 or NGL-1 ), MADCAM1 (also known as MACAM1 ), MCAM (also known as MUC18, CD146, MelCAM, METCAM or HEMCAM), MPZ (also known as HMSNIB, CMT2I or CMT2J), MPZL2 (also known as EVA), NCAM1 (also known as NCAM or CD56), NCAM2 (also known as NCAM21 or MGC51008), NECTIN1 (also known as PRR, PRR1 , PVRR1 , SK-12, HlgR, CLPED1 , CD1 1 1 or OFC7), NECTIN2 (also known as PVRR2, PRR2 or CD1 12), NECTIN3 (also known as nectin-3, PPR3, PVRR3, DKFZP566B0846, CDw1 13 or CD1 13), NECTIN4 (also known as nectin-4, PRR4 or LNIR), NE01 (also known as NGN, HsT17534, IGDCC2 or NTN1 R2), NFASC (also known as NRCAML, KIAA0756, FLJ46866 or NF), NRCAM (also known as KIAA0343 or Bravo), PECAM1 (also known as CD31 ), PTPRM (also known as RPTPU or hR-PTPu), PVR (also known as CD155, HVED, Necl-5, NECL5 or Tage4), R0B01 (also known as DUTT1 , FLJ21882 or SAX3), R0B02 (also known as KIAA1568), SDK1 (also known as FLJ31425), SIGLECL1 (also known as FLJ40235), SIRPA (also known as SHPS1 , SIRP, MYD-1 , BIT, P84, SHPS-1 , SIRPalpha, CD172a, SIRPalpha2, MFR or SIRP-ALPHA- 1 ), SIRPG (also known as bA77C3.1 , SIRP-B2, SIRPgamma or CD172g), SLAMF1 (also known as CD150), SLAMF6 (also known as KALI, NTBA, KALIb, Ly108, SF2000, NTB-A or CD352), THY1 (also known as CD90), UNC5A (also known as KIAA1976 or UNC5H1 ), UNC5B (also known as UNC5H2 or p53RDL1 ), UNC5D (also known as KIAA1777 or Unc5h4), VCAM1 (also known as CD106), CLMP (also known as ASAM, FLJ22415 or ACAM), CXADR (also known as CAR), ESAM (also known as W1 17m), GPA33 (also known as A33), IGSF1 1 (also known as BT-lgSF, MGC35227, Igsf13, VSIG3 or CT1 19), VSIG1 (also known as MGC44287), VSIG2 (also known as CTXL, CTH) and VSIG8.

[00097] In one form of the present invention, the IgSF CAM superfamily (IgSF CAMs) comprises: ALCAM (also known as CD166 or MEMD), BCAM (also known as CD239), BOC (also known as CDON2), CADM1 (also known as NECL2, ST17, BL2, SYNCAM, IGSF4A, Necl-2, SYNCAM 1 or RA175), CADM2 (also known as NECL3, Necl-3 or SynCAM2), CADM3 (also known as BlgR, FLJ10698, TSLL1 , NECL1 , SynCAM3 or Necl-1 ), CADM4 (also known as TSLL2, Necl-4 or SynCAM4), CD2, CD244 (also known as 2B4, NAIL, NKR2B4, Nmrk or SLAMF4), CD28, CD47 (also known as IAP or OA3), CD58, CD84 (also known as SLAMF5, hCD84 or mCD84), CD96 (also known as TACTILE), CHL1 (also known as CALL, L1 CAM2, FLJ44930 or MGC132578), CNTN1 (also known as F3 or GP135), CNTN2 (also known as TAG-1 or TAXI ), CNTN3 (also known as BIG-1 ), CNTN4 (also known as BIG-2), CNTN5 (also known as NB-2 or hNB-2), CNTN6 (also known as NB-3), CRTAM (also known as CD355), DSCAM (also known as CHD2-42 or CHD2-52), DSCAML1 (also known as KIAA1 132), F1 1 R (also known as PAM-1 , JCAM, JAM-1 , JAM-A, JAMA or CD321 ), FGFRL1 , GP6 (also known as GPVI), HEPACAM (also known as FLJ25530, hepaCAM or GLIALCAM), ICAM1 (also known as BB2 or CD54), ICAM2 (also known as CD102), ICAM3 (also known as CDW50, ICAM-R or CD50), ICAM4 (also known as CD242), ICAM5 (also known as TLN), IGSF5 (also known as JAM4), IZUM01 (also known as IZUMO, MGC34799 or OBF), IZUM01 R (also known as Folbp3 or JUNO), JAM2 (also known as VE-JAM, JAM-B, JAMB or CD322), JAM3 (also known as JAM-C or JAMC), JAML (also known as Gm638 or AMICA), L1 CAM (also known as CD171 ), LILRB2 (also known as LIR-2, ILT4, MIR-10, LIR2, CD85d or MIR10), LRFN1 (also known as KIAA1484 or SALM2), LRFN2 (also known as FIGLER2), LRFN3 (also known as MGC2656, SALM4 or FIGLER1 ), LRFN4 (also known as MGC3103, SALM3. or FIGLER6), LRFN5 (also known as FIGLER8, SALM5), LRRC4 (also known as NAG 14), LRRC4B (also known as DKFZp761 A179 or HSM), LRRC4C (also known as KIAA1580 or NGL-1 ), MADCAM1 (also known as MACAM1 ), MCAM (also known as MUC18, CD146, MelCAM, METCAM or HEMCAM), MPZ (also known as HMSNIB, CMT2I or CMT2J), MPZL2 (also known as EVA), NCAM1 (also known as NCAM or CD56), NCAM2 (also known as NCAM21 or MGC51008), NECTIN1 (also known as PRR, PRR1 , PVRR1 , SK-12, HlgR, CLPED1 , CD1 1 1 or OFC7), NECTIN2 (also known as PVRR2, PRR2 or CD1 12), NECTIN3 (also known as nectin-3, PPR3, PVRR3, DKFZP566B0846, CDw1 13 or CD1 13), NECTIN4 (also known as nectin-4, PRR4 or LNIR), NE01 (also known as NGN, HsT17534, IGDCC2 or NTN1 R2), NFASC (also known as NRCAML, KIAA0756, FLJ46866 or NF), NRCAM (also known as KIAA0343 or Bravo), PECAM1 (also known as CD31 ), PTPRM (also known as RPTPU or hR-PTPu), PVR (also known as CD155, HVED, Necl-5, NECL5 or Tage4), R0B01 (also known as DUTT1 , FLJ21882 or SAX3), R0B02 (also known as KIAA1568), SDK1 (also known as FLJ31425), SIGLECL1 (also known as FLJ40235), SIRPA (also known as SHPS1 , SIRP, MYD-1 , BIT, P84, SHPS-1 , SIRPalpha, CD172a, SIRPalpha2, MFR or SIRP-ALPHA- 1 ), SIRPG (also known as bA77C3.1 , SIRP-B2, SIRPgamma or CD172g), SLAMF1 (also known as CD150), SLAMF6 (also known as KALI, NTBA, KALIb, Ly108, SF2000, NTB-A or CD352), THY1 (also known as CD90), UNC5A (also known as KIAA1976 or UNC5H1 ), UNC5B (also known as UNC5H2 or p53RDL1 ), UNC5D (also known as KIAA1777 or Unc5h4), OPCML (also known as OPCM, OBCAM or IGLON1 ), NTM (also known as HNT, NTRI, IGLON2 or CEPU-1 ), LSAMP (also known as LAMP or IGLON3), NEGR1 (also known as KILON, MGC46680, Ntra or IGLON4) and IGLON5 (also known as LOC402665).

[00098] In one form of the present invention, the IgSF CAM superfamily (IgSF CAMs) comprises: ALCAM (also known as CD166 or MEMD), BCAM (also known as CD239), BOC (also known as CDON2), CADM1 (also known as NECL2, ST17, BL2, SYNCAM, IGSF4A, Necl-2, SYNCAM 1 or RA175), CADM2 (also known as NECL3, Necl-3 or SynCAM2), CADM3 (also known as BlgR, FLJ10698, TSLL1 , NECL1 , SynCAM3 or Necl-1 ), CADM4 (also known as TSLL2, Necl-4 or SynCAM4), CD2, CD244 (also known as 2B4, NAIL, NKR2B4, Nmrk or SLAMF4), CD28, CD47 (also known as IAP or OA3), CD58, CD84 (also known as SLAMF5, hCD84 or mCD84), CD96 (also known as TACTILE), CHL1 (also known as CALL, L1 CAM2, FLJ44930 or MGC132578), CNTN1 (also known as F3 or GP135), CNTN2 (also known as TAG-1 or TAXI ), CNTN3 (also known as BIG-1 ), CNTN4 (also known as BIG-2), CNTN5 (also known as NB-2 or hNB-2), CNTN6 (also known as NB-3), CRTAM (also known as CD355), DSCAM (also known as CHD2-42 or CHD2-52), DSCAML1 (also known as KIAA1 132), F1 1 R (also known as PAM-1 , JCAM, JAM-1 , JAM-A, JAMA or CD321 ), FGFRL1 , GP6 (also known as GPVI), HEPACAM (also known as FLJ25530, hepaCAM or GLIALCAM), ICAM1 (also known as BB2 or CD54), ICAM2 (also known as CD102), ICAM3 (also known as CDW50, ICAM-R or CD50), ICAM4 (also known as CD242), ICAM5 (also known as TLN), IGSF5 (also known as JAM4), IZUM01 (also known as IZUMO, MGC34799 or OBF), IZUM01 R (also known as Folbp3 or JUNO), JAM2 (also known as VE-JAM, JAM-B, JAMB or CD322), JAM3 (also known as JAM-C or JAMC), JAML (also known as Gm638 or AMICA), L1 CAM (also known as CD171 ), LILRB2 (also known as LIR-2, ILT4, MIR-10, LIR2, CD85d or MIR10), LRFN1 (also known as KIAA1484 or SALM2), LRFN2 (also known as FIGLER2), LRFN3 (also known as MGC2656, SALM4 or FIGLER1 ), LRFN4 (also known as MGC3103, SALM3. or FIGLER6), LRFN5 (also known as FIGLER8, SALM5), LRRC4 (also known as NAG 14), LRRC4B (also known as DKFZp761 A179 or HSM), LRRC4C (also known as KIAA1580 or NGL-1 ), MADCAM1 (also known as MACAM1 ), MCAM (also known as MUC18, CD146, MelCAM, METCAM or HEMCAM), MPZ (also known as HMSNIB, CMT2I or CMT2J), MPZL2 (also known as EVA), NCAM1 (also known as NCAM or CD56), NCAM2 (also known as NCAM21 or MGC51008), NECTIN1 (also known as PRR, PRR1 , PVRR1 , SK-12, HlgR, CLPED1 , CD1 1 1 or OFC7), NECTIN2 (also known as PVRR2, PRR2 or CD1 12), NECTIN3 (also known as nectin-3, PPR3, PVRR3, DKFZP566B0846, CDw1 13 or CD1 13), NECTIN4 (also known as nectin-4, PRR4 or LNIR), NE01 (also known as NGN, HsT17534, IGDCC2 or NTN1 R2), NFASC (also known as NRCAML, KIAA0756, FLJ46866 or NF), NRCAM (also known as KIAA0343 or Bravo), PECAM1 (also known as CD31 ), PTPRM (also known as RPTPU or hR-PTPu), PVR (also known as CD155, HVED, Necl-5, NECL5 or Tage4), R0B01 (also known as DUTT1 , FLJ21882 or SAX3), R0B02 (also known as KIAA1568), SDK1 (also known as FLJ31425), SIGLECL1 (also known as FLJ40235), SIRPA (also known as SHPS1 , SIRP, MYD-1 , BIT, P84, SHPS-1 , SIRPalpha, CD172a, SIRPalpha2, MFR or SIRP-ALPHA- 1 ), SIRPG (also known as bA77C3.1 , SIRP-B2, SIRPgamma or CD172g), SLAMF1 (also known as CD150), SLAMF6 (also known as KALI, NT BA, KALIb, Ly108, SF2000, NTB-A or CD352), THY1 (also known as CD90), UNC5A (also known as KIAA1976 or UNC5H1 ), UNC5B (also known as UNC5H2 or p53RDL1 ), UNC5D (also known as KIAA1777 or Unc5h4), SIGLEC1 (also known as SIGLEC-1 , CD169, FLJ00051 , FLJ00055, FLJ00073, FLJ32150, dJ1009E24.1 or sialoadhesin), SIGLEC10 (also known as SIGLEC-10, SLG2, PRO940 or MGC126774), SIGLEC1 1 , SIGLEC12 (also known as SLG, S2V, Siglec-XII, Siglec-12 or Siglec-L1 ), SIGLEC14, SIGLEC15 (also known as HsT1361 ), SIGLEC16 (also known as Siglec-P16), SIGLEC17P, SIGLEC18P, CD22 (also known as SIGLEC-2 or SIGLEC2), SIGLEC20P, SIGLEC21 P, SIGLEC22P, SIGLEC24P, SIGLEC25P, SIGLEC26P, SIGLEC27P, SIGLEC28P, SIGLEC29P, CD33 (also known as SIGLEC3, SIGLEC-3, p67 or FLJ00391 ), SIGLEC30P, SIGLEC31 P, MAG (also known as SIGLEC4A, SIGLEC-4A or S- MAG), SIGLEC5 (also known as OB-BP2, SIGLEC-5 or CD170), SIGLEC6 (also known as OB-BP1 , SIGLEC-6 or CD327), SIGLEC7 (also known as SIGLEC-7, p75/AIRM1 , QA79 or CD328), SIGLEC8 (also known as SIGLEC-8, SAF2, SIGLEC8L or MGC59785), and SIGLEC9 (also known as CD329).

[00099] In one form of the present invention, the IgSF CAM superfamily (IgSF CAMs) comprises: ALCAM (also known as CD166 or MEMD), BCAM (also known as CD239), BOC (also known as CDON2), CADM1 (also known as NECL2, ST17, BL2, SYNCAM, IGSF4A, Necl-2, SYNCAM 1 or RA175), CADM2 (also known as NECL3, Necl-3 or SynCAM2), CADM3 (also known as BlgR, FLJ10698, TSLL1 , NECL1 , SynCAM3 or Necl-1 ), CADM4 (also known as TSLL2, Necl-4 or SynCAM4), CD2, CD244 (also known as 2B4, NAIL, NKR2B4, Nmrk or SLAMF4), CD28, CD47 (also known as IAP or OA3), CD58, CD84 (also known as SLAMF5, hCD84 or mCD84), CD96 (also known as TACTILE), CHL1 (also known as CALL, L1 CAM2, FLJ44930 or MGC132578), CNTN1 (also known as F3 or GP135), CNTN2 (also known as TAG-1 or TAXI ), CNTN3 (also known as BIG-1 ), CNTN4 (also known as BIG-2), CNTN5 (also known as NB-2 or hNB-2), CNTN6 (also known as NB-3), CRTAM (also known as CD355), DSCAM (also known as CHD2-42 or CHD2-52), DSCAML1 (also known as KIAA1 132), F1 1 R (also known as PAM-1 , JCAM, JAM-1 , JAM-A, JAMA or CD321 ), FGFRL1 , GP6 (also known as GPVI), HEPACAM (also known as FLJ25530, hepaCAM or GLIALCAM), ICAM1 (also known as BB2 or CD54), ICAM2 (also known as CD102), ICAM3 (also known as CDW50, ICAM-R or CD50), ICAM4 (also known as CD242), ICAM5 (also known as TLN), IGSF5 (also known as JAM4), IZUM01 (also known as IZUMO, MGC34799 or OBF), IZUM01 R (also known as Folbp3 or JUNO), JAM2 (also known as VE-JAM, JAM-B, JAMB or CD322), JAM3 (also known as JAM-C or JAMC), JAML (also known as Gm638 or AMICA), L1 CAM (also known as CD171 ), LILRB2 (also known as LIR-2, ILT4, MIR-10, LIR2, CD85d or MIR10), LRFN1 (also known as KIAA1484 or SALM2), LRFN2 (also known as FIGLER2), LRFN3 (also known as MGC2656, SALM4 or FIGLER1 ), LRFN4 (also known as MGC3103, SALM3. or FIGLER6), LRFN5 (also known as FIGLER8, SALM5), LRRC4 (also known as NAG 14), LRRC4B (also known as DKFZp761 A179 or HSM), LRRC4C (also known as KIAA1580 or NGL-1 ), MADCAM1 (also known as MACAM1 ), MCAM (also known as MUC18, CD146, MelCAM, METCAM or HEMCAM), MPZ (also known as HMSNIB, CMT2I or CMT2J), MPZL2 (also known as EVA), NCAM1 (also known as NCAM or CD56), NCAM2 (also known as NCAM21 or MGC51008), NECTIN1 (also known as PRR, PRR1 , PVRR1 , SK-12, HlgR, CLPED1 , CD1 1 1 or OFC7), NECTIN2 (also known as PVRR2, PRR2 or CD1 12), NECTIN3 (also known as nectin-3, PPR3, PVRR3, DKFZP566B0846, CDw1 13 or CD1 13), NECTIN4 (also known as nectin-4, PRR4 or LNIR), NE01 (also known as NGN, HsT17534, IGDCC2 or NTN1 R2), NFASC (also known as NRCAML, KIAA0756, FLJ46866 or NF), NRCAM (also known as KIAA0343 or Bravo), PECAM1 (also known as CD31 ), PTPRM (also known as RPTPU or hR-PTPu), PVR (also known as CD155, HVED, Necl-5, NECL5 or Tage4), R0B01 (also known as DUTT1 , FLJ21882 or SAX3), R0B02 (also known as KIAA1568), SDK1 (also known as FLJ31425), SIGLECL1 (also known as FLJ40235), SIRPA (also known as SHPS1 , SIRP, MYD-1 , BIT, P84, SHPS-1 , SIRPalpha, CD172a, SIRPalpha2, MFR or SIRP-ALPHA- 1 ), SIRPG (also known as bA77C3.1 , SIRP-B2, SIRPgamma or CD172g), SLAMF1 (also known as CD150), SLAMF6 (also known as KALI, NTBA, KALIb, Ly108, SF2000, NTB-A or CD352), THY1 (also known as CD90), UNC5A (also known as KIAA1976 or UNC5H1 ), UNC5B (also known as UNC5H2 or p53RDL1 ) and UNC5D (also known as KIAA1777 or Unc5h4).

[000100] In one form of the present invention, the IgSF CAM superfamily (IgSF CAMs) comprises: ALCAM (also known as CD166), BCAM, MCAM, Neural Cell Adhesion Molecules (NCAMs), Intercellular Cell Adhesion Molecules (ICAMs), Vascular Cell Adhesion Molecules (VCAMs), Platelet-endothelial Cell Adhesion Molecule (PECAMs), L1 family including L1 (protein), CHL1 , Neurofascin and NrCAM, SIGLEC family including Myelin-associated glycoprotein (MAG, SIGLEC-4), CD22 and CD83, CTX family including CTX, Junctional adhesion molecule (JAM), BT-lgSF, Coxsackie virus and adenovirus receptor (CAR), VSIG, endothelial cell-selective adhesion molecule (ESAM), Nectins and related proteins, including CADM1 and other Synaptic Cell Adhesion Molecules, CD2, CD48, HEPACAM, HEPACAM2, Down syndrome cell adhesion molecule (DSCAM).

[000101 ] In one form of the present invention, the IgSF CAM superfamily (IgSF CAMs) comprises: ALCAM (also known as CD166), BCAM, MCAM, NCAM-1 , NCAM-2, ICAM-1 , ICAM-2, ICAM-3 (also known as CD50), ICAM-4, ICAM-5, VCAM-1 , PECAM-1 (also known as CD31 ), L1 (protein), CHL1 , Neurofascin, NrCAM, Myelin-associated glycoprotein (MAG, SIGLEC-4), CD22, CD83, CTX, Junctional adhesion molecule (JAM), BT-lgSF, Coxsackie virus and adenovirus receptor (CAR), VSIG, endothelial cell-selective adhesion molecule (ESAM), CADM1 , CADM2, CADM3, CADM4, CD2, CD48, HEPACAM, HEPACAM2, and Down syndrome cell adhesion molecule (DSCAM). 1. Modulators of ligand-independent activation of IgSF CAM by activated co-located GPCRs

[000102] In one form, the present invention comprises modulators of IgSF CAM activity where such IgSF CAM activity is induced by certain active co-located GPCRs.

[000103] In one form, the present invention comprises modulators of IgSF CAM ligand- independent activation of an IgSF CAM by certain activated co-located GPCRs.

[000104] In one form, the present invention comprises modulators wherein the modulators are modulators of IgSF CAM-dependent signalling induced by certain activated co-located GPCRs.

[000105] In one form of the present invention, the modulators of IgSF CAM ligand- independent activation of the IgSF CAM by certain activated co-located GPCRs act in the absence of any IgSF CAM ligand.

[000106] In one form of the present invention, the modulators of IgSF CAM ligand- independent activation of the IgSF CAM by certain activated co-located GPCRs act in the presence of a truncated ectodomain of an IgSF CAM.

[000107] In one form of the present invention, the modulators of IgSF CAM ligand- independent activation of the IgSF CAM by certain activated co-located GPCRs act in the presence of a truncated ectodomain of an IgSF CAM which is not greater than 40, not greater than 20, not greater than 10 or not greater than 5 amino acids in length.

[000108] In one form of the present invention, the modulators of IgSF CAM ligand- independent activation of the IgSF CAM by certain activated co-located GPCRs, contain the entire ectodomain of an IgSF CAM conjugated to an analogue, fragment or derivative of the transmembrane domain of an IgSF CAM which is greater than 5, greater than 10, or greater than 20 amino acids in length.

[000109] In one form of the present invention, the modulators of IgSF CAM ligand- independent activation of the IgSF CAM by certain activated co-located GPCRs act in the absence of the IgSF CAM ligand-binding ectodomain of an IgSF CAM.

[0001 10] In one form of the present invention, the modulators of IgSF CAM ligand- independent activation of the IgSF CAM by certain activated co-located GPCRs do not contain the ectodomain of an IgSF CAM. [0001 1 1 ] In one form of the present invention, the modulators of IgSF CAM ligand- independent activation of the IgSF CAM by certain activated co-located GPCRs do not contain an analogue, fragment or derivative of the ectodomain of an IgSF CAM.

[0001 12] In one form of the present invention, the modulators of IgSF CAM ligand- independent activation of the IgSF CAM by certain activated co-located GPCRs contain a fragment of the ectodomain of an IgSF CAM.

[0001 13] In one form of the present invention, the modulators of IgSF CAM ligand- independent activation of the IgSF CAM by certain activated co-located GPCRs inhibit or facilitate signalling that occurs through the C-terminal cytosolic tail of an IgSF CAM induced by an activated co-located GPCR.

[0001 14] In one form of the present invention, the modulators of IgSF CAM ligand- independent activation of the IgSF CAM by certain activated co-located GPCRs inhibit binding that occurs to the C-terminal cytosolic tail of an IgSF CAM.

[0001 15] In one form of the present invention, the modulators of IgSF CAM ligand- independent activation of the IgSF CAM by certain activated co-located GPCRs inhibit or facilitate the interaction between the IgSF CAM and certain GPCRs.

[0001 16] In one form of the present invention, the modulators of IgSF CAM ligand- independent activation of the IgSF CAM by certain activated co-located GPCRs inhibit or facilitate the capacity of an activated GPCR to modulate IgSF CAM-dependent signalling that is dependent upon proximity of an IgSF CAM and the certain GPCR.

[0001 17] In one form of the present invention, the modulators of IgSF CAM ligand- independent activation of the IgSF CAM by certain activated co-located GPCRs inhibit the capacity of an activated GPCR to modulate CAM-dependent signalling that is dependent upon proximity of the IgSF CAM and the certain GPCR.

[0001 18] In one form of the present invention, the modulators of IgSF CAM ligand- independent activation of the IgSF CAM by certain activated co-located GPCRs inhibit or facilitate the capacity of an activated GPCR to modulate IgSF CAM-dependent signalling that is dependent upon proximity of the IgSF CAM and the certain GPCR and/or inhibit or facilitate signalling that occurs through the C-terminal cytosolic tail of an IgSF CAM induced by an activated co-located GPCR. [0001 19] In one form of the present invention, the modulators of IgSF CAM ligand- independent activation of the IgSF CAM by certain activated co-located GPCRs inhibit the capacity of an activated GPCR to modulate CAM-dependent signalling that is dependent upon proximity of the IgSF CAM and the certain GPCR and/or inhibit signalling that occurs through the C-terminal cytosolic tail of the IgSF CAM induced by an activated co-located GPCR.

[000120] Throughout this specification, unless the context requires otherwise, an activated GPCR means a GPCR that is in an active state that may result from the binding of an agonist, partial agonist and/or allosteric modulator, and/or as a consequence of constitutive activity that does not necessitate ligand binding.

[000121 ] Throughout this specification, unless the context requires otherwise, the certain activated co-located GPCRs of the invention are GPCRs that are expressed in the same cell as the IgSF CAM and for which an effect on the IgSF CAM, indicative of modulation of IgSF CAM activation and/or modulation of induction of IgSF CAM-dependent signalling, is detected upon activation by cognate ligands of the certain co-located GPCRs or when the GPCRs are constitutively active.

[000122] In one embodiment, an effect on the IgSF CAM indicative of modulation of IgSF CAM activation is a change in intracellular trafficking such as that detected by a change in proximity of luciferase-conjugated IgSF CAM (such as IgSF CAM/Rluc8) to intracellular compartment markers such as fluorophore-labelled Rabs, such as Rab1 , Rab4, Rab5, Rab6, Rab7, Rab8, Rab9 and/or Rab1 1 (such as Venus-Rab1 , Venus-Rab4, Venus-Rab5, Venus- Rab6, Venus-Rab7, Venus-Rab8, Venus-Rab9 and/or Venus-Rab1 1 ), and/or a plasma membrane marker, such as a fluorophore-conjugated fragment of K-ras (such as Venus-K- ras) using bioluminescence resonance energy transfer (BRET) upon addition of a cognate ligand for the co-located GPCR (Tiulpakov et al., 2016).

[000123] In another embodiment, an effect on the IgSF CAM is a change in IgSF CAM- dependent signalling, such as detected by a change in proximity of luciferase-conjugated IgSF CAM (such as IgSF CAM-Rluc8) to an IgSF CAM-interacting group, such as fluorophore- labelled proteins interacting with the cytosolic tail of the IgSF CAM, such as IQGAP-1 , protein kinase C zeta (RKΰz), Dock7, MyD88, TIRAP, ERK1 /2, (Jules et al., 2013; Ramasamy et al., 2016), olfactory receptor 2T2, ADP/ATP translocase 2, Protein phosphatase 1 G, Intercellular adhesion molecule 1 , Protein DJ-1 (PARK7), Calponin-3, Drebrin, Filamin B, Ras-related protein Rab-13, Radixin/Ezrin/Moesin, Proteolipid protein 2, Coronin, S100 A1 1 , Succinyl-CoA ligase [GDP-forming] subunit alpha, Hsc70-interacting protein, Apoptosis Inhibitor 5, neuropilin, cleavage stimulation factor, growth factor receptor-bound protein 2, sec61 beta subunit, or Nck1.

[000124] In another embodiment, an effect on the IgSF CAM is a change in IgSF CAM- dependent signalling, such as detected by a change in canonical activation of NFKB upon activation of the certain co-located GPCRs by their cognate ligands as measured by one or more of the following:

• Activity of IkB kinase (IKK) by monitoring in vitro phosphorylation of a substrate, such as GST-IkBa;

• Detection of IkB Degradation Dynamics, including phosphorylation/ubiquitination and/or degradation of IKB and/or IkB-a;

• Detection of p65(Rel-A) phosphorylation/ubiquitination, such as by using antibodies, gel-shift, EMSA, and/or mass spectroscopy;

• Detection of cytosolic to nuclear shuttling/translocation of NFKB components/subunits, such as p65/phospho-p65;

• Detection of NFKB subunit dimerization/complexation;

• Detection of active NFKB components/subunits by binding to immobilized DNA sequence/oligonucleotide containing the NFKB response element/consensus NFKB binding motif, such as by using electrophoretic mobility shift assay or gel shift assay, SELEX, protein-binding microarray, or sequencing-based approaches;

• Chromatin-immunoprecipitation (ChIP) assays to detect NFKB in situ binding to DNA to the promoters and enhancers of specific genes;

• In vitro kinase assay for NFKB kinase activity;

• Measurement of NFKB transcriptional activity using NFKB reporter assays via transgene expression of reporter constructs, such as LacZ Flue, eGFP SEAP, and NF- gluc, using such approaches as plasmid transfection, reporter cell lines, mini-circles, retrovirus, or lentivirus;

• Measuring changes in expression of downstream targets of NFKB, such as cytokines, growth factors, adhesion molecules and mitochondrial anti-apoptotic genes, by real time PCR, protein, orfunctional assays (Note the pleiotropic nature of NFKB is reflected in its transcriptional targets that presently number approximately 500 (see http://www.bu.edu/nf-kb/aene-resources/target-aenes/ as at 7 ^th December 2018); and

• Measuring changes in function or structure induced by NFKB-dependent signalling, such as POLKADOTS in T-cells, adhesion in endothelial cells, activation in leucocytes, or oncogenicity.

[000125] In another embodiment, an effect on the IgSF CAM is a change in IgSF CAM dependent signalling, such as detected by a change in non-canonical activation of NFKB by measuring one or more of the following:

• Detection of NIK (NFKB-lnducing Kinase);

• Detecting I KKa Activation/phosphorylation;

• Detection of NIK kinase activity by ability to autophosphorylate or to phosphorylate a substrate by performing a kinase assay;

• Generation of p52-containing NFKB dimers, such as p52/RelB;

• Detection of Phospho-NFKB2 p100(Ser866/870);

• Detection of partial degradation (called processing) of the precursor p100 into p52;

• Detecting p52/RelB translocation into the nucleus;

• Detecting p52/RelB binding to NFKB sites;

• Measurement of NFKB transcriptional activity using NFKB reporter assays via transgene expression of reporter constructs, such as LacZ Flue, eGFP SEAP, NF-gluc, using such approaches as plasmid transfection, reporter cell lines, mini-circles, retrovirus, or lentivirus; and

• Measuring changes in expression of downstream targets of non-canonical signalling of NFKB, such as CXCL12, by real-time PCR, protein expression or by functional assays.

[000126] In one form of the invention, the modulator is isolated. [000127] In one form, the invention comprises a pharmaceutical composition comprising a modulator of IgSF CAM activity where such IgSF CAM activity is induced by certain active co located GPCRs as described herein.

[000128] In one form the invention comprises the use of a modulator of IgSF CAM activity where such IgSF CAM activity is induced by certain active co-located GPCRs for the treatment or prevention of an ailment.

2. Modulators of ligand-independent activation of members of the IgSF CAM superfamily by activated co-located GPCRs

[000129] In one form, the present invention comprises modulators of members of the IgSF CAM superfamily activity where such members of the IgSF CAM superfamily activity is induced by certain active co-located GPCRs.

[000130] In one form, the present invention comprises modulators of ligand-independent activation of members of the IgSF CAM superfamily by certain activated co-located GPCRs.

[000131 ] In one form, the present invention comprises modulators wherein the modulators are modulators of members of the IgSF CAM superfamily dependent signalling induced by certain activated co-located GPCRs.

[000132] In one form of the present invention, the modulators of ligand-independent activation of members of the IgSF CAM superfamily by certain activated co-located GPCRs act in the absence of any members of the IgSF CAM superfamily ligand.

[000133] In one form of the present invention, the modulators of members of the IgSF CAM superfamily ligand-independent activation of members of the IgSF CAM superfamily by certain activated co-located GPCRs act in the presence of a truncated ectodomain of members of the IgSF CAM superfamily.

[000134] In one form of the present invention, the modulators of ligand-independent activation of members of the IgSF CAM superfamily by certain activated co-located GPCRs act in the presence of a truncated ectodomain of members of the IgSF CAM superfamily which is not greater than 40, not greater than 20, not greater than 10 or not greater than 5 amino acids in length.

[000135] In one form of the present invention, the modulators of ligand-independent activation of members of the IgSF CAM superfamily by certain activated co-located GPCRs, consist of the entire ectodomain of a member of the IgSF CAM superfamily. [000136] In one form of the present invention, the modulators of ligand-independent activation of members of the IgSF CAM superfamily by certain activated co-located GPCRs, contain the entire ectodomain of members of the IgSF CAM superfamily conjugated to an analogue, fragment or derivative of the transmembrane domain of members of the IgSF CAM superfamily which is greater than 5, greater than 10, or greater than 20 amino acids in length.

[000137] In one form, the present invention comprises modulators of ligand-independent IgSF CAM activity where such IgSF CAM activity is induced by a co-located GPCR and where the modulators of IgSF CAM activity are analogues, fragments or derivatives of the C-terminal tail of IgSF CAM lacking serines or threonines, or with serines and threonines selectively mutated to other residues.

[000138] In one form, the present invention comprises modulators of ligand-independent IgSF CAM activity where such IgSF CAM activity is induced by a co-located GPCR and where the modulators of IgSF CAM activity are analogues, fragments or derivatives of the C-terminal tail of IgSF CAM lacking serines or threonines, or with serines and threonines mutated to other residues that are not negatively charged.

[000139] In one form of the present invention, the modulators of ligand-independent activation of members of the IgSF CAM superfamily by certain activated co-located GPCRs act in the absence of members of the IgSF CAM superfamily ligand-binding ectodomain of members of the IgSF CAM superfamily.

[000140] In one form of the present invention, the modulators of ligand-independent activation of members of the IgSF CAM superfamily by certain activated co-located GPCRs do not contain the ectodomain of members of the IgSF CAM superfamily.

[000141 ] In one form of the present invention, the modulators of ligand-independent activation of members of the IgSF CAM superfamily by certain activated co-located GPCRs do not contain an analogue, fragment or derivative of the ectodomain of members of the IgSF CAM superfamily.

[000142] In one form of the present invention, the modulators of ligand-independent activation of members of the IgSF CAM superfamily by certain activated co-located GPCRs contain a fragment of the ectodomain of members of the IgSF CAM superfamily.

[000143] In one form of the present invention, the modulators of ligand-independent activation of members of the IgSF CAM superfamily by certain activated co-located GPCRs inhibit or facilitate signalling that occurs through the C-terminal cytosolic tail of members of the IgSF CAM superfamily induced by an activated co-located GPCR.

[000144] In one form of the present invention, the modulators of ligand-independent activation of members of the IgSF CAM superfamily by certain activated co-located GPCRs inhibit binding that occurs to the C-terminal cytosolic tail of members of the IgSF CAM superfamily.

[000145] In one form of the present invention, the modulators of ligand-independent activation of members of the IgSF CAM superfamily by certain activated co-located GPCRs inhibit or facilitate the interaction between members of the IgSF CAM superfamily and certain GPCRs.

[000146] In one form of the present invention, the modulators of ligand-independent activation of members of the IgSF CAM superfamily by certain activated co-located GPCRs inhibit or facilitate the capacity of an activated GPCR to modulate members of the members of the IgSF CAM superfamily dependent signalling that is dependent upon proximity of members of the IgSF CAM superfamily and the certain GPCR.

[000147] In one form of the present invention, the modulators of ligand-independent activation of members of the IgSF CAM superfamily by certain activated co-located GPCRs inhibit the capacity of an activated GPCR to modulate members of the IgSF CAM superfamily -dependent signalling that is dependent upon proximity of the members of the IgSF CAM superfamily and the certain GPCR.

[000148] In one form of the present invention, the modulators of ligand-independent activation of members of the IgSF CAM superfamily by certain activated co-located GPCRs inhibit or facilitate the capacity of an activated GPCR to modulate members of the IgSF CAM superfamily-dependent signalling that is dependent upon proximity of members of the IgSF CAM superfamily and the certain GPCR and inhibit or facilitate signalling that occurs through the C-terminal cytosolic tail of members of the IgSF CAM superfamily induced by an activated co-located GPCR.

[000149] In one form of the present invention, the modulators of ligand-independent activation of members of the IgSF CAM superfamily by certain activated co-located GPCRs inhibit or facilitate the capacity of an activated GPCR to modulate members of the IgSF CAM superfamily-dependent signalling that is dependent upon proximity of members of the IgSF CAM superfamily and the certain GPCR or inhibit or facilitate signalling that occurs through the C-terminal cytosolic tail of members of the IgSF CAM superfamily induced by an activated co-located GPCR.

[000150] In one form of the present invention, the modulators of ligand-independent activation of members of the IgSF CAM superfamily by certain activated co-located GPCRs inhibit the capacity of an activated GPCR to modulate members of the IgSF CAM superfamily -dependent signalling that is dependent upon proximity of members of the IgSF CAM superfamily and the certain GPCR and/or inhibit signalling that occurs through the C-terminal cytosolic tail of members of the IgSF CAM superfamily induced by an activated co-located GPCR.

[000151 ] In one form of the invention, the modulator is isolated.

[000152] In one form, the invention comprises a pharmaceutical composition comprising a modulator of IgSF CAM superfamily activity where such IgSF CAM superfamily activity is induced by certain active co-located GPCRs as described herein.

[000153] In one form the invention comprises the use of a modulator of IgSF CAM superfamily activity where such IgSF CAM superfamily activity is induced by certain active co located GPCRs for the treatment or prevention of an ailment.

Co-located GPCRs

[000154] In one embodiment, the certain activated co-located GPCRs of the invention are those GPCRs that are expressed in the same cell as an IgSF CAM and are associated with an IgSF CAM-related disorder.

[000155] In one embodiment, the certain activated co-located GPCRs of the invention are those GPCRs that are expressed in the same cell as an IgSF CAM, are associated with an IgSF CAM-related disorder(s), and upon their removal and/or inhibition result in reduction or alleviation of an IgSF CAM-related disorder(s).

[000156] In one embodiment, the certain activated co-located GPCRs of the invention are those GPCRs that are implicated in inflammation.

[000157] In one embodiment, the certain activated co-located GPCRs of the invention are those GPCRs that are implicated in inflammation, and upon their removal and/or inhibition result in reduction or alleviation of the inflammation. [000158] In one embodiment, the certain activated co-located GPCRs of the invention are those GPCRs that are implicated in cell proliferation.

[000159] In one embodiment, the certain activated co-located GPCRs of the invention are those GPCRs that are implicated in cell proliferation, and upon their removal and/or inhibition result in reduction or alleviation of the cell proliferation.

[000160] Indeed there is evidence for many GPCRs being involved in inflammation to some degree, and these levels can be differentiated according to the level of evidence:

1 - No evidence found to date;

2 - Receptor structure, or motif within receptor is similar to known

inflammatory/immunological receptor or motif involved in an

inflammatory/immunological process;

3 - Receptor binds a ligand that mediates an inflammatory/immunological process;

4 - Receptor is associated with/involved in an inflammatory/immunological disease;

5 - At least one paper describing direct involvement of receptor in

inflammatory/immunological process;

6 - Receptor is expressed in inflammatory/immune cells; and

7 - Receptor’s involvement in inflammatory/immunological processes is well

characterised (as described in http://www.auidetopharmacoloav.org database).

[000161 ] Family A GPCRs (except olfactory, vomeronasal, opsins) and the current level of evidence for their involvement in inflammation (see key above):

[000162] Family A olfactory GPCRs and the current level of evidence for their involvement in inflammation (see key above):

[000163] Family A vomeronasal and opsin GPCRs and the current level of evidence for their involvement in inflammation (see key above):

[000164] Family B GPCRs and the current level of evidence for their involvement in inflammation (see key above):

[000165] Family C GPCRs and the current level of evidence for their involvement in inflammation (see key above):

[000166] Frizzled Family GPCRs and the current level of evidence for their involvement in inflammation (see key above):

[000167] Other 7TM proteins that have been classified as members of the GPCR superfamily and the current level of evidence for their involvement in inflammation (see key above):

[000168] In one embodiment, the certain activated co-located GPCRs of the invention are GPCRs selected from the group: ADGRA2, ADGRB2, ADGRB3, ADGRF3, ADGRG4, ADGRV1 , CELSR1 , CELSR2, CELSR3, 0X1 receptor, 0X2 receptor, PTH1 receptor, PTH2 receptor, AMY1 receptor, AMY2 receptor, AMY3 receptor, AM1 receptor, AM2 receptor, GPR63, GPR75, NMU2 receptor, OPN5, V1 B receptor, y6 receptor, 5-HT4 receptor, GPR101 , GPR1 19, GPR135, GPR137, GPR141 , GPR149, GPR150, GPR151 , GPR152, GPR157, GPR19, GPR25, GPR37, GPR37L1 , GPR50, GPR62, LGR5, MRGPRE, MRGPRF, NTS2 receptor, OPN4, OPN4, OR10A7, OR10AG1 , OR10Q1 , OR10W1 , OR12D3, OR13C2, OR13C3, OR13C4, OR13C5, OR13C8, OR13F1 , OR13G1 , OR1 A2, OR1 L1 , OR1 S1 , OR1 S2, OR2AK2, OR2D2, OR2D3, OR4A15, OR4C1 1 , OR4C12, OR4C13, OR4C15, OR4C16, OR4K13, OR4K14, OR4K15, OR4K17, OR4N5, OR5AC2, OR5AK2, OR5AP2, OR5AR1 , OR5AS1 , OR5B12, OR5B17, OR5B2, OR5B21, OR5B3, OR5D13, OR5D14, OR5D16, OR5D18, OR5F1 , OR5I1, OR5J2, OR5K3, OR5L1 , OR5L2, OR5M1, OR5M10, OR5M11, OR5M3, OR5M8, OR5M9, OR5R1, OR5T1, OR5T2, OR5T3, OR5W2, OR6C74, OR6K6, OR6M1 , OR6Q1 , OR6X1, OR8H1, OR8H2, OR8H3, OR8J1, OR8J3, OR8K1 , OR8K3, OR8K5, OR8U1 , OR8U8, OR9A4, OR9G1, OR9G4, OR9G9, OR9Q2, TAAR3, TPRA1 , U4 receptor, 5-HT1D receptor, 5-HT1E receptor, ADGRB1, AT2 receptor, BB1 receptor, BB3 receptor, CGRP receptor, CRF1 receptor, CRF2 receptor, ETA receptor, ETB receptor, FZD4, FZD5, FZD7, FZD8, FZD9, GABAB receptor, GABAB1 , GABAB2, GAL1 receptor, GIP receptor, GLP-1 receptor, GLP-2 receptor, glucagon receptor, GnRH2 receptor, GPER, GPR107, GPR139, GPR156, GPR158, GPR161, GPR171, GPR179, GPR39, GPR45, GPR88, GPRC5A, GPRC5B, GPRC5C, H3 receptor, HCA1 receptor, LPA1 receptor, LPA3 receptor, LPA4 receptor, MC2 receptor, MC4 receptor, mGlu2 receptor, mGlu3 receptor, motilin receptor, MRGPRD, MRGPRX1 , MRGPRX3, NK2 receptor, NPFF1 receptor, NPFF2 receptor, NPS receptor, NTS1 receptor, OR1D2, OR2AG1, OT receptor, PAC1 receptor, RXFP1 receptor, secretin receptor, TSH receptor, UT receptor, V1A receptor, V2 receptor, a2A-adrenoceptor, a2B-adrenoceptor, a2C-adrenoceptor, b1 -adrenoceptor, b3^GbhoobrίqG, 5-FIT1B receptor, 5-HT 1 F receptor, 5-FIT2B receptor, 5-FIT2C receptor, 5-FIT5A receptor, 5- HT6 receptor, 5-HT7 receptor, ADGRE4P, ADGRF1, ADGRG1, ADGRG3, ADGRG5, calcitonin receptor-like receptor, CB1 receptor, CB2 receptor, CCK1 receptor, CCK2 receptor, CT receptor, D1 receptor, D2 receptor, D3 receptor, D4 receptor, D5 receptor, FFA1 receptor, FFA3 receptor, FSH receptor, FZD1, FZD2, FZD3, GHRH receptor, GnRFU receptor, GPBA receptor, GPR1, GPR119, GPR12, GPR142, GPR143, GPR146, GPR148, GPR153, GPR160, GPR162, GPR17, GPR173, GPR174, GPR176, GPR18, GPR182, GPR20, GPR22, GPR26, GPR27, GPR3, GPR33, GPR35, GPR6, GPR61 , GPR78, GPR82, GPR83, GPR84, GPR85, GPR87, GPRC5D, GPRC6 receptor, HCA2 receptor, HCA3 receptor, kisspeptin receptor, LGR4, LGR6, LH receptor, LPA2 receptor, LPA6 receptor, M1 receptor, M2 receptor, M3 receptor, M4 receptor, M5 receptor, MAS1 L, MC3 receptor, MC5 receptor, MCH2 receptor, mGlu4 receptor, mGlu7 receptor, mGlu8 receptor, MRGPRG, NOP receptor, NPBW1 receptor, NPBW2 receptor, OPN3, OR11H1, OR2A1, OR2A2, OR2A4, OR2A42, OR2A7, OR2B11, OR2B6, OR2C1 , OR2C3, OR2J3, OR2L13, OR2T11, OR2T34, OR2W3, OR3A3, OR4D10, OR4M1 , OR4Q3, OR51A2, OR51A4, OR51A7, OR51B2, OR51B4, OR51 B5, OR51B6, OR51D1, OR51E1, OR51E1, OR51E2, OR51F1, OR51F2, OR51G1, OR51G2, OR51I1, OR51I2, OR51J1, OR51 L1 , OR51M1, OR51Q1, OR51S1, OR51T1, OR51V1, OR52A1, OR52A4, OR52A5, OR52B2, OR52B4, OR52B6, OR52D1, OR52E2, OR52E4, OR52E5, OR52E6, OR52E8, OR52H1, OR52I1, OR52I2, OR52J3, OR52K1 , OR52K2, OR52L1, OR52M1 , OR52N1 , OR52N2, OR52N4, OR52N5, OR52R1, OR52W1, OR56A1 , OR56A3, OR56A4, OR56A5, OR56B1 , OR56B4, OR6V1 , OR7D2, OR9A2, oxoglutarate receptor, P2RY10, P2RY8, P2Y12 receptor, P2Y4 receptor, PrRP receptor, QRFP receptor, RXFP2 receptor, RXFP4 receptor, sst1 receptor, sst2 receptor, sst3 receptor, sst4 receptor, sst5 receptor, TA1 receptor, TAAR2, TAAR5, TAAR6, TAAR8, TAAR9, TAS1 R1 , TAS1 R2, TAS1 R3, TAS2R1 , TAS2R10, TAS2R13, TAS2R14, TAS2R16, TAS2R19, TAS2R20, TAS2R3, TAS2R30, TAS2R31 , TAS2R38, TAS2R39, TAS2R4, TAS2R40, TAS2R41 , TAS2R42, TAS2R43, TAS2R45, TAS2R46, TAS2R5, TAS2R50, TAS2R60, TAS2R7, TAS2R8, TAS2R9, TRH1 receptor, Y1 receptor, Y2 receptor, Y5 receptor, a1A-adrenoceptor, a1 B-adrenoceptor, a1 D-adrenoceptor, d receptor, 5-HT1 A receptor, 5-HT2A receptor, A1 receptor, A2A receptor, A2B receptor, A3 receptor, ACKR1 , ACKR2, ACKR3, ACKR4, ADGRE1 , ADGRE2, ADGRE3, ADGRE5, apelin receptor, AT1 receptor, B1 receptor, B2 receptor, BB2 (GRP) receptor, BLT 1 receptor, BLT2 receptor, C3a receptor, C5a1 receptor, C5a2 receptor, CaS receptor, CCR1 , CCR10, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRL2, chemerin receptor, CX3CR1 , CXCR1 , CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CysLTI receptor, CysLT2 receptor, DP1 receptor, DP2 receptor, EP1 receptor, EP2 receptor, EP3 receptor, EP4 receptor, FFA2 receptor, FFA4 receptor, FP receptor, FPR1 , FPR2/ALX, FPR2/ALX, FPR3, FZD6, GAL2 receptor, GAL3 receptor, ghrelin receptor, GPR132, GPR15, GPR18, GPR183, GPR21 , GPR31 , GPR32, GPR34, GPR4, GPR55, GPR55, GPR65, GPR68, H1 receptor, H2 receptor, H4 receptor, IP receptor, LPA5 receptor, MAS1 , MC1 receptor, MCH1 receptor, mGlul receptor, mGlu5 receptor, MRGPRX2, MT1 receptor, MT2 receptor, NK1 receptor, NK3 receptor, NMU1 receptor, OXE receptor, P2Y1 receptor, P2Y1 1 receptor, P2Y13 receptor, P2Y14 receptor, P2Y2 receptor, P2Y6 receptor, PAF receptor, PAR1 , PAR2, PAR3, PAR4, PKR1 , PKR2, S1 P1 receptor, S1 P2 receptor, S1 P3 receptor, S1 P4 receptor, S1 P5 receptor, succinate receptor, TP receptor, VPAC1 receptor, VPAC2 receptor, XCR1 , b2^GbhoobrΐqG, k receptor, m receptor.

[000169] In one embodiment, the certain activated co-located GPCRs of the invention are GPCRs selected from the group: OX1 receptor, 0X2 receptor, PTH1 receptor, PTH2 receptor, AMY1 receptor, AMY2 receptor, AMY3 receptor, AM1 receptor, AM2 receptor, GPR63, GPR75, NMU2 receptor, OPN5, V1 B receptor, y6 receptor, 5-HT4 receptor, GPR101 , GPR1 19, GPR135, GPR137, GPR141 , GPR149, GPR150, GPR151 , GPR152, GPR157, GPR19, GPR25, GPR37, GPR37L1 , GPR50, GPR62, LGR5, MRGPRE, MRGPRF, NTS2 receptor, OPN4, OPN4, OR10A7, OR10AG1 , OR10Q1 , OR10W1 , OR12D3, OR13C2, OR13C3, OR13C4, OR13C5, OR13C8, OR13F1 , OR13G1 , OR1 A2, OR1 L1 , OR1 S1 , OR1 S2, OR2AK2, OR2D2, OR2D3, OR4A15, OR4C1 1 , OR4C12, OR4C13, OR4C15, OR4C16, OR4K13, OR4K14, OR4K15, OR4K17, OR4N5, OR5AC2, OR5AK2, OR5AP2, OR5AR1 , OR5AS1 , OR5B12, OR5B17, OR5B2, OR5B21 , OR5B3, OR5D13, OR5D14, OR5D16, OR5D18, OR5F1 , OR5I1, OR5J2, OR5K3, OR5L1 , OR5L2, OR5M1, OR5M10, OR5M11, OR5M3, OR5M8, OR5M9, OR5R1, OR5T1, OR5T2, OR5T3, OR5W2, OR6C74, OR6K6, OR6M1 , OR6Q1 , OR6X1, OR8H1, OR8H2, OR8H3, OR8J1, OR8J3, OR8K1 , OR8K3, OR8K5, OR8U1 , OR8U8, OR9A4, OR9G1, OR9G4, OR9G9, OR9Q2, TAAR3, TPRA1 , U4 receptor, 5-HT1D receptor, 5-HT1E receptor, ADGRB1, AT2 receptor, BB1 receptor, BB3 receptor, CGRP receptor, CRF1 receptor, CRF2 receptor, ETA receptor, ETB receptor, FZD4, FZD5, FZD7, FZD8, FZD9, GABAB receptor, GABAB1 , GABAB2, GAL1 receptor, GIP receptor, GLP-1 receptor, GLP-2 receptor, glucagon receptor, GnRH2 receptor, GPER, GPR107, GPR139, GPR156, GPR158, GPR161, GPR171, GPR179, GPR39, GPR45, GPR88, GPRC5A, GPRC5B, GPRC5C, H3 receptor, HCA1 receptor, LPA1 receptor, LPA3 receptor, LPA4 receptor, MC2 receptor, MC4 receptor, mGlu2 receptor, mGlu3 receptor, motilin receptor, MRGPRD, MRGPRX1 , MRGPRX3, NK2 receptor, NPFF1 receptor, NPFF2 receptor, NPS receptor, NTS1 receptor, OR1D2, OR2AG1, OT receptor, PAC1 receptor, RXFP1 receptor, secretin receptor, TSH receptor, UT receptor, V1A receptor, V2 receptor, a2A-adrenoceptor, a2B-adrenoceptor, a2C-adrenoceptor, b1 -adrenoceptor, b3^GbhoobrίqG, 5-FIT1B receptor, 5-HT 1 F receptor, 5-FIT2B receptor, 5-FIT2C receptor, 5-FIT5A receptor, 5- HT6 receptor, 5-HT7 receptor, ADGRE4P, ADGRF1, ADGRG1, ADGRG3, ADGRG5, calcitonin receptor-like receptor, CB1 receptor, CB2 receptor, CCK1 receptor, CCK2 receptor, CT receptor, D1 receptor, D2 receptor, D3 receptor, D4 receptor, D5 receptor, FFA1 receptor, FFA3 receptor, FSH receptor, FZD1, FZD2, FZD3, GHRH receptor, GnRFU receptor, GPBA receptor, GPR1, GPR119, GPR12, GPR142, GPR143, GPR146, GPR148, GPR153, GPR160, GPR162, GPR17, GPR173, GPR174, GPR176, GPR18, GPR182, GPR20, GPR22, GPR26, GPR27, GPR3, GPR33, GPR35, GPR6, GPR61 , GPR78, GPR82, GPR83, GPR84, GPR85, GPR87, GPRC5D, GPRC6 receptor, HCA2 receptor, HCA3 receptor, kisspeptin receptor, LGR4, LGR6, LH receptor, LPA2 receptor, LPA6 receptor, M1 receptor, M2 receptor, M3 receptor, M4 receptor, M5 receptor, MAS1 L, MC3 receptor, MC5 receptor, MCH2 receptor, mGlu4 receptor, mGlu7 receptor, mGlu8 receptor, MRGPRG, NOP receptor, NPBW1 receptor, NPBW2 receptor, OPN3, OR11H1, OR2A1, OR2A2, OR2A4, OR2A42, OR2A7, OR2B11, OR2B6, OR2C1 , OR2C3, OR2J3, OR2L13, OR2T11, OR2T34, OR2W3, OR3A3, OR4D10, OR4M1 , OR4Q3, OR51A2, OR51A4, OR51A7, OR51B2, OR51B4, OR51 B5, OR51B6, OR51D1, OR51E1, OR51E1, OR51E2, OR51F1, OR51 F2, OR51G1, OR51G2, OR51I1, OR51I2, OR51J1, OR51 L1 , OR51M1, OR51Q1, OR51S1, OR51T1, OR51V1, OR52A1, OR52A4, OR52A5, OR52B2, OR52B4, OR52B6, OR52D1, OR52E2, OR52E4, OR52E5, OR52E6, OR52E8, OR52H1, OR52I1, OR52I2, OR52J3, OR52K1 , OR52K2, OR52L1, OR52M1 , OR52N1 , OR52N2, OR52N4, OR52N5, OR52R1, OR52W1, OR56A1 , OR56A3, OR56A4, OR56A5, OR56B1, OR56B4, OR6V1, OR7D2, OR9A2, oxoglutarate receptor, P2RY10, P2RY8, P2Y12 receptor, P2Y4 receptor, PrRP receptor, QRFP receptor, RXFP2 receptor, RXFP4 receptor, sst1 receptor, sst2 receptor, sst3 receptor, sst4 receptor, sst5 receptor, TA1 receptor, TAAR2, TAAR5, TAAR6, TAAR8, TAAR9, TAS1 R1 , TAS1 R2, TAS1 R3, TAS2R1 , TAS2R10, TAS2R13, TAS2R14, TAS2R16, TAS2R19, TAS2R20, TAS2R3, TAS2R30, TAS2R31 , TAS2R38, TAS2R39, TAS2R4, TAS2R40, TAS2R41 , TAS2R42, TAS2R43, TAS2R45, TAS2R46, TAS2R5, TAS2R50, TAS2R60, TAS2R7, TAS2R8, TAS2R9, TRH1 receptor, Y1 receptor, Y2 receptor, Y5 receptor, a1A-adrenoceptor, a1 B-adrenoceptor, a1 D-adrenoceptor, d receptor, 5-HT1 A receptor, 5-HT2A receptor, A1 receptor, A2A receptor, A2B receptor, A3 receptor, ACKR1 , ACKR2, ACKR3, ACKR4, ADGRE1 , ADGRE2, ADGRE3, ADGRE5, apelin receptor, AT1 receptor, B1 receptor, B2 receptor, BB2 (GRP) receptor, BLT 1 receptor, BLT2 receptor, C3a receptor, C5a1 receptor, C5a2 receptor, CaS receptor, CCR1 , CCR10, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRL2, chemerin receptor, CX3CR1 , CXCR1 , CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CysLTI receptor, CysLT2 receptor, DP1 receptor, DP2 receptor, EP1 receptor, EP2 receptor, EP3 receptor, EP4 receptor, FFA2 receptor, FFA4 receptor, FP receptor, FPR1 , FPR2/ALX, FPR2/ALX, FPR3, FZD6, GAL2 receptor, GAL3 receptor, ghrelin receptor, GPR132, GPR15, GPR18, GPR183, GPR21 , GPR31 , GPR32, GPR34, GPR4, GPR55, GPR55, GPR65, GPR68, H1 receptor, H2 receptor, H4 receptor, IP receptor, LPA5 receptor, MAS1 , MC1 receptor, MCH1 receptor, mGlul receptor, mGlu5 receptor, MRGPRX2, MT1 receptor, MT2 receptor, NK1 receptor, NK3 receptor, NMU1 receptor, OXE receptor, P2Y1 receptor, P2Y1 1 receptor, P2Y13 receptor, P2Y14 receptor, P2Y2 receptor, P2Y6 receptor, PAF receptor, PAR1 , PAR2, PAR3, PAR4, PKR1 , PKR2, S1 P1 receptor, S1 P2 receptor, S1 P3 receptor, S1 P4 receptor, S1 P5 receptor, succinate receptor, TP receptor, VPAC1 receptor, VPAC2 receptor, XCR1 , b2^GbhoobrίqG, k receptor, m receptor.

[000170] In one embodiment, the certain activated co-located GPCRs of the invention are GPCRs selected from the group: 5-HT4 receptor, GPR101 , GPR1 19, GPR135, GPR137, GPR141 , GPR149, GPR150, GPR151 , GPR152, GPR157, GPR19, GPR25, GPR37, GPR37L1 , GPR50, GPR62, LGR5, MRGPRE, MRGPRF, NTS2 receptor, OPN4, OPN4, OR10A7, OR10AG1 , OR10Q1 , OR10W1 , OR12D3, OR13C2, OR13C3, OR13C4, OR13C5, OR13C8, OR13F1 , OR13G1 , OR1 A2, OR1 L1 , OR1 S1 , OR1 S2, OR2AK2, OR2D2, OR2D3, OR4A15, OR4C1 1 , OR4C12, OR4C13, OR4C15, OR4C16, OR4K13, OR4K14, OR4K15, OR4K17, OR4N5, OR5AC2, OR5AK2, OR5AP2, OR5AR1 , OR5AS1 , OR5B12, OR5B17, OR5B2, OR5B21 , OR5B3, OR5D13, OR5D14, OR5D16, OR5D18, OR5F1 , OR5I1 , OR5J2, OR5K3, OR5L1 , OR5L2, OR5M1 , OR5M10, OR5M1 1 , OR5M3, OR5M8, OR5M9, OR5R1 , OR5T1 , OR5T2, OR5T3, OR5W2, OR6C74, OR6K6, OR6M1 , OR6Q1 , OR6X1 , OR8H1 , OR8H2, OR8H3, OR8J1 , OR8J3, OR8K1 , OR8K3, OR8K5, OR8U1 , OR8U8, OR9A4, OR9G1 , OR9G4, OR9G9, OR9Q2, TAAR3, TPRA1, Y4 receptor, 5-HT1D receptor, 5-HT1E receptor, ADGRB1, AT2 receptor, BB1 receptor, BB3 receptor, CGRP receptor, CRF1 receptor, CRF2 receptor, ETA receptor, ETB receptor, FZD4, FZD5, FZD7, FZD8, FZD9, GABAB receptor, GABAB1, GABAB2, GAL1 receptor, GIP receptor, GLP-1 receptor, GLP-2 receptor, glucagon receptor, GnRH2 receptor, GPER, GPR107, GPR139, GPR156, GPR158, GPR161 , GPR171 , GPR179, GPR39, GPR45, GPR88, GPRC5A, GPRC5B, GPRC5C, H3 receptor, HCA1 receptor, LPA1 receptor, LPA3 receptor, LPA4 receptor, MC2 receptor, MC4 receptor, mGlu2 receptor, mGlu3 receptor, motilin receptor, MRGPRD, MRGPRX1 , MRGPRX3, NK2 receptor, NPFF1 receptor, NPFF2 receptor, NPS receptor, NTS1 receptor, OR1D2, OR2AG1, OT receptor, PAC1 receptor, RXFP1 receptor, secretin receptor, TSH receptor, UT receptor, V1 A receptor, V2 receptor, a2A-adrenoceptor, a2B-adrenoceptor, a2C-adrenoceptor, b1- adrenoceptor, b3^GbhoobrίqG, 5-FIT1B receptor, 5-FIT1F receptor, 5-FIT2B receptor, 5- FIT2C receptor, 5-FIT5A receptor, 5-FIT6 receptor, 5-FIT7 receptor, ADGRE4P, ADGRF1, ADGRG1 , ADGRG3, ADGRG5, calcitonin receptor-like receptor, CB1 receptor, CB2 receptor, CCK1 receptor, CCK2 receptor, CT receptor, D1 receptor, D2 receptor, D3 receptor, D4 receptor, D5 receptor, FFA1 receptor, FFA3 receptor, FSH receptor, FZD1, FZD2, FZD3, GHRH receptor, GnRFU receptor, GPBA receptor, GPR1, GPR119, GPR12, GPR142, GPR143, GPR146, GPR148, GPR153, GPR160, GPR162, GPR17, GPR173, GPR174, GPR176, GPR18, GPR182, GPR20, GPR22, GPR26, GPR27, GPR3, GPR33, GPR35, GPR6, GPR61 , GPR78, GPR82, GPR83, GPR84, GPR85, GPR87, GPRC5D, GPRC6 receptor, HCA2 receptor, HCA3 receptor, kisspeptin receptor, LGR4, LGR6, LH receptor, LPA2 receptor, LPA6 receptor, M1 receptor, M2 receptor, M3 receptor, M4 receptor, M5 receptor, MAS1L, MC3 receptor, MC5 receptor, MCH2 receptor, mGlu4 receptor, mGlu7 receptor, mGlu8 receptor, MRGPRG, NOP receptor, NPBW1 receptor, NPBW2 receptor, OPN3, OR11H1, OR2A1 , OR2A2, OR2A4, OR2A42, OR2A7, OR2B11, OR2B6, OR2C1, OR2C3, OR2J3, OR2L13, OR2T11 , OR2T34, OR2W3, OR3A3, OR4D10, OR4M1, OR4Q3, OR51A2, OR51A4, OR51A7, OR51B2, OR51 B4, OR51B5, OR51 B6, OR51D1, OR51E1, OR51E1, OR51E2, OR51F1, OR51F2, OR51G1, OR51G2, OR51I1, OR51I2, OR51J1, OR51L1, OR51M1, OR51Q1 , OR51S1, OR51T1, OR51V1, OR52A1, OR52A4, OR52A5, OR52B2, OR52B4, OR52B6, OR52D1, OR52E2, OR52E4, OR52E5, OR52E6, OR52E8, OR52H1, OR52I1 , OR52I2, OR52J3, OR52K1, OR52K2, OR52L1, OR52M1, OR52N1, OR52N2, OR52N4, OR52N5, OR52R1, OR52W1, OR56A1, OR56A3, OR56A4, OR56A5, OR56B1, OR56B4, OR6V1 , OR7D2, OR9A2, oxoglutarate receptor, P2RY10, P2RY8, P2Y12 receptor, P2Y4 receptor, PrRP receptor, QRFP receptor, RXFP2 receptor, RXFP4 receptor, sst1 receptor, sst2 receptor, sst3 receptor, sst4 receptor, sst5 receptor, TA1 receptor, TAAR2, TAAR5, TAAR6, TAAR8, TAAR9, TAS1R1, TAS1R2, TAS1R3, TAS2R1 , TAS2R10, TAS2R13, TAS2R14, TAS2R16, TAS2R19, TAS2R20, TAS2R3, TAS2R30, TAS2R31 , TAS2R38, TAS2R39, TAS2R4, TAS2R40, TAS2R41 , TAS2R42, TAS2R43, TAS2R45, TAS2R46, TAS2R5, TAS2R50, TAS2R60, TAS2R7, TAS2R8, TAS2R9, TRH1 receptor, Y1 receptor, Y2 receptor, Y5 receptor, a1A-adrenoceptor, a1 B-adrenoceptor, a1 D-adrenoceptor, d receptor, 5-HT1 A receptor, 5-HT2A receptor, A1 receptor, A2A receptor, A2B receptor, A3 receptor, ACKR1 , ACKR2, ACKR3, ACKR4, ADGRE1 , ADGRE2, ADGRE3, ADGRE5, apelin receptor, AT1 receptor, B1 receptor, B2 receptor, BB2 (GRP) receptor, BLT1 receptor, BLT2 receptor, C3a receptor, C5a1 receptor, C5a2 receptor, CaS receptor, CCR1 , CCR10, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRL2, chemerin receptor, CX3CR1 , CXCR1 , CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CysLTI receptor, CysLT2 receptor, DP1 receptor, DP2 receptor, EP1 receptor, EP2 receptor, EP3 receptor, EP4 receptor, FFA2 receptor, FFA4 receptor, FP receptor, FPR1 , FPR2/ALX, FPR2/ALX, FPR3, FZD6, GAL2 receptor, GAL3 receptor, ghrelin receptor, GPR132, GPR15, GPR18, GPR183, GPR21 , GPR31 , GPR32, GPR34, GPR4, GPR55, GPR55, GPR65, GPR68, H1 receptor, H2 receptor, H4 receptor, IP receptor, LPA5 receptor, MAS1 , MC1 receptor, MCH1 receptor, mGlul receptor, mGlu5 receptor, MRGPRX2, MT1 receptor, MT2 receptor, NK1 receptor, NK3 receptor, NMU1 receptor, OXE receptor, P2Y1 receptor, P2Y1 1 receptor, P2Y13 receptor, P2Y14 receptor, P2Y2 receptor, P2Y6 receptor, PAF receptor, PAR1 , PAR2, PAR3, PAR4, PKR1 , PKR2, S1 P1 receptor, S1 P2 receptor, S1 P3 receptor, S1 P4 receptor, S1 P5 receptor, succinate receptor, TP receptor, VPAC1 receptor, VPAC2 receptor, XCR1 , b2^GbhoobrίqG, K receptor, m receptor.

[000171 ] In one embodiment, the certain activated co-located GPCRs of the invention are GPCRs selected from the group: 5-FIT 1 D receptor, 5-FIT 1 E receptor, ADGRB1 , AT2 receptor, BB1 receptor, BB3 receptor, CGRP receptor, CRF1 receptor, CRF2 receptor, ETA receptor, ETB receptor, FZD4, FZD5, FZD7, FZD8, FZD9, GABAB receptor, GABAB1 , GABAB2, GAL1 receptor, GIP receptor, GLP-1 receptor, GLP-2 receptor, glucagon receptor, GnRH2 receptor, GPER, GPR107, GPR139, GPR156, GPR158, GPR161 , GPR171 , GPR179, GPR39, GPR45, GPR88, GPRC5A, GPRC5B, GPRC5C, H3 receptor, HCA1 receptor, LPA1 receptor, LPA3 receptor, LPA4 receptor, MC2 receptor, MC4 receptor, mGlu2 receptor, mGlu3 receptor, motilin receptor, MRGPRD, MRGPRX1 , MRGPRX3, NK2 receptor, NPFF1 receptor, NPFF2 receptor, NPS receptor, NTS1 receptor, OR1 D2, OR2AG1 , OT receptor, PAC1 receptor, RXFP1 receptor, secretin receptor, TSH receptor, UT receptor, V1 A receptor, V2 receptor, a2A-adrenoceptor, a2B-adrenoceptor, a2C-adrenoceptor, b1 -adrenoceptor, b3^GbhoobrίqG, 5-FIT1 B receptor, 5-FIT1 F receptor, 5-FIT2B receptor, 5-FIT2C receptor, 5-FIT5A receptor, 5- HT6 receptor, 5-HT7 receptor, ADGRE4P, ADGRF1 , ADGRG1 , ADGRG3, ADGRG5, calcitonin receptor-like receptor, CB1 receptor, CB2 receptor, CCK1 receptor, CCK2 receptor, CT receptor, D1 receptor, D2 receptor, D3 receptor, D4 receptor, D5 receptor, FFA1 receptor, FFA3 receptor, FSFI receptor, FZD1, FZD2, FZD3, GFIRFI receptor, GnRFII receptor, GPBA receptor, GPR1, GPR119, GPR12, GPR142, GPR143, GPR146, GPR148, GPR153, GPR160, GPR162, GPR17, GPR173, GPR174, GPR176, GPR18, GPR182, GPR20, GPR22, GPR26, GPR27, GPR3, GPR33, GPR35, GPR6, GPR61 , GPR78, GPR82, GPR83, GPR84, GPR85, GPR87, GPRC5D, GPRC6 receptor, HCA2 receptor, HCA3 receptor, kisspeptin receptor, LGR4, LGR6, LH receptor, LPA2 receptor, LPA6 receptor, M1 receptor, M2 receptor, M3 receptor, M4 receptor, M5 receptor, MAS1 L, MC3 receptor, MC5 receptor, MCH2 receptor, mGlu4 receptor, mGlu7 receptor, mGlu8 receptor, MRGPRG, NOP receptor, NPBW1 receptor, NPBW2 receptor, OPN3, OR11H1, OR2A1, OR2A2, OR2A4, OR2A42, OR2A7, OR2B11, OR2B6, OR2C1 , OR2C3, OR2J3, OR2L13, OR2T11, OR2T34, OR2W3, OR3A3, OR4D10, OR4M1 , OR4Q3, OR51A2, OR51A4, OR51A7, OR51B2, OR51B4, OR51 B5, OR51B6, OR51D1, OR51E1, OR51E1, OR51E2, OR51F1, OR51F2, OR51G1, OR51G2, OR51I1, OR51I2, OR51J1, OR51 L1 , OR51M1, OR51Q1, OR51S1, OR51T1, OR51V1, OR52A1, OR52A4, OR52A5, OR52B2, OR52B4, OR52B6, OR52D1, OR52E2, OR52E4, OR52E5, OR52E6, OR52E8, OR52H1, OR52I1, OR52I2, OR52J3, OR52K1 , OR52K2, OR52L1, OR52M1 , OR52N1 , OR52N2, OR52N4, OR52N5, OR52R1, OR52W1, OR56A1 , OR56A3, OR56A4, OR56A5, OR56B1, OR56B4, OR6V1, OR7D2, OR9A2, oxoglutarate receptor, P2RY10, P2RY8, P2Y12 receptor, P2Y4 receptor, PrRP receptor, QRFP receptor, RXFP2 receptor, RXFP4 receptor, sst1 receptor, sst2 receptor, sst3 receptor, sst4 receptor, sst5 receptor, TA1 receptor, TAAR2, TAAR5, TAAR6, TAAR8, TAAR9, TAS1R1, TAS1R2, TAS1R3, TAS2R1 , TAS2R10, TAS2R13, TAS2R14, TAS2R16, TAS2R19, TAS2R20, TAS2R3, TAS2R30, TAS2R31 , TAS2R38, TAS2R39, TAS2R4, TAS2R40, TAS2R41 , TAS2R42, TAS2R43, TAS2R45, TAS2R46, TAS2R5, TAS2R50, TAS2R60, TAS2R7, TAS2R8, TAS2R9, TRH1 receptor, Y1 receptor, Y2 receptor, Y5 receptor, a1A-adrenoceptor, a1 B-adrenoceptor, a1 D-adrenoceptor, d receptor, 5-HT1A receptor, 5-HT2A receptor, A1 receptor, A2A receptor, A2B receptor, A3 receptor, ACKR1, ACKR2, ACKR3, ACKR4, ADGRE1, ADGRE2, ADGRE3, ADGRE5, apelin receptor, AT1 receptor, B1 receptor, B2 receptor, BB2 (GRP) receptor, BLT 1 receptor, BLT2 receptor, C3a receptor, C5a1 receptor, C5a2 receptor, CaS receptor, CCR1, CCR10, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRL2, chemerin receptor, CX3CR1 , CXCR1 , CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CysLTI receptor, CysLT2 receptor, DP1 receptor, DP2 receptor, EP1 receptor, EP2 receptor, EP3 receptor, EP4 receptor, FFA2 receptor, FFA4 receptor, FP receptor, FPR1, FPR2/ALX, FPR2/ALX, FPR3, FZD6, GAL2 receptor, GAL3 receptor, ghrelin receptor, GPR132, GPR15, GPR18, GPR183, GPR21 , GPR31 , GPR32, GPR34, GPR4, GPR55, GPR55, GPR65, GPR68, H1 receptor, H2 receptor, H4 receptor, IP receptor, LPA5 receptor, MAS1, MC1 receptor, MCH1 receptor, mGlul receptor, mGlu5 receptor, MRGPRX2, MT1 receptor, MT2 receptor, NK1 receptor, NK3 receptor, NMU1 receptor, OXE receptor, P2Y1 receptor, P2Y11 receptor, P2Y13 receptor, P2Y14 receptor, P2Y2 receptor, P2Y6 receptor, PAF receptor, PAR1, PAR2, PAR3, PAR4, PKR1, PKR2, S1P1 receptor, S1P2 receptor, S1P3 receptor, S1P4 receptor, S1P5 receptor, succinate receptor, TP receptor, VPAC1 receptor, VPAC2 receptor, XCR1, b2^GbhoobrΐqG, k receptor, m receptor.

[000172] In one embodiment, the certain activated co-located GPCRs of the invention are GPCRs selected from the group: 5-HT1B receptor, 5-HT1F receptor, 5-HT2B receptor, 5- HT2C receptor, 5-HT5A receptor, 5-HT6 receptor, 5-HT7 receptor, ADGRE4P, ADGRF1, ADGRG1 , ADGRG3, ADGRG5, calcitonin receptor-like receptor, CB1 receptor, CB2 receptor, CCK1 receptor, CCK2 receptor, CT receptor, D1 receptor, D2 receptor, D3 receptor, D4 receptor, D5 receptor, FFA1 receptor, FFA3 receptor, FSFI receptor, FZD1, FZD2, FZD3, GFIRFI receptor, GnRFU receptor, GPBA receptor, GPR1, GPR119, GPR12, GPR142, GPR143, GPR146, GPR148, GPR153, GPR160, GPR162, GPR17, GPR173, GPR174, GPR176, GPR18, GPR182, GPR20, GPR22, GPR26, GPR27, GPR3, GPR33, GPR35, GPR6, GPR61 , GPR78, GPR82, GPR83, GPR84, GPR85, GPR87, GPRC5D, GPRC6 receptor, HCA2 receptor, HCA3 receptor, kisspeptin receptor, LGR4, LGR6, LH receptor, LPA2 receptor, LPA6 receptor, M1 receptor, M2 receptor, M3 receptor, M4 receptor, M5 receptor, MAS1L, MC3 receptor, MC5 receptor, MCH2 receptor, mGlu4 receptor, mGlu7 receptor, mGlu8 receptor, MRGPRG, NOP receptor, NPBW1 receptor, NPBW2 receptor, OPN3, OR11H1, OR2A1 , OR2A2, OR2A4, OR2A42, OR2A7, OR2B11, OR2B6, OR2C1, OR2C3, OR2J3, OR2L13, OR2T11 , OR2T34, OR2W3, OR3A3, OR4D10, OR4M1, OR4Q3, OR51A2, OR51A4, OR51A7, OR51B2, OR51 B4, OR51B5, OR51 B6, OR51D1, OR51E1, OR51E1, OR51E2, OR51F1, OR51F2, OR51G1, OR51G2, OR51I1, OR51I2, OR51J1, OR51L1, OR51M1, OR51Q1 , OR51S1, OR51T1, OR51V1, OR52A1, OR52A4, OR52A5, OR52B2, OR52B4, OR52B6, OR52D1, OR52E2, OR52E4, OR52E5, OR52E6, OR52E8, OR52H1, OR52I1 , OR52I2, OR52J3, OR52K1, OR52K2, OR52L1, OR52M1, OR52N1, OR52N2, OR52N4, OR52N5, OR52R1, OR52W1, OR56A1, OR56A3, OR56A4, OR56A5, OR56B1, OR56B4, OR6V1 , OR7D2, OR9A2, oxoglutarate receptor, P2RY10, P2RY8, P2Y12 receptor, P2Y4 receptor, PrRP receptor, QRFP receptor, RXFP2 receptor, RXFP4 receptor, sst1 receptor, sst2 receptor, sst3 receptor, sst4 receptor, sst5 receptor, TA1 receptor, TAAR2, TAAR5, TAAR6, TAAR8, TAAR9, TAS1R1, TAS1R2, TAS1R3, TAS2R1 , TAS2R10, TAS2R13, TAS2R14, TAS2R16, TAS2R19, TAS2R20, TAS2R3, TAS2R30, TAS2R31 , TAS2R38, TAS2R39, TAS2R4, TAS2R40, TAS2R41 , TAS2R42, TAS2R43, TAS2R45, TAS2R46, TAS2R5, TAS2R50, TAS2R60, TAS2R7, TAS2R8, TAS2R9, TRH1 receptor, Y1 receptor, Y2 receptor, Y5 receptor, a1A-adrenoceptor, a1 B-adrenoceptor, a1D-adrenoceptor, d receptor, 5-HT1 A receptor, 5-HT2A receptor, A1 receptor, A2A receptor, A2B receptor, A3 receptor, ACKR1 , ACKR2, ACKR3, ACKR4, ADGRE1 , ADGRE2, ADGRE3, ADGRE5, apelin receptor, AT1 receptor, B1 receptor, B2 receptor, BB2 (GRP) receptor, BLT1 receptor, BLT2 receptor, C3a receptor, C5a1 receptor, C5a2 receptor, CaS receptor, CCR1 , CCR10, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRL2, chemerin receptor, CX3CR1 , CXCR1 , CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CysLTI receptor, CysLT2 receptor, DP1 receptor, DP2 receptor, EP1 receptor, EP2 receptor, EP3 receptor, EP4 receptor, FFA2 receptor, FFA4 receptor, FP receptor, FPR1 , FPR2/ALX, FPR2/ALX, FPR3, FZD6, GAL2 receptor, GAL3 receptor, ghrelin receptor, GPR132, GPR15, GPR18, GPR183, GPR21 , GPR31 , GPR32, GPR34, GPR4, GPR55, GPR55, GPR65, GPR68, H1 receptor, H2 receptor, H4 receptor, IP receptor, LPA5 receptor, MAS1 , MC1 receptor, MCH1 receptor, mGlul receptor, mGlu5 receptor, MRGPRX2, MT1 receptor, MT2 receptor, NK1 receptor, NK3 receptor, NMU1 receptor, OXE receptor, P2Y1 receptor, P2Y1 1 receptor, P2Y13 receptor, P2Y14 receptor, P2Y2 receptor, P2Y6 receptor, PAF receptor, PAR1 , PAR2, PAR3, PAR4, PKR1 , PKR2, S1 P1 receptor, S1 P2 receptor, S1 P3 receptor, S1 P4 receptor, S1 P5 receptor, succinate receptor, TP receptor, VPAC1 receptor, VPAC2 receptor, XCR1 , b2^GbhoobrίqG, K receptor, m receptor.

[000173] In one embodiment, the certain activated co-located GPCRs of the invention are GPCRs selected from the group: 5-HT1 A receptor, 5-HT2A receptor, A1 receptor, A2A receptor, A2B receptor, A3 receptor, ACKR1 , ACKR2, ACKR3, ACKR4, ADGRE1 , ADGRE2, ADGRE3, ADGRE5, apelin receptor, AT1 receptor, B1 receptor, B2 receptor, BB2 (GRP) receptor, BLT1 receptor, BLT2 receptor, C3a receptor, C5a1 receptor, C5a2 receptor, CaS receptor, CCR1 , CCR10, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRL2, chemerin receptor, CX3CR1 , CXCR1 , CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CysLTI receptor, CysLT2 receptor, DP1 receptor, DP2 receptor, EP1 receptor, EP2 receptor, EP3 receptor, EP4 receptor, FFA2 receptor, FFA4 receptor, FP receptor, FPR1 , FPR2/ALX, FPR2/ALX, FPR3, FZD6, GAL2 receptor, GAL3 receptor, ghrelin receptor, GPR132, GPR15, GPR18, GPR183, GPR21 , GPR31 , GPR32, GPR34, GPR4, GPR55, GPR55, GPR65, GPR68, H1 receptor, H2 receptor, H4 receptor, IP receptor, LPA5 receptor, MAS1 , MC1 receptor, MCH1 receptor, mGlul receptor, mGlu5 receptor, MRGPRX2, MT1 receptor, MT2 receptor, NK1 receptor, NK3 receptor, NMU1 receptor, OXE receptor, P2Y1 receptor, P2Y1 1 receptor, P2Y13 receptor, P2Y14 receptor, P2Y2 receptor, P2Y6 receptor, PAF receptor, PAR1 , PAR2, PAR3, PAR4, PKR1 , PKR2, S1 P1 receptor, S1 P2 receptor, S1 P3 receptor, S1 P4 receptor, S1 P5 receptor, succinate receptor, TP receptor, VPAC1 receptor, VPAC2 receptor, XCR1 , b2-8RGbhoobrΐqG, k receptor, m receptor. [000174] In one embodiment, the certain activated co-located GPCRs of the invention are GPCRs selected from the group: AT 1 receptor, vasopressin receptor V2R, S1 P1 receptor, b2- adrenoceptor, orexin receptor 2, TRH receptor 1 , CCR1 , CCR2, CCR6, CCR7, CXCR2, CXCR4, CXCR6, somatostatin receptor 3, C5a receptor.

[000175] In one embodiment, the certain activated co-located GPCRs of the invention are GPCRs selected from the group: AT 1 receptor, vasopressin receptor V2R, S1 P1 receptor, b2- adrenoceptor, orexin receptor 2, TRH receptor 1 , CCR1 , CCR2, CCR6, CCR7, CXCR2, CXCR6, somatostatin receptor 3, C5a receptor.

[000176] In one embodiment, the certain activated co-located GPCRs of the invention are selected from the group: AT 1 receptor and C5a receptor.

[000177] In one embodiment, the certain activated co-located GPCR of the invention is AT 1 receptor.

[000178] In one embodiment, certain chemokine receptors are chemokine receptors that are co-expressed in the same cell as an IgSF CAM.

[000179] In one embodiment, certain chemokine receptors are chemokine receptors that are co-expressed in the same cell as an IgSF CAM, are implicated in inflammation, and are selected from the group: CCR1 , CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1 , CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7, CX3CR1 , XCR1 .

[000180] In one embodiment, certain chemokine receptors are chemokine receptors that are co-expressed in the same cell as an IgSF CAM, are implicated in inflammation, and are selected from the group: CCR1 , CCR2, CCR6, CCR7, CXCR2, CXCR4, CXCR6.

[000181 ] In one embodiment, certain chemokine receptors are chemokine receptors that are co-expressed in the same cell as an IgSF CAM, are implicated in inflammation, and are selected from the group: CCR1 , CCR2, CCR6, CCR7, CXCR2, CXCR6.

[000182] In one form of the invention, an IgSF CAM-independent certain co-located GPCR signalling pathway is the G q signalling pathway. In one form of the invention, an IgSF CAM- independent certain co-located GPCR signalling pathway is the Gi/o signalling pathway. In one form of the invention, an IgSF CAM-independent certain co-located GPCR signalling pathway is the Gs signalling pathway. In one form of the invention, an IgSF CAM-independent certain co-located GPCR signalling pathway is the calcium signalling pathway. In one form of the invention, an IgSF CAM-independent certain co-located GPCR signalling pathway is the phospholipase C signalling pathway. In another form of the invention, the an IgSF CAM- independent certain co-located GPCR signalling pathway is b-arrestin-mediated extracellular regulated kinase (ERK) signalling.

[000183] In a particularly preferred embodiment, where the activated co-located GPCR is activated ATi R, modulators of the invention do not modulate, or modulate to a lesser extent, one or more an IgSF CAM independent ATi R signalling pathways.

[000184] In a particularly preferred embodiment, where the activated co-located GPCR is activated ATi R, modulators of the invention do not inhibit, or inhibit to a lesser extent, one or more an IgSF CAM independent ATi R signalling pathways.

[000185] In one form of the invention, an IgSF CAM-independent ATi R signalling pathway is the Gq signalling pathway. In another form of the invention, an IgSF CAM-independent AT i R signalling pathway is b-arrestin-mediated extracellular regulated kinase (ERK) signalling.

[000186] In one form of the invention, an IgSF CAM-independent ATi R signalling pathway is the Gi/o signalling pathway. In another form of the invention, an IgSF CAM-independent CCR2 signalling pathway is b-arrestin-mediated extracellular regulated kinase (ERK) signalling. In another form of the invention, n IgSF CAM-independent CCR2 signalling pathway is the phospholipase C signalling pathway.

3. Modulators of IgSF CAM ligand-dependent activation of an IgSF CAM

[000187] In one form of the invention, an IgSF CAM ligand is a ligand that interacts with the ectodomain of an IgSF CAM to modulate activation of an IgSF CAM.

[000188] Preferably, an IgSF CAM ligand is a ligand that interacts with the ectodomain of an IgSF CAM to modulate activation of an IgSF CAM and does not interact with the transmembrane domain or cytosolic tail of an IgSF CAM or motifs contained therein.

[000189] In one form of the invention, an IgSF CAM ligand is a ligand that interacts with the extracellular V and/or C domains of an IgSF CAM ectodomain to activate an IgSF CAM. Preferably, an IgSF CAM ligand does not interact with the transmembrane domain or cytosolic tail of an IgSF CAM or motifs contained therein.

[000190] In one form, the present invention comprises modulators of IgSF CAM activity where such IgSF CAM activity is induced by its cognate ligand and where the modulators of IgSF CAM activity are analogues, fragments or derivatives of an IgSF CAM. [000191 ] In one form, the present invention comprises modulators of IgSF CAM activity where such IgSF CAM activity is induced by its cognate ligand and where the modulators of IgSF CAM activity are analogues, fragments or derivatives of the C-terminal tail of an IgSF CAM.

[000192] In one form, the present invention comprises modulators of IgSF CAM activity where such IgSF CAM activity is induced by its cognate ligand and where the modulators of IgSF CAM activity are analogues, fragments or derivatives of the C-terminal tail of an IgSF CAM lacking serines or threonines, or with serines and threonines selectively mutated to other residues.

[000193] In one form, the present invention comprises modulators of IgSF CAM activity where such IgSF CAM activity is induced by its cognate ligand and where the modulators of IgSF CAM activity are analogues, fragments or derivatives of the C-terminal tail of IgSF CAM lacking serines or threonines, or with serines and threonines mutated to other residues that are not negatively charged.

[000194] In one form of the invention, a modulator that modulates an IgSF CAM ligand- independent activation of an IgSF CAM by an activated co-located GPCR, such as activated angiotensin receptor, such as ATi R, also modulates an IgSF CAM ligand-dependent activation of an IgSF CAM.

[000195] In preferred embodiments of the invention, modulators of the invention do not modulate, or modulate differently, or modulate to a different extent, an IgSF CAM-independent signalling pathways associated with the certain activated co-located GPCR.

[000196] In a preferred embodiment, modulators of the invention do not inhibit, or inhibit to a lesser extent, one or more an IgSF CAM independent certain co-located GPCR signalling pathways.

[000197] In one form, the present invention comprises modulators of IgSF CAM activity where such IgSF CAM activity is induced by its cognate ligand and where the modulators of IgSF CAM activity are analogues, fragments or derivatives of ALCAM559-580 (SEQ ID NO: 6).

[000198] In one form, the present invention comprises modulators of IgSF CAM activity where such IgSF CAM activity is induced by its cognate ligand and where the modulators of IgSF CAM activity are analogues, fragments or derivatives of ALCAM559-580 (SEQ ID NO: 6) that differ by one, two, three, four, five, six, seven, eight, nine or ten amino acids. [000199] In one form, the present invention comprises a modulator of IgSF CAM activity where such IgSF CAM activity is induced by its cognate ligand and where the modulator of IgSF CAM activity is ALCAM _559-580 (SEQ ID NO: 6).

[000200] In one form, the present invention comprises modulators of IgSF CAM activity where such IgSF CAM activity is induced by its cognate ligand and where the modulators of IgSF CAM activity are analogues, fragments or derivatives of RAGE.

[000201 ] In one form, the present invention comprises modulators of IgSF CAM activity where such IgSF CAM activity is induced by its cognate ligand and where the modulators of IgSF CAM activity are analogues, fragments or derivatives of the cytosolic tail of RAGE.

[000202] In one form, the present invention comprises modulators of IgSF CAM activity where such IgSF CAM activity is induced by its cognate ligand and where the modulators of IgSF CAM activity are analogues, fragments or derivatives of RAGE _370-390 (SEQ ID NO: 7).

[000203] In one form, the present invention comprises modulators of IgSF CAM activity where such IgSF CAM activity is induced by its cognate ligand and where the modulators of IgSF CAM activity are analogues, fragments or derivatives of RAGE _370-390 (SEQ ID NO: 7) that differ by one, two, three, four, five, six, seven, eight, nine or ten amino acids.

[000204] In one form, the present invention comprises a modulator of IgSF CAM activity where such IgSF CAM activity is induced by its cognate ligand and where the modulator of IgSF CAM activity is RAGE370-390 (SEQ ID NO: 7).

[000205] In one form, the present invention comprises modulators of IgSF CAM activity where such IgSF CAM activity is induced by its cognate ligand and where the modulators of IgSF CAM activity are analogues, fragments or derivatives of S391 A-RAGE ₃₆ 2-404 (SEQ ID NO: 8).

[000206] In one form, the present invention comprises modulators of IgSF CAM activity where such IgSF CAM activity is induced by its cognate ligand and where the modulators of IgSF CAM activity are analogues, fragments or derivatives of S391 A-RAGE ₃₆ 2-404 (SEQ ID NO: 8) that differ by one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen or twenty amino acids.

[000207] In one form, the present invention comprises a modulator of IgSF CAM activity where such IgSF CAM activity is induced by its cognate ligand and where the modulator of IgSF CAM activity is S391 A-RAGE ₃₆₂ -404 (SEQ ID NO: 8). [000208] In one form, the present invention comprises modulators of IgSF CAM ligand- dependent activation of an IgSF CAM where the modulators of IgSF CAM ligand-dependent activation of an IgSF CAM are analogues, fragments or derivatives of IgSF CAM.

[000209] In one form of the invention the modulator of IgSF CAM ligand-dependent activation of an IgSF CAM is an analogue, fragment or derivative of ALCAM559-580 (SEQ ID NO: 6).

[000210] In one form of the invention the modulator of IgSF CAM ligand-dependent activation of an IgSF CAM is an analogue, fragment or derivative of ALCAM559-580 (SEQ ID NO:

6) that differs by one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen or twenty amino acids.

[00021 1 ] In one form of the invention the modulator of IgSF CAM ligand-dependent activation of an IgSF CAM is ALCAM559-580 (SEQ ID NO: 6).

[000212] In one form, the present invention comprises modulators of IgSF CAM ligand- dependent activation of an IgSF CAM where the modulators of IgSF CAM ligand-dependent activation of an IgSF CAM are analogues, fragments or derivatives of RAGE.

[000213] In one form, the present invention comprises modulators of IgSF CAM ligand- dependent activation of an IgSF CAM where the modulators of IgSF CAM ligand-dependent activation of an IgSF CAM are analogues, fragments or derivatives of the cytosolic tail of RAGE.

[000214] In one form of the invention the modulator of IgSF CAM ligand-dependent activation of an IgSF CAM is an analogue, fragment or derivative of RAGE370-390 (SEQ ID NO:

7).

[000215] In one form of the invention the modulator of IgSF CAM ligand-dependent activation of an IgSF CAM is an analogue, fragment or derivative of RAGE370-390 (SEQ ID NO: 7) that differs by one, two, three, four, five, six, seven, eight, nine or ten amino acids.

[000216] In one form of the invention the modulator of IgSF CAM ligand-dependent activation of an IgSF CAM is RAGE370-390 (SEQ ID NO: 7).

[000217] In one form of the invention the modulator of IgSF CAM ligand-dependent activation of an IgSF CAM is an analogue, fragment or derivative of S391 A-RAGE362-404 (SEQ ID NO: 8). [000218] In one form of the invention the modulator of IgSF CAM ligand-dependent activation of an IgSF CAM is an analogue, fragment or derivative of S391 A-RAGE ₃₆ 2-404 (SEQ ID NO: 8) that differs by one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen or twenty amino acids.

[000219] In one form of the invention the modulator of IgSF CAM ligand-dependent activation of an IgSF CAM is S391 A- RAG E362-404 (SEQ ID NO: 8).

[000220] In one form, the present invention comprises modulators wherein the modulators are modulators of IgSF CAM dependent signalling induced by its cognate ligand where the modulators of IgSF CAM dependent signalling induced by its cognate ligand are analogues, fragments or derivatives of IgSF CAM.

[000221 ] In one form, the present invention comprises modulators wherein the modulators are modulators of IgSF CAM dependent signalling induced by its cognate ligand where the modulators of IgSF CAM dependent signalling induced by its cognate ligand are analogues, fragments or derivatives of RAGE.

[000222] In one form of the present invention, the modulators of ligand-dependent activation of an IgSF CAM by its cognate ligand, contain the entire ectodomain of an IgSF CAM conjugated to an analogue, fragment or derivative of the transmembrane domain of an IgSF CAM which is greater than 5, greater than 10, or greater than 20 amino acids in length and the modulators of ligand-dependent activation of an IgSF CAM by its cognate ligand are analogues, fragments or derivatives of IgSF CAM.

[000223] In one form of the present invention, the modulators of ligand-dependent activation of an IgSF CAM by its cognate ligand, contain the entire ectodomain of an IgSF CAM conjugated to an analogue, fragment or derivative of the transmembrane domain of an IgSF CAM which is greater than 5, greater than 10, or greater than 20 amino acids in length and the modulators of ligand-dependent activation of an IgSF CAM by its cognate ligand are analogues, fragments or derivatives of RAGE.

[000224] In one form of the present invention, the modulators of ligand-dependent activation of an IgSF CAM by its cognate ligand contain a fragment of the ectodomain of an IgSF CAM and the modulators of ligand-dependent activation of an IgSF CAM by its cognate ligand are analogues, fragments or derivatives of IgSF CAM.

[000225] In one form of the present invention, the modulators of ligand-dependent activation of an IgSF CAM by its cognate ligand contain a fragment of the ectodomain of an IgSF CAM and the modulators of ligand-dependent activation of an IgSF CAM by its cognate ligand are analogues, fragments or derivatives of RAGE.

[000226] In one form of the present invention, the modulators of ligand-dependent activation of an IgSF CAM by its cognate ligand inhibit or facilitate signalling that occurs through the C- terminal cytosolic tail of an IgSF CAM and the modulators of ligand-dependent activation of an IgSF CAM by its cognate ligand are analogues, fragments or derivatives of IgSF CAM.

[000227] In one form of the present invention, the modulators of ligand-dependent activation of an IgSF CAM by its cognate ligand inhibit or facilitate signalling that occurs through the C- terminal cytosolic tail of an IgSF CAM and the modulators of ligand-dependent activation of an IgSF CAM by its cognate ligand are analogues, fragments or derivatives of RAGE.

[000228] In one form of the present invention, the modulators of ligand-dependent activation of an IgSF CAM by its cognate ligand inhibit binding that occurs to the C-terminal cytosolic tail of an IgSF CAM and the modulators of ligand-dependent activation of an IgSF CAM by its cognate ligand are analogues, fragments or derivatives of IgSF CAM.

[000229] In one form of the present invention, the modulators of ligand-dependent activation of an IgSF CAM by its cognate ligand inhibit binding that occurs to the C-terminal cytosolic tail of an IgSF CAM and the modulators of ligand-dependent activation of an IgSF CAM by its cognate ligand are analogues, fragments or derivatives of the cytosolic tail of IgSF CAM.

[000230] In one form of the present invention, the modulators of ligand-dependent activation of an IgSF CAM by its cognate ligand inhibit binding that occurs to the C-terminal cytosolic tail of an IgSF CAM and the modulators of ligand-dependent activation of an IgSF CAM by its cognate ligand are analogues, fragments or derivatives of ALCAM _559-58 o (SEQ ID NO: 6).

[000231 ] In one form of the present invention, the modulators of ligand-dependent activation of an IgSF CAM by its cognate ligand inhibit binding that occurs to the C-terminal cytosolic tail of an IgSF CAM and the modulators of ligand-dependent activation of an IgSF CAM by its cognate ligand are analogues, fragments or derivatives of ALCAM _559-58 o (SEQ ID NO: 6) that differs by one, two, three, four, five, six, seven, eight, nine or ten amino acids.

[000232] In one form of the present invention, the modulator of ligand-dependent activation of an IgSF CAM by its cognate ligand inhibits binding that occurs to the C-terminal cytosolic tail of an IgSF CAM and the modulator of ligand-dependent activation of an IgSF CAM by its cognate ligand is ALCAM _559-580 (SEQ ID NO: 6). [000233] In one form of the present invention, the modulator of ligand-dependent activation of an IgSF CAM by its cognate ligand is ALCAM _559-580 (SEQ ID NO: 6).

[000234] In one form of the present invention, the modulators of ligand-dependent activation of an IgSF CAM by its cognate ligand inhibit binding that occurs to the C-terminal cytosolic tail of an IgSF CAM and the modulators of ligand-dependent activation of an IgSF CAM by its cognate ligand are analogues, fragments or derivatives of RAGE.

[000235] In one form of the invention, the modulators of ligand-dependent activation of an IgSF CAM by its cognate ligand inhibit binding that occurs to the C-terminal cytosolic tail of an IgSF CAM and the modulators of ligand-dependent activation of an IgSF CAM by its cognate ligand are analogues, fragments or derivatives of the cytosolic tail of RAGE (RAGE _362-404 ) (SEQ ID NO: 31 ): LWQRRQRRGEERKAPENQEEEEERAELNQSEEPEAGESSTGGP.

[000236] In one form of the invention, the modulator of ligand-dependent activation of an IgSF CAM by its cognate ligand inhibit binding that occurs to the C-terminal cytosolic tail of an IgSF CAM and the modulators of ligand-dependent activation of an IgSF CAM by its cognate ligand are analogues, fragments or derivatives of RAGE370-390 (SEQ ID NO: 7).

[000237] In one form of the invention, the modulator of ligand-dependent activation of an IgSF CAM by its cognate ligand inhibit binding that occurs to the C-terminal cytosolic tail of an IgSF CAM and the modulators of ligand-dependent activation of an IgSF CAM by its cognate ligand are analogues, fragments or derivatives of RAGE _370-390 (SEQ ID NO: 7) that differs by one, two, three, four, five, six, seven, eight, nine or ten amino acids.

[000238] In one form of the present invention, the modulator of ligand-dependent activation of an IgSF CAM by its cognate ligand inhibits binding that occurs to the C-terminal cytosolic tail of an IgSF CAM and the modulator of ligand-dependent activation of an IgSF CAM by its cognate ligand is RAGE _370-390 (SEQ ID NO: 7).

[000239] In one form of the present invention, the modulator of ligand-dependent activation of an IgSF CAM by its cognate ligand is RAGE _370-390 (SEQ ID NO: 7).

[000240] In one form of the invention, the modulator of ligand-dependent activation of an IgSF CAM by its cognate ligand inhibit binding that occurs to the C-terminal cytosolic tail of an IgSF CAM and the modulators of ligand-dependent activation of an IgSF CAM by its cognate ligand are analogues, fragments or derivatives of S391 A-RAGE ₃₆ 2-404 (SEQ ID NO: 8). [000241 ] In one form of the invention, the modulator of ligand-dependent activation of an IgSF CAM by its cognate ligand inhibit binding that occurs to the C-terminal cytosolic tail of an IgSF CAM and the modulators of ligand-dependent activation of an IgSF CAM by its cognate ligand are analogues, fragments or derivatives of S391 A-RAGE ₃₆ 2- o4 (SEQ ID NO: 8) that differs by one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen or twenty amino acids.

[000242] In one form of the present invention, the modulator of ligand-dependent activation of an IgSF CAM by its cognate ligand inhibits binding that occurs to the C-terminal cytosolic tail of an IgSF CAM and the modulator of ligand-dependent activation of an IgSF CAM by its cognate ligand is S391 A-RAGE _{362- 04} (SEQ ID NO: 8).

[000243] In one form of the present invention, the modulator of ligand-dependent activation of an IgSF CAM by its cognate ligand is S391 A-RAGE ₃₆ 2- o4 (SEQ ID NO: 8).

[000244] In one form of the invention, the modulator is isolated.

[000245] In one form, the invention comprises a pharmaceutical composition comprising a modulator as described herein.

[000246] In one form the invention comprises the use of a modulator as described herein for the treatment or prevention of an ailment.

[000247] In one form of the invention, a modulator of the invention is an activator, an inhibitor, an allosteric modulator, or a non-functional mimic of the cytosolic tail of RAGE. A non functional substitute is a modulator that mimics the cytosolic tail of RAGE in the presence of certain co-located GPCRs, is not able to be activated by them or induce downstream RAGE- dependent signalling, and inhibits signalling that normally occurs through activation of the cytosolic tail of IgSF CAM and IgSF CAM-dependent signalling resulting therefrom.

[000248] In one form of the invention, a modulator of the invention is an activator, an inhibitor, an allosteric modulator, or a non-functional mimic of the transmembrane domain of RAGE or part thereof.

[000249] In one form of the invention, a non-functional substitute is a modulator that mimics the transmembrane domain of RAGE in the presence of certain co-located GPCRs, is not able to be activated by them or induce downstream RAGE-dependent signalling, and inhibits signalling that normally occurs through activation of the cytosolic tail of IgSF CAM and IgSF CAM-dependent signalling resulting therefrom. [000250] In one form of the invention, the modulator comprises a transmembrane domain of RAGE or a part thereof and a fragment of the RAGE ectodomain.

[000251 ] In one form of the invention, the modulator comprises a transmembrane domain of RAGE or a part thereof and a fragment of the cytosolic tail of RAGE.

[000252] In one form of the invention, the modulator comprises a transmembrane domain of RAGE or part thereof and a fragment of the RAGE ectodomain and a fragment of the cytosolic tail of RAGE.

[000253] In one form of the invention, modulators of the invention contain a fragment of the ectodomain of RAGE, which is not greater than 40, not greater than 20, not greater than 10 or not greater than 5 amino acids in length.

[000254] In one form of the invention, S391 A-RAGE _362-404 is a non-functional substitute for RAGE that in the presence of certain co-located GPCRs is not activated by them and inhibits IgSF CAM-dependent signalling. Expression of S391 A-RAGE _362-404 inhibits IgSF CAM ligand- independent activation of IgSF CAM by activated ATiR and IgSF CAM ligand-dependent activation of IgSF CAM. Furthermore, in one form of the invention, when S391 A-RAGE _362-404 is fused to a cell penetrating peptide (TAT) and a marker protein (mCherry), treatment with TAT-mCherry-S391 A-RAGE _362-404 oligopeptide inhibits IgSF CAM ligand-independent activation of IgSF CAM by activated ATiR to attenuate Ang ll-dependent pathology.

[000255] In one form of the invention, RAGE338-361 inhibits IgSF CAM ligand-independent activation of IgSF CAM by activated ATi R.

[000256] The sequence of RAGE338-361 is SEQ ID NO: 19:

[000257] [LGTLALALGILGGLGTAALLIGVI]

[000258] In one form, the present invention comprises modulators of IgSF CAM ligand- independent activation of IgSF CAM by certain activated co-located GPCRs that modulate transactivation of the cytosolic tail of IgSF CAM triggered by activation of such certain activated co-located GPCRs, such as an angiotensin receptor.

[000259] In one form, the present invention comprises modulators of IgSF CAM ligand- independent activation of the cytosolic tail of IgSF CAM by certain activated co-located GPCRs that bind to Ras GTPase-activating-like protein (IQGAP1 ) or other IgSF CAM-associated proteins, including protein kinase C zeta (RKΰz), Dock7, MyD88, TIRAP, IRAK4, ERK1/2, olfactory receptor 2T2, ADP/ATP translocase 2, Protein phosphatase 1 G, Intercellular adhesion molecule 1 , Protein DJ-1 (PARK7), Calponin-3, Drebrin, Filamin B, Ras-related protein Rab-13, Radixin/Ezrin/Moesin, Proteolipid protein 2, Coronin, S100 A1 1 , Succinyl-CoA ligase [GDP-forming] subunit alpha, Hsc70-interacting protein, Apoptosis Inhibitor 5, neuropilin, cleavage stimulation factor, growth factor receptor-bound protein 2, sec61 beta subunit, or Nck1 , or disrupt the binding of these elements to IgSF CAM, in order to modulate IgSF CAM transactivation by certain activated co-located GPCRs, such as an angiotensin receptor, such as ATi R.

[000260] In one form of the invention, the modulators of the invention bind to the cytosolic elements of the certain activated co-located GPCR, IgSF CAM and/or elements complexed with either, including IQGAP-1 , RKΰz, Dock7, MyD88, TIRAP, IRAK4, ERK1 /2, olfactory receptor 2T2, ADP/ATP translocase 2, Protein phosphatase 1 G, Intercellular adhesion molecule 1 , Protein DJ-1 (PARK7), Calponin-3, Drebrin, Filamin B, Ras-related protein Rab- 13, Radixin/Ezrin/Moesin, Proteolipid protein 2, Coronin, S100 A1 1 , Succinyl-CoA ligase [GDP-forming] subunit alpha, Hsc70-interacting protein, Apoptosis Inhibitor 5, neuropilin, cleavage stimulation factor, growth factor receptor-bound protein 2, sec61 beta subunit, or Nck1 to modulate IgSF CAM ligand-independent signalling through the cytosolic tail of IgSF CAM, by modulating these signalling elements required for IgSF CAM transactivation by certain activated co-located GPCRs, such as an angiotensin receptor, such as ATi R.

[000261 ] In one form of the invention, modulators of IgSF CAM ligand-independent activation of IgSF CAM by certain activated co-located GPCRs also modulate IgSF CAM ligand-dependent activation of the cytosolic tail of IgSF CAM, by binding to cytosolic elements of IgSF CAM and/or elements that complex with IgSF CAM in the cytosol (such as IQGAP-1 , RKΰz, Dock7, MyD88, IRAK4, TIRAP, ERK1/2, olfactory receptor 2T2, ADP/ATP translocase 2, Protein phosphatase 1 G, Intercellular adhesion molecule 1 , Protein DJ-1 (PARK7), Calponin-3, Drebrin, Filamin B, Ras-related protein Rab-13, Radixin/Ezrin/Moesin, Proteolipid protein 2, Coronin, S100 A1 1 , Succinyl-CoA ligase [GDP-forming] subunit alpha, Hsc70- interacting protein, Apoptosis Inhibitor 5, neuropilin, cleavage stimulation factor, growth factor receptor-bound protein 2, sec61 beta subunit, or Nck1 ) to inhibit IgSF CAM ligand-mediated signalling through these elements.

[000262] In some embodiments, the modulator is introduced by gene delivery (such as by using a virus or artificial non-viral gene delivery such as electroporation, micro injection, gene gun, impalefection, hydrostatic pressure, continuous infusion, sonication, lipofection, liposomes, nanobubbles and polymeric gene carriers) and the peptide fragment, biologically- active analogue or derivative being generated by the cell as a consequence of transcriptional and translational processes.

[000263] In some embodiments of this aspect, the modulator has a modified capacity to form a complex with certain co-located GPCRs, such as ATi R, or elements that complex with them. For example, the RAGE analogue or derivative may be distinguished from a wild-type RAGE polypeptide or fragment sequence by the substitution, addition, or deletion of at least one amino acid residue or addition or substitution of unusual or non-conventional amino-acids or non-amino acid residues.

[000264] In some embodiments, the modulator lacks or has a modification of serine-391 that is normally present in a wild-type human RAGE polypeptide. In illustrative examples of this type, the fragment, analogue or derivative of the cytosolic tail of RAGE lacks a serine at position 391 of the wild-type RAGE sequence (for example, the RAGE370-390 construct is truncated at Glu390). Suitably, the serine at position 391 is deleted or substituted with another amino acid residue, an analogue or derivative, in order to impair or abolish signalling conferred by a serine at this site following activation of a co-located GPCR. In one embodiment, the serine at position 391 is deleted or substituted with another amino acid residue selected from the group: alanine, aspartate, phenylalanine, histidine, lysine, arginine, tyrosine, asparagine, valine, glycine, cysteine or glutamate.

[000265] In some embodiments, the modulator lacks or has an impaired ability to bind Diaphanous 1 (Diaphl ) relative to human wild-type RAGE. In illustrative examples of this type, the peptide, or analogue, fragment or derivative thereof, either lacks the RAGE-Diaph1 binding site (such as RAGE370-390, RAGE374-390, or RAGE379-390) or has an altered Diaphl binding site (such as 366A/367A) in order to abolish or impair this site. Suitably, the residues at 366/367 are deleted or substituted with other residues (such as with alanine) in order to impair or abolish this site, and in doing so, improve affinity for binding to other targets, by reducing constraints induced by wild-type binding to Diaphl .

[000266] In one aspect of the invention, the modulator of the present invention includes isolated or purified peptides which comprise, consist, or consists essentially of an amino acid sequence represented by Formula I:

[000267] Z1 M Z2 (I)

[000268] wherein: [000269] Z1 is absent or is selected from at least one of a proteinaceous moiety comprising from about 1 to about 50 amino acid residues; and

[000270] M is the amino acid sequence as set forth in SEQ ID NO: 1 , or an analogue, fragment or derivative thereof; and

[000271 ] Z2 is absent or is a proteinaceous moiety comprising from about 1 to about 50 amino acid residues.

[000272] In some embodiments of the invention described above, the modulator (such as a fragment of the RAGE cytosolic tail, an analogue or derivative thereof as broadly described above and elsewhere herein) is able to penetrate a cell membrane. In non-limiting examples of this type, the RAGE modulator is conjugated, fused or otherwise linked to a cell membrane penetration molecule (e.g., the HIV TAT motif, as set forth in SEQ ID NO: 20 below).

[000273] SEQ ID NO: 20:

[000274] [YGRKKRRQRRR]

[000275] In some forms of the invention, the modulator is a non-peptide molecule that shares with the peptide modulator described above the capacity to bind to and/or interfere with elements associated with IgSF CAM ligand-independent activation of IgSF CAM by certain activated co-located GPCRs. These non-peptide modulators may or may not contain structural similarities to functionally important domains contained in peptide modulators.

[000276] In a preferred form, the non-peptide modulator contains any combination of one or more structural similarities to functionally important domains contained in the peptide modulators, as defined by the pharmacophore described vide infra.

[000277] In preferred forms of the invention, the modulator is an inhibitor.

[000278] In certain forms of the invention, in addition to being an inhibitor of IgSF CAM ligand-independent activation of IgSF CAM by a certain activated co-located GPCR, the modulator is an inhibitor of the certain co-located GPCR and/or an inhibitor of the certain co located GPCR signalling pathway.

[000279] In certain forms of the invention, in addition to being an inhibitor of IgSF CAM ligand-independent activation of IgSF CAM by a certain activated co-located GPCR, the modulator is an inhibitor of IgSF CAM ligand-dependent activation of IgSF CAM and/or an inhibitor of constitutively-active IgSF CAM and/or an inhibitor of a IgSF CAM signalling pathway.

[000280] In certain forms of the invention, where the certain co-located GPCR is ATi R, in addition to being an inhibitor of IgSF CAM ligand-independent activation of IgSF CAM, the modulator is an ATi R inhibitor and/or an inhibitor of an ATiR signalling pathway.

[000281 ] In certain forms of the invention, in addition to being an inhibitor of IgSF CAM ligand-independent activation of IgSF CAM by activated angiotensin receptor, preferably activated ATi R, the modulator is an inhibitor of IgSF CAM ligand-dependent activation of IgSF CAM and/or an inhibitor of constitutively-active IgSF CAM and/or an inhibitor of a IgSF CAM signalling pathway.

[000282] In certain forms of the invention, in addition to being an inhibitor of IgSF CAM ligand-independent activation of IgSF CAM by a certain activated co-located GPCR, the modulator is an inhibitor of the certain co-located GPCR and/or an inhibitor of the certain co located GPCR signalling pathway and an inhibitor of IgSF CAM ligand-dependent activation of IgSF CAM and/or an inhibitor of constitutively-active IgSF CAM and/or an inhibitor of a IgSF CAM signalling pathway.

[000283] In certain forms of the invention, in addition to being an inhibitor of IgSF CAM ligand-independent activation of IgSF CAM by activated angiotensin receptor, preferably activated ATi R, the modulator is an ATi R inhibitor and/or an inhibitor of an ATi R signalling pathway and an inhibitor of IgSF CAM ligand-dependent activation of IgSF CAM and/or an inhibitor of constitutively-active IgSF CAM and/or an inhibitor of a IgSF CAM signalling pathway.

[000284] In certain forms of the invention, the modulator is a non-functional substitute for the cytosolic tail of RAGE or a part thereof, which is not able to be activated by a co-located GPCR or facilitate downstream RAGE-dependent signalling and inhibits signalling that occurs through the cytosolic tail of IgSF CAM and IgSF CAM-dependent signalling.

[000285] In certain forms of the invention, the modulator is a non-functional substitute for the transmembrane domain of IgSF CAM or a part thereof, which is not able to be activated by a co-located GPCR or facilitate downstream IgSF CAM -dependent signalling and inhibits signalling that occurs through the cytosolic tail of IgSF CAM and IgSF CAM-dependent signalling. [000286] In certain forms of the invention, the modulator comprises a transmembrane domain of RAGE or a part thereof and a fragment of the RAGE ectodomain. In certain forms of the invention, the modulator comprises a transmembrane domain of RAGE or a part thereof and a fragment of the cytosolic tail of RAGE.

[000287] In certain forms of the invention, the modulator comprises a transmembrane domain of RAGE or part thereof and a fragment of the RAGE ectodomain and a fragment of the cytosolic tail of RAGE.

[000288] In certain forms of the invention, the modulators of IgSF CAM ligand-independent activation of IgSF CAM by certain activated co-located GPCRs contain a fragment of the ligand-binding ectodomain of human wild-type RAGE, which is not greater than 40, not greater than 20, not greater than 10 or not greater than 5 amino acids in length.

[000289] The inventors have discovered that a peptide comprising residues 370-390 of the cytosolic tail of RAGE (see SEQ ID NO: 7) is an inhibitory peptide, inhibiting both IgSF CAM ligand-independent and IgSF CAM ligand-dependent activation of full length IgSF CAM.

[000290] A solution NMR structure exists for RAGE ₃ 63-404 (Rai V et al., 2012) showing that the N-terminus (residues 363-376) of this peptide is ordered. A Rosetta-derived model exists for RAGE-362-404 (model4) which is consistent with the NMR structure (http://www.rcsb.orq/pdb/explore/explore.do?structureld=2LMB , accessed 25 August 2016)) and also suggests that the remainder of the peptide forms an alpha helix.

[000291 ] An initial model of RAGE _{3 0} -39owas constructed by truncating model4 (model4_ _{3 0} - 39o). Model4 is a theoretical model of the RAGE cytosolic tail, generated by inputting the sequence into the l-Tasser web server (http://zhanglab.ccmb.med.umich.edu/l-TASSER/). See also Yang et al { 2015), Roy et al { 2010) and Y Zhang (2008). All five models presented by the l-Tasser server predicted the region 370-390 to form a helix. The models and the NMR structure were aligned by the C-alpha carbons of the backbones of the peptide sequences. Model 4 was selected as the preferred model, as the predicted structure of the region corresponding to the Diaphanous 1 binding site in model4 was closest to the documented NMR structure for this region.

[000292] A 20 ns molecular dynamics simulation of model4 in water was run using GROMACS (Fless et al., 2008). The molecular dynamics simulation suggests that the alpha helix region of model4_ ₃₇ o- ₃₉ o is stable. Strong interactions are observed between a number of charged side chains, suggesting that these interactions stabilise the folded structure and that any conservation of these residues might result from their role in stabilising the peptide structure.

[000293] A Blast search was used to identify homologous sequences for RAGE370-390. The sequences were aligned as follows:

CLUSTAL 2.0.10 multiple sequence alignment

model4_37o-39o · pdb -GEERKAPENQ—EEEEERAELNQ- gi 1505855911 | ref | XP_004621364. RRRRGEERKVPENQ—EEEEERAELKQSGE

gi I 836716008 | ref | XP_012791097. RRRRGEERKVPENQ—EEEEERAELKQSGE

gi I 830242517 | ref | XP_012589882. RRR-GEQRKAPENR--EEEEERAELNQSEE

gi I 830242520 | ref | XP_012589883. RRR-GEQRKAPENR—EEEEERAELNQSEE

gi I 830242532 | ref | XP_012589884. RRR-GEQRKAPENR—EEEEERAELNQSEE

gi I 859958468 | ref | XP_012905636. RPR-REERKAPENQ—EEEEERAELNQSEE

gi I 505855913 I ref | XP_004621365. RRRRGEERKVPENQ- -EEEEERAELKQSGE

gi |8599584741 ref | XP_012905637. RPR-REERKAPENQ- -EEEEERAELNQSEE

gi I 674092933 | ref | XP_008819684. QHR-GEERKTPENQ—EDEEERAELNQSEE

gi I 852803202 | ref | XP_012890437. QHR-GEERKAPENQ- -EEEEERAELNQSEE

gi I 586986169 I ref | XP_006931651. RRQ-GEERKAPENQEEEEEEEREELNQSGE

gi I 752437365 I ref | XP_011235981. RHR-REERKAPENQ- -EEEEERAELNQSEE

gi I 671038558 | ref | XP_008710071. RHR-REERKAPENQ—EEEEERAELNQSVE

gi I 859958450 | ref | XP_012905633. RPR-REERKAPENQ- -EEEEERAELNQSEE

gi 110400994941 gb I OBS60144.1 | QPR-GEERKTPENQ—EDEEERAELNQSED

gi I 674092931 I ref | XP_008819683. QHR-GEERKTPENQ- -EDEEERAELNQSEE

gi I 641730582 | ref | XP_008155542. RHR-GEERKAPENQA-EEEEERAELNQSQE

gi I 641730580 | ref | XP_008155541. RHR-GEERKAPENQA-EEEEERAELNQSQE gi I 946738855 I ref | XP_014389946. RRR-GEERKAPENQ- -EEEEERAELHQSQE gi I 940771956 I ref I XP_006104444. RRR-GEERKAPENQ- -EEEEERAELHQSQE gi I 355748446 I gb I EHH52929.1 | RRQ-GEERKASENQ- -EEEEERAELNQSEE gi I 355561569 | gb | EHH18201.1 | RRQ-GEERKASENQ- -EEEEERAELNQSEE gi |5444288371 ref | XP_005553456. RRQ-GEERKASENQ- -EEEEERAELNQSEE gi I 635095937 | ref | XP_007971201. RRQ-GEERKASENQ- -EEEEERAELNQSEE gi I 402866556 I ref I XP_003897445. RRQ-REERKASENQ- -EEEEERAELNQSEE gi I 795466133 I ref | XP_011890032. RRQ-GEERKASENQ- -EEEEERAELNQSEE gi I 795466129 I ref | XP_011890031. RRQ-GEERKASENQ- -EEEEERAELNQSEE gi I 795317622 I ref | XP_011824818. RRQ-GEERKASENQ- -EEEEERAELNQSEE gi I 326693968 I ref | NP_001192046. RRQ-GEERKASENQ- -EEEEERAELNQSEE gi 17248020021 ref | XP_010376439. RRQ-GEERKAPENQ- -EEEEERAELNQSEE gi 17248019991 ref | XP_010376432. RRQ-GEERKAPENQ- -EEEEERAELNQSEE gi I 795178216 I ref | XP_011800170. RRQ-GEERKAPENQ- -EEEEERAELNQSEE gi |3121824781 gb | ADQ42279.1 | RRQ-GEERKASENQ- -EEEEERAELNQSEE gi I 795178211 I ref | XP_011800169. RRQ-GEERKAPENQ- -EEEEERAELNQSEE gi 1332800965 I ref | NP_001193858. QRR-GEERKAPENQ- -EEEEERAELNQSEE gi I 10835203 I ref I NP_001127.1 | QRR-GEERKAPENQ- -EEEEERAELNQSEE gi 1332800967 I ref | NP_001193861. QRR-GEERKAPENQ- -EEEEERAELNQSEE gi |8236728301 gb | AKI 71626.1 | QRR-GEERKAPENQ- -EEEEERAELNQSEE gi I 190846 I gb | AAA03574.1 | QRR-GEERKAPENQ- -EEEEERAELNQSEE gi 11943897381 dbj | BAG60385.1 | QRR-GEERKAPENQ- -EEEEERAELNQSEE gi 16949157151 ref | XP_009449249. QRQ-GEERKAPENQ—EEEEERAELNQSEE gi I 694915717 | ref | XP_009449250. QRQ-GEERKAPENQ— EEEEERAELNQSEE gi I 694915721 | ref | XP_009449252. QRQ-GEERKAPENQ— EEEEERAELNQSEE gi I 397519329 I ref | XP_003829814. QRQ-GEERKAPENQ- -EEEEERAELNQSEE gi I 397519323 I ref | XP_003829811. QRQ-GEERKAPENQ- -EEEEERAELNQSEE gi I 820970747 I ref | XP_012358508. RRQ-GEERKAPENQ- -EEEEERAELNQSEE gi | 8209707491 ref | XP_012358509. RRQ-GEERKAPENQ- -EEEEERAELNQSEE gi I 817330292 | ref | XP_012292176. RRR-GEERKAPENQ— EEEEEHAELNQSEE gi | 8173302941 ref | XP_012292177. RRR-GEERKAPENQ— EEEEEHAELNQSEE gi | 7256082501 ref | XP_010330526. RRR-GEERKAPENQ- -EEEEEHAELNQSEE gi I 725608252 I ref | XP_010330527. RRR-GEERKAPENQ- -EEEEEHAELNQSEE gi 12961977881 ref | XP_002746422. RRRRGEERKAPENQ- -EEEEEHAELNQSEE gi 18263201841 ref | XP_012509111. RGQ-GEERKAPENQ- -EEEEERAELNQSEE gi I 826320169 I ref | XP_012509105. RGQ-GEERKAPENQ- -EEEEERAELNQSEE gi 18263201751 ref | XP_012509107. RGQ-GEERKAPENQ- -EEEEERAELNQSEE gi I 826320172 | ref | XP_012509106. RGQ-GEERKAPENQ- -EEEEERAELNQSEE gi I 829933710 | ref | XP_012596554. RHQ-GEERKAPENQ- -EEEEERAELNQSEE gi I 829933718 | ref | XP_012596557. RHQ-GEERKAPENQ- -EEEEERAELNQSEE gi | 8299337221 ref | XP_012596558. RHQ-GEERKAPENQ- -EEEEERAELNQSEE gi | 7437311941 ref | XP_010959751. QRR-GEERKAPENQ-EEEEEERAELNQQEE gi | 5609050291 ref | XP_006178871. QRR-GEERKAPENQ-EEEEEERAELNQQEE gi | 5937598401 ref | XP_007118666. QRR-GEERKAPENQ-EEEEEERTELNQPEE gi I 560986474 I ref | XP_006215428. QRR-GEERKAPENQ-EEEEEERAELNQQEE gi I 927155182 | ref | XP_013833109. QRR-GQERKAPENQ-EEDEEERAELNQPED gi I 147225137 | emb | CAN13265.1 | QRR-GQERKAPENQ-EEDEEERAELNQPED gi I 178056480 | ref | NP_001116690. QRR-GQERKAPENQ-EEDEEERAELNQPED

gi I 162138238 | gb | ABX82823.1 | QRR-GQERKAPENQ-EEDEEERAELNQPED

gi I 471418692 | ref | XP_004390841. KHR-GEERKAPENQ— EEEEEHAELNQSEE

gi I 471418700 | ref | XP_004390845. KHR-GEERKAPENQ— EEEEEHAELNQSEE

gi 14714186941 ref | XP_004390842. KHR-GEERKAPENQ- -EEEEEHAELNQSEE

gi 18299337141 ref | XP_012596556. RHQ-GEERKAPENQ— EEEEERAELNQSEE

gi I 831224940 | ref | XP_012660273. QCQ-GEERKAPENQ— EEEEERTELNQSEE

gi 19841033511 ref | XP_015342983. RRQ-GEERKAPENQ- -EEEEERAELNQSEE

gi 15321085581 ref | XP_005339001. RRQ-GEERKAPENQ- -EEEEERAELNQSEE

gi 19555046461 ref | XP_014638416. QHR-REERKAPENQ- -EEEEERAELNQSEE

gi 14785000971 ref | XP_004424372. QHR-REERKAPENQ- -EEEEERAELNQSEE

gi 19555046501 ref | XP_014638417. QHR-REERKAPENQ- -EEEEERAELNQSEE

gi I 1048457071 | ref | XP_017510394 QCR-GEERKAPENQ— EEEEERAELSQSEE

gi 15899661711 ref | XP_006995615. QPR-REERKAPENQ— EDEEERAELNQSED

gi 15899661731 ref | XP_006995616. QPR-REERKAPENQ- -EDEEERAELNQSED

gi I 532056239 I ref I XP_005370828. QPR— EERKAPENE- -EDEEERAELNQSED

gi I 532056241 I ref I XP_005370829. QPR— EERKAPENE- -EDEEERAELNQSED

gi I 532056245 I ref I XP_005370831. QPR— EERKAPENE- -EDEEERAELNQSED

gi I 641730578 | ref | XP_008155540. RHR-GEERKAPENQA-EEEEERAELNQSQE

[000294] This analysis identified a number of strongly conserved residues in RAGE370-390 marked with as follows: ^* (asterisk) indicates positions which have a single, fully conserved residue. : (colon) indicates conservation between groups of strongly similar properties - scoring > 0.5 in the Gonnet PAM 250 matrix.. (period) indicates conservation between groups of weakly similar properties - scoring =< 0.5 in the Gonnet PAM 250 matrix:

[000295] Highly conserved residues are likely to play a structural role. Residues underlined are located on one face of the helix and likely represent the binding pharmacophore.

[000296] Examination of the model4_RAGE ₃₇ o- ₃₉ o structure and the molecular dynamics simulation results shows that a number of salt bridges are present in the structure. The molecular dynamics simulations show that these interactions are important structural features. Structural function is a likely reason for the conserved nature of these amino acids.

[000297] A number of strongly conserved amino acids are not involved in salt-bridge formation. These are present on one face of the RAGE370-390 helix and likely represent the binding interface. These are Glu380, Glu384, Glu387 and Leu388. Another highly conserved residue, Glu377 is also present on this face of the peptide and may also be involved in binding, in addition to forming an alpha-helix-stabilising salt bridge to Lys374.

[000298] In a preferred form of the invention, the modulator of IgSF CAM ligand- independent activation of IgSF CAM by a certain activated co-located GPCR, such as an angiotensin receptor, such as ATi R, is a peptide QEEEEERAELNQ as set forth in SEQ ID NO: 21 , or a derivative thereof.

[000299] SEQ ID NO: 21 : QEEEEERAELNQ.

[000300] The peptide may also have an initiating methionine and therefore have the sequence SEQ ID NO: 22: MQEEEEERAELNQ.

[000301 ] A pharmacophore for RAGE379-390 peptide derived from the structure model4_RAGE ₃₇ o-39o is represented below:

[000302] H4 is a hydrophobic residue, and P1 -P3 are polar residues, and distances are shown in Angstroms. A matrix of distances between site points is as follows, where P represents a polar site point (hydrogen bonding or charged), and H represents a hydrophobic site point. Distances are in Angstroms. A tolerance should be applied to the position of each point.

[000303] The molecular dynamics simulations show that the interacting groups of RAGE379- 390 are mobile and a tolerance should be applied to the position of each group of up to ± 10A provided the distances between the site points is positive in magnitude.

[000304] As would be understood by a person skilled in the art, additional, smaller pharmacophores can be generated by taking subsets of the above, and the present invention encompasses such pharmacophores, methods for using such to identify compounds, and compounds so identified.

[000305] In one form, the present invention further comprises a modulator of IgSF CAM ligand-independent activation of IgSF CAM by a certain activated co-located GPCR comprising two or more features selected from the group: a first charged or hydrogen bonding group (A), a second charged or hydrogen bonding group (B), a third charged or hydrogen bonding group (C), and a hydrophobic group (D) wherein the distances between the site points of the features are as follows, within a tolerance of up to ±10 A, provided the distances between the site points is positive in magnitude:

[000306] In a preferred form of the invention, the tolerance is up to ±5 A, provided the distances between the site points is positive in magnitude. In a preferred form of the invention, the tolerance is up to ±2 A, provided the distances between the site points is positive in magnitude. In a preferred form of the invention, the tolerance is up to ±1 A, provided the distances between the site points is positive in magnitude.

[000307] In a preferred form of the invention, the modulator comprises three or more features selected from the above-specified group.

[000308] In a preferred form of the invention, the modulator comprises four features from the above-specified group. [000309] In one form of the invention, there is provided a modulator characterised in that the modulator comprises at least two features chosen from one of the following combinations: AB, AC, AD, BC, BD, and CD.

[000310] In one form of the invention, there is provided a modulator, characterised in that the modulator comprises at least three features chosen from one of the following combinations: ABC, ABD, ACD, and BCD.

[00031 1 ] In one form of the invention, there is provided a modulator characterised in that the modulator comprises at least four features chosen from one of the following combinations: ABCD.

[000312] In one form of the invention, there is provided a modulator characterised in that the modulator comprises an additional charged or hydrogen bonding group (P1 ), consistent with the conserved stabilizing actions of E377 in RAGE370-390, and therefore comprises two or more features selected from the group: a first charged or hydrogen bonding group (A), a second charged or hydrogen bonding group (B), a third charged or hydrogen bonding group (C), a fourth charged or hydrogen group (D), and a hydrophobic group (E) wherein the distances between the site points of the features are as follows, within a tolerance of ±10 A:

[000313] The modulator of IgSF CAM ligand-independent activation of IgSF CAM may be a peptide, or a non-peptidyl compound.

[000314] In one form of the invention, the hydrophobic group is an amino acid residue selected from the group: Ala, Val, Leu, lie, Phe, Trp, Tyr.

[000315] In one form of the invention, the hydrophobic group is a chemical moiety selected from the group: Ci-s alkyl, Ci-s alkenyl, C3-6 cycloalkyl, aryl, substituted aryl, alkyl aryl, heteroaryl, alkyl heteroaryl.

[000316] "Alkyl" means an aliphatic hydrocarbon group, which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain.

[000317] "Lower alkyl" means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. The alkyl group may be optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, -NH(alkyl), -NH(cycloalkyl), -N(alkyl) ₂ , carboxy and -C(0)0-alkyl. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl.

[000318] "Alkenyl" means an aliphatic hydrocarbon group containing at least one carbon- carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain.

[000319] "Lower alkenyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, 2-butenyl and 3- methylbutenyl. The term "substituted alkenyl" means that the alkenyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and cycloalkyl.

[000320] "Alkynyl" means an aliphatic hydrocarbon group containing at least one carbon- carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain.

[000321 ] "Lower alkynyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl. The term "substituted alkynyl" means that the alkynyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and cycloalkyl.

[000322] "Aliphatic" means and includes straight or branched chains of paraffinic, olefinic or acetylenic carbon atoms. The aliphatic group can be optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of H, halo, halogen, alkyl, aryl, cycloalkyl, cycloalkylamino, alkenyl, heterocyclic, alkynyl, cycloalkylaminocarbonyl, hydroxyl, thio, cyano, hydroxy, alkoxy, alkylthio, amino, -NH(alkyl), -NH(cycloalkyl), - N(alkyl)2) carboxyl, -C(0)0-alkyl, heteroaryl, aralkyl, alkylaryl, aralkenyl, heteroaralkyl, alkylheteroaryl, heteroaralkenyl, heteroalkyl, carbonyl, hydroxyalkyl, aryloxy, aralkoxy, acyl, aroyl, nitro, amino, amido, ester, carboxylic acid aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkenyl, heterocyclyl, heterocyclenyl, carbamate, urea, ketone, aldehyde, cyano, sulfonamide, sulfoxide, sulfone, sulfonyl urea, sulfonyl, hydrazide, hydroxamate, S(alkyl)Y1 Y2N-alkyl-, Y1 Y2N-alkyl-, Y1 Y2NC(0)- and Y1 Y2NS0 ₂ -, wherein Y1 and Y2 can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, and aralkyl.

[000323] "Heteroaliphatic" means an otherwise aliphatic group that contains at least one heteroatom (such as oxygen, nitrogen or sulfur). The term heteroaliphatic includes substituted heteroaliphatic.

[000324] "Aryl" means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl.

[000325] "Heteroalkyl" means an alkyl as defined above, wherein one or more hydrogen atoms are substituted by a heteroatom selected from N, S, or O.

[000326] "Heteroaryl" means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms. The "heteroaryl" can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1 ,2,4- thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1 ,2- a]pyridinyl, imidazo[2,1 -b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1 ,2,4-triazinyl, benzothiazolyl and the like. The term "heteroaryl" also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like.

[000327] "Aralkyl" or "arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl.

[000328] "Alkylaryl" means an alkyl-aryl- group in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. Non-limiting example of a suitable alkylaryl group is tolyl. The bond to the parent moiety is through the aryl.

[000329] "Cycloalkyl" means a non-aromatic mono- or multi-cyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. The cycloalkyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1 -decalinyl, norbornyl, adamantyl and the like, as well as partially saturated species such as, for example, indanyl, tetrahydronaphthyl and the like. "Halogen" means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine and bromine.

[000330] "Ring system substituent" means a substituent attached to an aromatic or non- aromatic ring system which, for example, replaces an available hydrogen on the ring system. Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclyl, -C(=N-CN)-NH ₂ , -C(=NH)-NH ₂ , -C(=NH)-NH(alkyl), Y1 Y2N-, Y1 Y2N-alkyl-, Y1 Y2NC(0)-, Y1 Y2NS0 ₂ - and - S0 ₂ NY1 Y2, wherein Y1 and Y2 can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl. "Ring system substituent" may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system. Examples of such moieties are methylene dioxy, ethylenedioxy, -C(CH3)2- and the like which form moieties such as, for example:

[000331 ] [000332] It should be noted that in hetero-atom containing ring systems of this invention, there are no hydroxyl groups on carbon atoms adjacent to a N, O or S1 as well as there are no N or S groups on carbon adjacent to another heteroatom. Thus, for example, in the ring:

[000333]

[000334] there is no -OH attached directly to carbons marked 2 and 5.

[000335] It should also be noted that tautomeric forms such as, for example, the moieties:

[000337] are considered equivalent in certain embodiments of this invention.

[000338] "Alkynylalkyl" means an alkynyl-alkyl- group in which the alkynyl and alkyl are as previously described. Preferred alkynylalkyls contain a lower alkynyl and a lower alkyl group. The bond to the parent moiety is through the alkyl. Non-limiting examples of suitable alkynylalkyl groups include propargylmethyl.

[000339] "Heteroaralkyl" means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parent moiety is through the alkyl.

[000340] "Hydroxyalkyl" means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.

[000341 ] "Acyl" means an H-C(O)-, alkyl-C(O)- or cycloalkyl-C(O)-, group in which the various groups are as previously described. The bond to the parent moiety is through the carbonyl. Preferred acyls contain a lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl and propanoyl. [000342] "Aroyl" means an aryl-C(O)- group in which the aryl group is as previously described. The bond to the parent moiety is through the carbonyl. Non-limiting examples of suitable groups include benzoyl and 1 -naphthoyl.

[000343] "Alkoxy" means an alkyl-O- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n- propoxy, isopropoxy and n-butoxy. The bond to the parent moiety is through the ether oxygen.

[000344] "Aryloxy" means an aryl-O- group in which the aryl group is as previously described. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The bond to the parent moiety is through the ether oxygen.

[000345] “Alkylthio" means an alkyl-S- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkylthio groups include methylthio and ethylthio. The bond to the parent moiety is through the sulfur.

[000346] "Arylthio" means an aryl-S- group in which the aryl group is as previously described. Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. The bond to the parent moiety is through the sulfur.

[000347] "Aralkylthio" means an aralkyl-S- group in which the aralkyl group is as previously described. Non-limiting example of a suitable aralkylthio group is benzylthio. The bond to the parent moiety is through the sulfur.

[000348] "Alkoxycarbonyl" means an alkyl-O-CO- group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The bond to the parent moiety is through the carbonyl.

[000349] "Aralkoxycarbonyl" means an aralkyl-O-C(O)- group. Non-limiting example of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond to the parent moiety is through the carbonyl.

[000350] "Alkylsulfonyl" means an alkyl-S(C>2)- group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl.

[000351 ] "Arylsulfonyl" means an aryl-S(C>2)- group. The bond to the parent moiety is through the sulfonyl.

[000352] The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

[000353] By "stable compound” or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[000354] The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties.

[000355] When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, Greene et a/ (1991 ).

[000356] When any variable (e.g., aryl, heterocycle, R2) occurs more than one time in any constituent or in the present invention, its definition on each occurrence is independent of its definition at every other occurrence.

[000357] In one form of the invention, each of the charged or hydrogen bonding groups is an amino acid residue selected, independently, from the group: Asp, Glu.

[000358] In one form of the invention, each of the charged or hydrogen bonding groups is an amino acid residue having a carboxylic acid moiety.

[000359] In one form of the invention, each of the charged or hydrogen bonding groups is a chemical moiety selected, independently, from the group: carboxylic acid, Hydroxaymic acids, phosphonic and phosphinic acids, sulfonic and sulfinic acids, sulphonamides, acylsulfonamides and sulfonylureas, 2,2,2-Trifluoroethan-1 -ol and Trifluoromethylketones, tetrazoles, 5-Oxo-1 ,2,4-oxadiazole and 5-Oxo-1 ,2,4-thiadiazoles, Thiazolidinedione, Oxazolidinedione, and Oxadiazolidine-diones, 3-Hydroxyisoxazole and 3-Hydroxyisothiazoles, substituted phenols, squaric acids, 3- and 4-Hydroxyquinolin-2-ones, Tetronic and Tetramic Acids, Cyclopentane-1 , 3-diones and other cyclic and acyclic structures, including boronic acids, mercaptoazoles, and sulfonimidamides (Ballatore et ai, 2013).

[000360] In one form, the invention provides a method for identifying a non-peptidyl modulator of IgSF CAM ligand-independent activation of IgSF CAM by a certain activated co- located GPCR, such as an angiotensin receptor, such as ATi R, said method comprising the steps of: (1 ) comparing the three dimensional structure of the non-peptidyl compound with a pharmacophore comprising two or more features selected from the group: a first charged or hydrogen bonding group (A), a second charged or hydrogen bonding group (B), a third charged or hydrogen bonding group (C), and a hydrophobic group (D) wherein the distances in between the features are as follows, within a tolerance of ±10 A:

[000361 ] and (2) selecting a non-peptidyl compound with hydrophobic and/or charged or hydrogen bonding chemical moieties so located.

[000362] In a preferred form of the invention, the tolerance is up to ±5 A, provided the distances between the site points is positive in magnitude. In a preferred form of the invention, the tolerance is up to ±2 A, provided the distances between the site points is positive in magnitude. In a preferred form of the invention, the tolerance is up to ±1 A, provided the distances between the site points is positive in magnitude.

[000363] In a preferred form of the invention, the modulator comprises three or more features selected from the above-specified group.

[000364] In a preferred form of the invention, the modulator comprises four features from the above-specified group.

[000365] In one form of the invention, comparison of the three dimensional structure of the non-peptidyl compound with the pharmacophore involves comparison of a minimum energy structure of the non-peptidyl compound with the pharmacophore. [000366] An efficient means to select a non-peptidyl compound from a potentially large number of non-peptidyl compounds involves comparing non-peptidyl compounds against the pharmacophore of the invention using a computer program, for example Catalyst (MSI), to screen one or more computerised databases of three dimensional chemical structures of non- peptidyl compounds.

[000367] In one form of the invention, the modulator of IgSF CAM ligand-independent activation of IgSF CAM by a certain activated co-located GPCR, such as an angiotensin receptor, such as ATi R, is a peptide that has an amino acid sequence as set forth in SEQ ID NO: 7, or an analogue, fragment or derivative thereof that contains at least residues 379-390.

[000368] In one form of the invention, the modulator of IgSF CAM ligand-independent activation of IgSF CAM by a certain activated co-located GPCR, such as an angiotensin receptor, such as ATi R, is a peptide of the formula SEQ ID NO: 1 , or an analogue, fragment or derivative thereof.

[000369] In one form of the invention, the modulator of IgSF CAM ligand-independent activation of IgSF CAM by a certain activated co-located GPCR, such as an angiotensin receptor, such as ATi R, is a peptide of the formula SEQ ID NO: 2, or an analogue, fragment or derivative thereof.

[000370] In one form of the invention, the modulator of IgSF CAM ligand-independent activation of IgSF CAM by a certain activated co-located GPCR, such as an angiotensin receptor, such as ATi R, is a peptide of the formula SEQ ID NO: 3, or an analogue, fragment or derivative thereof.

[000371 ] In one form of the invention, the modulator of IgSF CAM ligand-independent activation of IgSF CAM by a certain activated co-located GPCR, such as an angiotensin receptor, such as ATi R, is a peptide of the formula SEQ ID NO: 4, or an analogue, fragment or derivative thereof.

[000372] In one form of the invention, the modulator of IgSF CAM ligand-independent activation of IgSF CAM by a certain activated co-located GPCR, such as an angiotensin receptor, such as ATi R, is a peptide of the formula SEQ ID NO: 5, or an analogue, fragment or derivative thereof.

[000373] In one form of the invention, the modulator of IgSF CAM ligand-independent activation of IgSF CAM by a certain activated co-located GPCR, such as an angiotensin receptor, such as ATiR, is a peptide of the formula SEQ ID NO: 6, or an analogue, fragment or derivative thereof.

[000374] In one form of the invention, the modulator of IgSF CAM ligand-independent activation of IgSF CAM by a certain activated co-located GPCR, such as an angiotensin receptor, such as ATiR, is a peptide of the formula SEQ ID NO: 7, or an analogue, fragment or derivative thereof.

[000375] In one form of the invention, the modulator of IgSF CAM ligand-independent activation of IgSF CAM by a certain activated co-located GPCR, such as an angiotensin receptor, such as ATiR, is a peptide of the formula SEQ ID NO: 8, or an analogue, fragment or derivative thereof.

[000376] In one form of the invention, the modulator of IgSF CAM ligand-independent activation of IgSF CAM by a certain activated co-located GPCR, such as an angiotensin receptor, such as ATiR, is a peptide of the formula SEQ ID NO: 19, or an analogue, fragment or derivative thereof.

[000377] In one form of the invention, the modulator of IgSF CAM ligand-independent activation of IgSF CAM by a certain activated co-located GPCR, such as an angiotensin receptor, such as ATiR, is a peptide of the formula SEQ ID NO: 21 , or an analogue, fragment or derivative thereof.

[000378] In one form of the invention, the modulator of IgSF CAM ligand-independent activation of IgSF CAM by a certain activated co-located GPCR, such as an angiotensin receptor, such as ATiR, is a peptide of the formula SEQ ID NO: 22, or an analogue, fragment or derivative thereof.

[000379] In one form of the invention, the modulator of IgSF CAM ligand-independent activation of IgSF CAM by a certain activated co-located GPCR, such as an angiotensin receptor, such as ATiR, is a S391 A-E392X-RAGE peptide as set forth in SEQ ID NO: 23, or an analogue or derivative thereof.

[000380] SEQ ID NO: 23: LWQRRQRRGEERKAPENQEEEEERAELNQA

[000381 ] In one form of the invention, the modulator of IgSF CAM ligand-independent activation of IgSF CAM by a certain activated co-located GPCR, such as an angiotensin receptor, such as ATiR, is a S391X-RAGE peptide as set forth in of SEQ ID NO: 24, or an analogue or derivative thereof. [000382] SEQ ID NO: 24: LWQRRQRRGEERKAPENQEEEEERAELNQ

[000383] Preferred specific derivatives include Q379EEEEERAELNR390, as set forth in SEQ ID NO: 25, Q379EEEEERAELNK390 as set forth in SEQ ID NO: 26, K379EEEEERAELNQ390 as set forth in SEQ ID NO: 27, K3 ₇ 9EEEERAELNK390 as set forth in SEQ ID NO: 28, and K3 ₇ 9EEEEERAELNR390 as set forth in SEQ ID NO: 29 below.

[000384] SEQ ID NO: 25: [Q379EEEEERAELNR390]

[000385] SEQ ID NO: 26: [Q379EEEEERAELN K ₃₉₀ ]

[000386] SEQ ID NO: 27: [K379EEEEERAELNQ390]

[000387] SEQ ID NO: 28: [K379EEEEERAELNK390]

[000388] SEQ ID NO: 29: [K379EEEEERAELNR390]

[000389] The term "derivative" as used herein in connection with modulators of the invention, such as SEQ ID NO: 1 to 8, 19, 21 to 31 , refers to a modulator characterised in that its primary structure is taken from or owes its derivation to the C-terminal cytosolic tail of RAGE or fragment thereof, but which includes amino acid additions, substitutions, truncations, chemical and/or biochemical modifications (acetylation, carboxylation, phosphorylation, glycosylation, ubiquitination, side chain methylation), labelling with radionucleotides or halogens, unusual or artificial amino acids (such as D-amino acids, N-methylated amino acids, fefra-substitution, b-peptides, pyroglutamic acid; 2-Aminoadipic acid; 3-Aminoadipic acid; beta-Alanine; beta- Aminopropionic acid; 2-Aminobutyric acid; 4-Aminobutyric acid; Piperidinic acid; 6- Aminocaproic acid; 2-Aminoheptanoic acid; 2-Aminoisobutyric acid; 3-Aminoisobutyric acid; 2-Aminopimelic acid; 2,4-Diaminobutyric acid; Desmosine; 2,2"-Diaminopimelic acid; 2,3- Diaminopropionic acid; N-Ethylglycine; N-Ethylasparagine; Hydroxylysine; allo- Hydroxylysine; 3-Hydroxyproline; 4-Hydroxyproline; Isodesmosine; allo-lsoleucine; N- Methylglycine; Sarcosine; N-Methylisoleucine; N-Methylvaline; Norvaline; Norleucine; Ornithine; Statine), retroinverted sequences, cyclic peptides, peptoids, or linkage to a non peptide drug, non-peptide label, non-peptide carrier, or non-peptide resin.

[000390] In one form of the invention, the modulator is a peptide comprising residues 343- 361 of wild-type RAGE (SEQ ID NO: 30) which is an inhibitory peptide, that inhibits both IgSF CAM ligand-independent and IgSF CAM ligand-dependent activation of IgSF CAM.

[000391 ] Substitutions encompass amino acid alterations in which an amino acid is replaced with a different naturally-occurring or a non-conventional amino acid residue. Such substitutions may be classified as "conservative", in which case an amino acid residue contained in a polypeptide is replaced with another naturally-occurring amino acid of similar character either in relation to polarity, side chain functionality, or size, for example Ser<®Thr<®Pro<®Hyp<®Gly<®Ala, Val<®lle<®Leu, His<®Lys<®Arg, Asn<®Gln<®Asp<®Glu or Phe<®Trp<®Tyr. It is to be understood that some non-conventional amino acids may also be suitable replacements for the naturally occurring amino acids. For example ornithine, homoarginine and dimethyllysine are related to His, Arg and Lys.

[000392] Substitutions encompassed by the present invention may also be "non conservative", in which an amino acid residue which is present in a polypeptide is substituted with an amino acid having different properties, such as a naturally-occurring amino acid from a different group (e.g. substituting a charged or hydrophobic amino acid with alanine), or alternatively, in which a naturally-occurring amino acid is substituted with a non-conventional amino acid.

[000393] Amino acid substitutions are typically of single residues, but may be of multiple residues, either clustered or dispersed. Preferably, amino acid substitutions are conservative.

[000394] Additions encompass the addition of one or more naturally occurring or non- conventional amino acid residues. Deletion encompasses the deletion of one or more amino acid residues.

[000395] As stated above the present invention includes peptides in which one or more of the amino acids has undergone sidechain modifications. Examples of side chain modifications contemplated by the present invention include modifications of amino groups such as by reductive alkylation by reaction with an aldehyde followed by reduction with NaBH^ amidination with methylacetimidate; acylation with acetic anhydride; carbamoylation of amino groups with cyanate; trinitrobenzylation of amino groups with 2,4,6-trinitrobenzene sulphonic acid (TNBS); acylation of amino groups with succinic anhydride and tetrahydrophthalic anhydride; and pyridoxylation of lysine with pyridoxal-5-phosphate followed by reduction with NaBH ₄ .

[000396] The guanidine group of arginine residues may be modified by the formation of heterocyclic condensation products with reagents such as 2,3-butanedione, phenylglyoxal and glyoxal.

[000397] The carboxyl group may be modified by carbodiimide activation via O-acylisourea formation followed by subsequent derivatisation, for example, to a corresponding amide. Sulphydryl groups may be modified by methods such as carboxymethylation with iodoacetic acid or iodoacetamide; performic acid oxidation to cysteic acid; formation of mixed disulfides with other thiol compounds; reaction with maleimide, maleic anhydride or other substituted maleimide; formation of mercurial derivatives using 4-chloromercuribenzoate, 4- chloromercuriphenylsulphonic acid, phenylmercury chloride, 2-chloromercuri-4-nitrophenol and other mercurials; carbamoylation with cyanate at alkaline pH. In a preferred form of the invention, any modification of cysteine residues must not affect the ability of the peptide to form the necessary disulfide bonds. It is also possible to replace the sulphydryl groups of cysteine with selenium equivalents such that the peptide forms a di-selenium bond in place of one or more of the disulfide bonds.

[000398] Tryptophan residues may be modified by, for example, oxidation with N- bromosuccinimide or alkylation of the indole ring with 2-hydroxy-5-nitrobenzyl bromide or sulphenyl halides. Tyrosine residues on the other hand, may be altered by nitration with tetranitromethane to form a 3-nitrotyrosine derivative.

[000399] Modification of the imidazole ring of a histidine residue may be accomplished by alkylation with iodoacetic acid derivatives or N-carbethoxylation with diethylpyrocarbonate. Proline residues may be modified by, for example, hydroxylation in the 4-position.

[000400] A list of some amino acids having modified side chains and other unnatural amino acids is shown in the following table:

[000401 ] These types of modifications may be important to stabilise the peptide if administered to an individual or for use as a diagnostic reagent. [000402] Conservative amino acid substitutions, as used herein, may include amino acid residues within a group which have sufficiently similar physicochemical properties, so that a substitution between members of the group will preserve the biological activity of the molecule (see for example Grantham, R., 1974). Particularly, conservative amino acid substitutions are preferably substitutions in which the amino acids originate from the same class of amino acids (e.g. basic amino acids, acidic amino acids, polar amino acids, amino acids with aliphatic side chains, amino acids with positively or negatively charged side chains, amino acids with aromatic groups in the side chains, amino acids the side chains of which can enter into hydrogen bridges, e.g. side chains which have a hydroxyl function). Conservative substitutions are in the present case for example substituting a basic amino acid residue (Lys, Arg, His) for another basic amino acid residue (Lys, Arg, His), substituting an aliphatic amino acid residue (Gly, Ala, Val, Leu, lie) for another aliphatic amino acid residue, substituting an aromatic amino acid residue (Phe, Tyr, Trp) for another aromatic amino acid residue, substituting threonine by serine or leucine by isoleucine. Further conservative amino acid exchanges will be known to the person skilled in the art. The isomer form should preferably be maintained, e.g. K is preferably substituted for R or H, while k is preferably substituted for r and h.

[000403] When considering replacement amino acids, preferred replacements of the present invention are those described as having a D of less than 100 in Grantham, R. (1974), the contents of which are incorporated by reference. Most preferred replacements are those described as having a D of less than 50.

[000404] Peptide modulators of the present invention include retro inverso isomers of, or modified or substituted variants of, SEQ ID NO: 1 to 8, 19, 21 to 31 , or peptides formed by additions thereto or deletions therefrom (Li et a!., 2010).

4. Modulators that are an analogue, fragment or derivative of an IgSF CAM

[000405] In one form of the invention, a modulator of the invention is an analogue, fragment or derivative of IgSF CAM that is an activator, an inhibitor, an allosteric modulator, or a non functional mimic of the cytosolic tail of IgSF CAM. In a preferred form of the invention, a non functional substitute is a modulator that mimics the cytosolic tail of IgSF CAM in the presence of certain co-located GPCRs, is not able to be activated by them or induce downstream IgSF CAM-dependent signalling, and inhibits signalling that normally occurs through activation of the cytosolic tail of IgSF CAM and IgSF CAM-dependent signalling resulting therefrom.

[000406] In one form of the invention, a modulator of the invention is an analogue, fragment or derivative of IgSF CAM that is an activator, an inhibitor, an allosteric modulator, or a non- functional mimic of the cytosolic tail of IgSF CAM. In a preferred form of the invention, a non functional substitute is a modulator that mimics the cytosolic tail of IgSF CAM in the presence of certain co-located GPCRs, is not able to be activated by them or induce downstream IgSF CAM-dependent signalling, and inhibits signalling that normally occurs through activation of the cytosolic tail of RAGE and RAGE-dependent signalling resulting therefrom.

[000407] In one form of the invention, a modulator of the invention is an analogue, fragment or derivative of IgSF CAM that is an activator, an inhibitor, an allosteric modulator, or a non functional mimic of the transmembrane domain of IgSF CAM or part thereof.

[000408] In one form of the invention, a non-functional substitute is a modulator that mimics the transmembrane domain of IgSF CAM in the presence of certain co-located GPCRs, is not able to be activated by them or induce downstream IgSF CAM-dependent signalling, and inhibits signalling that normally occurs through activation of the cytosolic tail of IgSF CAM and IgSF CAM-dependent signalling resulting therefrom.

[000409] In one form of the invention, a non-functional substitute is a modulator that mimics the transmembrane domain of IgSF CAM in the presence of certain co-located GPCRs, is not able to be activated by them or induce downstream IgSF CAM-dependent signalling, and inhibits signalling that normally occurs through activation of the cytosolic tail of RAGE and RAGE-dependent signalling resulting therefrom.

[000410] In one form of the invention, the modulator comprises a transmembrane domain of IgSF CAM or a part thereof and a fragment of the IgSF CAM ectodomain.

[00041 1 ] In one form of the invention, the modulator comprises a transmembrane domain of IgSF CAM or a part thereof and a fragment of the cytosolic tail of IgSF CAM.

[000412] In one form of the invention, the modulator comprises a transmembrane domain of IgSF CAM or part thereof and a fragment of the IgSF CAM ectodomain and a fragment of the cytosolic tail of IgSF CAM.

[000413] In one form of the invention, modulators of the invention contain a fragment of the ectodomain of IgSF CAM, which is not greater than 40, not greater than 20, not greater than 10 or not greater than 5 amino acids in length.

[000414] In one form, the present invention comprises modulators of RAGE ligand- independent activation of RAGE by certain activated co-located GPCRs, where these modulators are analogues, fragments or derivatives of IgSF CAM and that modulate transactivation of the cytosolic tail of RAGE triggered by activation of such certain activated co-located GPCRs, such as an angiotensin receptor.

[000415] In one form, the present invention comprises modulators of RAGE ligand- dependent activation of RAGE by its cognate ligand, where these modulators are analogues, fragments or derivatives of IgSF CAM.

[000416] In one form, the present invention comprises modulators of RAGE ligand- independent activation of RAGE by certain activated co-located GPCRs and RAGE ligand- dependent activation of RAGE by its cognate ligand, where these modulators are analogues, fragments or derivatives of IgSF CAM.

[000417] In one form, the present invention comprises modulators of IgSF CAM ligand- independent activation of the cytosolic tail of IgSF CAM by certain activated co-located GPCRs that bind to Ras GTPase-activating-like protein (IQGAP1 ) or other IgSF CAM-associated proteins, including protein kinase C zeta (RKΰz), Dock7, MyD88, TIRAP, IRAK4, ERK1/2, olfactory receptor 2T2, ADP/ATP translocase 2, Protein phosphatase 1 G, Intercellular adhesion molecule 1 , Protein DJ-1 (PARK7), Calponin-3, Drebrin, Filamin B, Ras-related protein Rab-13, Radixin/Ezrin/Moesin, Proteolipid protein 2, Coronin, S100 A1 1 , Succinyl-CoA ligase [GDP-forming] subunit alpha, Hsc70-interacting protein, Apoptosis Inhibitor 5, neuropilin, cleavage stimulation factor, growth factor receptor-bound protein 2, sec61 beta subunit, or Nck1 , or disrupt the binding of these elements to IgSF CAM, in order to modulate IgSF CAM transactivation by certain activated co-located GPCRs, such as an angiotensin receptor, such as ATi R. In a preferred form of the invention, the modulators are analogues, fragments or derivatives of IgSF CAM. In a preferred form of the invention, the modulators are analogues, fragments or derivatives of the cytosolic tail of IgSF CAM. In a particularly preferred form of the invention, the modulators are analogues, fragments or derivatives of ALCAM559-580. In another particularly preferred form of the invention, the modulators are analogues, fragments or derivatives of ALCAM559-580 that differ by one, two, three, four, five, six, seven, eight, nine or ten amino acids. In another particularly preferred form of the invention, the modulator is ALCAM559-580.

[000418] In one form, the present invention comprises modulators of RAGE ligand- independent activation of the cytosolic tail of RAGE by certain activated co-located GPCRs that bind to Ras GTPase-activating-like protein (IQGAP1 ) or other RAGE-associated proteins, including protein kinase C zeta (RKΰz), Dock7, MyD88, TIRAP, IRAK4, ERK1/2, olfactory receptor 2T2, ADP/ATP translocase 2, Protein phosphatase 1 G, Intercellular adhesion molecule 1 , Protein DJ-1 (PARK7), Calponin-3, Drebrin, Filamin B, Ras-related protein Rab- 13, Radixin/Ezrin/Moesin, Proteolipid protein 2, Coronin, S100 A1 1 , Succinyl-CoA ligase [GDP-forming] subunit alpha, Hsc70-interacting protein, Apoptosis Inhibitor 5, neuropilin, cleavage stimulation factor, growth factor receptor-bound protein 2, sec61 beta subunit, or Nck1 , or disrupt the binding of these elements to RAGE, in order to modulate RAGE transactivation by certain activated co-located GPCRs, such as an angiotensin receptor, such as ATiR, and where these modulators are analogues, fragments or derivatives of IgSF CAM. In a preferred form of the invention, the modulators are analogues, fragments or derivatives of the cytosolic tail of IgSF CAM. In a particularly preferred form of the invention, the modulators are analogues, fragments or derivatives of ALCAM _559-580 . In another particularly preferred form of the invention, the modulators are analogues, fragments or derivatives of ALCAM _559-580 that differ by one, two, three, four, five, six, seven, eight, nine or ten amino acids. In another particularly preferred form of the invention, the modulator is ALCAM _559-580 .

[000419] In one form of the invention, the modulators of the invention bind to the cytosolic elements of the certain activated co-located GPCR, IgSF CAM and/or elements complexed with either, including IQGAP-1 , RKΰz, Dock7, MyD88, TIRAP, IRAK4, ERK1/2, olfactory receptor 2T2, ADP/ATP translocase 2, Protein phosphatase 1 G, Intercellular adhesion molecule 1 , Protein DJ-1 (PARK7), Calponin-3, Drebrin, Filamin B, Ras-related protein Rab- 13, Radixin/Ezrin/Moesin, Proteolipid protein 2, Coronin, S100 A1 1 , Succinyl-CoA ligase [GDP-forming] subunit alpha, Hsc70-interacting protein, Apoptosis Inhibitor 5, neuropilin, cleavage stimulation factor, growth factor receptor-bound protein 2, sec61 beta subunit, or Nck1 to modulate IgSF CAM ligand-independent signalling through the cytosolic tail of IgSF CAM, by modulating these signalling elements required for IgSF CAM transactivation by certain activated co-located GPCRs, such as an angiotensin receptor, such as ATiR, and where these modulators are analogues, fragments or derivatives of IgSF CAM. In a preferred form of the invention, the modulators are analogues, fragments or derivatives of the cytosolic tail of IgSF CAM. In a particularly preferred form of the invention, the modulators are analogues, fragments or derivatives of ALCAM559-580. In another particularly preferred form of the invention, the modulators are analogues, fragments or derivatives of ALCAM559-580 that differ by one, two, three, four, five, six, seven, eight, nine or ten amino acids. In another particularly preferred form of the invention, the modulator is ALCAM559-580.

[000420] In one form of the invention, the modulators of the invention bind to the cytosolic elements of the certain activated co-located GPCR, RAGE and/or elements complexed with either, including IQGAP-1 , RKOz, Dock7, MyD88, TIRAP, IRAK4, ERK1/2, olfactory receptor 2T2, ADP/ATP translocase 2, Protein phosphatase 1 G, Intercellular adhesion molecule 1 , Protein DJ-1 (PARK7), Calponin-3, Drebrin, Filamin B, Ras-related protein Rab-13, Radixin/Ezrin/Moesin, Proteolipid protein 2, Coronin, S100 A1 1 , Succinyl-CoA ligase [GDP- forming] subunit alpha, Hsc70-interacting protein, Apoptosis Inhibitor 5, neuropilin, cleavage stimulation factor, growth factor receptor-bound protein 2, sec61 beta subunit, or Nck1 to modulate RAGE ligand-independent signalling through the cytosolic tail of RAGE, by modulating these signalling elements required for RAGE transactivation by certain activated co-located GPCRs, such as an angiotensin receptor, such as ATi R, and where these modulators are analogues, fragments or derivatives of IgSF CAM. In a preferred form of the invention, the modulators are analogues, fragments or derivatives of the cytosolic tail of IgSF CAM. In a particularly preferred form of the invention, the modulators are analogues, fragments or derivatives of ALCAM _559-580 . In another particularly preferred form of the invention, the modulators are analogues, fragments or derivatives of ALCAM _559-580 that differ by one, two, three, four, five, six, seven, eight, nine or ten amino acids. In another particularly preferred form of the invention, the modulator is ALCAM _559-580 .

[000421 ] In one form of the invention, modulators of IgSF CAM ligand-independent activation of IgSF CAM by certain activated co-located GPCRs also modulate IgSF CAM ligand-dependent activation of the cytosolic tail of IgSF CAM, by binding to cytosolic elements of IgSF CAM and/or elements that complex with IgSF CAM in the cytosol (such as IQGAP-1 , RKΰz, Dock7, MyD88, IRAK4, TIRAP, ERK1/2, olfactory receptor 2T2, ADP/ATP translocase 2, Protein phosphatase 1 G, Intercellular adhesion molecule 1 , Protein DJ-1 (PARK7), Calponin-3, Drebrin, Filamin B, Ras-related protein Rab-13, Radixin/Ezrin/Moesin, Proteolipid protein 2, Coronin, S100 A1 1 , Succinyl-CoA ligase [GDP-forming] subunit alpha, Hsc70- interacting protein, Apoptosis Inhibitor 5, neuropilin, cleavage stimulation factor, growth factor receptor-bound protein 2, sec61 beta subunit, or Nck1 ) to inhibit IgSF CAM ligand-mediated signalling through these elements. In a preferred form of the invention, the modulators are analogues, fragments or derivatives of IgSF CAM. In a preferred form of the invention, the modulators are analogues, fragments or derivatives of the cytosolic tail of IgSF CAM. In a particularly preferred form of the invention, the modulators are analogues, fragments or derivatives of ALCAM559-580. In another particularly preferred form of the invention, the modulators are analogues, fragments or derivatives of ALCAM559-580 that differ by one, two, three, four, five, six, seven, eight, nine or ten amino acids. In another particularly preferred form of the invention, the modulator is ALCAM559-580.

[000422] In one form of the invention, modulators of RAGE ligand-independent activation of RAGE by certain activated co-located GPCRs also modulate RAGE ligand-dependent activation of the cytosolic tail of RAGE, by binding to cytosolic elements of RAGE and/or elements that complex with RAGE in the cytosol (such as IQGAP-1 , RKΰz, Dock7, MyD88, IRAK4, TIRAP, ERK1/2, olfactory receptor 2T2, ADP/ATP translocase 2, Protein phosphatase 1 G, Intercellular adhesion molecule 1 , Protein DJ-1 (PARK7), Calponin-3, Drebrin, Filamin B, Ras-related protein Rab-13, Radixin/Ezrin/Moesin, Proteolipid protein 2, Coronin, S100 A1 1 , Succinyl-CoA ligase [GDP-forming] subunit alpha, Hsc70-interacting protein, Apoptosis Inhibitor 5, neuropilin, cleavage stimulation factor, growth factor receptor-bound protein 2, sec61 beta subunit, or Nck1 ) to inhibit RAGE ligand-mediated signalling through these elements, and where the modulators are analogues, fragments or derivatives of IgSF CAM. In a preferred form of the invention, the modulators are analogues, fragments or derivatives of the cytosolic tail of IgSF CAM. In a particularly preferred form of the invention, the modulators are analogues, fragments or derivatives of ALCAM559-580. In another particularly preferred form of the invention, the modulators are analogues, fragments or derivatives of ALCAM ₅ 59-58o that differ by one, two, three, four, five, six, seven, eight, nine or ten amino acids. In another particularly preferred form of the invention, the modulator is ALCAM559-580.

[000423] In some embodiments, the modulator is introduced by gene delivery (such as by using a virus or artificial non-viral gene delivery such as electroporation, microinjection, gene gun, impalefection, hydrostatic pressure, continuous infusion, sonication, lipofection, liposomes, nanobubbles and polymeric gene carriers) and the peptide fragment, biologically- active analogue or derivative being generated by the cell as a consequence of transcriptional and translational processes.

[000424] In some embodiments, the modulator has a modified capacity to form a complex with certain co-located GPCRs, such as ATi R, or elements that complex with them. For example, the IgSF CAM analogue, fragment or derivative may be distinguished from a wild- type IgSF CAM polypeptide or fragment sequence by the substitution, addition, or deletion of at least one amino acid residue or addition or substitution of unusual or non-conventional amino-acids or non-amino acid residues.

[000425] In one aspect of the invention, the modulator of the present invention includes isolated or purified peptides which comprise, consist, or consists essentially of an amino acid sequence represented by Formula I:

[000426] Z1 M Z2 (I)

[000427] wherein:

[000428] Z1 is absent or is selected from at least one of a proteinaceous moiety comprising from about 1 to about 50 amino acid residues; and [000429] M is the amino acid sequence as set forth in SEQ ID NO: 6, or an analogue, fragment or derivative thereof; and

[000430] Z2 is absent or is a proteinaceous moiety comprising from about 1 to about 50 amino acid residues.

[000431 ] In some embodiments of the invention described above, the modulator (such as a fragment of the IgSF CAM cytosolic tail, an analogue or derivative thereof as broadly described above and elsewhere herein) is able to penetrate a cell membrane. In non-limiting examples of this type, the modulator is conjugated, fused or otherwise linked to a cell membrane penetration molecule (e.g., the HIV TAT motif, as set forth in SEQ ID NO: 20 below).

[000432] SEQ ID NO: 20:

[000433] [YGRKKRRQRRR]

[000434] In some forms of the invention, the modulator is a non-peptide molecule that shares with the peptide modulator described above the capacity to bind to and/or interfere with elements associated with IgSF CAM ligand-independent activation of IgSF CAM by certain activated co-located GPCRs. These non-peptide modulators may or may not contain structural similarities to functionally important domains contained in peptide modulators.

[000435] In some forms of the invention, the modulator is a non-peptide molecule that shares with the peptide modulator described above the capacity to bind to and/or interfere with elements associated with RAGE ligand-independent activation of RAGE by certain activated co-located GPCRs. These non-peptide modulators may or may not contain structural similarities to functionally important domains contained in peptide modulators.

[000436] In preferred forms of the invention, the modulator is an inhibitor.

[000437] In certain forms of the invention, in addition to being an inhibitor of IgSF CAM ligand-independent activation of IgSF CAM by a certain activated co-located GPCR, the modulator is an inhibitor of the certain co-located GPCR and/or an inhibitor of the certain co located GPCR signalling pathway.

[000438] In certain forms of the invention, in addition to being an inhibitor of RAGE ligand- independent activation of RAGE by a certain activated co-located GPCR, the modulator is an inhibitor of the certain co-located GPCR and/or an inhibitor of the certain co-located GPCR signalling pathway. [000439] In certain forms of the invention, in addition to being an inhibitor of IgSF CAM ligand-independent activation of IgSF CAM by a certain activated co-located GPCR, the modulator is an inhibitor of IgSF CAM ligand-dependent activation of IgSF CAM and/or an inhibitor of constitutively-active IgSF CAM and/or an inhibitor of an IgSF CAM signalling pathway.

[000440] In certain forms of the invention, in addition to being an inhibitor of RAGE ligand- independent activation of RAGE by a certain activated co-located GPCR, the modulator is an inhibitor of RAGE ligand-dependent activation of RAGE and/or an inhibitor of constitutively- active RAGE and/or an inhibitor of a RAGE signalling pathway.

[000441 ] In certain forms of the invention, where the certain co-located GPCR is ATi R, in addition to being an inhibitor of IgSF CAM ligand-independent activation of IgSF CAM, the modulator is an ATi R inhibitor and/or an inhibitor of an ATiR signalling pathway.

[000442] In certain forms of the invention, where the certain co-located GPCR is ATi R, in addition to being an inhibitor of RAGE ligand-independent activation of RAGE, the modulator is an ATi R inhibitor and/or an inhibitor of an ATi R signalling pathway.

[000443] In certain forms of the invention, in addition to being an inhibitor of IgSF CAM ligand-independent activation of IgSF CAM by activated angiotensin receptor, preferably activated ATi R, the modulator is an inhibitor of IgSF CAM ligand-dependent activation of IgSF CAM and/or an inhibitor of constitutively-active IgSF CAM and/or an inhibitor of an IgSF CAM signalling pathway.

[000444] In certain forms of the invention, in addition to being an inhibitor of RAGE ligand- independent activation of RAGE by activated angiotensin receptor, preferably activated ATi R, the modulator is an inhibitor of RAGE ligand-dependent activation of RAGE and/or an inhibitor of constitutively-active RAGE and/or an inhibitor of a RAGE signalling pathway.

[000445] In certain forms of the invention, in addition to being an inhibitor of IgSF CAM ligand-independent activation of IgSF CAM by a certain activated co-located GPCR, the modulator is an inhibitor of the certain co-located GPCR and/or an inhibitor of the certain co located GPCR signalling pathway and an inhibitor of IgSF CAM ligand-dependent activation of IgSF CAM and/or an inhibitor of constitutively-active IgSF CAM and/or an inhibitor of an IgSF CAM signalling pathway.

[000446] In certain forms of the invention, in addition to being an inhibitor of RAGE ligand- independent activation of RAGE by a certain activated co-located GPCR, the modulator is an inhibitor of the certain co-located GPCR and/or an inhibitor of the certain co-located GPCR signalling pathway and an inhibitor of RAGE ligand-dependent activation of RAGE and/or an inhibitor of constitutively-active RAGE and/or an inhibitor of a RAGE signalling pathway.

[000447] In certain forms of the invention, in addition to being an inhibitor of IgSF CAM ligand-independent activation of IgSF CAM by activated angiotensin receptor, preferably activated ATi R, the modulator is an ATi R inhibitor and/or an inhibitor of an ATi R signalling pathway and an inhibitor of IgSF CAM ligand-dependent activation of IgSF CAM and/or an inhibitor of constitutively-active IgSF CAM and/or an inhibitor of an IgSF CAM signalling pathway.

[000448] In certain forms of the invention, in addition to being an inhibitor of RAGE ligand- independent activation of RAGE by activated angiotensin receptor, preferably activated ATi R, the modulator is an ATi R inhibitor and/or an inhibitor of an ATi R signalling pathway and an inhibitor of RAGE ligand-dependent activation of RAGE and/or an inhibitor of constitutively- active RAGE and/or an inhibitor of a RAGE signalling pathway.

[000449] In certain forms of the invention, the modulator is a non-functional substitute for the cytosolic tail of IgSF CAM or a part thereof, which is not able to be activated by a co located GPCR or facilitate downstream IgSF CAM-dependent signalling and inhibits signalling that occurs through the cytosolic tail of IgSF CAM and IgSF CAM-dependent signalling.

[000450] In certain forms of the invention, the modulator is a non-functional substitute for the cytosolic tail of IgSF CAM or a part thereof, which is not able to be activated by a co located GPCR or facilitate downstream IgSF CAM-dependent signalling and inhibits signalling that occurs through the cytosolic tail of RAGE and RAGE-dependent signalling.

[000451 ] In certain forms of the invention, the modulator is a non-functional substitute for the transmembrane domain of IgSF CAM or a part thereof, which is not able to be activated by a co-located GPCR or facilitate downstream IgSF CAM-dependent signalling and inhibits signalling that occurs through the cytosolic tail of IgSF CAM and IgSF CAM-dependent signalling.

[000452] In certain forms of the invention, the modulator is a non-functional substitute for the transmembrane domain of IgSF CAM or a part thereof, which is not able to be activated by a co-located GPCR or facilitate downstream IgSF CAM-dependent signalling and inhibits signalling that occurs through the cytosolic tail of RAGE and RAGE-dependent signalling. [000453] In certain forms of the invention, the modulator comprises a transmembrane domain of IgSF CAM or a part thereof and a fragment of the IgSF CAM ectodomain. In certain forms of the invention, the modulator comprises a transmembrane domain of IgSF CAM or a part thereof and a fragment of the cytosolic tail of IgSF CAM.

[000454] In certain forms of the invention, the modulator comprises a transmembrane domain of IgSF CAM or part thereof and a fragment of the IgSF CAM ectodomain and a fragment of the cytosolic tail of IgSF CAM.

[000455] In certain forms of the invention, the modulators of IgSF CAM ligand-independent activation of IgSF CAM by certain activated co-located GPCRs contain a fragment of the ligand-binding ectodomain of IgSF CAM, which is not greater than 40, not greater than 20, not greater than 10 or not greater than 5 amino acids in length.

[000456] In certain forms of the invention, the modulators of RAGE ligand-independent activation of RAGE by certain activated co-located GPCRs contain a fragment of the ligand binding ectodomain of IgSF CAM, which is not greater than 40, not greater than 20, not greater than 10 or not greater than 5 amino acids in length.

5. Methods for modulating ligand-independent activation of an IgSF CAM or FI AGE

[000457] In a related aspect, the present invention provides methods for modulating ligand- independent activation of an IgSF CAM by an activated certain co-located GPCR, such as angiotensin receptor, such as ATi R, in a cell or tissue of an animal or of animal origin (which may or may not be of a human or of human origin) using a modulator as described herein.

[000458] In a related aspect, the present invention provides methods for modulating ligand- independent activation of RAGE by an activated certain co-located GPCR, such as angiotensin receptor, such as ATi R, in a cell or tissue of an animal or of animal origin (which may or may not be of a human or of human origin) using a modulator as described herein that is an analogue, fragment or derivative of IgSF CAM.

[000459] In some aspects these methods include truncating or mutating an IgSF CAM such that it is unable to bind IgSF CAM ligands to its ectodomain, or that binding IgSF CAM ligands to its ectodomain is impaired by exposing the cell to a modulator that modulates the binding of IgSF CAM ligands to IgSF CAM. [000460] In some forms of the invention, the modulation of the IgSF CAM ligand- independent signalling pathway, is distinct from and/or significantly more than the modulation of the IgSF CAM ligand-dependent signalling pathway.

[000461 ] In some forms of the invention, the inhibition of the IgSF CAM ligand-independent signalling pathway, is distinct from and/or significantly more than the inhibition of the IgSF CAM ligand-dependent signalling pathway.

[000462] The method may comprise administering a modulator to a patient.

6. Methods for modulating ligand-dependent activation of an IgSF CAM

[000463] In a related aspect, the present invention provides methods for modulating IgSF CAM ligand-dependent activation of an IgSF CAM by a cognate ligand in a cell or tissue of an animal or of animal origin (which may or may not be of a human or of human origin) using a modulator as described herein.

[000464] In a related aspect, the present invention provides methods for modulating RAGE ligand-dependent activation of RAGE by a cognate ligand in a cell or tissue of an animal or of animal origin (which may or may not be of a human or of human origin) using a modulator as described herein that is an analogue, fragment or derivative of IgSF CAM.

[000465] The method may comprise administering a modulator to a patient.

7. Methods for modulating both IgSF CAM ligand-dependent and IgSF CAM ligand- independent activation of an IgSF CAM

[000466] In another related aspect, the present invention provides methods for inhibiting an IgSF CAM ligand-dependent activation of an IgSF CAM by IgSF CAM ligands (including AGE- modified proteins, lipids or DNA, members of the S100 calgranulin family of proteins, FIMGB1 , amyloid and Mac-1 ) and subsequent downstream signalling pathways in a cell, tissue or animal in addition to modulating an IgSF CAM ligand-independent activation of an IgSF CAM by certain activated co-located GPCRs.

[000467] In one aspect of the invention, these methods comprise using a modulator as described herein, including fragments, analogues or derivatives of the cytosolic tail of an IgSF CAM, to prevent or inhibit activation of both an IgSF CAM-ligand dependent activation of an IgSF CAM and an IgSF CAM ligand-independent activation of an IgSF CAM by certain activated co-located GPCRs. In one aspect of the invention, IgSF CAM-dependent signalling is impaired by exposing the cell to an inhibitor that inhibits the binding of signalling elements to the cytosolic tail of an IgSF CAM resulting in inhibition of both an IgSF CAM ligand-mediated activation of an IgSF CAM and an IgSF CAM ligand-independent activation of an IgSF CAM by certain activated co-located GPCRs.

[000468] In one aspect of the invention, these methods comprise using a modulator as described herein, including fragments, analogues or derivatives of the cytosolic tail of RAGE, to prevent activation of both an IgSF CAM-ligand dependent activation of an IgSF CAM and an IgSF CAM ligand-independent activation of an IgSF CAM by certain activated co-located GPCRs.

[000469] In one aspect of the invention, IgSF CAM-dependent signalling is impaired by exposing the cell to an inhibitor that inhibits the binding of signalling elements to the cytosolic tail of an IgSF CAM resulting in inhibition of both an IgSF CAM ligand-mediated activation of an IgSF CAM and an IgSF CAM ligand-independent activation of an IgSF CAM by certain activated co-located GPCRs. In one aspect of the invention, these methods comprise using a modulator as described herein, including fragments, analogues or derivatives of a IgSF CAM, to take the place of the transmembrane domain of an IgSF CAM and therein prevent activation of both an IgSF CAM-ligand dependent activation of an IgSF CAM and an IgSF CAM ligand- independent activation of an IgSF CAM by certain activated co-located GPCRs.

8. Methods for modulating both RAGE ligand-dependent and RAGE ligand-independent activation of RAGE using modulators that are analogues, fragments or derivatives of IgSF CAM

[000470] In another related aspect, the present invention provides methods for inhibiting RAGE ligand-dependent activation of RAGE by RAGE ligands (including AGE-modified proteins, lipids or DNA, members of the S100 calgranulin family of proteins, HMGB1 , amyloid and Mac-1 ) and subsequent downstream signalling pathways in a cell, tissue or animal in addition to modulating RAGE ligand-independent activation of RAGE by certain activated co located GPCRs where the modulator is an analogue, fragment or derivative of IgSF CAM.

[000471 ] In one aspect of the invention, these methods comprise using a modulator as described herein where the modulator is an analogue, fragment or derivative of IgSF CAM, to prevent or inhibit activation of both RAGE-ligand dependent activation of RAGE and RAGE ligand-independent activation of RAGE by certain activated co-located GPCRs. In one aspect of the invention, RAGE-dependent signalling is impaired by exposing the cell to an inhibitor that inhibits the binding of signalling elements to the cytosolic tail of RAGE resulting in inhibition of both RAGE ligand-mediated activation of RAGE and RAGE ligand-independent activation of RAGE by certain activated co-located GPCRs.

[000472] In one aspect of the invention, these methods comprise using a modulator as described herein where the modulator is an analogue, fragment or derivative of IgSF CAM, to prevent activation of both RAGE-ligand dependent activation of RAGE and RAGE ligand- independent activation of RAGE by certain activated co-located GPCRs.

[000473] In one aspect of the invention, RAGE-dependent signalling is impaired by exposing the cell to an inhibitor that inhibits the binding of signalling elements to the cytosolic tail of RAGE resulting in inhibition of both RAGE ligand-mediated activation of RAGE and RAGE ligand-independent activation of RAGE by certain activated co-located GPCRs. In one aspect of the invention, these methods comprise using a modulator as described herein where the modulator is an analogue, fragment or derivative of IgSF CAM, to take the place of the transmembrane domain of RAGE and therein prevent activation of both RAGE-ligand dependent activation of RAGE and RAGE ligand-independent activation of RAGE by certain activated co-located GPCRs.

[000474] In specific embodiments, the modulator comprises, consists, or consists essentially of an amino acid sequence as set forth in SEQ ID NO: 1 , or an analogue, fragment or derivative thereof.

[000475] In specific embodiments, the modulator comprises, consists, or consists essentially of an amino acid sequence as set forth in SEQ ID NO: 1 , or an analogue, fragment or derivative thereof that differs by one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen or twenty amino acids.

[000476] In specific embodiments, the modulator comprises, consists, or consists essentially of an amino acid sequence as set forth in SEQ ID NO: 2, or an analogue, fragment or derivative thereof.

[000477] In specific embodiments, the modulator comprises, consists, or consists essentially of an amino acid sequence as set forth in SEQ ID NO: 2, or an analogue, fragment or derivative thereof that differs by one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen or twenty amino acids. [000478] In specific embodiments, the modulator comprises, consists, or consists essentially of an amino acid sequence as set forth in SEQ ID NO: 3, or an analogue, fragment or derivative thereof.

[000479] In specific embodiments, the modulator comprises, consists, or consists essentially of an amino acid sequence as set forth in SEQ ID NO: 3, or an analogue, fragment or derivative thereof that differs by one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen or twenty amino acids.

[000480] In specific embodiments, the modulator comprises, consists, or consists essentially of an amino acid sequence as set forth in SEQ ID NO: 4, or an analogue, fragment or derivative thereof.

[000481 ] In specific embodiments, the modulator comprises, consists, or consists essentially of an amino acid sequence as set forth in SEQ ID NO: 4, or an analogue, fragment or derivative thereof that differs by one, two, three, four, five, six, seven, eight, nine, or ten amino acids.

[000482] In specific embodiments, the modulator comprises, consists, or consists essentially of an amino acid sequence as set forth in SEQ ID NO: 5, or an analogue, fragment or derivative thereof.

[000483] In specific embodiments, the modulator comprises, consists, or consists essentially of an amino acid sequence as set forth in SEQ ID NO: 5, or an analogue, fragment or derivative thereof that differs by one, two, three, four, five, six, seven, eight, nine, or ten amino acids.

[000484] In specific embodiments, the modulator comprises, consists, or consists essentially of an amino acid sequence as set forth in SEQ ID NO: 6, or an analogue, fragment or derivative thereof.

[000485] In specific embodiments, the modulator comprises, consists, or consists essentially of an amino acid sequence as set forth in SEQ ID NO: 6, or an analogue, fragment or derivative thereof that differs by one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen or twenty amino acids. [000486] In one aspect of the invention, the modulator comprises the cytosolic domain of a IgSF CAM or a part thereof, which is not greater than 40, not greater than 20, not greater than 10 or not greater than 5 amino acids in length.

[000487] In one aspect of the invention, these methods comprise using a modulator as described herein that is a fragment, analogue or derivative of RAGE, to take the place of the transmembrane domain of an IgSF CAM and therein prevent activation of both an IgSF CAM- ligand dependent activation of an IgSF CAM and an IgSF CAM ligand-independent activation of an IgSF CAM by certain activated co-located GPCRs. In one aspect of the invention, the modulator comprises the cytosolic domain of RAGE or a part thereof, which is not greater than 40, not greater than 20, not greater than 10 or not greater than 5 amino acids in length.

[000488] In one aspect of the invention, these methods comprise using a modulator as described herein that is a fragment, analogue or derivative of IgSF CAM, to take the place of the transmembrane domain of an IgSF CAM and therein prevent activation of both an IgSF CAM-ligand dependent activation of an IgSF CAM and an IgSF CAM ligand-independent activation of an IgSF CAM by certain activated co-located GPCRs. In one aspect of the invention, the modulator comprises the cytosolic domain of IgSF CAM or a part thereof, which is not greater than 40, not greater than 20, not greater than 10 or not greater than 5 amino acids in length.

[000489] In one aspect, inhibition of the IgSF CAM ligand-dependent activation of an IgSF CAM occurs at the same time as inhibition of the IgSF CAM ligand-independent activation of an IgSF CAM by certain activated co-located GPCR.

[000490] In one aspect, inhibition of the RAGE ligand-dependent activation of RAGE occurs at the same time as inhibition of the RAGE ligand-independent activation of RAGE by certain activated co-located GPCR where the modulator is an analogue, fragment or derivative of IgSF CAM.

[000491 ] In one aspect, these methods comprise silencing, truncating, modifying or mutating an IgSF CAM such that an IgSF CAM, or analogues, fragments or derivatives thereof, are a non-functional substitute for the cytosolic tail of wild type IgSF CAM or a part thereof, which are unable to be activated by either ligand-dependent or ligand-independent pathways or facilitate downstream signalling and so inhibit signalling that occurs through the cytosolic tail of an IgSF CAM and IgSF CAM-dependent signalling.

[000492] In one aspect, these methods comprise silencing, truncating, modifying or mutating an IgSF CAM such that an IgSF CAM, or analogues, fragments or derivatives thereof, are a non-functional substitute for the cytosolic tail of wild type IgSF CAM or a part thereof, which are unable to be activated by either ligand-dependent or ligand-independent pathways or facilitate downstream signalling and so inhibit signalling that occurs through the cytosolic tail of RAGE and RAGE-dependent signalling.

[000493] In one aspect, these methods comprise silencing, truncating, modifying or mutating RAGE such that RAGE, or analogues, fragments or derivatives thereof, are a non functional substitute for the cytosolic tail of wild type IgSF CAM or a part thereof, which is unable to be activated by either ligand-dependent or ligand-independent pathways or facilitate downstream signalling and so inhibit signalling that occurs through the cytosolic tail of an IgSF CAM and IgSF CAM-dependent signalling.

[000494] In one aspect, the modulators of an IgSF CAM ligand-independent activation of an IgSF CAM by certain activated co-located GPCRs contain a fragment of the ligand-binding ectodomain of human wild-type IgSF CAM, which is not greater than 40, not greater than 20, not greater than 10 or not greater than 5 amino acids in length.

[000495] In one aspect, the modulators of an IgSF CAM ligand-independent activation of an IgSF CAM by certain activated co-located GPCRs contain a fragment of the ligand-binding ectodomain of human wild-type RAGE, which is not greater than 40, not greater than 20, not greater than 10 or not greater than 5 amino acids in length.

[000496] In one aspect, these methods comprise silencing, truncating, modifying or mutating IgSF CAM such that an IgSF CAM, or analogues, fragments or derivatives thereof, modulate common elements involved in signalling mediated by the cytosolic tail of an IgSF CAM (such as RKΰz, Diaphl , MyD88, TIRAP, NFKB). Association with activation of an IgSF CAM by either IgSF CAM ligand-dependent or IgSF CAM ligand-independent activation pathways.

[000497] In one aspect, these methods comprise silencing, truncating, modifying or mutating RAGE such that RAGE, or analogues, fragments or derivatives thereof, modulates common elements involved in signalling mediated by the cytosolic tail of an IgSF CAM (such as RKΰz, Diaphl , MyD88, TIRAP, NFKB). Association with activation of an IgSF CAM by either IgSF CAM ligand-dependent or IgSF CAM ligand-independent activation pathways.

[000498] In one aspect, these methods comprise the use of a modulator that modulates an IgSF CAM ligand-independent activation of an IgSF CAM by activated certain co-located GPCR, such as angiotensin receptor, such as AT i R, in addition to a modulator that modulates an IgSF CAM ligand-dependent activation of an IgSF CAM (such as by a modulator that modulates the binding of an IgSF CAM ligands to the IgSF CAM ectodomain).

[000499] The method may comprise administering a modulator to a patient.

9. Methods for modulating IgSF CAM ligand-independent activation of an IgSF CAM by certain activated co-located GPCRs while also modulating IgSF CAM-independent signalling via certain co-located G PC FIs.

[000500] In one aspect, the invention provides a method for modulating an IgSF CAM- independent, certain co-located GPCR signalling pathway induced following activation by a cognate ligand as well as modulating an IgSF CAM ligand-independent activation of an IgSF CAM by a certain activated co-located GPCR.

[000501 ] In one form, the invention provides a method for modulating an IgSF CAM- independent, certain co-located GPCR signalling pathway induced following activation by a cognate ligand at the same time as modulating an IgSF CAM ligand-independent activation of an IgSF CAM by a certain activated co-located GPCR.

[000502] The method may comprise administering a modulator to a patient.

10. Methods for modulating ligand-dependent activation of an IgSF CAM

[000503] In a related aspect, the present invention provides methods for modulating ligand- dependent activation of an IgSF CAM by a cognate ligand in a cell or tissue of an animal or of animal origin (which may or may not be of a human or of human origin).

[000504] The method may comprise administering a modulator to a patient.

11. Methods for modulating both ligand-dependent and ligand-independent activation of an IgSF CAM

[000505] In another related aspect, the present invention provides methods for inhibiting ligand-dependent activation of an IgSF CAM by cognate ligand and subsequent downstream signalling pathways in a cell, tissue or animal in addition to modulating ligand-independent activation of an IgSF CAM by certain activated co-located GPCRs.

[000506] In one aspect of the invention, these methods comprise using a modulator as described herein to take the place of the cytosolic tail of an IgSF CAM in binding interactions and therein prevent activation of both ligand-dependent activation of an IgSF CAM and ligand- independent activation of an IgSF CAM by certain activated co-located GPCRs. In a preferred form of the invention, the modulator is a fragment, analogue or derivative of the cytosolic tail of an IgSF CAM. In one aspect of the invention, signalling is impaired by exposing the cell to an inhibitor that inhibits the binding of signalling elements to the cytosolic tail of an IgSF CAM resulting in inhibition of both ligand-mediated activation of an IgSF CAM and ligand- independent activation of an IgSF CAM by certain activated co-located GPCRs.

[000507] In one aspect of the invention, these methods comprise using a modulator as described herein to take the place of the cytosolic tail of an IgSF CAM in binding interactions and therein prevent activation of both ligand-dependent activation of an IgSF CAM and ligand- independent activation of an IgSF CAM by certain activated co-located GPCRs. In a preferred form of the invention, the modulator is a fragment, analogue or derivative of the cytosolic tail of RAGE. In one aspect of the invention, signalling is impaired by exposing the cell to an inhibitor that inhibits the binding of signalling elements to the cytosolic tail of an IgSF CAM resulting in inhibition of both ligand-mediated activation of an IgSF CAM and ligand- independent activation of an IgSF CAM by certain activated co-located GPCRs.

[000508] In one aspect of the invention, these methods comprise using a modulator as described herein to take the place of the transmembrane domain of an IgSF CAM and therein prevent activation of both ligand dependent activation of an IgSF CAM and ligand-independent activation of an IgSF CAM by certain activated co-located GPCRs. In a preferred form of the invention, the modulator is a fragment, analogue or derivative of the cytosolic tail of an IgSF CAM. In one aspect of the invention, the modulator comprises the cytosolic domain of an IgSF CAM or a part thereof, which is not greater than 40, not greater than 20, not greater than 10 or not greater than 5 amino acids in length.

[000509] In one aspect of the invention, these methods comprise using a modulator as described herein to take the place of the transmembrane domain of an IgSF CAM and therein prevent activation of both ligand dependent activation of an IgSF CAM and ligand-independent activation of an IgSF CAM by certain activated co-located GPCRs. In a preferred form of the invention, the modulator is a fragment, analogue or derivative of the cytosolic tail of RAGE. In one aspect of the invention, the modulator comprises the cytosolic domain of RAGE or a part thereof, which is not greater than 40, not greater than 20, not greater than 10 or not greater than 5 amino acids in length.

[000510] In one aspect, inhibition of the ligand-dependent activation of an IgSF CAM occurs at the same time as inhibition of the ligand-independent activation of an IgSF CAM by certain activated co-located GPCR. [00051 1 ] In one aspect, these methods comprise silencing, truncating, modifying or mutating an IgSF CAM such that an IgSF CAM, or analogues, fragments or derivatives thereof, are a non-functional substitute for the cytosolic tail of wild type an IgSF CAM or a part thereof, which are unable to be activated by either ligand-dependent or ligand-independent pathways or facilitate downstream signalling and so inhibit signalling that occurs through the cytosolic tail of an IgSF CAM dependent signalling.

[000512] In one aspect, these methods comprise silencing, truncating, modifying or mutating RAGE such that RAGE, or analogues, fragments or derivatives thereof, are a non functional substitute for the cytosolic tail of wild type IgSF CAM or a part thereof, which is unable to be activated by either ligand-dependent or ligand-independent pathways or facilitate downstream signalling and so inhibit signalling that occurs through the cytosolic tail of an IgSF CAM dependent signalling.

[000513] In one aspect, the modulators of ligand-independent activation of an IgSF CAM by certain activated co-located GPCRs contain a fragment of the ligand-binding ectodomain of human wild-type IgSF CAM which is not greater than 40, not greater than 20, not greater than 10 or not greater than 5 amino acids in length.

[000514] In one aspect, the modulators of ligand-independent activation of an IgSF CAM by certain activated co-located GPCRs contain a fragment of the ligand-binding ectodomain of human wild-type RAGE which is not greater than 40, not greater than 20, not greater than 10 or not greater than 5 amino acids in length.

[000515] In one aspect, these methods comprise silencing, truncating, modifying or mutating an IgSF CAM such that an IgSF CAM, or analogues, fragments or derivatives thereof, modulates common elements involved in signalling mediated by the cytosolic tail of an IgSF CAM. Association with activation of IgSF CAM by either ligand-dependent or ligand- independent activation pathways.

[000516] In one aspect, these methods comprise silencing, truncating, modifying or mutating RAGE such that RAGE, or analogues, fragments or derivatives thereof, modulate common elements involved in signalling mediated by the cytosolic tail of an IgSF CAM. Association with activation of IgSF CAM by either ligand-dependent or ligand-independent activation pathways.

[000517] In one aspect, these methods comprise the use of a modulator that modulates ligand-independent activation of an IgSF CAM by activated certain co-located GPCR, such as angiotensin receptor, such as ATi R, in addition to a modulator that modulates ligand- dependent activation of an IgSF CAM (such as by a modulator that modulates the binding of ligands to the IgSF CAM ectodomain).

[000518] The method may comprise administering a modulator to a patient.

12. Methods of screening candidate agents

[000519] In one form, the present invention comprises methods of screening candidate agents, such as a fragment or derivative of RAGE, such as RAGE _370-390 or such as the mCherry-TAT-S391 A-RAGE _362-404 peptide (A Peptide), or such as a fragment or derivative of IgSF CAM such as ALCAM _559-580 , for their ability to modulate (i.e. activate, inhibit or allosterically modulate), IgSF CAM ligand-independent activation of IgSF CAM by activated certain co-located GPCR, such as angiotensin receptor, such as ATiR (also known as IgSF CAM ligand-independent transactivation of IgSF CAM). These methods generally comprise, consist or consist essentially of: a. contacting an IgSF CAM polypeptide with a GPCR polypeptide in the presence of a candidate agent, such as RAGE _370-390 or such as the mCherry-TAT-S391 A- R AG E ₃₆₂ -4 ₀₄ peptide (A Peptide) or such as ALCAM _559-580 , where the GPCR polypeptide is constitutively active and/or is activated by addition of an agonist, partial agonist or allosteric modulator of that GPCR; and b. detecting whether the candidate agent, such as RAGE _370-390 or such as the mCherry-TAT-S391 A-RAGE ₃₆₂ -404 peptide (A Peptide) or such as ALCAM559-580, is a modulator of IgSF CAM ligand-independent activation of IgSF CAM by activated co-located GPCR by detecting an effect indicative of modulation of IgSF CAM activation by the presence of the candidate agent, such as RAGE _{370- 390} or such as the mCherry-TAT-S391 A-RAGE _362-404 peptide (A Peptide) or such as ALCAM _559-580 , and/or by detecting IgSF CAM-dependent signalling that is modulated by the presence of the candidate agent, such as RAGE _370-390 or such as the mCherry-TAT-S391 A-RAGE _362-404 peptide (A Peptide) or such as ALCAM559-580.

[000520] In one form, the present invention comprises methods of screening candidate agents for their ability to modulate IgSF CAM ligand-independent activation of IgSF CAM by activated certain co-located GPCR, comprising the steps: a. contacting an IgSF CAM polypeptide with a GPCR polypeptide in the presence of a candidate agent, where the GPCR polypeptide is constitutively active and/or is activated by addition of an agonist, partial agonist or allosteric modulator of that GPCR; and b. detecting whether the candidate agent is a modulator of IgSF CAM ligand- independent activation of IgSF CAM by activated co-located GPCR by detecting an effect indicative of modulation of IgSF CAM activation by the presence of the candidate agent, and/or by detecting IgSF CAM-dependent signalling that is modulated by the presence of the candidate agent.

[000521 ] In one form of the invention, the candidate agent is an analogue, fragment or derivative of RAGE.

[000522] In a preferred form of the invention, the candidate agent is a fragment or derivative of RAGE.

[000523] In one form of the invention, the candidate agent is an analogue, fragment or derivative of a member of the IgSF CAM superfamily (an IgSF CAM).

[000524] In a preferred form of the invention, the candidate agent is a fragment or derivative of a member of the IgSF CAM superfamily (an IgSF CAM).

[000525] In a particularly preferred form of the invention, the candidate agent is RAGE370-

390

[000526] In another particularly preferred form of the invention, the candidate agent is the mCherry-TAT-S391A-RAGE _362-404 peptide (A Peptide).

[000527] In another particularly preferred form of the invention, the candidate agent is

ALCAM559-580·

[000528] In a preferred form of the invention, the activated certain co-located GPCR is an angiotensin receptor.

[000529] In a particularly preferred form of the invention, the activated certain co-located GPCR is ATiR.

[000530] In some embodiments, the screening methods further comprise detecting whether the candidate agent, such as a fragment or derivative of RAGE, such as RAGE370-390 or such as the mCherry-TAT-S391A-RAGE _362-404 peptide (A Peptide), or such as a fragment or derivative of IgSF CAM such as ALCAM559-580, is a modulator (such as activator, inhibitor or allosteric modulator) of the certain co-located GPCR, such as angiotensin receptor, such as an ATi R, or a signalling pathway of the certain co-located GPCR, such as an angiotensin receptor signalling pathway, such as an ATi R signalling pathway, in the presence or absence of IgSF CAM. In some embodiments, the candidate agent, such as a fragment or derivative of RAGE, such as RAGE _370-390 or such as the mCherry-TAT-S391 A-RAGE ₃₆₂ -4 ₀₄ peptide (A Peptide), or such as a fragment or derivative of IgSF CAM such as ALCAM _559-580 , that results in greater modulation of the signal when the IgSF CAM polypeptide is present compared to when it is absent is selective for modulating IgSF CAM-ligand independent activation of IgSF CAM by activated co-located GPCR over IgSF CAM-independent signalling resulting from activation of the co-located GPCR.

[000531 ] In one form, the invention comprises peptides identified as modulators by said methods.

[000532] In one form, the invention comprises compounds identified as modulators by said methods.

[000533] In some embodiments, the screening methods further comprise detecting whether the candidate agent, such as a fragment or derivative of RAGE, such as RAGE _370-390 or such as the mCherry-TAT-S391A-RAGE _362-404 peptide (A Peptide), or such as a fragment or derivative of IgSF CAM such as ALCAM _559-580 is a modulator (such as activator, inhibitor, allosteric modulator or functional substitute) of IgSF CAM or an IgSF CAM signalling pathway in the presence or absence of the certain co-located GPCR, such as an angiotensin receptor, such as ATi R. In some embodiments, the candidate agent, such as a fragment or derivative of RAGE, such as RAGE _370-390 or such as the mCherry-TAT-S391 A-RAGE ₃₆₂ -4 ₀₄ peptide (A Peptide), or such as a fragment or derivative of IgSF CAM such as ALCAM _559-580 , that results in greater modulation of the IgSF CAM-dependent signal when the GPCR polypeptide is present compared to when it is absent is selective for modulating IgSF CAM-ligand independent activation of IgSF CAM by activated co-located GPCR.

[000534] In some embodiments, the screening methods further comprise detecting whether the candidate agent, such as a fragment or derivative of RAGE, such as RAGE _370-390 or such as the mCherry-TAT-S391 A-RAGE ₃ 62-404 peptide (A Peptide), or such as a fragment or derivative of IgSF CAM such as ALCAM _559-580 , is a modulator (such as activator, inhibitor, allosteric modulator or functional substitute) of an IgSF CAM polypeptide or an IgSF CAM signalling pathway as well as the certain co-located GPCR, such as angiotensin receptor, such as an ATi R, or a signalling pathway of the certain co-located GPCR, such as an angiotensin receptor signalling pathway, such as an ATi R signalling pathway. [000535] In some embodiments, the screening method further comprises the step of using an inhibitor of IgSF CAM ligand binding to the IgSF CAM ectodomain that as such inhibits activation of IgSF CAM in an IgSF CAM ligand-dependent manner.

[000536] In some embodiments, the screening method further comprises use of an IgSF CAM polypeptide that is mutated and/or truncated such that it is not able to bind IgSF CAM ligands to its ectodomain and as such is not able to be activated in an IgSF CAM ligand- dependent manner.

[000537] In some embodiments, binding of IgSF CAM ligands to the ectodomain of IgSF CAM is impaired by exposing the cell to a modulator that modulates the binding of IgSF CAM ligands to IgSF CAM.

[000538] In some embodiments the use of an IgSF CAM polypeptide that is mutated and/or truncated such that it is not able to bind IgSF CAM ligands and as such is not able to be activated in an IgSF CAM ligand-dependent manner occurs before, after or in parallel with a screen involving an IgSF CAM polypeptide that is able to bind IgSF CAM ligands.

[000539] Suitably, a candidate agent or a derivative of a candidate agent, such as a fragment or derivative of RAGE, such as RAGE _370-390 or such as the mCherry-TAT-S391 A- R AG E _362-404 peptide (A Peptide), or such as a fragment or derivative of IgSF CAM such as ALCAM _559-580 , which modulates IgSF CAM ligand-independent activation of IgSF CAM by activated certain co-located GPCR, such as angiotensin receptor, such as ATiR, and that suitably modulates a certain co-located GPCR, such as angiotensin receptor, such as ATiR, and/or a signalling pathway of the certain co-located GPCR, such as an angiotensin receptor signalling pathway, such as an ATiR signalling pathway and/or that inhibits IgSF CAM ligand- dependent activation of IgSF CAM and/or inhibits constitutively-active IgSF CAM and/or an IgSF CAM signalling pathway, is particularly useful for treating, preventing or managing an IgSF CAM-related disorder.

[000540] In certain embodiments, the screening method assesses proximity of the IgSF CAM polypeptide to the certain co-located GPCR, such as angiotensin receptor, such as AT 1 R, using a proximity screening assay. In illustrative examples of this type, the IgSF CAM polypeptide is coupled (e.g., conjugated or otherwise linked) to a first reporter component and the certain co-located GPCR, such as angiotensin receptor, such as ATiR, is coupled (e.g., conjugated or otherwise linked) to a second reporter component. Proximity of the first and second reporter components generates a signal capable of detection by the detector. The first and second reporter components constitute a complementary pair, in the sense that the first reporter component may be interchanged with the second reporter component without appreciably affecting the functioning of the invention. The first and second reporter components can be the same or different.

[000541 ] In one embodiment, the proximity screening assay is that described in patent W02008055313 (Dimerix Bioscience Pty Ltd; also US8283127, US8568997, EP2080012, CA2669088, CN101657715), also known as Receptor Heteromer Investigation Technology or Receptor-HIT (Jaeger et al., 2014). With this method, IgSF CAM is coupled to a first reporter component, the certain co-located GPCR, such as angiotensin receptor, such as ATi R, is unlabeled with respect to the proximity screening assay, and a GPCR-interacting group is linked to the complementary second reporter component, whose interaction with the complex is modulated upon binding a ligand selective for the unlabeled GPCR or the heteromer complex specifically. Preferred examples of GPCR-interacting groups are arrestins, G proteins and ligands. Alternatively, the certain co-located GPCR, such as angiotensin receptor, such as ATi R, is coupled to a first reporter component, IgSF CAM is unlabeled with respect to the proximity screening assay, and an IgSF CAM-interacting group is linked to the complementary second reporter component, whose interaction with the complex is modulated upon binding a ligand selective for the unlabeled IgSF CAM or the heteromer complex specifically. Preferred examples of IgSF CAM-interacting groups are proteins interacting with the cytosolic tail of IgSF CAM, such as IQGAP-1 , Diaphanous 1 , Dock7, MyD88, TIRAP, IRAK4, ERK1 /2, and RKOz (Jules et al., 2013; Ramasamy et al., 2016).

[000542] Reporter components can include enzymes, luminescent or bioluminescent molecules, fluorescent molecules, and transcription factors or other molecules coupled to IgSF CAM, the certain co-located GPCR or the interacting group by linkers incorporating enzyme cleavage sites. In short any known molecule, organic or inorganic, proteinaceous or non- proteinaceous or complexes thereof, capable of emitting a detectable signal as a result of their spatial proximity.

[000543] Preferably, signal generated by the proximity of the first and second reporter components in the presence of the reporter component initiator is selected from the group consisting of: luminescence, fluorescence and colorimetric change.

[000544] In some embodiments, the luminescence is produced by a bioluminescent protein selected from the group consisting of luciferase, galactosidase, lactamase, peroxidase, or any protein capable of luminescence in the presence of a suitable substrate. [000545] Preferable combinations of first and second reporter components include a luminescent reporter component with a fluorescent reporter component, a luminescent reporter component with a non-fluorescent quencher, a fluorescent reporter component with a non-fluorescent quencher, first and second fluorescent reporter components capable of resonance energy transfer. However, useful combinations of first and second reporter components are by no means limited to such.

[000546] In some embodiments, the screening methods further comprise detecting proximity of the first and second reporter components to one another to thereby determine whether the candidate agent, such as a fragment or derivative of RAGE, such as RAGE _370-390 or such as the mCherry-TAT-S391 A-RAGE _362-404 peptide (A Peptide), or such as a fragment or derivative of IgSF CAM such as ALCAM _559-580 , modulates the interaction between the IgSF CAM polypeptide and the certain co-located GPCR, such as angiotensin receptor, such as ATi R. Generally, this is achieved when proximity of the first and second reporter components generates a proximity signal that is altered by the modulation by the candidate agent, such as a fragment or derivative of RAGE, such as RAGE _370-390 or such as the S391 A-RAGE Peptide, or such as a fragment or derivative of IgSF CAM such as ALCAM _559-580 , of the proximity between the IgSF CAM polypeptide and the certain co-located GPCR, such as angiotensin receptor, such as ATi R.

[000547] One or both of the IgSF CAM and certain co-located GPCR, such as angiotensin receptor, such as ATiR, may be in soluble form or expressed on the cell surface.

[000548] In some embodiments, the IgSF CAM and certain co-located GPCR, such as angiotensin receptor, such as ATiR, are located in, partially in, or on a single membrane; for example, both are expressed at the surface of a host cell.

[000549] In another embodiment of the invention, the certain co-located GPCR, such as an angiotensin receptor, such as AT R, is pre-assembled with IgSF CAM in a pre-formed complex at the cell membrane.

[000550] In another embodiment of the invention, following activation of the certain co located GPCR, such as angiotensin receptor, such as AT R, by engagement of cognate ligand, such as Ang II for ATiR, signalling is triggered that involves the cytosolic tail of IgSF CAM.

[000551 ] In one embodiment of the invention, activation of the cytosolic tail of IgSF CAM is associated with changes in its structural conformation and/or affinity for binding partners. [000552] In one embodiment of the invention, monitoring of the structural conformation of IgSF CAM and/or affinity for binding partners occurs when the cytosolic tail of IgSF CAM has been mutated and/or truncated such that it can no longer be activated by IgSF CAM ligands or by IgSF CAM ligand-independent activation of IgSF CAM by certain activated co-located GPCRs.

[000553] In one embodiment of the invention, monitoring structural conformation and/or affinity for binding partners occurs in the presence of agents that inhibit binding and/or activation of IgSF CAM by IgSF CAM ligands or IgSF CAM ligand-independent activation of IgSF CAM by certain activated co-located GPCRs.

[000554] In one embodiment of the invention, monitoring recruitment of binding partners occurs prior to activation of IgSF CAM by IgSF CAM ligands or IgSF CAM ligand-independent activation of IgSF CAM by certain activated co-located GPCRs.

[000555] In one embodiment of the invention, monitoring recruitment and activation of signalling mediators and/or binding partners to the IgSF CAM cytosolic tail occurs subsequent to activation of IgSF CAM by IgSF CAM ligands or IgSF CAM ligand-independent activation of IgSF CAM by certain activated co-located GPCRs.

[000556] In one embodiment of the invention, monitoring recruitment of binding partners following activation of IgSF CAM by IgSF CAM ligands or IgSF CAM ligand-independent activation of IgSF CAM by certain activated co-located GPCRs occurs in the presence of agents that inhibit binding and/or activation of IgSF CAM by IgSF CAM ligands.

[000557] Further embodiments of the invention comprise methods of screening candidate agents, such as a fragment or derivative of RAGE, such as RAGE _370-390 or such as the mCherry-TAT-S391 A-RAGE _362-404 peptide (A Peptide), or such as a fragment or derivative of IgSF CAM such as ALCAM _559-580 , for their ability to modulate (such as activate, inhibit or otherwise modulate) IgSF CAM ligand-independent activation of IgSF CAM by a certain co located GPCR, such as angiotensin receptor, such as ATiR, by detecting modulation of the IgSF CAM-mediated signalling. Such methods may include the step of measuring canonical activation of N FKB, by measuring one or more of the following:

• Activity of IkB kinase (IKK) by monitoring in vitro phosphorylation of a substrate, such as GST-IkBa;

• Detection of IkB Degradation Dynamics including phosphorylation/ubiquitination and/or degradation of IKB and/or IkB-a; • Detection of p65(Rel-A) phosphorylation/ubiquitination, such as by using antibodies, gel-shift, EMSA, or mass spectroscopy;

• Detection of cytoplasmatic to nuclear shuttling/translocation of NFKB components/subunits, such as p65/phospho-p65;

• Detection of NFKB subunit dimerization/complexation;

• Detection of active NFKB components/subunits by binding to immobilized DNA sequence/oligonucleotide containing the NFKB response element/consensus NFKB binding, such as by using Electrophoretic mobility shift assay or gel shift assay, SELEX, protein-binding microarray, or sequencing-based approaches;

• Chromatin-immunoprecipitation (ChIP) assays to detect NFKB in situ binding to DNA to the promoters and enhancers of specific genes;

• In vitro kinase assay for NFKB kinase activity;

• Measurement of NFKB transcriptional activity using NFKB reporter assays via transgene expression of reporter constructs, such as LacZ Flue, eGFP SEAP, NF-gluc, using approaches such as plasmid transfection, reporter cell lines, mini-circles, retrovirus, or lentivirus;

• Measuring changes in expression of downstream targets of NFKB (such as cytokines, growth factors, adhesion molecules and mitochondrial anti-apoptotic genes by real time PCR, protein, or functional assays) (Note the pleiotropic nature of NFKB is reflected in its transcriptional targets that presently number over 500 (see http://www.bu.edu/nf-kb/aene-resources/target-aenes/ accessed 7 ^th December 2018) and;

• Measuring changes in function or structure induced by NFKB-dependent signalling, such as POLKADOTS in T-cells, adhesion in endothelial cells, activation in leucocytes, or oncogenicity.

[000558] Additionally or alternately, such methods may include measuring signals arising from the non-canonical actions of NF-KB, by measuring one or more of the following:

Detection of NIK (NFKB-lnducing Kinase);

Detecting IKKa Activation/phosphorylation; • Detection of NIK kinase activity by ability to autophosphorylate or to phosphorylate a substrate by performing a kinase assay;

• Generation of p52-containing NFKB dimers, such as p52/RelB;

• Detection of Phospho-NFKB2 p100(Ser866/870);

• Detection of partial degradation (called processing) of the precursor p100 into p52;

• Detecting p52/RelB translocation into the nucleus;

• Detecting p52/RelB binding to KB sites;

• Measurement of NFKB transcriptional activity using NFKB reporter assays via transgene expression of reporter constructs, such as LacZ Flue, eGFP SEAP, NF-gluc, using approaches such as plasmid transfection, reporter cell lines, mini-circles, retrovirus, or lentivirus;

• Measuring changes in expression of downstream targets of non-canonical signalling of NFKB (such as CXCL12) by real-time PCR, protein expression or by functional assays.

[000559] In one embodiment, an effect on the IgSF CAM indicative of modulation of IgSF CAM activation is a change in intracellular trafficking such as that detected by a change in proximity of luciferase-conjugated IgSF CAM (such as IgSF CAM/Rluc8) to intracellular compartment markers such as fluorophore-labelled Rabs, such as Rab1 , Rab4, Rab5, Rab6, Rab7, Rab8, Rab9 and/or Rab1 1 (such as Venus-Rab1 , Venus-Rab4, Venus-Rab5, Venus- Rab6, Venus-Rab7, Venus-Rab8, Venus-Rab9 and/or Venus-Rab1 1 ), and/or a plasma membrane marker, such as a fluorophore-conjugated fragment of K-ras (such as Venus-K- ras) using bioluminescence resonance energy transfer (BRET) upon addition of a cognate ligand for the co-located GPCR (Tiulpakov et al., 2016).

[000560] In another embodiment, an effect on the IgSF CAM is a change in IgSF CAM- dependent signalling, such as detected by a change in proximity of luciferase-conjugated IgSF CAM (such as IgSF CAM-Rluc8) to an IgSF CAM-interacting group, such as fluorophore- labelled proteins interacting with the cytosolic tail of the IgSF CAM, such as IQGAP-1 , protein kinase C zeta (RKΰz), Dock7, MyD88, TIRAP, ERK1 /2, (Jules et al., 2013; Ramasamy et al., 2016), olfactory receptor 2T2, ADP/ATP translocase 2, Protein phosphatase 1 G, Intercellular adhesion molecule 1 , Protein DJ-1 (PARK7), Calponin-3, Drebrin, Filamin B, Ras-related protein Rab-13, Radixin/Ezrin/Moesin, Proteolipid protein 2, Coronin, S100 A1 1 , Succinyl-CoA ligase [GDP-forming] subunit alpha, Hsc70-interacting protein, Apoptosis Inhibitor 5, neuropilin, cleavage stimulation factor, growth factor receptor-bound protein 2, sec61 beta subunit, or Nck1 .

[000561 ] In another aspect, the present invention provides methods of identifying a candidate agent that is a modulator (such as activator, inhibitor, allosteric modulator or functional substitute), such as a fragment or derivative of RAGE, such as RAGE370-390 or such as the mCherry-TAT-S391 A-RAGE ₃₆₂ -4 ₀₄ peptide (A Peptide), or such as a fragment or derivative of IgSF CAM such as ALCAM559-580, that modulates (i.e., activates, inhibits or otherwise modulates) IgSF CAM ligand-independent activation of IgSF CAM following activation of a certain co-located GPCR by a cognate ligand, such as ATi R by Angll, or if the certain co-located GPCR is constitutively active, and that suitably modulates a certain co located GPCR, such as an angiotensin receptor, such as ATi R, and/or that modulates an IgSF CAM polypeptide or an IgSF CAM signalling pathway. In a preferred form of the invention, such a modulator is an inhibitor of one or both of the IgSF CAM or certain co-located GPCR, such as an angiotensin receptor, such as ATi R, or of the IgSF CAM signalling pathway. In a particularly preferred form of the invention, the modulation of the IgSF CAM signalling pathway is distinct from and/or occurs to a significantly different extent to the modulation of classical certain co-located GPCR signalling pathways, such as ATiR signalling pathways, such as the Gq signalling pathway. In a particularly preferred form of the invention, the inhibition of the IgSF CAM signalling pathway is distinct from and/or greater than the inhibition of classical certain co-located GPCR signalling pathways, such as ATiR signalling pathways, such as the Gq signalling pathway.

[000562] In one form, the present invention comprises methods of screening candidate agents, where such candidate agents are fragments or derivatives of RAGE, such as RAGE ₃₇₀ - ₃₉₀ or such as the mCherry-TAT-S391 A-RAGE _362-404 peptide (A Peptide), for their ability to modulate (i.e. inhibit or allosterically modulate), IgSF CAM ligand-dependent activation of IgSF CAM. These methods generally comprise, consist or consist essentially of: a. contacting an IgSF CAM polypeptide, with or without the presence of a GPCR polypeptide, with a candidate agent, where such a candidate agent is a fragment or derivative of RAGE, such as RAGE370-390 or such as the mCherry- TAT-S391 A-RAGE ₃₆₂ -4 ₀₄ peptide (A Peptide); and b. detecting whether the candidate agent, where such a candidate agent is a fragment or derivative of RAGE, such as RAGE _370-390 or such as the mCherry- TAT-S391 A-RAGE ₃₆₂ -4 ₀₄ peptide (A Peptide), is a modulator of IgSF CAM ligand-dependent activation of IgSF CAM by detecting an effect indicative of modulation of IgSF CAM activation by the presence of the candidate agent, where such a candidate agent is a fragment or derivative of RAGE, such as RAGE370-390 or such as the mCherry-TAT-S391 A-RAGE ₃₆₂ -404 peptide (A Peptide), and/or by detecting IgSF CAM-independent signalling that is modulated by the presence of the candidate agent, where such a candidate agent is a fragment or derivative of RAGE, such as RAGE ₃ o- ₃ 9o or such as the mCherry-TAT-S391 A-RAGE ₃₆₂ -4 ₀₄ peptide (A Peptide).

[000563] In one form, the present invention comprises methods of screening candidate agents, where such candidate agents are fragments or derivatives of RAGE, for their ability to modulate IgSF CAM ligand-dependent activation of IgSF CAM comprising the steps of: a. contacting an IgSF CAM polypeptide, with or without the presence of a GPCR polypeptide, with a candidate agent, where such a candidate agent is a fragment or derivative of RAGE; and b. detecting whether the candidate agent is a modulator of IgSF CAM ligand- dependent activation of IgSF CAM by detecting an effect indicative of modulation of IgSF CAM activation by the presence of the candidate agent, and/or by detecting IgSF CAM-independent signalling that is modulated by the presence of the candidate agent.

[000564] In some embodiments, the screening methods further comprise detecting whether the candidate agent, where such a candidate agent is a fragment or derivative of RAGE, such as RAG E ₃ 7 _O -39 _O or such as the mCherry-TAT-S391 A-RAGE ₃₆ 2- ₄ o4 peptide (A Peptide), is a modulator (such as activator, inhibitor or allosteric modulator) of a certain co-located GPCR, such as angiotensin receptor, such as an ATi R, or a signalling pathway of the certain co located GPCR, such as an angiotensin receptor signalling pathway, such as an ATi R signalling pathway, in the presence or absence of IgSF CAM.

[000565] In one form, the invention comprises peptides identified as modulators by said methods.

[000566] In one form, the invention comprises compounds identified as modulators by said methods. [000567] In some embodiments, the screening methods further comprise detecting whether the candidate agent, where such a candidate agent is a fragment or derivative of RAGE, such as RAGE _370-390 or such as the mCherry-TAT-S391 A-RAGE ₃₆₂ -4 ₀₄ peptide (A Peptide), is a modulator (such as activator, inhibitor, allosteric modulator or functional substitute) of IgSF CAM or an IgSF CAM signalling pathway in the presence or absence of a certain co-located GPCR, such as an angiotensin receptor, such as ATi R. In some embodiments, the candidate agent, where such a candidate agent is a fragment or derivative of RAGE, such as RAGE ₃₇₀ - ₃₉₀ or such as the mCherry-TAT-S391 A-RAGE _362-404 peptide (A Peptide), that results in greater modulation of the IgSF CAM-dependent signal when the GPCR polypeptide is absent compared to when it is present is selective for modulating IgSF CAM-ligand dependent activation of IgSF CAM.

[000568] In some embodiments, the screening methods further comprise detecting whether the candidate agent, where such a candidate agent is a fragment or derivative of RAGE, such as RAGE370-390 or such as the mCherry-TAT-S391 A-RAGE ₃₆₂ -4 ₀₄ peptide (A Peptide), is a modulator (such as activator, inhibitor, allosteric modulator or functional substitute) of an IgSF CAM polypeptide or an IgSF CAM signalling pathway as well as a certain co-located GPCR, such as angiotensin receptor, such as an AT 1 R, or a signalling pathway of a certain co-located GPCR, such as an angiotensin receptor signalling pathway, such as an ATi R signalling pathway.

[000569] In some embodiments, the screening method further comprises the step of using an inhibitor of IgSF CAM ligand binding to the IgSF CAM ectodomain that as such inhibits activation of IgSF CAM in an IgSF CAM ligand-dependent manner.

[000570] In some embodiments, the screening method further comprises use of an IgSF CAM polypeptide that is mutated and/or truncated such that it is not able to bind IgSF CAM ligands to its ectodomain and as such is not able to be activated in an IgSF CAM ligand- dependent manner.

[000571 ] In some embodiments, binding of IgSF CAM ligands to the ectodomain of IgSF CAM is impaired by exposing the cell to a modulator that modulates the binding of IgSF CAM ligands to IgSF CAM.

[000572] In some embodiments the use of an IgSF CAM polypeptide that is mutated and/or truncated such that it is not able to bind IgSF CAM ligands and as such is not able to be activated in an IgSF CAM ligand-dependent manner occurs before, after or in parallel with a screen involving an IgSF CAM polypeptide that is able to bind IgSF CAM ligands. [000573] Suitably, a candidate agent or a derivative of a candidate agent, where such a candidate agent is a fragment or derivative of RAGE, such as RAGE370-390 or such as the mCherry-TAT-S391 A-RAGE ₃₆₂ -4 ₀₄ peptide (A Peptide), which modulates IgSF CAM ligand- dependent activation of IgSF CAM is particularly useful for treating, preventing or managing an IgSF CAM-related disorder.

[000574] In certain embodiments, the screening method assesses proximity of the IgSF CAM polypeptide to a certain co-located GPCR, such as angiotensin receptor, such as ATi R, using a proximity screening assay. In illustrative examples of this type, the IgSF CAM polypeptide is coupled (e.g., conjugated or otherwise linked) to a first reporter component and a certain co-located GPCR, such as angiotensin receptor, such as ATiR, is coupled (e.g., conjugated or otherwise linked) to a second reporter component. Proximity of the first and second reporter components generates a signal capable of detection by the detector. The first and second reporter components constitute a complementary pair, in the sense that the first reporter component may be interchanged with the second reporter component without appreciably affecting the functioning of the invention. The first and second reporter components can be the same or different.

[000575] In one embodiment, the proximity screening assay is that described in patent W02008055313 (Dimerix Bioscience Pty Ltd; also US8283127, US8568997, EP2080012, CA2669088, CN101657715), also known as Receptor Heteromer Investigation Technology or Receptor-HIT (Jaeger et al., 2014). With this method, IgSF CAM is coupled to a first reporter component, a certain co-located GPCR, such as angiotensin receptor, such as ATi R, is unlabeled with respect to the proximity screening assay, and a GPCR-interacting group is linked to the complementary second reporter component, whose interaction with the complex is modulated upon binding a ligand selective for an unlabeled GPCR or the heteromer complex specifically. Preferred examples of GPCR-interacting groups are arrestins, G proteins and ligands. Alternatively, a certain co-located GPCR, such as angiotensin receptor, such as ATi R, is coupled to a first reporter component, IgSF CAM is unlabeled with respect to the proximity screening assay, and an IgSF CAM-interacting group is linked to the complementary second reporter component, whose interaction with the complex is modulated upon binding a ligand selective for the unlabeled IgSF CAM or the heteromer complex specifically. Preferred examples of IgSF CAM-interacting groups are proteins interacting with the cytosolic tail of IgSF CAM, such as IQGAP-1 , Diaphanous 1 , Dock7, MyD88, TIRAP, IRAK4, ERK1 /2, and R^z (Jules et al., 2013; Ramasamy et al., 2016).

[000576] Reporter components can include enzymes, luminescent or bioluminescent molecules, fluorescent molecules, and transcription factors or other molecules coupled to IgSF CAM, a certain co-located GPCR or the interacting group by linkers incorporating enzyme cleavage sites. In short any known molecule, organic or inorganic, proteinaceous or non- proteinaceous or complexes thereof, capable of emitting a detectable signal as a result of their spatial proximity.

[000577] Preferably, signal generated by the proximity of the first and second reporter components in the presence of the reporter component initiator is selected from the group consisting of: luminescence, fluorescence and colorimetric change.

[000578] In some embodiments, the luminescence is produced by a bioluminescent protein selected from the group consisting of luciferase, galactosidase, lactamase, peroxidase, or any protein capable of luminescence in the presence of a suitable substrate.

[000579] Preferable combinations of first and second reporter components include a luminescent reporter component with a fluorescent reporter component, a luminescent reporter component with a non-fluorescent quencher, a fluorescent reporter component with a non-fluorescent quencher, first and second fluorescent reporter components capable of resonance energy transfer. However, useful combinations of first and second reporter components are by no means limited to such.

[000580] In some embodiments, the screening methods further comprise detecting proximity of the first and second reporter components to one another to thereby determine whether the candidate agent, where such a candidate agent is a fragment or derivative of RAGE, such as RAGE _370-390 or such as the mCherry-TAT-S391 A-RAGE ₃₆₂ -4 ₀₄ peptide (A Peptide), modulates the interaction between the IgSF CAM polypeptide and a certain co located GPCR, such as angiotensin receptor, such as ATi R. Generally, this is achieved when proximity of the first and second reporter components generates a proximity signal that is altered by the modulation by the candidate agent, where such a candidate agent is a fragment or derivative of RAGE, such as RAGE _370-390 or such as the mCherry-TAT-S391 A-RAGE ₃₆₂ -4 ₀₄ peptide (A Peptide), of the proximity between the IgSF CAM polypeptide and a certain co located GPCR, such as angiotensin receptor, such as ATi R.

[000581 ] One or both of the IgSF CAM and certain co-located GPCR, such as angiotensin receptor, such as ATi R, may be in soluble form or expressed on the cell surface.

[000582] In some embodiments, the IgSF CAM and certain co-located GPCR, such as angiotensin receptor, such as ATi R, are located in, partially in, or on a single membrane; for example, both are expressed at the surface of a host cell. [000583] In another embodiment of the invention, a certain co-located GPCR, such as an angiotensin receptor, such as ATi R, is pre-assembled with IgSF CAM in a pre-formed complex at the cell membrane.

[000584] In another embodiment of the invention, following activation of a certain co-located GPCR, such as angiotensin receptor, such as ATi R, by engagement of cognate ligand, such as Ang II for ATi R, signalling is triggered that involves the cytosolic tail of IgSF CAM.

[000585] In one embodiment of the invention, activation of the cytosolic tail of IgSF CAM is associated with changes in its structural conformation and/or affinity for binding partners.

[000586] In one embodiment of the invention, monitoring of the structural conformation of IgSF CAM and/or affinity for binding partners occurs when the cytosolic tail of IgSF CAM has been mutated and/or truncated such that it can no longer be activated by IgSF CAM ligands or by IgSF CAM ligand-independent activation of IgSF CAM by certain activated co-located GPCRs.

[000587] In one embodiment of the invention, monitoring structural conformation and/or affinity for binding partners occurs in the presence of agents that inhibit binding and/or activation of IgSF CAM by IgSF CAM ligands or IgSF CAM ligand-independent activation of IgSF CAM by certain activated co-located GPCRs.

[000588] In one embodiment of the invention, monitoring recruitment of binding partners occurs prior to activation of IgSF CAM by IgSF CAM ligands or IgSF CAM ligand-independent activation of IgSF CAM by certain activated co-located GPCRs.

[000589] In one embodiment of the invention, monitoring recruitment and activation of signalling mediators and/or binding partners to the IgSF CAM cytosolic tail occurs subsequent to activation of IgSF CAM by IgSF CAM ligands or IgSF CAM ligand-independent activation of IgSF CAM by certain activated co-located GPCRs.

[000590] In one embodiment of the invention, monitoring recruitment of binding partners following activation of IgSF CAM by IgSF CAM ligands or IgSF CAM ligand-independent activation of IgSF CAM by certain activated co-located GPCRs occurs in the presence of agents that inhibit binding and/or activation of IgSF CAM by IgSF CAM ligands.

[000591 ] Further embodiments of the invention comprise methods of screening candidate agents, where such a candidate agent is a fragment or derivative of RAGE, such as RAGE ₃₇₀ - ₃₉₀ or such as the mCherry-TAT-S391 A-RAGE _362-404 peptide (A Peptide), for their ability to modulate (such as inhibit or otherwise modulate) IgSF CAM ligand-dependent activation of IgSF CAM by detecting modulation of the IgSF CAM-mediated signalling. Such methods may include the step of measuring canonical activation of NFKB, by measuring one or more of the following:

• Activity of IkB kinase (IKK) by monitoring in vitro phosphorylation of a substrate, such as GST-IkBa;

• Detection of IkB Degradation Dynamics including phosphorylation/ubiquitination and/or degradation of IKB and/or IkB-a;

• Detection of p65(Rel-A) phosphorylation/ubiquitination, such as by using antibodies, gel-shift, EMSA, or mass spectroscopy;

• Detection of cytoplasmatic to nuclear shuttling/translocation of NFKB components/subunits, such as p65/phospho-p65;

• Detection of NFKB subunit dimerization/complexation;

• Detection of active NFKB components/subunits by binding to immobilized DNA sequence/oligonucleotide containing the NFKB response element/consensus NFKB binding, such as by using Electrophoretic mobility shift assay or gel shift assay, SELEX, protein-binding microarray, or sequencing-based approaches;

• Chromatin-immunoprecipitation (ChIP) assays to detect NFKB in situ binding to DNA to the promoters and enhancers of specific genes;

• In vitro kinase assay for NFKB kinase activity;

• Measurement of NFKB transcriptional activity using NFKB reporter assays via transgene expression of reporter constructs, such as LacZ Flue, eGFP SEAP, NF-gluc, using approaches such as plasmid transfection, reporter cell lines, mini-circles, retrovirus, or lentivirus;

• Measuring changes in expression of downstream targets of NFKB (such as cytokines, growth factors, adhesion molecules and mitochondrial anti-apoptotic genes by real time PCR, protein, or functional assays) (Note the pleiotropic nature of NFKB is reflected in its transcriptional targets that presently number over 500 (see http://www.bu.edu/nf-kb/aene-resources/taraet-genes/ accessed 7 ^th December 2018) and; • Measuring changes in function or structure induced by NFKB-dependent signalling, such as POLKADOTS in T-cells, adhesion in endothelial cells, activation in leucocytes, or oncogenicity.

[000592] Additionally or alternately, such methods may include measuring signals arising from the non-canonical actions of NF-KB, by measuring one or more of the following:

• Detection of NIK (NFKB-lnducing Kinase);

• Detecting I KKa Activation/phosphorylation;

• Detection of NIK kinase activity by ability to autophosphorylate or to phosphorylate a substrate by performing a kinase assay;

• Generation of p52-containing NFKB dimers, such as p52/RelB;

• Detection of Phospho-NFKB2 p100(Ser866/870);

• Detection of partial degradation (called processing) of the precursor p100 into p52;

• Detecting p52/RelB translocation into the nucleus;

• Detecting p52/RelB binding to KB sites;

• Measurement of NFKB transcriptional activity using NFKB reporter assays via transgene expression of reporter constructs, such as LacZ Flue, eGFP SEAP, NF-gluc, using approaches such as plasmid transfection, reporter cell lines, mini-circles, retrovirus, or lentivirus;

• Measuring changes in expression of downstream targets of non-canonical signalling of NFKB (such as CXCL12) by real-time PCR, protein expression or by functional assays.

[000593] In one embodiment, an effect on the IgSF CAM indicative of modulation of IgSF CAM activation is a change in intracellular trafficking such as that detected by a change in proximity of luciferase-conjugated IgSF CAM (such as IgSF CAM/Rluc8) to intracellular compartment markers such as fluorophore-labelled Rabs, such as Rab1 , Rab4, Rab5, Rab6, Rab7, Rab8, Rab9 and/or Rab1 1 (such as Venus-Rab1 , Venus-Rab4, Venus-Rab5, Venus- Rab6, Venus-Rab7, Venus-Rab8, Venus-Rab9 and/or Venus-Rab1 1 ), and/or a plasma membrane marker, such as a fluorophore-conjugated fragment of K-ras (such as Venus-K- ras) using bioluminescence resonance energy transfer (BRET) upon addition of a cognate ligand for the co-located GPCR (Tiulpakov et al., 2016).

[000594] In another embodiment, an effect on the IgSF CAM is a change in IgSF CAM- dependent signalling, such as detected by a change in proximity of luciferase-conjugated IgSF CAM (such as IgSF CAM-Rluc8) to an IgSF CAM-interacting group, such as fluorophore- labelled proteins interacting with the cytosolic tail of the IgSF CAM, such as IQGAP-1 , protein kinase C zeta (RKΰz), Dock7, MyD88, TIRAP, ERK1 /2, (Jules et al., 2013; Ramasamy et al., 2016), olfactory receptor 2T2, ADP/ATP translocase 2, Protein phosphatase 1 G, Intercellular adhesion molecule 1 , Protein DJ-1 (PARK7), Calponin-3, Drebrin, Filamin B, Ras-related protein Rab-13, Radixin/Ezrin/Moesin, Proteolipid protein 2, Coronin, S100 A1 1 , Succinyl-CoA ligase [GDP-forming] subunit alpha, Hsc70-interacting protein, Apoptosis Inhibitor 5, neuropilin, cleavage stimulation factor, growth factor receptor-bound protein 2, sec61 beta subunit, or Nck1 .

[000595] In another aspect, the present invention provides methods of identifying a candidate agent that is a modulator (such as activator, inhibitor, allosteric modulator or functional substitute), where such a modulator is a fragment or derivative of RAGE, such as RAGE370-390 or such as the mCherry-TAT-S391 A-RAGE ₃₆₂ -404 peptide (A Peptide), that modulates (i.e., activates, inhibits or otherwise modulates) IgSF CAM ligand-independent activation of IgSF CAM following activation of a certain co-located GPCR by a cognate ligand, such as ATi R by Angll, or if the certain co-located GPCR is constitutively active, and that suitably modulates a certain co-located GPCR, such as an angiotensin receptor, such as AT 1 R, and/or that modulates an IgSF CAM polypeptide or an IgSF CAM signalling pathway. In one form of the invention, such a modulator is an inhibitor of the IgSF CAM or of the IgSF CAM signalling pathway. In a particularly preferred form of the invention, the modulation of the IgSF CAM signalling pathway is distinct from and/or occurs to a significantly different extent to the modulation of classical certain co-located GPCR signalling pathways, such as ATi R signalling pathways, such as the Gq signalling pathway. In a particularly preferred form of the invention, the inhibition of the IgSF CAM signalling pathway is distinct from and/or greater than the inhibition of classical certain co-located GPCR signalling pathways, such as ATi R signalling pathways, such as the Gq signalling pathway.

[000596] In one form, the present invention comprises methods of screening candidate agents, where such candidate agents are fragments or derivatives of members of the IgSF CAM superfamily, such as ALCAM _559-580 , for their ability to modulate (i.e. inhibit or allosterically modulate), IgSF CAM ligand-dependent activation of IgSF CAM. These methods generally comprise, consist or consist essentially of: a. contacting an IgSF CAM polypeptide, with or without the presence of a GPCR polypeptide, with a candidate agent, where such a candidate agent is a fragment or derivative of a member of the IgSF CAM superfamily, such as ALCAM559-580; and b. detecting whether the candidate agent, where such a candidate agent is a fragment or derivative of a member of the IgSF CAM superfamily, such as ALCAM _559-580 , is a modulator of IgSF CAM ligand-dependent activation of IgSF CAM by detecting an effect indicative of modulation of IgSF CAM activation by the presence of the candidate agent, where such a candidate agent is a fragment or derivative of a member of the IgSF CAM superfamily, such as ALCAM _559-580 , and/or by detecting IgSF CAM-independent signalling that is modulated by the presence of the candidate agent, where such a candidate agent is a fragment or derivative of a member of the IgSF CAM superfamily, such as ALCAM559-580.

[000597] In one form, the present invention comprises methods of screening candidate agents, where such candidate agents are fragments or derivatives of members of the IgSF CAM superfamily, for their ability to modulate IgSF CAM ligand-dependent activation of IgSF CAM comprising the steps of: a. contacting an IgSF CAM polypeptide, with or without the presence of a GPCR polypeptide, with a candidate agent, where such a candidate agent is a fragment or derivative of a member of the IgSF CAM superfamily, such as ALCAM559-580; and b. detecting whether the candidate agent is a modulator of IgSF CAM ligand- dependent activation of IgSF CAM by detecting an effect indicative of modulation of IgSF CAM activation by the presence of the candidate agent, and/or by detecting IgSF CAM-independent signalling that is modulated by the presence of the candidate agent.

[000598] In some embodiments, the screening methods further comprise detecting whether the candidate agent, where such a candidate agent is a fragment or derivative of a member of the IgSF CAM superfamily, such as ALCAM _559-580 , is a modulator (such as activator, inhibitor or allosteric modulator) of a certain co-located GPCR, such as angiotensin receptor, such as an ATiR, or a signalling pathway of the certain co-located GPCR, such as an angiotensin receptor signalling pathway, such as an ATiR signalling pathway, in the presence or absence of IgSF CAM.

[000599] In one form, the invention comprises peptides identified as modulators by said methods.

[000600] In one form, the invention comprises compounds identified as modulators by said methods.

[000601 ] In some embodiments, the screening methods further comprise detecting whether the candidate agent, where such a candidate agent is a fragment or derivative of a member of the IgSF CAM superfamily, such as ALCAM _559-580 , is a modulator (such as activator, inhibitor, allosteric modulator or functional substitute) of IgSF CAM or an IgSF CAM signalling pathway in the presence or absence of a certain co-located GPCR, such as an angiotensin receptor, such as ATiR. In some embodiments, the candidate agent, where such a candidate agent is a fragment or derivative of a member of the IgSF CAM superfamily, such as ALCAM _559-580 , that results in greater modulation of the IgSF CAM-dependent signal when the GPCR polypeptide is absent compared to when it is present is selective for modulating IgSF CAM- ligand dependent activation of IgSF CAM.

[000602] In some embodiments, the screening methods further comprise detecting whether the candidate agent, where such a candidate agent is a fragment or derivative of a member of the IgSF CAM superfamily, such as ALCAM _559-580 , is a modulator (such as activator, inhibitor, allosteric modulator or functional substitute) of an IgSF CAM polypeptide or an IgSF CAM signalling pathway as well as a certain co-located GPCR, such as angiotensin receptor, such as an ATiR, or a signalling pathway of a certain co-located GPCR, such as an angiotensin receptor signalling pathway, such as an ATiR signalling pathway.

[000603] In some embodiments, the screening method further comprises the step of using an inhibitor of IgSF CAM ligand binding to the IgSF CAM ectodomain that as such inhibits activation of IgSF CAM in an IgSF CAM ligand-dependent manner.

[000604] In some embodiments, the screening method further comprises use of an IgSF CAM polypeptide that is mutated and/or truncated such that it is not able to bind IgSF CAM ligands to its ectodomain and as such is not able to be activated in an IgSF CAM ligand- dependent manner. [000605] In some embodiments, binding of IgSF CAM ligands to the ectodomain of IgSF CAM is impaired by exposing the cell to a modulator that modulates the binding of IgSF CAM ligands to IgSF CAM.

[000606] In some embodiments the use of an IgSF CAM polypeptide that is mutated and/or truncated such that it is not able to bind IgSF CAM ligands and as such is not able to be activated in an IgSF CAM ligand-dependent manner occurs before, after or in parallel with a screen involving an IgSF CAM polypeptide that is able to bind IgSF CAM ligands.

[000607] Suitably, a candidate agent or a derivative of a candidate agent, where such a candidate agent is a fragment or derivative of a member of the IgSF CAM superfamily, such as ALCAM559-580, which modulates IgSF CAM ligand-dependent activation of IgSF CAM is particularly useful for treating, preventing or managing an IgSF CAM-related disorder.

[000608] In certain embodiments, the screening method assesses proximity of the IgSF CAM polypeptide to a certain co-located GPCR, such as angiotensin receptor, such as ATi R, using a proximity screening assay. In illustrative examples of this type, the IgSF CAM polypeptide is coupled (e.g., conjugated or otherwise linked) to a first reporter component and a certain co-located GPCR, such as angiotensin receptor, such as ATiR, is coupled (e.g., conjugated or otherwise linked) to a second reporter component. Proximity of the first and second reporter components generates a signal capable of detection by the detector. The first and second reporter components constitute a complementary pair, in the sense that the first reporter component may be interchanged with the second reporter component without appreciably affecting the functioning of the invention. The first and second reporter components can be the same or different.

[000609] In one embodiment, the proximity screening assay is that described in patent W02008055313 (Dimerix Bioscience Pty Ltd; also US8283127, US8568997, EP2080012, CA2669088, CN101657715), also known as Receptor Heteromer Investigation Technology or Receptor-HIT (Jaeger et al., 2014). With this method, IgSF CAM is coupled to a first reporter component, a certain co-located GPCR, such as angiotensin receptor, such as ATi R, is unlabeled with respect to the proximity screening assay, and a GPCR-interacting group is linked to the complementary second reporter component, whose interaction with the complex is modulated upon binding a ligand selective for an unlabeled GPCR or the heteromer complex specifically. Preferred examples of GPCR-interacting groups are arrestins, G proteins and ligands. Alternatively, a certain co-located GPCR, such as angiotensin receptor, such as ATi R, is coupled to a first reporter component, IgSF CAM is unlabeled with respect to the proximity screening assay, and an IgSF CAM-interacting group is linked to the complementary second reporter component, whose interaction with the complex is modulated upon binding a ligand selective for the unlabeled IgSF CAM or the heteromer complex specifically. Preferred examples of IgSF CAM-interacting groups are proteins interacting with the cytosolic tail of IgSF CAM, such as IQGAP-1 , Diaphanous 1 , Dock7, MyD88, TIRAP, IRAK4, ERK1 /2, and R^z (Jules et al., 2013; Ramasamy et al., 2016).

[000610] Reporter components can include enzymes, luminescent or bioluminescent molecules, fluorescent molecules, and transcription factors or other molecules coupled to IgSF CAM, a certain co-located GPCR or the interacting group by linkers incorporating enzyme cleavage sites. In short any known molecule, organic or inorganic, proteinaceous or non- proteinaceous or complexes thereof, capable of emitting a detectable signal as a result of their spatial proximity.

[00061 1 ] Preferably, signal generated by the proximity of the first and second reporter components in the presence of the reporter component initiator is selected from the group consisting of: luminescence, fluorescence and colorimetric change.

[000612] In some embodiments, the luminescence is produced by a bioluminescent protein selected from the group consisting of luciferase, galactosidase, lactamase, peroxidase, or any protein capable of luminescence in the presence of a suitable substrate.

[000613] Preferable combinations of first and second reporter components include a luminescent reporter component with a fluorescent reporter component, a luminescent reporter component with a non-fluorescent quencher, a fluorescent reporter component with a non-fluorescent quencher, first and second fluorescent reporter components capable of resonance energy transfer. However, useful combinations of first and second reporter components are by no means limited to such.

[000614] In some embodiments, the screening methods further comprise detecting proximity of the first and second reporter components to one another to thereby determine whether the candidate agent, where such a candidate agent is a fragment or derivative of a member of the IgSF CAM superfamily, such as ALCAM _559-580 , modulates the interaction between the IgSF CAM polypeptide and a certain co-located GPCR, such as angiotensin receptor, such as ATi R. Generally, this is achieved when proximity of the first and second reporter components generates a proximity signal that is altered by the modulation by the candidate agent, where such a candidate agent is a fragment or derivative of a member of the IgSF CAM superfamily, such as ALCAM _559-580 , of the proximity between the IgSF CAM polypeptide and a certain co-located GPCR, such as angiotensin receptor, such as ATi R. [000615] One or both of the IgSF CAM and certain co-located GPCR, such as angiotensin receptor, such as ATi R, may be in soluble form or expressed on the cell surface.

[000616] In some embodiments, the IgSF CAM and certain co-located GPCR, such as angiotensin receptor, such as ATi R, are located in, partially in, or on a single membrane; for example, both are expressed at the surface of a host cell.

[000617] In another embodiment of the invention, a certain co-located GPCR, such as an angiotensin receptor, such as ATi R, is pre-assembled with IgSF CAM in a pre-formed complex at the cell membrane.

[000618] In another embodiment of the invention, following activation of a certain co-located GPCR, such as angiotensin receptor, such as ATi R, by engagement of cognate ligand, such as Ang II for ATi R, signalling is triggered that involves the cytosolic tail of IgSF CAM.

[000619] In one embodiment of the invention, activation of the cytosolic tail of IgSF CAM is associated with changes in its structural conformation and/or affinity for binding partners.

[000620] In one embodiment of the invention, monitoring of the structural conformation of IgSF CAM and/or affinity for binding partners occurs when the cytosolic tail of IgSF CAM has been mutated and/or truncated such that it can no longer be activated by IgSF CAM ligands or by IgSF CAM ligand-independent activation of IgSF CAM by certain activated co-located GPCRs.

[000621 ] In one embodiment of the invention, monitoring structural conformation and/or affinity for binding partners occurs in the presence of agents that inhibit binding and/or activation of IgSF CAM by IgSF CAM ligands or IgSF CAM ligand-independent activation of IgSF CAM by certain activated co-located GPCRs.

[000622] In one embodiment of the invention, monitoring recruitment of binding partners occurs prior to activation of IgSF CAM by IgSF CAM ligands or IgSF CAM ligand-independent activation of IgSF CAM by certain activated co-located GPCRs.

[000623] In one embodiment of the invention, monitoring recruitment and activation of signalling mediators and/or binding partners to the IgSF CAM cytosolic tail occurs subsequent to activation of IgSF CAM by IgSF CAM ligands or IgSF CAM ligand-independent activation of IgSF CAM by certain activated co-located GPCRs.

[000624] In one embodiment of the invention, monitoring recruitment of binding partners following activation of IgSF CAM by IgSF CAM ligands or IgSF CAM ligand-independent activation of IgSF CAM by certain activated co-located GPCRs occurs in the presence of agents that inhibit binding and/or activation of IgSF CAM by IgSF CAM ligands.

[000625] Further embodiments of the invention comprise methods of screening candidate agents, where such a candidate agent is a fragment or derivative of a member of the IgSF CAM superfamily, such as ALCAM559-580, for their ability to modulate (such as inhibit or otherwise modulate) IgSF CAM ligand-dependent activation of IgSF CAM by detecting modulation of the IgSF CAM-mediated signalling. Such methods may include the step of measuring canonical activation of NFKB, by measuring one or more of the following:

• Activity of IkB kinase (IKK) by monitoring in vitro phosphorylation of a substrate, such as GST-IkBa;

• Detection of IkB Degradation Dynamics including phosphorylation/ubiquitination and/or degradation of IKB and/or IkB-a;

• Detection of p65(Rel-A) phosphorylation/ubiquitination, such as by using antibodies, gel-shift, EMSA, or mass spectroscopy;

• Detection of cytoplasmatic to nuclear shuttling/translocation of NFKB components/subunits, such as p65/phospho-p65;

• Detection of NFKB subunit dimerization/complexation;

• Detection of active NFKB components/subunits by binding to immobilized DNA sequence/oligonucleotide containing the NFKB response element/consensus NFKB binding, such as by using Electrophoretic mobility shift assay or gel shift assay, SELEX, protein-binding microarray, or sequencing-based approaches;

• Chromatin-immunoprecipitation (ChIP) assays to detect NFKB in situ binding to DNA to the promoters and enhancers of specific genes;

• In vitro kinase assay for NFKB kinase activity;

• Measurement of NFKB transcriptional activity using NFKB reporter assays via transgene expression of reporter constructs, such as LacZ Flue, eGFP SEAP, NF-gluc, using approaches such as plasmid transfection, reporter cell lines, mini-circles, retrovirus, or lentivirus;

Measuring changes in expression of downstream targets of NFKB (such as cytokines, growth factors, adhesion molecules and mitochondrial anti-apoptotic genes by real- time PCR, protein, or functional assays) (Note the pleiotropic nature of NFKB is reflected in its transcriptional targets that presently number over 500 (see http://www.bu.edu/nf-kb/gene-resources/target-aenes/ accessed 2 ^nd December 2018) and;

• Measuring changes in function or structure induced by NFKB-dependent signalling, such as POLKADOTS in T-cells, adhesion in endothelial cells, activation in leucocytes, or oncogenicity.

[000626] Additionally or alternately, such methods may include measuring signals arising from the non-canonical actions of NF-KB, by measuring one or more of the following:

• Detection of NIK (NFKB-lnducing Kinase);

• Detecting I KKa Activation/phosphorylation;

• Detection of NIK kinase activity by ability to autophosphorylate or to phosphorylate a substrate by performing a kinase assay;

• Generation of p52-containing NFKB dimers, such as p52/RelB;

• Detection of Phospho-NFKB2 p100(Ser866/870);

• Detection of partial degradation (called processing) of the precursor p100 into p52;

• Detecting p52/RelB translocation into the nucleus;

• Detecting p52/RelB binding to KB sites;

• Measurement of NFKB transcriptional activity using NFKB reporter assays via transgene expression of reporter constructs, such as LacZ Flue, eGFP SEAP, NF-gluc, using approaches such as plasmid transfection, reporter cell lines, mini-circles, retrovirus, or lentivirus;

• Measuring changes in expression of downstream targets of non-canonical signalling of NFKB (such as CXCL12) by real-time PCR, protein expression or by functional assays.

[000627] In one embodiment, an effect on the IgSF CAM indicative of modulation of IgSF CAM activation is a change in intracellular trafficking such as that detected by a change in proximity of luciferase-conjugated IgSF CAM (such as IgSF CAM/Rluc8) to intracellular compartment markers such as fluorophore-labelled Rabs, such as Rab1 , Rab4, Rab5, Rab6, Rab7, Rab8, Rab9 and/or Rab1 1 (such as Venus-Rab1 , Venus-Rab4, Venus-Rab5, Venus- Rab6, Venus-Rab7, Venus-Rab8, Venus-Rab9 and/or Venus-Rab1 1 ), and/or a plasma membrane marker, such as a fluorophore-conjugated fragment of K-ras (such as Venus-K- ras) using bioluminescence resonance energy transfer (BRET) upon addition of a cognate ligand for the co-located GPCR (Tiulpakov et al., 2016).

[000628] In another embodiment, an effect on the IgSF CAM is a change in IgSF CAM- dependent signalling, such as detected by a change in proximity of luciferase-conjugated IgSF CAM (such as IgSF CAM-Rluc8) to an IgSF CAM-interacting group, such as fluorophore- labelled proteins interacting with the cytosolic tail of the IgSF CAM, such as IQGAP-1 , protein kinase C zeta (RKΰz), Dock7, MyD88, TIRAP, ERK1 /2, (Jules et al., 2013; Ramasamy et al., 2016), olfactory receptor 2T2, ADP/ATP translocase 2, Protein phosphatase 1 G, Intercellular adhesion molecule 1 , Protein DJ-1 (PARK7), Calponin-3, Drebrin, Filamin B, Ras-related protein Rab-13, Radixin/Ezrin/Moesin, Proteolipid protein 2, Coronin, S100 A1 1 , Succinyl-CoA ligase [GDP-forming] subunit alpha, Hsc70-interacting protein, Apoptosis Inhibitor 5, neuropilin, cleavage stimulation factor, growth factor receptor-bound protein 2, sec61 beta subunit, or Nck1 .

[000629] In another aspect, the present invention provides methods of identifying a candidate agent that is a modulator (such as activator, inhibitor, allosteric modulator or functional substitute), where such a candidate agent is a fragment or derivative of a member of the IgSF CAM superfamily, such as ALCAM _559-580 , that modulates (i.e., activates, inhibits or otherwise modulates) IgSF CAM ligand-independent activation of IgSF CAM following activation of a certain co-located GPCR by a cognate ligand, such as ATi R by Angll, or if the certain co-located GPCR is constitutively active, and that suitably modulates a certain co located GPCR, such as an angiotensin receptor, such as ATi R, and/or that modulates an IgSF CAM polypeptide or an IgSF CAM signalling pathway. In one form of the invention, such a modulator is an inhibitor of the IgSF CAM or of the IgSF CAM signalling pathway. In a particularly preferred form of the invention, the modulation of the IgSF CAM signalling pathway is distinct from and/or occurs to a significantly different extent to the modulation of classical certain co-located GPCR signalling pathways, such as ATiR signalling pathways, such as the Gq signalling pathway. In a particularly preferred form of the invention, the inhibition of the IgSF CAM signalling pathway is distinct from and/or greater than the inhibition of classical certain co-located GPCR signalling pathways, such as ATiR signalling pathways, such as the Gq signalling pathway. [000630] In one form, the present invention comprises methods of screening candidate agents, where candidate agents are fragments or derivatives of members of the IgSF CAM superfamily, such as ALCAM _559-580 , for their ability to modulate (i.e. activate, inhibit or allosterically modulate) RAGE ligand-independent activation of RAGE by activated certain co located GPCR, such as angiotensin receptor, such as ATiR, or such as a certain complement receptor, such as C5a receptor 1 (also known as RAGE ligand-independent transactivation of RAGE). These methods generally comprise, consist or consist essentially of: a. Contacting a RAGE polypeptide with a GPCR polypeptide in the presence of a candidate agent, where the candidate agent is a fragment or derivative of a member of the IgSF CAM superfamily, such as ALCAM _559-580 , where the GPCR polypeptide is constitutively active and/or is activated by addition of an agonist, partial agonist or allosteric modulator of that GPCR; and b. detecting whether the candidate agent, where the candidate agent is a fragment or derivative of a member of the IgSF CAM superfamily, such as ALCAM _559-580 , is a modulator of RAGE ligand-independent activation of RAGE by activated co-located GPCR by detecting an effect indicative of modulation of RAGE activation by the presence of the candidate agent, where the candidate agent is a fragment or derivative of a member of the IgSF CAM superfamily, such as ALCAM _559-580 , and/or by detecting RAGE-dependent signalling that is modulated by the presence of the candidate agent, where the candidate agent is a fragment or derivative of a member of the IgSF CAM superfamily, such as ALCAM _559-580 .

[000631 ] In one form, the present invention comprises methods of screening candidate agents, where candidate agents are fragments or derivatives of members of the IgSF CAM superfamily, for their ability to modulate RAGE ligand-independent activation of RAGE by activated certain co-located GPCR, comprising the steps of: a. Contacting a RAGE polypeptide with a GPCR polypeptide in the presence of a candidate agent, where the GPCR polypeptide is constitutively active and/or is activated by addition of an agonist, partial agonist or allosteric modulator of that GPCR; and b. detecting whether the candidate agent is a modulator of RAGE ligand- independent activation of RAGE by activated co-located GPCR by detecting an effect indicative of modulation of RAGE activation by the presence of the candidate agent, and/or by detecting RAGE-dependent signalling that is modulated by the presence of the candidate agent.

[000632] In some embodiments, the screening methods further comprise detecting whether the candidate agent, where the candidate agent is a fragment or derivative of a member of the IgSF CAM superfamily, such as ALCAM _559-580 , is a modulator (such as activator, inhibitor or allosteric modulator) of the certain co-located GPCR, such as angiotensin receptor, such as an ATi R or such as a certain complement receptor, such as C5a receptor 1 or a signalling pathway of the certain co-located GPCR, such as an angiotensin receptor signalling pathway, such as an ATi R signalling pathway or such as a certain C5a receptor 1 signalling pathway, such as a C5a receptor 1 signalling pathway, in the presence or absence of RAGE. In some embodiments, the candidate agent, where the candidate agent is a fragment or derivative of a member of the IgSF CAM superfamily, such as ALCAM _559-580 , that results in greater modulation of the signal when the RAGE polypeptide is present compared to when it is absent is selective for modulating RAGE-ligand independent activation of RAGE by activated co located GPCR over RAGE-independent signalling resulting from activation of the co-located GPCR.

[000633] In one form, the invention comprises peptides identified as modulators by said methods.

[000634] In one form, the invention comprises compounds identified as modulators by said methods.

[000635] In some embodiments, the screening methods further comprise detecting whether the candidate agent, where the candidate agent is a fragment or derivative of a member of the IgSF CAM superfamily, such as ALCAM _559-580 , is a modulator (such as activator, inhibitor, allosteric modulator or functional substitute) of RAGE or a RAGE signalling pathway in the presence or absence of the certain co-located GPCR, such as an angiotensin receptor, such as ATi R, or such as a certain complement receptor, such as C5a receptor 1 . In some embodiments, the candidate agent, where the candidate agent is a fragment or derivative of a member of the IgSF CAM superfamily, such as ALCAM _559-580 , that results in greater modulation of the RAGE-dependent signal when the GPCR polypeptide is present compared to when it is absent is selective for modulating RAGE-ligand independent activation of RAGE by activated co-located GPCR.

[000636] In some embodiments, the screening methods further comprise detecting whether the candidate agent, where the candidate agent is a fragment or derivative of a member of the IgSF CAM superfamily, such as ALCAM _559-580 , is a modulator (such as activator, inhibitor, allosteric modulator or functional substitute) of a RAGE polypeptide or a RAGE signalling pathway as well as the certain co-located GPCR, such as angiotensin receptor, such as an ATi R, or such as a certain complement receptor, such as C5a receptor 1 , or a signalling pathway of the certain co-located GPCR, such as an angiotensin receptor signalling pathway, such as an ATi R signalling pathway or such as a certain complement receptor signalling pathway, such as a C5a receptor 1 signalling pathway.

[000637] In some embodiments, the screening method further comprises the step of using an inhibitor of RAGE ligand binding to the RAGE ectodomain that as such inhibits activation of RAGE in a RAGE ligand-dependent manner.

[000638] In some embodiments, the screening method further comprises use of a RAGE polypeptide that is mutated and/or truncated such that it is not able to bind RAGE ligands to its ectodomain and as such is not able to be activated in a RAGE ligand-dependent manner.

[000639] In some embodiments, binding of RAGE ligands to the ectodomain of RAGE is impaired by exposing the cell to a modulator that modulates the binding of RAGE ligands to RAGE.

[000640] In some embodiments the use of a RAGE polypeptide that is mutated and/or truncated such that it is not able to bind RAGE ligands and as such is not able to be activated in a RAGE ligand-dependent manner occurs before, after or in parallel with a screen involving a RAGE polypeptide that is able to bind RAGE ligands.

[000641 ] Suitably, a candidate agent or a derivative of a candidate agent, where the candidate agent or derivative of the candidate agent is a fragment or derivative of a member of the IgSF CAM superfamily, such as ALCAM559-580, which modulates RAGE ligand- independent activation of RAGE by activated certain co-located GPCR, such as angiotensin receptor, such as an ATi R or such as a certain complement receptor, such as C5a receptor 1 , and that suitably modulates a certain co-located GPCR, such as angiotensin receptor, such as an ATi R or such as a certain complement receptor, such as C5a receptor 1 and/or a signalling pathway of the certain co-located GPCR, such as an angiotensin receptor signalling pathway, such as an ATi R signalling pathway or such as a certain complement receptor signalling pathway, such as a C5a signalling pathway and/or that inhibits RAGE ligand- dependent activation of RAGE and/or inhibits constitutively-active RAGE and/or a RAGE signalling pathway, is particularly useful for treating, preventing or managing a RAGE-related disorder. [000642] In certain embodiments, the screening method assesses proximity of the RAGE polypeptide to the certain co-located GPCR, such as angiotensin receptor, such as ATi R, or such as a certain complement receptor, such as C5a receptor 1 , using a proximity screening assay. In illustrative examples of this type, the RAGE polypeptide is coupled (e.g., conjugated or otherwise linked) to a first reporter component and the certain co-located GPCR, such as angiotensin receptor, such as an ATi R or such as a certain complement receptor, such as C5a receptor 1 , is coupled (e.g., conjugated or otherwise linked) to a second reporter component. Proximity of the first and second reporter components generates a signal capable of detection by the detector. The first and second reporter components constitute a complementary pair, in the sense that the first reporter component may be interchanged with the second reporter component without appreciably affecting the functioning of the invention. The first and second reporter components can be the same or different.

[000643] In one embodiment, the proximity screening assay is that described in patent W02008055313 (Dimerix Bioscience Pty Ltd; also US8283127, US8568997, EP2080012, CA2669088, CN101657715), also known as Receptor Heteromer Investigation Technology or Receptor-HIT (Jaeger et at., 2014). With this method, RAGE is coupled to a first reporter component, the certain co-located GPCR, such as angiotensin receptor, such as ATi R or such as a certain complement receptor, such as C5a receptor 1 is unlabeled with respect to the proximity screening assay, and a GPCR-interacting group is linked to the complementary second reporter component, whose interaction with the complex is modulated upon binding a ligand selective for the unlabeled GPCR or the heteromer complex specifically. Preferred examples of GPCR-interacting groups are arrestins, G proteins and ligands. Alternatively, the certain co-located GPCR, such as angiotensin receptor, such as ATi R or such as a certain complement receptor, such as C5a receptor 1 is coupled to a first reporter component, RAGE is unlabeled with respect to the proximity screening assay, and a RAGE-interacting group is linked to the complementary second reporter component, whose interaction with the complex is modulated upon binding a ligand selective for the unlabeled RAGE or the heteromer complex specifically. Preferred examples of RAGE-interacting groups are proteins interacting with the cytosolic tail of RAGE, such as IQGAP-1 , Diaphanous 1 , Dock7, MyD88, TIRAP, IRAK4, ERK1/2, and RKOz (Jules et al., 2013; Ramasamy et al., 2016).

[000644] Reporter components can include enzymes, luminescent or bioluminescent molecules, fluorescent molecules, and transcription factors or other molecules coupled to RAGE, the certain co-located GPCR or the interacting group by linkers incorporating enzyme cleavage sites. In short any known molecule, organic or inorganic, proteinaceous or non- proteinaceous or complexes thereof, capable of emitting a detectable signal as a result of their spatial proximity.

[000645] Preferably, signal generated by the proximity of the first and second reporter components in the presence of the reporter component initiator is selected from the group consisting of: luminescence, fluorescence and colorimetric change.

[000646] In some embodiments, the luminescence is produced by a bioluminescent protein selected from the group consisting of luciferase, galactosidase, lactamase, peroxidase, or any protein capable of luminescence in the presence of a suitable substrate.

[000647] Preferable combinations of first and second reporter components include a luminescent reporter component with a fluorescent reporter component, a luminescent reporter component with a non-fluorescent quencher, a fluorescent reporter component with a non-fluorescent quencher, first and second fluorescent reporter components capable of resonance energy transfer. However, useful combinations of first and second reporter components are by no means limited to such.

[000648] In some embodiments, the screening methods further comprise detecting proximity of the first and second reporter components to one another to thereby determine whether the candidate agent, where the candidate agent is a fragment or derivative of a member of the IgSF CAM superfamily, such as ALCAM559-580, modulates the interaction between the RAGE polypeptide and the certain co-located GPCR, such as angiotensin receptor, such as ATi R or such as a certain complement receptor, such as C5a receptor 1 . Generally, this is achieved when proximity of the first and second reporter components generates a proximity signal that is altered by the modulation by the candidate agent, where the candidate agent is a fragment or derivative of a member of the IgSF CAM superfamily, such as ALCAM559-580, of the proximity between the RAGE polypeptide and the certain co located GPCR, such as angiotensin receptor, such as ATi R or such as a certain complement receptor, such as C5a receptor 1 .

[000649] One or both of the RAGE and certain co-located GPCR, such as angiotensin receptor, such as ATi R or such as a certain complement receptor, such as C5a receptor 1 , may be in soluble form or expressed on the cell surface.

[000650] In some embodiments, the RAGE and certain co-located GPCR, such as angiotensin receptor, such as ATi R or such as a certain complement receptor, such as C5a receptor 1 , are located in, partially in, or on a single membrane; for example, both are expressed at the surface of a host cell. [000651 ] In another embodiment of the invention, the certain co-located GPCR, such as an angiotensin receptor, such as ATi R or such as a certain complement receptor, such as C5a receptor 1 , is pre-assembled with RAGE in a pre-formed complex at the cell membrane.

[000652] In another embodiment of the invention, following activation of the certain co located GPCR, such as angiotensin receptor, such as ATi R or such as a certain complement receptor, such as C5a receptor 1 , by engagement of cognate ligand, such as Ang 11 for AT i R or C5a for C5a receptor 1 , signalling is triggered that involves the cytosolic tail of RAGE.

[000653] In one embodiment of the invention, activation of the cytosolic tail of RAGE is associated with changes in its structural conformation and/or affinity for binding partners.

[000654] In one embodiment of the invention, monitoring of the structural conformation of RAGE and/or affinity for binding partners occurs when the cytosolic tail of RAGE has been mutated and/or truncated such that it can no longer be activated by RAGE ligands or by RAGE ligand-independent activation of RAGE by certain activated co-located GPCRs.

[000655] In one embodiment of the invention, monitoring structural conformation and/or affinity for binding partners occurs in the presence of agents that inhibit binding and/or activation of RAGE by RAGE ligands or RAGE ligand-independent activation of RAGE by certain activated co-located GPCRs.

[000656] In one embodiment of the invention, monitoring recruitment of binding partners occurs prior to activation of RAGE by RAGE ligands or RAGE ligand-independent activation of RAGE by certain activated co-located GPCRs.

[000657] In one embodiment of the invention, monitoring recruitment and activation of signalling mediators and/or binding partners to the RAGE cytosolic tail occurs subsequent to activation of RAGE by RAGE ligands or RAGE ligand-independent activation of RAGE by certain activated co-located GPCRs.

[000658] In one embodiment of the invention, monitoring recruitment of binding partners following activation of RAGE by RAGE ligands or RAGE ligand-independent activation of RAGE by certain activated co-located GPCRs occurs in the presence of agents that inhibit binding and/or activation of RAGE by RAGE ligands.

[000659] Further embodiments of the invention comprise methods of screening candidate agents, where candidate agents are fragments or derivatives of members of the IgSF CAM superfamily, such as ALCAM _559-580 , for their ability to modulate (such as activate, inhibit or otherwise modulate) RAGE ligand-independent activation of RAGE by a certain co-located GPCR, such as angiotensin receptor, such as ATiR or such as a certain complement receptor, such as C5a receptor 1 , by detecting modulation of the RAGE-mediated signalling. Such methods may include the step of measuring canonical activation of NFKB, by measuring one or more of the following:

• Activity of IkB kinase (IKK) by monitoring in vitro phosphorylation of a substrate, such as GST-IkBa;

• Detection of IkB Degradation Dynamics including phosphorylation/ubiquitination and/or degradation of IKB and/or IkB-a;

• Detection of p65(Rel-A) phosphorylation/ubiquitination, such as by using antibodies, gel-shift, EMSA, or mass spectroscopy;

• Detection of cytoplasmatic to nuclear shuttling/translocation of NFKB components/subunits, such as p65/phospho-p65;

• Detection of NFKB subunit dimerization/complexation;

• Detection of active NFKB components/subunits by binding to immobilized DNA sequence/oligonucleotide containing the NFKB response element/consensus NFKB binding, such as by using Electrophoretic mobility shift assay or gel shift assay, SELEX, protein-binding microarray, or sequencing-based approaches;

• Chromatin-immunoprecipitation (ChIP) assays to detect NFKB in situ binding to DNA to the promoters and enhancers of specific genes;

• In vitro kinase assay for NFKB kinase activity;

• Measurement of NFKB transcriptional activity using NFKB reporter assays via transgene expression of reporter constructs, such as LacZ Flue, eGFP SEAP, NF-gluc, using approaches such as plasmid transfection, reporter cell lines, mini-circles, retrovirus, or lentivirus;

• Measuring changes in expression of downstream targets of NFKB (such as cytokines, growth factors, adhesion molecules and mitochondrial anti-apoptotic genes by real time PCR, protein, or functional assays) (Note the pleiotropic nature of NFKB is reflected in its transcriptional targets that presently number over 500 (see http://www.bu.edu/nf-kb/aene-resources/taraet-genes/ accessed 7 ^th December 2018) and; • Measuring changes in function or structure induced by NFKB-dependent signalling, such as POLKADOTS in T-cells, adhesion in endothelial cells, activation in leucocytes, or oncogenicity.

[000660] Additionally or alternately, such methods may include measuring signals arising from the non-canonical actions of NF-KB, by measuring one or more of the following:

• Detection of NIK (NFKB-lnducing Kinase);

• Detecting I KKa Activation/phosphorylation;

• Detection of NIK kinase activity by ability to autophosphorylate or to phosphorylate a substrate by performing a kinase assay;

• Generation of p52-containing NFKB dimers, such as p52/RelB;

• Detection of Phospho-NFKB2 p100(Ser866/870);

• Detection of partial degradation (called processing) of the precursor p100 into p52;

• Detecting p52/RelB translocation into the nucleus;

• Detecting p52/RelB binding to KB sites;

• Measurement of NFKB transcriptional activity using NFKB reporter assays via transgene expression of reporter constructs, such as LacZ Flue, eGFP SEAP, NF-gluc, using approaches such as plasmid transfection, reporter cell lines, mini-circles, retrovirus, or lentivirus;

• Measuring changes in expression of downstream targets of non-canonical signalling of NFKB (such as CXCL12) by real-time PCR, protein expression or by functional assays.

[000661 ] In one embodiment, an effect on the RAGE indicative of modulation of RAGE activation is a change in intracellular trafficking such as that detected by a change in proximity of luciferase-conjugated RAGE (such as RAGE/Rluc8) to intracellular compartment markers such as fluorophore-labelled Rabs, such as Rab1 , Rab4, Rab5, Rab6, Rab7, Rab8, Rab9 and/or Rab1 1 (such as Venus-Rab1 , Venus-Rab4, Venus-Rab5, Venus-Rab6, Venus-Rab7, Venus-Rab8, Venus-Rab9 and/or Venus-Rab1 1 ), and/or a plasma membrane marker, such as a fluorophore-conjugated fragment of K-ras (such as Venus-K-ras) using bioluminescence resonance energy transfer (BRET) upon addition of a cognate ligand for the co-located GPCR (Tiulpakov et al., 2016).

[000662] In another embodiment, an effect on the RAGE is a change in RAGE-dependent signalling, such as detected by a change in proximity of luciferase-conjugated RAGE (such as RAGE-Rluc8) to a RAGE-interacting group, such as fluorophore-labelled proteins interacting with the cytosolic tail of the RAGE, such as IQGAP-1 , protein kinase C zeta (RKOz), Dock7, MyD88, TIRAP, ERK1 /2, (Jules et al., 2013; Ramasamy et al., 2016), olfactory receptor 2T2, ADP/ATP translocase 2, Protein phosphatase 1 G, Intercellular adhesion molecule 1 , Protein DJ-1 (PARK7), Calponin-3, Drebrin, Filamin B, Ras-related protein Rab-13, Radixin/Ezrin/Moesin, Proteolipid protein 2, Coronin, S100 A1 1 , Succinyl-CoA ligase [GDP- forming] subunit alpha, Hsc70-interacting protein, Apoptosis Inhibitor 5, neuropilin, cleavage stimulation factor, growth factor receptor-bound protein 2, sec61 beta subunit, or Nck1 .

[000663] In another aspect, the present invention provides methods of identifying a candidate agent that is a modulator (such as activator, inhibitor, allosteric modulator or functional substitute), where the modulator is a fragment or derivative of a member of the IgSF CAM superfamily, such as ALCAM _559-580 , that modulates (i.e., activates, inhibits or otherwise modulates) RAGE ligand-independent activation of RAGE following activation of a certain co located GPCR by a cognate ligand, such as ATiR or such as a certain complement receptor, such as C5a receptor 1 or if the certain co-located GPCR is constitutively active, and that suitably modulates a certain co-located GPCR, such as an angiotensin receptor, such as ATi R or such as a certain complement receptor, such as C5a receptor 1 , and/or that modulates a RAGE polypeptide or a RAGE signalling pathway. In a preferred form of the invention, such a modulator is an inhibitor of one or both of the RAGE or certain co-located GPCR, such as an angiotensin receptor, such as ATiR or such as a certain complement receptor, such as C5a receptor 1 , or of the RAGE signalling pathway. In a particularly preferred form of the invention, the modulation of the RAGE signalling pathway is distinct from and/or occurs to a significantly different extent to the modulation of classical certain co-located GPCR signalling pathways, such as ATiR signalling pathways, such as the Gq signalling pathway, or C5a receptor 1 signalling pathways, such as the Gi signalling pathway. In a particularly preferred form of the invention, the inhibition of the RAGE signalling pathway is distinct from and/or greater than the inhibition of classical certain co-located GPCR signalling pathways, such as ATiR signalling pathways, such as the Gq signalling pathway, or such as C5a receptor 1 signalling pathways, such as the Gi signalling pathway. [000664] The present invention includes modulators identified by any of the aforementioned methods and the use of such modulators to modulate activity as described herein.

[000665] The present invention also includes pharmaceutical compositions containing said modulators, and the use of said pharmaceutical compositions for the treatment or prevention of an ailment in a patient in need of such treatment.

[000666] The present invention includes the use of a modulator of the present invention in the manufacture of a medicament to treat an ailment.

[000667] Throughout this specification, unless the context requires otherwise, an activated GPCR means a GPCR that is in an active state that may result from the binding of an agonist, partial agonist and/or allosteric modulator, and/or as a consequence of constitutive activity that does not necessitate ligand binding.

[000668] Throughout this specification, unless the context requires otherwise, the certain activated co-located GPCRs of the invention are GPCRs that are expressed in the same cell as an IgSF CAM and for which an effect on an IgSF CAM, indicative of modulation of an IgSF CAM activation and/or modulation of induction of IgSF CAM-dependent signalling, is detected upon activation by cognate ligands of the certain co-located GPCRs or when the GPCRs are constitutively active.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGURE 1 .

[000669] Figure 1 A. The induction of p65 expression in CHO cells (which lack AT1 R) exposed to Ang II (1 mM) for 2 hours in the presence or absence of transfection with pCI neo (empty vector) or an IgSF CAM, specifically murine ALCAM, or the cytosolic tail of human ALCAM551 -583, compared to their respective untreated control shown as fold change. Grey columns are untreated, white columns are Ang ll-treated. Individual replicates are shown.

[000670] Figure 1 B. The induction of p65 expression in AT1 R-CHO cells (which express human AT 1 R) exposed to Ang II (1 mM) for 2 hours in the presence or absence of transfection with pCI neo (empty vector) or an IgSF CAM, specifically full length human ALCAM1-583, compared to their respective untreated control shown as fold change. Grey columns are untreated, white columns are Ang ll-treated. Individual replicates are shown.

[000671 ] Figure 1 C. The induction of p65 expression in AT 1 R-CHO cells exposed to Ang II (1 mM) for 2 hours in the presence or absence of transfection with pCI neo (empty vector) or an IgSF CAM, specifically full length murine ALCAMI- ₅ 83, compared to their respective untreated control shown as fold change. Grey columns are untreated, white columns are Ang ll-treated. Individual replicates are shown.

[000672] Figure 1 D. The induction of p65 expression in AT 1 R-CFIO cells exposed to Ang II (1 mM) for 2 hours in the presence or absence of transfection with pCI neo (empty vector) or an IgSF CAM, specifically full-length chicken EpCAM, compared to their respective untreated control shown as fold change. Grey columns are untreated, white columns are Ang ll-treated. Individual replicates are shown.

[000673] Figure 1 E. The induction of p65 expression in AT 1 R-CFIO cells exposed to Ang II (1 mM) for 2 hours in the presence or absence of transfection with pCI neo (empty vector) or the cytosolic tail of an IgSF CAM, specifically the cytosolic tail of ALCAM _551-583 , compared to their respective untreated control shown as fold change and its modulation by cotransfection with RAGE _370-390 . Grey columns are untreated, white columns are Ang ll-treated. Individual replicates are shown.

[000674] Figure 1 F. The induction of p65 expression in AT 1 R-CFIO cells exposed to Ang II (1 mM) for 2 hours in the presence or absence of transfection with pCI neo (empty vector) or the cytosolic tail of an IgSF CAM, specifically the cytosolic tails of ALCAM, BCAM, MCAM, EpCAM and CADM4 or pCIneo (empty vector) compared to their respective untreated control shown as fold change. Grey columns are untreated, white columns are Ang ll-treated. Individual replicates are shown.

[000675] Figure 1 G. The induction of p65 expression in AT 1 R-CFIO cells exposed to Ang II (1 mM) for 2 hours in the presence or absence of transfection with pCI neo (empty vector) or the cytosolic tail of an IgSF CAM, specifically the cytosolic tails of EpCAM and CADM4, or the cytosolic tail of RAGE (RAGE370-404), compared to their respective untreated control shown as fold change. Grey columns are untreated, white columns are Ang ll-treated. Individual replicates are shown.

[000676] Figure 1 FI. The induction of PCNA expression in AT 1 R-CFIO cells exposed to Ang II (1 mM) for 2 hours in the presence or absence of transfection with the pCI neo (empty vector) or the cytosolic tail of an IgSF CAM, specifically the cytosolic tails of EpCAM and CADM4 compared to their respective untreated control shown as fold change. Grey columns are untreated, white columns are Ang ll-treated. Individual replicates are shown.

FIGURE 2. [000677] Figure 2A. The induction of ICAM-1 expression in adult retinal pigment epithelial (ARPE) cells exposed to Ang II (1 mM) in the presence or absence of transfection of pCI neo (empty vector) or a fragment of an IgSF CAM, more specifically the cytosolic tail of an IgSF CAM, even more specifically the cytosolic tail of ALCAM where the cytosolic tail of ALCAM is residues 551 -583, and its modulation by co-transfection with a fragment of RAGE, specifically RAGE370-390, compared to their respective untreated control shown as fold change. Grey columns are untreated, white columns are Angll-treated and striped bars are treated with RAGE370-390 + Angll. Individual replicates are shown.

[000678] Figure 2B. The induction of ICAM-1 expression in adult retinal pigment epithelial (ARPE) cells exposed to Ang II (1 mM) in the presence or absence of transfection of pCI neo (empty vector)or a fragment of an IgSF CAM, more specifically the cytosolic tail of an IgSF CAM, even more specifically the cytosolic tail of MCAM where the cytosolic tail of MCAM is residues 584-637, and its modulation by co-transfection with a fragment of RAGE, specifically RAGE370-390, compared to their respective untreated control shown as fold change. Grey columns are untreated, white columns are Angll-treated and striped bars are treated with RAGE370-390 + Angll. Individual replicates are shown.

[000679] Figure 2C. The induction of ICAM-1 expression in adult retinal pigment epithelial (ARPE) cells exposed to Ang II (1 mM) in the presence or absence of transfection of pCI neo (empty vector) or a fragment of an IgSF CAM, more specifically an IgSF CAM cytosolic tail, even more specifically the cytosolic tail of ALCAM where the cytosolic tail of ALCAM is residues 551 -583 or the cytosolic tail of BCAM where the cytosolic tail of BCAM is residues 569-628, and its modulation by treatment with a fragment of RAGE, specifically the mCherry- TAT-S391 A-RAGE ₃₆₂ -4 ₀₄ oligopeptide (A Peptide), compared to their respective untreated control shown as fold change. Grey columns are untreated, white columns are Angll-treated and striped bars are treated with mCherry-TAT-S391 A-RAGE ₃₆₂ -4 ₀₄ + Angll. Individual replicates are shown.

FIGURE 3

[000680] Figure 3A. The induction of p65 expression in CHO cells (which lack AT1 R) exposed to Ang II (1 mM) in the presence or absence of transfection with pCI neo (empty vector) or a fragment of an IgSF CAM, specifically the cytosolic tail of human ALCAM (hALCAM ₅ 5i-583 or hALCAM ₅ 59-58o), compared to their respective untreated control shown as fold change. Grey columns are untreated and white columns are Angll-treated. Individual replicates are shown. [000681 ] Figure 3B. The induction of p65 expression in AT1 -CHO cells exposed to Ang II (1 mM) in the presence of transfection with : pCI neo (empty vector) or an IgSF CAM, specifically full length mouse ALCAM (murine ALCAM _1-583 ); or a derivative of an IgSF CAM, specifically the cytosolic tail of human ALCAM omitting all serine and threonine residues (hALCAM _559-58 o); or murine ALCAM1- ₅₈₃ together with ALCAM _559-580 . Data are compared to their respective untreated control shown as fold change. Grey columns are untreated and white columns are Angll-treated. Individual replicates are shown.

[000682] Figure 3C. The induction of PCNA expression in AT1 -CFIO cells exposed to Ang II (1 mM) in the presence of transfection with: pCI neo (empty vector) or an IgSF CAM, specifically full length mouse ALCAM (murine ALCAM1-583); or a derivative of an IgSF CAM, specifically the cytosolic tail of human ALCAM omitting all serine and threonine residues (hALCAM ₅ 59-58o); or murine ALCAM1 -583 together with ALCAM559-580. Data are compared to their respective untreated control shown as fold change. Grey columns are untreated and white columns are Angll-treated. Individual replicates are shown.

[000683] Figure 3D. The induction of p65 expression in AT1 -CFIO cells exposed to Ang II (1 mM) in the presence of transfection with: pCI neo (empty vector) or full length chicken EpCAM; or a derivative of an IgSF CAM, specifically the cytosolic tail of human ALCAM omitting all serine and threonine residues (hALCAM _559-58 o); or chicken EpCAM together with ALCAM559-580. Data are compared to their respective untreated control shown as fold change. Grey columns are untreated and white columns are Angll-treated. Individual replicates are shown.

[000684] Figure 3E. The induction of p65 expression in AT1 -CFIO cells exposed to Ang II (1 mM) in the presence of transfection with: pCI neo (empty vector) or the full length human ALCAM (specifically ALCAMI- ₅₈ 3 (SEQUENCE ID NO# 9) or a derivative of an IgSF CAM, specifically the cytosolic tail of human ALCAM omitting all serine and threonine residues (hALCAM ₅₅₉ -58o); or human ALCAM1-583 together with human ALCAM559-580. Data are compared to their respective untreated control shown as fold change. Grey columns are untreated and white columns are Angll-treated. Individual replicates are shown.

[000685] Figure 3F. The induction of PCNA expression in AT1 -CHO cells exposed to Ang II (1 mM) in the presence of transfection with: pCI neo (empty vector) or the full length human ALCAM (specifically ALCAMI- ₅₈ 3 (SEQUENCE ID NO# 9) or a derivative of an IgSF CAM, specifically the cytosolic tail of human ALCAM omitting all serine and threonine residues (hALCAM ₅ 59-58o); or human ALCAM1.533 together with human ALCAM559-580. Grey columns are untreated and white columns are Ang 11 -treated. Individual replicates are shown. Data are compared to their respective untreated control shown as fold change.

[000686] Figure 3G. The induction of p65 expression in AT1 -CHO cells exposed to Ang II (1 mM) in the presence of transfection with the cytosolic tail of human ALCAM (specifically ALCAM _55i-583 (SEQUENCE ID NO# 1 ) in addition to transfection with a derivative of an IgSF CAM, specifically the cytosolic tail of human ALCAM omitting all serine and threonine residues (hALCAM _559-58 o), or a derivative of the RAGE cytosolic tail, specifically RAGE _379-390 (SEQ ID NO: 21 ). Grey columns are untreated and white columns are Ang ll-treated. Individual replicates are shown. Data are compared to their respective untreated control shown as fold change.

[000687] Figure 3H. The induction of p65 expression in AT1 -CFIO cells exposed to Ang II (1 mM) in the presence of transfection with the cytosolic tail of human BCAM (specifically BCAM _569-628 (SEQUENCE ID NO# 2) in addition to transfection with a derivative of an IgSF CAM, specifically the cytosolic tail of human ALCAM omitting all serine and threonine residues (hALCAM _559-58 o), or a derivative of the RAGE cytosolic tail, specifically RAGE _379-390 (SEQ ID NO: 21 ). Grey columns are untreated and white columns are Ang ll-treated. Individual replicates are shown. Data are compared to their respective untreated control shown as fold change.

[000688] Figure 3I. The induction of p65 expression in AT1 -CFIO cells exposed to Ang II (1 mM) in the presence of transfection with the cytosolic tail of human MCAM (specifically MCAM _584-637 (SEQUENCE ID NO# 3)) in addition to transfection with a derivative of an IgSF CAM, specifically the cytosolic tail of human ALCAM omitting all serine and threonine residues (hALCAM _559-58 o), or a derivative of the RAGE cytosolic tail, specifically RAGE _379-390 (SEQ ID NO: 21 ). Grey columns are untreated and white columns are Ang ll-treated. Individual replicates are shown. Data are compared to their respective untreated control shown as fold change.

[000689] Figure 3J. The induction of p65 expression in AT1 -CFIO cells exposed to Ang II (1 mM) in the presence of transfection with: pCI neo (empty vector); the cytosolic tail of human EpCAM (specifically EpCAM ₂ 89-3i4 (SEQUENCE ID NO# 4)) in addition to transfection with a derivative of an IgSF CAM, specifically the cytosolic tail of human ALCAM omitting all serine and threonine residues (hALCAM ₅ 59-58o), or a derivative of the RAGE cytosolic tail, specifically RAGE379-390 (SEQ ID NO: 21 ). Grey columns are untreated and white columns are Angll- treated. Individual replicates are shown. Data are compared to their respective untreated control shown as fold change. [000690] Figure 3K. The induction of p65 expression in AT1 -CHO cells exposed to Ang II (1 mM) in the presence of transfection with the cytosolic tail of human CADM4 (specifically CADM4 _346-388 (SEQUENCE ID NO# 5)) with or without additional transfection with a derivative of the RAGE cytosolic tail, specifically RAGE379-390 (SEQ ID NO: 21 ). Grey columns are untreated and white columns are Ang 11 -treated. Individual replicates are shown. Data are compared to their respective untreated control shown as fold change.

FIGURE 4

[000691 ] Figure 4A. The induction of PCNA expression in CFIO cells exposed to the IgSF ligand, S100A8/A9 (1 mM) for 2 hours in the presence or absence of transfection of or pCIneo (empty vector) or an IgSF CAM, specifically full length murine ALCAM1-583, and its modulation by co-transfection with a fragment of cytosolic tail of ALCAM, specifically ALCAM559-580 or a fragment of the cytosolic tail of RAGE, specifically RAGE370-390, compared to their respective untreated control shown as fold change. Grey columns are untreated, white columns are S100A8/A9-treated. Individual replicates are shown.

[000692] Figure 4B. The induction of PCNA expression in CFIO cells exposed to the IgSF ligand S100A8/A9 (1 mM) for 2 hours in the presence or absence of transfection of pCIneo (empty vector) or full length RAGE, and its modulation by co-transfection with a fragment of cytosolic tail of ALCAM, specifically ALCAM559-580 compared their respective untreated control shown as fold change. Grey columns are untreated, white columns are S100A8/A9-treated. Individual replicates are shown.

FIGURE 5

[000693] Figure 5A. The induction of p65 expression in AT 1 R-CHO cells exposed to Ang II (1 mM) for two hours in the presence of transfection of a derivative of an IgSF CAM, specifically the cytosolic tail of human ALCAM omitting all serine and threonine residues (hALCAM ₅ 59-58o (SEQ ID NO: 6), S391 A-RAGE362-404 or a derivative of the RAGE cytosolic tail, specifically RAGE379-390 (SEQ ID NO: 21 ) compared to their respective untreated control shown as fold change.. Grey columns are untreated, white columns are Angll-treated. Individual replicates are shown.

[000694] Figure 5B. The induction of p65 expression in AT 1 R-CHO cells exposed to Ang II (1 mM) for two hours in the presence or absence of transfection of pCIneo (empty vector) or full length murine ALCAM, and its modulation by co-transfection with a fragment of RAGE, specifically RAGE _370-390 compared to their respective untreated control shown as fold change. Grey columns are untreated, white columns are Angll-treated. Individual replicates are shown. FIGURE 6

[000695] Figure 6A. The induction of p65 expression in AT 1 R-CFIO cells exposed to Ang II (1 mM) for two hours in the presence or absence of transfection of pCI neo (empty vector) or full length human RAGE, and its modulation by co-transfection with a derivative of an IgSF CAM, specifically the cytosolic tail of human ALCAM omitting all serine and threonine residues (hALCAM ₅ 59-58o). Grey columns are untreated, white columns are Ang 11 -treated. Individual replicates are shown. Data are compared to their respective untreated control shown as fold change.

[000696] Figure 6B. The induction of ICAM-1 expression in adult retinal pigment epithelial (ARPE) cells exposed to C5a (1 mM) in the presence or absence of transfection with: pCIneo (empty vector) or a derivative of an IgSF CAM, specifically the cytosolic tail of ALCAM omitting all serine and threonine residues (ALCAM _559-580 ); both the C5a receptor 1 (C5aR1 ) and full length RAGE (RAGE1-4 ₀₄ ); or C5aR1 , full length RAGE (RAGE1-4 ₀₄ ) and ALCAM _559-580 . Grey columns are untreated and white columns are C5a-treated. Individual replicates are shown. Data are compared to their respective untreated control shown as fold change.

FIGURE 7

[000697] Figure 7A. The induction of p65 expression in AT 1 R-CFIO cells exposed to Ang II (1 mM) for two hours in the presence or absence of transfection of full length human mutant S391 A-RAGE, and its modulation by co-transfection with pCI neo (empty vector) or a fragment of RAGE, specifically RAGE370-404, or a fragment of an IgSF CAM, specifically the cytosolic tail of human ALCAM or CADM4 compared to their respective untreated control shown as fold change. Grey columns are untreated, white columns are Angll-treated. Individual replicates are shown.

[000698] Figure 7B. The induction of PCNA expression in CHO cells exposed to Ang II (1 mM) for two hours in the presence or absence of transfection of pCI neo (empty vector) or full length human mutant S391 A-RAGE, and its modulation by co-transfection with a fragment of RAGE, specifically RAGE370-404, or a fragment of an IgSF CAM, specifically the cytosolic tail of human ALCAM, compared to their respective untreated control shown as fold change. Grey columns are untreated, white columns are Angll-treated. Individual replicates are shown.

FIGURE 8 [000699] Figure 8A. Arginine vasopressin (AVP)-induced recruitment of b-qh'beί^L/bhue proximal to ALCAM/Rluc8 in the presence of vasopressin receptor 2 (V2R). AVP-induced recruitment of bqGGbeΐ^L/bhue to V2R/Rluc8 included as a control.

[000700] Figure 8B. Sphingosine-1 -phosphate (S1 P)-induced recruitment of b- arrestin2/Venus proximal to ALCAM/Rluc8 in the presence of S1 P receptor 1 (S1 PR1 ). S1 P- induced recruitment of bqGGbeΐ^L/bhue to S1 PR1 /Rluc8 included as a control.

[000701 ] Figure 8C. Isoproterenol (Isop)-induced recruitment of b-bhΌbί^L/bhue proximal to ALCAM/Rluc8 in the presence of b2 Adrenergic receptor (b2AR). Isop-induced recruitment of bqGGbeΐ^L/bhue to b2AR/RIuo8 included as a control.

[000702] Figure 8D. Orexin A (OxA)-induced recruitment of b-q beί^L/bhue proximal to ALCAM/Rluc8 in the presence of Orexin receptor 2 (OxR2). OxA-induced recruitment of bqGGbeΐ^L/bhue to OxR2/Rluc8 included as a control.

[000703] Figure 8E. Thyrotrophin-releasing hormone (TRH)-induced recruitment of b- arrestin2/Venus proximal to ALCAM/Rluc8 in the presence of Thyrotrophin-releasing hormone receptor 1 (TRHR1 ). TRH-induced recruitment of bqGGbeΐ^L/bhue to TRHR1 /Rluc8 included as a control.

[000704] Figure 8E. Thyrotrophin-releasing hormone (TRH)-induced recruitment of b- arrestin2/Venus proximal to ALCAM/Rluc8 in the presence of Thyrotrophin-releasing hormone receptor 1 (TRHR1 ). TRH-induced recruitment of bqGGbeΐ^L/bhue to TRHR1 /Rluc8 included as a control.

[000705] Figure 8F. CC chemokine ligand 3 (CCL3)-induced recruitment of b- arrestin2/Venus proximal to ALCAM/Rluc8 in the presence of CC chemokine receptor 1 (CCR1 ). CCL3-induced recruitment of bqGGbeΐ^L/bhue to CCR1/Rluc8 included as a control.

[000706] Figure 8G. CC chemokine ligand 2 (CCL2)-induced recruitment of b- arrestin2/Venus proximal to ALCAM/Rluc8 in the presence of CC chemokine receptor 2 (CCR2). CCL2-induced recruitment of bqGGbeΐ^L/bhue to CCR2/Rluc8 included as a control.

[000707] Figure 8H. CC chemokine ligand 20 (CCL20)-induced recruitment of b- arrestin2/Venus proximal to ALCAM/Rluc8 in the presence of CC chemokine receptor 6 (CCR6). CCL20-induced recruitment of bqGGbeΐ^L/bhue to CCR6/Rluc8 included as a control. [000708] Figure 81. CC chemokine ligand 19 (CCL19)-induced recruitment of b- arrestin2/Venus proximal to ALCAM/Rluc8 in the presence of CC chemokine receptor 7 (CCR7). CCL19-induced recruitment of bqGGbeΐ^L/bhue to CCR7/Rluc8 included as a control.

[000709] Figure 8J. CXC chemokine ligand 8 (CXCL8)-induced recruitment of b- arrestin2/Venus proximal to ALCAM/Rluc8 in the presence of CXC chemokine receptor 2 (CXCR2). CXCL8-induced recruitment of bqGGbeΐ^L/bhue to CXCR2/Rluc8 included as a control.

[000710] Figure 8K. CXC chemokine ligand 16 (CXCL16)-induced recruitment of b- arrestin2/Venus proximal to ALCAM/Rluc8 in the presence of CXC chemokine receptor 6 (CXCR6). CXCL16-induced recruitment of bqGGbeΐ^L/bhue to CXCR6/Rluc8 included as a control.

[00071 1 ] Figure 8L. Somatostatin (SST)-induced recruitment of b-qh'beί^L/bhue proximal to ALCAM/Rluc8 in the presence of somatostatin receptor 3 (SSTR3). SST-induced recruitment of bqGGbeΐ^L/bhue to SSTR3/Rluc8 included as a control.

FIGURE 9

[000712] Figure 9A. Thyrotrophin-releasing hormone (TRFI)-induced change in BRET ratio observed between ALCAM/Rluc8 and Venus-tagged Thyrotrophin-releasing hormone receptor 1 (TRFIR1 /Venus; 100ng cDNA transfected/well of a 6-well plate). Lack of TRFI- induced change in BRET ratio when ALCAM/Rluc8 expressed in absence of TRFIR1 /Venus as a control.

[000713] Figure 9B. BRET saturation curve with ALCAM/Rluc8 and TRFIR1/Venus.

[000714] Figure 9C. Angiotensin II (Angll)-induced change in BRET ratio observed between ALCAM/Rluc8 and Venus-tagged Angiotensin II receptor 1 (ATi/Venus; 100ng cDNA transfected/well of a 6-well plate). Lack of Angll-induced change in BRET ratio when ALCAM/Rluc8 expressed in absence of ATi/Venus as a control.

[000715] Figure 9D. BRET saturation curves with ALCAM/Rluc8 and ATi/Venus in cells co transfected with pcDNA3 or ALCAM cDNA.

[000716] Figure 9E. BRET saturation curves with ALCAM/Rluc8 and ATi/Venus in cells co transfected with pcDNA3 or RAGE cDNA. [000717] Figure 9F. CXC chemokine ligand 12 (CXCL12) treatment reduces proximity of b- arrestin2/Venus to ALCAM/Rluc8 in the presence of CXC chemokine receptor 4 (CXCR4). CXCL12-induced recruitment of bqGGbeΐ^L/bhue to CXCR4/Rluc8 included as a control.

[000718] Figure 9G. CCL2-induced change in BRET ratio observed between ALCAM/Rluc8 and CCR2/Venus (100ng cDNA transfected/well of a 6-well plate). Lack of CCL2-induced change in BRET ratio when ALCAM/Rluc8 expressed in absence of CCR2/Venus as a control.

[000719] Figure 9H. BRET saturation curves with ALCAM/Rluc8 and CCR2/Venus in cells co-transfected with pcDNA3 or RAGE cDNA or ALCAM cDNA.

[000720] Figure 9I. BRET saturation curves with ALCAM/Rluc8 and CXCR6/Venus in cells co-transfected with pcDNA3 or RAGE cDNA or ALCAM cDNA.

[000721 ] Figure 9J. BRET saturation curves with ALCAM/Rluc8 and b2ABL/bhu5 in cells co-transfected with pcDNA3 or RAGE cDNA or ALCAM cDNA.

[000722] Figure 9K. BRET saturation curves with ALCAM/Rluc8 and AT i/Venus in cells co transfected with pcDNA3 or EPCAM cDNA.

[000723] Figure 9L. BRET saturation curves with ALCAM/Rluc8 and CCR2/Venus in cells co-transfected with pcDNA3 or EPCAM cDNA.

FIGURE 10

[000724] Figure 10A. Angll-induced recruitment of b-q beί^L/bhue proximal to human ALCAM/Rluc8 in the presence, but not in the absence, of ATi .

[000725] Figure 10B. Angll-induced recruitment of b-qh'beί^L/bhue proximal to mouse ALCAM/Rluc8 in the presence, but not in the absence, of ATi .

[000726] Figure 10C. Angll-induced recruitment of b-3hΌ5ίίh2/BIuo8 proximal to mouse ALCAM/Venus in the presence, but not in the absence, of ATi .

FIGURE 1 1

[000727] Figure 1 1 A. Angll-induced recruitment of b-qP'beί^L/bhue proximal to

EPCAM/Rluc8 in the presence, but not in the absence, of ATi .

[000728] Figure 1 1 B. Angll-induced recruitment of b-3hΌ5ίίh2/BIuo8 proximal to

EPCAM/Venus in the presence, but not in the absence, of ATi . [000729] Figure 1 1 C. Angll-induced change in BRET ratio observed between EPCAM/Rluc8 and ATi/Venus (100ng cDNA transfected/well of 6-well plate). Lack of Angll- induced change in BRET ratio when EPCAM/Rluc8 expressed in absence of ATi/Venus as a control.

[000730] Figure 1 1 D. BRET saturation curves with EPCAM/Rluc8 and ATi/Venus in cells co-transfected with pcDNA3 or RAGE cDNA or ALCAM cDNA.

[000731 ] Figure 1 1 E. BRET saturation curves with EPCAM/Rluc8 and CCR2/Venus in cells co-transfected with pcDNA3 or RAGE cDNA or ALCAM cDNA.

[000732] Figure 1 1 F. BRET saturation curves with EPCAM/Rluc8 and ATi/Venus in cells co-transfected with pcDNA3 or EPCAM cDNA.

[000733] Figure 1 1 G. BRET saturation curves with EPCAM/Rluc8 and CCR2/Venus in cells co-transfected with pcDNA3 or EPCAM cDNA.

FIGURE 12

[000734] Figure 12A. Angll-induced recruitment of b-qP'beί^L/bhue proximal to

CADM4/Rluc8 in the presence, but not in the absence, of ATi.

[000735] Figure 12B. Angll-induced recruitment of b-3hΌ5ίίh2/RIuo8 proximal to

CADM4/Venus in the presence, but not in the absence, of ATi.

[000736] Figure 12C. Angll-induced change in BRET ratio observed between

CADM4/Rluc8 and ATi/Venus (100ng cDNA transfected/well of 6-well plate). Lack of Angll- induced change in BRET ratio when CADM4/Rluc8 expressed in absence of ATi/Venus as a control.

[000737] Figure 12D. BRET saturation curves with CADM4/Rluc8 and ATi/Venus in cells co-transfected with pcDNA3 or RAGE cDNA or ALCAM cDNA.

[000738] Figure 12E. BRET saturation curves with CADM4/Rluc8 and CCR2/Venus in cells co-transfected with pcDNA3 or RAGE cDNA or ALCAM cDNA.

FIGURE 13

[000739] Figure 13A. BRET saturation curves with RAGE/Rluc8 and ATi/Venus in cells co transfected with pcDNA3 or ALCAM cDNA. [000740] Figure 13B. BRET saturation curves with RAGE/Rluc8 and CCR2/Venus in cells co-transfected with pcDNA3 or ALCAM cDNA.

[000741 ] Figure 13C. BRET saturation curves with RAGE/Rluc8 and CXCR6/Venus in cells co-transfected with pcDNA3 or ALCAM cDNA.

[000742] Figure 13D. BRET saturation curves with RAGE/Rluc8 and ATi/Venus in cells co transfected with pcDNA3 or EPCAM cDNA.

[000743] Figure 13E. BRET saturation curves with RAGE/Rluc8 and CCR2/Venus in cells co-transfected with pcDNA3 or EPCAM cDNA.

EXAMPLES

In each of the following examples independently, the following general materials and methods apply, unless the context requires otherwise.

Cell culture

[000744] Adult retinal pigment epithelial (ARPE) cells were cultured in Dulbecco's modified Eagle's medium (DMEM)/F12 endothelial cell growth supplement (ECGS) supplemented media. Chinese Hamster Ovary (CHO) cells were cultured using F12 media (10% FCS with 2mM glutamine). Human microvascular endothelial cells (HMEC) were cultured in MCDB 131 medium (10% FCS with 10mM glutamine, EGF and hydrocortisone).

Generation of transgenic Chinese Hamster Ovary Cells

[000745] 100ng of ATiR-Rluc8 construct was transfected into CHO cells using

Lipofectamine 2000 (Thermo). Stable transfectants were selected using G418. AT1R-CHO were then transiently transfected with the IgSF CAM and/or RAGE constructs using Lipofectamine 2000 (Invitrogen) and incubated for 16h.

Generation of oligonucleotides

[000746] Oligonucleotides were designed and ordered to generate the ALCAM, BCAM and MCAM intracellular (cytosolic) domains. These included a 5’ Nhel site, Kozak sequence and initiating Methionine and then DNA sequences corresponding to ALCAM residues 552-583, BCAM residues 569-628 and MCAM residues 584-637 respectively (Note that as residue 551 of ALCAM is Methionine, the cytosolic tail of ALCAM effectively corresponded to residues 551 - 583). The pCIneo parental vector was digested with Nhel and Notl restriction enzymes, and the DNA of the fragments of the ALCAM, BCAM and MCAM tails/cytosolic domains were ligated into the digested plasmid. After transformation and recovery, colonies were screened and individual clones sequenced. The sequence of the insert was confirmed by DNA sequencing (Micromon, Monash University). A full-length clone of Mouse ALCAM (BC027280) was purchased from Origene. The untagged clone was supplied in the vector pCMV6. Overlapping DNA sequences were ordered to generate the ALCAM559-580 fragment oligonucleotide. These included a 5’ Nhel site, Kozak sequence and initiating Methionine and then DNA sequences corresponding to ALCAM residues 559-580. The pCIneo parental vector was digested with Nhel and Notl restriction enzymes, and the ALCAM559-580 construct DNA was ligated into the digested plasmid. After transformation and recovery, colonies were screened and individual clones sequenced.

Cellular expression of pro-inflammatory markers and mediators by quantitative real-time PCR

[000747] After 2 hours of exposure to Ang II (1 mM) cells were placed in Trizol, mRNA extracted and cDNA synthesized. Changes in the gene expression of the NFKB subunit, p65 (RelA) or NFKB-activated target genes (e.g ICAM-1) were estimated by quantitative real-time RT-PCR, performed using the TaqMan system based on real-time detection of accumulated fluorescence (ABI Prism 7700, Perkin-Elmer Inc, PE Biosystems, Foster City, CA, USA). Gene expression was normalized to 18S mRNA and reported as fold change compared to the level of expression in untreated control mice/cells, which were given an arbitrary value of 1 .

Bioluminescence resonance energy transfer (BRET)

[000748] BRET is an established technology for studying protein-protein proximity in live cells, particularly involving GPCRs (Pfleger and Eidne, 2006). One protein of interest was linked to a bioluminescent donor enzyme, Rluc8, a variant of Renilla luciferase, and a second linked to an acceptor fluorophore, Venus, a variant of green fluorescent protein. If in close proximity (<10 nm), energy resulting from the rapid oxidation of a cell-permeable coelenterazine substrate by the donor can transfer to the acceptor, which in turn fluoresces at a longer characteristic wavelength.

[000749] Plasmids were transiently co-expressed in human embryonic kidney (HEK) 293FT cells and BRET measurements taken at 37°C using a CLARIOstar plate reader (BMG Labtech, Mornington, Victoria, Australia) with 420-480 nm (‘donor emission’) and 520-620 nm (‘acceptor emission’) filters.

[000750] The BRET ratio was calculated by subtracting the ratio of‘acceptor emission’ over ‘donor emission’ for a cell sample expressing Rluc8-tagged protein alone from the same ratio for a cell sample expressing both Rluc8 and Venus-tagged proteins. Alternatively, the ligand- induced BRET signal was calculated by subtracting the ratio of‘acceptor emission’ over‘donor emission’ for a vehicle-treated cell sample from the same ratio for a second aliquot of the same cells treated with agonist.

[000751 ] For the BRET kinetic assays, the final pre-treatment reading is presented at the zero time point (time of ligand/vehicle addition). For the BRET saturation assays, fluorescence after light excitation was measured on an EnVision 2102 multi-label plate reader (PerkinElmer, Glen Waverley, Victoria, Australia) using a 485/14 excitation filter, 535/25 emission filter and D505 mirror. The fluorescence/luminescence ratio was generated by dividing the fluorescence values in arbitrary units (obtained with the EnVision) by the luminescence values also in arbitrary units (obtained as part of the BRET assay).

[000752] For Receptor-FIIT assays, cells were transfected with a Rluc8-tagged CAM and b- arrestin2/Venus, or a Venus-tagged CAM and b-qP'beί^/RIuod. GPCRs untagged with respect to the BRET system were then co-expressed in the HEK293FT cells, or the cells were transfected with pcDNA3 as a control. These cells were then treated with an appropriate cognate agonist selective for the co-expressed GPCR, in order to promote recruitment of the BRET-tagged b-3hΌ3ίϊh2 to that GPCR. A ligand-induced BRET signal was indicative of recruitment of the BRET-tagged b-3hΌ3ίϊh2 proximal to the BRET-tagged CAM, thereby indicating close proximity between the CAM and the activated GPCR.

Statistics

[000753] Continuous data are expressed as mean ± SEM. Differences in the mean among groups were compared using 2-way ANOVA. Pair-wise multiple comparisons were made with Student-Newman-Keuls post-hoc analysis to detect significant differences between groups. P<0.05 was considered statistically significant.

EXAMPLE 1. TRANSACTIVATION OF THE CYTOSOLIC TAIL OF ALCAM BY A CO- LOCATED GPCR

[000754] This example shows that expression of the cytosolic tail of an IgSF CAM, specifically ALCAM ₅₅ I-583 (SEQ ID NO: 1 ), BCAM ₅₆ 9-628 (SEQ ID NO: 2), MCAM ₅₈ 4-637 (SEQ ID NO: 3), EpCAM ₂ 89-3i4 (SEQ ID NO: 4) or CADM4 _346-388 (SEQ ID NO: 5) enables Ang II to induce expression of the key pro-inflammatory transcription factor, p65-NFKB, in Chinese Hamster Ovary (CHO) cells expressing ATi R, providing evidence for IgSF CAM ligand-independent transactivation of the cytosolic tail of an IgSF CAM, following activation of a GPCR by its cognate ligand, specifically AT1 R by Ang II.

[000755] CHO cells express few cell surface receptors, and specifically do not express endogenous ATi R or IgSF CAMs on their surface, making them an ideal system to explore the role of the ATi R-lgSF CAM interaction. In addition, CHO cells do not express toll-like receptors (TLRs) that potentially have the capacity to bind ligands that also activate IgSF CAMs, and be activated by them (e.g. S100 proteins), resulting in activation of NFKB.

[000756] In the absence of expression of the AT 1 receptor, Ang II (1 mM) is unable to induce proinflammatory signaling, specifically the induction of p65 gene expression, in CHO cells (Figure 1 A), even in the presence of expression of IgSF CAMs or their cytosolic tails.

[000757] Stable transfection of CHO cells with the human ATi R gene (SEQ ID NO: 15) alone, generates AT1 R-CHO cells, and confers classical responsiveness to exogenous Ang II (1 mM), but not the ability for Ang II to induce expression of the pro-inflammatory transcription factor, p65-NFKB in AT1 R-CHO cells.

[000758] Transfection of AT1 R-CHO cells with an IgSF CAM, specifically full length human ALCAMI-583 (SEQ ID NO: 9), confers the ability of Ang II to induce expression of the pro- inflammatory transcription factor, p65-NFKB when compared to empty plasmid alone (pCIneo;

Figure 1 B).

[000759] Transfection of AT1 R-CHO cells with an IgSF CAM, specifically full length murine ALCAMi-583 (SEQ ID NO: 16), confers the ability of Ang II to induce expression of the pro- inflammatory transcription factor, p65-NFKB when compared to empty plasmid alone (pCIneo; Figure 1 C). T ransfection of AT 1 R-CHO cells with an IgSF CAM, specifically full length chicken EpCAM (SEQ ID NO: 17), also confers the ability of Ang II to induce expression of the pro- inflammatory transcription factor, p65-NFKB when compared to empty plasmid alone (pCIneo; Figure 1 D). Together these data exemplify that the transactivation mechanism described in this invention is not specific to the human species.

[000760] Transfection of ATi R-CHO cells with the cytosolic tail of a IgSF CAM, specifically human ALCAM _551-583 (SEQ ID NO: 1 ), also confers the ability of Ang II to induce expression of the pro-inflammatory transcription factor, p65-NFKB when compared to empty plasmid alone (pCIneo vector; Figure 1 E). [000761 ] Transfection of AT1 R-CHO cells with the cytosolic tail of another IgSF CAM, specifically specifically ALCAM _551-583 (SEQ ID NO: 1 ), BCAM _569-628 (SEQ ID NO: 2), MCAM _{584- 637} (SEQ ID NO: 3), EpCAM _289-3i4 (SEQ ID NO: 4) or CADM4 _346-388 (SEQ ID NO: 5) also confers the ability of Ang II to induce expression of the key pro-inflammatory transcription factor, p65- N FKB (Figure 1 F), when compared to empty plasmid alone (pCIneo vector).

[000762] T ransfection of AT 1 R-CFIO cells with another IgSF CAM cytosolic tail, specifically EpCAM ₂₈ 9-3i4 (SEQ ID NO: 4) or CADM4 _{3 6-388} (SEQ ID NO: 5) also confers the ability of Ang II to induce expression of the key pro-inflammatory transcription factor, p65-NFKB (Figure 1 G), and the p65-NFKB dependent induction of expression of proliferating cell nuclear antigen (PCNA) when compared to empty plasmid alone (pCIneo vector; Figure IH).

[000763] Serving as a positive control, transactivation of the cytosolic tail of RAGE _370-4 o ₄ following activation of the AT1 R by Ang II in AT 1 R-CFIO cells, also induces the expression of the key pro-inflammatory transcription factor, p65-NFKB (Figure IG).

[000764] As the IgSF CAM ligand-binding ectodomain is absent, this example demonstrates that the transactivation of any of the family of IgSF CAMs by activated co-located GPCR, specifically AT 1 R, is therefore IgSF CAM-ligand independent.

[000765] Although members of the same IgSF CAM family, the cytosolic tails of these proteins share limited sequence homology between each other. They also share limited sequence homology with the cytosolic tail of RAGE, with the one exception of CADM4 (sequence = QEGEAREAFLNGS) and RAGE ₃₇ 9- ₃ 9 ₂ (sequence = QEEEEERAELNQS).

EXAMPLE 2. MODULATION OF IGSF CAM LIGAND-INDEPENDENT TRANSACTIVATION OF AN IGSF CAM BY AN ACTIVATED CO-LOCATED GPCR IN HUMAN ARPE CELLS

[000766] This example describes using specific components of an IgSF CAM cytosolic tail, specifically ALCAM55i-58 ₃ (SEQ ID NO: 1 ), BCAM569-628 (SEQ ID NO: 2), or MCAMs8 ₄ -63 ₇ (SEQ ID NO: 3) to modulate IgSF CAM ligand-independent signalling induced in human ARPE cells following activation of a GPCR by its cognate ligand, specifically AT1 receptor by Ang II in human ARPE cells.

[000767] Unlike CHO cells, ARPE cells have a replete renin angiotensin aldosterone system including endogenous expression of the AT1 receptor. By contrast, endogenous expression of RAGE and IgSF CAMs is low or absent. [000768] Transfection of ARPE cells with only the cytosolic tail of an IgSF CAM, specifically ALC AM551 -583 (SEQ ID NO: 1 ), confers the ability of Ang II to induce pro-inflammatory signalling, exemplified by the NFKB-dependent induction in ICAM-1 gene expression, when compared to empty plasmid alone (pCIneo vector, Figure 2A).

[000769] Transfection of ARPE cells with only the cytosolic tail an IgSF CAM, specifically MCAM ₅ 84-637 (SEQ ID NO: 3) also confers the ability of Ang II to induce pro-inflammatory signalling, exemplified by the NFKB-dependent induction in ICAM-1 gene expression, when compared to empty plasmid alone (pCIneo vector, Figure 2B).

[000770] Transfection of ARPE cells with only the cytosolic tail an IgSF CAM, specifically BCAM _569-628 (SEQ ID NO: 2) or ALCAM _551-583 (SEQ ID NO: 1 ), confers the ability of Ang II to induce pro-inflammatory signalling, exemplified by the NFKB-dependent induction in ICAM-1 gene expression, when compared to empty plasmid alone (pCIneo vector; Figure 2C).

[000771 ] EXAMPLE 3. INHIBITION OF ACTIVATION OF IGSF CAMs WITH A SELECTIVELY TRUNCATED FORM OF THE CYTOSOLIC TAIL OF AN IGSF CAM

[000772] This example shows that a selectively-truncated construct of the cytosolic tail of an IgSF CAM, specifically ALCAM559-580, is able to inhibit IgSF CAM ligand-independent transactivation of the cytosolic tail of an IgSF CAM in CHO cells.

[000773] The cytoplasmic domain of human ALCAM contains two serines and two threonines. These are known to be dispensable for ALCAM-mediated adhesion (Zimmerman, Nelissen et al. 2004) and are not considered to be targets for PKC-mediated phosphorylation. However, without wishing to be bound by theory, the inventors believe these residues play a structural role in facilitating signalling mediated by the cytoplasmic tail leading to the induction of NFKB. Therefore an ALCAM construct was generated in which these serines and threonines were specifically omitted as a consequence of selective truncation of the cytosolic tail, generating ALCAM _559-58 o (SEQ ID NO: 6).

[000774] In AT1 R-CHO cells expressing human AT1 receptor, cotransfected with ALCAM559-580 (SEQ ID NO: 6), activation of the AT1 receptor by its cognate ligand, Ang II, failed to increase the expression of p65, confirming that this construct did not contain transactivatable targets, unlike the full cytoplasmic domain of ALCAM, specifically ALCAM551 - 583 (SEQ ID NO:1 ; Figure 3A).

[000775] Co-transfection with AT1 R-CHO cells with a selectively-truncated construct of the cytosolic tail of an IgSF CAM, specifically ALCAM559-580 (SEQ ID NO: 6) prevents induction in the expression of the key pro-inflammatory transcription factor, p65-NFKB (Figure 3B) and the p65-NFKB dependent induction of expression of proliferating cell nuclear antigen (PCNA; Figure 3C) induced by Ang II via AT1 R-dependent transactivation of full length ALCAM _{I -5} 83 when compared to empty plasmid alone (pCIneo vector).

[000776] Co-transfection with AT1R-CHO cells with a selectively-truncated construct of the cytosolic tail of an IgSF CAM, specifically ALCAM559-580 (SEQ ID NO: 6) prevents induction in the expression of the key pro-inflammatory transcription factor, p65-NFKB (Figure 3D) induced by Ang II via AT1 R-dependent transactivation of full length chicken EpCAM (SEQ ID NO: 17) when compared to empty plasmid alone (pCIneo vector).

[000777] Co-transfection with AT ₁ R-CHO cells with a selectively-truncated construct of the cytosolic tail of an IgSF CAM, specifically ALCAM _559-580 (SEQ ID NO: 6) prevents induction in the expression of the key pro-inflammatory transcription factor, p65-NFKB (Figure 3E) and the P65-NFKB dependent induction of expression of proliferating cell nuclear antigen (Figure 3F) induced by Ang II via AT 1 R-dependent transactivation of cytosolic tail of human ALCAM _551-583 (SEQ ID NO: 1 ) when compared to empty plasmid alone (pCIneo vector).

[000778] Co-transfection with AT ₁ R-CHO cells with a selectively-truncated construct of the cytosolic tail of an IgSF CAM, specifically ALCAM _559-580 (SEQ ID NO: 6) prevents induction in the expression of the key pro-inflammatory transcription factor, p65-NFKB (Figure 3G) induced by Ang II via AT1 R-dependent transactivation of the cytosolic tail of human ALCAM, specifically ALCAM _551-583 (SEQ ID NO: 1 ) when compared to empty plasmid alone (pCIneo vector).

[000779] Co-transfection with AT1R-CHO cells with a selectively-truncated construct of the cytosolic tail of an IgSF CAM, specifically ALCAM559-580 (SEQ ID NO: 6) prevents induction in the expression of the key pro-inflammatory transcription factor, p65-NFKB (Figure 3H) induced by Ang II via AT1 R-dependent transactivation of the cytosolic tail of human BCAM, specifically BCAM ₅ 69-628 (SEQ ID NO: 2) when compared to empty plasmid alone (pCIneo vector).

[000780] Co-transfection with AT ₁ R-CHO cells with a selectively-truncated construct of the cytosolic tail of an IgSF CAM, specifically ALCAM _559-580 (SEQ ID NO: 6) prevents induction in the expression of the key pro-inflammatory transcription factor, p65-NFKB (Figure 31) induced by Ang II via AT 1 R-dependent transactivation of the cytosolic tail of human MCAM, specifically MCAM _584-637 (SEQ ID NO: 3) when compared to empty plasmid alone (pCIneo vector). [000781 ] Co-transfection with AT1R-CHO cells with a selectively-truncated construct of the cytosolic tail of an IgSF CAM, specifically ALCAM559-580 (SEQ ID NO: 6) prevents induction in the expression of the key pro-inflammatory transcription factor, p65-NFKB (Figure 3J) induced by Ang II via AT1 R-dependent transactivation of the cytosolic tail of human EpCAM, specifically EpCAM ₂ 89-3i4 (SEQ ID NO: 4) when compared to empty plasmid alone (pCIneo vector).

[000782] These findings demonstrate the ability of peptides derived from the cytosolic tail of an IgSF CAM, specifically ALCAM _559-580 (SEQ ID NO: 6), to modulate pro-inflammatory signalling mediated by an IgSF CAM, specifically ALCAM, BCAM, MCAM, and EpCAM. Furthermore, this example demonstrates that IgSF CAM-ligand independent activation of an IgSF CAM, specifically ALCAM, BCAM, MCAM, and EpCAM, by activated co-located GPCR is inhibited by a fragment of the cytosolic tail of ALCAM, specifically ALCAM _559-580 (SEQ ID NO: 6).

[000783] EXAMPLE 4. MODULATION OF LIGAND-MEDIATED ACTIVATION OF IGSF CAMS WITH A SELECTIVELY TRUNCATED FORM OF THE CYTOSOLIC TAIL OF ALCAM OR RAGE _370-390 , AS WELL AS MODULATION OF LIGAND-MEDIATED ACTIVATION OF RAGE WITH A SELECTIVELY TRUNCATED FORM OF THE CYTOSOLIC TAIL OF ALCAM.

[000784] The ectodomain of IgSF CAMs may also be activated by extracellular ligands, triggering intracellular signalling mediated by their cytosolic tail. For example, the ectodomain of full length ALCAM may be activated by S100A8/A9 leading to NFKB-dependent induction of expression of proliferating cell nuclear antigen (PCNA; Figure 4A). This ligand-dependent signalling is not observed following transfection with inhibitory ALCAM or RAGE constructs in which the ectodomain has been deleted.

[000785] Ligand-dependent signalling via an activated IgSF CAM, specifically murine ALCAM, is inhibited by ALCAM559-580 (SEQ ID NO: 6).

[000786] Ligand-dependent signalling via an activated IgSF CAM, specifically ALCAM, is also inhibited by truncated peptides derived from the RAGE cytosolic tail, specifically RAGE370- ₃₉₀ (SEQ ID NO: 7).

[000787] The ectodomain of RAGE may also be activated by extracellular ligands, triggering intracellular signalling mediated by its cytosolic tail. For example, RAGE may be activated by S100A8/A9 leading to NFKB-dependent induction of expression of proliferating cell nuclear antigen (PCNA; Figure 4B). This ligand-dependent signalling via full length RAGE is also inhibited by ALCAM559-580 (SEQ ID NO: 6). [000788] These data demonstrate that ligand-dependent signalling mediated by full length IgSF CAMs, specficially activation of ALCAM _{I -5} 83 by S100A8/A9, can be modulated by peptides derived from the cytosolic tail of IgSF CAMs, specifically ALCAM _559-580 (SEQ ID NO: 6), or peptides derived from the cytosolic tail of RAGE, specifically RAGE _370-390 .

[000789] Furthermore, this example demonstrates that ligand-dependent activation of full length RAGE, specifically RAGEi- o4 by S100A8/A9, can also be modulated by a selectively- truncated construct of the cytosolic tail of an IgSF CAM, specifically ALCAM _559-580 (SEQ ID NO: 6).

[000790] EXAMPLE 5. MODULATION OF ACTIVATION OF IGSF CAMs WITH A SELECTIVELY TRUNCATED FORM OF THE CYTOSOLIC TAIL OF RAGE.

[000791 ] This example describes using specific components of the RAGE cytosolic tail, specifically RAGE _370-390 (SEQ ID NO: 7) to modulate ligand-dependent activation of an IgSF CAM, specifically by S100AA8/A9, as well as ligand-independent transactivation of an IgSF CAM induced following activation of a GPCR by its cognate ligand, specifically AT1 receptor by Ang II.

[000792] The RAGE cytosolic tail is not able to mediate proinflammatory signalling when residue Serine391 has been mutated or deleted. Consequently, when RAGE _370-390 (SEQ ID NO: 7) or RAGE _379-390 (SEQ ID NO: 21 ) is expressed in AT 1 R-CFIO cells, no induction of p65 expression is observed following exposure to S100A8/9 (Figure 4A) or Ang II (Figure 5A and B).

[000793] Co-transfection of ATi R-CFIO cells with a selectively-truncated construct of the cytosolic tail of RAGE, specifically RAGE379-390 (SEQ ID NO: 21 ) prevents induction of the expression of the key pro-inflammatory transcription factor, p65-NFKB induced by Ang II via AT1 R-dependent transactivation of the cytosolic tail of an IgSF CAM, specifically ALCAM551- ₅₈₃ (SEQ ID NO: 1 ), BCAM _569-628 (SEQ ID NO: 2), MCAM _584-637 (SEQ ID NO: 3), EpCAM _289-3i4 (SEQ ID NO: 4) or CADM4 _346-388 (SEQ ID NO: 5), when compared to empty plasmid alone (pCIneo vector; Figures 3G-K).

[000794] Transfection of ARPE cells with only the cytosolic tail of an IgSF CAM, specifically ALC AM551 -583 (SEQ ID NO: 1 ), confers the ability of Ang II to induce pro-inflammatory signalling, exemplified by the NFKB-dependent induction in ICAM-1 gene expression, when compared to empty plasmid alone (pCIneo vector). This signalling is inhibited by RAGE _370-390 (SEQ ID

NO: 7; Figure 2A). [000795] Transfection of ARPE cells with only the cytosolic tail an IgSF CAM, specifically MCAM ₅ 84-637 (SEQ ID NO: 3) also confers the ability of Ang II to induce pro-inflammatory signalling, exemplified by the NFKB-dependent induction in ICAM- 1 gene expression, when compared to empty plasmid alone (pCIneo vector). This signalling is also inhibited by RAGE370- 390 (SEQ ID NO: 7; Figure 2B).

[000796] Transfection of ARPE cells with only the cytosolic tail an IgSF CAM, specifically BCAM ₅ 69-628 (SEQ ID NO: 2) also confers the ability of Ang II to induce pro-inflammatory signalling, exemplified by the NFKB-dependent induction in ICAM- 1 gene expression, when compared to empty plasmid alone (pCIneo vector). This signalling is also inhibited by a S391 A- R AG E ₃ 62-404 oligopeptide encompassing the entire cytosolic tail of RAGE in which the serine391 residue required for transactivation has been mutated to alanine (S391 A-RAGE ₃₆ 2- 404; SEQ ID NO: 8 Figure 2C). The S391 A-RAGE362-404 oligopeptide also inhibited proinflammatory signalling induced by Ang II in ARPE cells mediated by the cytosolic tail of ALCAM (SEQ ID NO: 1 ; Figure 2C).

[000797] Taken together, these examples demonstrate that the IgSF CAM-ligand independent activation of IgSF CAM by activated co-located GPCR is inhibited by a derivative of RAGE.

[000798] Transfection of AT1 R-CHO cells with an IgSF CAM, specifically full length murine ALCAMI-583 (SEQ ID NO: 16), confers the ability of Ang II to induce expression of the pro- inflammatory transcription factor, p65-NFKB when compared to empty plasmid alone (pCIneo). This ligand-independent transactivation is also inhibited by R AG E370-390 (Figure 5B).

[000799] T ransfection of AT ₁ R-CHO cells with the cytosolic tail of an IgSF CAM, specifically human ALCAM _55i-583 (SEQ ID NO: 1 ), confers the ability of Ang II to induce expression of the pro-inflammatory transcription factor, p65-NFKB when compared to empty plasmid alone (pCIneo). This ligand-independent transactivation is also inhibited by RAGE _370-390 (Figure 1 E).

[000800] These findings demonstrate the ability of peptides derived from the RAGE cytosolic tail to modulate pro-inflammatory signalling mediated by the cytosolic tail of an IgSF CAM, and specifically the cytosolic tail of ALCAM. Furthermore, this example demonstrates that IgSF CAM-ligand independent transactivation of IgSF CAM by activated co-located GPCR is inhibited by a fragment of RAGE.

EXAMPLE 6. MODULATION OF RAGE LIGAND-INDEPENDENT ACTIVATION OF RAGE BY AN ACTIVATED CO-LOCATED GPCR IN HUMAN ARPE CELLS WITH A SELECTIVELY TRUNCATED FORM OF THE CYTOSOLIC TAIL OF ALCAM [000801 ] This example describes using a derivative of an IgSF CAM cytosolic tail, specifically ALCAM559-580 (SEQ ID NO: 6) to modulate RAGE ligand-independent signalling induced via transactivation of full length RAGE1-404 in human ARPE cells following activation of a GPCR by its cognate ligand.

[000802] Expression of ALCAM _559-580 (SEQ ID NO: 6) inhibits the induction of p65 expression mediated by full length human RAGE _1-404 following its transactivation by an activated co-located GPCR, specifically AT1 receptor activated by Ang II in AT1 R-CHO cells

(Figure 6A).

[000803] C5aR1 (SEQ ID NO: 18) is the receptor for complement 5a. Activation of the C5aR1 by its cognate ligand, C5a, increases the expression of ICAM-1 in ARPE, and this expression is increased in the presence of full length RAGE1-404 (Figure 6B).

[000804] Co-expression of a selectively truncated form of the cytosolic tail of ALCAM, specifically ALCAM559-580 (SEQ ID NO: 6) inhibits RAGE-dependent induction of the expression of ICAM-1 following the transactivation of RAGE by the C5a receptor 1.

[000805] These data demonstrate that constructs derived from the cytosolic tail of IgSF CAMs, specifically ALCAM559-580 (SEQ ID NO: 6), can modulate RAGE-dependent signalling initiated following activation of a co-located GPCR, specifically AT 1 R and C5aR1 .

EXAMPLE 7. FUNCTIONAL COMPETITION BETWEEN FULL LENGTH RAGE AND THE CYTOSOLIC TAILS OF IGSF CAMS

[000806] This example describes competition between the cytosolic tail of IgSF CAMs and the cytosolic tail of full length RAGE, with respect to transactivation by a co-located GPCR and the induction of downstream pro-inflammatory signalling.

[000807] T ransfection of AT 1 R-CHO cells with S391 A-RAGE1-404 fails to confer the ability of Ang II to induce expression of the pro-inflammatory transcription factor, p65-NFKB when compared to empty plasmid alone (pCIneo) as S391 A-RAGE is unable to be transactivated by a co-located GPCR, specifically the AT1 R by Ang II, as indicated by the expression of the key pro-inflammatory transcription factor, p65-NFKB (Figure 7A), and the p65-NFKB dependent induction of expression of proliferating cell nuclear antigen (PCNA) when compared to empty plasmid alone (pCIneo vector; Figure 7B).

[000808] In the presence of S391 A-RAGE1-404, over-expression of the cytosolic tail of an IgSF CAM, specifically ALCAM _55I -583 (SEQ I D NO: 1 ) or CADM4 ₃₃ 6-388 (SEQ I D NO: 5) is able to overcome inhibition of transactivation by full length mutant S391 A-RAGE and be transactivated themselves (Figure 7A and 7B). In particular, ALCAM551-583 (SEQ ID NO: 1 ) was transactivated by a co-located GPCR, specifically the AT1 R by Ang II, as indicated by the expression of the key pro-inflammatory transcription factor, p65-NFKB (Figure 7A), and the P65-NFKB dependent induction of expression of proliferating cell nuclear antigen when compared to empty plasmid alone (pCIneo vector; Figure 7B).

[000809] By contrast, transactivation of the cytosolic tail of an IgSF CAM, specifically ALCAM ₅₅ I-583 (SEQ ID NO: 1 ) or BCAM ₅₆ 9-628 (SEQ ID NO: 2), in ARPE cells, is inhibited by the S391 A-RAGE ₃ 62-404 oligopeptide (SEQ ID NO: 8; Figure 2C).

[000810] This example demonstrates that RAGE and IgSF CAMs share common intracellular signalling pathways mediated by their respective cytosolic tails.

[00081 1 ] EXAMPLE 8. BRET INDICATES CLOSE PROXIMITY OF IgSF CAM TO CERTAIN ACTIVATED GPCRS WHEN CO-EXPRESSED IN LIVE CELLS

[000812] In this example, we demonstrate close proximity between ALCAM and certain activated co-located GPCRs.

[000813] T reatment of cells co-expressing Rluc8-labelled GPCR and b-qh'beί^L/bhue with an appropriate cognate agonist for that GPCR resulted in the induction of a robust ligand- induced BRET signal consistent with recruitment of b-3GGb3ίϊh2 to the activated Rluc8-labelled GPCR. This was observed for V2R with AVP (Figure 8A), S1 PR1 with S1 P (Figure 8B), 2AR with isoproterenol (Figure 8C), OxR2 with OxA (Figure 8D), TRHR1 with TRH (Figure 8E), CCR1 with CCL3 (Figure 8F), CCR2 with CCL2 (Figure 8G), CCR6 with CCL20 (Figure 8H), CCR7 with CCL19 (Figure 8I), CXCR2 with CXCL8 (Figure 8J), CXCR6 with CXCL16 (Figure 8K) and SSTR3 with SST (Figure 8L).

[000814] Receptor-HIT: Treatment of cells co-expressing Rluc8-labelled ALCAM (ALCAM/Rluc8) and b-qh'beί^L/bhue in the presence of V2R (Figure 8A), S1 PR1 (Figure 8B), $2AR (Figure 8C), OxR2 (Figure 8D), TRHR1 (Figure 8E), CCR1 (Figure 8F), CCR2 (Figure 8G), CCR6 (Figure 8H), CCR7 (Figure 8I), CXCR2 (Figure 8J), CXCR6 (Figure 8K) and SSTR3 (Figure 8L) with the appropriate cognate agonist for that GPCR resulted in the induction of a clear ligand-induced BRET signal consistent with recruitment of b-qhΌeί^ to the GPCR. This in turn is indicative of ALCAM proximity to the activated GPCR.

[000815] EXAMPLE 9. BRET INDICATES CLOSE PROXIMITY OF IgSF CAM TO CERTAIN ACTIVATED GPCRS WHEN CO-EXPRESSED IN LIVE CELLS AND THIS PROXIMITY IS MODULATED BY GPCR LIGAND, AS WELL AS CO-EXPRESSION OF UNTAGGED IgSF CAM OR RAGE

[000816] In this example, we demonstrate close proximity between ALCAM and certain activated co-located GPCRs. Furthermore, we demonstrate that this proximity can be modulated by treatment with the cognate ligand for the GPCR. It can also be modulated with co-expression of untagged IgSF CAM, specifically ALCAM, or RAGE.

[000817] Treatment of cells expressing ALCAM/Rluc8 and TRHR1 /Venus with TRH reduced the BRET signal between them (Figure 9A), consistent with a decrease in proximity or relative orientation of the Rluc8 and Venus. Furthermore, co-expression of ALCAM/Rluc8 and TRHR1 /Venus resulted in a saturation curve indicative of close proximity (Figure 9B).

[000818] Treatment of cells expressing ALCAM/Rluc8 and ATi/Venus with Angll reduced the BRET signal between them (Figure 9C), consistent with a decrease in proximity or relative orientation of the Rluc8 and Venus. Furthermore, co-expression of ALCAM/Rluc8 and AT i/Venus resulted in a saturation curve indicative of close proximity (Figure 9D and 9E). This curve was flattened by co-expression with untagged ALCAM (Figure 9D) or RAGE (Figure 9E), consistent with ALCAM or RAGE competing with ALCAM/Rluc8 for interaction with AT i/Venus.

[000819] Treatment of cells co-expressing Rluc8-labelled ALCAM (ALCAM/Rluc8) and b- arrestin2/Venus in the presence of CXCR4 (Figure 9F) with CXCL12 resulted in the induction of a clear ligand-induced decrease in BRET signal consistent with a reduction in proximity between b-3GGb3ίϊh2 and ALCAM, or a conformational change resulting in less resonance energy transfer between Rluc8 and Venus. This in turn is indicative of a change in proximity of ALCAM to the activated GPCR to which the b-q beί^L/bhue is recruited.

[000820] T reatment of cells expressing ALCAM/Rluc8 and CCR2/Venus with CCL2 reduced the BRET signal between them (Figure 9G), consistent with a decrease in proximity or relative orientation of the Rluc8 and Venus. Furthermore, co-expression of ALCAM/Rluc8 and CCR2/Venus (Figure 9H), CXCR6/Venus (Figure 9I) or b2ARL/bhu5 (Figure 9J) resulted in saturation curves indicative of close proximity that were flattened by co-expression with untagged ALCAM or RAGE, consistent with ALCAM or RAGE competing with ALCAM/Rluc8 for interaction with the Venus-tagged GPCR.

[000821 ] Co-expression of ALCAM/Rluc8 and ATi/Venus (Figure 9K) or CCR2/Venus (Figure 9L) resulted in saturation curves indicative of close proximity that were flattened by co-expression with untagged EpCAM, consistent with EpCAM competing with ALCAM/Rluc8 for interaction with the Venus-tagged GPCR. [000822] This example demonstrated that there is specific proximity between IgSF CAM, specifically ALCAM, and certain GPCRs.

[000823] EXAMPLE 10. BRET INDICATES CLOSE PROXIMITY OF IgSF CAM, FROM DIFFERENT SPECIES, TO A GPCR, AND THAT IT IS OBSERVED USING DIFFERENT BRET ORIENTATIONS

[000824] In this example, we demonstrate that proximity to AT i is observed with both human and mouse ALCAM, as well as EpCAM, and with two configurations of BRET donor and acceptor.

[000825] Receptor-HIT: Treatment of cells co-expressing Rluc8-labelled ALCAM (ALCAM/Rluc8) and b-qh'beί^L/bhue resulted in an Angll-induced BRET signal in the presence, but not in the absence, of ATi with both human ALCAM (Figure 10A) and mouse ALCAM (Figure 10B). Treatment of cells co-expressing Venus-labelled mouse ALCAM (ALCAM/Venus) and b-q beί^/RIuod also resulted in an Angll-induced BRET signal in the presence, but not in the absence, of ATi (Figure 10C).

[000826] This example demonstrates that both human and mouse ALCAM exhibit proximity to ATi, indicating that it is observed with different species. This example also demonstrates that both BRET donor/acceptor orientations can detect proximity between IgSF CAM, specifically ALCAM, and GPCR, specifically ATi.

[000827] EXAMPLE 1 1 . BRET INDICATES CLOSE PROXIMITY OF EPCAM TO A GPCR AND THAT IT IS OBSERVED USING DIFFERENT BRET ORIENTATIONS

[000828] Receptor-HIT: Treatment of cells co-expressing Rluc8-labelled EpCAM (EpCAM/Rluc8) and b-qP'beί^L/bhiie resulted in an Angll-induced BRET signal in the presence, but not in the absence, of ATi (Figure 1 1 A). Treatment of cells co-expressing Venus-labelled EpCAM (EpCAM/Venus) and b-bh'beί^/RIuod also resulted in an Angll- induced BRET signal in the presence, but not in the absence, of ATi (Figure 1 1 B).

[000829] Treatment of cells expressing EpCAM/Rluc8 and ATi/Venus with Angll reduced the BRET signal between them (Figure 1 1 C), consistent with a decrease in proximity or relative orientation of the Rluc8 and Venus. Co-expression of EpCAM/Rluc8 and ATi/Venus (Figure 1 1 D and 1 1 F) or CCR2/Venus (Figure 1 1 E and 1 1 G) resulted in saturation curves indicative of close proximity. These curves were flattened by co-expression with untagged ALCAM or RAGE (Figure 1 1 D and 1 1 E) or EpCAM (Figure 1 1 F and 1 1 G), consistent with ALCAM, RAGE or EpCAM competing with EpCAM/Rluc8 for interaction with ATi/Venus. [000830] This example demonstrates that EpCAM also exhibits specific proximity to certain GPCRs, and this is observed with both orientations of BRET donor and acceptor.

[000831 ] EXAMPLE 12. BRET INDICATES CLOSE PROXIMITY OF CADM4 TO A GPCR AND THAT IT IS OBSERVED USING DIFFERENT BRET ORIENTATIONS

[000832] Receptor-HIT: Treatment of cells co-expressing Rluc8-labelled CADM4 (CADM4/Rluc8) and b-qh'beί^L/bhiie resulted in an Angll-induced BRET signal in the presence, but not in the absence, of ATi (Figure 12A). Treatment of cells co-expressing Venus-labelled CADM4 (CADM4/Venus) and b-bh'beί^/RIuod also resulted in an Angll- induced BRET signal in the presence, but not in the absence, of ATi (Figure 12B).

[000833] Treatment of cells expressing CADM4/Rluc8 and ATi/Venus with Angll reduced the BRET signal between them (Figure 1 2C), consistent with a decrease in proximity or relative orientation of the Rluc8 and Venus. Co-expression of CADM4/Rluc8 and ATi/Venus (Figure 12D) or CCR2/Venus (Figure 12E) resulted in saturation curves indicative of close proximity. These curves were flattened by co-expression with untagged ALCAM or RAGE, consistent with ALCAM or RAGE competing with CADM4/Rluc8 for interaction with AT i/Venus.

[000834] This example demonstrates that CADM4 also exhibits specific proximity to certain GPCRs, and this is observed with both orientations of BRET donor and acceptor.

[000835] EXAMPLE 13. BRET INDICATES CLOSE PROXIMITY OF RAGE TO A GPCR THAT IS REDUCED BY CO-EXPRESSION OF IGSF CAM

[000836] Co-expression of RAGE/Rluc8 and ATi/Venus (Figure 13A and 13D) or CCR2/Venus (Figure 13B and 13E) or CXCR6/Venus (Figure 13C) resulted in saturation curves indicative of close proximity. These curves were flattened by co-expression with untagged ALCAM (Figure 13A, 13B and 13C) or untagged EpCAM (Figure 13D and 13E), consistent with ALCAM or EpCAM competing with RAGE/Rluc8 for interaction with AT i/Venus.

[000837] This example demonstrates that RAGE also exhibits specific proximity to certain GPCRs and this is specifically reduced by IgSF CAMs.

BRIEF DESCRIPTION OF THE SEQUENCES

[000838] SEQ ID NO: 1 - Peptide sequence of cytosolic tail of ALCAM (corresponds to residues 551 -583 of ALCAM, with initial Methionine already present):

MKKSKTASKHVNKDLGNMEENKKLEENNHKTEA

[000839] SEQ ID NO: 2 - BCAM cytosolic tail sequence (corresponds to residues 569-628 of BCAM plus an initiating Methionine):

MYCVRRKGGPCCRQRREKGAPPPGEPGLSHSGSEQPEQTGLLMGGASGGARGGSGGF

GDEC

[000840] SEQ ID NO: 3 - MCAM cytosolic tail sequence (corresponds to residues 584-637 of MCAM plus an initiating Methionine):

MKKGKLPCRRSGKQEITLPPSRKSELVVEVKSDKLPEEMGLLQGSSGDKRAPGDQ

[000841 ] SEQ ID NO: 4 - EpCAM cytosolic tail sequence (corresponds to residues 289-314 of EpCAM plus an initiating Methionine):

MSRKKRMAKYEKAEIKEMGEMHRELNA

[000842] SEQ ID NO: 5 - CADM4 cytosolic tail sequence (corresponds to residues 346-388 of EpCAM plus an initiating Methionine):

MSVRQKGSYLTHEASGLDEQGEAREAFLNGSDGHKRKEEFFI

[000843] SEQ ID NO: 6 - Peptide sequence of ALCAM _559-580 (corresponds to residues 559- 580 of ALCAM plus an initiating Methionine): MKHVNKDLGNMEENKKLEENNHK

[000844] SEQ ID NO: 7 - Peptide sequence of RAGE _370-390 (corresponds to residues 370- 390 of RAGE plus an initiating Methionine): MGEERKAPENQEEEEERAELNQ

[000845] SEQ ID NO: 8 - Peptide sequence of S391 A-RAGE ₃₆ 2-404 (corresponds to residues 362-404 of RAGE with mutation of Serine 391 to Alanine plus an initiating Methionine): MLWQRRQRRGEERKAPENQEEEEERAELNQAEEPEAGESSTGGP

[000846] SEQ ID NO: 9 - Full length Human ALCAM (583 amino acids). GenBank: AAB59499.1 :

MESKGASSCRLLFCLLISATVFRPGLGWYTVNSAYGDTIIIPCRLDVPQNLMFGKWKYEK PD

GSPVFIAFRSSTKKSVQYDDVPEYKDRLNLSENYTLSISNARISDEKRFVCMLVTED NVFEA

PTIVKVFKQPSKPEIVSKALFLETEQLKKLGDCISEDSYPDGNITWYRNGKVLHPLE GAVVIIF

KKEMDPVTQLYTMTSTLEYKTTKADIQMPFTCSVTYYGPSGQKTIHSEQAVFDIYYP TEQVT

IQVLPPKNAIKEGDNITLKCLGNGNPPPEEFLFYLPGQPEGIRSSNTYTLMDVRRNA TGDYK CSLIDKKSMIASTAITVHYLDLSLNPSGEVTRQIGDALPVSCTISASRNATVVWMKDNIR LRS

SPSFSSLHYQDAGNYVCETALQEVEGLKKRESLTLIVEGKPQIKMTKKTDPSGLSKT IICHVE

GFPKPAIQWTITGSGSVINQTEESPYINGRYYSKIIISPEENVTLTCTAENQLERTV NSLNVSAI

SIPEHDEADEISDENREKVNDQAKLIVGIVVGLLLAALVAGVVYWLYMKKSKTASKH VNKDL

GNMEENKKLEENNHKTEA

[000847] SEQ ID NO: 10: Full length Human BCAM (628 amino acids). NP_005572.2.:

MEPPDAPAQARGAPRLLLLAVLLAAHPDAQAEVRLSVPPLVEVMRGKSVILDCTPTG THDH

YMLEWFLTDRSGARPRLASAEMQGSELQVTMHDTRGRSPPYQLDSQGRLVLAEAQVG DE

RDYVCVVRAGAAGTAEATARLNVFAKPEATEVSPNKGTLSVMEDSAQEIATCNSRNG NPA

PKITWYRNGQRLEVPVEMNPEGYMTSRTVREASGLLSLTSTLYLRLRKDDRDASFHC AAH

YSLPEGRHGRLDSPTFHLTLHYPTEHVQFWVGSPSTPAGWVREGDTVQLLCRGDGSP SP

EYTLFRLQDEQEEVLNVNLEGNLTLEGVTRGQSGTYGCRVEDYDAADDVQLSKTLEL RVA

YLDPLELSEGKVLSLPLNSSAVVNCSVHGLPTPALRWTKDSTPLGDGPMLSLSSITF DSNGT

YVCEASLPTVPVLSRTQNFTLLVQGSPELKTAEIEPKADGSWREGDEVTLICSARGH PDPKL

SWSQLGGSPAEPIPGRQGWVSSSLTLKVTSALSRDGISCEASNPHGNKRHVFHFGTV SPQ

TSQAGVAVMAVAVSVGLLLLVVAVF7YCVRRKGGPCCRQRREKGAPPPGEPGLSHSG SE

QPEQTGLLMGGASGGARGGSGGFGDEC

[000848] SEQ ID NO: 1 1 : Full length Human MCAM (646 amino acids). NP_006491 .2.:

MGLPRLVCAFLLAACCCCPRVAGVPGEAEQPAPELVEVEVGSTALLKCGLSQSQGNL SHV

DWFSVHKEKRTLIFRVRQGQGQSEPGEYEQRLSLQDRGATLALTQVTPQDERIFLCQ GKR

PRSQEYRIQLRVYKAPEEPNIQVNPLGIPVNSKEPEEVATCVGRNGYPIPQVIWYKN GRPLK

EEKNRVHIQSSQTVESSGLYTLQSILKAQLVKEDKDAQFYCELNYRLPSGNHMKESR EVTV

PVFYPTEKVWLEVEPVGMLKEGDRVEIRCLADGNPPPHFSISKQNPSTREAEEETTN DNGV

LVLEPARKEHSGRYECQGLDLDTMISLLSEPQELLVNYVSDVRVSPAAPERQEGSSL TLTC

EAESSQDLEFQWLREETGQVLERGPVLQLHDLKREAGGGYRCVASVPSIPGLNRTQL VNV

AIFGPPWMAFKERKVWVKENMVLNLSCEASGHPRPTISWNVNGTASEQDQDPQRVLS TLN

VLVTPELLETGVECTASNDLGKNTSILFLELVNLTTLTPDSNTTTGLSTSTASPHTR ANSTST

ERKLPEPESRGVVIVAVIVCILVLAVLGAVLYFLYKKGKLPCRRSGKQEITLPPSRK SELVVEV

KSDKLPEEMGLLQGSSGDKRAPGDQGEKYIDLRH

[000849] SEQ ID NO: 12: Full length Human EpCAM (314 amino acids).

MAPPQVLAFGLLLAAATATFAAAQEECVCENYKLAVNCFVNNNRQCQCTSVGAQNTV ICSK

LAAKCLVMKAEMNGSKLGRRAKPEGALQNNDGLYDPDCDESGLFKAKQCNGTSMCWC V

NTAGVRRTDKDTEITCSERVRTYWIIIELKHKAREKPYDSKSLRTALQKEITTRYQL DPKFITSI

LYENNVITIDLVQNSSQKTQNDVDIADVAYYFEKDVKGESLFHSKKMDLTVNGEQLD LDPG QTLIYYVDEKAPEFSMQGLKAGVIAVIVVVVIAVVAGIVVLVISRKKRMAKYEKAEIKEM GEM

HRELNA

[000850] SEQ ID NO: 13: Full length Human CADM4 (388 amino acids).

MGRARRFQWPLLLLWAAAAGPGAGQEVQTENVTVAEGGVAEITCRLHQYDGSIVVIQ NPA

RQTLFFNGTRALKDERFQLEEFSPRRVRIRLSDARLEDEGGYFCQLYTEDTHHQIAT LTVLV

APENPVVEVREQAVEGGEVELSCLVPRSRPAATLRWYRDRKELKGVSSSQENGKVWS VA

STVRFRVDRKDDGGIIICEAQNQALPSGHSKQTQYVLDVQYSPTARIHASQAVVREG DTLVL

TCAVTGNPRPNQIRWNRGNESLPERAEAVGETLTLPGLVSADNGTYTCEASNKHGHA RAL

YVLVVYDPGAVVEAQTSVPYAIVGGILALLVFLIICVLVGMVWCSVRQKGSYLTHEA SGLDE

QGEAREAFLNGSDGHKRKEEFFI

[000851 ] SEQ ID NO: 14 - Full length polypeptide sequence of RAGE (404 amino acids), UniProtKB Accession No. Q15109:

MAAGTAVGAWVLVLSLWGAVVGAQNITARIGEPLVLKCKGAPKKPPQRLEWKLNTGRTEA

WKVLSPQGGGPWDSVARVLPNGSLFLPAVGIQDEGIFRCQAMNRNGKETKSNYRVRV YQI

PGKPEIVDSASELTAGVPNKVGTCVSEGSYPAGTLSWHLDGKPLVPNEKGVSVKEQT RRH

PETGLFTLQSELMVTPARGGDPRPTFSCSFSPGLPRHRALRTAPIQPRVWEPVPLEE VQLV

VEPEGGAVAPGGTVTLTCEVPAQPSPQIHWMKDGVPLPLPPSPVLILPEIGPQDQGT YSCV

ATHSSHGPQESRAVSISIIEPGEEGPTAGSVGGSGLGTLALALGILGGLGTAALLIG VILWQR

RQRRGEERKAPENQEEEEERAELNQSEEPEAGESSTGGP

[000852] SEQ ID NO: 15 - Full length polypeptide sequence of human AT1 R, UniProtKB Accession No. P30556:

MILNSSTEDGIKRIQDDCPKAGRHNYIFVMIPTLYSIIFVVGIFGNSLVVIVIYFYMKLK TVASVF

LLNLALADLCFLLTLPLWAVYTAMEYRWPFGNYLCKIASASVSFNLYASVFLLTCLS IDRYLAI

VHPMKSRLRRTMLVAKVTCIIIWLLAGLASLPAIIHRNVFFIENTNITVCAFHYESQ NSTLPIGL

GLTKNILGFLFPFLIILTSYTLIWKALKKAYEIQKNKPRNDDIFKIIMAIVLFFFFS WIPHQIFTFLD

VLIQLGIIRDCRIADIVDTAMPITICIAYFNNCLNPLFYGFLGKKFKRYFLQLLKYI PPKAKSHSN

LSTKMSTLSYRPSDNVSSSTKKPAPCFEVE

[000853] SEQ ID NO: 16 - Full length polypeptide sequence of mouse (murine) ALCAM, UniProtKB Accession No. Q61490:

MASKVSPSCRLVFCLLISAAVLRPGLGWYTVNSAYGDTIVMPCRLDVPQNLMFGKWKYEK

PDGSPVFIAFRSSTKKSVQYDDVPEYKDRLSLSENYTLSIANAKISDEKRFVCMLVT EDNVF

EAPTLVKVFKQPSKPEIVNKAPFLETDQLKKLGDCISRDSYPDGNITWYRNGKVLQP VEGEV

AILFKKEIDPGTQLYTVTSSLEYKTTRSDIQMPFTCSVTYYGPSGQKTIYSEQEIFD IYYPTEQ

VTIQVLPPKNAIKEGDNITLQCLGNGNPPPEEFMFYLPGQPEGIRSSNTYTLTDVRR NATGD YKCSLIDKRNMAASTTITVHYLDLSLNPSGEVTKQIGDTLPVSCTISASRNATVVWMKDN IRL

RSSPSFSSLHYQDAGNYVCETALQEVEGLKKRESLTLIVEGKPQIKMTKKTDPSGLS KTIICH

VEGFPKPAIHWTITGSGSVINQTEESPYINGRYYSKIIISPEENVTLTCTAENQLER TVNSLNV

SAISIPEHDEADDISDENREKVNDQAKLIVGIVVGLLLAALVAGVVYWLYMKKSKTA SKHVNK

DLGNMEENKKLEENNHKTEA

[000854] SEQ ID NO: 17 - Full length polypeptide sequence of chicken EpCAM, UniProtKB

Accession No. A0A1 D5PWY3 with two polymorphisms (E94G and T158I):

MELLRGAALLLLLCAAACAQDSCTCTKNKRVTNCKLIDNVCHCNSIGSSVSVNCEILTSK CLL

MKAEMANTKSGRREKPKDALQDTDGLYDPECGNNGLFKAKQCNGTTCWCVNTAGVRR T

DKHDTDLKCNQLVRTTWIIIEMRHAERKTPLNAESLIRYLKDTITSRYMLDGRYISG VVYENP

TITIDLKQNSSDKTPGDVDITDVAYYFEKDVKDDSIFLNNKLNMNIDNEELKFDNMM VYYVDE

VPPEFSMKSLTAGVIAVIVIVVLAIVAGIIGLVLSRRRKGKYVKAEMKEMNEMHRGL NA

[000855] SEQ ID NO: 18 - Full length polypeptide sequence of human C5aR1 , UniProtKB Acession No. P21730:

MNSFNYTTPDYGHYDDKDTLDLNTPVDKTSNTLRVPDILALVIFAVVFLVGVLGNALVVW VT

AFEAKRTINAIWFLNLAVADFLSCLALPILFTSIVQHHHWPFGGAACSILPSLILLN MYASILLL

ATISADRFLLVFKPIWCQNFRGAGLAWIACAVAWGLALLLTIPSFLYRVVREEYFPP KVLCGV

DYSHDKRRERAVAIVRLVLGFLWPLLTLTICYTFILLRTWSRRATRSTKTLKVVVAV VASFFIF

WLPYQVTGIMMSFLEPSSPTFLLLNKLDSLCVSFAYINCCINPIIYVVAGQGFQGRL RKSLPS

LLRNVLTEESVVRESKSFTRSTVDTMAQKTQAV

[000856] SEQ ID NO: 31 - Peptide sequence of RAGE _362-404 (corresponds to residues 362- 404 of RAGE): LWQRRQRRGEERKAPENQEEEEERAELNQSEEPEAGESSTGGP

CONCLUSIONS

[000857] Activation of certain co-located GPCRs by their cognate ligands, such as activation of AT1 R by Ang II, triggers inflammation through pathways distinct from classical canonical signalling via GPCRs that induce, for example, calcium influx, inositol phosphate synthesis and activation of PKA. Here, the inventors show that ligand-independent activation of the cytosolic tail of IgSF CAM, specifically ALCAM, BCAM and MCAM can trigger activation of NFKB and NFKB-dependent signalling following activation of certain co-located GPCRs by their cognate ligands.

[000858] Even though the ectodomain has historically been considered to be essential for functions of IgSF CAMs and their superfamily members, without wishing to be bound by theory, the inventors believe the ligand-independent activation of the cytosolic tail of IgSF CAM superfamily members by certain activated co-located GPCRs is an important mechanism inducing downstream effector activation and signalling.

[000859] The inventors show that in CHO cells and ARPE cells proinflammatory signalling mediated by the cytosolic tail of IgSF CAM superfamily members can be selectively inhibited by non-signalling peptides derived from the cytosolic tail of RAGE, specifically RAGE ₃ o- ₃ 9oand S391 A-RAGE ₃ 62-404. These peptides are able to inhibit proinflammatory signalling following the activation of the AT1 receptor by Ang II that is mediated by the cytosolic tail of IgSF CAMs, specifically ALCAM, BCAM and MCAM.

[000860] Furthermore, the inventors demonstrate that non-signaling peptides derived from the cytosolic tail of IgSF CAMs, specifically ALCAM, have the capacity to modulate signalling mediated by full length RAGE.

[000861 ] The disclosure of every patent, patent application, and publication cited herein is hereby incorporated herein by reference in its entirety.

[000862] The citation of any reference herein should not be construed as an admission that such reference is available as“Prior Art” to the instant application.

[000863] Throughout this specification, unless the context requires otherwise, the word "comprise" or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

[000864] Throughout the specification the aim has been to describe the preferred embodiments of the invention without limiting the invention to any one embodiment or specific collection of features. Those of skill in the art will therefore appreciate that, in light of the instant disclosure, various modifications and changes can be made in the particular embodiments exemplified without departing from the scope of the present invention. All such modifications and changes are intended to be included within the scope of the appended claims.

[000865] As used herein,“isolated” when describing a peptide modulator of the invention means a peptide described herein that is not in a natural state (e.g. it is disassociated from a larger protein molecule or cellular debris in which it naturally occurs or is normally associated with), or is a non-naturally occurring fragment of a naturally occurring protein (e.g. the peptide comprises less than 25%, preferably less than 10% and most preferably less than 5% of the naturally occurring protein). Isolated also may mean that the amino acid sequence of the peptide does not occur in nature, for example, because the sequence is modified from a naturally occurring sequence (e.g. by alteration of certain amino acids, including basic (i.e. cationic) amino acids such as arginine, tryptophan, or lysine), or because the sequence does not contain flanking amino acids which are present in nature. The term“isolated” may mean that the peptide or amino acid sequence is a man-made sequence or polypeptide and may be non-naturally occurring.

[000866] Likewise, “isolated” as used in connection with nucleic acids which encode peptides embraces all of the foregoing, e.g. the isolated nucleic acids are disassociated from adjacent nucleotides with which they are associated in nature, and can be produced recombinantly, synthetically, by purification from biological extracts, and the like. Isolated nucleic acids can contain a portion that encodes one of the foregoing peptides and another portion that codes for another peptide or protein. The isolated nucleic acids also can be labeled. The nucleic acids include codons that are preferred for animal, bacterial, plant, or fungal usage. In certain embodiments, the isolated nucleic acid is a vector, such as an expression vector, which includes a nucleic acid that encodes one of the foregoing isolated peptides. A general method for the construction of any desired DNA sequence is provided, e.g., in Brown J. et al. (1979), Methods in Enzymology, 68:109; Sambrook J, Maniatis T (1989), supra.

[000867] The term“amino acid” or“residue” as used herein includes any one of the twenty naturally-occurring amino acids, the D-form of any one of the naturally-occurring amino acids, non-naturally occurring amino acids, and derivatives, analogues and mimetics thereof. Any amino acid, including naturally occurring amino acids, may be purchased commercially or synthesized by methods known in the art. Examples of non-naturally-occurring amino acids include norleucine (“Nle”), norvaline (“Nva”), b-Alanine, L- or D-naphthalanine, ornithine (“Orn”), homoarginine (homoArg) and others well known in the peptide art, including those described in M. Bodanzsky, “Principles of Peptide Synthesis,” 1st and 2nd revised ed., Springer-Verlag, New York, N.Y., 1984 and 1993, and Stewart and Young, “Solid Phase Peptide Synthesis,” 2nd ed., Pierce Chemical Co., Rockford, III., 1984, both of which are incorporated herein by reference.

[000868] Common amino acids may be referred to by their full name, standard single-letter notation (lUPAC), or standard three-letter notation for example: A, Ala, alanine; C, Cys, cysteine; D, Asp, aspartic acid (aspartate); E, Glu, glutamic acid (glutamate); F, Phe, phenylalanine; G, Gly, glycine; H, His, histidine; I, lie isoleucine; K, Lys, lysine; L, Leu, leucine; M, Met, methionine; N, Asn, asparagine; P, Pro, proline; Q, Gin, glutamine; R, Arg, arginine; S, Ser, serine; T, Thr, threonine; V, Val, valine; W, Trp, tryptophan; X, Hyp, hydroxyproline; Y, Tyr, tyrosine. Any and all of the amino acids in the compositions herein can be naturally occurring, synthetic, and derivatives or mimetics thereof.

[000869] Non-peptide analogues of peptides, e.g., those that provide a stabilized structure or lessened biodegradation, are also contemplated. Peptide mimetic analogues can be prepared based on a selected peptide by replacement of one or more residues by non-peptide moieties. Preferably, the non-peptide moieties permit the peptide to retain its natural conformation, or stabilize a preferred, e.g., bioactive, conformation. One example of methods for preparation of non-peptide mimetic analogues from peptides is described in Nachman et al., Regul. Pept. 57:359-370 (1995). The term“peptide” as used herein embraces all of the foregoing.

[000870] As mentioned above, the peptide of the present invention may be composed either of naturally occurring amino acids, i.e. L-amino acids, or of D-amino acids, i.e. of an amino acid sequence comprising D-amino acids in retro-inverso order as compared to the native sequence. The term“retro-inverso” refers to an isomer of a linear peptide in which the direction of the sequence is reversed and the chirality of each amino acid residue is inverted. Thus, any sequence herein, being present in L-form is also inherently disclosed herein as a D- enantiomeric (retro-inverso) peptide sequence. D-enantiomeric (retro-inverso) peptide sequences according to the invention can be constructed, e.g. by synthesizing a reverse of the amino acid sequence for the corresponding native L-amino acid sequence. In D-retro- inverso enantiomeric peptides, e.g. a component of the isolated peptide, the positions of carbonyl and amino groups in each single amide bond are exchanged, while the position of the side-chain groups at each alpha carbon is preserved.

[000871 ] Preparation of a component of the isolated peptide modulators of embodiments of the invention as defined above having D-enantiomeric amino acids can be achieved by chemically synthesizing a reverse amino acid sequence of the corresponding naturally occurring L-form amino acid sequence or by any other suitable method known to a skilled person. Alternatively, the D-retro-inverso-enantiomeric form of a peptide or a component thereof may be prepared using chemical synthesis as disclosed above utilizing an L-form of an peptide or a component thereof as a matrix for chemical synthesis of the D-retro-inverso- enantiomeric form.

[000872] Various changes may be made including the addition of various side groups that do not affect the manner in which a peptide modulator of embodiments of the invention functions, or which favourably affect the manner in which a peptide modulator of embodiments of the invention functions. Such changes may involve adding or subtracting charge groups, substituting amino acids, adding lipophilic moieties that do not affect binding but that affect the overall charge characteristics of the peptide modulator of embodiments of the invention facilitating delivery across the blood-brain barrier, etc. For each such change, no more than routine experimentation is required to test whether the molecule functions according to the invention. One simply makes the desired change or selects the desired peptide and applies it in a fashion as described in detail in the examples.

[000873] In one form of the invention, the term“sequence identity” as defined herein means that the sequences are compared as follows. To determine the percent identity of two amino acid sequences, the sequences can be aligned for optimal comparison purposes (e.g., gaps can be introduced in the sequence of a first amino acid sequence). The amino acids at corresponding amino acid positions can then be compared. When a position in the first sequence is occupied by the same amino acid as the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences. For example, where a particular peptide is said to have a specific percent identity to a reference polypeptide of a defined length, the percent identity is relative to the reference peptide. Thus, a peptide that is 50% identical to a reference polypeptide that is 100 amino acids long can be a 50 amino acid polypeptide that is completely identical to a 50 amino acid long portion of the reference polypeptide. It might also be a 100 amino acid long polypeptide, which is 50% identical to the reference polypeptide over its entire length. Such a determination of percent identity of two sequences can be accomplished using a mathematical algorithm.

[000874] A preferred, non-limiting example of a mathematical algorithm utilized for the comparison of two sequences is the algorithm of Karlin et al. (1993), PNAS USA, 90:5873- 5877. Such an algorithm is incorporated into the NBLAST program, which can be used to identify sequences having the desired identity to the amino acid sequence of the invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al., (1997), Nucleic Acids Res, 25:3389-3402. When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., NBLAST) can be used. The sequences further may be aligned using Version 9 of the Genetic Computing Group's GAP (global alignment program), using the default (BLOSUM62) matrix (values-4 to +1 1) with a gap open penalty of -12 (for the first null of a gap) and a gap extension penalty of -4 (per each additional consecutive null in the gap). After alignment, percentage identity is calculated by expressing the number of matches as a percentage of the number of amino acids in the claimed sequence. The described methods of determination of the percent identity of two amino acid sequences can be applied correspondingly to nucleic acid sequences.

[000875] In one embodiment a peptide modulator of embodiments of the invention may be linked directly or via a linker. A“linker” in the present context is usually a peptide, oligopeptide or polypeptide and may be used to link multiples of the peptides to one another. The peptides of the invention selected to be linked to one another can be identical sequences, or are selected from any of the peptides of the invention. A linker can have a length of 1 -10 amino acids, more preferably a length of 1 to 5 amino acids and most preferably a length of 1 to 3 amino acids. In certain embodiments, the linker is not required to have any secondary structure forming properties, i.e. does not require a a-helix or b-sheet structure forming tendency, e.g. if the linker is composed of at least 35% of glycine residues. As mentioned hereinbefore, a linker can be a cleavable peptide such as an MMP peptide which can be cleaved intracellularly by normal cellular processes, effectively raising the intracellular dose of the previously linked peptides, while keeping the extracellular dose low enough to not be considered toxic. The use of a(n) intracellularly/endogenously cleavable peptide, oligopeptide, or polypeptide sequence as a linker permits the peptides to separate from one another after delivery into the target cell. Cleavable oligo- or polypeptide sequences in this context also include protease cleavable oligo- or polypeptide sequences, wherein the protease cleavage site is typically selected dependent on the protease endogenously expressed by the treated cell. The linker as defined above, if present as an oligo- or polypeptide sequence, can be composed either of D-amino acids or of naturally occurring amino acids, i.e. L-amino acids. As an alternative to the above, coupling or fusion of the peptides can be accomplished via a coupling or conjugating agent, e.g. a cross-linking reagent.

[000876] There are several intermolecular cross-linking reagents which can be utilized, see for example, Means and Feeney, Chemical Modification of Proteins, Holden-Day, 1974, pp. 39-43. Among these reagents are, for example, N-succinimidyl 3-(2-pyridyldithio)propionate (SPDP) or N,N'-(1 ,3-phenylene)bismaleimide; N,N'-ethylene-bis-(iodoacetamide) or other such reagent having 6 to 1 1 carbon methylene bridges; and 1 ,5-difluoro-2, 4-dinitrobenzene. Other cross-linking reagents useful for this purpose include: p,p'-difluoro-m,m'- dinitrodiphenylsulfone; dimethyl adipimidate; phenol-1 ,4-disulfonylchloride; hexamethylenediisocyanate or diisothiocyanate, or azophenyl-p-diisocyanate; glutaraldehyde and disdiazobenzidine. Cross-linking reagents may be homobifunctional, i.e., having two functional groups that undergo the same reaction. A preferred homobifunctional cross-linking reagent is bismaleimidohexane (BMH). BMH contains two maleimide functional groups, which react specifically with sulfhydryl-containing compounds under mild conditions (pH 6.5-7.7). The two maleimide groups are connected by a hydrocarbon chain. Therefore, BMH is useful for irreversible cross-linking of proteins (or polypeptides) that contain cysteine residues. Cross-linking reagents may also be heterobifunctional. Heterobifunctional cross-linking reagents have two different functional groups, for example an amine-reactive group and a thiol-reactive group, that will cross-link two proteins having free amines and thiols, respectively. Examples of heterobifunctional cross-linking reagents are succinimidyl 4-(N- maleimidomethyl)cyclohexane-1 -carboxylate (SMCC), m-maleimidobenzoyl-N- hydroxysuccinimide ester (MBS), and succinimide 4-(p-maleimidophenyl)butyrate (SMPB), an extended chain analogue of MBS. The succinimidyl group of these cross-linking reagents with a primary amine, and the thiol-reactive maleimide forms a covalent bond with the thiol of a cysteine residue. Because cross-linking reagents often have low solubility in water, a hydrophilic moiety, such as a sulfonate group, may be added to the cross-linking reagent to improve its water solubility. Sulfo-MBS and sulfo-SMCC are examples of cross-linking reagents modified for water solubility. Many cross-linking reagents yield a conjugate that is essentially non-cleavable under cellular conditions. Therefore, some cross-linking reagents contain a covalent bond, such as a disulfide, that is cleavable under cellular conditions. For example, Traut's reagent, dithiobis (succinimidylpropionate) (DSP), and N-succinimidyl 3-(2- pyridyldithio)propionate (SPDP) are well-known cleavable cross-linkers. The use of a cleavable cross-linking reagent permits the peptides to be separated after delivery into the target cell, if desired, provided the cell is capable of cleaving a particular sequence of the crosslinker reagent. For this purpose, direct disulfide linkage may also be useful. Chemical cross-linking may also include the use of spacer arms. Spacer arms provide intramolecular flexibility or adjust intramolecular distances between conjugated moieties and thereby may help preserve biological activity. A spacer arm may be in the form of a protein (or polypeptide) moiety that includes spacer amino acids, e.g. proline. Alternatively, a spacer arm may be part of the cross-linking reagent, such as in“long-chain SPDP” (Pierce Chem. Co., Rockford, III., cat. No. 21651 H). Numerous cross-linking reagents, including the ones discussed above, are commercially available. Detailed instructions for their use are readily available from the commercial suppliers. A general reference on protein cross-linking and conjugate preparation is: Wong, Chemistry of Protein Conjugation and Cross-Linking, CRC Press (1991 ).

[000877] In one embodiment, peptide modulators may also contain a“derivative”,“variant”, or“functional fragment”, i.e. a sequence of a peptide that is derived from the naturally occurring (L-amino-acid) sequence of a peptide of the invention as defined above by way of substitution(s) of one or more amino acids at one or more sites of the amino acid sequence, by way of deletion(s) of one or more amino acids at any site of the naturally occurring sequence, and/or by way of insertion(s) of one or more amino acids at one or more sites of the naturally occurring peptide sequence.“Derivatives” shall retain their biological activity if used as peptides of the invention. Derivatives in the context of the present invention may also occur in the form of their L- or D-amino-acid sequences as defined above, or both.

[000878] If substitution(s) of amino acid(s) are carried out for the preparation of a derivative of the peptides of the invention, conservative (amino acid) substitutions are preferred. Conservative (amino acid) substitutions typically include substitutions within the following groups: glycine and alanine; valine, isoleucine and leucine; aspartic acid (aspartate) and glutamic acid (glutamate); asparagine and glutamine; serine and threonine; lysine and arginine; and phenylalanine and tyrosine. Thus, preferred conservative substitution groups are aspartate-glutamate; asparagine-glutamine; valine-leucine-isoleucine; alanine-valine; and phenylalanine-tyrosine. By such mutations e.g. stability and/or effectiveness of a peptide may be enhanced. If mutations are introduced into the peptide, the peptide remains (functionally) homologous, e.g. in sequence, in function, and in antigenic character or other function. Such mutated components of the peptide can possess altered properties that may be advantageous over the non-altered sequences of the peptides of the invention for certain applications (e.g. increased pH optimum, increased temperature stability etc.).

[000879] In one embodiment, a derivative of the peptide of the invention is defined as having substantial identity with the non-modified sequences of the peptide of the invention. Particularly preferred are amino acid sequences which have at least 30% sequence identity, preferably at least 50% sequence identity, even preferably at least 60% sequence identity, even preferably at least 75% sequence identity, even more preferably at least 80%, yet more preferably 90% sequence identity and most preferably at least 95% or even 99% sequence identity to the naturally occurring analogue. Appropriate methods for synthesis or isolation of a functional derivative of the peptides of the invention as well as for determination of percent identity of two amino acid sequences are described above. Additionally, methods for production of derivatives of the peptides as disclosed above are well known and can be carried out following standard methods which are well known by a person skilled in the art (see e.g., Sambrook J, Maniatis T (1989)).

[000880] As a further embodiment, the invention provides pharmaceutical compositions or medicaments comprising the modulators as defined herein. In certain embodiments, such pharmaceutical compositions or medicaments comprise the modulators as well as an optional linker, as defined herein.

[000881 ] Additionally, such a pharmaceutical composition or medicament can comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle. A“pharmaceutically acceptable carrier, adjuvant, or vehicle” according to the invention refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity or physiological targeting of the modulator with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the pharmaceutical compositions of this invention include, but are not limited to those that can be applied cranially or intracranially, or that can cross the blood- brain barrier (BBB). Notwithstanding this, the pharmaceutical compositions of the invention can include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[000882] The pharmaceutical compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, cerebrally, or via an implanted reservoir.

[000883] The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. The pharmaceutical compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the pharmaceutical compositions of this invention may be aqueous or oleaginous suspension. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1 ,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[000884] As such, any bland fixed oil may be employed including synthetic mono- or di glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[000885] The pharmaceutically acceptable compositions herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavouring or colouring agents may also be added.

[000886] Alternatively, the pharmaceutical composition as defined herein may be administered in the form of suppository for rectal administration. Such a suppository can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and, therefore, will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[000887] The pharmaceutical composition as defined herein may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the brain, other intra-cranial tissues, the eye, or the skin. Suitable formulations are readily prepared for each of these areas or organs.

[000888] For topical applications, the pharmaceutical composition as defined herein may be formulated in a suitable ointment containing modulators as identified herein, suspended or dissolved in one or more carriers. Carriers for topical administration of the peptide include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical composition as defined herein can be formulated in a suitable lotion or cream containing the peptide suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[000889] The pharmaceutical composition as defined herein may also be administered by nasal aerosol or inhalation. Such a composition may be prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents. The pharmaceutically acceptable composition or medicament herein is formulated for oral or parenteral administration, e.g. by injection.

[000890] For treatment purposes, a non-toxic, effective amount of the modulator may be used for preparation of a pharmaceutical composition as defined above. Therefore, an amount of the modulator may be combined with the carrier material(s) to produce a composition as defined above.

[000891 ] The pharmaceutical composition is typically prepared in a single (or multiple) dosage form, which will vary depending upon the host treated and the particular mode of administration. Usually, the pharmaceutical composition is formulated so that a dosage range per dose of 0.0001 to 100 mg/kg body weight/day of the peptide can be administered to a patient receiving the pharmaceutical composition. Preferred dosage ranges per dose vary from 0.01 mg/kg body weight/day to 50 mg/kg body weight/day, even further preferred dosage ranges per dose range from 0.1 mg/kg body weight/day to 10 mg/kg body weight/day.

[000892] However, dosage ranges and treatment regimens as mentioned above may be adapted suitably for any particular patient dependent upon a variety of factors, including the activity of the specific modulator employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician and the severity of the particular disease being treated. In this context, administration may be carried with in an initial dosage range, which may be varied over the time of treatment, e.g. by increasing or decreasing the initial dosage range within the range as set forth above. Alternatively, administration may be carried out in a continuous manner by administering a specific dosage range, thereby maintaining the initial dosage range over the entire time of treatment. Both administration forms may furthermore be combined, e.g. if the dosage range is to be adapted (increased or decreased) between various sessions of the treatment but kept constant within the single session so that dosage ranges of the various sessions differ from each other.

[000893] When used therapeutically, the modulators of the invention are administered in therapeutically effective amounts. In general, a therapeutically effective amount means an amount necessary to delay the onset of, inhibit the progression of, or halt altogether the particular condition being treated. Generally, a therapeutically effective amount will vary with the subject's age and condition, as well as the nature and extent of the disease in the subject, all of which can be determined by one of ordinary skill in the art. The dosage may be adjusted by the individual physician, particularly in the event of any complications being experienced. [000894] In one aspect, the invention provides for the use of the IgSF CAM modulators described herein for the manufacture of a medicament for treating, preventing or managing an IgSF CAM-related disorder in a patient in need of such treatment.

[000895] In one aspect, the invention provides a method for treating, preventing or managing an IgSF CAM-related disorder in a patient in need of such treatment, the method comprising administration of an effective amount of a modulator of an IgSF CAM.

[000896] In one aspect, the invention provides a method for treating, preventing or managing an IgSF CAM-related disorder in a patient in need of such treatment, characterised in that the IgSF CAM -related disorder is selected from the group: cardiovascular disorders; digestive disorders; cancers; neurological disorders; respiratory disorders; connective tissue disorders; kidney disorders; genital disorders; skin disorders; eye disorders; and endocrine disorders.

[000897] In one aspect, the invention provides a method for treating, preventing or managing an IgSF CAM-related disorder in a patient in need of such treatment, characterised in that the disorder is a cardiovascular disorder selected from the group: atherosclerosis, ischaemic heart disease, myocarditis, endocarditis, cardiomyopathy, acute rhematic fever, chronic rhematic heart disease, cerebrovascular disease/stroke, heart failure, vascular calcification, peripheral vascular disease, and lymphangitis.

[000898] In one aspect, the invention provides a method for treating, preventing or managing an IgSF CAM-related disorder in a patient in need of such treatment, characterised in that the disorder is a digestive system disorder selected from the group: periodontitis, oesophagitis, gastritis, gastro-duodenal ulceration, Crohn’s disease, ulcerative colitis, ischaemic colitis, enteritis and enterocolitis, peritonitis, alcoholic liver disease, hepatitis, toxic liver disease, biliary cirrhosis, hepatic fibrosis/cirrhosis, non-alcoholic fatty liver disease/non alcoholic steatohepatitis (NAFLD/NASFI), liver trauma and recovery from liver injury, trauma or surgery.

[000899] In one aspect, the invention provides a method for treating, preventing or managing an IgSF CAM-related disorder in a patient in need of such treatment, characterised in that the disorder is a cancer selected from the group: malignant neoplasms of lip, oral cavity and pharynx, malignant neoplasms of digestive organs, malignant neoplasms of respiratory and intrathoracic organs, malignant neoplasms of bone and articular cartilage, melanoma and other malignant neoplasms of skin, malignant neoplasms of mesothelial and soft tissue, malignant neoplasm of breast, malignant neoplasms of female genital organs, malignant neoplasms of male genital organs, malignant neoplasms of urinary tract, malignant neoplasms of eye, brain and other parts of central nervous system, malignant neoplasms of thyroid and other endocrine glands, malignant neoplasms of lymphoid, haematopoietic and related tissue, malignant neoplasms of ill-defined, secondary and/or unspecified sites.

[000900] In one aspect, the invention provides a method for treating, preventing or managing an IgSF CAM-related disorder in a patient in need of such treatment, characterised in that the disorder is a neurological disorder and is selected from the group: inflammatory diseases of the central nervous system, systemic atrophies primarily affecting the central nervous system, extrapyramidal and movement disorders, Parkinson’s disease, demyelinating diseases of the central nervous system, Alzheimer's disease, circumscribed brain atrophy, Lewy body disease, epilepsy, migraine, neuropathic pain, diabetic neuropathy, polyneuropathies, glioma development and progression, spinal cord trauma, and ischaemic brain injury/stroke, brain trauma and recovery from brain injury, trauma or surgery.

[000901 ] In one aspect, the invention provides a method for treating, preventing or managing an IgSF CAM-related disorder in a patient in need of such treatment, characterised in that the disorder is a mental disorder and is selected from the group: dementia, Alzheimer's disease, vascular dementia, addiction, schizophrenia, major affective disorder, depression, mania, bipolar disorder, and anxiety disorder.

[000902] In one aspect, the invention provides a method for treating, preventing or managing an IgSF CAM-related disorder in a patient in need of such treatment, characterised in that the disorder is a respiratory (pulmonary) disorder and is selected from the group: Acute upper respiratory infections, rhinitis, nasopharyngitis, sinusitis, laryngitis, influenza and pneumonia, acute bronchitis, acute bronchiolitis, asthma, chronic obstructive pulmonary disease (COPD), bronchiectasis, emphysema, chronic lung diseases due to external agents, Acute Respiratory Distress Syndrome (ARDS), pulmonary eosinophilia, and pleuritic, lung trauma and recovery from lung injury, trauma or surgery.

[000903] In one aspect, the invention provides a method for treating, preventing or managing an IgSF CAM-related disorder in a patient in need of such treatment, characterised in that the disorder is a connective tissue disorder and is selected from the group: osteoarthritis, infectious arthritis, rheumatoid arthritis, psoriatic and enteropathic arthropathies, juvenile arthritis, gout and other crystal arthropathies, diabetic arthropathy, polyarteritis nodosa, Churg-Strauss, mucocutaneous lymph node syndrome [Kawasaki], hypersensitivity angiitis, Goodpasture syndrome, thrombotic microangiopathy, Wegener granulomatosis, Aortic arch syndrome [Takayasu], giant cell arteritis, polymyalgia rheumatica, microscopic polyangiitis, hypocomplementaemic vasculitis, systemic lupus erythematosus, dermatopolymyositis, polymyositis, systemic sclerosis, CR(E)ST syndrome, Sicca syndrome [Sjogren], mixed connective tissue disease, Behget disease, traumatic muscle damage, sprain, strain, and fracture.

[000904] In one aspect, the invention provides a method for treating, preventing or managing an IgSF CAM-related disorder in a patient in need of such treatment, characterised in that the disorder is a kidney disorder and is selected from the group: glomerulonephritis, nephritis, diabetic kidney disease, interstitial nephritis, obstructive and reflux nephropathy, acute renal failure, and chronic kidney disease.

[000905] In one aspect, the invention provides a method for treating, preventing or managing an IgSF CAM-related disorder in a patient in need of such treatment, characterised in that the disorder is a genital disorder and is selected from the group: prostatitis, prostatic hypertrophy, prostatic dysplasia, salpingitis, oophoritis, pelvic inflammatory disease (RID), polycystic ovarian syndrome, cervicitis, cervical dysplasia, vaginitis, vulvitis.

[000906] In one aspect, the invention provides a method for treating, preventing or managing an IgSF CAM-related disorder in a patient in need of such treatment, characterised in that the disorder is a skin disorder selected from the group: dermatitis, eczema, pemphigus/pemphygoid, psoriasis, pityriasis rosea, lichen planus, urticarial, erythrema multiforme, erythema nordosum, sunburn, keratosis, photoageing skin ulceration, superficial skin injury, and open wound.

[000907] In one aspect, the invention provides a method for treating, preventing or managing an IgSF CAM-related disorder in a patient in need of such treatment, characterised in that the disorder is an eye disorder selected from the group: keratitis, conjunctivitis, retinitis, glaucoma, scleritis, episcleritis, chorioretinal inflammation, diabetic retinopathy, macular oedema, retinopathy of prematurity, and optic neuritis, eye trauma and recovery from eye injury, trauma or surgery.

[000908] In one aspect, the invention provides a method for treating, preventing or managing an IgSF CAM-related disorder in a patient in need of such treatment, characterised in that the disorder is an endocrine disorder selected from the group: diabetes mellitus, insulin resistance, impaired glucose tolerance and thyroiditis.

[000909] In one aspect, the invention provides a method for treating, preventing or managing an IgSF CAM-related disorder the method comprising administration of an effective amount of a combination of a modulator of an IgSF CAM with a modulator of the co-located GPCR and/or a modulator of the co-located GPCR signalling pathway, preferably wherein the modulator of the co-located GPCR and/or the modulator of the co-located GPCR signalling pathway is administered at a lower dose than normally administered for the treatment of a disorder related to the co-located GPCR, or wherein the modulator of the co-located GPCR and/or the modulator of the co-located GPCR signalling pathway is administered at a lower dose than normally administered for the treatment of a disorder related to IgSF CAM.

[000910] As mentioned above, one aspect of the invention relates to nucleic acid sequences and their derivatives which code for an isolated peptide modulator or variant thereof and other nucleic acid sequences which hybridize to a nucleic acid molecule consisting of the above described nucleotide sequences, under stringent conditions. The term“stringent conditions” as used herein refers to parameters with which the art is familiar. Nucleic acid hybridization parameters may be found in references which compile such methods, e.g. Molecular Cloning: A Laboratory Manual, J. Sambrook, et al., eds., Second Edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989, or Current Protocols in Molecular Biology, F. M. Ausubel, et al., eds., John Wiley & Sons, Inc., New York. More specifically, stringent conditions, as used herein, refers to hybridization at 65° C. in hybridization buffer (3.5xSSC, 0.02% Ficoll, 0.02% Polyvinyl pyrrolidone, 0.02% Bovine Serum Albumin, 25 mMNaH2P04 (pH7), 0.5% SDS, 2 mM EDTA). SSC is 0.15 M Sodium Chloride/0.15 M Sodium Citrate, pH 7; SDS is Sodium Dodecyl Sulphate; and EDTA is Ethylene diaminetetraacetic acid. After hybridization, the membrane upon which the DNA is transferred is washed at 2xSSC at room temperature and then at 0.1 xSSC/0.1 xSDS at 65 °C.

[00091 1 ] The present invention furthermore provides kits comprising the abovementioned pharmaceutical composition (in one or more containers) in at least one of the above formulations and an instruction manual or information brochure regarding instructions and/or information with respect to application of the pharmaceutical composition.

Type-1 angiotensin II receptor (ATiR) polypeptides

[000912] The G protein-dependent signalling by ATi R is vital for normal cardiovascular homeostasis, yet detrimental in chronic dysfunction, which associates with cell death and tissue fibrosis, and leads to cardiac hypertrophy and heart failure (Ma et al., 2010).

[000913] Despite its high medical relevance and decades of research, the structure of ATi R and the binding mode of well established ATi R blockers (ARBs) were only recently elucidated (Zhang et al., 2015). The structure indicated that the extracellular part of ATi R consists of the N-terminal segment ECL1 (Glu91 -Phe96 of the human ATi R) linking helices II and III, ECL2 (His166 to Me191 of the human ATi R) linking helices IV and V, and ECL3 (Ile270 to Cys274 of the human ATi R) linking helices VI to VII. Two disulphide bonds help to shape the extracellular side of ATi R with Cys18-Cys 274 connecting the N terminus and ECL3, and Cys101 -Cys180 connecting helix III and ECL2 (similar to the chemokine receptor CXCR4, which shares around 36% sequence identity with ATi R).

[000914] In specific embodiments of the present invention, the ATi R polypeptide comprises a ATi R protein sequence or shares at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity or similarity with an ATi R protein sequence.

[000915] In some embodiments, the ATi R protein sequence corresponds to a mammalian AT1 R protein sequence. Suitable ATi R sequences may suitably be from mammal selected from the group comprising human (UniProtKB Accession No. P30556), sheep (UniProtKB Accession No. 077590), cow (UniProtKB Accession No. P25104), rabbit (UniProtKB Accession No. P34976), guinea pig (UniProtKB Accession No. Q9WV26), pig (UniProtKB Accession No. P30555), chimpanzee (UniProtKB Accession No. Q9GLN9), gerbil (UniProtKB Accession No. 035210, rat (UniProtKB Accession No. P29089), mouse (UniProtKB Accession No. P29754), cat (UniProtKB Accession No. M3VVA2), Tasmanian devil (UniProtKB Accession No. G3W0M6), horse (UniProtKB Accession No. F7D1 N0), and panda (UniProtKB Accession No. D2HWD9).

[000916] In some preferred embodiments, the ATi R protein sequence corresponds to a human ATi R protein sequence. In some embodiments, the ATi R polypeptide comprises a human full-length wild-type ATi R protein sequence (UniProtKB Accession No. P30556), as set forth below, or a functional fragment of the wild-type ATi R protein sequence.

[000917] MILNSSTEDGIKRIQDDCPKAGRHNYIFVMIPTLYSIIFVVGIFGNSLVVIVIYFYMK LKTVASVFLLNLALADLCFLLTLPLWAVYTAMEYRWPFGNYLCKIASASVSFNLYASVFL LTC LSIDRYLAIVHPMKSRLRRTMLVAKVTCIIIWLLAGLASLPAIIHRNVFFIENTNITVCA FHYESQ NSTLPIGLGLTKNILGFLFPFLIILTSYTLIWKALKKAYEIQKNKPRNDDIFKIIMAIVL FFFFSWIP HQIFTFLDVLIQLGIIRDCRIADIVDTAMPITICIAYFNNCLNPLFYGFLGKKFKRYFLQ LLKYIPP KAKSHSNLSTKMSTLSYRPSDNVSSSTKKPAPCFEVE [SEQ ID NO: 15].

[000918] In one form of the invention, the ATi R polypeptide comprises a truncated form of a mammalian wild-type AT i R protein sequence. For example, the AT i R polypeptide sequence may comprise the human wild-type ATi R protein sequence with a C-terminal truncation (e.g., amino acid residues 320-359 may be truncated). Alternatively or in addition, the ATi R polypeptide sequence may comprise the wild-type ATi R protein sequence with a N-terminal truncation. Alternatively or in addition to a C-terminal or N-terminal truncation, a truncation may be performed to remove an internal section of the wild-type ATi R protein sequence (e.g., amino acid residues 7-16 may be truncated). By way of a non-limiting illustrative example, a ATi R polypeptide suitable for using with the present invention comprised amino acid residues 2-6 and 17-319 of the human wild-type ATi R protein sequence as set forth in SEQ ID NO: 15.

Constructs and nucleotide sequences encoding ATiR polypeptides

[000919] The present invention also encompasses isolated polynucleotide sequences and constructs encoding ATi R polypeptides as broadly described above and elsewhere herein. Also contemplated are host cells comprising those polynucleotide sequences or constructs.

[000920] In some embodiments, the polynucleotide sequences comprise a sequence that corresponds to a human ATi R nucleotide (i.e., corresponding to the AGTR1 gene) sequence as set forth for example in GenBank Accession Nos. KR71 1424.1 , KR71 1423.1 , KR71 1422.1 , KR71 1421 .1 , KJ896399.1 , KJ896398.1 , NM_032049.3, NM_031850.3, NM_004835.4, NM 000685.4, NM_009585.3, DQ895601 .2, BC068494.1 , BC022447.1 , DQ892388.2, and AK291541 .1 . In representative examples of this type, the polynucleotide comprises an ATi R nucleotide sequence that shares at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity with any one of these sequences.

[000921 ] In some embodiments, an ATi R polynucleotide coding sequence comprises a nucleotide sequence that encodes a polypeptide having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 92%, 95%, 99% or 100% sequence identity to a wild type mammalian ATi R polynucleotide, or a fragment thereof. In some embodiments, the ATi R polynucleotide comprises a nucleotide sequence that hybridises to an open reading frame for a wild type mammalian ATi R protein, or a fragment thereof under low, medium or high stringency conditions.

[000922] Those skilled in the field of the invention will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such functional variations and modifications. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations or any two or more of said steps or features. The present invention is not to be limited in scope by the specific embodiments described herein, which are intended for the purpose of exemplification only. Functionally-equivalent products, compositions and methods are clearly within the scope of the invention, as described herein. Furthermore, the present invention is performed without undue experimentation using, unless otherwise indicated, conventional techniques of molecular biology, microbiology, neurobiology, virology, recombinant DNA technology, peptide synthesis in solution, solid phase peptide synthesis, and immunology, or techniques cited herein.

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