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US 11,028,142 B2Granted
Compositions and methods for TCR reprogramming using fusion proteins
AssigneeTcr2 Therapeutics Inc.
InventorsPatrick Baeuerle, Gregory Sieczkiewicz, Robert Hofmeister
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Abstract
Provided herein are T-cell receptor (TCR) fusion proteins (TFPs), T-cells engineered to express one or more TFPs, and methods of use thereof for the treatment of diseases, including cancer.
Claims30
A T cell from a human subject, wherein the T cell comprises a recombinant nucleic acid molecule encoding a T cell receptor (TCR) fusion protein (TFP) comprising:
- (a) a TCR subunit comprising (i) an extracellular domain, (ii) a transmembrane domain, and (iii) a TCR intracellular domain comprising a stimulatory domain from an intracellular signaling domain;
- and
- (b) a murine, human or humanized scFv or single domain antibody comprising an antigen binding domain;
- and a pharmaceutically acceptable carrier;
- wherein the TCR subunit and the antigen binding domain are operatively linked;
- wherein the extracellular domain, the transmembrane domain and the intracellular signaling domain are derived from a single subunit, wherein the single subunit is CD3 epsilon or wherein the single subunit is CD3 gamma;
- wherein the extracellular domain comprises an extracellular domain of the single subunit;
- wherein the TFP functionally interacts with an endogenous TCR when expressed in a T cell;
- and
- wherein the T cell exhibits increased cytotoxicity to a human cell expressing an antigen that specifically interacts with the antigen binding domain compared to a T cell not containing the TFP.
7 more elements
A pharmaceutical composition comprising a T cell from a human subject, wherein the T cell comprises a recombinant nucleic acid molecule encoding a T cell receptor (TCR) fusion protein (TFP) comprising:
- (a) a TCR subunit comprising (i) an extracellular domain, (ii) a transmembrane domain, and (iii) a TCR intracellular domain comprising a stimulatory domain from an intracellular signaling domain;
- and
- (b) a murine, human or humanized single domain antibody comprising an antigen binding domain;
- and a pharmaceutically acceptable carrier;
- wherein the TCR subunit and the antigen binding domain are operatively linked;
- wherein the extracellular domain, the transmembrane domain and the intracellular signaling domain are derived from a single subunit, wherein the single subunit is CD3 epsilon;
- wherein the single subunit consists of an amino acid sequence with amino acids 23-207 of SEQ ID NO:
- 56;
- wherein the TFP functionally interacts with an endogenous TCR when expressed in a T cell;
- wherein the T cell exhibits increased cytotoxicity to a human cell expressing an antigen that specifically interacts with the antigen binding domain compared to a T cell not containing the TFP;
- wherein the TFP lacks a costimulatory domain and lacks a heterologous stimulatory domain;
- wherein the antigen binding domain is connected to the TCR extracellular domain by a linker;
- and
- wherein the linker comprises (G4S)n, wherein G is glycine, S is serine, and n is an integer from 1 to 4.
11 more elements
A pharmaceutical composition comprising a T cell from a human subject, wherein the T cell comprises a recombinant nucleic acid molecule encoding a T cell receptor (TCR) fusion protein (TFP) comprising:
- (a) a TCR subunit comprising (i) an extracellular domain, (ii) a transmembrane domain, and (iii) a TCR intracellular domain comprising a stimulatory domain from an intracellular signaling domain;
- and
- (b) a murine, human or humanized scFv comprising an antigen binding domain;
- and a pharmaceutically acceptable carrier;
- wherein the TCR subunit and the antigen binding domain are operatively linked;
- wherein the extracellular domain, the transmembrane domain and the intracellular signaling domain are derived from a single subunit, wherein the single subunit is CD3 epsilon;
- wherein the single subunit consists of an amino acid sequence with amino acids 23-207 of SEQ ID NO:
- 56;
- wherein the TFP functionally interacts with an endogenous TCR when expressed in a T cell;
- wherein the T cell exhibits increased cytotoxicity to a human cell expressing an antigen that specifically interacts with the antigen binding domain compared to a T cell not containing the TFP;
- wherein the TFP lacks a costimulatory domain and lacks a heterologous stimulatory domain;
- wherein the antigen binding domain is connected to the TCR extracellular domain by a linker;
- wherein the linker comprises (G4S)n, wherein G is glycine, S is serine, and n is an integer from 1 to 4;
- wherein the antigen binding domain comprises an anti-CD19 binding domain;
- and
- wherein the anti-CD19 binding domain comprises (i) a light chain (LC) CDR1, LC CDR2 and LC CDR3 amino acid sequence of SEQ ID NO:
- 25, SEQ ID NO:
- 27 and SEQ ID NO:
- 29, respectively;
- (ii) a heavy chain (HC) CDR1, HC CDR2 and HC CDR3 amino acid sequence of SEQ ID NO:
- 31, SEQ ID NO:
- 33 and SEQ ID NO:
- 35, respectively.
20 more elements
Dependencies are inferred from the claim text.