Antibodies to EphA3
View Patent ↗The current invention relates to high-affinity antibodies to EphA3 that have reduced immunogenicity when administered to a human to treat diseases and method of using such antibodies.
1. An anti-EphA3 antibody, comprising:
a V H region that comprises
a CDR3 having the amino acid sequence GGYYEDFDS (SEQ ID NO:43), SGYYEEFDS (SEQ ID NO:41), SGVYEDFDS (SEQ ID NO:44), SGYYEDFDS (SEQ ID NO:39), SGYYEDFDV (SEQ ID NO:45), or SGYYEDFDI (SEQ ID NO:46);
a CDR2 having the amino acid sequence DIYPGSGNTNYDEKFQG (SEQ ID NO:49); and
a CDR1 having the amino acid sequence GYWMN (SEQ ID NO:48); and
a V L region that comprises
a CDR3 having the amino acid sequence GQYANYPYT (SEQ ID NO:57), VQYANYPYT (SEQ ID NO:61), VQYSNYPYT (SEQ ID NO:60), AQYANYPYT (SEQ ID NO:59), VQYAKYPYT (SEQ ID NO:58), VGYANYPYT (SEQ ID NO:62), VRYANYPYT (SEQ ID NO:63), or VQYLNYPYT (SEQ ID NO:64);
a CDR2 having the amino acid sequence AASSLQS (SEQ ID NO:68), and
a CDR1 having the amino acid sequence RASQGIISYLA (SEQ ID NO:66).
2. The anti-EphA3 antibody of claim 1 , wherein the V H region a FR4 that has the amino acid sequence WGQGTTVTVSS (SEQ ID NO:47).
3. The anti-EphA3 antibody of 1, wherein the CDR3 of the V H region comprises GGYYEDFDS (SEQ ID NO:43) and the CDR3 of the V L region comprises GQYANYPYT (SEQ ID NO:57).
4. The anti-EphA3 antibody of claim 1 , wherein the V H region comprises a V-segment having the V-segment amino acid sequence of SEQ ID NO:1, 2, 3, 4, or 5.
5. The anti-EphA3 antibody of claim 4 , wherein the V H region comprises the amino acid sequence of SEQ ID NO:1, 2, 3, 4, or 5.
6. The anti-EphA3 antibody of claim 1 , wherein the V H region comprises a V-segment having the V-segment amino acid sequence of SEQ ID NO:5.
7. The anti-EphA3 antibody of claim 6 , wherein the V H region comprises the amino acid sequence of SEQ ID NO:5.
8. The anti-EphA3 antibody of claim 1 , wherein the V L region comprises a FR4 having the FR4 amino acid sequence FGQGTKLEIK (SEQ ID NO:69).
9. The anti-EphA3 antibody of claim 1 , wherein the V L region comprises a V-segment having the V-segment amino acid sequence of SEQ ID NO:11, 12, 13, 19, 20, 21, 22, or 23.
10. The anti-EphA3 antibody of claim 9 , wherein the V L region comprises the amino acid sequence of SEQ ID NO:11, 12, 13, 19, 20, 21, 22, or 23.
11. The anti-EphA3 antibody of claim 1 , wherein the V L region comprises a V-segment that has the V-segment amino acid sequence of SEQ ID NO:13.
12. The anti-EphA3 antibody of claim 11 , wherein the V L region comprise the amino acid sequence of SEQ ID NO:13.
13. The anti-EphA3 antibody of claim 1 , wherein the antibody comprises a V H region and a V L region selected from the group consisting of:
a) SEQ ID NO:1 and SEQ ID NO:20,
b) SEQ ID NO:2 and SEQ ID NO:11,
c) SEQ ID NO: 2 and SEQ ID NO:12,
d) SEQ ID NO:2 and SEQ ID NO:19,
e) SEQ ID NO:2 and SEQ ID NO:21,
f) SEQ ID NO:2 and SEQ ID NO:22,
g) SEQ ID NO:2 and SEQ ID NO:23,
h) SEQ ID NO:3 and SEQ ID NO:11,
i) SEQ ID NO:3 and SEQ ID NO:12,
j) SEQ ID NO:3 and SEQ ID NO:21,
k) SEQ ID NO:3 and SEQ ID NO:22,
l) SEQ ID NO:4 and SEQ ID NO:11,
m) SEQ ID NO:4 and SEQ ID NO:13,
n) SEQ ID NO:5 and SEQ ID NO:11,
o) SEQ ID NO:5 and SEQ ID NO:13, and
p) SEQ ID NO:5 and SEQ ID NO:21.
14. The anti-EphA3 antibody of claim 1 , wherein the V H region comprises the amino acid sequence of SEQ ID NO:5 and the V L region comprises the amino acid sequence of SEQ ID NO:13.
15. The anti-EphA3 antibody of claim 1 , wherein the V H region or the V L region, or both the V H and V L region amino acid sequences comprise a methionine at the N-terminus.
16. The anti-EphA3 antibody of claim 1 , wherein the antibody is an IgG.
17. The anti-EphA3 antibody of claim 16 , wherein the antibody is a IgG1 or IgG3.
18. The anti-EphA3 antibody of claim 16 , wherein the antibody is a IgG2 or IgG4.
19. The anti-EphA3 antibody of claim 16 , wherein the antibody comprises a heavy chain constant region having the amino acid sequence set forth in SEQ ID NO:24.
20. The anti-EphA3 antibody of claim 1 , wherein the antibody comprises a kappa light chain constant region having the amino acid sequence set forth in SEQ ID NO:25.
21. An anti-EphA3 antibody that has a heavy chain amino acid sequence and a light chain amino acid sequence that comprises SEQ ID NO:26 and SEQ ID NO:27, SEQ ID NO:28 and SEQ ID NO:29, SEQ ID NO:30 and SEQ ID NO:31, SEQ ID NO:32 and SEQ ID NO:33, or SEQ ID NO:34 and SEQ ID NO:35.
22. An antibody preparation comprising the anti-EphA3 antibody of claim 1 , wherein the heavy chain constant region is hypofucosylated or afucosylated.
23. The anti-EphA3 antibody of claim 1 , wherein the antibody is a (Fab′) 2 .
24. The anti-EphA3 antibody of claim 1 , wherein the antibody is PEGylated.
25. The anti-EphA3 antibody of claim 1 , wherein the antibody activates EphA3.
26. The anti-EphA3 antibody of claim 1 , wherein the antibody has an affinity of better than 10 nM.
27. The anti-EphA3 antibody of claim 26 , wherein the antibody has an affinity of better than 1 nM.
28. An anti-EphA3 antibody that has a heavy chain amino acid sequence that comprises SEQ ID NO:30 and a light chain amino acid sequence that comprises and SEQ ID NO:31, wherein the antibody is afucosylated.
29. An antibody preparation comprising the anti-EphA3 antibody of claim 28 , wherein the antibody preparation is hypofucosylated.