Compositions for inhibiting MASP-2 dependent complement activation

1. An isolated human monoclonal antibody, or antigen binding fragment thereof, that binds to human MASP-2, comprising:

(i) a heavy chain variable region comprising three complementarity determining regions (CDRs), comprising a CDR-H1 comprising the amino acid sequence STSAA (SEQ ID NO:29), a CDR-H2 comprising the amino acid sequence LGRTYYRSKWYNDYAV (SEQ ID NO:33), and a CDR-H3 comprising the amino acid sequence AVYYCARD (SEQ ID NO:38); and

(ii) a light chain variable region comprising three CDRs, comprising a CDR-L1 comprising the amino acid sequence GXNXGXKXVHW (SEQ ID NO:92), wherein X at position 2 is N or D and wherein X at position 4 is I or L and wherein X at position 6 is S or K and wherein X at position 8 is N or R, a CDR-L2 comprising the amino acid sequence DSDRPSG (SEQ ID NO:49), and CDR-L3 comprising the amino acid sequence VWDXXTDHV (SEQ ID NO:94), wherein X at position 4 is T or I and wherein X at position 5 is T or A, and wherein the isolated antibody or antigen-binding fragment thereof binds to human MASP-2 and inhibits MASP-2 dependent complement activation.

2. The isolated antibody of claim 1 , wherein the amino acid sequence set forth in SEQ ID NO:92 contains an N at position 2.

3. The isolated antibody of claim 1 , wherein the amino acid sequence set forth in SEQ ID NO:92 contains a D at position 2.

4. The isolated antibody of claim 1 , wherein the amino acid sequence set forth in SEQ ID NO:92 contains an I at position 4.

5. The isolated antibody of claim 1 , wherein the amino acid sequence set forth in SEQ ID NO:92 contains an L at position 4.

6. The isolated antibody of claim 1 , wherein the amino acid sequence set forth in SEQ ID NO:92 contains an S at position 6.

7. The isolated antibody of claim 1 , wherein the amino acid sequence set forth in SEQ ID NO:92 contains a K at position 6.

8. The isolated antibody of claim 1 , wherein the amino acid sequence set forth in SEQ ID NO:92 contains an N at position 8.

9. The isolated antibody of claim 1 , wherein the amino acid sequence set forth in SEQ ID NO:92 contains an R at position 8.

10. The isolated antibody of claim 1 , wherein the amino acid sequence set forth in SEQ ID NO:94 contains a T at position 4.

11. The isolated antibody of claim 1 , wherein the amino acid sequence set forth in SEQ ID NO:94 contains an I at position 4.

12. The isolated antibody of claim 1 , wherein the amino acid sequence set forth in SEQ ID NO:94 contains a T at position 5.

13. The isolated antibody of claim 1 , wherein the amino acid sequence set forth in SEQ ID NO:94 contains an A at position 5.

14. The isolated antibody of claim 1 , wherein the light chain variable region comprises a CDR-L1 comprising the amino acid sequence GXNXGXKXVHW (SEQ ID NO:92), wherein X at position 2 is D and wherein X at position 4 is L and wherein X at position 6 is K and wherein X at position 8 is R, a CDR-L2 comprising the amino acid sequence DSDRPSG (SEQ ID NO:49), and CDR-L3 comprising the amino acid sequence VWDXXTDHV (SEQ ID NO:94), wherein X at position 4 is I and wherein X at position 5 is A.

15. The isolated antibody of claim 1 , wherein the light chain variable region comprises a CDR-L1 comprising the amino acid sequence GXNXGXKXVHW (SEQ ID NO:92), wherein X at position 2 is N and wherein X at position 4 is I and wherein X at position 6 is S and wherein X at position 8 is N, a CDR-L2 comprising the amino acid sequence DSDRPSG (SEQ ID NO:49), and CDR-L3 comprising the amino acid sequence VWDXXTDHV (SEQ ID NO:94), wherein X at position 4 is T and wherein X at position 5 is T.

16. The isolated antibody of claim 1 , wherein the antibody or antigen-binding fragment thereof is selected from the group consisting of a Fab, a Fab′ fragment, a F(ab′) 2 fragment and a whole antibody.

17. The isolated antibody of claim 1 , wherein the antibody or antigen-binding fragment thereof is selected from the group consisting of a single chain antibody, an ScFv, and a univalent antibody lacking a hinge region.

18. The isolated antibody of claim 1 , wherein said antibody binds human MASP-2 with a K D of 10 nM or less.

19. The antibody of claim 1 , wherein said antibody inhibits C4 activation in an in vitro assay in 1% human serum at an IC 50 of 10 nM or less.

20. The antibody of claim 1 , wherein said antibody inhibits C4 activation in 90% human serum with an IC 50 of 30 nM or less.

21. The antibody of claim 1 , wherein said antibody inhibits C3b deposition in an in vitro assay in 1% human serum at an IC 50 of 10 nM or less.

22. The antibody of claim 1 , wherein said antibody inhibits C3b deposition in 90% human serum with an IC 50 of 30 nM or less.

23. The antibody of claim 1 , wherein the antibody is a single chain molecule.

24. The antibody of claim 1 , wherein the antibody does not substantially inhibit the classical pathway.

25. An isolated monoclonal antibody, or antigen-binding fragment thereof, that binds to human MASP-2, comprising a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:21 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:25.

26. An isolated monoclonal antibody, or antigen-binding fragment thereof, that binds to human MASP-2, comprising a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:21 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:27.

27. A composition comprising the fully human monoclonal anti-MASP-2 antibody, or fragment thereof, of claim 1 , 25 or 26 and a pharmaceutically acceptable excipient.

28. The composition of claim 27 , wherein the composition is formulated for systemic delivery.

29. The composition of claim 27 , wherein the composition is formulated for intra-arterial, intravenous, intracranial, intramuscular, inhalational, nasal or subcutaneous administration.

30. The composition of claim 27 , wherein the composition is formulated for subcutaneous administration.

31. An article of manufacture comprising a unit dose of a human monoclonal anti-MASP-2 antibody of claim 1 , 25 or 26 suitable for therapeutic administration to a human subject, wherein the unit dose is the range of from 1 mg to 1000 mg.