Anti-HER3/HER4 antibodies binding to the beta-hairpin of HER3 and the beta-hairpin of HER4
The invention relates to anti-HER3/HER4 antigen binding proteins, e.g. anti-HER3/HER4 antibodies, that bind to the beta-hairpin of HER3 and the beta-hairpin of HER4, methods for selecting these antigen binding proteins, their preparation and use as medicament.
1. An isolated antibody that binds to human HER3 and binds to human HER4, wherein the antibody comprises
(a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:25;
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:26;
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:27;
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:28;
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:29; and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:30.
2. An isolated antibody that binds to human HER3 and binds to human HER4, wherein the antibody comprises
i) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:38;
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:39;
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:27;
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:40;
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:41; and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:30; or
ii) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:38;
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:39;
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:27;
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:40;
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:42; and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:30; or
iii) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:25;
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:39;
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:27;
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:40;
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:41; and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:30; or
iv) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:25;
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:39;
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:27;
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:40;
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:42; and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:30.
3. An antibody comprising:
a) a VH sequence of SEQ ID NO:33 and a VL sequence of SEQ ID NO:36; or
b) a VH sequence of SEQ ID NO:33 and a VL sequence of SEQ ID NO:37; or
c) a VH sequence of SEQ ID NO:34 and a VL sequence of SEQ ID NO:36; or
d) a VH sequence of SEQ ID NO:34 and a VL sequence of SEQ ID NO:37; or
e) a VH sequence of SEQ ID NO:35 and a VL sequence of SEQ ID NO:36; or
f) a VH sequence of SEQ ID NO:35 and a VL sequence of SEQ ID NO:37.
4. The antibody of claim 1 or claim 2 , which is a full length IgG1 antibody or IgG4 antibody.
5. The antibody of claim 1 or claim 2 , which is a Fab fragment.
6. An immunoconjugate comprising the antibody of claim 1 or claim 2 and a cytotoxic agent.
7. A pharmaceutical formulation comprising the antibody of claim 1 or claim 2 and a pharmaceutically acceptable carrier.
8. The antibody of claim 2 , wherein the antibody comprises
(a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:38;
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:39;
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:27;
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:40;
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:41; and
f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:30.
9. The antibody of claim 2 , wherein the antibody comprises
(a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:38;
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:39;
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:27;
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:40;
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:42; and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:30.
10. The antibody of claim 2 , wherein the antibody comprises
(a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:25;
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:39;
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:27;
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:40;
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:41; and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:30.
11. The antibody of claim 2 , wherein the antibody comprises
(a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:25;
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:39;
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:27;
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:40;
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:42; and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:30.
12. The antibody of claim 3 , wherein the antibody comprises a VH sequence of SEQ ID NO:33 and a VL sequence of SEQ ID NO:36.
13. The antibody of claim 3 , wherein the antibody comprises a VH sequence of SEQ ID NO:33 and a VL sequence of SEQ ID NO:37.
14. The antibody of claim 3 , wherein the antibody comprises a VH sequence of SEQ ID NO:34 and a VL sequence of SEQ ID NO:36.
15. The antibody of claim 3 , wherein the antibody comprises a d) a VH sequence of SEQ ID NO:34 and a VL sequence of SEQ ID NO:37.
16. The antibody of claim 3 , wherein the antibody comprises a VH sequence of SEQ ID NO:35 and a VL sequence of SEQ ID NO:36.
17. The antibody of claim 3 , wherein the antibody comprises a VH sequence of SEQ ID NO:35 and a VL sequence of SEQ ID NO:37.