CANCER IMMUNOTHERAPY BY DISRUPTING PD-1/PD-L1 SIGNALING

• US 20150125463A1
• Filed: 05/13/2013
• Published: 05/07/2015
• Est. Priority Date: 05/15/2012
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Jure-Kunkel, Maria, Cogswell, John P., Goldberg, Stacie M., Gupta, Ashok Kumar, Wang, Xi-Tao, Wigginton, Jon M.
• Granted Patent: US 9,856,320 B2
• Time in Patent Office: Days
• US Class Current: 424/142.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/507 Comprising a combination of two or more separate antibodies
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 16/2803 against the immunoglobulin superfamily
• CPC Class Codes: C07K 16/2818 against CD28 or CD152
• CPC Class Codes: C07K 16/2827 against B7 molecules, e.g. CD80, CD86
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: G01N 2333/70596 Molecules with a "CD"-designation not provided for elsewhere in G01N2333/705
• CPC Class Codes: G01N 2800/52 Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
• CPC Class Codes: G01N 33/57492 involving compounds localized on the membrane of tumor or cancer cells
• CPC Class Codes: 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

Abstract

The disclosure provides a method for immunotherapy of a cancer patient, comprises administering to the patient an Ab that inhibits signaling from the PD-1/PD-L1 signaling pathway, or a combination of such Ab and an anti-CTLA-4 Ab. This disclosure also provides a method for immunotherapy of a cancer patient comprising selecting a patient who is a suitable candidate for immunotherapy based on an assessment that the proportion of cells in a test tissue sample from the patient that express PD-L1 on the cell surface exceeds a predetermined threshold level, and administering an anti-PD-1 Ab to the selected subject. The disclosure additionally provides rabbit mAbs that bind specifically to a cell surface-expressed PD-L1 antigen in a FFPE tissue sample, and an automated IHC method for assessing cell surface expression in FFPE tissues using the provided anti-PD-L1 Abs.

Claims

1. A method of treating a subject afflicted with a cancer comprising administering to the subject a therapeutically effective amount of an antibody or an antigen-binding portion thereof that disrupts the interaction between Programmed Death-1 (PD-1) and Programmed Death Ligand-1 (PD-L1), wherein the antibody or antigen-binding portion thereof binds specifically to PD-1 or to PD-11.

2. The method of claim 1, wherein the cancer is selected from the group consisting of melanoma, renal cell carcinoma, squamous non-small cell lung cancer (NSCLC), non-squamous NSCLC, colorectal cancer, castration-resistant prostate cancer, ovarian cancer, gastric cancer, hepatocellular carcinoma, pancreatic carcinoma, squamous cell carcinoma of the head and neck, carcinomas of the esophagus, gastrointestinal tract and breast, and a hematological malignancy.

3. The method of claim 1, wherein the therapeutically effective amount of the antibody or antigen-binding portion thereof comprises a dose ranging from 0.1 to 10.0 mg/kg body weight which is administered at a dosing schedule of once per week, once every two weeks, or once a month.

4. A method for immunotherapy of a subject afflicted with cancer, which method comprises:

(a) selecting a subject that is a suitable candidate for immunotherapy, the selecting comprising;

(i) providing a test tissue sample obtained from a patient with cancer of the tissue, the test tissue sample comprising tumor cells and tumor-infiltrating inflammatory cells;

(ii) assessing the proportion of cells in the test tissue sample that express PD-L1 on the cell surface; and

(iii) selecting the subject as a suitable candidate based on an assessment that the proportion of cells in the test tissue sample that express PD-L1 on the cell surface exceeds a predetermined threshold level; and

(b) administering a composition comprising a therapeutically effective amount of an anti-PD-1 antibody to the selected subject.

5. The method of claim 4, wherein the proportion of cells that express PD-L1 is assessed by performing an assay to determine the presence of PD-L1 polypeptide on the surface of cells in the test tissue sample.

6. The method of claim 5, wherein the test tissue sample is a formalin-fixed paraffin-embedded (FFPE) tissue sample.

7. The method of claim 6, wherein the presence of PD-L1 polypeptide is determined using an automated IHC assay.

8. The method of claim 7, wherein the IHC assay is performed using an anti-PD-L1 monoclonal antibody to bind to the PD-L1 polypeptide, wherein the anti-PD-L monoclonal antibody is selected from 28-8, 28-1, 28-12, 29-8, and 5H1.

9. The method of claim 4, wherein the predetermined threshold level is 1% of tumor cells or a single tumor-infiltrating inflammatory cell expressing cell surface PD-L1 as determined by automated IHC using mAb 28-8.

10. A method for treatment of a subject afflicted with cancer, which method comprises:

(a) selecting a subject that is not suitable for anti-PD-1 antibody immunotherapy, the selecting comprising;

(i) providing a test tissue sample obtained from a patient with cancer of the tissue, the test tissue sample comprising tumor cells and tumor-infiltrating inflammatory cells;

(ii) assessing the proportion of cells in the test tissue sample that express PD-L1 on the cell surface; and

(iii) selecting the subject as not suitable for anti-PD-1 antibody immunotherapy based on an assessment that the proportion of cells in the test tissue sample that express PD-L1 on the cell surface is less than a predetermined threshold level; and

(b) administering a standard-of-care therapeutic other than an anti-PD-1 antibody to the selected subject.

11. The method of claim 10, wherein the proportion of cells in the test tissue sample that express PD-L1 on the cell surface is determined with a monoclonal antibody or an antigen-binding portion thereof that binds specifically to a cell surface-expressed PD-L1 polypeptide in a formalin-fixed, paraffin-embedded (FFPE) tissue sample.

12. The method of claim 11, wherein the monoclonal antibody or antigen binding portion thereof comprises the CDR1, CDR2 and CDR3 regions in a heavy chain variable region comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO:

35, and the CDR1, CDR2 and CDR3 regions in a light chain variable region comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO;

36.

13. The method of claim 11, wherein the monoclonal antibody or antigen binding portion thereof comprises a heavy chain variable region comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO:

35, and a light chain variable region comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO;

36.

14. A method of treating a subject afflicted with a cancer comprising administering to the subject:

(a) an antibody or an antigen-binding portion thereof that specifically binds to and inhibits Programmed Death-1 (PD-1); and

(b) an antibody or an antigen-binding portion thereof that specifically binds to and inhibits Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4);

each antibody being administered at a dosage ranging from 0.1 to 20.0 mg/kg body weight in a concurrent regimen comprising;

(i) an induction dosing schedule comprising combined administration of the anti-PD-1 and anti-CTLA-4 antibodies at a dosing frequency of at least once every 2, 3 or 4 weeks, or at least once a month, for at least 2, 4, 6, 8 or 10 doses, followed by administration of the anti-PD-1 alone at a dosing frequency of at least once every 2, 3 or 4 weeks, or at least once a month, for at least 2, 4, 6, 8 or 12 doses;

followed by

(ii) a maintenance dosing schedule comprising combined administration of the anti-PD-1 and anti-CTLA-4 antibodies at a dosing frequency of at least once every 8, 12 or 16 weeks, or at least once a quarter, for at least 4, 6, 8, 10, 12 or 16 doses.

15. The method of claim 14, wherein the anti-PD-1 and anti-CTLA-4 antibodies are administered at the following dosages:

(a) 0.1 mg/kg anti-PD-1 antibody and 3 mg/kg of anti-CTLA-4 antibody;

(b) 0.3 mg/kg anti-PD-1 antibody and 3 mg/kg of anti-CTLA-4 antibody;

(c) 1 mg/kg anti-PD-1 antibody and 3 mg/kg of anti-CTLA-4 antibody;

(d) 3 mg/kg anti-PD-1 antibody and 3 mg/kg of anti-CTLA-4 antibody;

(e) 5 mg/kg anti-PD-1 antibody and 3 mg/kg of anti-CTLA-4 antibody;

(f) 10 mg/kg anti-PD-1 antibody and 3 mg/kg of anti-CTLA-4 antibody;

(g) 0.1 mg/kg anti-PD-1 antibody and 1 mg/kg of anti-CTLA-4 antibody;

(h) 0.3 mg/kg anti-PD-1 antibody and 1 mg/kg of anti-CTLA-4 antibody;

(i) 1 mg/kg anti-PD-1 antibody and 1 mg/kg of anti-CTLA-4 antibody;

(j) 3 mg/kg anti-PD-1 antibody and 1 mg/kg of anti-CTLA-4 antibody;

(k) 5 mg/kg anti-PD-1 antibody and 1 mg/kg of anti-CTLA-4 antibody;

or

(l) 10 mg/kg anti-PD-1 antibody and 1 mg/kg of anti-CTLA-4 antibody.

20. A kit for treating a subject afflicted with a cancer, the kit comprising:

(a) a dosage ranging from 0.1 to 20.0 mg/kg body weight of an antibody or an antigen-binding portion thereof that specifically binds to and inhibits PD-1;

(b) a dosage ranging from 0.1 to 20.0 mg/kg body weight of an antibody or an antigen-binding portion thereof that specifically binds to and inhibits CTLA-4; and

(c) instructions for using the anti-PD-1 and anti-CTLA-4 antibodies the concurrent regimen method of claim 14.

22. The method of claim 15, wherein the anti-PD-1 antibody is nivolumab.

23. The method of claim 15, wherein the anti-CTLA-4 antibody is ipilimumab.

16. A method of treating a subject afflicted with a cancer, the subject having previously been treated with an anti-CTLA-4 antibody, which method comprises administering to the subject in a sequenced regimen an antibody or an antigen-binding portion thereof that specifically binds to and inhibits PD-1 at a dosage ranging from 0.1 to 20.0 mg/kg body weight and at a dosing frequency of at least once every week, at least once every 2, 3 or 4 weeks, or at least once a month, for up to 6 to up to 72 doses.

17. The method of claim 16, wherein the anti-PD-1 antibody is nivolumab.

21. A kit for treating a subject afflicted with a cancer, the kit comprising:

(a) a dosage ranging from 0.1 to 20.0 mg/kg body weight of an antibody or an antigen-binding portion thereof that specifically binds to and inhibits PD-1; and

(b) instructions for using the anti-PD-1 antibody in the sequenced regimen method of claim 16.

18. The method of 16, wherein the anti-CTLA-4 antibody is ipilimumab.

19. (canceled)