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Last Updated: March 29, 2024

Claims for Patent: 10,150,813


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Summary for Patent: 10,150,813
Title:Anti-B7-H4 antibodies and immunoconjugates
Abstract: The disclosure provides anti-B7-H4 antibodies and immunoconjugates and methods of using the same.
Inventor(s): Leong; Steven R. (Berkeley, CA), Polson; Andrew (San Francisco, CA), Polakis; Paul (Mill Valley, CA), Wu; Yan (Foster City, CA), Liang; Wei-Ching (Foster City, CA), Firestein; Ron (Burlingame, CA)
Assignee: Genentech, Inc. (South San Francisco, CA)
Application Number:14/773,334
Patent Claims:1. An isolated antibody that binds to B7-H4, wherein the antibody comprises: (a) (i) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 7, (ii) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 10, and (iii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 6; or (b) (i) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 41, (ii) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 44, and (iii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 40.

2. An isolated antibody that binds to B7-H4, wherein the antibody comprises: (a) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 5, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 6, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 7; or (b) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 39, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 40, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 41.

3. The antibody of claim 2, further comprising a heavy chain framework FR3 sequence of SEQ ID NO: 51, 52 or 53.

4. An isolated antibody that binds to B7-H4, wherein the antibody comprises: (a) (i) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 7, (ii) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 10, (iii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 6, (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 8, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 9, and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 10; or (b) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 39, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 40, (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 41, (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 42, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 43, and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 44.

5. The antibody of claim 4, which is a monoclonal antibody.

6. The antibody of claim 4, which is a human, humanized, or chimeric antibody.

7. The antibody of claim 4, which is an antibody fragment that binds B7-H4.

8. The antibody of claim 4, wherein B7-H4 is human B7-H4 of SEQ ID NO: 73.

9. An isolated antibody that binds to B7-H4, wherein the antibody comprises: (a) (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 8, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 9, and (iii) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 10; or (b) (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 42, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 43, and (iii) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 44.

10. The antibody of claim 9, further comprising a light chain framework FR3 sequence of SEQ ID NO: 47.

11. The antibody of claim 4, wherein the antibody comprises (a) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 4; or (b) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 3; or (c) a VH sequence as in (a) and a VL sequence as in (b); or (d) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 36; or (e) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 35; or (f) a VH sequence as in (d) and a VL sequence as in (e); or (g) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 37; or (h) a VH sequence as in (g) and a VL sequence as in (e); or (i) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 38; or (j) a VH sequence as in (i) and a VL sequence as in (e).

12. The antibody of claim 11, comprising a VH sequence of SEQ ID NO: 4, a VH sequence of SEQ ID NO: 36, a VH sequence of SEQ ID NO: 37, or a VH sequence of SEQ ID NO: 38.

13. The antibody of claim 11, comprising a VL sequence of SEQ ID NO: 3 or a VL sequence of SEQ ID NO: 35.

14. An isolated antibody that binds to B7-H4 comprising (a) a VH sequence of SEQ ID NO: 4 and a VL sequence of SEQ ID NO: 3; or (b) a VH sequence of SEQ ID NO: 36 and a VL sequence of SEQ ID NO: 35; or (c) a VH sequence of SEQ ID NO: 37 and a VL sequence of SEQ ID NO: 35; or (d) a VH sequence of SEQ ID NO: 38 and a VL sequence of SEQ ID NO: 35.

15. The antibody of claim 4, which is an IgG1, IgG2a or IgG2b antibody.

16. Isolated nucleic acid encoding the antibody of claim 4.

17. A host cell comprising the nucleic acid of claim 16.

18. A method of producing an antibody comprising culturing the host cell of claim 17 so that the antibody is produced.

19. An immunoconjugate comprising the antibody of claim 4 and a cytotoxic agent.

20. The immunoconjugate of claim 19 having the formula Ab-(L-D)p, wherein: (a) Ab is the antibody; (b) L is a linker; (c) D is a drug selected from a maytansinoid, an auristatin, a calicheamicin, a pyrrolobenzodiazepine, and a nemorubicin derivative; and (d) p ranges from 1-8.

21. The immunoconjugate of claim 20, wherein D is an auristatin.

22. The immunoconjugate of claim 21, wherein D has formula D.sub.E ##STR00048## and wherein R.sup.2 and R.sup.6 are each methyl, R.sup.3 and R.sup.4 are each isopropyl, R.sup.5 is H, is sec-butyl, each R.sup.8 is independently selected from CH.sub.3, O--CH.sub.3, OH, and H; R.sup.9 is H; and R.sup.1-8 is C(R.sup.8).sub.2C(R.sup.8).sub.2-aryl.

23. The immunoconjugate of claim 20, wherein the drug is MMAE.

24. The immunoconjugate of claim 20, wherein D is a pyrrolobenzodiazepine of Formula A: ##STR00049## wherein the dotted lines indicate the optional presence of a double bond between C1 and C2 or C2 and C3; R.sup.2 is independently selected from H, OH, .dbd.O, .dbd.CH.sub.2, CN, R, OR, .dbd.CH--R.sup.D, .dbd.C(R.sup.D).sub.2, O--SO.sub.2--R, CO.sub.2R and COR, and optionally further selected from halo or dihalo, wherein R.sup.D is independently selected from R, CO.sub.2R, COR, CHO, CO.sub.2H, and halo; R.sup.6 and R.sup.9 are independently selected from H, R, OH, OR, SH, SR, NH.sub.2, NHR, NRR', NO.sub.2, Me.sub.3Sn and halo; R.sup.7 is independently selected from H, R, OH, OR, SH, SR, NH.sub.2, NHR, NRR', NO.sub.2, Me.sub.3Sn and halo; Q is independently selected from O, S and NH; R.sup.11 is either H, or R or, where Q is O, SO.sub.3M, where M is a metal cation; R and R' are each independently selected from optionally substituted C.sub.1-8 alkyl, C.sub.3-8 heterocyclyl and C.sub.5-20 aryl groups, and optionally in relation to the group NRR', R and R' together with the nitrogen atom to which they are attached form an optionally substituted 4-, 5-, 6- or 7-membered heterocyclic ring; R.sup.12, R.sup.16, R.sup.19 and R.sup.17 are as defined for R.sup.2, R.sup.6, R.sup.9 and R.sup.7 respectively; R'' is a C3-12 alkylene group, which chain may be interrupted by one or more heteroatoms and/or aromatic rings that are optionally substituted; and X and X' are independently selected from O, S and N(H).

25. The immunoconjugate of claim 24, wherein D has the structure: ##STR00050## wherein n is 0 or 1.

26. The immunoconjugate of claim 20, wherein D is a nemorubicin derivative.

27. The immunoconjugate of claim 26, wherein D has a structure selected from: ##STR00051##

28. The immunoconjugate of claim 20, wherein the linker is cleavable by a protease.

29. The immunoconjugate of claim 28, wherein the linker comprises a val-cit dipeptide or a Phe-homoLys dipeptide.

30. The immunoconjugate of claim 20, wherein the linker is acid-labile.

31. The immunoconjugate of claim 30, wherein the linker comprises hydrazone.

32. The immunoconjugate of claim 22 having the formula: ##STR00052## wherein S is a sulfur atom.

33. The immunoconjugate of claim 25 having the formula: ##STR00053##

34. The immunoconjugate of claim 27 having a formula selected from: ##STR00054## ##STR00055##

35. The immunoconjugate of claim 20, wherein p ranges from 2-5.

36. The immunoconjugate of claim 20, wherein the antibody is an isolated antibody that binds to B7-H4 comprising (a) a VH sequence of SEQ ID NO: 4 and a VL sequence of SEQ ID NO: 3; or (b) a VH sequence of SEQ ID NO: 36 and a VL sequence of SEQ ID NO: 35; or (c) a VH sequence of SEQ ID NO: 37 and a VL sequence of SEQ ID NO: 35; or (d) a VH sequence of SEQ ID NO: 38 and a VL sequence of SEQ ID NO: 35.

37. A pharmaceutical formulation comprising the immunoconjugate of claim 20 and a pharmaceutically acceptable carrier.

38. The pharmaceutical formulation of claim 37, further comprising an additional therapeutic agent.

39. The pharmaceutical formulation of claim 38, wherein the additional therapeutic agent is Avastin.RTM. (bevacizumab).

40. A method of treating an individual having a B7-H4-positive cancer, the method comprising administering to the individual an effective amount of the immunoconjugate of claim 20.

41. The method of claim 40, wherein the B7-H4-positive cancer is selected from breast cancer, ovarian cancer, and endometrial cancer.

42. The method of claim 41, further comprising administering an additional therapeutic agent to the individual.

43. The method of claim 42, wherein the additional therapeutic agent is Avastin.RTM. (bevacizumab).

44. A method of inhibiting proliferation of an B7-H4-positive cell, the method comprising exposing the cell to the immunoconjugate of claim 20 under conditions permissive for binding of the immunoconjugate to B7-H4 on the surface of the cell, thereby inhibiting proliferation of the cell.

45. The method of claim 44, wherein the cell is a breast, ovarian, or endometrial cancer cell.

46. The antibody of claim 4 conjugated to a label.

47. The antibody of claim 46, wherein the label is a positron emitter.

48. The antibody of claim 47, wherein the positron emitter is .sup.89Zr.

49. A method of detecting human B7-H4 in a biological sample comprising contacting the biological sample with the anti-B7-H4 antibody of claim 4 under conditions permissive for binding of the anti-B7-H4 antibody to a naturally occurring human B7-H4, and detecting whether a complex is formed between the anti-B7-H4 antibody and a naturally occurring human B7-H4 in the biological sample.

50. The method of claim 49, wherein the anti-B7-H4 antibody is an antibody as in claim 4.

51. The method of claim 49, wherein the biological sample is a breast cancer sample, ovarian cancer sample, or endometrial cancer sample.

52. A method for detecting an B7-H4-positive cancer comprising (i) administering a labeled anti-B7-H4 antibody to a subject having or suspected of having a B7-H4-positive cancer, wherein the labeled anti-B7-H4 antibody comprises the anti-B7-H4 antibody of claim 4, and (ii) detecting the labeled anti-B7-H4 antibody in the subject, wherein detection of the labeled anti-B7-H4 antibody indicates a B7-H4-positive cancer in the subject.

53. The method of claim 52, wherein the labeled anti-B7-H4 antibody is an antibody as in claim 14 that is labeled.

54. The method of claim 52, wherein the labeled anti-B7-H4 antibody comprises an anti-B7-H4 antibody conjugated to a positron emitter.

55. The method of claim 54, wherein the positron emitter is .sup.89Zr.

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