Combination of anti-KIR and anti-CTLA-4 antibodies to treat cancer

Patent metadata

Field	Value
Publication number	US-10688180-B2
Application number	US-201715703126-A
Country	US
Kind code	B2
Filing date	Sep 13, 2017
Priority date	Oct 23, 2012
Publication date	Jun 23, 2020
Grant date	Jun 23, 2020

Abstract

Provided are methods for clinical treatment of cancer (e.g., solid tumors or hematological malignancies) using an anti-KIR antibody in combination with an anti-CTLA-4 antibody.

First claim

What is claimed is:

1. A method of treating cancer in a human patient diagnosed with non-small cell lung cancer (NSCLC), castrate resistant prostate cancer (CRPC) and/or melanoma, the method comprising administering to the patient an anti-KIR antibody which blocks the activity of at least one of the inhibitory KIR2DL1, KIR2DL2 and KIR2DL3 receptors and an anti-CTLA-4 antibody which blocks the activity of CTLA-4, (A) for at least one cycle during an induction phase, followed by (B) at least one cycle during a maintenance phase, wherein:
(a) the anti-KIR antibody comprises the CDR1, CDR2 and CDR3 domains in a heavy chain variable region having the sequences set forth in SEQ ID NO:3, and the CDR1, CDR2 and CDR3 domains in a light chain variable region having the sequences set forth in SEQ ID NO:5;
(b) the anti-CTLA-4 antibody comprises the CDR1, CDR2 and CDR3 domains in a heavy chain variable region having the sequences set forth in SEQ ID NO:19, and the CDR1, CDR2 and CDR3 domains in a light chain variable region having the sequences set forth in SEQ ID NO:20; and
(c) the anti-KIR antibody is administered at a dose of 0.1, 0.3, or 1 mg/kg, and the anti-CTLA-4 antibody is administered at a dose of 3 or 10 mg/kg during both phases.

2. The method of claim 1 , wherein the anti-KIR antibody and anti-CTLA-4 antibody are administered at the following doses during either the induction or maintenance phase:
(a) 0.1 mg/kg anti-KIR antibody and 3 mg/kg of anti-CTLA-4 antibody;
(b) 0.3 mg/kg anti-KIR antibody and 3 mg/kg of anti-CTLA-4 antibody;
(c) 1 mg/kg anti-KIR antibody and 3 mg/kg of anti-CTLA-4 antibody;
(d) 0.1 mg/kg anti-KIR antibody and 10 mg/kg of anti-CTLA-4 antibody; or
(e) 1 mg/kg anti-KIR antibody and 10 mg/kg of anti-CTLA-4 antibody.

3. The method of claim 1 , wherein the anti-KIR and anti-CTLA-4 antibodies are formulated for intravenous administration.

4. The method of claim 1 , wherein:
(a) the anti-KIR and anti-CTLA-4 antibodies are administered on (1) day 1, week 1, (2) day 22, week 4, (3) day 43, week 7, and (4) day 64, week 10 of the induction phase;
(b) the induction phase ends on day 84 of week 12; and/or
(c) the anti-KIR and anti-CTLA-4 antibodies are administered on day 1 of week 24, day 1 of week 36, day 1 of week 48, and day 1 of week 60 of the maintenance phase.

5. The method of claim 1 , wherein the anti-KIR and anti-CTLA-4 antibodies are administered simultaneously.

6. The method of claim 1 , wherein the anti-CTLA-4 antibody is administered before or after administration of the anti-KIR antibody.

7. The method of claim 1 , wherein the treatment produces at least one therapeutic effect chosen from a reduction in size of a tumor, reduction in number of metastatic lesions over time, complete response, partial response, and stable disease.

8. The method of claim 1 , wherein the cancer is an advanced refractory cancer.

9. The method of claim 1 , wherein the anti-KIR antibody comprises:
(a) a heavy chain variable region CDR1 having the sequence set forth in SEQ ID NO:7;
(b) a heavy chain variable region CDR2 having the sequence set forth in SEQ ID NO:8;
(c) a heavy chain variable region CDR3 having the sequence set forth in SEQ ID NO:9;
(d) a light chain variable region CDR1 having the sequence set forth in SEQ ID NO:10;
(e) a light chain variable region CDR2 having the sequence set forth in SEQ ID NO:11; and
(f) a light chain variable region CDR3 having the sequence set forth in SEQ ID NO:12.

10. The method of claim 1 , wherein the anti-KIR antibody comprises:
(a) heavy and/or light chain variable regions having the sequences set forth in SEQ ID NOs: 3 and/or 5, respectively; or
(b) heavy and/or light chains having the sequences set forth in SEQ ID NOs:1 and/or 2, respectively.

11. The method of claim 1 , wherein the anti-CTLA-4 antibody comprises:
(a) a heavy chain variable region CDR1 having the sequence set forth in SEQ ID NO:21;
(b) a heavy chain variable region CDR2 having the sequence set forth in SEQ ID NO:22;
(c) a heavy chain variable region CDR3 having the sequence set forth in SEQ ID NO:23;
(d) a light chain variable region CDR1 having the sequence set forth in SEQ ID NO:24;
(e) a light chain variable region CDR2 having the sequence set forth in SEQ ID NO:25; and
(f) a light chain variable region CDR3 having the sequence set forth in SEQ ID NO:26.

12. The method of claim 1 , wherein the anti-CTLA-4 antibody comprises:
(a) heavy and/or light chain variable regions having the sequences set forth in SEQ ID NOs: 19 and/or 20, respectively; or
(b) heavy and/or light chains having the sequences set forth in SEQ ID NOs:17 and/or 18, respectively.

13. A method of treating cancer in a human patient diagnosed with non-small cell lung cancer (NSCLC), castrate resistant prostate cancer (CRPC) and/or melanoma, the method comprising administering to the patient an anti-KIR antibody and an anti-CTLA-4 antibody for at least one cycle during an induction phase, followed by at least one cycle during a maintenance phase, wherein the anti-KIR antibody is administered at a dose of 0.1, 0.3, or 1 mg/kg, and the anti-CTLA-4 antibody is administered at a dose of 3 or 10 mg/kg during both phases, and wherein:
(a) the anti-KIR antibody comprises:
(i) a heavy chain variable region CDR1 having the sequence set forth in SEQ ID NO:7;
(ii) a heavy chain variable region CDR2 having the sequence set forth in SEQ ID NO:8;
(iii) a heavy chain variable region CDR3 having the sequence set forth in SEQ ID NO:9;
(iv) a light chain variable region CDR1 having the sequence set forth in SEQ ID NO:10;
(v) a light chain variable region CDR2 having the sequence set forth in SEQ ID NO:11;
(vi) a light chain variable region CDR3 having the sequence set forth in SEQ ID NO:12; and
(b) the anti-CTLA-4 antibody comprises:
(i) a heavy chain variable region CDR1 having the sequence set forth in SEQ ID NO:21;
(ii) a heavy chain variable region CDR2 having the sequence set forth in SEQ ID NO:22;
(iii) a heavy chain variable region CDR3 having the sequence set forth in SEQ ID NO:23;
(iv) a light chain variable region CDR1 having the sequence set forth in SEQ ID NO:24;
(v) a light chain variable region CDR2 having the sequence set forth in SEQ ID NO:25;
(vi) a light chain variable region CDR3 having the sequence set forth in SEQ ID NO:26.

14. The method of claim 13 wherein
(a) the anti-KIR antibody comprises a heavy and a light chain variable region having the sequences set forth in SEQ ID NOs: 3 and 5, respectively; and
(b) the anti-CTLA-4 antibody comprises a heavy and a light chain variable region having the sequences set forth in SEQ ID NOs: 19 and 20, respectively.

15. The method of claim 13 wherein:
(a) the anti-KIR antibody comprises a heavy and a light chain having the sequences set forth in SEQ ID NOs:1 and 2, respectively; and
(b) the anti-CTLA-4 antibody comprises a heavy and a light chain having the sequences set forth in SEQ ID NOs:17 and 18, respectively.

Assignees

• Bristol Myers Squibb Co
• Innate Pharma

Inventors

• Graziano Robert F
• Gupta Ashok K
• Kim Su Young
• Wigginton Jon
• Andre Pascale

Classifications

• C07K16/2803 Primary

  against the immunoglobulin superfamily · CPC title

• A61K39/3955 Primary

  against proteinaceous materials, e.g. enzymes, hormones, lymphokines · CPC title

• C07K16/2818

  against CD28 or CD152 · CPC title

• A61K2039/507

  Comprising a combination of two or more separate antibodies · CPC title

• A61K2039/545

  characterised by the dose, timing or administration schedule · CPC title