Binding molecules specific for her3 and uses thereof

Patent metadata

Field	Value
Publication number	US-2016237162-A1
Application number	US-201415023858-A
Country	US
Kind code	A1
Filing date	Sep 23, 2014
Priority date	Sep 24, 2013
Publication date	Aug 18, 2016
Grant date	—

Abstract

Provided herein are antibodies and antigen binding fragments thereof that bind the extracellular domain of the HER3 receptor and inhibit various HER3 receptor related functions via ligand-dependent and/or ligand-independent mechanisms. Also provided are compositions with increased half-life, as well as compositions and methods for diagnosing and treating diseases associated with HER3 mediated signal transduction.

First claim

What is claimed is:

1 . A method of resensitizing a tumor or tumor cell in a subject to a HER targeted therapy, comprising administering to the subject a therapeutically effective amount of an antibody or antigen binding fragment thereof which specifically binds to an epitope within the extracellular domain of HER3, wherein
(i) the antibody or antigen binding fragment thereof binds to the same HER3 epitope as an antibody or antigen-binding fragment thereof comprising the heavy chain variable region (VH) and light chain variable region (VL) of CL16 or 2C2; or (ii) the antibody or antigen binding fragment thereof competitively inhibits HER3 binding by an antibody or antigen-binding fragment thereof comprising the VH and VL of CL16 or 2C2; or (iii) the antibody or antigen binding fragment thereof comprises
(A) an antibody VL, wherein the VL comprises the amino acid sequence:

[FW 1 ]X 1 GSX 2 SNIGLNYVS[FW 2 ]RNNQRPS[FW 3 ]AAWDDX 3 X 4 X 5 GE

X 6 [FW 4 ]

wherein [FW 1 ], [FW 2 ], [FW 3 ] and [FW 4 ] represent VL framework regions, and
wherein
(a) X 1 represents amino acid residues Arginine (R) or Serine (S),
(b) X 2 represents amino acid residues Serine (S) or Leucine (L),
(c) X 3 represents amino acid residues Serine (S) or Glycine (G),
(d) X 4 represents amino acid residues Leucine (L) or Proline (P),
(e) X 5 represents amino acid residues Arginine (R), Isoleucine (I), Proline (P) or Serine (S), and
(f) X 6 represents amino acid residues Valine (V) or Alanine (A), and

(B) an antibody VH, wherein the VH comprises the amino acid sequence:

[FW 5 ]YYYMQ[FW 6 ]X 7 IGSSGGVTNYADSVKG[FW 7 ]VGLGDAFDI

[FW 8 ]

wherein [FW 5 ], [FW 6 ], [FW 7 ] and [FW 8 ] represent VH framework regions, and
wherein X 7 represents amino acid residues Tyrosine (Y), Isoleucine (I) or Valine (V).

2 . The method of claim 1 further comprising administering to the subject a therapeutically effective amount of a HER targeted therapy.

3 . The method of claim 1 , wherein the cancer is characterized as expressing heregulin.

4 . The method of claim 1 , wherein the HER targeted therapy is an anti-EGFR antibody, anti-HER2 antibody, anti-HER3 antibody or anti-HER4 antibody or a small molecule inhibiting the activity of EGFR, HER2, HER3 or HER4.

5 . The method of claim 4 , wherein the HER targeted therapy is an anti-EGFR antibody.

6 . The method of claim 1 , wherein the cancer was previous treated with the HER targeted therapy and had acquired resistance to the HER targeted therapy.

7 . The method of claim 1 , wherein the tumor is a lung cancer tumor.

8 . The method of claim 1 , wherein the tumor or tumor cell had acquired resistance to the HER targeted therapy following treatment with the HER targeted therapy.

9 . The method of claim 1 , wherein the antibody or antigen binding fragment thereof is administered after surgical removal of a tumor of the cancer.

10 . The method of claim 2 , wherein the HER targeted therapy and the antibody or antigen binding fragment thereof are administered after surgical removal of a tumor of the cancer.

11 . The method of claim 2 , further comprising administering an anti-cancer agent.

12 . The method of claim 11 , wherein the anticancer agent is an antimetabolite, alkylating agent, topoisomerase inhibitor, or microtubule targeting agent.

13 . The method of claim 2 , wherein the antibody or antigen binding fragment thereof is administered for a first period of time and a second period of time, wherein there is a period of rest between the first period of time and the second period of time, wherein the antibody or antigen binding fragment thereof is not administered to the subject during the period of rest.

14 . The method of claim 13 , wherein the HER targeted therapy is administered during the first period of time and the second period of time, and wherein the HER targeted therapy is not administered to the subject during the period of rest.

15 . The method of claim 13 , wherein the period of rest is 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, or 26 weeks.

16 . A method of resensitizing a HER2 amplified tumor or tumor cell in a subject to a HER2 targeted therapy, comprising administering to the subject a therapeutically effective amount of an antibody or antigen binding fragment thereof which specifically binds to an epitope within the extracellular domain of HER3, wherein
(i) the antibody or antigen binding fragment thereof binds to the same HER3 epitope as an antibody or antigen-binding fragment thereof comprising the heavy chain variable region (VH) and light chain variable region (VL) of CL16 or 2C2; or (ii) the antibody or antigen binding fragment thereof competitively inhibits HER3 binding by an antibody or antigen-binding fragment thereof comprising the VH and VL of CL16 or 2C2; or (iii) the antibody or antigen binding fragment thereof comprises
(A) an antibody VL, wherein the VL comprises the amino acid sequence:

[FW 1 ]X 1 GSX 2 SNIGLNYVS[FW 2 ]RNNQRPS[FW 3 ]AAWDDX 3 X 4 X 5 GE

X 6 [FW 4 ]

wherein [FW 1 ], [FW 2 ], [FW 3 ] and [FW 4 ] represent VL framework regions, and
wherein
(a) X 1 represents amino acid residues Arginine (R) or Serine (S),
(b) X 2 represents amino acid residues Serine (S) or Leucine (L),
(c) X 3 represents amino acid residues Serine (S) or Glycine (G),
(d) X 4 represents amino acid residues Leucine (L) or Proline (P),
(e) X 5 represents amino acid residues Arginine (R), Isoleucine (I), Proline (P) or Serine (S), and
(f) X 6 represents amino acid residues Valine (V) or Alanine (A), and

(B) an antibody VH, wherein the VH comprises the amino acid sequence:

[FW 5 ]YYYMQ[FW 6 ]X 7 IGSSGGVTNYADSVKG[FW 7 ]VGLGDAFDI

[FW 8 ]

wherein [FW 5 ], [FW 6 ], [FW 7 ] and [FW 8 ] represent VH framework regions, and
wherein X 7 represents amino acid residues Tyrosine (Y), Isoleucine (I) or Valine (V).

17 . The method of claim 16 further comprising administering to the subject a therapeutically effective amount of a HER2 targeted therapy.

18 . The method of claim 16 , wherein the cancer is characterized as expressing hereguli

Assignees

• Medimmune Llc

Inventors

• Chowdhury Partha S
• Tice David
• Xiao Zhan
• Steiner Philipp
• Kinneer Krista
• Rebelatto Marlon
• Pierce Andrew

Classifications

• C07K2317/33

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

• A61K2039/507

  Comprising a combination of two or more separate antibodies · CPC title

• C07K2317/76

  Antagonist effect on antigen, e.g. neutralization or inhibition of binding · CPC title

• A61K2039/505

  comprising antibodies · CPC title

• C07K2317/73

  Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation · CPC title