Anti-PMEL17 antibodies and immunoconjugates

Patent metadata

Field	Value
Publication number	US-9597411-B2
Application number	US-201514705525-A
Country	US
Kind code	B2
Filing date	May 6, 2015
Priority date	May 1, 2012
Publication date	Mar 21, 2017
Grant date	Mar 21, 2017

Abstract

The invention provides anti-PMEL17 antibodies and immunoconjugates and methods of using the same.

First claim

What is claimed is:

1. An immunoconjugate comprising an antibody that binds PMEL17 and a cytotoxic agent, wherein the antibody comprises:
a) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 3, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 4, (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 5, (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 6, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 7, and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 8; or
b) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 13, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 14, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 15, (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 16, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 7, and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 8; or
c) HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3 of the antibody produced by hybridoma 7509(31D1.6.7) having ATCC Accession No. PTA-12862.

2. The immunoconjugate 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: 1; or
b) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 2; 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: 9; or
e) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 10; 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 VH sequence of the antibody produced by hybridoma 7509(31D1.6.7) having ATCC Accession No. PTA-12862; or
h) a VL sequence having at least 95% sequence identity to the VL sequence of the antibody produced by hybridoma 7509(31D1.6.7) having ATCC Accession No. PTA-12862; or
i) a VH sequence as in (g) and a VL sequence as in (h).

3. The immunoconjugate of claim 2 , comprising a VH sequence having the amino acid sequence of SEQ ID NO: 1, a VH sequence having the amino acid sequence of SEQ ID NO: 9, or a VH sequence of the antibody produced by hybridoma 7509(31D1.6.7) having ATCC Accession No. PTA-12862.

4. The immunoconjugate of claim 2 , comprising a VL sequence having the amino acid sequence of SEQ ID NO: 2, a VL sequence having the amino acid sequence of SEQ ID NO: 10, or a VL sequence of the antibody produced by hybridoma 7509(31D1.6.7) having ATCC Accession No. PTA-12862.

5. The immunoconjugate of claim 1 , comprising (a) a VH sequence having the amino acid sequence of SEQ ID NO: 1 and a VL sequence having the amino acid sequence of SEQ ID NO: 2; or (b) a VH sequence having the amino acid sequence of SEQ ID NO: 9 and a VL sequence having the amino acid sequence of SEQ ID NO: 10; or (c) a VH sequence of the antibody produced by hybridoma 7509(31D1.6.7) having ATCC Accession No. PTA-12862 and a VL sequence of the antibody produced by hybridoma 7509(31D1.6.7) having ATCC Accession No. PTA-12862.

6. The immunoconjugate of claim 1 , which is an IgG1, IgG2a or IgG2b antibody.

7. The immunoconjugate of claim 1 having the formula Ab-(L-D)p, wherein:
(a) Ab is the antibody;
(b) L is a linker;
(c) D is a cytotoxic agent; and
(d) p ranges from 1-8.

8. The immunoconjugate of claim 7 , wherein D is an auristatin.

9. The immunoconjugate of claim 8 , 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.

10. The immunoconjugate of claim 7 , wherein the drug is MMAE.

11. The immunoconjugate of claim 7 , 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 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).

12. The immunoconjugate of claim 11 , wherein D has a structure selected from:

wherein R E and R E″ are each independently selected from H or R D , wherein R D is independently selected from R, CO 2 R, COR, CHO, CO 2 H, and halo;
wherein Ar 1 and Ar 3 are each independently optionally substituted C 5-20 aryl; and
wherein n is 0 or 1.

13. The immunoconjugate of claim 7 , wherein D is a pyrrolobenzodiazepine of Formula B:

wherein the horizontal wavy line indicates the covalent attachment site to the linker;
R V1 and R V2 are independently selected from H, methyl, ethyl, phenyl, fluoro-substituted phenyl, and C 5-6 heterocyclyl; and
n is 0 or 1.

14. The immunoconjugate of claim 7 , wherein D is a nemorubicin derivative.

15. The immunoconjugate of claim 14 , wherein D has a structure selected from:

16. The immunoconjugate of claim 7 , wherein the linker is cleavable by a protease.

17. The immunoconjugate of claim 16 , wherein the linker comprises a val-cit dipeptide or a Phe-Lys dipeptide.

18. The immunoconjugate of claim 7 , wherein the linker is acid-labile.

19. The immunoconjugate of claim 18 , wherein the linker comprises hydrazone.

20. The immunoconjugate of claim 7 having the formula:

wherein S is a sulfur atom.

21. The immunoconjugate of claim 7 having the formula:

22. The immunoconjugate of claim 7 having a formula selected from:

Assignees

• Genentech Inc

Inventors

• Chen Youjun
• Mallet William
• Polakis Paul
• Tan Christine
• Asundi Jyoti
• Clark Suzanna

Classifications

• C07K2317/56

  variable (Fv) region, i.e. VH and/or VL · CPC title

• A61K47/6849

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

• C07K2317/33

  Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity · CPC title

• C07K16/28 Primary

  against receptors, cell surface antigens or cell surface determinants · CPC title

• C07K2317/77

  Internalization into the cell · CPC title