# US 11,299,544 B2 · Biomarkers and methods of treating PD-1 and PD-L1 related conditions

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- Number: US 11,299,544 B2
- Document ID: US11299544B2
- Status: Granted
- Kind: B2
- Application number: 14/850,462
- Filed: 2015-09-10
- Published: 2016-08-04
- Granted: 2022-04-12
- Earliest claimed: 2013-03-15
- Assignees: Genentech, Inc.
- Applicants: Genentech, Inc.
- Inventors: Daniel Shin-Yu Chen; Priti Hegde; Hartmut Koeppen; Marcin Kowanetz
- Web page: https://patentgrep.com/patent/US11299544B2

## CPC

- C07K 16/2827: {against B7 molecules, e.g. CD80, CD86}
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/08: of the prostate
- A61P 13/10: of the bladder
- A61P 13/12: of the kidneys
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 17/00: Drugs for dermatological disorders
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/02: Immunomodulators
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C12Q 1/6886: for cancer (immunoassay for cancer G01N33/575)
- G01N 33/5758: {involving compounds serving as markers for tumours, cancers or neoplasias, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides or metabolites}
- G01N 33/5759: {involving compounds localised on the membrane of tumour or cancer cells}
- G01N 33/6854: {Immunoglobulins}
- G01N 33/6869: {Interleukin}
- G06Q 30/0251: Targeted advertisements
- A61K 2039/505: {comprising antibodies}
- A61K 2039/545: {characterised by the dose, timing or administration schedule}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- G01N 2333/5412: IL-6
- G01N 2333/70532: B7 molecules, e.g. CD80, CD86
- G01N 2800/52: Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)
- G06Q: INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR ADMINISTRATIVE, COMMERCIAL, FINANCIAL, MANAGERIAL OR SUPERVISORY PURPOSES; SYSTEMS OR METHODS SPECIALLY ADAPTED FOR ADMINISTRATIVE, COMMERCIAL, FINANCIAL, MANAGERIAL OR SUPERVISORY PURPOSES, NOT OTHERWISE PROVIDED FOR
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

Provided herein are biomarkers for the treatment of pathological conditions, such as cancer, and method of using PD-1/PD-L1 pathway antagonists. In particular, provided are biomarkers for patient selection and prognosis in cancer, as well as methods of therapeutic treatment, articles of manufacture and methods for making them, diagnostic kits, methods of detection and methods of advertising related thereto.

## Claims

### Claim 1

A method for treating a metastatic non-small cell lung cancer in an individual who is likely to have an increased clinical benefit from treatment with an anti-PD-L1 antibody, the method comprising:
(a) detecting the presence of a PD-L1 protein in tumor infiltrating immune cells in a tumor tissue sample obtained from the individual; and
(b) determining the level of PD-L1 protein in tumor infiltrating immune cells in the tumor tissue sample, wherein the tumor infiltrating immune cells include T lymphocytes, and wherein the tumor tissue sample from the individual has a detectable expression level of the PD-L1 protein in tumor infiltrating immune cells covering ≥ 10% of tumor area in the tumor tissue sample, thereby indicating that the individual is likely to have an increased clinical benefit from treatment with the anti-PD-L1 antibody; and
(c) administering an effective amount of an anti-PD-L1 antibody to the individual,
wherein the tumor tissue sample from the individual is obtained prior to treatment with the anti-PD-L1 antibody, and wherein the anti-PD-L1 antibody is atezolizumab (MPDL3280A).

### Claim 2 (depends on 1)

The method of claim 1, further comprising detecting presence or level of PD-1, PD-L2, or both PD-1 and PD-L2.

### Claim 3 (depends on 1, 2)

The method of claim 1 or 2, further comprising detecting presence or level of one or more T-cell related markers.

### Claim 4 (depends on 3)

The method of claim 3, wherein the one or more T-cell related markers is CD8A, IFN-g, EOMES, Granzyme-A, Granzyme-B, CXCL9, or a combination thereof.

### Claim 5 (depends on 1)

The method of claim 1, further comprising detecting presence or level of CX3CL1, CD45RO, IDO1, Galectin 9, MIC-A, MIC-B, CTLA-4, or a combination thereof.

### Claim 6 (depends on 1)

The method of claim 1, wherein the tumor tissue sample further comprises tumor cells, stromal cells, or a combination thereof.

### Claim 7 (depends on 1)

The method of claim 1, wherein the tumor tissue sample is formalin-fixed and paraffin-embedded, archival, fresh, or frozen.

### Claim 8 (depends on 1)

The method of claim 1, wherein the increased clinical benefit comprises a relative increase in one or more of the following: objective response rate (ORR), overall survival (OS), progression free survival (PFS), complete response (CR), partial response (PR), or a combination thereof.

### Claim 9 (depends on 8)

The method of claim 8, wherein the increased clinical benefit comprises a relative increase in ORR.

### Claim 10 (depends on 1)

The method of claim 1, wherein PD-L1 protein is detected in the tumor tissue sample using immunohistochemistry (IHC), immunofluorescence, radioimmunoassay, immunodetection methods, or a combination thereof.

### Claim 11 (depends on 1)

The method of claim 1, wherein PD-L1 protein is detected using IHC.

### Claim 12 (depends on 11)

The method of claim 11, wherein PD-L1 protein is detected using an anti-PD-L1 antibody.

### Claim 13 (depends on 11)

The method of claim 11, wherein PD-L1 protein is detected as a weak staining intensity by IHC.

### Claim 14 (depends on 11)

The method of claim 11, wherein PD-L1 protein is detected as a moderate staining intensity by IHC.

### Claim 15 (depends on 11)

The method of claim 11, wherein PD-L1 protein is detected as a strong staining intensity by IHC.

### Claim 16 (depends on 11)

The method of claim 11, wherein staining is membrane staining, cytoplasmic staining, or a combination thereof.

### Claim 17 (depends on 1)

The method of claim 1, further comprising administering an effective amount of a second therapeutic agent to the individual, wherein the second therapeutic agent is a cytotoxic agent, a chemotherapeutic agent, a growth inhibitory agent, a radiation therapy agent, anti-angiogenic agent, or a combination thereof.

### Claim 18 (depends on 4)

The method of claim 4, wherein PD-1, PD-L2, the one or more T-cell related markers, or a combination thereof are detected in the tumor tissue sample using FACS, Western blot, ELISA, immunoprecipitation, immunohistochemistry, immunofluorescence, radioimmunoassay, dot blotting, immunodetection methods, HPLC, surface plasmon resonance, optical spectroscopy, mass spectrometry, qPCR, RT-qPCR, multiplex qPCR or RT-qPCR, RNA-seq, microarray analysis, SAGE, MassARRAY technique, FISH, or a combination thereof.

### Claim 19 (depends on 4)

The method of claim 4, wherein the one or more T-cell related markers are detected in the tumor tissue sample by protein expression.

### Claim 20 (depends on 4)

The method of claim 4, wherein the one or more T-cell related markers are detected in the tumor tissue sample by nucleic acid expression.

### Claim 21 (depends on 20)

The method of claim 20, wherein an increased level of the one or more T-cell related markers in the tumor tissue sample compared to the level of the one or more T-cell related markers in a reference sample indicates that the individual is likely to have an increased clinical benefit from treatment with the anti-PD-L1 antibody.

### Claim 22 (depends on 20)

The method of claim 20, wherein the one or more T-cell related markers are detected using RT-qPCR or RNA-seq.

### Claim 23 (depends on 21)

The method of claim 21, wherein the reference sample is:
(a) a sample from one or more individuals with the cancer who is not the individual undergoing treatment;
(b) a sample from one or more healthy individuals who is not the individual undergoing treatment; or
(c) a sample from the individual undergoing treatment.

### Claim 24 (depends on 21)

The method of claim 21, wherein the reference sample is a tissue sample, a plasma sample, or a serum sample.

### Claim 25

A method for treating a metastatic non-small cell lung cancer in an individual who is likely to have an increased clinical benefit from treatment with an anti-PD-L1 antibody, the method comprising:
(a) detecting presence of a PD-L1 protein in tumor infiltrating immune cells in a tumor tissue sample obtained from the individual; and
(b) determining the level of PD-L1 protein in tumor infiltrating immune cells in the tumor tissue sample, wherein the tumor infiltrating immune cells include T lymphocytes, and wherein the tumor tissue sample from the individual has a detectable expression level of the PD-L1 protein in tumor infiltrating immune cells covering ≥ 10% of tumor area in the tumor tissue sample, thereby indicating that the individual is likely to have an increased clinical benefit from treatment with the anti-PD-L1 antibody; and
(c) administering an effective amount of an anti-PD-L1 antibody to the individual,
wherein the tumor tissue sample from the individual is obtained prior to treatment with the anti-PD-L1 antibody, wherein the anti-PD-L1 antibody is atezolizumab (MPDL3280A), wherein the increased clinical benefit comprises a relative increase in ORR, and wherein the PD-L1 protein is detected using IHC.

### Claim 26 (depends on 25)

The method of claim 25, wherein the IHC is performed using the Ventana Benchmark XT or Benchmark Ultra system.