Humanized anti-FGF19 antagonists and methods using same
The present invention concerns antagonists of the FGF19/FGFR4 pathways, and the uses of same.
1. A method for treating a cancer associated with expression and/or activity of FGF 19, the method comprising administering an effective amount of an anti-FGF19 antibody, comprising:
(a) a light chain comprising: (i) hypervariable region (HVR)-L1 comprising sequence A1-A11, wherein A1-A11 is KASQDINSFLA (SEQ ID NO: 11); (ii) HVR-L2 comprising sequence B I-B7, wherein B1-B7 is RANRLVD (SEQ ID NO:2), RANRLVS (SEQ ID NO: 13), or RANRLVE (SEQ ID NO: 14); and (iii) HVR-L3 comprising sequence C1-C9, wherein C1-C9 is LQYDEFPLT (SEQ ID NO:3); and
(b) a heavy chain comprising: (i) HVR-H1 comprising sequence D1-D10, wherein D1-D10 is GFSLTTYGVH (SEQ ID NO:4); (ii) HVR-H2 comprising sequence E1-E17, wherein E1-E17 is GVIWPGGGTDYNAAFIS (SEQ ID NO:7); and (iii) HVR-H3 comprising sequence F1-F13, wherein F1-F13 is VRKEYANLYAMDY (SEQ ID NO:8) to an individual in need of such treatment.
2. The method of claim 1 , wherein the cancer is selected from the group consisting of breast cancer, colorectal cancer, lung cancer, esophageal cancer, bladder cancer, ovarian cancer, pancreatic cancer, and hepatocellular carcinoma.
3. The method of claim 2 , wherein the cancer is colorectal cancer or hepatocellular carcinoma.
4. The method of claim 3 , wherein the cancer is hepatocellular carcinoma.
5. The method of claim 1 , further comprising administering to the subject an effective amount of a second medicament, wherein the anti-FGF19 antibody is a first medicament.
6. The method of claim 5 , wherein the second medicament is another antibody, a chemotherapeutic agent, a cytotoxic agent, an anti-angiogenic agent, an immunosuppressive agent, a prodrug, a cytokine, a cytokine antagonist, cytotoxic radiotherapy, a corticosteroid, an anti-emetic, a cancer vaccine, an analgesic, or a growth-inhibitory agent.
7. The method of claim 6 , wherein the second medicament is tamoxifen, letrozole, exemestane, anastrozole, irinotecan, cetuximab, fulvestrant, vinorelbine, erlotinib, bevacizumab, vincristine, imatinib, sorafenib, lapatinib, or trastuzumab.
8. The method of claim 5 , wherein the second medicament is administered prior to or subsequent to the administration of the anti-FGF19 antibody.
9. The method of claim 5 , wherein the second medicament is administered concurrently with the anti-FGF19 antibody.
10. The method of claim 1 , wherein the antibody is humanized.
11. The method of claim 1 , wherein B1-B7 is RANRLVD (SEQ ID NO:2).
12. The method of claim 1 , wherein B1-B7 is RANRLVS (SEQ ID NO:13).
13. The method of claim 1 , wherein B1-B7 is RANRLVE (SEQ ID NO:14).
14. The method of claim 1 , wherein LC-FR1 comprises SEQ ID NO:42, LC-FR2 comprises SEQ ID NO:43, LC-FR3 comprises SEQ ID NO:44, and LC-FR4 comprises SEQ ID NO:45.
15. The method of claim 14 , wherein HC-FR1 comprises SEQ ID NO:46, HC-FR2 comprises SEQ ID NO:47, HC-FR3 comprises SEQ ID NO:48, and HC-FR4 comprises SEQ ID NO:49.
16. The method of claim 1 , wherein the antibody comprises a human consensus framework sequence.
17. The method of claim 16 , wherein the human consensus framework sequence comprises a human K subgroup 1 consensus framework sequence.
18. The method of claim 16 , wherein the human consensus framework sequence comprises a heavy chain human subgroup III consensus framework sequence.