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. An isolated antibody that specifically binds HtrA1, wherein the antibody comprises a binding domain comprising the following six hypervariable regions (HVRs):
(a) an HVR-H1 comprising the amino acid sequence of SYIMS (SEQ ID NO: 39);
(b) an HVR-H2 comprising the amino acid sequence of YISNGGGTTYYSDTIKG (SEQ ID NO: 40);
(c) an HVR-H3 comprising the amino acid sequence of QNFRSDGSSMDY (SEQ ID NO: 41);
(d) an HVR-L1 comprising the amino acid sequence of RASESVDSYGKSFMH (SEQ ID NO: 42);
(e) an HVR-L2 comprising the amino acid sequence of LASKLES (SEQ ID NO: 43); and
(f) an HVR-L3 comprising the amino acid sequence of QQNNEDPYT (SEQ ID NO: 44).
2. The antibody of claim 1 , wherein the antibody comprises a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 45 and a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 46.
3. The antibody of claim 1 , wherein the antibody is monoclonal, humanized, or chimeric.
4. The antibody of claim 1 , wherein the antibody is an antibody fragment that binds to HtrA1.
5. The antibody of claim 4 , wherein the antibody fragment is selected from the group consisting of Fab, Fab′-SH, Fv, scFv, and (Fab′) 2 fragments.
6. The antibody of claim 5 , wherein the antibody fragment is a Fab.
7. The antibody of claim 6 , wherein the Fab comprises a truncation in the upper hinge of the heavy chain constant region.
8. The antibody of claim 7 , wherein the heavy chain constant region terminates at position 221 (EU numbering).
9. The antibody of claim 1 , wherein the antibody is a bispecific antibody.
10. An isolated nucleic acid encoding the antibody of claim 1 .
11. A method of producing an antibody, the method comprising culturing a host cell comprising a vector comprising an isolated nucleic of claim 10 and recovering the antibody from the host cell or the host cell culture medium.
12. A pharmaceutical composition comprising an antibody of claim 1 and further comprising at least one pharmaceutically acceptable carrier, excipient, or diluent.
13. A combination therapy comprising an antibody of claim 1 and a Factor D antagonist, wherein the Factor D antagonist is an anti-Factor D antibody.
14. The combination therapy of claim 13 , wherein the anti-Factor D antibody is lampalizumab.
15. 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 the antibody of claim 1 .
16. The method of claim 15 , wherein the HtrA1-associated disorder or the ocular disorder is age-related macular degeneration (AMD), diabetic retinopathy, retinopathy of prematurity, or polypoidal choroidal vasculopathy.
17. The method of claim 15 , further comprising the step of administering a Factor D antagonist, wherein the Factor D antagonist is an anti-Factor D antibody.
18. The method of claim 17 , wherein the anti-Factor D antibody is lampalizumab.
19. The method of claim 15 , wherein the antibody is administered by a long-acting delivery system.
20. The method of claim 19 , wherein the long-acting delivery system is a PLGA-based solid implant or an implantable port delivery system.
21. An isolated antibody that specifically binds HtrA1, wherein the antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 45 and a VL domain comprising the amino acid sequence of SEQ ID NO: 46.