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US 2026/0167693 A1Published application
Polynucleotides, polypeptides, cells, and compositions comprising synthetic immune receptors with methods of manufacture and treatment
AssigneeAngeles Therapeutics, Inc.
InventorPreet M Chaudhary
Life of this patent
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Abstract
The disclosures herein provide synthetic immune receptors (SIRs), nucleic acids encoding the SIRs, and methods of making and using the SIRs, in, for example, adoptive cell therapy.
Claims22
At least one recombinant polynucleotide encoding a synthetic immune receptor (SIR) wherein the SIR comprises:
- a heterodimer of T-cell receptor (TCR) constant chains or functional variants thereof selected from (a)(i) and (a)(ii), (a)(i) and (a)(iii), (a)(iv) and (a)(v), (a)(vi) and (a)(vi), (a)(i) and (a)(vi), a(ii) and a(vi), a(iii) and a(vi), a(iv) and a(vi), and a(v) and a(vi) below;
- wherein the polynucleotide encoding the SIR is expressed in a T cell with impaired or abolished expression of one or more endogenous TCR chains, and/or
- wherein the polynucleotide encoding the TCR constant chains or functional variants of the TCR constant chains comprises one or more mutations that:
- enhance the expression and/or pairing of encoded TCR constant chains or functional variants thereof, and/or
- reduce the pairing of the encoded TCR constant chains or functional variants thereof with the endogenous chains
- wherein the SIR comprises:
- (a) a T-cell receptor (TCR) constant chain or a functional variant thereof having an amino acid sequence selected from the group consisting of:
- a T-cell receptor α (Cα) constant chain or region which may comprise an optional accessory module;
- a T-cell receptor beta (Cβ) constant chain or region which may comprise an optional accessory module;
- a pre-TCRα constant chain or region which may comprise an optional accessory module;
- a T cell receptor γ (Cγ) constant chain or region which may comprise an optional accessory module;
- a T cell receptor δ (Cδ) constant chain or region which may comprise an optional accessory module;
- a T cell receptor constant chain region fused to a CD3z chain region and which may comprise an optional accessory module;
- (b) an optional linker;
- and
- (c) one or more non-natural TCR antigen binding domain(s) linked to (a) selected from the group consisting of:
- (1) an antibody;
- (2) an antibody fragment selected from the group consisting of a Fv, a Fab, and a (Fab′) 2;
- (3) a heavy chain variable region of an antibody (vH domain) and a light chain variable region of an antibody (vL domain) specific for a target antigen, such that one of said vH and vL domains is attached to a first of said two TCR constant chains of (a) and the other of said vH and vL domains is attached to a second of said TCR constant chains of (a);
- (4) a single chain variable fragment (scFv);
- (5) a single domain antibody (SDAB);
- (6) a camelid VHH domain;
- (7) a monomeric variable region of an antibody;
- (8) a non-immunoglobulin antigen binding scaffold optionally selected from the group consisting of a DARPIN, an affibody, an affilin, an adnectin, an affitin, an obody, a repebody, a fynomer, an alphabody, an avimer, an atrimer, a centyrin, a pronectin, an anticalin, a Kunitz domain, an armadillo repeat protein and a functional fragment thereof;
- (9) a receptor or a fragment thereof;
- and
- (10) a ligand or a fragment thereof.
24 more elements
A recombinant T cell or a stem cell that can differentiate into a T cell comprising at least one recombinant polynucleotide encoding a synthetic immune receptor (SIR), wherein the SIR comprises a heterodimer of T-cell receptor (TCR) constant chains or functional variants thereof selected from (a)(i) and (a)(ii), (a)(i) and (a)(iii), (a)(iv) and (a)(v), (a)(vi) and (a)(vi), (a)(i) and (a)(vi), a(ii) and a(vi), a(iii) and a(vi), a(iv) and a(vi), and a(v) and a(vi) below,
- wherein the T cell has impaired or abolished expression of one or more endogenous TCR chains or the stem cell has been engineered to result in impaired or abolished expression of one or more endogenous TCR chains in the T cell, and/or
- wherein the polynucleotide encoding the TCR constant chains or functional variants of the TCR constant chains comprise one or more mutations that enhance the expression and/or pairing of encoded TCR constant chains or functional variants thereof, and/or reduce the pairing of the encoded TCR constant chains or functional variants thereof with the endogenous TCR chains;
- wherein the encoded SIR comprises
- (a) a T-cell receptor (TCR) constant chain or a functional variant thereof having an amino acid sequence selected from the group consisting of
- (i) a T-cell receptor α (Cα) constant chain or region which may comprise an optional accessory module;
- (ii) a T-cell receptor beta (Cβ) constant chain or region which may comprise an optional accessory module;
- (iii) a pre-TCRα constant chain or region which may comprise an optional accessory module;
- (iv) a T cell receptor γ (Cγ) constant chain or region which may comprise an optional accessory module;
- (v) a T cell receptor δ (Cδ) constant chain or region which may comprise an optional accessory module;
- and
- (vi) a T cell receptor constant chain region fused to a CD3z chain region and which may comprise an optional accessory module;
- (b) an optional linker;
- and
- (c) one or more non-natural TCR antigen binding domain(s) linked to (a) selected from the group consisting of:
- (1) an antibody;
- (2) an antibody fragment selected from the group consisting of a Fv, a Fab, and a (Fab′)2;
- (3) a heavy chain variable region of an antibody (vH domain) and a light chain variable region of an antibody (vL domain) specific for a target antigen, such that one of said vH and vL domains is attached to a first of said two TCR constant chains of (a) and the other of said vH and vL domains is attached to a second of said TCR constant chains of (a);
- (4) a single chain variable fragment (scFv);
- (5) a single domain antibody (SDAB);
- (6) a camelid VHH domain;
- (7) a monomeric variable region of an antibody;
- (8) a non-immunoglobulin antigen binding scaffold optionally selected from the group consisting of a DARPIN, an affibody, an affilin, an adnectin, an affitin, an obody, a repebody, a fynomer, an alphabody, an avimer, an atrimer, a centyrin, a pronectin, an anticalin, a Kunitz domain, an armadillo repeat protein and a functional fragment thereof;
- (9) a receptor or a fragment thereof, and
- (10) a ligand or a fragment thereof.
21 more elements
A method of making a SIR-expressing T cell or stem cell that can differentiate into a T cell, comprising steps:
- A)—introducing into a T cell or stem cell that can differentiate into a T cell at least one recombinant polynucleotide encoding a synthetic immune receptor (SIR), wherein the SIR comprises a heterodimer of T-cell receptor (TCR) constant chains or functional variants thereof selected from (a)(i) and (a)(ii), (a)(i) and (a)(iii), (a)(iv) and (a)(v), (a)(vi) and (a)(vi), (a)(i) and (a)(vi), a(ii) and a(vi), a(iii) and a(vi), a(iv) and a(vi), and a(v) and a(vi) below,
- wherein the polynucleotide encoding the TCR constant chains or functional variants of the TCR constant chains comprise one or more mutations that:
- enhance the expression and/or pairing of encoded TCR constant chains or functional variants thereof, and/or reduce the pairing of the encoded TCR constant chains or functional variants thereof with the endogenous TCR chains;
- wherein the encoded SIR comprises:
- (a) a T-cell receptor (TCR) constant chain or a functional variant thereof having an amino acid sequence selected from the group consisting of:
- (i) a T-cell receptor α (Cα) constant chain or region which may comprise an optional accessory module;
- (ii) a T-cell receptor beta (Cβ) constant chain or region which may comprise an optional accessory module;
- (iii) a pre-TCRα constant chain or region which may comprise an optional accessory module;
- (iv) a T cell receptor γ (Cγ) constant chain or region which may comprise an optional accessory module;
- (v) a T cell receptor δ (Cδ) constant chain or region which may comprise an optional accessory module;
- and
- (vi) a T cell receptor constant chain region fused to a CD3z chain region and which may comprise an optional accessory module;
- and
- (b) an optional linker;
- and
- (c) one or more non-natural TCR antigen binding domain(s) linked to (a) selected from the group consisting of:
- (1) an antibody;
- (2) an antibody fragment selected from the group consisting of a Fv, a Fab, and a (Fab′)2;
- (3) a heavy chain variable region of an antibody (vH domain) and a light chain variable region of an antibody (vL domain) specific for a target antigen, such that one of said vH and vL domains is attached to a first of said two TCR constant chains of (a) and the other of said vH and vL domains is attached to a second of said TCR constant chains of (a);
- (4) a single chain variable fragment (scFv);
- (5) a single domain antibody (SDAB);
- (6) a camelid VHH domain;
- (7) a monomeric variable region of an antibody;
- (8) a non-immunoglobulin antigen binding scaffold optionally selected from the group consisting of a DARPIN, an affibody, an affilin, an adnectin, an affitin, an obody, a repebody, a fynomer, an alphabody, an avimer, an atrimer, a centyrin, a pronectin, an anticalin, a Kunitz domain, an armadillo repeat protein and a functional fragment thereof;
- (9) a receptor or a fragment thereof;
- and
- (10) a ligand or a fragment thereof;
- and
- optionally
- B)—reducing or abolishing the expression of one or more endogenous TCR chains in the T cell or stem cell that can differentiate into a T cell, wherein optionally the endogenous TCR chain is selected from the group consisting of TCRα, TCRβ1, TCRβ2, TCRγ and TCRδ;
- and/or
- C)—reducing or abolishing the expression of an HLA and/or β2 microglobulin;
- and/or
- D)—reducing or abolishing the expression of one or more target antigens to a form that is no longer recognized by the SIR;
- wherein, where indicated, steps A, B, C and/or D can be carried out concurrently or sequentially in any order.
32 more elements
Dependencies are inferred from the claim text.