AUTOANTIGENS FOR THE DIAGNOSTIC OF ENDOMETRIOSIS

Title:

AUTOANTIGENS FOR THE DIAGNOSTIC OF ENDOMETRIOSIS

Document Type and Number:

WIPO Patent Application WO/2000/047739

Kind Code:

A2

Abstract:

The invention pertains to a technique to discover auto-antigens found in patients having endometriosis. Furthermore, the invention comprises polypeptide auto-antigens which were discovered using this technique, as well as cDNA clones that encode these auto-antigens. Finally, the invention pertains to methods and diagnostic kits which utilize these polypeptides to detect endometriosis.

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Inventors:

DESAI DIPTY
KURN NURITH

Application Number:

PCT/US2000/002710

Publication Date:

August 17, 2000

Filing Date:

February 02, 2000

Export Citation:

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Assignee:

DADE BEHRING INC (US)

International Classes:

C07K14/47; C12N15/12; C12Q1/68; C12Q1/6883; (IPC1-7): C12N15/12; C07K14/47; C12Q1/68; G01N33/564

Domestic Patent References:

WO1994028021A1

1994-12-08

Other References:

ROBERT K. POPE ET AL.: "Cloning, characterization, and chromosomal localization of human Supervillin (SVIL)" GENOMICS, vol. 52, 1998, pages 342-351, XP000921000
KERSI N. PESTONJAMASP ET AL.: "Supervillin (p205): A novel membrane-associated, F-Actin-binding protein in the Villin/Gelsolin superfamily" JOURNAL OF CELL BIOLOGY, vol. 139, December 1997 (1997-12), pages 1255-1269, XP002140590
SUBBI PILLAI ET AL.: "Antibodies to endometrial transferrin and alpha 2-Heremans Schmidt (HS) glycoprotein in patients with endometriosis" AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, vol. 35, no. 5, 1996, pages 483-494, XP000910506
MICHAEL WALTER ET AL.: "Autoreactive epitopes within the human alpha-enolase and their recognition by sera from patients with endometriosis" JOURNAL OF AUTOIMMUNITY, vol. 8, no. 6, December 1995 (1995-12), pages 931-945, XP000911010

Attorney, Agent or Firm:

Ruszala, Lois K. (IL, US)
Zounek, Nikolai (Patentanwaltskanzlei Zounek Industriepark Kalle-Albert Rheingaustrasse 190 Wiesbaden, DE)

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Claims:

What is claimed is:

1.

A method for detecting endometriosis in a patient comprising detecting the presence of auto antibodies in said patient which bind to one or more polypeptides selected from the group consisting of a polypeptide comprising the amino acid sequence of SEQ ID NO: 1325, and fragments thereof having the same immunological specificity toward autoantibodies associated with endometriosis, wherein the presence of said antibodies is indicative of endometriosis in said patient.

2.	The method of claim 1 wherein said detection of said auto antibodies in said patient comprises: (a) combining body fluid from said pateint with said one or more polypeptides; (b) forming a complex between said autoantibodies and said one or more polypeptides; (c) detecting the complex.

3.

The method of claim 2 wherein said one or more polypeptides are selected from the group consisting of a polypeptide comprising the amino acid sequence of SEQ ID NO: 14,16,18, 23, and 25, and fragments thereof having the same immunological specificity toward auto antibodies associated with endometriosis.

4.

The method of claim 1 wherin the method is selected from the group consisting of radioimmunoassay, immunoprecipitation assay, enzymelinked immunoassay (ELISA), depletion enzymelinked immunoassay (DELISA), Western Blot, particle agglutination assay, luminescent oxygenchannelling immunoassay, proximitybased immunoassay, and biosensorbased immunoassay.

5.	A method for monitoring an endometriosis patient comprising periodically conducting the assay of claim 4.

6.	The method of claim 5 wherein the fluid is selected from the group consisting of sera, plasma, sweat, urine, and saliva.

7.	The method of claim 2 wherein the one or more polypeptides are bound to a solid support.

8.	The method of claim 7 where the solid support is selected from the group consisting of beads, microparticles, microtiter plates, and membranes.

9.	The method of claim 2 wherein said complex is detected using a detection molecule, said detection molecule comprising an antibody molecule that is labeled with a label, said antibody molecule binds to human antibodies.

10.	The method of claim 9 wherein said labeled antibody molecule is selected from the group consisting of a polyclonal antibody, a monoclonal antibody, a singlechain antibody, and fragments thereof.

11.	The method of claim 9 wherein said label is selected from the group consisting of radioactive molecules, fluorescent molecules, chemiluminescers, dyes, oligonucleotides, enzymes, coenzymes, enzyme substrates, small organic molecules, and solid surfaces.

12.	The method of claim 2 wherein said one or more polypeptides are labeled.

13.	The method of claim 12 wherein said label is selected from the group consisting of radioactive molecules, fluorescent molecules, chemiluminescers, dyes, oligonucleotides, enzymes, coenzymes, enzyme substrates, small organic molecules and solid surfaces.

14.	The method of claim 1 wherein said autoantibodies are found in patient fluid selected from the group consisting of sera, plasma, sweat, urine, and saliva.

15.

A method for detecting endometriosis comprising: (a) contacting a fluid from a patient with one or more polypeptides selected from the group consisting of a polypeptide comprising the amino acid sequence of SEQ ID NO: 1325, and fragments thereof having the same immunologicial specificity to autoantibodies of endometriosis, to capture antibodies in the fluid that bind to the polypeptide which are immobilized on a solid surface; (b) applying a detection molecule to the captured antibodies bound to the polypeptide, the detection molecule having the capacity to specifically bind to the captured antibodies; (c) detecting the bound detection molecule.

16.

The method of claim 15 wherein the one or more polypeptides are selected from the group consisting of a polypeptide comprising the amino acid sequence of SEQ ID NO: 14, 16,18,23, and 25, and fragments thereof having the same immunologicial specificity toward autoantibodies associated with endomitriosis.

17.

A kit for detecting endometriosis comprising: (a) one or more polypeptides selected from the group consisting of a polypeptide comprising the amino acid sequence of SEQ ID NO: 1325, and fragments thereof having the same immunologicial specificity to autoantibodies of endometriosis; (b) a detection molecule capable of binding to human antibodies.

18.

The kit of claim 17 wherein the one or more polypeptides are selected from the group consisting of a polypeptide comprising the amino acid sequence of SEQ ID NO: 14,16,18, 23, and 25, and fragments thereof having the same immunologicial specificity toward autoantibodies associated with endomitriosis.

19.	The kit according to claim 18 wherein the one or more polypeptide are bound to a solid support.

20.	The kit according to claim 19 wherein the detection molecule comprises a labeled antibody molecule which binds to human antibodies.

21.	A reagent for detecting endometriosis comprising one or more polypeptides selected from the group consisting of a polypeptide comprising the amino acid sequence of SEQ ID NO: 1325, and fragments thereof having the same immunologicial specificity to autoantibodies of endometriosis.

22.	The reagent of claim 21 wherein the polypeptide is labeled.

23.	The reagent of claim 22 wherein said label is selected from the group consisting of radioactive molecules, fluorescent molecules, chemiluminescers, dyes, oligonucleotides, enzymes, coenzymes, enzyme substrates, small organic molecules and solid surfaces.

24.

A reagent for detecting endometriosis comprising one or more polypeptides selected from the group consisting of a polypeptide comprising the amino acid sequence of SEQ ID NO: 14,16,18,23, and 25, and fragments thereof having the same immunologicial specificity toward autoantibodies associated with endomitriosis.

25.	The reagent of claim 24 wherein the polypeptide is labeled.

26.	The reagent of claim 25 wherein said label is selected from the group consisting of radioactive molecules, fluorescent molecules, chemiluminescers, dyes, oligonucleotides, enzymes, coenzymes, enzyme substrates, small organic molecules and solid surfaces.

27.	A method for detecting autoantigens found in endometriosis patients comprising screening an endometriotic cDNA expression library with pooled fluid from normal and endometriosis patients.

28.	The method of claim 27 wherein the pooled fluid is selected from the group consisting of sera, plasma, sweat, urine, and saliva.

29.	The method of claim 27 wherein the pooled fluid is sera.

30.	An isolated polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 13, and fragments thereof having the same immunologicial specificity toward autoantibodies associated with endomitriosis.

31.	An isolated polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 14, and fragments thereof having the same immunologicial specificity toward autoantibodies associated with endomitriosis.

32.	An isolated polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 15, and fragments thereof having the same immunologicial specificity toward autoantibodies associated with endomitriosis.

33.	An isolated polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 16, and fragments thereof having the same immunologicial specificity toward autoantibodies associated with endomitriosis.

34.	An isolated polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 17, and fragments thereof having the same immunologicial specificity toward autoantibodies associated with endomitriosis.

35.	An isolated polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 18, and fragments thereof having the same immunologicial specificity toward autoantibodies associated with endomitriosis.

36.	An isolated polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 19 and 20, and fragments thereof having the same immunologicial specificity toward autoantibodies associated with endomitriosis.

37.	An isolated polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 21, and fragments thereof having the same immunologicial specificity toward autoantibodies associated with endomitriosis.

38.	An isolated polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 22, and fragments thereof having the same immunologicial specificity toward autoantibodies associated with endomitriosis.

39.	An isolated polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 23, and fragments thereof having the same immunologicial specificity toward autoantibodies associated with endomitriosis.

40.	An isolated polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 24, and fragments thereof having the same immunologicial specificity toward autoantibodies associated with endomitriosis.

41.	An isolated polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 25, and fragments thereof having the same immunologicial specificity toward autoantibodies associated with endomitriosis.

42.

An isolated nucleic acid molecule comprising a polynucleotide selected from the group consisting of : (a) a polynucleotide of SEQ ID NO: 1 or a polynucleotide which h) bridizes to SEQ ID NO: 1; (b) a polynucleotide encoding a polypeptide of a translation of SEQ ID NO: 1 or a polypeptide encoded by a cDNA sequence which hybridizes to SEQ ID NO: 1; (c) a polynucleotide encoding a polypeptide with similar immunological specificity to the polypeptide encoded by one or more of SEQ ID NO: 1; (d) a polynucleotide which is a variant of SEQ ID NO: 1.

43.

An isolated nucleic acid molecule comprising a polynucleotide selected from the group consisting of : (a) a polynucleotide of SEQ ID NO: 2 or a polynucleotide which hybridizes to SEQ ID NO: 2; (b) a polynucleotide encoding a polypeptide of a translation of SEQ ID NO: 2 or a polypeptide encoded by a cDNA sequence which hybridizes to SEQ ID NO: 2; (c) a polynucleotide encoding a polypeptide with similar immunological specificity to the polypeptide encoded by one or more of SEQ ID NO: 2; (d) a polynucleotide which is a variant of SEQ ID NO : 2.

44.

An isolated nucleic acid molecule comprising a polynucleotide selected from the group consisting of : (a) a polynucleotide of SEQ ID NO: 3 or a polynucleotide which hybridizes to SEQ ID NO: 3; (b) a polynucleotide encoding a polypeptide of a translation of SEQ ID NO: 3 or a polypeptide encoded by a cDNA sequence which hybridizes to SEQ ID NO : 3; (c) a polynucleotide encoding a polypeptide with similar immunological specificity to the polypeptide encoded by one or more of SEQ ID NO: 3; (d) a polynucleotide which is a variant of SEQ ID NO: 3.

45.

An isolated nucleic acid molecule comprising a polynucleotide selected from the group consisting of : (a) a polynucleotide of SEQ ID NO: 4 or a polynucleotide which hybridizes to SEQ ID NO: 4; (b) a polynucleotide encoding a polypeptide of a translation of SEQ ID NO: 4 or a polypeptide encoded by a cDNA sequence which hybridizes to SEQ ID NO: 4; (c) a polynucleotide encoding a polypeptide with similar immunological specificity to the polypeptide encoded by one or more of SEQ ID NO: 4; (d) a polynucleotide which is a variant of SEQ ID NO: 4.

46.

An isolated nucleic acid molecule comprising a polynucleotide selected from the group consisting of : (a) a polynucleotide of SEQ ID NO: 5 or a polynucleotide which hybridizes to SEQ ID NO: 5; (b) a polynucleotide encoding a polypeptide of a translation of SEQ ID NO: 5 or a polypeptide encoded by a cDNA sequence which hybridizes to SEQ ID NO: 5; (c) a polynucleotide encoding a polypeptide with similar immunological specificity to the polypeptide encoded by one or more of SEQ ID NO: 5; (d) a polynucleotide which is a variant of SEQ ID NO: 5.

47.

An isolated nucleic acid molecule comprising a polynucleotide selected from the group consisting of : (a) a polynucleotide of SEQ ID NO: 6 or a polynucleotide which hybridizes to SEQ ID NO: 6; (b) a polynucleotide encoding a polypeptide of a translation of SEQ ID NO: 6 or a polypeptide encoded by a cDNA sequence which hybridizes to SEQ ID NO: 6; (c) a polynucleotide encoding a polypeptide with similar immunological specificity to the polypeptide encoded by one or more of SEQ ID NO: 6; (d) a polynucleotide which is a variant of SEQ ID NO: 6.

48.

An isolated nucleic acid molecule comprising a polynucleotide selected from the group consisting of : (a) a polynucleotide of SEQ ID NO: 7 or a polynucleotide which hybridizes to SEQ ID NO: 7; (b) a polynucleotide encoding a polypeptide of a translation of SEQ ID NO: 7 or a polypeptide encoded by a cDNA sequence which hybridizes to SEQ ID NO: 7; (c) a polynucleotide encoding a polypeptide with similar immunological specificity to the polypeptide encoded by one or more of SEQ ID NO: 7; (d) a polynucleotide which is a variant of SEQ ID NO: 7.

49.

An isolated nucleic acid molecule comprising a polynucleotide selected from the group consisting of : (a) a polynucleotide of SEQ ID NO: 8 or a polynucleotide which hybridizes to SEQ ID NO: 8; (b) a polynucleotide encoding a polypeptide of a translation of SEQ ID NO: 8 or a polypeptide encoded by a cDNA sequence which hybridizes to SEQ ID N0: 8; (c) a polynucleotide encoding a polypeptide with similar immunological specificity to the polypeptide encoded by one or more of SEQ ID NO: 8; (d) a polynucleotide which is a variant of SEQ ID NO: 8.

50.

An isolated nucleic acid molecule comprising a polynucleotide selected from the group consisting of (a) a polynucleotide of SEQ ID N0: 9 or a polynucleotide which hybridizes to SEQ ID NO: 9; (b) a polynucleotide encoding a polypeptide of a translation of SEQ ID NO: 9 or a polypeptide encoded by a cDNA sequence which hybridizes to SEQ ID NO: 9; (c) a polynucleotide encoding a polypeptide with similar immunological specificity to the polypeptide encoded by one or more of SEQ ID NO: 9; (d) a polynucleotide which is a variant of SEQ ID NO: 9. 51.

51.

An isolated nucleic acid molecule comprising a polynucleotide selected from the group consisting of : (a) a polynucleotide of SEQ ID NO: 10 or a polynucleotide which hybridizes to SEQ ID NO: 1; (b) a polynucleotide encoding a polypeptide of a translation of SEQ ID NO: 10 or a polypeptide encoded by a cDNA sequence which hybridizes to SEQ ID NO: 10; (c) a polynucleotide encoding a polypeptide with similar immunological specificity to the polypeptide encoded by one or more of SEQ ID NO: 10; (d) a polynucleotide which is a variant of SEQ ID NO: 10.

52.

An isolated nucleic acid molecule comprising a polynucleotide selected from the group consisting of : (a) a polynucleotide of SEQ ID NO: 11 or a polynucleotide which hybridizes to SEQ ID NO:11; (b) a polynucleotide encoding a polypeptide of a translation of SEQ ID NO: 11 or a polypeptide encoded by a cDNA sequence which hybridizes to SEQ ID NO: 11; (c) a polynucleotide encoding a polypeptide with similar immunological specificity to the polypeptide encoded by one or more of SEQ ID NO: 11; (d) a polynucleotide which is a variant of SEQ ID NO: 11.

53.

An isolated nucleic acid molecule comprising a polynucleotide selected from the group consisting of : (a) a polynucleotide of SEQ ID NO: 12 or a polynucleotide which hybridizes to SEQ ID NO: 12; (b) a polynucleotide encoding a polypeptide of a translation of SEQ ID NO: 12 or a polypeptide encoded by a cDNA sequence which hybridizes to SEQ ID NO: 12; (c) a polynucleotide encoding a polypeptide with similar immunological specificity to the polypeptide encoded by one or more of SEQ ID NO: 12; (d) a polynucleotide which is a variant of SEQ ID NO: 12.

Description:

INTERNATIONALSEARCHREPORT International ApplicationNo PCT/US00/02710 C.(Continuation)DOCUMENTSCONSIDEREDTOBERELEVANT CategoryCitationofdocument,withindication,whereappropriate,o ftherelevantpassages RelevanttoclaimNo. XKERSIN.PESTONJAMASPETAL.:30,42 "Supervillin(p205):Anovel membrane-associated,F-Actin-binding proteinintheVillin/Gelsolin superfamily" JOURNALOFCELLBIOLOGY, vol.139,December1997(1997-12),pages 1255-1269,XP002140590 abstract page1261,left-handcolumn,last paragraph-right-handcolumn,paragraph1 page1263,right-handcolumn,paragraph2 -page1268,left-handcolumn,paragraph3; figure12 AWO9428021A(MEDICALUNIVERSITYOFSOUTH1,2, CAROLINA)8December1994(1994-12-08)4-15,17, 21-23, 30,42 page3,line7-page4,line9 page4,line30-page16,line25 page18,line20-page22,line13 ASUBBIPILLAIETAL.:"Antibodiesto1,2, endometrialtransferrinandalpha4-15,17, 2-HeremansSchmidt(HS)glycoproteinin21-23, patientswithendometriosis"30,42 AMERICANJOURNALOFREPRODUCTIVE IMMUNOLOGY, vol.35,no.5,1996,pages483-494, XP000910506 thewholedocument AMICHAELWALTERET AL.:"Autoreactive1,2, epitopeswithinthehumanalpha-enolase4-15,17, andtheirrecognitionbyserafrom21-23, patientswithendometriosis"30,42 JOURNALOFAUTOIMMUNITY, vol.8,no.6,December1995(1995-12), pages931-945,XP000911010 thewholedocument IrationalapplicationNo. INTERNATIONALSEARCHREPORTPCT/US00/02710 Box IObservationswherecertainclaimswerefoundunsearchable(Continu ationofitem1offirstsheet) ThisIntemationalSearchReporthasnotbeenestablishedinrespectof certainclaimsunderArticle17(2)(a)forthefollowingreasons: 1.njClaimsNos.: becausetheyrelatetosubjectmatternotrequiredtobesearchedbythi sAuthority,namety: 2.0Claims Nos.: becausetheyrelatetopartsoftheIntemationalApplicationthatdono tcomplywiththeprescribedrequirementstosuch anextentthatnomeaningful International Searchcanbecarriedout,specifically: 3.g Claims Nos.: becausetheyaredependentclaimsandarenotdraftedinaccordancewit hthesecondandthirdsentencesofRule6.4(a). Box11Observationswhereunityofinventionislacking(Continuation ofitem2offirstsheet) ThisIntemationalSearchingAuthorityfoundmultipleinventionsint hisinternationalapplication,asfollows: seeadditionalsheet(s) 1.t As ahrequiredadditionalsearchfeesweretimelypaidbytheapplicant,t hisInternationalSearchReportcoversalt 7 searchable claims. 2.JAsailsearchableclaimscouldbesearchedwithouteffortjustifyi nganadditionalfee,thisAuthoritydidnotinvitepayment ofanyadditionalfee. 3.n As onlysomeoftherequiredadditionalsearchfeesweretimelypaidbythe applicant,thisInternationalSearchReport covers onlythoseclaimsforwhichfeeswerepaid,specificallyclaimsNos.: 4.gNorequiredadditionalsearchfeesweretimelypaidbytheapplican t.Consequently,thisInternationalSearchReportis restrictedtotheinventionfirstmentionedintheclaims ; itiscoveredbyclaimsNos.: 21-23partially,30,42 RemarkonProtestThe additionalsearchfeeswereaccompaniedbytheapplicant'sprotest. u No protestaccompaniedaccompaniedpaymentpaymentadditionalsearchf ees. L-I FURTHER INFORMATION CONTINUED FROM PCT/ISA/210 1. Claims: 1,2,4-15,17,21-23 partially, 30,42 Polypeptide of sequence SEQ ID NO: 13; nucleic acid molecule encoding the same of sequence SEQ ID NO: 1; use of the polypeptides for detecting and monitoring endometriosis in a patient, kit and reagent therefor.

2. Claims: 1-26 partially, 31,43 Polypeptide of sequence SEQ ID NO: 14; nucleic acid molecule encoding the same of sequence SEQ ID NO: 2; use of the polypeptides for detecting and monitoring endometriosis in a patient, kit and reagent therefor.

3. Claims: 1,2,4-15 17 21-23 partially, 33,44 Polypeptide of sequence SEQ ID NO: 15; nucleic acid molecule encoding the same of sequence SEQ ID NO: 3; use of the polypeptides for detecting and monitoring endometriosis in a patient, kit and reagent therefor.

4. Claims: 1-26 partially, 33,45 Polypeptide of sequence SEQ ID NO: 16; nucleic acid molecule encoding the same of sequence SEQ ID NO: 4; use of the polypeptides for detecting and monitoring endometriosis in a patient, kit and reagent therefor.

5. Claims: 17 21-23 partially, 34,46 Polypeptide of sequence SEQ ID NO: 17; nucleic acid molecule encoding the same of sequence SEQ ID NO: 5; use of the polypeptides for detecting and monitoring endometriosis in a patient, kit and reagent therefor.

6. Claims: 1-26 partially, 35,47 Polypeptide of sequence SEQ ID NO: 18; nucleic acid molecule encoding the same of sequence SEQ ID NO: 6; use of the polypeptides for detecting and monitoring endometriosis in a patient, kit and reagent therefor.

7. Claims: 1,2,4-15 17 21-23 partially, 36,48 Polypeptide of sequence SEQ ID NO: 19; nucleic acid molecule encoding the same of sequence SEQ ID NO: 7; use of the polypeptides for detecting and monitoring endometriosis in a patient, kit and reagent therefor.

FURTHER INFORMATION CONTINUED FROM PCT/ISA/210 8. Claims: 1,2,4-15 17 21-23 partially, 37,49 Polypeptide of sequence SEQ ID NO: 20; nucleic acid molecule encoding the same of sequence SEQ ID NO: 8; use of the polypeptides for detecting and monitoring endometriosis in a patient, kit and reagent therefor.

9. Claims: 1,2,4-15,17,21-23 partially, 38,50 Polypeptide of sequence SEQ ID NO: 21; nucleic acid molecule encoding the same of sequence SEQ ID NO: 9; use of the polypeptides for detecting and monitoring endometriosis in a patient, kit and reagent therefor.

10. Claims: 1-26 partially, 39,51 Polypeptide of sequence SEQ ID NO: 22; nucleic acid molecule encoding the same of sequence SEQ ID NO: 10; use of the polypeptides for detecting and monitoring endometriosis in a patient, kit and reagent therefor.

11. Claims: 1,2,4-15,17,21-23 partially, 40,52 Polypeptide of sequence SEQ ID NO: 23; nucleic acid molecule encoding the same of sequence SEQ ID NO: 11; use of the polypeptides for detecting and monitoring endometriosis in a patient, kit and reagent therefor.

12. Claims: 1-26 partially, 41,53 Polypeptide of sequence SEQ ID NO: 24; nucleic acid molecule encoding the same of sequence SEQ ID NO: 12; use of the polypeptides for detecting and monitoring endometriosis in a patient, kit and reagent therefor.

13. Claims: 27-29 Method for detecting endometriosis auto-antigens by screening an endometriotic cDNA expression library INTERNATIONALSEARCHREPORT Intemational Application No rmatio on patent family membes l PatentdocumentPublication Patent family Publication citedinsearchreportdatemember(s)date WO9428021A08-12-1994AU6960694A20-12-1994

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