Treatment of Cancer Using Inhibitors of TGF-BETA and PD-1

Patent metadata

Field	Value
Publication number	US-2016289315-A1
Application number	US-201615089579-A
Country	US
Kind code	A1
Filing date	Apr 3, 2016
Priority date	Apr 3, 2015
Publication date	Oct 6, 2016
Grant date	—

Abstract

The present disclosure relates, in general, to combination therapy using an inhibitor of transforming growth factor beta (TGFβ) and an inhibitor of programmed cell death protein 1 (PD-1) for treating cancer or preventing recurrence of cancer diseases such as lung cancer, prostate cancer, breast cancer, hepatocellular cancer, esophageal cancer, colorectal cancer, pancreatic cancer, bladder cancer, kidney cancer, ovarian cancer, stomach cancer, fibrotic cancer, glioma and melanoma, and metastases thereof.

First claim

1 . A method for treating cancer or preventing the recurrence of cancer comprising administering to a subject in need thereof therapeutically effective amounts of an inhibitor of transforming growth factor beta (TGFβ3) and an inhibitor of Programmed cell death protein 1 (PD-1).

2 . The method of claim 1 , wherein the TGFβ inhibitor is an antibody that binds TGFβ1, TGFβ2 and TGFβ3.

3 . The method of claim 1 , wherein the TGFβ inhibitor is an antibody that binds to TGFβ1, TGFβ2 with greater affinity than to TGFβ3.

4 . (canceled)

5 . The method of claim 2 , wherein the TGFβ antibody binds to TGFβ1, TGFβ2 and TGFβ3 with an affinity Kd of 10 −6 M or less.

6 . The method of claim 1 wherein the TGFβ inhibitor is an antibody comprising:
(a) a heavy chain CDR1 amino acid sequence set forth in SEQ ID NOs: 13, 19 and 25, or a variant thereof having at least 85% identity thereto;
(b) a heavy chain CDR2 amino acid sequence set forth in SEQ ID NOs: 14, 20 and 26, or a variant thereof having at least 85% identity thereto;
(c) a heavy chain CDR3 amino acid sequence set forth in SEQ ID NOs: 15, 21 and 27, or a variant thereof having at least 85% identity thereto;
(d) a light chain CDR1 amino acid sequence set forth in SEQ ID NOs: 16, 22 and 28, or a variant thereof having at least 85% identity thereto;
(e) a light chain CDR2 amino acid sequence set forth in SEQ ID NOs: 17, 23 and 29, or a variant thereof having at least 85% identity thereto; and
(f) a light chain CDR3 amino acid sequence set forth in SEQ ID NOs: 18, 24 and 30, or a variant thereof having at least 85% identity thereto.

7 . The method of claim 1 wherein the TGFβ inhibitor is an antibody that comprises an amino acid sequence at least 85% identical to a heavy chain variable region amino acid sequence set forth in SEQ ID NOs: 2, 6 and 10.

8 . The method of claim 7 wherein the antibody further comprises an amino acid sequence at least 85% identical to a light chain variable region amino acid sequence set forth in SEQ ID NOs: 4, 8 and 12.

9 . The method of claim 1 wherein the TGFβ inhibitor is an antibody comprising:
a) a heavy chain CDR1 amino acid sequence set forth in SEQ ID NO: 25, or a variant thereof in which one or two amino acids have been changed;
b) a heavy chain CDR2 amino acid sequence set forth in SEQ ID NO: 26, or a variant thereof in which one or two amino acids have been changed;
c) a heavy chain CDR3 amino acid sequence set forth in SEQ ID NO: 27, or a variant thereof in which one or two amino acids have been changed;
d) a light chain CDR1 amino acid sequence set forth in SEQ ID NO: 28, or a variant thereof in which one or two amino acids have been changed;
e) a light chain CDR2 amino acid sequence set forth in SEQ ID NO: 29, or a variant thereof in which one or two amino acids have been changed; and
f) a light chain CDR3 amino acid sequence set forth in SEQ ID NO: 30, or a variant thereof in which one or two amino acids have been changed.

10 . The method of claim 1 wherein the TGFβ inhibitor is an antibody comprising:
a) a heavy chain CDR1 amino acid sequence set forth in SEQ ID NO: 13, or a variant thereof in which one or two amino acids have been changed;
b) a heavy chain CDR2 amino acid sequence set forth in SEQ ID NO: 14, or a variant thereof in which one or two amino acids have been changed;
c) a heavy chain CDR3 amino acid sequence set forth in SEQ ID NO: 15, or a variant thereof in which one or two amino acids have been changed;
d) a light chain CDR1 amino acid sequence set forth in SEQ ID NO: 16, or a variant thereof in which one or two amino acids have been changed;
e) a light chain CDR2 amino acid sequence set forth in SEQ ID NO: 17, or a variant thereof in which one or two amino acids have been changed; and
f) a light chain CDR3 amino acid sequence set forth in SEQ ID NO: 18, or a variant thereof in which one or two amino acids have been changed.

11 . The method of claim 1 wherein the TGFβ inhibitor is an antibody comprising:
g) a heavy chain CDR1 amino acid sequence set forth in SEQ ID NO: 19, or a variant thereof in which one or two amino acids have been changed;
h) a heavy chain CDR2 amino acid sequence set forth in SEQ ID NO: 20, or a variant thereof in which one or two amino acids have been changed;
i) a heavy chain CDR3 amino acid sequence set forth in SEQ ID NO: 21, or a variant thereof in which one or two amino acids have been changed;
j) a light chain CDR1 amino acid sequence set forth in SEQ ID NO: 22, or a variant thereof in which one or two amino acids have been changed;
k) a light chain CDR2 amino acid sequence set forth in SEQ ID NO: 23, or a variant thereof in which one or two amino acids have been changed; and
l) a light chain CDR3 amino acid sequence set forth in SEQ ID NO: 24, or a variant thereof in which one or two amino acids have been changed.

12 . The method of claim 5 wherein i) the heavy chain variable region amino acid sequence is set forth in SEQ ID NO: 10 and the light chain variable region amino acid sequence is set forth in SEQ ID NO: 12; or
ii) the heavy chain variable region amino acid sequence is set forth in SEQ ID NO: 2 and the light chain variable region amino acid sequence is set forth in SEQ ID NO: 4; or
iii) the heavy chain variable region amino acid sequence is set forth in SEQ ID NO: 6 and the light chain variable region amino acid sequence is set forth in SEQ ID NO: 8.

13 .- 14 . (canceled)

15 . The method of claim 1 wherein the antibody further comprises a heavy chain constant region, wherein the heavy chain constant region is a modified or unmodified IgG, IgM, IgA, IgD, IgE, a fragment thereof, or combinations thereof.

16 . The method of claim 15 further comprising a human light chain constant region attached to said light chain variable region.

17 . The method of claim 1 , wherein the PD-1 inhibitor is an antibody that binds PD-1.

18 . The method of claim 1 wherein the TGFβ inhibitor is an antibody and the PD-1 inhibitor is an antibody.

19 . The method of claim 1 , wherein the cancer is selected from the group consisting of esophageal cancer, pancreatic cancer, metastatic pancreatic cancer, metastatic adenocarcinoma of the pancreas, bladder cancer, stomach cancer, fibrotic cancer, glioma, malignant glioma, diffuse intrinsic pontine glioma, recurrent childhood brain neoplasm renal cell carcinoma, clear-cell metastatic renal cell carcinoma, kidney cancer, prostate cancer, metastatic castration resistant prostate cancer, stage IV prostate cancer, metastatic melanoma, melanoma, malignant melanoma, recurrent melanoma of the skin, melanoma brain metastases, stage IIIA skin melanoma; stage IIIB skin melanoma, stage IIIC skin melanoma; stage IV skin melanoma, malignant melanoma of head and neck, lung cancer, non small cell lung cancer (NSCLC), squamous cell non-small cell lung cancer, breast cancer, recurrent metastatic breast cancer, hepatocellular carcinoma, hodgkin's lymphoma, follicular lymphoma, non-hodgkin's lymphoma, advanced B-cell NHL, HL including diffuse large B-cell lymphoma (DLBCL), multiple myeloma, chronic myeloid leukemia, adult acute myeloid leukemia in remission; adult acute myeloid leukemia with Inv(16)(p13.1q22); CBFB-MYH11; adult acute myeloid leukemia with t(16;16)(p13.1;q22); CBFB-MYH11; adult acute myeloid leukemia with t(8;21)(q22;q22); RUNX1-RUNX1T1; adult acute myeloid leukemia with t(9;11)(p22;q23); MLLT3-MLL; adult acute promyelocytic leukemia with t(15;17)(q22;q12); PML-RARA; alkylating agent-related acute myeloid leukemia, chronic lymphocytic leukemia, richter's

Assignees

• Xoma Technology Ltd
• Univ California

Inventors

• Mirza Amer M
• Akhurst Rosemary J
• Li Ou

Classifications

• A61P35/04

  specific for metastasis · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

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

• A61P35/02

  specific for leukemia · CPC title

• C07K16/22 Primary

  against growth factors {; against growth regulators} · CPC title