Chimeric antigen receptor and methods of use thereof
AssigneeThe Regents of the University of California
InventorsChia-Yung Wu, James Onuffer, Wendell A. Lim
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Abstract
The present disclosure provides a heterodimeric, conditionally active chimeric antigen receptor (CAR), and a nucleic acid comprising a nucleotide sequence encoding the CAR. The present disclosure provides cells genetically modified to produce the CAR. A CAR of the present disclosure can be used in various methods, which are also provided.
Claims29
One or more isolated nucleic acids comprising a nucleotide sequence(s) encoding a heterodimeric chimeric antigen receptor (CAR) comprising:
- a first polypeptide comprising a first member of a dimerization pair, a first transmembrane domain, and an intracellular signaling domain;
- and
- a second polypeptide comprising an antigen-binding domain that comprises a single chain antibody variable region that specifically binds to CD19 or an antigen expressed by an immune cell, a second member of the dimerization pair, and a second transmembrane domain;
- wherein the first and second members of the dimerization pair are located intracellularly when the first and second peptides are expressed in a host immune cell and
- wherein the first polypeptide does not comprise an antigen-binding domain and the second polypeptide does not comprise an intracellular signaling domain capable of inducing immune activation,
- wherein a dimerizing agent dimerizes the first and second polypeptides to form the heterodimeric CAR when the first and second polypeptides are expressed by the host immune cell with the dimerizing agent bound between the dimerization pair members of the first and second polypeptides, and wherein activation of the immune cell by the formed heterodimeric CAR binding CD19 or said antigen is increased as compared to activation of the immune cell in the absence of the dimerizing agent.
One or more isolated nucleic acids comprising a nucleotide sequence(s) encoding a heterodimeric chimeric antigen receptor (CAR) comprising:
- a first polypeptide comprising a first member of a dimerization pair, a first transmembrane domain, and an intracellular signaling domain;
- and
- a second polypeptide comprising an antigen-binding domain that comprises a single chain antibody variable region, a second member of the dimerization pair, and a second transmembrane domain;
- wherein the first and second members of the dimerization pair are located intracellularly when the first and second peptides are expressed in a host immune cell,
- wherein the single chain antibody variable region specifically binds to an antigen selected from the group consisting of:
- CD19, CD20, CD38, CD30, Her2/neu, ERBB2, CA125, MUC-1, prostate-specific membrane antigen (PSMA), CD44 surface adhesion molecule, mesothelin, carcinoembryonic antigen (CEA), epidermal growth factor receptor (EGFR), EGFRvIII, vascular endothelial growth factor receptor-2 (VEGFR2), high molecular weight-melanoma associated antigen (HMW-MAA), MAGE-A1, IL-13R-a2 and GD2;
- and
- wherein the first polypeptide does not comprise an antigen-binding domain and the second polypeptide does not comprise an intracellular signaling domain capable of inducing immune activation, wherein a dimerizing agent dimerizes the first and second polypeptides to form the heterodimeric CAR when the first and second polypeptides are expressed by the host immune cell with the dimerizing agent bound between the dimerization pair members of the first and second polypeptides, and wherein activation of the immune cell by the formed heterodimeric CAR binding said antigen is increased as compared to activation of the immune cell in the absence of the dimerizing agent.
Dependencies are inferred from the claim text.