Single-chain bispecific chimeric antigen receptors for the treatment of cancer
AssigneeThe Regents of the University of California
InventorsYvonne Yu-hsuan CHEN, Eugenia ZAH
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Abstract
Methods and compositions are provided concerning a bispecific chimeric antigen receptor (CAR) targeting BCMA and CS1, particularly in multiple myeloma patients. The bispecific CAR has advantages over dual or separate BCMA and CS1 CAR molecules. In some embodiments, there is a bispecific chimeric antigen receptor comprising a) a bispecific extracellular binding domain comprising both i) a BCMA-binding region and ii) a CSI-binding region; b) a single transmembrane domain; and, c) a single cytoplasmic region comprising a primary intracellular signaling domain.
Claims157
A bispecific chimeric antigen receptor (CAR) comprising:
- a) a bispecific extracellular binding domain comprising i) one or more BCMA-binding regions, and ii) one or more CS1-binding regions separated by one or more linkers;
- b) a single transmembrane domain;
- and,
- c) a single cytoplasmic region comprising a primary intracellular signaling domain.
A bispecific chimeric antigen receptor (CAR) comprising:
- i) a bispecific extracellular binding domain comprising a BCMA single-chain variable fragment (scFv) and a CS1-specific scFv separated by a linker;
- wherein the BCMA-specific scFv comprises CDR1, CDR2, and CDR3 from the heavy and light chains of C11D5.3 or J22.9-xi antibodies and wherein the CS1-specific scFv comprises CDR1, CDR2, and CDR3 from the heavy and light chains of Luc90 or huLuc63 antibodies and wherein the linker comprises G4S;
- ii) a hinge spacer between 8-300 amino acids in length;
- iii) one CD28 transmembrane domain;
- and,
- iv) one cytoplasmic region comprising 4-1BB co-stimulatory domain and CD3zeta intracellular signaling domain.
A bispecific chimeric antigen receptor (CAR) comprising:
- i) a bispecific extracellular binding domain comprising a BCMA-binding region comprising a dAPRIL fragment and a CS1-specific scFv separated by a linker;
- wherein the CS1-specific scFv comprises CDR1, CDR2, and CDR3 from the heavy and light variable chains of Luc90 or huLuc63 antibodies and wherein the linker comprises G4S;
- ii) a hinge spacer between 8-300 amino acids in length;
- iii) one CD28 transmembrane domain;
- and,
- iv) one cytoplasmic region comprising 4-1BB co-stimulatory domain and CD3zeta intracellular signaling domain.
A chimeric antigen receptor (CAR) comprising:
- a) an extracellular binding domain comprising a BCMA-binding region and an extracellular spacer of SEQ ID NO:172 or 73;
- b) a single transmembrane domain;
- and,
- c) a single cytoplasmic region comprising a primary intracellular signaling domain.
The CAR of claim 103, wherein the dAPRIL fragment is at least 80% identical to SEQ ID NO:38.
The CAR of any one of claims 76-108, wherein the single cytoplasmic region further comprises one or more costimulatory domains.
A chimeric antigen receptor (CAR) comprising:
- a) an extracellular binding domain comprising a BCMA scFv of SEQ ID NO:22 or 25 and an extracellular spacer of SEQ ID NO:172;
- b) a single transmembrane domain of SEQ ID NO:76;
- and,
- c) a cytoplasmic region comprising a costimulatory domain of SEQ ID NO:77 and a primary intracellular signaling domain of SEQ ID NO:78.
A method of treating a patient with multiple myeloma comprising administering to the patient a composition comprising a population of cells expressing a chimeric antigen receptor (CAR) comprising:
- a) a bispecific extracellular binding domain comprising i) a dAPRIL fragment or a BCMA single-chain variable fragment (scFv) and ii) a CS1-specific scFv separated by a linker;
- wherein the BCMA-specific scFv comprises CDR1, CDR2, and CDR3 from the heavy and light chains of C11D5.3 or J22.9-xi antibodies and wherein the CS1-specific scFv comprises CDR1, CDR2, and CDR3 from the heavy and light chains of murine Luc90 or huLuc63 antibodies and wherein the linker comprises G4S;
- b) a hinge spacer between 8-300 amino acids in length;
- c) one CD28 transmembrane domain;
- and,
- d) one cytoplasmic region comprising 4-1BB co-stimulatory domain and CD3zeta intracellular signaling domain.
A bispecific chimeric antigen receptor (CAR) comprising in order from the amino to carboxy end of the CAR:
- i) a bispecific extracellular binding domain comprising a BCMA-specific scFv comprising SEQ ID NO:25;
- a (G4S)4 linker;
- and a CS1-specific scFv comprising SEQ ID NO:56;
- ii) a hinge spacer comprising a IgG4 hinge with CH2 and/or CH3 regions and wherein the hinge spacer is between 100-250 amino acids in length;
- iii) one CD28 transmembrane domain;
- and,
- iv) one cytoplasmic region comprising 4-1BB co-stimulatory domain and CD3zeta intracellular signaling domain.
A bispecific chimeric antigen receptor (CAR) comprising in order from the amino to carboxy end of the CAR:
- i) a bispecific extracellular binding domain comprising a CS1-specific scFv comprising SEQ ID NO:56;
- a (G4S)4 linker;
- and a BCMA-specific scFv comprising SEQ ID NO:25;
- ii) a hinge spacer comprising a IgG4 hinge and wherein the spacer is between 4-50 amino acids in length;
- iii) one CD28 transmembrane domain;
- and,
- iv) one cytoplasmic region comprising 4-1BB co-stimulatory domain and CD3zeta intracellular signaling domain.
A bispecific chimeric antigen receptor (CAR) comprising in order from the amino to carboxy end of the CAR:
- i) a bispecific extracellular binding domain comprising a BCMA-specific scFv comprising SEQ ID NO:25;
- a (G4S)4 linker;
- and a CS1-specific scFv comprising SEQ ID NO:47;
- ii) a hinge spacer comprising a IgG4 hinge and wherein the spacer is between 4-50 amino acids in length;
- iii) one CD28 transmembrane domain;
- and,
- iv) one cytoplasmic region comprising 4-1BB co-stimulatory domain and CD3zeta intracellular signaling domain.
A method of treating a patient with multiple myeloma comprising administering to the patient a composition comprising a population of cells expressing a bispecific chimeric antigen receptor (CAR) comprising in order from the amino to carboxy end of the CAR:
- i) a bispecific extracellular binding domain comprising a BCMA-specific scFv comprising SEQ ID NO:25;
- a (G4S)4 linker;
- and a CS1-specific scFv comprising SEQ ID NO:56;
- ii) a hinge spacer comprising a IgG4 hinge, CH2, and CH3 region and wherein the spacer is between 200-250 amino acids in length;
- iii) one CD28 transmembrane domain;
- and,
- iv) one cytoplasmic region comprising 4-1BB co-stimulatory domain and CD3zeta intracellular signaling domain.
A method of treating a patient with multiple myeloma comprising administering to the patient a composition comprising a population of cells expressing a bispecific chimeric antigen receptor (CAR) comprising in order from the amino to carboxy end of the CAR:
- i) a bispecific extracellular binding domain comprising a CS1-specific scFv comprising SEQ ID NO:56;
- a (G4S)4 linker;
- and a and BCMA-specific scFv comprising SEQ ID NO:25;
- ii) a hinge spacer comprising a IgG4 hinge and wherein the spacer is between 4-50 amino acids in length;
- iii) one CD28 transmembrane domain;
- and,
- iv) one cytoplasmic region comprising 4-1BB co-stimulatory domain and CD3zeta intracellular signaling domain.
A method of treating a patient with multiple myeloma comprising administering to the patient a composition comprising a population of cells expressing a bispecific chimeric antigen receptor (CAR) comprising in order from the amino to carboxy end of the CAR:
- i) a bispecific extracellular binding domain comprising a BCMA-specific scFv comprising SEQ ID NO:25;
- a (G4S)4 linker;
- and a CS1-specific scFv comprising SEQ ID NO:47;
- ii) a hinge spacer comprising a IgG4 hinge and wherein the spacer is between 4-50 amino acids in length;
- iii) one CD28 transmembrane domain;
- and,
- iv) one cytoplasmic region comprising 4-1BB co-stimulatory domain and CD3zeta intracellular signaling domain.
Dependencies are inferred from the claim text.