# US 12,214,037 B2 · Treatment of cancer using humanized anti-BCMA chimeric antigen receptor

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- Number: US 12,214,037 B2
- Document ID: US12214037B2
- Status: Granted
- Kind: B2
- Application number: 17/359,211
- Filed: 2021-06-25
- Published: 2022-03-03
- Granted: 2025-02-04
- Earliest claimed: 2014-07-21
- Assignees: Novartis AG; The Trustees of the University of Pennsylvania
- Applicants: The Trustees of the University of Pennsylvania; Novartis AG
- Inventors: Jennifer Brogdon; Eugene Choi; Hilmar Erhard Ebersbach; David Jonathan Glass; Heather Huet; Carl H. June; Joan Mannick; Michael C. Milone; Leon Murphy; Gabriela Plesa; Celeste Richardson; Marco Ruella; Reshma Singh; Yongqiang Wang; Qilong Wu
- Web page: https://patentgrep.com/patent/US12214037B2

## CPC

- A61K 40/11: T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61P 35/02: specific for leukemia
- C07K 14/7051: {T-cell receptor (TcR)-CD3 complex}
- C07K 16/28: against receptors, cell surface antigens or cell surface determinants
- C07K 16/2878: {against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95}
- A61K 35/12: Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells (vaccines or medicinal preparations containing antigens or antibodies A61K39/00)
- A61K 38/177: {Receptors; Cell surface antigens; Cell surface determinants}
- A61K 39/395: Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61P 35/00: Antineoplastic agents
- C07H 21/04: with deoxyribosyl as saccharide radical
- C07K 14/705: Receptors; Cell surface antigens; Cell surface determinants {(tumour specific antigens C07K14/4748)}
- C07K 14/70578: {NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95 (NGF-receptor C07K14/71, TNF-receptor C07K14/7151)}
- C07K 14/7151: {for tumor necrosis factor [TNF], for lymphotoxin [LT]}
- C07K 19/00: Hybrid peptides {, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/622: Single chain antibody (scFv)
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- C07K 2319/00: Fusion polypeptide
- C07K 2319/03: containing a transmembrane segment
- C07K 2319/30: Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
- C07K 2319/33: fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
- C07K 2319/70: containing domain for protein-protein interaction
- C07K 2319/74: containing a fusion for binding to a cell surface receptor
- C12N 5/00: Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor; (plant reproduction by tissue culture techniques A01H4/00)
- C12N 15/63: Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## 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.

## Claims

### Claim 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.

### Claim 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.

### Claim 3 (depends on 2)

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.

### Claim 4 (depends on 2)

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.

### Claim 5 (depends on 2)

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.

### Claim 6 (depends on 5)

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.

### Claim 7 (depends on 2)

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

### Claim 8 (depends on 2)

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

### Claim 9 (depends on 8)

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

### Claim 10 (depends on 2)

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 5×107 or 1 to 5×108 cells.

### Claim 11 (depends on 2)

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/or
(b) a heavy chain variable region comprising:
(i) the amino acid sequence of SEQ ID NO: 79;
(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: 79; or
(iii) an amino acid sequence with 95-99% identity to the amino acid sequence of SEQ ID NO: 79.

### Claim 12 (depends on 2)

The method of claim 2, wherein:
(a) the encoded anti-BCMA binding domain comprises:
(i) the amino acid sequence of SEQ ID NO: 49;
(ii) an amino acid sequence having at least one, two, or three modifications but not more than 30, 20, or 10 modifications to SEQ ID NO: 49; or
(iii) an amino acid sequence with 95-99% identity to SEQ ID NO: 49;
(b) the anti-BCMA binding domain comprises a nucleotide sequence of SEQ ID NO: 64, or a sequence with 95-99% identity thereto;
(c) the nucleic acid molecule encodes a CAR comprising:
(i) the amino acid sequence of SEQ ID NO: 109;
(ii) an amino acid sequence having at least one, two, or three modifications but not more than 30, 20, or 10 modifications to SEQ ID NO: 109; or
(iii) an amino acid sequence with 95-99% identity to SEQ ID NO: 109; or
(d) the nucleic acid molecule comprises the nucleotide sequence of SEQ ID NO: 124, or a nucleotide sequence with 95-99% identity to SEQ ID NO: 124.

### Claim 13 (depends on 2)

The method of claim 2, wherein:
(i) the encoded CAR comprises a transmembrane domain that comprises a transmembrane domain of a protein selected from the group consisting of the alpha, beta, or zeta chain of the T-cell receptor, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, and CD154; or
(ii) the encoded transmembrane domain comprises the amino acid sequence of SEQ ID NO: 6, an amino acid sequence comprising at least one, two, or three modifications but not more than 20, 10, or 5 modifications of the amino acid sequence of SEQ ID NO:6, or a sequence with 95-99% identity to the amino acid sequence of SEQ ID NO:6; or (ii) the nucleic acid sequence encoding the transmembrane domain comprises the nucleotide sequence of SEQ ID NO:17, or the nucleotide sequence with 95-99% identity thereto.

### Claim 14 (depends on 2)

The method of claim 2, wherein the encoded anti-BCMA binding domain is connected to the transmembrane domain by a hinge region, wherein:
(i) the encoded hinge region comprises the amino acid sequence of SEQ ID NO:2, or a sequence with 95-99% identity thereto; or
(ii) the nucleic acid sequence encoding the hinge region comprises the nucleotide sequence of SEQ ID NO: 13, or a sequence with 95-99% identity thereto.

### Claim 15 (depends on 2)

The method of claim 2, wherein:
(i) the sequences comprising the intracellular signaling domain are expressed in the same frame and as a single polypeptide chain;
(ii) the isolated nucleic acid molecule comprises a nucleic acid sequence encoding the intracellular signaling domain comprising the nucleotide sequence of SEQ ID NO:18, or a sequence with 95-99% identity thereto, and/or the nucleotide sequence of SEQ ID NO:20 or SEQ ID NO:21, or a sequence with 95-99% identity thereto; or
(iii) the isolated nucleic acid molecule further comprises a leader sequence which encodes the amino acid sequence of SEQ ID NO: 1.

### Claim 16 (depends on 2)

The method of claim 2, wherein the isolated nucleic acid molecule encodes a CAR comprising the amino acid sequence of a light chain variable region comprising the amino acid sequence of SEQ ID NO: 94, and the amino acid sequence of a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 79.