# US 11,078,278 B2 · Treatment of renal cell carcinoma

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- Number: US 11,078,278 B2
- Document ID: US11078278B2
- Status: Granted
- Kind: B2
- Application number: 15/577,661
- Filed: 2016-05-27
- Published: 2018-06-14
- Granted: 2021-08-03
- Earliest claimed: 2015-05-29
- Assignees: Bristol-Myers Squibb Company
- Applicants: Bristol-Myers Squibb Company
- Inventors: Jason Samuel Simon; Petra B. Ross-Macdonald
- Web page: https://patentgrep.com/patent/US11078278B2

## CPC

- C07K 16/2818: {against CD28 or CD152}
- A61K 39/39533: {against materials from animals}
- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 35/00: Antineoplastic agents
- C07K 14/70503: {Immunoglobulin superfamily}
- C07K 14/70521: {CD28, CD152}
- C07K 14/7056: {Lectin superfamily, e.g. CD23, CD72}
- C07K 14/70575: {NGF/TNF-superfamily, e.g. CD70, CD95L, CD153, CD154 (NGF C07K14/48, TNF C07K14/525)}
- C07K 14/70578: {NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95 (NGF-receptor C07K14/71, TNF-receptor C07K14/7151)}
- C07K 16/2803: {against the immunoglobulin superfamily}
- A61K 2039/505: {comprising antibodies}
- A61K 2039/507: {Comprising a combination of two or more separate antibodies}
- A61K 2039/545: {characterised by the dose, timing or administration schedule}
- A61K 2039/55: {characterised by the host/recipient, e.g. newborn with maternal antibodies}
- C07K 2317/21: from primates, e.g. man
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- 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)
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

This disclosure provides methods for treating a subject afflicted with a tumor derived from a renal cell carcinoma. The methods comprise administering a first dose to a subject of an anti-PD-1 antibody or antigen-binding portion thereof and/or an anti-PD-L1 antibody or antigen-binding portion thereof, and administering a second dose to the subject, wherein the subject exhibited differential expression in one or more biomarker genes, e.g., CTLA-4, TIGIT, and/or PD-L2, following administration of the first dose.

## Claims

### Claim 1

A method for treating a subject afflicted with a tumor derived from a renal cell carcinoma comprising:
(i) administering a first dose of an anti-PD-1 antibody or an anti-PD-L1 antibody to the subject who exhibits an increased expression level of MICB, PVRIG, SPI1, CLEC2B, and NKG7 in a tumor biopsy obtained from the subject, relative to a reference expression level of MICB, PVRIG, SPI1, CLEC2B, and NKG7, wherein the reference expression level corresponds to the average expression level of MICB, PVRIG, SPI1, CLEC2B, and NKG7 as measured in tumor biopsies from a patient population affected with a tumor derived from a renal cell carcinoma; and
(ii) administering a second dose of the anti-PD-1 antibody or the anti-PD-L1 antibody to the subject, wherein a tumor sample obtained from the subject exhibits an increased expression level of PVRIG, NKG7, CD244, NKTR, TNFSF8, TNFSF13B, TNFRSF14, SPI1, CLEC2B, CTLA-4, TIGIT, PD-L2, or any combination thereof on about day 8 after the administration of the first dose of the anti-PD-1 antibody or the anti-PD-L1 antibody, relative to the expression level of PVRIG, NKG7, CD244, NKTR, TNFSF8, TNFSF13B, TNFRSF14, SPI1, CLEC2B, CTLA-4, TIGIT, PD-L2, or any combination thereof in a tumor sample prior to the administration of the first dose of the anti-PD-1 antibody or the anti-PD-L1 antibody.

### Claim 2 (depends on 1)

The method of claim 1, wherein the first dose of the anti-PD-1 antibody is administered at a flat dose of at least about 240 mg.

### Claim 3 (depends on 1)

The method of claim 1, wherein the first dose of the anti-PD-1 antibody comprises more than one dose, and wherein the first dose of the anti-PD-1 antibody is administered at a flat dose of at least about 240 mg once about every 2 weeks.

### Claim 4 (depends on 1)

The method of claim 1, which further comprises administering one or more additional anti-cancer agents.

### Claim 5 (depends on 4)

The method of claim 4, wherein the anti-cancer agent is selected from the group consisting of an antibody or antigen-binding portion thereof that binds specifically to CTLA-4 and inhibits CTLA-4 activity (“anti-CTLA-4 antibody”), a chemotherapy, a platinum-based doublet chemotherapy, a tyrosine kinase inhibitor, an anti-VEGF inhibitor, and any combination thereof.

### Claim 6 (depends on 5)

The method of claim 5, wherein the anti-cancer agent is ipilimumab.

### Claim 7 (depends on 5)

The method of claim 5, wherein the first dose of the anti-PD-1 antibody comprises more than one dose, and wherein the first dose of the anti-PD-1 antibody is administered at a dose of about 1 mg/kg body weight once about every three weeks.

### Claim 8 (depends on 1)

The method of claim 1, wherein the first dose of the anti-PD-L1 antibody is administered at a flat dose of at least about 1200 mg.

### Claim 9 (depends on 1)

The method of claim 1, wherein after the administration of the first dose, the subject further exhibits an increased T cell count in the tumor.

### Claim 10 (depends on 1)

The method of claim 1, wherein:
(i) the expression level of MICB, PVRIG, SPI1, CLEC2B, NKG7, or any combination thereof is a protein expression level measured by an immunohistochemistry, an ELISA, a western blot, a protein array or any combination thereof; or
(ii) the expression level of MICB, PVRIG, SPI1, CLEC2B, NKG7, or any combination thereof is a polynucleotide expression level measured by an in situ hybridization, a DNA or RNA array or polynucleotide hybridization technique, a tumor sequencing technique, a quantitative polymerase chain reaction (PCR), or any combination thereof.

### Claim 11 (depends on 1)

The method of claim 1, wherein the anti-PD-1 antibody is nivolumab or pembrolizumab.

### Claim 12 (depends on 1)

The method of claim 1, wherein the anti-PD-L1 antibody is BMS-936559, MPDL3280A, MEDI4736, or MSB0010718C.

### Claim 13 (depends on 1)

The method of claim 1, wherein the first dose of the anti-PD-1 antibody is administered at a flat dose of at least about 480 mg.

### Claim 14 (depends on 1)

The method of claim 1, wherein the first dose comprises more than one dose, and wherein the first dose of the anti-PD-1 antibody is administered at a flat dose of at least about 480 mg once about every 4 weeks.

### Claim 15 (depends on 1)

The method of claim 1, wherein the second dose of the anti-PD-1 antibody is administered as a flat dose of at least 240 mg.

### Claim 16 (depends on 1)

The method of claim 1, wherein the second dose of the anti-PD-1 antibody comprises more than one dose, and wherein the second dose of the anti-PD-1 antibody is administered at a flat dose of at least about 240 mg once about every 2 weeks.

### Claim 17 (depends on 1)

The method of claim 1, wherein the second dose of the anti-PD-1 antibody is administered as a flat dose of at least 480 mg.

### Claim 18 (depends on 1)

The method of claim 1, wherein the second dose of the anti-PD-1 antibody comprises more than one dose, and wherein the second dose of the anti-PD-1 antibody is administered at a flat dose of at least about 480 mg once about every 4 weeks.