Antibodies specifically binding to MASP-3 for the treatment of various diseases and disorders
The present invention relates to MASP-3 inhibitory antibodies and compositions comprising such antibodies for use in inhibiting the adverse effects of MASP-3 dependent complement activation.
1. An isolated antibody, or antigen-binding fragment thereof, that binds to MASP-3 comprising: a heavy chain variable region comprising a HC-CDR1 set forth as SEQ Id NO:84 (GKWIE); a HC-CDR2 set forth as SEQ ID NO:86 (EILPGTGSTNYNEKFKG) or SEQ ID NO:275 (EILPGTGSTNYAQKFQG); and a HC-CDR3 set forth as SEQ ID NO:88 (SEDV); and a light chain variable region comprising a LC-CDR1 set forth as SEQ ID NO: 142 (KSSQSLLNSRTRKNYLA), SEQ lD NO:257 (KSSQSLLQSRTRKNYLA); SEQ ID NO:258 (KSSQSLLASRTRKNYLA); or SEQ lD NO:259 (KSSQSLLNTRTRKNYLA), a LC-CDR2 set forth as SEQ ID NO: 144 (WASTRES); and a LC-CDR3 set forth as SEQ ID NO:161 (KQSYNIPT).
2. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the LC-CDR1 comprises SEQ ID NO:258.
3. The antibody or antigen binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment is selected from the group consisting of a human antibody, a humanized antibody, a chimeric antibody, a murine antibody, and an antigen-binding fragment of any of the foregoing.
4. The antibody or antigen-binding fragment thereof of claim 1 , wherein said antibody or antigen binding fragment thereof is selected from the group consisting of a single chain antibody, an ScFv, a Fab fragment, an Fab′ fragment, an F(ab′)2 fragment, a univalent antibody lacking a hinge region and a whole antibody.
5. The antibody or antigen-binding fragment thereof of claim 1 , further comprising an immunoglobulin constant region.
6. The antibody or antigen binding fragment thereof of claim 3 , wherein the antibody or antigen-binding fragment is humanized.
7. The antibody or antigen-binding fragment thereof of claim 1 , wherein said antibody binds to the serine protease domain of human MASP-3 with an affinity of less than 500 pM.
8. The antibody or antigen-binding fragment thereof of 1 , wherein said antibody inhibits alternative pathway activation in mammalian blood.
9. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the HC-CDR2 comprises SEQ ID NO:86.
10. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the HC-CDR2 comprises SEQ ID NO:275.
11. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the LC-CDR1 comprises SEQ ID NO:142.
12. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the LC-CDR1 comprises SEQ ID NO:257.
13. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the LC-CDR1 comprises SEQ ID NO:259.
14. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the HC-CDR1 comprises SEQ ID NO:84, the HC-CDR2 comprises SEQ ID NO:86, the HC-CDR3 comprises SEQ ID NO:88, the LC-CDR1 comprises SEQ ID NO:258, the LC-CDR2 comprises SEQ ID NO:144 and the LC-CDR3 comprises SEQ ID NO:161.
15. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the HC-CDR1 comprises SEQ ID NO:84, the HC-CDR2 comprises SEQ ID NO:275, the HC-CDR3 comprises SEQ ID NO:88; the LC-CDR1 comprises SEQ ID NO:258, the LC-CDR2 comprises SEQ ID NO:144 and the LC-CDR3 comprises SEQ ID NO:161.
16. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the heavy chain variable region comprises the amino acid sequence set forth as SEQ ID NO:30.
17. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the light chain variable region comprises the amino acid sequence set forth as SEQ ID NO:45.
18. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the heavy chain variable region comprises the amino acid sequence set forth as SEQ ID NO:30 and the light chain variable region comprises the amino acid sequence set forth as SEQ ID NO:45.
19. The isolated antibody or antigen-binding fragment thereof of claim 6 , wherein the heavy chain variable region comprises the amino acid sequence set forth as SEQ ID NO:254.
20. The isolated antibody or antigen-binding fragment thereof of claim 6 , wherein the heavy chain variable region comprises the amino acid sequence set forth as SEQ ID NO:255.
21. The isolated antibody or antigen-binding fragment thereof of claim 6 , wherein the light chain variable region comprises the amino acid sequence set forth as SEQ ID NO:256.
22. The isolated antibody or antigen-binding fragment thereof of claim 6 , wherein the light chain variable region comprises the amino acid sequence set forth as SEQ ID NO:280.
23. An isolated antibody or antigen-binding fragment thereof that binds to human MASP-3, comprising a heavy chain variable region comprising SEQ ID NO:254 or SEQ ID NO:255 and a light chain variable region comprising SEQ ID NO:256 or SEQ ID NO:280.
24. The isolated antibody or antigen-binding fragment thereof of claim 23 , wherein the heavy chain variable region comprises SEQ ID NO:254 and the light chain variable region comprises SEQ ID NO:256.
25. The isolated antibody or antigen-binding fragment thereof of claim 23 , wherein the heavy chain variable region comprises SEQ ID NO:255 and the light chain variable region comprises SEQ ID NO:256.
26. The isolated antibody or antigen-binding fragment thereof of claim 23 , wherein the heavy chain variable region comprises SEQ 1D NO:254 and the light chain variable region comprises SEQ ID NO: 280.
27. The isolated antibody or antigen-binding fragment thereof of claim 23 , wherein the heavy chain variable region comprises SEQ ID NO:255 and the light chain variable region comprises SEQ ID NO: 280.
28. The isolated antibody of claim 23 , wherein the antibody is selected from the group consisting of a single chain antibody, an ScFv, a Fab fragment, an Fab′ fragment, an F(ab′)2 fragment, a univalent antibody lacking a hinge region and a whole antibody.
29. The isolated antibody of claim 23 , further comprising an immunoglobulin constant region.
30. A composition comprising the antibody or antigen-binding fragment of any of claims 1 , 6 or 22 and a pharmaceutically acceptable excipient.