Anti-mesothelin antibodies and immunoconjugates
The invention provides anti-mesothelin antibodies and immunoconjugates and methods of using the same.
1. An isolated antibody that binds to mesothelin, wherein the antibody comprises (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:20, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:21, (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO:22, (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO:17, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO:18, and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO:19.
2. The antibody of claim 1 , which is a monoclonal antibody.
3. The antibody of claim 1 , which is a human, humanized, or chimeric antibody.
4. The antibody of claim 1 , which is an antibody fragment that binds mesothelin.
5. The antibody of claim 1 , wherein mesothelin is human mesothelin of SEQ ID NO:43.
6. The antibody of claim 1 , wherein the antibody binds an epitope of SEQ ID NO:43, wherein the epitope comprises E153 and D174 according to the numbering of SEQ ID NO:43, and that optionally has one or more of the following characteristics:
(a) does not exhibit reduced binding to glycosylated forms of mesothelin compared to unglycosylated forms of mesothelin;
(b) does not block binding of mesothelin to Mucin 16 (MUC16); and/or
(c) binds mesothelin with an affinity of less than or equal to 5 nM.
7. The antibody of claim 6 , wherein the antibody does not block binding of mesothelin to MUC16.
8. The antibody of claim 7 , wherein the antibody does not block binding of glycosylated forms of mesothelin to MUC16 compared to unglycosylated forms of mesothelin.
9. The antibody of claim 6 , wherein the antibody does not exhibit reduced binding to glycosylated forms of mesothelin compared to unglycosylated forms of mesothelin.
10. The antibody of claim 1 , further comprising a light chain variable domain comprising a framework FR2 sequence of SEQ ID NO:25 and an FR3 sequence of SEQ ID NO:27.
11. The antibody of claim 1 , wherein the antibody comprises
(a) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:8;
(b) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:4; or
(c) a VH sequence as in (a) and a VL sequence as in (b).
12. The antibody of claim 1 , comprising a VH sequence of SEQ ID NO:8.
13. The antibody of claim 1 , comprising a VL sequence of SEQ ID NO:4.
14. The antibody of claim 1 , which is an IgG1, IgG2a or IgG2b antibody.
15. The antibody of claim 1 conjugated to a label.
16. The antibody of claim 15 , wherein the label is a positron emitter.
17. The antibody of claim 16 , wherein the positron emitter is 89 Zr.
18. An antibody comprising a VH sequence of SEQ ID NO:8 and a VL sequence of SEQ ID NO:4.
19. An immunoconjugate having the formula Ab-(L-D)p, wherein:
(a) Ab is the antibody of claim 1 ;
(b) L is a linker;
(c) D is a drug of formula D E
and wherein R 2 and R 6 are each methyl, R 3 and R 4 are each isopropyl, R 5 is H, R 7 is sec-butyl, each R 8 is independently selected from CH 3 , O—CH 3 , OH, and H; R 9 is H; and R 18 is —C(R 8 ) 2 —C(R 8 ) 2 -aryl; and
(d) p ranges from 1-8.
20. The immunoconjugate of claim 19 , wherein the drug is an auristatin.
21. The immunoconjugate of claim 20 , wherein the drug is monomethyl auristatin E (MMAE).
22. The immunoconjugate of claim 19 , wherein the linker is cleavable by a protease.
23. The immunoconjugate of claim 22 , wherein the linker comprises a val-cit dipeptide.
24. The immunoconjugate of claim 19 having the formula:
wherein S is a sulfur atom.
25. The immunoconjugate of claim 24 , wherein p ranges from 2-5.
26. The immunoconjugate of claim 24 , comprising the antibody of claim 6 .
27. The immunoconjugate of claim 24 , comprising the antibody of claim 18 .
28. A pharmaceutical formulation comprising the immunoconjugate of claim 19 and a pharmaceutically acceptable carrier.
29. The pharmaceutical formulation of claim 28 , further comprising an additional therapeutic agent.
30. The pharmaceutical formulation of claim 29 , wherein the additional therapeutic agent is gemcitabine.
31. The pharmaceutical formulation of claim 29 , wherein the additional therapeutic agent is an anti-MUC16 antibody conjugated to a cytotoxic agent.