Combination of anti-KIR and anti-CS1 antibodies to treat multiple myeloma

Patent metadata

Field	Value
Publication number	US-10494433-B2
Application number	US-201415032919-A
Country	US
Kind code	B2
Filing date	Nov 5, 2014
Priority date	Nov 6, 2013
Publication date	Dec 3, 2019
Grant date	Dec 3, 2019

Abstract

Provided are methods for clinical treatment of multiple myeloma using an anti-KIR antibody in combination with an anti-CS 1 antibody.

First claim

What is claimed is:

1. A method of treating multiple myeloma in a human patient, the method comprising administering to the patient:
(a) an IgG4 anti-KIR antibody comprising the CDR1, CDR2 and CDR3 domains in a heavy chain variable region having the sequence set forth in SEQ ID NO:3, and the CDR1, CDR2 and CDR3 domains in a light chain variable region having the sequence set forth in SEQ ID NO:5 at a dose of 0.1-20 mg/kg body weight, and
(b) an IgG1 anti-CS1 antibody comprising the CDR1, CDR2 and CDR3 domains in a heavy chain variable region having the sequence set forth in SEQ ID NO:19, and the CDR1, CDR2 and CDR3 domains in a light chain variable region having the sequence set forth in SEQ ID NO:21 at a dose of 0.1-6.0 mg/kg body weight,
wherein (A) the anti-CS1 antibody is administered weekly for a total of 8 doses over 8 weeks and the anti-KIR antibody is administered every 4 weeks for a total of 2 doses over 8 weeks during an induction phase, followed by (B) administration of the anti-CS1 antibody every 2 weeks and administration of the anti-KIR antibody every 4 weeks during a maintenance phase,

wherein administration of the anti-KIR and anti-CSI antibodies has a synergistic effect on treatment compared to administration of either antibody alone, and
wherein the antibodies are formulated separately or together in a pharmaceutically acceptable carrier.

2. The method of claim 1 , wherein the anti-KIR antibody and anti-CS1 antibody are administered at the following doses during the induction and/or maintenance phase:
(a) 0.1 mg/kg anti-KIR antibody and 6.0 mg/kg of anti-CS1 antibody;
(b) 0.3 mg/kg anti-KIR antibody and 6.0 mg/kg of anti-CS1 antibody;
(c) 1 mg/kg anti-KIR antibody and 6.0 mg/kg of anti-CS1 antibody; or
(d) 3 mg/kg anti-KIR antibody and 6.0 mg/kg of anti-CS1 antibody.

3. The method of claim 1 , wherein the anti-KIR and anti-CS1 antibodies are formulated for intravenous administration.

4. The method of claim 1 , wherein the anti-KIR and anti-CS1 antibodies are administered simultaneously.

5. The method of claim 1 , wherein the anti-KIR and anti-CS1 antibodies are administered separately.

6. The method of claim 1 , wherein the treatment produces at least one therapeutic effect chosen from complete response, very good partial response, partial response, and stable disease.

7. 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.

8. The method of claim 1 , wherein the anti-KIR antibody comprises heavy and light chain variable regions having the sequences set forth in SEQ ID NOs:3 and 5, respectively.

9. The method of claim 1 , wherein the anti-KIR antibody comprises heavy and light chains having the sequences set forth in SEQ ID NOs:1 and 2, respectively.

10. The method of claim 1 , wherein the anti-CS1 antibody comprises
(a) a heavy chain variable region CDR1 having the sequence set forth in SEQ ID NO:23;
(b) a heavy chain variable region CDR2 having the sequence set forth in SEQ ID NO:24;
(c) a heavy chain variable region CDR3 having the sequence set forth in SEQ ID NO:25;
(d) a light chain variable region CDR1 having the sequence set forth in SEQ ID NO:26;
(e) a light chain variable region CDR2 having the sequence set forth in SEQ ID NO:27; and
(f) a light chain variable region CDR3 having the sequence set forth in SEQ ID NO:28.

11. The method of claim 1 , wherein the anti-CS1 antibody comprises heavy and light chain variable regions having the sequences set forth in SEQ ID NOs:19 and 21, respectively.

12. A composition comprising:
(a) an IgG4 anti-KIR antibody comprising the CDR1, CDR2 and CDR3 domains in a heavy chain variable region having the sequence set forth in SEQ ID NO:3, and the CDR1, CDR2 and CDR3 domains in a light chain variable region having the sequence set forth in SEQ ID NO:5 at a dose of 0.1-20 mg/kg body weight, and
(b) an IgG1 anti-CS1 antibody comprising the CDR1, CDR2 and CDR3 domains in a heavy chain variable region having the sequence set forth in SEQ ID NO:19, and the CDR1, CDR2 and CDR3 domains in a light chain variable region having the sequence set forth in SEQ ID NO:21 at a dose of 0.1-6.0 mg/kg body weight,
wherein the anti-KIR and anti-CS1 antibodies are formulated at doses that have a synergistic effect on treatment compared to administration of either antibody alone when (A) the anti-CS1 antibody is administered weekly for a total of 8 doses over 8 weeks and the anti-KIR antibody is administered every 4 weeks for a total of 2 doses over 8 weeks during an induction phase, followed by (B) administration of the anti-CS1 antibody every 2 weeks and administration of the anti-KIR antibody every 4 weeks during a maintenance phase.

13. A method of treating multiple myeloma in a human patient, the method comprising administering to the patient the composition of claim 12 .

14. A kit for treating multiple myeloma in a human patient, the kit comprising:
(a) an IgG4 anti-KIR antibody comprising the CDR1, CDR2 and CDR3 domains in a heavy chain variable region having the sequence set forth in SEQ ID NO:3, and the CDR1, CDR2 and CDR3 domains in a light chain variable region having the sequence set forth in SEQ ID NO:5 at a dose of 0.1-20 mg/kg body weight;
(b) an IgG1 anti-CS1 antibody comprising the CDR1, CDR2 and CDR3 domains in a heavy chain variable region having the sequence set forth in SEQ ID NO:19, and the CDR1, CDR2 and CDR3 domains in a light chain variable region having the sequence set forth in SEQ ID NO:21 at a dose of 0.1-6.0 mg/kg body weight;
wherein the anti-KIR and anti-CS1 antibodies are formulated at doses that have a synergistic effect on treatment compared to administration of either antibody alone when (A) the anti-CS1 antibody is administered weekly for a total of 8 doses over 8 weeks and the anti-KIR antibody is administered every 4 weeks for a total of 2 doses over 8 weeks during an induction phase, followed by (B) administration of the anti-CS1 antibody every 2 weeks and administration of the anti-KIR antibody every 4 weeks during a maintenance phase, and
(c) instructions for using the anti-KIR antibody and anti-CS1 antibody in a method of treating multiple myeloma in a human patient.

Assignees

• Bristol Myers Squibb Co
• Innate Pharma

Inventors

• Andre Pascale
• Blery Mathieu
• Bonnafous Cecile
• Gupta Ashok K
• Salter-Cid Luisa M
• Robbins Michael Darron

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07K2317/90

  characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin · CPC title

• C07K16/2803 Primary

  against the immunoglobulin superfamily · CPC title

• A61K2039/545

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

• C07K2317/76

  Antagonist effect on antigen, e.g. neutralization or inhibition of binding · CPC title