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1. (WO2011050194) METHODS AND COMPOSITIONS FOR MODULATING HEPSIN ACTIVATION OF MACROPHAGE-STIMULATING PROTEIN
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CLAIMS

We claim:

1. A method of identifying a candidate inhibitor substance that inhibits hepsin activation of pro-macrophage-stimulating protein (pro-MSP), said method comprising: (a) contacting a candidate substance with a first sample comprising hepsin and a pro-MSP substrate, and (b) comparing amount of pro-MSP substrate activation in the sample with amount of pro-MSP substrate activation in a reference sample comprising similar amounts of hepsin and pro-MSP substrate as the first sample but that has not been contacted with said candidate substance, whereby a decrease in amount of pro-MSP substrate activation in the first sample compared to the reference sample indicates that the candidate substance is capable of inhibiting hepsin activation of single chain MSP (pro-MSP).

2. The method of claim 1, wherein hepsin in the sample is in an effective amount for activating said pro-MSP.

3. The method of claim 1, wherein the pro-MSP substrate is a polypeptide comprising pro-MSP or fragment thereof comprising a wild type form of the Arg483-Val484 peptide linkage.

4. An antagonist molecule that inhibits interaction of hepsin and pro-MSP.

5. The antagonist molecule of claim 4, wherein the molecule comprises an antibody or fragment thereof.

6. The antagonist molecule of claim 4, wherein the molecule comprises a polypeptide comprising a Kunitz domain 1 sequence.

7. The antagonist of claim 4, wherein the molecule comprises a small organic molecule.

8. The molecule of claim 6, wherein the molecule comprises a polypeptide comprising a Kunitz domain (KD) sequence which is capable of inhibiting pro-MSP activation by hepsin.

9. The molecule of claim 8, wherein the Kunitz domain (KD) sequence comprises a Kunitz domain 1 sequence (KD-1).

10. The molecule of claim 9, wherein the KD-1 sequence is that of human hepatocyte growth factor activator inhibitor- 1, -IB (HAI-1, HAI-1B), or variant thereof.

11. The molecule of claim 8, wherein the Kunitz domain (KD) sequence is one or both of the Kunitz domains of human hepatocyte growth factor activator inhibitor-2 (HAI-2), or variant thereof.

12. The molecule of claim 6, wherein the molecule comprises at least a portion of human hepatocyte growth factor activator inhibitor- 1, -IB, or -2 (HAI-1, HAI-1B or HAI-2), or variant thereof.

13. The molecule of claim 12, wherein the portion comprises a Kunitz domain (KD) sequence which is capable of inhibiting pro-MSP activation by hepsin.

14. The molecule of claim 13, wherein the Kunitz domain (KD) sequence is:

(i) Kunitz domain 1 sequence (KD-1) of human hepatocyte growth factor activator inhibitor-1, -IB (HAI-1, HAI-1B), or variant thereof; or

(ii) one or both of the Kunitz domains of human hepatocyte growth factor activator inhibitor-2 (HAI-2), or variant thereof.

15. The molecule of claim 6, wherein the molecule competes with hepsin for binding to

Ron.

16. The molecule of claim 6, wherein the molecule competes with pro-MSP for binding to hepsin.

17. The molecule of claim 16, wherein the molecule comprises a mutant MSP which is capable of binding hepsin and has reduced Ron activating activity compared to wild type MSP.

18. The molecule of claim 17, wherein the mutant MSP is devoid of at least a portion of MSP β chain.

19. The molecule of any one of claims 6 to 18, wherein the molecule is linked to a toxin.

20. An isolated nucleic acid encoding the molecule of any one of claims 6 to 18.

21. A vector comprising the nucleic acid of claim 20.

22. A host cell comprising the nucleic acid of claim 20 or the vector of claim 21.

23. A method of making the molecule of any one of claims 6 to 18, comprising expressing a vector of claim 21 in a host cell capable of expressing the molecule.

24. A composition comprising a molecule of any one of claims 6 to 18 and a carrier.

25. The composition of claim 24, wherein the carrier is a pharmaceutically acceptable carrier.

26. An article of manufacture comprising a container and a composition contained within the container, wherein the composition comprises a molecule of any one of claims 6 to 18.

27. The molecule of any one of claims 6 to 18 or 20 for the treatment of a pathological condition associated with activation of Ron in a subject.

28. A composition comprising purified pro-MSP and hepsin proteins.

29. A method of inhibiting a biological activity associated with pro-MSP/Ron activation, said method comprising contacting a cell or tissue with an effective amount of an antagonist molecule of any of the preceding claims.

30. A method of treating a pathological condition associated with pro-MSP/Ron activation in a subject, said method comprising administering to the subject an effective amount of an antagonist molecule of any of the preceding claims.

31. The method of claim 29 or 30, wherein the condition is a cancer, a tumor, a cell proliferative disorder, or an immune disorder.

32. The method of claim 31 , wherein the cancer is breast cancer, colorectal cancer, lung cancer, papillary carcinoma, colon cancer, pancreatic cancer, ovarian cancer, cervical cancer, central nervous system cancer, prostate cancer, osteogenic sarcoma, renal carcinoma, hepatocellular carcinoma, bladder cancer, gastric carcinoma, head and neck squamous carcinoma, melanoma or leukemia.

33. A method for detecting MSP in a sample comprising (a) contacting the sample with hepsin under conditions permitting hepsin proteolyitic processing of MSP, and (b) detecting present of hepsin activated MSP.

34. A method for detecting hepsin in a sample comprising (a) contacting the sample with MSP under conditions permitting hesin proteolytic processing of MSP, and (b) detecting presence of hepsin activated MSP.