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US 12,753,218 B2Granted
Dual CAR expressing T cells individually linked to CD28 and 4-1BB
AssigneeThe Trustees of the University of Pennsylvania
InventorsJames L. Riley, Colby Maldini
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Abstract
The present invention relates to modified immune cells or precursors thereof, comprising dual (a first and a second) chimeric receptors (e.g. CARs). One aspect includes a first CAR comprising a 4-1BB intracellular domain and a second CAR comprising a CD28 intracellular domain. Another aspect includes a method for treating of an HIV infected mammal using a modified T cell comprising a first CD4 CAR comprising a 4-1BB intracellular domain and a second CD4 CAR comprising a CD28 intracellular domain.
Claims26
A nucleic acid comprising:
- (a) a first polynucleotide sequence encoding a first chimeric antigen receptor comprising:
- (i) a first target-specific binding domain,
- (ii) a first transmembrane domain, wherein the first transmembrane domain is a 4-1BB or a CD8α transmembrane domain,
- (iii) a first intracellular domain of a 4-1BB costimulatory molecule, and
- (iv) a CD3z intracellular signaling domain;
- and
- (b) a second polynucleotide sequence encoding a second chimeric antigen receptor comprising:
- (i) a second target-specific binding domain,
- (ii) a second transmembrane domain, wherein the second transmembrane domain is a CD28 transmembrane domain,
- (iii) a second intracellular domain of a CD28 costimulatory molecule, and
- (iv) a CD3z intracellular signaling domain;
- wherein the first target-specific binding domain of the first chimeric antigen receptor and the second target-specific binding domain of the second chimeric antigen receptor bind to the same target and are identical in amino acid sequence;
- wherein the first polynucleotide and second polynucleotide are separated by a linker, wherein the linker comprises an internal ribosome entry site (IRES), a furin cleavage site, a self-cleaving peptide, or any combination thereof;
- and
- wherein expression of the first and second polynucleotide by a T cell confers greater proliferative capacity to the T cell compared to expression of only the first or second polynucleotide by the T cell.
12 more elements
A nucleic acid comprising:
- (a) a first polynucleotide sequence encoding a first chimeric antigen receptor comprising the extracellular domain of a CD4 molecule, a CD8α transmembrane domain, a 4-1BB costimulatory domain, and a CD3z intracellular signaling domain;
- and
- (b) a second polynucleotide sequence encoding a second chimeric antigen receptor comprising the extracellular domain of a CD4 molecule, a CD28 transmembrane domain, a CD28 costimulatory domain, and a CD3z intracellular signaling domain;
- wherein the first polynucleotide and second polynucleotide are separated by a linker, wherein the linker comprises an internal ribosome entry site (IRES), a furin cleavage site, a self-cleaving peptide, or any combination thereof.
1 more element
Dependencies are inferred from the claim text.