Generation of anti-FN14 monoclonal antibodies by ex-vivo accelerated antibody evolution
View Patent ↗The present invention relates generally to anti-FN14 antibodies. In particular, the anti-FN14 antibodies described herein are useful for the treatment of diseases, such as a variety of cancers, associated with expression of FN14.
1. An isolated antibody, or an antigen-binding fragment thereof, that binds to human FN14, comprising:
(a) a heavy chain variable region comprising the VHCDR1 amino acid sequence set forth in SEQ ID NO:79, and the VHCDR2 amino acid sequence set forth in SEQ ID NO:92 wherein Xaa at position 4 is Asp or Tyr and the VHCDR3 amino acid sequence set forth in SEQ ID NO:93, wherein Xaa at position 2 is Ala or Gly, Xaa at position 4 is Ser or Thr, and Xaa at position 5 is Ser or Gly; and
(b) a light chain variable region comprising the VLCDR1 amino acid sequence set forth in SEQ ID NO:86, and the VLCDR2 amino acid sequence set forth in SEQ ID NO:39 and the VLCDR3 amino acid sequence set forth in SEQ ID NO:94,wherein Xaa at position 3 is Ala or lle.
2. The isolated antibody of claim 1 wherein the VHCRD2 of the heavy chain variable region according to (a) comprises SEQ ID NO:82.
3. The isolated antibody of claim 1 wherein the VHCRD3 of the heavy chain variable region according to (a) comprises SEQ ID NO:84.
4. The isolated antibody of claim 1 wherein the VHCRD2 of the heavy chain variable region according to (a) comprises SEQ ID NO:81.
5. The isolated antibody of claim 1 wherein the VHCRD3 of the heavy chain variable region according to (a) comprises SEQ ID NO:83.
6. The isolated antibody of claim 1 wherein the VHCRD3 of the heavy chain variable region according to (a) comprises SEQ ID NO:76.
7. The isolated antibody of claim 1 wherein the VHCDR3 of the light chain variable region according to (b) comprises SEQ ID NO:41.
8. The isolated antibody of claim 1 wherein the VHCDR3 of the light chain variable region according to (b) comprises SEQ ID NO:36.
9. The isolated antibody of claim 1 wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:67.
10. The isolated antibody of claim 1 wherein the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:25.
11. The isolated antibody of claim 1 wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:66.
12. The isolated antibody of claim 1 wherein the antibody is humanized.
13. The isolated antibody, or antigen binding fragment thereof, of claim 12 wherein the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:91.
14. The isolated antibody, or antigen binding fragment thereof, of claim 12 wherein the heavy chain variable region comprises the amino acid set forth in SEQ ID NO:90.
15. The isolated antibody of claim 1 wherein the antibody is selected from the group consisting of a single chain antibody, a ScFv, a univalent antibody lacking a hinge region, and a minibody.
16. The isolated antibody of claim 1 wherein the antibody is selected from the group consisting of a Fab, a Fab' fragment, a F(ab') 2 fragment and a whole antibody.
17. The isolated antibody of claim 1 wherein the antibody is conjugated to a drug or a toxin.
18. The isolated antibody of claim 1 comprising a human IgG Fc domain.
19. The isolated antibody of claim 18 wherein the human IgG Fc domain is modified such that the antibody has enhanced .ADCC activity as compared to the antibody having the unmodified human IgG Fc domain.
20. An isolated antibody, or an antigen-binding fragment thereof, that binds to human FN14, comprising a heavy chain variable region comprising any one of the amino acid sequences set forth in SEQ ID NOs:67, 66 or 65.
21. The isolated antibody of claim 20 wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:67 and wherein said antibody further comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:25.
22. The isolated antibody of claim 20 wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:66 and wherein said antibody further comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:24.
23. The isolated antibody of claim 20 wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:65 and wherein said antibody further comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:23.
24. The isolated antibody of claim 20 wherein the antibody is selected from the group consisting of a single chain antibody, a ScFv, a univalent antibody lacking a hinge region, and a minibody.
25. The isolated antibody of claim 20 wherein the antibody is selected from the group consisting of a Fab, a Fab' fragment, a F(ab') 2 fragment and a whole antibody.
26. The isolated antibody of claim 20 wherein the antibody is conjugated to a drug or a toxin.
27. The isolated antibody of claim 20 comprising a human IgG Fc domain.
28. The isolated antibody of claim 27 wherein the human IgG Fc domain is modified such that the antibody has enhanced ADCC activity as compared to the antibody having the unmodified human IgG Fc domain.
29. An isolated antibody, or an antigen-binding fragment thereof, that binds to human FN14, comprising a light chain variable region comprising any one of the amino acid sequences set forth in SEQ ID NOs:25, 24 or 23.
30. The isolated antibody of claim 29 wherein the light chain variable region comprises SEQ ID NO:25 and wherein said antibody further comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:67.
31. The isolated antibody of claim 29 wherein the light chain variable region comprises SEQ ID NO:24 and wherein said antibody further comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:66.
32. The isolated antibody of claim 29 wherein the light chain variable region comprises SEQ ID NO:23 and wherein said antibody further comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:65.
33. The isolated antibody of claim 29 wherein the antibody is selected from the group consisting of a single chain antibody, a ScFv, a univalent antibody lacking a hinge region, and a minibody.
34. The isolated antibody of claim 29 Wherein the antibody is selected from the group consisting of a Fab, a Fab' fragment, a F(ab') 2 fragment and a whole antibody.
35. The isolated antibody of claim 29 wherein the antibody is conjugated to a drug or a toxin.
36. The isolated antibody of claim 29 comprising a human IgG Fc domain.
37. The isolated antibody of claim 36 wherein the human IgG Fc domain is modified such that the antibody has enhanced ADCC activity as compared to the antibody having the unmodified human IgG Fc domain.
38. A composition comprising a physiologically acceptable carrier and a therapeutically effective amount of the isolated antibody or antigen-binding fragment thereof according to claim 1 .