T cell receptor

Abstract

The present invention provides an engineered T cell receptor (TCR) comprising at least one of the following amino acid residues: L96 of the α chain; R9 of the β chain; Y10 of the β chain; T24 of the α chain; V19 of the α chain; T20 of the α chain; M50 of the α chain; T5 of the α chain; Q8 of the α chain; S86 of the α chain; F39 of the α chain; D55 of the α chain; R43 of the β chain; A66 of the α chain; V19 of the β chain; L21 of the β chain; L103 of the β chain; T3 of the α chain; S7 of the α chain; P9 of the α chain; M11 of the α chain; A16 of the α chain; T18 of the α chain; L21 of the α chain; S22 of the α chain; D26 of the α chain; F40 of the α chain; S47 of the α chain; R48 of the α chain; Q49 of the α chain; I51 of the α chain; L52 of the α chain; V53 of the α chain; T67 of the α chain; E68 of the α chain; N74 of the α chain; F76 of the α chain; N79 of the α chain; Q81 of the α chain; A83 of the α chain; K90 of the α chain; S92 of the α chain; D93 of the α chain; and M101 of the α chain; wherein the at least one amino acid residue is not present in the corresponding germline TCR amino acid sequence.

1 . An engineered T cell receptor (TCR) comprising at least one of the following amino acid residues:
 L96 of the α chain; R9 of the β chain; Y10 of the β chain; T24 of the α chain; T20 of the α chain; M50 of the α chain; T5 of the α chain; Q8 of the α chain; S86 of the α chain; F39 of the α chain; D55 of the α chain; R43 of the β chain; A66 of the α chain; L21 of the β chain; L103 of the chain; T3 of the α chain; P9 of the α chain; A16 of the α chain; T18 of the α chain; L21 of the α chain; S22 of the α chain; D26 of the α chain; F40 of the α chain; S47 of the α chain; R48 of the α chain; Q49 of the α chain; I51 of the α chain; L52 of the α chain; V53 of the α chain; T67 of the α chain; E68 of the α chain; N74 of the α chain; F76 of the α chain; N79 of the α chain; Q81 of the α chain; A83 of the α chain; K90 of the α chain; S92 of the α chain; D93 of the α chain; and M101 of the α chain;   
       wherein the at least one amino acid residue is not present in the corresponding germline TCR amino acid sequence. 
     
     
         2 . An engineered TCR according to  claim 1  wherein the at least one amino acid residue is selected from:
 L96 of the α chain; 
 R9 of the β chain; 
 Y10 of the β chain; 
 T24 of the α chain; 
 T20 of the α chain; 
 M50 of the α chain; 
 T5 of the α chain; 
 Q8 of the α chain; 
 S86 of the α chain; 
 F39 of the α chain; 
 D55 of the α chain; or 
 R43 of the β chain. 
 
     
     
         3 . An engineered cell surface expressed T cell receptor (TCR) comprising at least one of the following amino acid residues:
 L96 of the α chain; R9 of the β chain; Y10 of the β chain; T24 of the α chain; V19 of the α chain; T20 of the α chain; M50 of the α chain; T5 of the α chain; Q8 of the α chain; S86 of the α chain; F39 of the α chain; D55 of the α chain; R43 of the β chain; A66 of the α chain; V19 of the chain; L21 of the β chain; L103 of the β chain; T3 of the α chain; S7 of the α chain; P9 of the α chain; M11 of the α chain; A16 of the α chain; T18 of the α chain; L21 of the α chain; S22 of the α chain; D26 of the α chain; F40 of the α chain; S47 of the α chain; R48 of the α chain; Q49 of the α chain; I51 of the α chain; L52 of the α chain; V53 of the α chain; T67 of the α chain; E68 of the α chain; N74 of the α chain; F76 of the α chain; N79 of the α chain; Q81 of the α chain; A83 of the α chain; K90 of the α chain; S92 of the α chain; D93 of the α chain; and M101 of the α chain;   
       wherein the cell is human, and the at least one amino acid residue is not present in the corresponding germline TCR amino acid sequence. 
     
     
         4 . An engineered TCR according to  claim 3  wherein the at least one amino acid residue is selected from:
 L96 of the α chain; 
 R9 of the β chain; 
 Y10 of the β chain; 
 T24 of the α chain; 
 V19 of the α chain; 
 T20 of the α chain; 
 M50 of the α chain; 
 T5 of the α chain; 
 Q8 of the α chain; 
 S86 of the α chain; 
 F39 of the α chain; 
 D55 of the α chain; or 
 R43 of the chain. 
 
     
     
         5 . An engineered TCR which comprises L96 of the α chain, R9 of the β chain, Y10 of the β chain, T24 of the α chain, or a plurality of amino acid residues set forth in  claim 1 . 
     
     
         6 - 9 . (canceled) 
     
     
         10 . An engineered TCR according to  claim 5 , further comprising V19 of the α chain; V19 of the β chain; S7 of the α chain; or M11 of the α chain. 
     
     
         11 . An engineered TCR according to  claim 5  which comprises L96 of the α chain; R9 of the β chain and Y10 of the β chain. 
     
     
         12 . An engineered TCR according to  claim 3  which comprises
 (i) V19 of the α chain; R9 of the β chain and Y10 of the β chain; 
 (ii) of L96 of the α chain; R9 of the β chain; Y10 of the β chain; T24 of the α chain; V19 of the α chain; T20 of the α chain; M50 of the α chain; T5 of the α chain; Q8 of the α chain; S86 of the α chain; F39 of the α chain; D55 of the α chain; and R43 of the β chain; 
 (iii) L96 of the α chain; R9 of the β chain; Y10 of the β chain; T24 of the α chain; V19 of the α chain; T20 of the α chain; M50 of the α chain; T5 of the α chain; Q8 of the α chain; and S86 of the α chain; or 
 (iv) L96 of the α chain; R9 of the β chain; Y10 of the β chain; T24 of the α chain; V19 of the α chain; T20 of the α chain; M50 of the α chain; T5 of the α chain; Q8 of the α chain; S86 of the α chain; F39 of the α chain; D55 of the α chain; R43 of the β chain; A66 of the α chain; V19 of the β chain; L21 of the β chain; L103 of the β chain; T3 of the α chain; S7 of the α chain; P9 of the α chain; M11 of the α chain; A16 of the α chain; T18 of the α chain; L21 of the α chain; S22 of the α chain; D26 of the α chain; F40 of the α chain; S47 of the α chain; R48 of the α chain; Q49 of the α chain; I51 of the α chain; L52 of the α chain; V53 of the α chain; T67 of the α chain; E68 of the α chain; N74 of the α chain; F76 of the α chain; N79 of the α chain; Q81 of the α chain; A83 of the α chain; K90 of the α chain; S92 of the α chain; D93 of the α chain; and M101 of the α chain. 
 
     
     
         13 - 15 . (canceled) 
     
     
         16 . A nucleic acid sequence encoding a TCR α chain and/or a β chain as defined in  claim 1 . 
     
     
         17 . (canceled) 
     
     
         18 . A vector comprising a nucleic acid sequence according to  claim 16 . 
     
     
         19 . (canceled) 
     
     
         20 . A cell comprising a vector according  claim 18 . 
     
     
         21 - 22 . (canceled) 
     
     
         23 . A pharmaceutical composition comprising a vector according to  claim 18 . 
     
     
         24 - 25 . (canceled) 
     
     
         26 . A method for treating a disease which comprises the step of administering a cell according to  claim 20  to a subject. 
     
     
         27 . A method for producing a cell according to  claim 20  which comprises the step of transducing a cell in vitro or ex vivo with a vector. 
     
     
         28 . A method for increasing the cell surface expression of a TCR which comprises the steps of:
 (i) providing a TCR α chain and/or β chain sequence;   (ii) determining an amino acid residue of the TCR α chain and/or β chain at one or more positions selected from:   96 of the α chain; 9 of the β chain; 10 of the β chain; 24 of the α chain; 19 of the α chain; 20 of the α chain; 50 of the α chain; 5 of the α chain; 8 of the α chain; 86 of the α chain; 39 of the α chain; 55 of the α chain; 43 of the β chain; 66 of the α chain; 19 of the β chain; 21 of the β chain; 103 of the β chain; 3 of the α chain; 7 of the α chain; 9 of the α chain; 11 of the α chain; 16 of the α chain; 18 of the α chain; 21 of the α chain; 22 of the α chain; 26 of the α chain; 40 of the α chain; 47 of the α chain; 48 of the α chain; 49 of the α chain; 51 of the α chain; 52 of the α chain; 53 of the α chain; 67 of the α chain; 68 of the α chain; 74 of the α chain; 76 of the α chain; 79 of the α chain; 81 of the α chain; 83 of the α chain; 90 of the α chain; 92 of the α chain; 93 of the α chain; and 101 of the α chain; and   (iii) altering the amino acid residue at one or more of the positions listed in step (ii) to an amino acid residue selected from:   L96 of the α chain; R9 of the β chain; Y10 of the β chain; T24 of the α chain; V19 of the α chain; T20 of the α chain; M50 of the α chain; T5 of the α chain; Q8 of the α chain; S86 of the α chain; F39 of the α chain; D55 of the α chain; R43 of the β chain; A66 of the α chain; V19 of the β chain; L21 of the β chain; L103 of the β chain; T3 of the α chain; S7 of the α chain; P9 of the α chain; M11 of the α chain; A16 of the α chain; T18 of the α chain; L21 of the α chain; S22 of the α chain; D26 of the α chain; F40 of the α chain; S47 of the α chain; R48 of the α chain; Q49 of the α chain; I51 of the α chain; L52 of the α chain; V53 of the α chain; T67 of the α chain; E68 of the α chain; N74 of the α chain; F76 of the α chain; N79 of the α chain; Q81 of the α chain; A83 of the α chain; K90 of the α chain; S92 of the α chain; D93 of the α chain; and M101 of the α chain.   
     
     
         29 - 31 . (canceled) 
     
     
         32 . A method for selecting a high expression TCR which comprises the steps of:
 (i) providing a group of TCR amino acid sequences; and   (ii) selecting a TCR amino acid sequence comprising at least one amino acid residue selected from:   L96 of the α chain; R9 of the β chain; Y10 of the β chain; T24 of the α chain; V19 of the α chain; T20 of the α chain; M50 of the α chain; T5 of the α chain; Q8 of the α chain; S86 of the α chain; F39 of the α chain; D55 of the α chain; R43 of the β chain; A66 of the α chain; V19 of the β chain; L21 of the β chain; L103 of the β chain; T3 of the α chain; S7 of the α chain; P9 of the α chain; M11 of the α chain; A16 of the α chain; T18 of the α chain; L21 of the α chain; S22 of the α chain; D26 of the α chain; F40 of the α chain; S47 of the α chain; R48 of the α chain; Q49 of the α chain; I51 of the α chain; L52 of the α chain; V53 of the α chain; T67 of the α chain; E68 of the α chain; N74 of the α chain; F76 of the α chain; N79 of the α chain; Q81 of the α chain; A83 of the α chain; K90 of the α chain; S92 of the α chain; D93 of the α chain; and M101 of the α chain.   
     
     
         33 - 34 . (canceled) 
     
     
         35 . A method for determining the strength of a TCR which comprises the steps of:
 (i) providing a TCR α chain and/or β chain sequence; and   (ii) determining if the TCR sequence comprises at least one amino acid residue selected from:   L96 of the α chain; R9 of the β chain; Y10 of the β chain; T24 of the α chain; V19 of the α chain; T20 of the α chain; M50 of the α chain; T5 of the α chain; Q8 of the α chain; S86 of the α chain; F39 of the α chain; D55 of the α chain; R43 of the β chain; A66 of the α chain; V19 of the β chain; L21 of the β chain; L103 of the β chain; T3 of the α chain; S7 of the α chain; P9 of the α chain; M11 of the α chain; A16 of the α chain; T18 of the α chain; L21 of the α chain; S22 of the α chain; D26 of the α chain; F40 of the α chain; S47 of the α chain; R48 of the α chain; Q49 of the α chain; I51 of the α chain; L52 of the α chain; V53 of the α chain; T67 of the α chain; E68 of the α chain; N74 of the α chain; F76 of the α chain; N79 of the α chain; Q81 of the α chain; A83 of the α chain; K90 of the α chain; S92 of the α chain; D93 of the α chain; and M101 of the α chain;   
       wherein a sequence which comprises at least one of the recited amino acid residues is determined to be a high expression TCR and a sequence which does not comprise at least one of the recited amino acid sequences is determined to be a low expression TCR. 
     
     
         36 - 37 . (canceled) 
     
     
         38 . A cell, isolated from a human subject and transduced with a nucleic acid sequence according to  claim 16 . 
     
     
         39 . (canceled)