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

Patent metadata

Field	Value
Publication number	US-12186278-B2
Application number	US-202217811606-A
Country	US
Kind code	B2
Filing date	Jul 11, 2022
Priority date	Dec 22, 2015
Publication date	Jan 7, 2025
Grant date	Jan 7, 2025

Abstract

Provided are compositions and 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 composition or dosage formulation each comprising:
(a) 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; and wherein the mesothelin binding domain comprises:
(i) 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
(ii) 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

(b) a PD-L1 inhibitor 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:
(i) a heavy chain complementarity determining region 1 (HC CDR1) amino acid sequence selected from 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
(ii) a HC CDR1 amino acid sequence selected from 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;

wherein the cell or the population of immune effector cells expressing the CAR and the PD-L1 inhibitor are in different compositions or dosage formulations or compositions; and
wherein the PD-L1 inhibitor is administered to a subject having a disease associated with mesothelin expression at least 2 days prior to administration of the cell or the population of immune effector cells expressing the CAR.

2. The composition or dosage formulation of claim 1 , wherein the composition or dosage formulation comprises a single dose of the CAR-expressing cell and a single dose of the PD-L1 inhibitor.

3. The composition or dosage formulation of claim 2 , wherein:
(a) 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; or

(b) 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.

4. The composition or dosage formulation of claim 2 , wherein the composition or dosage formulation of the CAR-expressing cell is administered:
(a) at least 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or 2 weeks after the composition or dosage formulation of PDL1 inhibitor is administered; or
(b) 2 days after the composition or dosage formulation of the PD-L1 inhibitor is administered.

5. The composition or dosage formulation 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.

6. The composition or dosage formulation of claim 5 , wherein the one or more subsequent doses of the CAR-expressing cell are administered:
(a) 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;
(b) at least 5 days after the previous dose of the CAR-expressing cell.

7. The composition or dosage formulation 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, BAP058-Clone M, BAP058-Clone N, and BAP058-Clone O.89.

8. The composition or dosage formulation of claim 1 , wherein the anti-PD-L1 antibody molecule comprises:
(a) a heavy chain variable region comprising:
(i) an amino acid sequence of a heavy chain variable region selected from the group consisting of SEQ ID NOs: 304, 306, 316, 318, 324, 326, 332, 334, 336, 338, 340, 342, 348, 350, 356, 358, 364, 366, 377, 382, 391, 393, and 398;
(ii) an amino acid sequence having at least one, two or three modifications but not more than 30, 20 or 10 modifications to the amino acid sequence of a heavy chain variable region selected from the group consisting of SEQ ID NOs: 304, 306, 316, 318, 324, 326, 332, 334, 336, 338, 340, 342, 348, 350, 356, 358, 364, 366, 377, 382, 391, 393, and 398; or
(iii) an amino acid sequence with 95-99% identity to the amino acid sequence of a heavy chain variable region selected from the group consisting of SEQ ID NOs: 304, 306, 316, 318, 324, 326, 332, 334, 336, 338, 340, 342, 348, 350, 356, 358, 364, 366, 377, 382, 391, 393, and 398; and

(b) a light chain variable region comprising:
(i) an amino acid sequence of a light chain variable region selected from the group consisting of SEQ ID NOs: 308, 310, 312, 314, 320, 322, 330, 328, 344, 346, 352, 354, 360, 362, 368, 370, 372 and 374;
(ii) an amino acid sequence having at least one, two or three modifications but not more than 30, 20 or 10 modifications to the amino acid sequence of any light chain variable region selected from the group consisting of SEQ ID NOs: 308, 310, 312, 314, 320, 322, 330, 328, 344, 346, 352, 354, 360, 362, 368, 370, 372 and 374; or
(iii) an amino acid sequence with 95-99% identity to the amino acid sequence of any light chain variable region selected from the group consisting of SEQ ID NOs: 308, 310, 312, 314, 320, 322, 330, 328, 344, 346, 352, 354, 360, 362, 368, 370, 372 and 374.

9. The composition or dosage formulation of claim 1 , wherein the anti-PD-L1 antibody molecule comprises:
(a) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 304 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 308;
(b) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 304 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 312;
(c) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 304 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 372;
(d) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 316 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 320;
(e) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 316 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 352;
(f) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 324 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 328;
(g) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 324 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 360;
(h) a heavy chain variable domain comprising the amino acid sequence of SEQ

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