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US 2019/0338012 A1Published application
T cell receptor
AssigneeUCL Business PLC
InventorsHans STAUSS, Sharyn THOMAS, Ben WILLCOX, Fiyaz MOHAMMED
Life of this patent
Estimating the term…
Abstract
TCR The present invention relates to an engineered T cell receptor (TCR). In particular, the present invention relates to methods for expression of a TCR when expressed as an exogenous TCR, to methods for selecting a TCR with high cell surface expression when expressed as an exogenous TCR and to methods for identifying residues which contribute to the cell surface expression level of a TCR. The present invention also relates to an engineered TCR which has a high level of cell surface expression when expressed as an exogenous TCR compared to the corresponding germline TCR sequence.
Claims33
A method 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:
- an aliphatic, non-polar amino acid or a methionine at position 96 of the α chain;
- an aliphatic, polar charged amino acid or a glutamine at position 9 of the β chain;
- an aromatic amino acid at position 10 of the β chain;
- an aliphatic, polar uncharged amino acid at position 24 of the α chain;
- an aliphatic, non-polar amino acid or a methionine at position 19 of the α chain;
- an aliphatic, polar uncharged amino acid at position 20 of the α chain;
- an aliphatic, polar uncharged amino acid or a isoleucine, leucine or valine at position 50 of the α chain;
- an aliphatic, polar uncharged amino acid at position 5 of the α chain;
- an aliphatic, polar uncharged amino acid, a glutamic acid, lysine or arginine at position 8 of the α chain;
- an aliphatic, polar uncharged amino acid or alanine at position 86 of the α chain;
- an aromatic amino acid at position 39 of the α chain;
- an aliphatic, polar charged amino acid or asparagine at position 55 of the α chain;
- an aliphatic, polar charged amino acid or a glutamine at position 43 of the β chain;
- an aliphatic, non-polar amino acid or a serine at position 66 of the α chain;
- an aliphatic, non-polar amino acid or a methionine at position 19 of the β chain;
- an aliphatic, non-polar amino acid or a methionine at position 21 of the β chain;
- an aliphatic, non-polar amino acid or a methionine at position 103 of the β chain;
- an aliphatic, polar uncharged amino acid at position 3 of the α chain;
- an aliphatic, polar uncharged amino acid or alanine at position 7 of the α chain;
- an aliphatic, non-polar amino acid at position 9 of the α chain;
- an aliphatic, non-polar amino acid or a isoleucine, leucine or valine at position 11 of the α chain;
- an aliphatic, non-polar amino acid or a serine at position 16 of the α chain;
- an aliphatic, polar uncharged amino acid at position 18 of the α chain;
- an aliphatic, non-polar amino acid or a methionine at position 21 of the α chain;
- an aliphatic, polar uncharged amino acid or alanine at position 22 of the α chain;
- an aliphatic, polar charged amino acid or asparagine at position 26 of the α chain;
- an aromatic amino acid at position 40 of the α chain;
- an aliphatic, polar uncharged amino acid or alanine at position 47 of the α chain;
- an aliphatic, polar charged amino acid or a glutamine at position 48 of the α chain;
- an aliphatic, polar uncharged amino acid, glutamic acid, lysine or arginine at position 49 of the α chain;
- an aliphatic, non-polar amino acid or a methionine at position 51 of the α chain;
- an aliphatic, non-polar amino acid or a methionine at position 52 of the α chain;
- an aliphatic, non-polar amino acid or a methionine at position 53 of the α chain;
- an aliphatic, polar uncharged amino acid at position 67 of the α chain;
- an aliphatic, polar charged amino acid or a glutamine at position 68 of the α chain;
- an aliphatic, polar uncharged amino acid or an aspartic acid or histidine at position 74 of the α chain;
- an aromatic amino acid at position 76 of the α chain;
- an aliphatic, polar uncharged amino acid or an aspartic acid or histidine at position 79 of the α chain;
- an aliphatic, polar uncharged amino acid, glutamic acid, lysine or arginine at position 81 of the α chain;
- an aliphatic, non-polar amino acid or a serine at position 83 of the α chain;
- an aliphatic, polar charged amino acid or a glutamine at position 90 of the α chain;
- an aliphatic, polar uncharged amino acid or alanine at position 92 of the α chain;
- an aliphatic, polar charged amino acid or asparagine at position 93 of the α chain;
- an aliphatic, non-polar amino acid or a isoleucine, leucine or valine at position 101 of the α chain;
- with the proviso that when only one amino acid is altered in step (iii) the altered amino acid generated does not consist of an amino acid residue specified for the given position selected from group (I):
- (I) 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;
- and
- when two or more amino acid residues are altered in step (iii) at least one of the altered amino acid residues generated is not an amino acid residue specified for the given position selected from group (I).
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A method for selecting a TCR which comprises the steps of:
- (i) providing one or more TCR α chain and/or β chain sequences;
- and
- (ii) selecting a TCR amino acid sequence comprising one or more amino acid residues selected from:
- an aliphatic, non-polar amino acid or a methionine at position 96 of the α chain;
- an aliphatic, polar charged amino acid or a glutamine at position 9 of the β chain;
- an aromatic amino acid at position 10 of the β chain;
- an aliphatic, polar uncharged amino acid at position 24 of the α chain;
- an aliphatic, non-polar amino acid or a methionine at position 19 of the α chain;
- an aliphatic, polar uncharged amino acid at position 20 of the α chain;
- an aliphatic, polar uncharged amino acid or a isoleucine, leucine or valine at position 50 of the α chain;
- an aliphatic, polar uncharged amino acid at position 5 of the α chain;
- an aliphatic, polar uncharged amino acid, a glutamic acid, lysine or arginine at position 8 of the α chain;
- an aliphatic, polar uncharged amino acid or alanine at position 86 of the α chain;
- an aromatic amino acid at position 39 of the α chain;
- an aliphatic, polar charged amino acid or asparagine at position 55 of the α chain;
- an aliphatic, polar charged amino acid or a glutamine at position 43 of the β chain;
- an aliphatic, non-polar amino acid or a serine at position 66 of the α chain;
- an aliphatic, non-polar amino acid or a methionine at position 19 of the β chain;
- an aliphatic, non-polar amino acid or a methionine at position 21 of the β chain;
- an aliphatic, non-polar amino acid or a methionine at position 103 of the β chain;
- an aliphatic, polar uncharged amino acid at position 3 of the α chain;
- an aliphatic, polar uncharged amino acid or alanine at position 7 of the α chain;
- an aliphatic, non-polar amino acid at position 9 of the α chain;
- an aliphatic, polar uncharged amino acid or a isoleucine, leucine or valine at position 11 of the α chain;
- an aliphatic, non-polar amino acid or a serine at position 16 of the α chain;
- an aliphatic, polar uncharged amino acid at position 18 of the α chain;
- an aliphatic, non-polar amino acid or a methionine at position 21 of the α chain;
- an aliphatic, polar uncharged amino acid or alanine at position 22 of the α chain;
- an aliphatic, polar charged amino acid or asparagine at position 26 of the α chain;
- an aromatic amino acid at position 40 of the α chain;
- an aliphatic, polar uncharged amino acid or alanine at position 47 of the α chain;
- an aliphatic, polar charged amino acid or a glutamine at position 48 of the α chain;
- an aliphatic, polar uncharged amino acid, glutamic acid, lysine or arginine at position 49 of the α chain;
- an aliphatic, non-polar amino acid or a methionine at position 51 of the α chain;
- an aliphatic, non-polar amino acid or a methionine at position 52 of the α chain;
- an aliphatic, non-polar amino acid or a methionine at position 53 of the α chain;
- an aliphatic, polar uncharged amino acid at position 67 of the α chain;
- an aliphatic, polar charged amino acid or a glutamine at position 68 of the α chain;
- an aliphatic, polar uncharged amino acid or an aspartic acid or histidine at position 74 of the α chain;
- an aromatic amino acid at position 76 of the α chain;
- an aliphatic, polar uncharged amino acid or an aspartic acid or histidine at position 79 of the α chain;
- an aliphatic, polar uncharged amino acid, glutamic acid, lysine or arginine at position 81 of the α chain;
- an aliphatic, non-polar amino acid or a serine at position 83 of the α chain;
- an aliphatic, polar charged amino acid or a glutamine at position 90 of the α chain;
- an aliphatic, polar uncharged amino acid or alanine at position 92 of the α chain;
- an aliphatic, polar charged amino acid or asparagine at position 93 of the α chain;
- an aliphatic, polar uncharged amino acid or a isoleucine, leucine or valine at position 101 of the α chain;
- with the proviso that when only one amino acid is selected in step (ii) the amino acid does not consist of an amino acid residue specified for the given position selected from group (I):
- (I) 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;
- and
- when two or more amino acid residues are selected in step (ii) at least one of the amino acid residues selected is not an amino acid residue specified for the given position selected from group (I).
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20-22. (canceled)
An engineered T cell receptor (TCR) comprising one or more of the following amino acid residues:
- an aliphatic, non-polar amino acid or a methionine at position 96 of the α chain;
- an aliphatic, polar charged amino acid or a glutamine at position 9 of the β chain;
- an aromatic amino acid at position 10 of the β chain;
- an aliphatic, polar uncharged amino acid at position 24 of the α chain;
- an aliphatic, non-polar amino acid or a methionine at position 19 of the α chain;
- an aliphatic, polar uncharged amino acid at position 20 of the α chain;
- an aliphatic, polar uncharged amino acid or a isoleucine, leucine or valine at position 50 of the α chain;
- an aliphatic, polar uncharged amino acid at position 5 of the α chain;
- an aliphatic, polar uncharged amino acid, a glutamic acid, lysine or arginine at position 8 of the α chain;
- an aliphatic, polar uncharged amino acid or alanine at position 86 of the α chain;
- an aromatic amino acid at position 39 of the α chain;
- an aliphatic, polar charged amino acid or asparagine at position 55 of the α chain;
- an aliphatic, polar charged amino acid or a glutamine at position 43 of the β chain;
- an aliphatic, non-polar amino acid or a serine at position 66 of the α chain;
- an aliphatic, non-polar amino acid or a methionine at position 19 of the β chain;
- an aliphatic, non-polar amino acid or a methionine at position 21 of the β chain;
- an aliphatic, non-polar amino acid or a methionine at position 103 of the β chain;
- an aliphatic, polar uncharged amino acid at position 3 of the α chain;
- an aliphatic, polar uncharged amino acid or alanine at position 7 of the α chain;
- an aliphatic, non-polar amino acid at position 9 of the α chain;
- an aliphatic, polar uncharged amino acid or a isoleucine, leucine or valine at position 11 of the α chain;
- an aliphatic, non-polar amino acid or a serine at position 16 of the α chain;
- an aliphatic, polar uncharged amino acid at position 18 of the α chain;
- an aliphatic, non-polar amino acid or a methionine at position 21 of the α chain;
- an aliphatic, polar uncharged amino acid or alanine at position 22 of the α chain;
- an aliphatic, polar charged amino acid or asparagine at position 26 of the α chain;
- an aromatic amino acid at position 40 of the α chain;
- an aliphatic, polar uncharged amino acid or alanine at position 47 of the α chain;
- an aliphatic, polar charged amino acid or a glutamine at position 48 of the α chain;
- an aliphatic, polar uncharged amino acid, glutamic acid, lysine or arginine at position 49 of the α chain;
- an aliphatic, non-polar amino acid or a methionine at position 51 of the α chain;
- an aliphatic, non-polar amino acid or a methionine at position 52 of the α chain;
- an aliphatic, non-polar amino acid or a methionine at position 53 of the α chain;
- an aliphatic, polar uncharged amino acid at position 67 of the α chain;
- an aliphatic, polar charged amino acid or a glutamine at position 68 of the α chain;
- an aliphatic, polar uncharged amino acid or an aspartic acid or histidine at position 74 of the α chain;
- an aromatic amino acid at position 76 of the α chain;
- an aliphatic, polar uncharged amino acid or an aspartic acid or histidine at position 79 of the α chain;
- an aliphatic, polar uncharged amino acid, glutamic acid, lysine or arginine at position 81 of the α chain;
- an aliphatic, non-polar amino acid or a serine at position 83 of the α chain;
- an aliphatic, polar charged amino acid or a glutamine at position 90 of the α chain;
- an aliphatic, polar uncharged amino acid or alanine at position 92 of the α chain;
- an aliphatic, polar charged amino acid or asparagine at position 93 of the α chain;
- an aliphatic, polar uncharged amino acid or a isoleucine, leucine or valine at position 101 of the α chain;
- wherein the one or more amino acid residues is not present in the corresponding germline TCR amino acid sequence;
- with the proviso that when the engineered TCR has only one altered amino acid compared to the corresponding germline sequence the altered amino acid does not consist of an amino acid residue specified for the given position selected from group (I):
- (I) 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;
- and
- when the engineered TCR has two or more altered amino acid residues compared to the corresponding germline sequence at least one of the altered amino acid residues is not an amino acid residue specified for the given position selected from group (I).
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Dependencies are inferred from the claim text.