Methods for identifying chimeric antigen receptor-targeting ligands and uses thereof
AssigneeMassachusetts Institute of Technology
InventorsDarrell J. IRVINE, Karl Dane WITTRUP, Naveen MEHTA, Leyuan MA, Benjamin COSSETTE
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Abstract
The disclosure features chimeric antigen receptor (CAR) ligands, methods for making the same, and immunomodulatory compositions comprising the CAR ligands. The disclosure also features compositions and methods of using the immunomodulatory compositions, for example, to stimulate activation of CAR expressing cells.
Claims57
A method for identifying a peptide ligand that selectively binds a chimeric antigen receptor (CAR), wherein the method comprises:
- (i) providing a cellular library comprising a population of cells that display at least 106 unique variable peptides, wherein the variable peptides are 5 or more amino acid residues in length;
- and
- (ii) selecting a peptide sequence motif that binds the CAR antigen-recognition domain with a binding affinity (KD) of at least 5 μM.
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A method for identifying a peptide ligand with enhanced binding to a CAR antigen recognition domain, wherein the method comprises:
- (i) providing a cellular library comprising a population of cells that display at least 106 unique variable peptides, wherein the variable peptides comprise an amino acid sequence from N-terminus to C-terminus represented by the formula:
- [A]x-[M]-[B]z;
- wherein A, if present, is any amino acid residue;
- wherein M is a sequence motif comprising an amino acid sequence represented by the formula:
- N′-[Xaa]n-Cys-[Xaa]m-Cys-[Xaa]n-C′, wherein the sequence motif is capable of forming an intra-peptidyl disulfide bridge;
- wherein Xaa is any amino acid residue;
- n=1-10 amino acid residues;
- m=1-7 amino acid residues;
- wherein B, if present, is any amino acid residue;
- x and z are each integers from 1-20;
- wherein either A is present or B is present, or both A and B are present;
- and
- (ii) selecting a peptide that binds the CAR antigen-recognition domain.
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Dependencies are inferred from the claim text.