Anti-HtrA1 antibodies and methods of use thereof
The present invention provides anti-HtrA1 antibodies (including bispecific anti-HtrA1 anti-Factor D antibodies) and methods of making and using the same, for example, in methods of treating HtrA1-associated disorders, ocular disorders, and/or complement-associated disorders.
1. A method of treating an HtrA1-associated disorder or an ocular disorder in a human subject in need thereof, the method comprising administering a therapeutically effective amount of an antibody that specifically binds HtrA1, wherein the antibody comprises a binding domain comprising the following six HVRs:
(a) HVR-H1 comprises the amino acid sequence of DSEMH (SEQ ID NO: 7);
(b) HVR-H2 comprises the amino acid sequence of GVDPETEGAAYNQKFKG (SEQ ID NO: 8);
(c) HVR-H3 comprises the amino acid sequence of GYDYDYALDY (SEQ ID NO: 3);
(d) HVR-L1 comprises the amino acid sequence of RASSSVEFIH (SEQ ID NO: 9);
(e) HVR-L2 comprises the amino acid sequence of ATSNLAS (SEQ ID NO: 10); and
(f) HVR-L3 comprises the amino acid sequence of QQWSSAPWT (SEQ ID NO: 11).
2. The method of claim 1 , wherein the HtrA1-associated disorder or the ocular disorder is age-related macular degeneration (AMD), diabetic retinopathy, retinopathy of prematurity, or polypoidal choroidal vasculopathy.
3. The method of claim 2 , wherein the HtrA1-associated disorder is early dry AMD, intermediate dry AMD, or advanced dry AMD.
4. The method of claim 3 , wherein the advanced dry AMD is geographic atrophy.
5. The method of claim 1 , further comprising the step of administering a Factor D antagonist, wherein the Factor D antagonist is an anti-Factor D antibody.
6. The method of claim 5 , wherein the anti-Factor D antibody is lampalizumab.
7. The method of claim 1 , wherein the antibody is administered intravitreally, ocularly, intraocularly, juxtasclerally, subtenonly, superchoroidally, or topically.
8. The method of claim 7 , wherein the antibody is administered intravitreally by injection.
9. The method of claim 1 , wherein the antibody is administered by a long-acting delivery system.
10. The method of claim 9 , wherein the long-acting delivery system is a PLGA-based solid implant or an implantable port delivery system.
11. A method of treating an HtrA1-associated disorder or an ocular disorder in a human subject in need thereof, the method comprising administering to the human subject a therapeutically effective amount of an antibody that specifically binds HtrA1, wherein the antibody comprises a binding domain comprising the following six HVRs:
(a) an HVR-H1 comprising the amino acid sequence of DSEX 1 H (SEQ ID NO: 1), wherein X 1 is Met or Leu;
(b) an HVR-H2 comprising the amino acid sequence of GVDPETX 2 GAAYNQKFKG (SEQ ID NO: 2), wherein X 2 is Glu or Asp;
(c) an HVR-H3 comprising the amino acid sequence of GYDYDYALDY (SEQ ID NO: 3);
(d) an HVR-L1 comprising the amino acid sequence of RASSSVX 3 FIH (SEQ ID NO: 4), wherein X 3 is Glu or Asn;
(e) an HVR-L2 comprising the amino acid sequence of ATSX 4 LAS (SEQ ID NO: 5), wherein X 4 is Asn, His or Glu; and
(f) an HVR-L3 comprising the amino acid sequence of QQWX 5 SX 6 PWT (SEQ ID NO: 6), wherein X 5 is Ser or Tyr and X 6 is Ala or Asn.
12. A method of treating an HtrA1-associated disorder or an ocular disorder in a human subject in need thereof, the method comprising administering to the human subject a therapeutically effective amount of an antibody that specifically binds HtrA1, wherein the antibody comprises a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 21 and a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 22.
13. A method of treating an HtrA1-associated disorder or an ocular disorder in a human subject in need thereof, the method comprising administering to the human subject a therapeutically effective amount of an antibody that specifically binds HtrA1, wherein the antibody comprises a VH domain comprising an amino acid sequence having at least 96% sequence identity to the amino acid sequence of SEQ ID NO: 21 and a VL domain comprising an amino acid sequence having at least 96% sequence identity to the amino acid sequence of SEQ ID NO: 22.
14. A method of treating an HtrA1-associated disorder or an ocular disorder in a human subject in need thereof, the method comprising administering to the human subject a therapeutically effective amount of an antibody that specifically binds HtrA1, wherein the antibody comprises a VH domain comprising an amino acid sequence having at least 97% sequence identity to the amino acid sequence of SEQ ID NO: 21 and a VL domain comprising an amino acid sequence having at least 97% sequence identity to the amino acid sequence of SEQ ID NO: 22.
15. A method of treating an HtrA1-associated disorder or an ocular disorder in a human subject in need thereof, the method comprising administering to the human subject a therapeutically effective amount of an antibody that specifically binds HtrA1, wherein the antibody comprises a VH domain comprising an amino acid sequence having at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 21 and a VL domain comprising an amino acid sequence having at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 22.
16. A method of treating an HtrA1-associated disorder or an ocular disorder in a human subject in need thereof, the method comprising administering to the human subject a therapeutically effective amount of an antibody that specifically binds HtrA1, wherein the antibody comprises a VH domain comprising an amino acid sequence having at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 21 and a VL domain comprising an amino acid sequence having at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 22.
17. A method of treating an HtrA1-associated disorder or an ocular disorder in a human subject in need thereof, the method comprising administering to the human subject a therapeutically effective amount of an antibody that specifically binds HtrA1, wherein the antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 21 and a VL domain comprising the amino acid sequence of SEQ ID NO: 22.
18. A method of treating an HtrA1-associated disorder or an ocular disorder in a human subject in need thereof, the method comprising administering to the human subject a therapeutically effective amount of an antibody that specifically binds HtrA1, wherein the antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 160 and a light chain amino acid sequence of SEQ ID NO: 159.
19. A method of treating geographic atrophy in a human subject in need thereof, the method comprising administering to the human subject a therapeutically effective amount of an antibody that specifically binds HtrA 1 , wherein the antibody comprises a binding domain comprising the following six HVRs:
(i) an HVR-H1 comprising the amino acid sequence of DSEX 1 H (SEQ ID NO: 1), wherein X 1 is Met or Leu;
(ii) an HVR-H2 comprising the amino acid sequence of GVDPETX 2 GAAYNQKFKG (SEQ ID NO: 2), wherein X 2 is Glu or Asp;
(iii) an HVR-H3 comprising the amino acid sequence of GYDYDYALDY (SEQ ID NO: 3);
(iv) an HVR-L1 comprising the amino acid sequence of RASSSVX 3 FIH (SEQ ID NO: 4), wherein X 3 is Glu or Asn;
(v) an HVR-L2 comprising the amino acid sequence of ATSX 4 LAS (SEQ ID NO: 5), wherein X 4 is Asn, His or Glu; and
(vi) an HVR-L3 comprising the amino acid sequence of QQWX 5 SX 6 PWT (SEQ ID NO: 6), wherein X 5 is Ser or Tyr and X 6 is Ala or Asn.
20. The method of claim 19 , further comprising the step of administering a Factor D antagonist, wherein the Factor D antagonist is an anti-Factor D antibody.
21. The method of claim 20 , wherein the anti-Factor D antibody is lampalizumab.
22. A method of treating wet AMD in a human subject in need thereof, the method comprising administering to the human subject a therapeutically effective amount of an antibody that specifically binds HtrA1, wherein the antibody comprises a binding domain comprising the following six HVRs:
(i) an HVR-H1comprising the amino acid sequence of DSEX 1 H (SEQ ID NO: 1), wherein X 1 is Met or Leu;
(ii) an HVR-H2 comprising the amino acid sequence of GVDPETX 2 GAAYNQKFKG (SEQ ID NO: 2), wherein X 2 is Glu or Asp;
(iii) an HVR-H3 comprising the amino acid sequence of GYDYDYALDY (SEQ ID NO: 3);
(iv) an HVR-L1 comprising the amino acid sequence of RASSSVX 3 FIH (SEQ ID NO: 4), wherein X 3 is Glu or Asn;
(v) an HVR-L2 comprising the amino acid sequence of ATSX 4 LAS (SEQ ID NO: 5), wherein X 4 is Asn, His or Glu; and
(vi) an HVR-L3 comprising the amino acid sequence of QQWX 5 SX 6 PWT (SEQ ID NO: 6), wherein X 5 is Ser or Tyr and X 6 is Ala or Asn.
23. The method of claim 22 , further comprising the step of administering a Factor D antagonist, wherein the Factor D antagonist is an anti-Factor D antibody.
24. The method of claim 23 , wherein the anti-Factor D antibody is lampalizumab.
25. A method of treating geographic atrophy in a human subject in need thereof, the method comprising administering to the human subject a therapeutically effective amount of an antibody that specifically binds HtrA1, wherein the antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 21 and a VL domain comprising the amino acid sequence of SEQ ID NO: 22.
26. The method of claim 25 , further comprising the step of administering a Factor D antagonist, wherein the Factor D antagonist is an anti-Factor D antibody.
27. The method of claim 26 , wherein the anti-Factor D antibody is lampalizumab.
28. A method of treating wet AMD in a human subject in need thereof, the method comprising administering to the human subject a therapeutically effective amount of an antibody that specifically binds HtrA1, wherein the antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 21 and a VL domain comprising the amino acid sequence of SEQ ID NO: 22.
29. The method of claim 28 , further comprising the step of administering a Factor D antagonist, wherein the Factor D antagonist is an anti-Factor D antibody.
30. The method of claim 29 , wherein the anti-Factor D antibody is lampalizumab.
31. A method of treating geographic atrophy in a human subject in need thereof, the method comprising administering to the human subject a therapeutically effective amount of an antibody that specifically binds HtrA1, wherein the antibody is a full-length antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 160 and a light chain comprising the amino acid sequence of SEQ ID NO: 159.
32. The method of claim 31 , further comprising the step of administering a Factor D antagonist, wherein the Factor D antagonist is an anti-Factor D antibody.
33. The method of claim 32 , wherein the anti-Factor D antibody is lampalizumab.
34. A method of treating wet AMD in a human subject in need thereof, the method comprising administering to the human subject a therapeutically effective amount of an antibody that specifically binds HtrA1, wherein the antibody is a full-length antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 160 and a light chain comprising the amino acid sequence of SEQ ID NO: 159.
35. The method of claim 34 , further comprising the step of administering a Factor D antagonist, wherein the Factor D antagonist is an anti-Factor D antibody.
36. The method of claim 35 , wherein the anti-Factor D antibody is lampalizumab.
37. A combination therapy comprising:
(a) an antibody that specifically binds HtrA 1 , wherein the antibody comprises a binding domain comprising the following six HVRs:
(i) HVR-H1 comprises the amino acid sequence of DSEMH (SEQ ID NO: 7);
(ii) HVR-H2 comprises the amino acid sequence of GVDPETEGAAYNQKFKG (SEQ ID NO: 8);
(iii) HVR-H3 comprises the amino acid sequence of GYDYDYALDY (SEQ ID NO: 3);
(iv) HVR-L1 comprises the amino acid sequence of RASSSVEFIH (SEQ ID NO: 9);
(v) HVR-L2 comprises the amino acid sequence of ATSNLAS (SEQ ID NO: 10); and
(vi) HVR-L3 comprises the amino acid sequence of QQWSSAPWT (SEQ ID NO: 11); and
(b) a Factor D antagonist, wherein the Factor D antagonist is an anti-Factor D antibody.
38. The combination therapy of claim 37 , wherein the anti-Factor D antibody is lampalizumab.
39. A combination therapy comprising:
(a) an antibody that specifically binds HtrA1, wherein the antibody comprises a binding domain comprising the following six HVRs:
(i) an HVR-H1 comprising the amino acid sequence of DSEX 1 H (SEQ ID NO: 1), wherein X 1 is Met or Leu;
(ii) an HVR-H2 comprising the amino acid sequence of GVDPETX 2 GAAYNQKFKG (SEQ ID NO: 2), wherein X 2 is Glu or Asp;
(iii) an HVR-H3 comprising the amino acid sequence of GYDYDYALDY (SEQ ID NO: 3);
(iv) an HVR-L1 comprising the amino acid sequence of RASSSVX 3 FIH (SEQ ID NO: 4), wherein X 3 is Glu or Asn;
(v) an HVR-L2 comprising the amino acid sequence of ATSX 4 LAS (SEQ ID NO: 5), wherein X 4 is Asn, His or Glu; and
(vi) an HVR-L3 comprising the amino acid sequence of QQWX 5 SX 6 PWT (SEQ ID NO: 6), wherein X 5 is Ser or Tyr and X 6 is Ala or Asn; and
(b) a Factor D antagonist, wherein the Factor D antagonist is an anti-Factor D antibody.
40. The combination therapy of claim 39 , wherein the anti-Factor D antibody is lampalizumab.
41. A combination therapy comprising:
(a) an antibody that specifically binds HtrA1, wherein the antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 21 and a VL domain comprising the amino acid sequence of SEQ ID NO: 22; and
(b) a Factor D antagonist, wherein the Factor D antagonist is an anti-Factor D antibody.
42. The combination therapy of claim 41 , wherein the anti-Factor D antibody is lampalizumab.
43. A combination therapy comprising:
(a) an antibody that specifically binds HtrA1, wherein the antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 160 and a light chain amino acid sequence of SEQ ID NO: 159; and
(b) a Factor D antagonist, wherein the Factor D antagonist is an anti-Factor D antibody.
44. The combination therapy of claim 43 , wherein the anti-Factor D antibody is lampalizumab.