Material and methods for treating or preventing HER-3 associated diseases
Described herein are materials and methods for treating subjects having a HER-3 associated disease, by administering a first agent that binds to HER-3, in combination with a second agent that binds and/or inhibits another member of the HER family. The first and the second agent may be a biologic, such as an antigen-binding protein, or a small molecular tyrosine kinase inhibitor, for example.
1. A method of treating a cancer associated with HER-3 in a subject, comprising administering to the subject a first agent and a second agent, wherein said first agent is an isolated antigen-binding protein which binds to HER-3, comprising:
(a) 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;
(b) 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;
(c) 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; or
(d) 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;
and said second agent is cetuximab.
2. The method of claim 1 , wherein said first agent is an antigen-binding protein that binds to HER-3, and comprises the heavy chain amino acid sequence of SEQ ID NO:42 and the light chain amino acid sequence of SEQ ID NO:44.
3. The method of claim 1 , wherein said first agent is an antigen-binding protein that binds to HER-3, and comprises the heavy chain amino acid sequence of SEQ ID NO:54 and the light chain amino acid sequence of SEQ ID NO: 56.
4. The method of claim 1 , wherein said first agent is an antigen-binding protein that binds to HER-3, and comprises the heavy chain amino acid sequence of SEQ ID NO:70 and the light chain amino acid sequence of SEQ ID NO:72.
5. The method of claim 1 , wherein said first agent is an antigen-binding protein that binds to HER-3, and comprises the heavy chain amino acid sequence of SEQ ID NO:92 and the light chain amino acid sequence of SEQ ID NO:94.
6. The method of claim 1 , wherein said first agent is an antigen-binding protein that binds to HER-3, and comprises the heavy chain amino acid sequence of SEQ ID NO:96 and the light chain amino acid sequence of SEQ ID NO:98.
7. The method of claim 1 , wherein said antigen-binding protein is directed against the extracellular domain of HER-3.
8. The method of claim 1 , wherein binding of said antigen-binding protein to HER-3 reduces HER-3-mediated signal transduction.
9. The method of claim 1 , wherein binding of said antigen-binding protein to HER-3 reduces HER-3 phosphorylation.
10. The method of any one of claim 1 , wherein binding of said antigen-binding protein to HER-3 reduces cell proliferation.
11. The method of any one of claim 1 , wherein binding of said antigen-binding protein to HER-3 reduces cell migration.
12. The method of any one of claim 1 , wherein binding of said antigen-binding protein to HER-3 increases the downregulation of HER-3.
13. The method of any one of claim 1 , wherein said antigen-binding protein that binds to HER-3 is an antibody.
14. The method of claim 13 , wherein said antibody is a monoclonal antibody, a recombinant antibody, a human antibody, a chimeric antibody, a multispecific antibody, or an antibody fragment thereof.
15. The method of claim 14 , wherein said antibody fragment is a Fab fragment, a Fab′ fragment, a F(ab′)2 fragment, a Fv fragment, a diabody, or a single chain antibody molecule.
16. The method of claim 14 , wherein said antibody is of the IgG1-, IgG2-, IgG3- or IgG4-type.
17. The method of claim 1 , wherein said antigen-binding protein is coupled to an effector group.
18. The method of claim 17 , wherein said effector group is a radioisotope or radionuclide, a toxin, or a therapeutic or chemotherapeutic group.
19. The method of claim 18 , wherein said therapeutic or chemotherapeutic group is selected from the group consisting of calicheamicin, auristatin-PE, geldanamycin, maytansine and derivatives thereof.
20. The method of claim 1 , optionally comprising administering a further therapeutic agent and/or radiation therapy.
21. The method of claim 20 , wherein the further therapeutic agent is an anti-neoplastic agent.
22. The method of claim 21 , wherein the anti-neoplastic agent is an anti-tumor antibody or a chemotherapeutic agent.
23. The method of claim 22 , wherein the chemotherapeutic agent is selected from the group consisting of capecitabine, anthracycline, doxorubicin, cyclophosphamide, paclitaxel, docetaxel, cisplatin, gemcitabine, and carboplatin.
24. The method of claim 1 , wherein said first agent and said second agent are administered by intravenous, subcutaneous, intramuscular or oral administration.
25. The method of claim 1 , wherein said cancer is selected from the group consisting of breast cancer, ovarian cancer, prostate cancer, colon cancer, renal cancer, lung cancer, pancreatic cancer, epidermoid carcinoma, fibrosarcoma, melanoma, head and neck cancer, nasopharyngeal carcinoma, and squamous cell carcinoma.
26. The method of claim 25 , comprising administering said first agent at a dose of about 1 to about 20 mg/kg body weight, at least once every 6 weeks.
27. The method of claim 25 , comprising administering said second agent at a dose of about 1 to about 20 mg/kg body weight, at least once every 6 weeks.
28. The method of claim 25 , further comprising, after the administering, monitoring the therapeutic outcome.
29. A method of treating a cancer associated with HER-3 in a subject, comprising administering to the subject a first agent and a second agent, wherein said first agent is an isolated binding protein which binds to HER-3, comprising a heavy chain amino acid sequence selected from the group consisting of SEQ ID NOs:42, 54, 70, 92, and 96, and a light chain, and said second agent is cetuximab.
30. A method of treating a cancer associated with HER-3 in a subject, comprising administering to the subject a first agent and a second agent, wherein said first agent is an isolated binding protein which binds to HER-3, comprising a light chain amino acid sequence selected from the group consisting of SEQ ID NOs:44, 56, 72, 94, and 98, and a heavy chain, and said second agent is cetuximab.
31. A method of treating a cancer associated with HER-3 in a subject, comprising administering to the subject a first agent and a second agent, wherein said first agent is an antigen-binding protein that binds to HER-3 and comprises the heavy chain amino acid sequence of SEQ ID NO:70 and the light chain amino acid sequence of SEQ ID NO:72, and wherein said second agent is cetuximab.