Anti-gpc3 antibodies and immunoconjugates

Patent metadata

Field	Value
Publication number	US-2016017049-A1
Application number	US-201514718932-A
Country	US
Kind code	A1
Filing date	May 21, 2015
Priority date	May 22, 2014
Publication date	Jan 21, 2016
Grant date	—

Abstract

The invention provides anti-GPC3 antibodies and immunoconjugates and methods of using the same.

First claim

1 . An isolated antibody that binds human GPC3, wherein the antibody binds to an epitope selected from:
a) an epitope within amino acids 25 to 137 of human GPC3; b) an epitope spanning the furin cleavage site at amino acids R358/S359 of human GPC3; c) an epitope within amino acids 420 to 470 of human GPC3; and d) an epitope within amino acids 470 to 509 of human GPC3.

2 . The antibody of claim 1 , wherein the antibody binds to an epitope within amino acids 25 to 137 of human GPC3.

3 . (canceled)

4 . The antibody of claim 2 , wherein the antibody binds to GPC3 from cynomolgus monkey, mouse, and rat.

5 . (canceled)

6 . The antibody of claim 1 , wherein the antibody comprises HVR-H1 comprising the amino acid sequence of SEQ ID NO: 4, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 5, HVR-H3 comprising the amino acid sequence of SEQ ID NO: 6, HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 8, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 9.

7 . (canceled)

8 . The antibody of claim 6 , wherein the antibody comprises:
a) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 2; b) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 3; c) a VH sequence having the amino acid sequence of SEQ ID NO: 2; d) a VL sequence having the amino acid sequence of SEQ ID NO: 3; e) a humanized VH based on the amino acid sequence of SEQ ID NO: 2; f) a humanized VL sequence based on the amino acid sequence of SEQ ID NO: 3; or e) a VH as in (a), (c), or (e), and a VL as in (b), (d), or (f).

9 . (canceled)

10 . The antibody of claim 1 , wherein the antibody binds to an epitope spanning the furin cleavage site at amino acids R358/S359 of human GPC3.

11 . The antibody of claim 10 , wherein the antibody binds to full-length mature human GPC3 but does not bind to an N-terminal fragment of human GPC3 consisting of amino acids 25 to 358 of SEQ ID NO: 1, and does not bind to a C-terminal fragment of human GPC3 consisting of amino acids 359 to 560 or amino acids 359 to 580 of SEQ ID NO: 1.

12 . (canceled)

13 . The antibody of claim 11 wherein the antibody comprises HVR-H1 comprising the amino acid sequence of SEQ ID NO: 28, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 29, HVR-H3 comprising the amino acid sequence of SEQ ID NO: 30, HVR-L1 comprising the amino acid sequence of SEQ ID NO: 31, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 33.

14 . (canceled)

15 . The antibody of claim 13 , wherein the antibody comprises:
a) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 26; b) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 27; c) a VH sequence having the amino acid sequence of SEQ ID NO: 26; d) a VL sequence having the amino acid sequence of SEQ ID NO: 27; e) a humanized VH based on the amino acid sequence of SEQ ID NO: 26; f) a humanized VL sequence based on the amino acid sequence of SEQ ID NO: 27; or g) a VH as in (a), (c), or (e), and a VL as in (b), (d), or (f).

16 . (canceled)

17 . The antibody of claim 1 , wherein the antibody binds to an epitope within amino acids 420 to 470 of human GPC3.

18 . (canceled)

19 . The antibody of claim 17 , wherein the antibody binds to GPC3 from cynomolgus monkey, rhesus macaque, mouse, and rat.

20 . (canceled)

21 . The antibody of claim 17 , wherein the antibody comprises HVR-H1 comprising the amino acid sequence of SEQ ID NO: 20, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 21, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 22, HVR-L1 comprising the amino acid sequence of SEQ ID NO: 23, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 24, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 25.

22 . (canceled)

23 . The antibody of claim 21 , wherein the antibody comprises:
a) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 18; b) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 19; c) a VH sequence having the amino acid sequence of SEQ ID NO: 18; d) a VL sequence having the amino acid sequence of SEQ ID NO: 19; e) a humanized VH based on the amino acid sequence of SEQ ID NO: 18; f) a humanized VL sequence based on the amino acid sequence of SEQ ID NO: 19; or g) a VH as in (a), (c), or (e), and a VL as in (b), (d), or (f).

24 . (canceled)

25 . The antibody of claim 1 , wherein the antibody binds to an epitope within amino acids 470 to 509 of human GPC3.

26 . The antibody of claim 25 , wherein the antibody binds to cynomolgus monkey GPC3 and does not bind to rat GPC3.

27 . (canceled)

28 . (canceled)

29 . The antibody of claim 25 , wherein the antibody comprises HVR-H1 comprising the amino acid sequence of SEQ ID NO: 12, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 13, HVR-H3 comprising the amino acid sequence of SEQ ID NO: 14, HVR-L1 comprising the amino acid sequence of SEQ ID NO: 15, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 16, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 17.

30 . (canceled)

31 . The antibody of claim 29 , wherein the antibody comprises:
a) VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 10; b) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 11; c) a VH sequence having the amino acid sequence of SEQ ID NO: 10; d) a VL sequence having the amino acid sequence of SEQ ID NO: 11; e) a humanized VH based on the amino acid sequence of SEQ ID NO: 10; f) a humanized VL sequence based on the amino acid sequence of SEQ ID NO: 11; g) a VH as in (a), (c), or (e), and a VL as in (b), (d), or (f).

32 . (canceled)

33 . (canceled)

34 . (canceled)

35 . (canceled)

36 . (canceled)

37 . The antibody of claim 1 , which is a monoclonal antibody.

38 . The antibody of claim 1 , which is a human, humanized, or chimeric antibody.

39 . The antibody of claim 1 , which is an antibody fragment that binds GPC3.

40 . The antibody of claim 1 , wherein GPC3 is human GPC3 comprising amino acids 25 to 580 of SEQ ID NO: 1.

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

42 . An isolated nucleic acid encoding the antibody of claim 1 .

43 . A host cell comprising the nucleic acid of claim 42 .

44 . A method of producing an antibody comprising culturing the host cell of claim 43 so that the antibody is produced.

45 . An immunoconjugate comprising the antibody of claim 1 and a cytotoxic agent.

46 . The immunoconjugate of claim 45 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 cytotoxic agent; and
(d) p ranges from 1-8.

Assignees

• Genentech Inc

Inventors

• Polakis Paul
• Chen Youjun

Classifications

• A61K47/48561

  Human Necessities · mapped topic

• A61K47/48715

  Human Necessities · mapped topic

• A61K47/486

  Human Necessities · mapped topic

• C07K16/28

  against receptors, cell surface antigens or cell surface determinants · 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