T cell-antigen coupler with various construct optimizations
First Claim
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1. A nucleic acid sequence encoding a CD19 Trifunctional T cell-antigen coupler (CD19-TAC) comprising:
- (a) a first polynucleotide encoding a ligand that selectively binds a CD 19 antigen;
(b) a second polynucleotide encoding a humanized variant of a UCHT1 (huUCHT1) that binds a CD3 protein associated with a TCR complex on a T cell expressing said CD-19-TAC, wherein the huUCHT1 comprises an amino acid sequence having at least 80% sequence identity with SEQ ID NO;
46 and having an Y to T substitution at position 177 of SEQ ID NO;
46 (Y177T); and
(c) a third polynucleotide encoding a T cell anchoring co-receptor domain polypeptide comprising a CD4 cytosolic domain and a CD4 transmembrane domain;
wherein the ligand encoded by (a), the huUCHT1 encoded by (b), and the polypeptide encoded by (c) are fused directly to each other, or joined by at least one linker.
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Abstract
A trifunctional molecule is provided, comprising (i) a target-specific ligand, (ii) a ligand that binds a protein associated with a TCR complex, and (iii) a T cell receptor signaling domain polypeptide. Variants of the molecule are provided, including variants that exhibit optimized surface expression, transduction efficiency, and effector functionality. Variations include, for example, different ligands that bind CD3 epsilon (e.g., OKT3, L2K, F6A, UCHT1 and humanized UCHT1), different signaling domains, and different linkers between domains.
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Citations
18 Claims
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1. A nucleic acid sequence encoding a CD19 Trifunctional T cell-antigen coupler (CD19-TAC) comprising:
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(a) a first polynucleotide encoding a ligand that selectively binds a CD 19 antigen; (b) a second polynucleotide encoding a humanized variant of a UCHT1 (huUCHT1) that binds a CD3 protein associated with a TCR complex on a T cell expressing said CD-19-TAC, wherein the huUCHT1 comprises an amino acid sequence having at least 80% sequence identity with SEQ ID NO;
46 and having an Y to T substitution at position 177 of SEQ ID NO;
46 (Y177T); and(c) a third polynucleotide encoding a T cell anchoring co-receptor domain polypeptide comprising a CD4 cytosolic domain and a CD4 transmembrane domain; wherein the ligand encoded by (a), the huUCHT1 encoded by (b), and the polypeptide encoded by (c) are fused directly to each other, or joined by at least one linker. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18)
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Specification