Antibodies directed to HER-3 and uses thereof
View Patent ↗The present invention relates to binding proteins that bind to HER-3 and polynucleotides encoding the same. Expression vectors and host cells comprising the same for the production of the binding protein of the invention are also provided. In addition, the invention provides compositions and methods for diagnosing and treating diseases associated with HER-3 mediated signal transduction and/or its ligand heregulin.
1. An isolated binding protein that binds to HER-3, comprising a heavy chain amino acid sequence that comprises a CDRH1 having the sequence of SEQ ID NO: 236, a CDRH2 having the sequence of SEQ ID NO: 258, and a CDRH3 having the sequence of SEQ ID NO: 283; and a light chain amino acid sequence that comprises a CDRL1 having the sequence of SEQ ID No: 320, a CDRL2 having the sequence of SEQ ID NO: 343, and a CDRL3 having the sequence of SEQ ID NO: 360.
2. An isolated binding protein that binds to HER-3, comprising a heavy chain amino acid sequence that comprises a CDRH1 having the sequence of SEQ ID NO: 236, a CDRH2 having the sequence of SEQ ID NO: 258, and a CDRH3 having the sequence of SEQ ID NO: 285; and a light chain amino acid sequence that comprises a CDRL1 having the sequence of SEQ ID No: 320, a CDRL2 having the sequence of SEQ ID NO: 343, and a CDRL3 having the sequence of SEQ ID NO: 360.
3. An isolated binding protein that binds to HER-3, comprising a heavy chain amino acid sequence that comprises a CDRH1 having the sequence of SEQ ID NO: 251, a CDRH2 having the sequence of SEQ ID NO: 278, and a CDRH3 having the sequence of SEQ ID NO: 309; and a light chain amino acid sequence that comprises a CDRL1 having the sequence of SEQ ID No: 334, a CDRL2 having the sequence of SEQ ID NO: 356, and a CDRL3 having the sequence of SEQ ID NO: 381.
4. An isolated binding protein that binds to HER-3, comprising a heavy chain amino acid sequence that comprises a CDRH1 having the sequence of SEQ ID NO: 252, a CDRH2 having the sequence of SEQ ID NO: 280, and a CDRH3 having the sequence of SEQ ID NO: 313; and a light chain amino acid sequence that comprises a CDRL1 having the sequence of SEQ ID No: 337, a CDRL2 having the sequence of SEQ ID NO: 351, and a CDRL3 having the sequence of SEQ ID NO: 385.
5. The isolated binding protein of claim 4 , wherein the binding protein is directed against the extracellular domain of HER-3.
6. The isolated binding protein of claim 4 , wherein the binding of the binding protein to HER-3 reduces HER-3-mediated signal transduction.
7. The isolated binding protein of claim 4 , wherein the binding of the binding protein to HER-3 reduces HER-3 phosphorylation.
8. The isolated binding protein of claim 4 , wherein the binding of the binding protein to HER-3 reduces cell proliferation.
9. The isolated binding protein of claim 4 , wherein the binding of the binding protein to HER-3 reduces cell migration.
10. The isolated binding protein of claim 4 , wherein the binding of the binding protein to HER-3 increases the downregulation of HER-3.
11. The isolated binding protein of claim 4 , which is an antibody.
12. The isolated binding protein of claim 11 , wherein the antibody is selected from the group consisting of a monoclonal antibody, a recombinant antibody, a humanized antibody, a chimeric antibody, a multispecific antibody, and an antibody fragment thereof.
13. The isolated binding protein of claim 12 , wherein the antibody fragment is selected from the group consisting of a Fab fragment, a Fab′ fragment, a F(ab′)2 fragment, a Fv fragment, a diabody, and a single chain antibody molecule.
14. The isolated binding protein of claim 11 , wherein antibody is selected from the group consisting of the IgG1-, IgG2-, IgG3- and IgG4-type.
15. The isolated binding protein of claim 11 , wherein the binding protein is coupled to a labelling group.
16. The isolated binding protein of claim 15 , wherein the labelling group is selected from the group consisting of a radioisotope or radionuclide, a fluorescent group, an enzymatic group, a chemiluminescent group, a biotinyl group, a leucine zipper pair sequence, a binding site for secondary antibodies, a metal binding domain and a epitope tag.
17. The isolated binding protein of claim 11 , wherein the binding protein is coupled to an effector group.
18. The isolated binding protein of claim 17 , wherein the effector group is selected from the group consisting of a radioisotope, a radionuclide, a toxin, a therapeutic group, and a chemotherapeutic group.
19. The isolated binding protein of claim 18 , wherein the therapeutic or chemotherapeutic group is selected from the group consisting of calicheamicin, auristatin-PE, geldanamycin, maytansine and derivatives thereof.
20. A pharmaceutical composition comprising as an active agent at least one isolated binding protein of claim 4 , and a pharmaceutically acceptable carrier, diluent or adjuvant.
21. The composition of claim 20 for therapeutic use.
22. The composition of claim 20 for diagnostic use.
23. A kit comprising the isolated binding protein of claim 4 .
24. The kit of claim 23 , comprising a further therapeutic agent.
25. The kit of claim 24 , wherein the further therapeutic agent is an antineoplastic agent.
26. The kit of claim 25 , wherein the anti-neoplastic agent is an anti-tumor antibody or a chemotherapeutic agent.
27. An isolated binding protein that binds to HER-3, comprising a heavy chain amino acid sequence that comprises a CDRH1 having the sequence of SEQ ID NO: 256, a CDRH2 having the sequence of SEQ ID NO: 282, and a CDRH3 having the sequence of SEQ ID NO: 315; and a light chain amino acid sequence that comprises a CDRL1 having the sequence of SEQ ID No: 340, a CDRL2 having the sequence of SEQ ID NO: 344, and a CDRL3 having the sequence of SEQ ID NO: 387.
28. The isolated binding protein of claim 27 , wherein the binding protein is directed against the extracellular domain of HER-3.
29. The isolated binding protein of claim 27 , wherein the binding of the binding protein to HER-3 reduces HER-3-mediated signal transduction.
30. The isolated binding protein of claim 27 , wherein the binding of the binding protein to HER-3 reduces HER-3 phosphorylation.
31. The isolated binding protein of claim 27 , wherein the binding of the binding protein to HER-3 reduces cell proliferation.
32. The isolated binding protein of claim 27 , wherein the binding of the binding protein to HER-3 reduces cell migration.
33. The isolated binding protein of claim 27 , wherein the binding of the binding protein to HER-3 increases the downregulation of HER-3.
34. The isolated binding protein of claim 27 , which is an antibody.
35. The isolated binding protein of claim 34 , wherein the antibody is selected from the group consisting of a monoclonal antibody, a recombinant antibody, a humanized antibody, a chimeric antibody, a multispecific antibody, and an antibody fragment thereof.
36. The isolated binding protein of claim 35 , wherein the antibody fragment is selected from the group consisting of a Fab fragment, a Fab′ fragment, a F(ab′)2 fragment, a Fv fragment, a diabody, and a single chain antibody molecule.
37. The isolated binding protein of claim 34 , wherein antibody is selected from the group consisting of the IgG1-, IgG2-, IgG3- and IgG4-type.
38. The isolated binding protein of claim 34 , wherein the binding protein is coupled to a labelling group.
39. The isolated binding protein of claim 38 , wherein the labelling group is selected from the group consisting of a radioisotope or radionuclide, a fluorescent group, an enzymatic group, a chemiluminescent group, a biotinyl group, a leucine zipper pair sequence, a binding site for secondary antibodies, a metal binding domain and a epitope tag.
40. The isolated binding protein of claim 34 , wherein the binding protein is coupled to an effector group.
41. The isolated binding protein of claim 40 , wherein the effector group is selected from the group consisting of a radioisotope, a radionuclide, a toxin, a therapeutic group, and a chemotherapeutic group.
42. The isolated binding protein of claim 41 , wherein the therapeutic or chemotherapeutic group is selected from the group consisting of calicheamicin, auristatin-PE, geldanamycin, maytansine and derivatives thereof.
43. An isolated binding protein that binds to HER-3, comprising the heavy chain amino acid sequence of SEQ ID NO: 70, and light chain amino acid sequence of SEQ ID NO: 72.
44. A pharmaceutical composition comprising as an active agent at least one isolated binding protein of claim 27 or 43 , and a pharmaceutically acceptable carrier, diluent or adjuvant.
45. The pharmaceutical composition of claim 44 for therapeutic use.
46. The pharmaceutical composition of claim 44 for diagnostic use.
47. The pharmaceutical composition of claim 44 , comprising a further therapeutic agent.
48. A method for treating a cancer associated with HER-3 in a patient, comprising administering a pharmaceutically effective amount of the pharmaceutical composition of claim 47 .
49. The pharmaceutical composition of claim 47 , wherein the further therapeutic agent is an anti-neoplastic agent.
50. A method for treating a cancer associated with HER-3 in a patient, comprising administering a pharmaceutically effective amount of the pharmaceutical composition of claim 49 .
51. The pharmaceutical composition of claim 49 , wherein the anti-neoplastic agent is an anti-tumor antibody or a chemotherapeutic agent.
52. A method for treating a cancer associated with HER-3 in a patient, comprising administering a pharmaceutically effective amount of the pharmaceutical composition of claim 51 .
53. The pharmaceutical composition of claim 51 , wherein the anti-neoplastic agent is cetuximab.
54. A method for treating a cancer associated with HER-3 in a patient, comprising administering a pharmaceutically effective amount of the pharmaceutical composition of claim 53 .
55. A kit comprising the isolated binding protein of claim 27 or 43 .
56. The kit of claim 55 , comprising a further therapeutic agent.
57. The kit of claim 56 , wherein the further therapeutic agent is an anti-neoplastic agent.
58. The kit of claim 57 , wherein the anti-neoplastic agent is an anti-tumor antibody or a chemotherapeutic agent.
59. The kit of claim 57 , wherein the anti-neoplastic agent is cetuximab.
60. An isolated binding protein that binds to HER-3, comprising the heavy chain amino acid sequence of SEQ ID NO: 92, and light chain amino acid sequence of SEQ ID NO: 94.
61. An isolated binding protein that binds to HER-3, comprising the heavy chain amino acid sequence of SEQ ID NO: 96, and light chain amino acid sequence of SEQ ID NO: 98.
62. An isolated binding protein that binds to HER-3, comprising the heavy chain amino acid sequence of SEQ ID NO: 54, and light chain amino acid sequence of SEQ ID NO: 56.