Mesothelin chimeric antigen receptor (CAR) and antibody against PD-L1 inhibitor for combined use in anticancer therapy

Patent metadata

Field	Value
Publication number	US-11413340-B2
Application number	US-201616065387-A
Country	US
Kind code	B2
Filing date	Dec 21, 2016
Priority date	Dec 22, 2015
Publication date	Aug 16, 2022
Grant date	Aug 16, 2022

Abstract

Provided are compositions for use in methods for treating diseases associated with expression of mesothelin comprising administering a cell that expresses a chimeric antigen receptor (CAR) specific to mesothelin in combination with a PD-L1 inhibitor.

First claim

What is claimed is:

1. A method of treating a subject having a disease associated with mesothelin expression, comprising administering to the subject:
i) a cell, or a population of immune effector cells expressing, a chimeric antigen receptor (CAR), wherein the CAR comprises a mesothelin binding domain, a transmembrane domain, and an intracellular signaling domain; wherein the mesothelin binding domain comprises:
(a) a heavy chain complementarity determining region 1 (HC CDR1), a heavy chain complementarity determining region 2 (HC CDR2), and a heavy chain complementarity determining region 3 (HC CDR3) of an anti-mesothelin antibody selected from the group consisting of M1, M2, M3, M4, M5, M6, M7, M8, M9, M10, M11, M12, M13, M14, M15, M16, M17, M18, M19, M20, M21, M22, M23, and M24; and
(b) a light chain complementarity determining region 1 (LC CDR1), a light chain complementarity determining region 2 (LC CDR2), and a light chain complementarity determining region 3 (LC CDR3) of an anti-mesothelin antibody selected from the group consisting of M1, M2, M3, M4, M5, M6, M7, M8, M9, M10, M11, M12, M13, M14, M15, M16, M17, M18, M19, M20, M21, M22, M23, and M24; and

ii) a PD-L1 inhibitor, wherein the PD-L1 inhibitor is administered prior to administration of the cell comprising a CAR; and wherein the PD-L1 inhibitor is an anti-PD-L1 antibody molecule selected from the group consisting of YW243.55.S70, MPDL3280A (atezolizumab), MEDI-4736, MSB-0010718C (avelumab), MDX-1105, and an anti-PD-L1 antibody molecule comprising:
(a) a heavy chain complementarity determining region 1 (HC CDR1) amino acid sequence selected from the group consisting of SEQ ID NO: 287, 290, or 195, a HC CDR2 amino acid sequence of SEQ ID NO: 288, and a HC CDR3 amino acid sequence of SEQ ID NO: 289; and a light chain complementarity determining region 1 (LC CDR1) amino acid sequence of SEQ ID NO: 295, a LC CDR2 amino acid sequence of SEQ ID NO: 296, and a LC CDR3 amino acid sequence of SEQ ID NO: 297; or
(b) a HC CDR1 amino acid sequence selected from the group consisting of SEQ ID NOs: 287, 290, or 195, a HC CDR2 amino acid sequence of SEQ ID NO: 291, and a HC CDR3 amino acid sequence of SEQ ID NO: 292; and a LC CDR1 amino acid sequence of SEQ ID NO: 298, a LC CDR2 amino acid sequence of SEQ ID NO: 299, and a LC CDR3 amino acid sequence of SEQ ID NO: 300.

2. The method of claim 1 , wherein the treatment comprises:
(i) administration of the CAR-expressing cell and the PD-L1 inhibitor for a treatment interval, and wherein the treatment interval comprises a single dose of the PD-L1 inhibitor and a single dose of the CAR-expressing cell; or
(ii) a single dose of the CAR-expressing cell and a single dose of the PD-L1 inhibitor.

3. The method of claim 2 , wherein the treatment or treatment interval:
(i) is initiated upon administration of the dose of the PD-L1 inhibitor and completed upon administration of the dose of the CAR-expressing cell;
(ii) further comprises one or more subsequent doses of the PD-L1 inhibitor.

4. The method of claim 2 , wherein the dose of the CAR-expressing cell is administered:
(i) at least 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or 2 weeks after the dose of PDL1 inhibitor is administered; or
(ii) 2 days after the dose of the PD-L1 inhibitor is administered.

5. The method of claim 1 , wherein the CAR-expressing cell and the PD-L1 inhibitor is administered for a treatment interval, wherein the treatment interval comprises a first and second dose of the PD-L1 inhibitor and a dose of the CAR-expressing cell, and wherein the dose of the CAR-expressing cell is administered after administration of the first dose of the PD-L1 inhibitor but before the administration of the second dose of the PD-L1 inhibitor.

6. The method of claim 5 , wherein:
(i) the treatment interval is initiated upon administration of the first dose of the PD-L1 inhibitor and completed upon administration of the second dose of the PD-L1 inhibitor;
(ii) the second dose of the PD-L1 inhibitor is administered at least 5 days, 7 days, 1 week, 2 weeks, or 3 weeks after administration of the first dose of the PD-L1 inhibitor;
(iii) the dose of the CAR-expressing cell is administered at least 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or 2 weeks after administration of the first dose of the PD-L1 inhibitor; or
(iv) the second dose of the PD-L1 inhibitor is administered at least 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or 2 weeks after administration of the dose of the CAR-expressing cell.

7. The method of claim 2 , wherein the treatment or treatment interval:
(i) is repeated one or more times; or
(ii) is followed by one or more subsequent treatment intervals wherein the one or more subsequent treatment intervals is administered at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or 2 weeks, after the completion of the first or previous treatment interval.

8. The method of claim 3 , wherein one or more subsequent doses of the PD-L1 inhibitor is administered:
(i) after the completion of one or more treatment intervals;
(ii) after the administration of the single dose of the PD-L1 inhibitor;
(iii) at least 5 days, 7 days, 2 weeks, 3 weeks or 4 weeks, after the previous dose of PD-L1 inhibitor;
(iv) at least 1, 2, 3, 4, 5, 6, or 7 days, after the initial dose of the CAR-expressing cell; or
(v) prior to the first dose of the CAR-expressing cell.

9. The method of claim 8 , wherein a dose of the PD-L1 inhibitor is administered every 5 days, 7 days, 2 weeks, 3 weeks, or 4 days after the previous dose of PD-L1 inhibitor or after the completion of one or more treatment intervals.

10. The method of claim 2 , wherein the treatment interval comprises a dose of CAR-expressing cells administered 2 days after the dose of the PD-L1 inhibitor is administered, and wherein the treatment interval is repeated twice, and wherein the treatment intervals are initiated 3 days after the completion of the previous treatment interval.

11. The method of claim 10 , wherein one or more subsequent doses of the PDL1 inhibitor is administered every 5 days, 7 days, 2 weeks, 3 weeks, or 4 weeks, after the second treatment interval.

12. The method of claim 2 , wherein one or more subsequent doses of a CAR-expressing cell is administered to the subject after the initial dose of the CAR-expressing cell.

13. The method of claim 12 , wherein the one or more subsequent doses of the CAR-expressing cell are administered:
(i) at least 2 days, 3 days, 4 days, 5 days, 6 days, 7 days or 2 weeks, after the previous dose of the CAR-expressing cell;
(ii) at least 5 days after the previous dose of the CAR-expressing cell.

14. The method of claim 2 , wherein the dose of CAR-expressing cells:
(i) comprises at least about 1-3×10 7 to 1-3×10 8 cells;
(ii) is about 1-3×10 7 cells; or
(iii) is about 1-3×10 8 cells.

15. The method of claim 2 , wherein the dose of the PD-L1 inhibitor is about 1 to 30 mg/kg, about 5 to 25 mg/kg, about 10 to 20 mg/kg, or about 1 to 5 mg/kg.

16. The method of claim 1 , wherein the PD-L1 inhibitor comprises an antibody molecule, a small molecule, a polypeptide, a fusion protein, or an inhibitory nucleic acid.

17. The method of claim 1 , wherein the anti PD-L1 antibody molecule is selected from the group consisting of BAP058-hum01, BAP058-hum02, BAP058-hum03, BAP058-hum04, BAP058-hum05, BAP058-hum06, BAP058-hum07, BAP058-hum08, BAP058-hum09, BAP058-hum010, BAP058-hum011, BAP058-hum012, BAP058-hum013, BAP058-hum014, BAP058-hum015, BAP058-hum016, BAP058-hum017, BAP058-Clone K, BAP058-Clone L, BAP05

Assignees

• Novartis Ag
• Univ Pennsylvania
• Dana Farber Cancer Inst Inc
• Harvard College

Inventors

• Brogdon Jennifer
• Chang Hwai Wen
• Engels Boris
• Freeman Gordon James
• Frey Gerhard Johann
• Mataraza Jennifer Marie
• Singh Reshma
• Sharpe Arlene Helen

Classifications

• A61K39/395

  Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum · CPC title

• C07K2317/76

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

• C07K16/2827

  against B7 molecules, e.g. CD80, CD86 · CPC title

• C07K2317/622

  Single chain antibody (scFv) · CPC title

• C07K16/30

  from tumour cells · CPC title