Compositions and methods for gamma delta tcr reprogramming using fusion proteins
AssigneeTcr2 Therapeutics Inc.
InventorsJian DING, Robert HOFMEISTER, Patrick Alexander BAEUERLE, Dario GUTIERREZ, Robert TIGHE, Julio GOMEZ RODRIGUEZ
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Abstract
Provided herein are recombinant nucleic acids encoding T cell receptor (TCR) fusion proteins (TFPs), modified γδ T cells expressing the encoded molecules, and methods of use thereof for the treatment of diseases, including cancer.
Claims156
A cell comprising a recombinant nucleic acid encoding a T cell receptor (TCR) fusion protein (TFP) comprising:
- (a) a TCR-integrating subunit comprising:
- at least a portion of a TCR extracellular domain,
- (ii) a transmembrane domain, and
- (iii) an intracellular domain comprising a stimulatory domain from an intracellular signaling domain of CD3 epsilon, CD3 gamma, or CD3 delta, or CD3 zeta;
- and
- (b) an antibody or fragment thereof comprising an antigen binding domain;
- wherein the TCR-integrating subunit and the antibody are operatively linked, wherein the cell is a gamma delta (γδ) T cell, and wherein the expressed TFP functionally incorporates into a γδ TCR complex of the γδ T cell.
A cell comprising a recombinant nucleic acid encoding T cell receptor (TCR) fusion protein (TFP) comprising:
- (a) a TCR-integrating subunit comprising:
- at least a portion of a TCR extracellular domain,
- (ii) a transmembrane domain, and
- (iii) an intracellular domain comprising a stimulatory domain from an intracellular signaling domain of CD3 epsilon, CD3 gamma, CD3 delta, or CD3 zeta;
- and
- (b) an antigen binding domain comprising a ligand or a fragment thereof;
- wherein the TCR-integrating subunit and the antigen binding domain are operatively linked, wherein the cell is a γδ T cell;
- and
- wherein the expressed TFP functionally incorporates into a γδ TCR complex of the γδ T cell.
The cell of any one of the preceding claims, wherein the TCR-integrating subunit and the antibody domain or the antigen binding domain are operatively linked by a linker sequence.
The cell of any one of the preceding claims, wherein the transmembrane domain is a transmembrane domain from CD3 epsilon, CD3 gamma, CD3 delta, TCR gamma or TCR delta.
The cell of any one of the preceding claims, wherein the intracellular domain is derived from at least in part CD3 epsilon, only CD3 gamma, or only CD3 delta.
The cell of any one of the preceding claims, wherein the TCR-integrating subunit comprises (i) at least a portion of a TCR extracellular domain, (ii) a TCR transmembrane domain, and (iii) a TCR intracellular domain, wherein at least two of (i), (ii), and (iii) are from the same TCR subunit.
The cell of any one of the preceding claims, wherein the TCR extracellular domain comprises an extracellular domain or portion thereof of a protein selected from the group consisting of a TCR gamma chain, a TCR delta chain, a CD3 epsilon TCR subunit, a CD3 gamma TCR subunit, a CD3 delta TCR subunit, functional fragments thereof, and amino acid sequences thereof having at least one but not more than 20 modifications.
The cell of any one of the preceding claims, wherein the TCR-integrating subunit comprises a transmembrane domain comprising a transmembrane domain of a protein selected from the group consisting of a TCR gamma chain, a TCR delta chain, a CD3 zeta chain, a CD3 epsilon TCR subunit, a CD3 gamma TCR subunit, or a CD3 delta TCR subunit, functional fragments thereof, and amino acid sequences thereof having at least one but not more than 20 modifications.
The cell of any one of the preceding claims, wherein the TCR-integrating subunit comprises a TCR intracellular domain comprising a stimulatory domain of a protein selected from an intracellular signaling domain of CD3 epsilon, CD3 gamma or CD3 delta, or an amino acid sequence having at least one modification thereto.
The cell of any one of the preceding claims, wherein the TCR-integrating subunit comprises an intracellular domain comprising a stimulatory domain of a functional signaling domain of CD3 zeta, or an amino acid sequence having at least one modification thereto.
The cell of any one of the preceding claims, further comprising a sequence encoding a costimulatory domain.
The cell of any one of the preceding claims, wherein the at least one but not more than 20 modifications thereto comprise a modification of an amino acid that mediates cell signaling or a modification of an amino acid that is phosphorylated in response to a ligand binding to the TFP.
The cell of any one of the preceding claims, wherein the γδ T cell is an allogenic T cell.
The cell of any one of the preceding claims, wherein the γδ T cell is a Vδ1+Vδ2−γ∂T cell.
The cell of any one of the preceding claims, further comprising a first nucleic acid encoding an inhibitory molecule that comprises a first polypeptide comprising at least a portion of an inhibitory molecule, associated with a second polypeptide comprising a positive signal from an intracellular signaling domain.
The cell of any one of the preceding claims, wherein the cell further comprises a second nucleic acid encoding IL-15.
The recombinant nucleic acid of any one of the preceding claims.
Dependencies are inferred from the claim text.