Treatment of cancer using humanized anti-BCMA chimeric antigen receptor

Patent metadata

Field	Value
Publication number	US-12214037-B2
Application number	US-202117359211-A
Country	US
Kind code	B2
Filing date	Jun 25, 2021
Priority date	Jul 21, 2014
Publication date	Feb 4, 2025
Grant date	Feb 4, 2025

Abstract

The invention provides compositions and methods for treating diseases associated with expression of BCMA. The invention also relates to chimeric antigen receptor (CAR) specific to BCMA vectors encoding the same, and recombinant T cells comprising the BCMA CAR. The invention also includes methods of administering a genetically modified T cell expressing a CAR that comprises a BCMA binding domain.

First claim

What is claimed is:

1. A method of providing an anti-tumor immunity in a mammal comprising administering to the mammal an effective amount of a cell comprising an isolated nucleic acid molecule encoding a chimeric antigen receptor polypeptide (CAR), wherein the CAR comprises an anti-B-cell maturation antigen (BCMA) binding domain, a transmembrane domain, and an intracellular signaling domain, and wherein said anti-BCMA binding domain comprises:
(i) a heavy chain complementarity determining region 1 (HC CDR1) comprising the amino acid sequence of SEQ ID NO: 394, a heavy chain complementarity determining region 2 (HC CDR2) comprising the amino acid sequence of SEQ ID NO: 434, and a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of SEQ ID NO: 474, a light chain complementarity determining region 1 (LC CDR1) comprising the amino acid sequence of SEQ ID NO: 514, a light chain complementarity determining region 2 (LC CDR2) comprising the amino acid sequence of SEQ ID NO: 554, and a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of SEQ ID NO: 594;
(ii) a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 634, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 674, a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 714, a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 754, a LC CDR2 comprising the amino acid sequence of SEQ ID NO: 794, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 834; or
(iii) a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 874, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 914, a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 954, a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 994, a LC CDR2 comprising the amino acid sequence of SEQ ID NO: 1034, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 1074; and
wherein the encoded intracellular signaling domain comprises the amino acid sequence of SEQ ID NO: 7 and the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 10.

2. A method of treating a mammal having a disease associated with expression of B-cell maturation antigen (BCMA), comprising administering to the mammal an effective amount of a cell comprising an isolated nucleic acid molecule encoding a chimeric antigen receptor polypeptide (CAR), wherein the CAR comprises an anti-BCMA binding domain, a transmembrane domain, and an intracellular signaling domain, and wherein said anti-BCMA binding domain comprises:
(i) a heavy chain complementarity determining region 1 (HC CDR1) comprising the amino acid sequence of SEQ ID NO: 394, a heavy chain complementarity determining region 2 (HC CDR2) comprising the amino acid sequence of SEQ ID NO: 434, and a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of SEQ ID NO: 474; a light chain complementarity determining region 1 (LC CDR1) comprising the amino acid sequence of SEQ ID NO: 514, a light chain complementarity determining region 2 (LC CDR2) comprising the amino acid sequence of SEQ ID NO: 554, and a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of SEQ ID NO: 594;
(ii) a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 634, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 674, a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 714, a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 754, a LC CDR2 comprising the amino acid sequence of SEQ ID NO: 794, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 834; or
(iii) a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 874, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 914, a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 954, a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 994, a LC CDR2 comprising the amino acid sequence of SEQ ID NO: 1034, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 1074; and
wherein the encoded intracellular signaling domain comprises the amino acid sequence of SEQ ID NO: 7 and the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 10.

3. The method of claim 2 , wherein the disease associated with BCMA expression is:
(i) a cancer or malignancy, or a precancerous condition chosen from one or more of a myelodysplastic syndrome or a preleukemia, or
(ii) a non-cancer related indication associated with expression of BCMA.

4. The method of claim 2 , wherein the disease is an acute leukemia chosen from one or more of B-cell acute lymphoblastic leukemia (“BALL”), T-cell acute lymphoblastic leukemia (“TALL”), and acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), B cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse large B cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell- or a large cell-follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma, mantle cell lymphoma, Marginal zone lymphoma, multiple myeloma, myelodysplastic syndrome, non-Hodgkin's lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom macroglobulinemia, a prostate cancer, pancreatic cancer, lung cancer, a plasma cell proliferative disorder, monoclonal gammapathy of undetermined significance (MGUS), a plasmacytoma, systemic amyloid light chain amyloidosis, and POEMS syndrome, or a combination thereof.

5. The method of claim 2 , wherein the cell is administered in combination with one or more of:
(i) an agent that increases the efficacy of the cell comprising the CAR nucleic acid or CAR polypeptide;
(ii) an agent that ameliorates one or more side effects associated with administration of the cell comprising the CAR nucleic acid or CAR polypeptide; or
(iii) an agent that treats the disease associated with BCMA.

6. The method of claim 5 , wherein the agent of (i) is an mTOR inhibitor and the mammal is administered a low, immune-enhancing, dose of an mTOR inhibitor.

7. The method of claim 2 , wherein the cell is administered in combination with a PD-L1 inhibitor.

8. The method of claim 2 , wherein the cell expressing the CAR molecule is administered in combination with a cell comprising a CD19 CAR molecule.

9. The method of claim 8 , wherein the disease associated with BCMA is multiple myeloma.

10. The method of claim 2 , wherein the cell expressing the CAR molecule is administered to the mammal in a single dose or by two, three, or more separate administrations of a partial dose,
optionally wherein a first percentage of the total dose is administered on a first day of treatment, a second percentage of the total dose is administered on a subsequent day of treatment, and optionally, a third percentage of the total dose is administered on a yet subsequent day of treatment,
optionally wherein 10% of the total dose of cells is administered on the first day, 30% of the total dose of cells is administered on the second day, and the remaining 60% of the total dose of cells is administered on the third day of treatment, and
optionally wherein the total cell dose comprises 1 to 5×10 7 or 1 to 5×10 8 cells.

11. The method of claim 2 , wherein the isolated nucleic acid molecule encodes a CAR comprising:
(a) a light chain variable region comprising:
(i) the amino acid sequence of SEQ ID NO: 94;
(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 SEQ ID NO: 94; or
(iii) an amino acid sequence with 95-99% identity to the amino acid sequence of SEQ ID NO: 94; and

Assignees

• Univ Pennsylvania
• Novartis Ag

Inventors

• Brogdon Jennifer
• Choi Eugene
• Ebersbach Hilmar Erhard
• Glass David Jonathan
• Huet Heather
• June Carl H
• Mannick Joan
• Milone Michael C
• Murphy Leon
• Plesa Gabriela
• Richardson Celeste
• Ruella Marco
• Singh Reshma
• Wang Yongqiang
• Wu Qilong

Classifications

• A61K40/11 Primary

  T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells · CPC title

• C07K2319/74

  containing a fusion for binding to a cell surface receptor · CPC title

• C07K14/70578

  NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95 (NGF-receptor C07K14/71, TNF-receptor C07K14/7151) · CPC title

• A61K39/39558

  against tumor tissues, cells, antigens · CPC title

• A61K39/3955

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