Anti-b7-h4 antibodies and immunoconjugates

Patent metadata

Field	Value
Publication number	US-2017239366-A1
Application number	US-201615386577-A
Country	US
Kind code	A1
Filing date	Dec 21, 2016
Priority date	Mar 14, 2013
Publication date	Aug 24, 2017
Grant date	—

Abstract

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

First claim

1 - 19 . (canceled)

20 . An immunoconjugate comprising an antibody that binds to B7-H4 and a cytotoxic agent, wherein the antibody comprises:
(a)(i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 29, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 30, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 31; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 32, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33, and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 34; or (b)(i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 58, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 59, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 60; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 61, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 62, and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 63.

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

22 . The immunoconjugate of claim 20 , wherein the cytotoxic agent is an auristatin.

23 . 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, 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.

24 . The immunoconjugate of claim 20 , wherein the cytotoxic agent is MMAE.

25 . The immunoconjugate of claim 21 , 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, and
R 11 is either H or R; or Q is O and R 11 is 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 C 3-12 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).

26 . The immunoconjugate of claim 25 , wherein D has the structure:

wherein n is 0 or 1.

27 . The immunoconjugate of claim 20 , wherein the cytotoxic agent is a nemorubicin derivative.

28 . The immunoconjugate of claim 21 , wherein D has a structure selected from:

29 . The immunoconjugate of claim 21 , wherein the linker is cleavable by a protease.

30 . The immunoconjugate of claim 29 , wherein the linker comprises a valine-citrulline dipeptide, an alanine-phenylalanine dipeptide, a phenylalanine-lysine dipeptide, a phenylalanine-homolysine dipeptide, or a N-methyl-valine-citrulline dipeptide.

31 . The immunoconjugate of claim 21 , wherein the linker is acid-labile.

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

33 . The immunoconjugate of claim 21 having the formula:

wherein S is a sulfur atom.

34 . The immunoconjugate of claim 21 having the formula:

35 . The immunoconjugate of claim 21 having a formula selected from:

36 . The immunoconjugate of claim 21 , wherein p ranges from 2-5.

37 . The immunoconjugate of claim 20 , wherein the antibody comprises:
(a) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 28; or (b) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 27; 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: 56; or (e) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 55; or (f) a VH sequence as in (d) and a VL sequence as in (e); or (g) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 57; or (h) a VH sequence as in (d) and a VL sequence as in (g).

38 . The immunoconjugate of claim 20 , wherein comprising the antibody of claim 15 comprises (a) a VH sequence of SEQ ID NO: 28 and a VL sequence of SEQ ID NO: 27; or (b) a VH sequence of SEQ ID NO: 56 and a VL sequence of SEQ ID NO: 55; or (c) a VH sequence of SEQ ID NO: 56 and a VL sequence of SEQ ID NO: 57.

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

40 . The pharmaceutical formulation of claim 39 , further comprising an additional therapeutic agent.

41 . The pharmaceutical formulation of claim 40 , wherein the additional therapeutic agent is Avastin® (bevacizumab).

42 .- 57 . (canceled)

Assignees

• Genentech Inc

Inventors

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

Classifications

• G01N33/5759

  involving compounds localised on the membrane of tumour or cancer cells · CPC title

• C07K16/2827 Primary

  against B7 molecules, e.g. CD80, CD86 · CPC title

• C07K2317/34

  Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues · CPC title

• C07K16/3069

  Reproductive system, e.g. ovaria, uterus, testes, prostate · CPC title

• C07K2317/77

  Internalization into the cell · CPC title