Diagnostic and therapeutic methods for cancer

Patent metadata

Field	Value
Publication number	US-11473151-B2
Application number	US-202016867125-A
Country	US
Kind code	B2
Filing date	May 5, 2020
Priority date	Nov 6, 2017
Publication date	Oct 18, 2022
Grant date	Oct 18, 2022

Abstract

The present invention provides diagnostic methods, therapeutic methods, and compositions for the treatment of cancer (e.g., a bladder cancer (e.g., UC, e.g., mUC), a kidney cancer, a lung cancer, a liver cancer, an ovarian cancer, a pancreatic cancer, a colorectal cancer, or a breast cancer). The invention is based, at least in part, on the discovery that expression levels of one or more biomarkers described herein in a sample from an individual having cancer can be used in methods of identifying an individual having a cancer who may benefit with an anti-cancer therapy that includes an immunotherapy (e.g., a PD-L1 axis binding antagonist such as an anti-PD-L1 antibody (e.g., atezolizumab)) and a suppressive stromal antagonist (e.g., a TGF-β antagonist), methods for selecting a therapy for an individual having cancer, methods of treating an individual having cancer, methods for assessing a response or monitoring the response of an individual to treatment with an anti-cancer therapy that includes an immunotherapy (e.g., a PD-L1 axis binding antagonist such as an anti-PD-L1 antibody (e.g., atezolizumab)) and a suppressive stromal antagonist (e.g., a TGF-β antagonist), and related kits, anti-cancer therapies, and uses.

First claim

What is claimed is:

1. A method of identifying and treating an individual having a cancer who may benefit from treatment with an anti-cancer therapy comprising a PD-L1 binding antagonist and a TGF-β antagonist, the method comprising:
(i) determining the expression level of the following genes in a sample from the individual prior to treatment with the PD-L1 binding antagonist and the TGF-β antagonist:
ACTA2, ADAM19, COMP, CTGF, TGFB1, and TGFBR2,

wherein the expression level of ACTA2, ADAM19, COMP, CTGF, TGFB1, and TGFBR2 in the sample is at or above a reference expression level of ACTA2, ADAM19, COMP, CTGF, TGFB1, and TGFBR2;
thereby identifying the individual as one who may benefit from treatment with an anti-cancer therapy comprising a PD-L1 binding antagonist and a TGF-β antagonist, wherein the cancer is urothelial carcinoma (UC), non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), or pancreatic ductal adenocarcinoma (PDAC), and wherein the PD-L1 binding antagonist is an anti-PD-L1 antibody comprising the following hypervariable regions (HVRs):
(a) an HVR-H1 sequence of GFTFSDSWIH (SEQ ID NO: 63);
(b) an HVR-H2 sequence of AWISPYGGSTYYADSVKG (SEQ ID NO: 64);
(c) an HVR-H3 sequence of RHWPGGFDY (SEQ ID NO: 65);
(d) an HVR-L1 sequence of RASQDVSTAVA (SEQ ID NO: 66);
(e) an HVR-L2 sequence of SASFLYS (SEQ ID NO: 67); and
(f) an HVR-L3 sequence of QQYLYHPAT (SEQ ID NO: 68); and

(ii) administering an effective amount of an anti-cancer therapy comprising a PD-L1 binding antagonist and a TGF-β antagonist to the individual identified in step (i) as being one who may benefit from treatment with an anti-cancer therapy comprising a PD-L1 binding antagonist and a TGF-β antagonist.

2. A method of treating an individual having a cancer, the method comprising administering to the individual an anti-cancer therapy comprising a PD-L1 binding antagonist and a TGF-β antagonist, wherein prior to treatment the expression level of ACTA2, ADAM19, COMP, CTGF, TGFB1, and TGFBR2 in the sample has been determined to be at or above a reference expression level of ACTA2, ADAM19, COMP, CTGF, TGFB1, and TGFBR2, wherein the cancer is UC, NSCLC, TNBC, or PDAC, and wherein the PD-L1 binding antagonist is an anti-PD-L1 antibody comprising the following HVRs:
(a) an HVR-H1 sequence of GFTFSDSWIH (SEQ ID NO: 63);
(b) an HVR-H2 sequence of AWISPYGGSTYYADSVKG (SEQ ID NO: 64);
(c) an HVR-H3 sequence of RHWPGGFDY (SEQ ID NO: 65);
(d) an HVR-L1 sequence of RASQDVSTAVA (SEQ ID NO: 66);
(e) an HVR-L2 sequence of SASFLYS (SEQ ID NO: 67); and
(f) an HVR-L3 sequence of QQYLYHPAT (SEQ ID NO: 68).

3. The method of claim 2 , further comprising determining:
(i) the expression level in the sample of one or more additional genes selected from PD-L1, CD8A, CXCL10, CXCL9, GZMA, GZMB, IFNG, PRF1, and TBX21; and/or
(ii) a tumor mutational burden (TMB) score in a tumor sample from the individual.

4. The method of claim 2 , wherein:
(i) a tumor from the individual has an immune excluded phenotype characterized by the localization of CD8+ T-cells in the peri-tumoral stromal compartment;
(ii) the reference expression level is determined from a population of individuals having a cancer;
(iii) the expression level is a nucleic acid expression level;
(iv) the expression level is a protein expression level; and/or
(v) the sample is a tissue sample, a cell sample, a whole blood sample, a plasma sample, a serum sample, or a combination thereof.

5. The method of claim 2 , wherein the TGF-β antagonist is a polypeptide, a small molecule, or a nucleic acid.

6. The method of claim 5 , wherein:
(i) the polypeptide is an anti-TGF-β antibody, a soluble TGF-β receptor, or a peptide;
(ii) the small molecule is galunisertib (LY2157299), LY2382770, LY3022859, SB-431542, SD208, SM16, tranilast, pirfenidone, TEW-7197, PF-03446962, or pyrrole-imidazole polyamide; or
(iii) the nucleic acid is trabedersen (AP12009) or belagenpumatucel-L.

7. The method of claim 6 , wherein:
(i) the anti-TGF-β antibody is fresolimumab, metelimumab, lerdelimumab, 1D11, 2G7, or derivatives thereof; or
(ii) the peptide is disitertide (P144).

8. The method of claim 2 , wherein the anti-PD-L1 antibody is atezolizumab.

9. The method of claim 2 , wherein the anti-PD-L1 antibody comprises:
(a) a VH domain comprising the amino acid sequence of SEQ ID NO: 69; and
(b) a VL domain comprising the amino acid sequence of SEQ ID NO: 70.

10. The method of claim 2 , further comprising administering an additional therapeutic agent to the individual.

11. The method of claim 10 , wherein the additional therapeutic agent is an immunotherapy agent, a cytotoxic agent, a growth inhibitory agent, a radiation therapy agent, an anti-angiogenic agent, or a combination thereof.

12. The method of claim 1 , wherein the anti-PD-L1 antibody is atezolizumab.

13. The method of claim 1 , wherein the cancer is a UC.

14. The method of claim 13 , wherein the UC is a metastatic UC.

15. The method of claim 2 , wherein the cancer is a UC.

16. The method of claim 15 , wherein the UC is a metastatic UC.

17. The method of claim 1 , wherein the reference expression level is determined from a population of individuals having the cancer.

18. The method of claim 17 , wherein the reference expression level is a median expression level or is determined by principal component analysis of Z-score-transformed expression levels.

19. The method of claim 2 , wherein the reference expression level is determined from a population of individuals having the cancer.

20. The method of claim 19 , wherein the reference expression level is a median expression level or is determined by principal component analysis of Z-score-transformed expression levels.

21. A method of treating an individual having a metastatic UC, the method comprising administering to the individual an anti-cancer therapy comprising atezolizumab and an anti-TGF-β antibody, wherein prior to treatment the expression level of ACTA2, ADAM19, COMP, CTGF, TGFB1, and TGFBR2 in the sample has been determined to be at or above a reference expression level of ACTA2, ADAM19, COMP, CTGF, TGFB1, and TGFBR2.

Assignees

• Genentech Inc

Inventors

• Guan Yinghui
• Senbabaoglu Yasin
• Turley Shannon
• Wang Yulei

Classifications

• G01N33/57585

  involving compounds identifiable in body fluids · CPC title

• G01N33/5758 Primary

  involving compounds serving as markers for tumours, cancers or neoplasias, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides or metabolites · CPC title

• C12Q2600/106

  Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism · CPC title

• G01N2800/52

  Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis · CPC title

• G01N2333/70596

  Molecules with a "CD"-designation not provided for elsewhere in G01N2333/705 · CPC title