Anti-LRP5 antibodies and methods of use

Patent metadata

Field	Value
Publication number	US-9522954-B2
Application number	US-201514879702-A
Country	US
Kind code	B2
Filing date	Oct 9, 2015
Priority date	Jan 18, 2012
Publication date	Dec 20, 2016
Grant date	Dec 20, 2016

Abstract

The invention provides anti-LRP5 antibodies and methods of making and using the same.

First claim

What is claimed is:

1. An isolated nucleic acid encoding an antibody that binds to Low-density lipoprotein receptor-related protein 5 (LRP5), wherein the antibody potentiates Norrin activity and/or Norrin/Fzd4 (Frizzled4) signaling, wherein the antibody comprises (a) HVR-H1 comprising the amino acid sequence GFTFSSYAMX 1 , wherein X 1 is H or S (SEQ ID NO: 28), (b) HVR-H2 comprising the amino acid sequence GX 1 ISX 2 X 3 GX 4 STYYADSVKG, wherein X 1 is A or G, X 2 is A or S, X 3 is P or S, X 4 is S or W (SEQ ID NO: 26), or SRISSNGGSTYYADSVKG (SEQ ID NO: 27), (c) HVR-H3 comprising the amino acid sequence YYRYAPYRSLGMDV (SEQ ID NO: 23) or WIPQSYPFX 1 SYKSGFDY, wherein X 1 is A or R (SEQ ID NO: 24), (d) HVR-L1 comprising the amino acid sequence RASQGISSYLA (SEQ ID NO: 29) or RASQX 1 X 2 X 3 X 4 YLA, wherein X 1 is A, G, S or V, X 2 is I or M, X 3 is F, G, S or Y, and X 4 is G, S or Y (SEQ ID NO: 30); (e) HVR-L2 comprising the amino acid sequence AASSLQS (SEQ ID NO: 31) or DASX 1 X 2 ES, wherein X 1 is S or T and X 2 is L or R (SEQ ID NO: 32); and (f) HVR-L3 comprising the amino acid sequence QQYYX 1 YPFT, wherein X 1 is L or S (SEQ ID NO: 33).

2. The nucleic acid of claim 1 , wherein the antibody comprises (a) HVR-H1 comprising the amino acid sequence GFTFSSYAMS (SEQ ID NO: 48), (b) HVR-H2 comprising the amino acid sequence GAISSSGSSTYYADSVKG (SEQ ID NO: 49), (c) HVR-H3 comprising the amino acid sequence YYRYAPYRSLGMDV (SEQ ID NO: 23), (d) HVR-L1 comprising the amino acid sequence RASQGISSYLA (SEQ ID NO: 29); (e) HVR-L2 comprising the amino acid sequence AASSLQS (SEQ ID NO: 31); and (f) HVR-L3 comprising the amino acid sequence QQYYSYPFT (SEQ ID NO: 47).

3. The nucleic acid of claim 1 , wherein the antibody comprises (a) HVR-H1 comprising the amino acid sequence GFTFSSYAMS (SEQ ID NO: 48), (b) HVR-H2 comprising the amino acid sequence GAISAPGSSTYYADSVKG (SEQ ID NO: 50), (c) HVR-H3 comprising the amino acid sequence YYRYAPYRSLGMDV (SEQ ID NO: 23), (d) HVR-L1 comprising the amino acid sequence RASQGISSYLA (SEQ ID NO: 29); (e) HVR-L2 comprising the amino acid sequence AASSLQS (SEQ ID NO: 31); and (f) HVR-L3 comprising the amino acid sequence QQYYSYPFT (SEQ ID NO: 47).

4. The nucleic acid of claim 1 , wherein the antibody comprises (a) HVR-H1 comprising the amino acid sequence GFTFSSYAMS (SEQ ID NO: 48), (b) HVR-H2 comprising the amino acid sequence GAISSPGWSTYYADSVKG (SEQ ID NO: 51), (c) HVR-H3 comprising the amino acid sequence YYRYAPYRSLGMDV (SEQ ID NO: 23), (d) HVR-L1 comprising the amino acid sequence RASQGISSYLA (SEQ ID NO: 29); (e) HVR-L2 comprising the amino acid sequence AASSLQS (SEQ ID NO: 31); and (f) HVR-L3 comprising the amino acid sequence QQYYSYPFT (SEQ ID NO: 47).

5. The nucleic acid of claim 1 , wherein the antibody comprises (a) HVR-H1 comprising the amino acid sequence GFTFSSYAMS (SEQ ID NO: 48), (b) HVR-H2 comprising the amino acid sequence GGISSPGSSTYYADSVKG (SEQ ID NO: 52), (c) HVR-H3 comprising the amino acid sequence YYRYAPYRSLGMDV (SEQ ID NO: 23), (d) HVR-L1 comprising the amino acid sequence RASQGISSYLA (SEQ ID NO: 29); (e) HVR-L2 comprising the amino acid sequence AASSLQS (SEQ ID NO: 31); and (f) HVR-L3 comprising the amino acid sequence QQYYLYPFT (SEQ ID NO: 53).

6. The nucleic acid of claim 1 , wherein the antibody comprises (a) HVR-H1 comprising the amino acid sequence GFTFSSYAMH (SEQ ID NO: 43), (b) HVR-H2 comprising the amino acid sequence SRISSNGGSTYYADSVKG (SEQ ID NO: 27), (c) HVR-H3 comprising the amino acid sequence WIPQSYPFRSYKSGFDY (SEQ ID NO: 54), (d) HVR-L1 comprising the amino acid sequence RASQGISSYLA (SEQ ID NO: 29); (e) HVR-L2 comprising the amino acid sequence DASSLES (SEQ ID NO: 46); and (f) HVR-L3 comprising the amino acid sequence QQYYSYPFT (SEQ ID NO: 47).

7. The nucleic acid of claim 1 , wherein the antibody comprises (a) HVR-H1 comprising the amino acid sequence GFTFSSYAMH (SEQ ID NO: 43), (b) HVR-H2 comprising the amino acid sequence SRISSNGGSTYYADSVKG (SEQ ID NO: 27), (c) HVR-H3 comprising the amino acid sequence WIPQSYPFASYKSGFDY (SEQ ID NO: 44), (d) HVR-L1 comprising the amino acid sequence RASQSIYYYLA (SEQ ID NO: 55); (e) HVR-L2 comprising the amino acid sequence DASSLES (SEQ ID NO: 46); and (f) HVR-L3 comprising the amino acid sequence QQYYSYPFT (SEQ ID NO: 47).

8. The nucleic acid of claim 1 , wherein the antibody comprises (a) HVR-H1 comprising the amino acid sequence GFTFSSYAMH (SEQ ID NO: 43), (b) HVR-H2 comprising the amino acid sequence SRISSNGGSTYYADSVKG (SEQ ID NO: 27), (c) HVR-H3 comprising the amino acid sequence WIPQSYPFASYKSGFDY (SEQ ID NO: 44), (d) HVR-L1 comprising the amino acid sequence RASQVIYGYLA (SEQ ID NO: 56); (e) HVR-L2 comprising the amino acid sequence DASTRES (SEQ ID NO: 57); and (f) HVR-L3 comprising the amino acid sequence QQYYSYPFT (SEQ ID NO: 47).

9. The nucleic acid of claim 1 , wherein the antibody comprises (a) HVR-H1 comprising the amino acid sequence GFTFSSYAMH (SEQ ID NO: 43), (b) HVR-H2 comprising the amino acid sequence SRISSNGGSTYYADSVKG (SEQ ID NO: 27), (c) HVR-H3 comprising the amino acid sequence WIPQSYPFASYKSGFDY (SEQ ID NO: 44), (d) HVR-L1 comprising the amino acid sequence RASQGIFYYLA (SEQ ID NO: 58); (e) HVR-L2 comprising the amino acid sequence DASTLES (SEQ ID NO: 59); and (f) HVR-L3 comprising the amino acid sequence QQYYSYPFT (SEQ ID NO: 47).

10. The nucleic acid of claim 1 , wherein the antibody comprises (a) HVR-H1 comprising the amino acid sequence GFTFSSYAMH (SEQ ID NO: 43), (b) HVR-H2 comprising the amino acid sequence SRISSNGGSTYYADSVKG (SEQ ID NO: 27), (c) HVR-H3 comprising the amino acid sequence WIPQSYPFASYKSGFDY (SEQ ID NO: 44), (d) HVR-L1 comprising the amino acid sequence RASQAIYSYLA (SEQ ID NO: 60); (e) HVR-L2 comprising the amino acid sequence DASSLES (SEQ ID NO: 46); and (f) HVR-L3 comprising the amino acid sequence QQYYSYPFT (SEQ ID NO: 47).

11. The nucleic acid of claim 1 , wherein the antibody comprises (a) HVR-H1 comprising the amino acid sequence GFTFSSYAMH (SEQ ID NO: 43), (b) HVR-H2 comprising the amino acid sequence SRISSNGGSTYYADSVKG (SEQ ID NO: 27), (c) HVR-H3 comprising the amino acid sequence WIPQSYPFASYKSGFDY (SEQ ID NO: 44), (d) HVR-L1 comprising the amino acid sequence RASQVMGYYLA (SEQ ID NO: 45); (e) HVR-L2 comprising the amino acid sequence DASSLES (SEQ ID NO: 46); and (f) HVR-L3 comprising the amino acid sequence QQYYSYPFT (SEQ ID NO: 47).

12. The nucleic acid of claim 1 , wherein the antibody comprises (a) HVR-H1 comprising the amino acid sequence GFTFSSYAMH (SEQ ID NO: 43), (b) HVR-H2 comprising the amino acid sequence SRISSNGGSTYYADSVKG (SEQ ID NO: 27), (c) HVR-H3 comprising the amino acid sequence WIPQSYPFASYKSGFDY (SEQ ID NO: 44), (d) HVR-L1 comprising the amino acid sequence RASQGISSYLA (SEQ ID NO: 29); (e) HVR-L2 comprising the amino acid sequence DASSLES (SEQ ID NO: 46); and (f) HVR-L3 comprising the amino acid sequence QQYYSYPFT (SEQ ID NO: 47).

13. The nucleic acid of claim 1 , wherein the antibody is a monoclonal antibody.

14. The nucleic acid of claim 1 , wherein the antibody is a human, humanized, or chimeric antibody.

15. The nucleic acid of claim 1 , wherein the antibody is an antibody fragment that binds LRP5.

16. The nucleic acid of claim 1 , wherein the antibody is a full length IgG1 antibody.

17. The nucleic acid of claim 1 , wherein the antibody further comprises one or more heavy chain variable domain framework sequences selected from the group consisting of SEQ ID NO: 34-37.

18. An isolated nucleic acid encoding an antibody comprising a VH sequence of one of SEQ ID NOs: 1 to 11 and a VL sequence of one of SEQ ID NOs: 12 to

Assignees

• Genentech Inc
• Genentech Inc

Inventors

• Wu Yan
• Ye Weilan
• Burton Jeremy Bryant
• Chiu Cecilia

Classifications

• A61K39/395

  Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum · CPC title

• C07K2317/21

  from primates, e.g. man · CPC title

• A61K47/6849

  the antibody targeting a receptor, a cell surface antigen or a cell surface determinant · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• C07H21/04

  with deoxyribosyl as saccharide radical · CPC title