US2022332790A1PendingUtilityA1

Trifunctional t cell-antigen coupler and methods and uses thereof

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Assignee: UNIV MCMASTERPriority: Feb 7, 2014Filed: Jun 23, 2022Published: Oct 20, 2022
Est. expiryFeb 7, 2034(~7.5 yrs left)· nominal 20-yr term from priority
Inventors:Jonathan BramsonChristopher W. HelsenGalina DenisovaRajanish GiriKenneth Anthony Mwawasi
C07K 2319/00C07K 14/7051C07K 16/32C07K 2317/31C07K 16/2809C07K 2319/03C07K 2317/622C07K 2317/73C07K 14/70514A61P 35/02C07K 2318/20A61P 35/00A61K 35/17A61K 40/4205A61K 40/32A61K 40/31A61K 40/11C12N 5/0636A61K 2039/5156C07K 2319/02C07K 2318/10A61K 39/0005A61K 38/00C07K 16/2878C07K 2319/33
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Claims

Abstract

A trifunctional molecule comprising a target-specific ligand, a ligand that binds a protein associated with the TCR complex and a T cell receptor signaling domain polypeptide is provided. Engineering T cells with this novel receptor engenders anti-gen specific activation of numerous T cell functions, including cytokine production, degranulation and cytolysis.

Claims

exact text as granted — not AI-modified
1 . A nucleic acid comprising:
 a. a first polynucleotide encoding a target-specific ligand;   b. a second polynucleotide encoding a ligand that binds a protein associated with the TCR complex; and   c. a third polynucleotide encoding a T cell receptor signaling domain polypeptide.   
     
     
         2 . The nucleic acid of  claim 1 , wherein the target-specific ligand binds a tumor antigen. 
     
     
         3 . The nucleic acid of  claim 1  or  2 , wherein the target-specific ligand is a designed ankyrin repeat (DARPin) polypeptide or scFv. 
     
     
         4 . The nucleic acid of any one of  claims 1 - 3 , wherein the protein associated with the TCR complex is CD3. 
     
     
         5 . The nucleic acid of any one of  claims 1 - 4 , wherein the ligand that binds a protein associated with the TCR complex is a single chain antibody. 
     
     
         6 . The nucleic acid of any one of  claims 1 - 5 , wherein the ligand that binds a protein associated with the TCR complex is UCHT1, or a variant thereof. 
     
     
         7 . The nucleic acid of any one of  claims 1 - 6 , wherein the T cell receptor signaling domain polypeptide comprises a cytosolic domain and a transmembrane domain. 
     
     
         8 . The nucleic acid of  claim 7 , wherein the cytosolic domain is a CD4 cytosolic domain and the transmembrane domain is a CD4 transmembrane domain. 
     
     
         9 . The nucleic acid of any one of  claims 1 - 8 , wherein the first polynucleotide and third polynucleotide are fused to the second polynucleotide. 
     
     
         10 . The nucleic acid of any one of  claims 1 - 8 , wherein the second polynucleotide and third polynucleotide are fused to the first polynucleotide. 
     
     
         11 . A polypeptide encoded by the nucleic acid of any one of  claims 1 - 10 . 
     
     
         12 . An expression vector comprising the nucleic acid of any one of  claims 1 - 10 . 
     
     
         13 . A T-cell expressing the nucleic acid of any one of  claims 1 - 10 . 
     
     
         14 . A vector construct comprising:
 a. a first polynucleotide encoding a target-specific ligand;   b. a second polynucleotide encoding a ligand that binds a protein associated with the TCR complex; and   c. a third polynucleotide encoding a T cell receptor signaling domain polypeptide, and   d. a promoter functional in a mammalian cell.   
     
     
         15 . The vector construct of  claim 14 , wherein the first polynucleotide and third polynucleotide are fused to the second polynucleotide to provide a T cell antigen coupler fusion and the coding sequence of the T cell antigen coupler fusion is operably connected to the promoter. 
     
     
         16 . The vector construct of  claim 14 , wherein the second polynucleotide and third polynucleotide are fused to the first polynucleotide to provide a T cell antigen coupler fusion and the coding sequence of the T cell antigen coupler fusion is operably connected to the promoter. 
     
     
         17 . The vector construct of any one of  claims 14 - 16 , wherein the target-specific ligand binds a tumor antigen. 
     
     
         18 . The vector construct of any one of  claims 14 - 17 , wherein the target-specific ligand is a designed ankyrin repeat {DARPin) polypeptide or scFv. 
     
     
         19 . The vector construct of any one of  claims 14 - 18 , wherein the protein associated with the TCR complex is CD3. 
     
     
         20 . The vector construct of any one of  claims 14 - 19 , wherein the ligand that binds a protein associated with the TCR complex is a single chain antibody. 
     
     
         21 . The vector construct of any one of  claims 14 - 20 , wherein the ligand that binds a protein associated with the TCR complex is UCHT1, or a variant thereof. 
     
     
         22 . The vector construct of any one of  claims 13 - 21 , wherein the T cell receptor signaling domain polypeptide comprises a cytosolic domain and a transmembrane domain. 
     
     
         23 . The vector construct of  claim 22 , wherein the cytosolic domain is a CD4 cytosolic domain and the transmembrane domain is a CD4 transmembrane domain. 
     
     
         24 . The vector construct of any one of  claims 14 - 23 , wherein the first polynucleotide and third polynucleotides are fused to the second polynucleotide. 
     
     
         25 . An isolated T cell transfected with the vector construct of any one of  claims 14 - 24 . 
     
     
         26 . A pharmaceutical composition comprising the T cell of  claim 13  or  25  and a carrier. 
     
     
         27 . A use of a T cell for treating cancer in a subject in need thereof, wherein the T cell expresses a nucleic acid comprising:
 a. a first polynucleotide encoding a target-specific ligand;   b. a second polynucleotide encoding a ligand that binds a protein associated with the TCR complex; and   c. a third polynucleotide encoding a T cell receptor signaling domain polypeptide.   
     
     
         28 . The use of  claim 27 , wherein the target-specific ligand binds an antigen on a cancerous cell. 
     
     
         29 . The use of  claim 27  or  28 , wherein the target-specific ligand is a designed ankyrin repeat (DARPin) polypeptide or scFv. 
     
     
         30 . The use of any one of  claims 27 - 29 , wherein the protein associated with the TCR complex is CD3. 
     
     
         31 . The use of any one of  claims 27 - 30 , wherein the ligand that binds a protein associated with the TCR complex is a single chain antibody. 
     
     
         32 . The use of any one of  claims 27 - 31 , wherein the ligand that binds a protein associated with the TCR complex is UCHT1, or a variant thereof. 
     
     
         33 . The use of any one of  claims 27 - 32 , wherein the T cell receptor signaling domain polypeptide comprises a cytosolic domain and a transmembrane domain. 
     
     
         34 . The use of  claim 33 , wherein the cytosolic domain is a CD4 cytosolic domain and the transmembrane domain is a CD4 transmembrane domain. 
     
     
         35 . The use of any one of  claims 27 - 34 , wherein the first polynucleotide and third polynucleotide are fused to the second polynucleotide. 
     
     
         36 . The use of any one of  claims 27 - 34 , wherein the second polynucleotide and third polynucleotide are fused to the first polynucleotide.

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