Anti-B7-H4 antibodies and immunoconjugates

Patent metadata

Field	Value
Publication number	US-10150813-B2
Application number	US-201414773334-A
Country	US
Kind code	B2
Filing date	Mar 13, 2014
Priority date	Mar 14, 2013
Publication date	Dec 11, 2018
Grant date	Dec 11, 2018

Abstract

The disclosure provides anti-B7-H4 antibodies and immunoconjugates and methods of using the same.

First claim

What is claimed is:

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 E

and wherein R 2 and R 6 are each methyl, R 3 and R 4 are each isopropyl, R 5 is H, is sec-butyl, each R 8 is independently selected from CH 3 , O—CH 3 , OH, and H; R 9 is H; and R 1-8 is C(R 8 ) 2 C(R 8 ) 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:

wherein the dotted lines indicate the optional presence of a double bond between C1 and C2 or C2 and C3;
R 2 is independently selected from H, OH, ═O, ═CH 2 , CN, R, OR, ═CH—R D , ═C(R D ) 2 , O—SO 2 —R, CO 2 R and COR, and optionally further selected from halo or dihalo, wherein R D is independently selected from R, CO 2 R, COR, CHO, CO 2 H, and halo;
R 6 and R 9 are independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, NO 2 , Me 3 Sn and halo;
R 7 is independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, NO 2 , Me 3 Sn and halo;
Q is independently selected from O, S and NH;
R 11 is either H, or R or, where Q is O, SO 3 M, where M is a metal cation;
R and R′ are each independently selected from optionally substituted C 1-8 alkyl, C 3-8 heterocyclyl and C 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 12 , R 16 , R 19 and R 17 are as defined for R 2 , R 6 , R 9 and R 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:

wherein n is 0 or 1.

26. The immunocon

Assignees

• Genentech Inc

Inventors

• Leong Steven R
• Polson Andrew
• Polakis Paul
• Wu Yan
• Liang Wei-Ching
• Firestein Ron

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61K47/6849

  the antibody targeting a receptor, a cell surface antigen or a cell surface determinant · CPC title

• A61K47/6855

  the tumour determinant being from breast cancer cell · CPC title

• A61K47/6801

  Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent · CPC title