Anti-LRP5 antibodies and methods of use

{
  "publication_number": "US9522954B2",
  "country": "US",
  "kind": "B2",
  "title": "Anti-LRP5 antibodies and methods of use",
  "abstract": "The invention provides anti-LRP5 antibodies and methods of making and using the same.",
  "claims": [
    "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 22.",
    "19. The nucleic acid of claim 18, wherein the antibody comprises the VH sequence of SEQ ID NO: 1 and the VL sequence of SEQ ID NO: 12.",
    "20. The nucleic acid of claim 18, wherein the antibody comprises the VH sequence of SEQ ID NO: 2 and the VL sequence of SEQ ID NO: 13.",
    "21. The nucleic acid of claim 18, wherein the antibody comprises the VH sequence of SEQ ID NO: 3 and the VL sequence of SEQ ID NO: 14.",
    "22. The nucleic acid of claim 18, wherein the antibody comprises the VH sequence of SEQ ID NO: 4 and the VL sequence of SEQ ID NO: 15.",
    "23. The nucleic acid of claim 18, wherein the antibody comprises the VH sequence of SEQ ID NO: 5 and the VL sequence of SEQ ID NO: 16.",
    "24. The nucleic acid of claim 18, wherein the antibody comprises the VH sequence of SEQ ID NO: 6 and the VL sequence of SEQ ID NO: 17.",
    "25. The nucleic acid of claim 18, wherein the antibody comprises the VH sequence of SEQ ID NO: 7 and the VL sequence of SEQ ID NO: 18.",
    "26. The nucleic acid of claim 18, wherein the antibody comprises the VH sequence of SEQ ID NO: 8 and the VL sequence of SEQ ID NO: 19.",
    "27. The nucleic acid of claim 18, wherein the antibody comprises the VH sequence of SEQ ID NO: 9 and the VL sequence of SEQ ID NO: 20.",
    "28. The nucleic acid of claim 18, wherein the antibody comprises the VH sequence of SEQ ID NO: 10 and the VL sequence of SEQ ID NO: 21.",
    "29. The nucleic acid of claim 18, wherein the antibody comprises the VH sequence of SEQ ID NO: 11 and the VL sequence of SEQ ID NO: 22.",
    "30. A host cell comprising the nucleic acid of claim 1 or 18.",
    "31. A method of producing an antibody comprising culturing the host cell of claim 30 so that the antibody is produced."
  ],
  "description_excerpt": "The present invention relates to anti-LRP5 antibodies and methods of using the same.\n\nIt is now well established that angiogenesis is an important contributor to the pathogenesis of a variety of disorders. These include solid tumors and metastasis, intraocular neovascular diseases such as retinopathies, e.g., diabetic retinopathy, retinal vein occlusion (RVO), wet age-related macular degeneration (AMD), neovascular glaucoma, immune rejection of transplanted corneal tissue and other tissues, and rheumatoid arthritis. Duda et al. J. Clin. Oncology 25(26): 4033-42 (2007); Kesisis et al. Curr. Pharm. Des. 13: 2795-809 (2007); Zhang & Ma Prog. Ret. & Eye Res. 26: 1-37 (2007).\n\nThe retina receives its blood supply from retinal vessels, which supply the inner part of the retina, and choroidal vessels, which supply the outer part. Damage to retinal vessels occurs in several disease processes including diabetic retinopathy, retinopathy of prematurity, and central and branched retinal vein occlusions (ischemic retinopathies). Retinal ischemia from this damage results in undesirable neovascularization. Choroidal neovascularization occurs in a number of other disease processes, including AMD. In contrast, incomplete vascularization of the retina is a hallmark in patients with certain genetic diseases, e.g. familial exudative vitreoretinopathy (FEVR), Coats' disease, and Norrie disease caused by mutation of the Wnt receptor Frizzled4 (Fzd4), the co-receptor LRP5 or the secreted ligand Norrin (Berger et al. Nature Genet. 1:199-203 (1992); Chen et al. Nature Genet. 1:204-208 (1992); Robitaille et al. Nature Genet.",
  "cpc": [
    "C07K 16/28",
    "A61K 2039/505",
    "A61K 39/395",
    "A61K 47/6849",
    "A61P 27/02",
    "A61P 9/10",
    "C07H 21/04",
    "C07K 2317/21",
    "C07K 2317/24",
    "C07K 2317/56",
    "C07K 2317/567",
    "C07K 2317/75",
    "C07K 2317/92"
  ],
  "ipc": [
    "C07K 16/28",
    "A61K 39/395",
    "C07H 21/04"
  ],
  "assignees": [
    "Genentech Inc"
  ],
  "inventors": [
    "Yan Wu",
    "Weilan Ye",
    "Jeremy Bryant Burton",
    "Cecilia Chiu"
  ],
  "filing_date": "2015-10-09",
  "publication_date": "2016-12-20",
  "grant_date": "2016-12-20",
  "priority_date": "2012-01-18",
  "application_number": "US-201514879702-A",
  "family_id": "47604271",
  "cited_by_count": 3,
  "citations": [
    "WO2009036338A2",
    "WO2010030813A2",
    "US20100129375A1"
  ]
}