Inhibition of factor B, the alternative complement pathway and methods related thereto
Disclosed are novel inhibitors of the alternative complement pathway and particularly, novel anti-factor B antibodies. Also disclosed is the use of such inhibitors to reduce or prevent airway hyperresponsiveness and/or airway inflammation by selectively inhibiting the alternative complement pathway, thereby treating diseases in which such conditions play a role. Also disclosed is the use of such inhibitors to reduce or prevent other diseases and conditions, including ischemia-reperfusion injury, by inhibition of the alternative complement pathway.
1. A fusion protein comprising:
a) an antibody or antigen-binding fragment thereof that selectively binds to factor B, wherein the antibody or antigen-binding fragment thereof prevents formation of a C3bBb complex, and wherein the antibody or antigen binding fragment thereof selectively binds to factor B at the same epitope as the anti-factor B monoclonal antibody 1379 (produced by ATCC Deposit No. PTA-6230); and
b) a targeting moiety comprising a CR2 protein comprising at least the short consensus repeat 1 (SCR1) and short consensus repeat 2 (SCR2) domains, C3, C3d, C3dg, iC3b, C3b, or an antibody that selectively binds to the CR2 protein, C3, C3d, C3dg, iC3b, or C3b.
2. The fusion protein of claim 1 , wherein the antibody or antigen-binding fragment thereof selectively binds to factor B from multiple mammalian species.
3. The fusion protein of claim 2 , wherein the antibody or antigen-binding fragment thereof selectively binds to factor B from human and an animal selected from the group consisting of non-human primates, mouse, rat, pig, horse, and rabbit.
4. The fusion protein of claim 1 , wherein the antigen-binding fragment is an Fab.
5. The fusion protein of claim 1 , wherein the antibody or antigen-binding fragment thereof is a humanized antibody or antigen-binding fragment thereof against factor B.
6. The fusion protein of claim 1 , wherein the targeting moiety comprises CR2.
7. A method of specifically inhibiting activation of the alternative complement pathway in an animal, comprising administering to the animal a fusion protein according to claim 1 .
8. The method of claim 7 , wherein the animal is a mammal.
9. The method of claim 8 , wherein the animal is a human.
10. A method of reducing or preventing airway hyperresponsiveness (AHR) or airway inflammation in an animal, comprising administering a fusion protein according to claim 1 to an animal that has, or is at risk of developing, airway hyperresponsiveness associated with inflammation or airway inflammation.
11. The method of claim 10 , wherein the animal is a mammal.
12. The method of claim 11 , wherein the animal is a human.
13. The method of claim 12 , wherein the animal has rhinitis.
14. The method of claim 12 , wherein the animal has sinusitis.
15. The fusion protein of claim 1 , wherein the antibody that selectively binds to factor B is of a non-complement activating isotype or subclass.
16. The fusion protein of claim 1 , wherein the antibody that selectively binds to factor B is a monoclonal antibody.
17. The fusion protein of claim 1 , wherein the antibody that selectively binds to factor B is a bispecific antibody.
18. The fusion protein of claim 1 , wherein the antibody that selectively binds to factor B is a monovalent antibody.
19. The fusion protein of claim 1 , wherein the antibody that selectively binds to factor B is the monoclonal antibody 1379 (produced by ATCC deposit No. PTA-6230).
20. The fusion protein of claim 1 , wherein the antibody that selectively binds to factor B is a chimeric antibody.
21. The fusion protein of claim 1 , wherein the targeting moiety comprises the CR2 protein comprising at least the SCR1 and SCR2 domains.
22. The fusion protein of claim 1 , wherein the targeting moiety comprises C3.
23. The fusion protein of claim 1 , wherein the targeting moiety comprises C3d.
24. The fusion protein of claim 1 , wherein the targeting moiety comprises C3dg.
25. The fusion protein of claim 1 , wherein the targeting moiety comprises iC3b.
26. The fusion protein of claim 1 , wherein the targeting moiety comprises C3b.
27. The fusion protein of claim 1 , wherein the targeting moiety comprises an antibody that selectively binds to the CR2 protein, C3, C3d, C3dg, iC3b, or C3b.