Compositions for inhibiting MASP-2 dependent complement activation

Patent metadata

Field	Value
Publication number	US-9475885-B2
Application number	US-201514660040-A
Country	US
Kind code	B2
Filing date	Mar 17, 2015
Priority date	May 4, 2011
Publication date	Oct 25, 2016
Grant date	Oct 25, 2016

Abstract

The present invention relates to anti-MASP-2 inhibitory antibodies and compositions comprising such antibodies for use in inhibiting the adverse effects of MASP-2 dependent complement activation.

First claim

The invention claimed is:

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.

Assignees

• Omeros Corp

Inventors

• Dudler Thomas
• Gombotz Wayne R
• Parent James Brian
• Tedford Clark E
• Kavlie Anita
• Hagemann Urs Beat
• Reiersen Herald
• Kiprijanov Sergej

Classifications

• C07K2317/33

  Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity · CPC title

• C07K2317/53

  Hinge · CPC title

• C07K2317/565

  Complementarity determining region [CDR] · CPC title

• C07K2317/622

  Single chain antibody (scFv) · CPC title

• C07K2317/92

  Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value · CPC title