received by the International Bureau on 7 April 2014 (07.04.2014)

WHAT IS CLAIMED IS:

1. An isolated antibody that specifically binds human R-spondin 3 (RSP03), which comprises:

(a) a heavy chain CDRl comprising DYSIH (SEQ ID NO:78), KASGYTFTDYS (SEQ ID NO:9), or KASGYTFTSYTF (SEQ ID NO:34), a heavy chain CDR2 comprising YIYPSNGDSGYNQKFK (SQ ID NO:79) or IYPSNGDS (SEQ ID NO: 10), and a heavy chain CDR3 comprising TYFANNFD (SEQ ID NO:80), ATYFANYFDY (SEQ ID NO: 1 1), or ATYFANNFDY (SEQ ID NO:35); and

(b) a light chain CDRl comprising KASQSVDYDGDSYMN (SEQ ID NO:81) or QSVDYDGDSYM (SEQ ID NO: 12), a light chain CDR2 comprising AASNLES (SEQ ID NO:82) or AAS (SEQ ID NO: 13), and a light chain CDR3 comprising QQSNEDPLT (SEQ ID NO: 14) or QQSNEDPLTF (SEQ ID NO:83).

2. The antibody of claim 1, which comprises:

(a) a heavy chain CDRl comprising DYSIH (SEQ ID NO:78) or KASGYTFTDYS (SEQ ID NO:9), a heavy chain CDR2 comprising YIYPSNGDSGYNQKFK (SQ ID NO:79), and a heavy chain CDR3 comprising TYFANNFD (SEQ ID NO: 80); and a light chain CDRl comprising KASQSVDYDGDSYMN (SEQ ID NO:81), a light chain CDR2 comprising AASNLES (SEQ ID NO:82), and a light chain CDR3 comprising QQSNEDPLTF (SEQ ID NO:83);

(b) a heavy chain CDRl comprising KASGYTFTDYS (SEQ ID NO:9) or KASGYTFTSYTF (SEQ ID NO:34), a heavy chain CDR2 comprising IYPSNGDS (SEQ ID NO: 10), and a heavy chain CDR3 comprising ATYFANYFDY (SEQ ID NO: 1 1 ) or ATYFANNFDY (SEQ ID NO:35), and a light chain CDRl comprising QSVDYDGDSYM (SEQ ID NO: 12), a light chain CDR2 comprising AAS (SEQ ID NO: 13), and a light chain CDR3 comprising QQSNEDPLT (SEQ ID NO: 14); or

(c) a heavy chain CDRl comprising KASGYTFTDYS (SEQ ID NO:9) or DYSIH (SEQ ID NO:78), a heavy chain CDR2 comprising IYPSNGDS (SEQ ID NO: 10), and a heavy chain CDR3 comprising TYFANNFD (SEQ ID NO: 80); and a light chain CDRl comprising QSVDYDGDSYM (SEQ ID NO: 12), a light chain CDR2 comprising AAS (SEQ ID NO: 13), and a light chain CDR3 comprising QQSNEDPLT (SEQ ID NO: 14).

3. The antibody of claim 1, which comprises: (a) a heavy chain variable region having at least 90% sequence identity to SEQ ID N0.44, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID O:36, SEQ ID NO:37, SEQ ID NO:45, or SEQ ID NO:62; and

(b) a light chain variable region having at least 90% sequence identity to SEQ ID NO:86, SEQ ID NO: 17, or SEQ ID NO:72.

The antibody of claim 3, which comprises:

(a) a heavy chain variable region comprising SEQ ID NO:44 and a light chain variable region comprising SEQ ID NO: 17, SEQ ID NO:72, or SEQ ID NO:86;

(b) a heavy chain variable region comprising SEQ ID NO: 15 and a light chain variable region comprising SEQ ID NO: 17 or SEQ ID NO:72;

(c) a heavy chain variable region comprising SEQ ID NO: 16 and a light chain variable region comprising SEQ ID NO: 17 or SEQ ID NO:72;

(d) a heavy chain variable region comprising SEQ ID NO:36 and a light chain variable region comprising SEQ ID NO: 17 or SEQ ID NO:72;

(e) a heavy chain variable region comprising SEQ ID NO:37 and a light chain variable region comprising SEQ ID NO: 17 or SEQ ID NO:72;

(f) a heavy chain variable region comprising SEQ ID NO:45 and a light chain variable region comprising SEQ ID NO: 17, SEQ ID NO:72, or SEQ ID NO:86; or

(g) a heavy chain variable region comprising SEQ ID NO:62 and a light chain variable region comprising SEQ ID NO: 17, SEQ ID N0:72, or SEQ ID NO:86.

An isolated antibody that competes with the antibody according to any one of claims 1-4 for specific binding to RSP03.

The antibody according to any one of claims 1-5, which is a recombinant antibody, a monoclonal antibody, a chimeric antibody, a bispecific antibody, a humanized antibody, a human antibody, an IgGl antibody, an IgG2 antibody, or an antibody fragment comprising an antigen binding site.

An antibody comprising the heavy chain variable region encoded by the plasmid deposited with ATCC as PTA- 120420 and the light chain variable region encoded by the plasmid deposited with ATCC as PTA- 120421.

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8. The antibody according to any one of claims 1-7, which inhibits binding of RSP03 to at least one leucine-rich repeat containing G protein coupled receptor (LGR).

9. The antibody of claim 8, wherein the LGR is selected from the group consisting of LGR5, LGR4, and LGR6.

10. The antibody according to any one of claims 1-9, which

(a) inhibits RSP03 signaling;

(b) inhibits activation of β-catenin;

(c) inhibits β-catenin signaling;

(d) inhibits tumor growth;

(e) induces expression of differentiation markers in a tumor;

(f) induces cells in a tumor to differentiate; or

(g) reduces the frequency of cancer stem cells in a tumor.

1 1. A pharmaceutical composition comprising the antibody according to any one of claims 1 -7 and a pharmaceutically acceptable carrier.

12. An isolated polynucleotide molecule comprising a polynucleotide that encodes an antibody according to any one of claims 1-7.

13. A cell comprising:

(a) the antibody according to any one of claims 1-7; or

(b) the polynucleotide of claim 12.

14. The use of the antibody according to any one of claims 1-7 for inhibiting tumor growth.

15. The use of the antibody according to any one of claims 1-7 for inducing differentiation of tumor cells.

16. The use of the antibody according to any one of claims 1-7 for reducing the frequency of cancer stem cells in a tumor.

17. The use of the antibody according to any one of claims 1-7 for inhibiting β-catenin signaling in a cell.

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18. The use of the antibody of claim 17, wherein the cell is a tumor cell.

19. The use of the antibody according to any one of claims 14-16 or 18, wherein the tumor is a pancreatic tumor, lung tumor, colorectal tumor, or ovarian tumor.

20. The use of the antibody according to any one of claims 1-7 for treating cancer.

21. The use of the antibody of claim 20, wherein the cancer is colorectal cancer, pancreatic cancer, lung cancer, or ovarian cancer.

22. The use of the antibody according to any one of claims 14-16 or 18-21, wherein the tumor or the cancer has a RSPO gene fusion.

23. The use of the antibody according to any one of claims 14-16 or 18-21, further comprising a step of determining if the tumor or cancer has a RSPO gene fusion.

24. The use of the antibody of claim 22 or claim 23, wherein the RSPO gene fusion is a RSP02 gene fusion or a RSP03 gene fusion.

25. The use of the antibody according to any one of claims 1-7 for treating a disease associated with activation of β-catenin.

26. The use of the antibody according to any one of claims 14-16 or 18-25, which comprises administering at least one additional therapeutic agent.

27. The use of the antibody of claim 26, wherein the additional therapeutic agent is a chemotherapeutic agent, an angiogenesis inhibitor, an additional antibody.

28. A method of identifying a tumor for treatment with an antibody according to any one of claims 1-7 comprising: determining if the tumor that has a RSPO gene fusion.

29. The method of claim 28, wherein the RSPO gene fusion is a RSP02 gene fusion or a RSP03 gene fusion. The method according to claim 28 or claim 29, wherein the RSPO gene fusion is determined by a PCR-based assay, microarray analysis, or nucleotide sequencing.