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 RGKMG (SEQ ID NO:28), a CDR-H2 comprising the amino acid sequence LAHIFSSDEKSYRTSI, (SEC ID NO: 32) and a CDR-H3 comprising the amino acid sequence YYCARIRX (SEQ ID NO:90:), wherein X at position 8 is A or R; and

(ii) a light chain variable region comprising three CDRs, comprising a CDR-L1 comprising the amino acid sequence GXKLGDKXAYW (SEQ ID NO:91),wherein X at position 2 is D or E and wherein X at position 8 is F or Y, a CDR-L2 comprising the amino acid sequence DXXRPSG (SEQ ID NO:93), wherein X at position 2 is N or K and wherein X at position 3 K or Q, and CDR-L3 compromising the amino acid sequence AWDSSTAVF (SEQ ID NO: 51), 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:90 contains an R at position 8.

3. The isolated antibody of claim 1 , wherein the amino acid sequence set forth in SEQ ID NO:91 contains an E at position 2.

4. The isolated antibody of claim 1 , wherein the amino acid sequence set forth in SEQ ID NO:91 contains a Y at position 8.

5. The isolated antibody of claim 1 , wherein CDR-L2 of the light chain variable region comprises SEQ ID NO:93, and wherein the amino acid sequence set forth in SEQ ID NO:93 contains a K at position 2.

6. The isolated antibody of claim 1 , wherein CDR-L2 of the light chain variable region comprises SEQ ID NO: 93, and wherein the amino acid sequence set forth in SEQ ID NO:93 contains a Q at position 3.

7. The isolated antibody of claim 1 , wherein the heavy chain variable region comprises a CDR-H1 comprising the amino acid sequence RGKMG (SEQ ID NO:28), a CDR-H2 comprising the amino acid sequence LAHIFSSDEKSYRTSL (SEQ ID NO: 32) and a CDR-H3 comprising the amino acid sequence YYCARIRX (SED ID NO:90), wherein X at position 8 is R; and

wherein the light chain variable region comprises a CDR-L1 comprising the amino acid sequence GXKLGDKXAYW (SED ID NO:91), wherein X at position 2 is E and wherein X at position 8 is Y, a CDR-L2 comprising the amino acid sequence DXXRPSG (SEQ ID NO:93), wherein X at position 2 is K and wherein X at position 3 is Q, and CDR-L3 of the light chain variable region comprises SEQ ID NO:51.

8. 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.

9. 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.

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

11. 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.

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

13. The antibody of claim 1 , wherein said antibody binds an epitope in the CCP1 domain of MASP-2.

14. 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.

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

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

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

18. 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:18, or SEQ ID NO:20 and a light chain variable region comarising the amino acid sequence set forth in SEQ ID NO:22 or SEQ ID NO:24.

19. The isolated monoclonal antibody, or antigen-binding fragment thereof of claim 18 comprising a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:20 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:24.

20. A composition comprising the fully human monoclonal anti-MASP-2 antibody, or fragment thereof, of claim 1 , 18 or 19 and a pharmaceutically acceptable excipient.

21. The composition of claim 20 , wherein the composition is formulated for systemic delivery.

22. The composition of claim 21 , wherein the composition is formulated for intra-arterial, intravenous, intracranial, intramuscular, inhalational, nasal or subcutaneous administration.

23. The composition of claim 21 , wherein the composition is formulated tor subcutaneous administration.

24. An article of manufacture comprising a unit dose of a human monoclonal anti-MASP-2 antibody of claim 1 , 18 or 19 suitable for therapeutic administration to a human subject, wherein the unit dose is the range of from 1 mg to 1000 mg.