T-cell receptor
The present invention provides a T-cell receptor (TCR) which binds to a peptide from latent membrane protein 2 (LMP-2) from the Epstein Barr Virus (EBV) having the amino acid sequence CLGGLLTMV (SEQ ID No. 1) when presented by a major histocampatability complex (MHC) molecule. The present invention also provides a nucleotide sequence encoding such a TCR, a vector comprising such a nucleotide sequence and its use to produce a EBV-specific T-cell. The present invention also provides the use of EBV-specific T-cell for cellular immunotherapy.
1. An isolated T-cell receptor (TCR) which binds to a peptide from latent membrane protein 2 (LMP-2) from the Epstein Barr Virus (EBV), said peptide having the amino acid sequence CLGGLLTMV (SEQ ID No. 1) when presented by a major histocampatability complex (MHC) molecule, the TCR comprising an α chain and a β chain,
wherein the α chain comprises three complementarity determining regions (CDRs) having the following amino acid sequences:
(SEQ ID No. 4)
CDR1α-TSDQSYG
(SEQ ID No. 5)
CDR2α-QGSYDEQ
(SEQ ID No. 2)
CDR3α-FCAMREGSGSARQLTFGSGTQLTVLPD
and wherein the β chain comprises three complementarity determining regions (CDRs) having the following amino acid sequences:
(SEQ ID No. 6)
CDR1β-SSHAT
(SEQ ID No. 7)
CDR2β-FNYEAQ
(SEQ ID No. 3)
CDR3β-ASSLGPAGIQETQYFGPGTRLLVL.
2. A TCR according to claim 1 which comprises the amino acid sequence shown as SEQ ID No. 8 or a variant thereof having at least 80% amino acid sequence identity.
3. A TCR according to claim 1 which comprises one or more mutations at the TCR α chain/β chain interface, such that when the TCR α chain and β chain are expressed in a T-cell, the frequency of mis-pairing between these chains and the endogenous TCR α chain and β chain is reduced.
4. A TCR according to claim 3 , wherein the constant region domains of the α chain and β chain each comprise an additional cysteine residue, enabling the formation of an extra disulphide bond between the α chain and the β chain.
5. A method for treating or preventing a disease associated with Epstein Barr Virus (EBV) in a subject comprising the step of adoptive transfer of a EBV-specific T-cell to the subject, wherein the EBV-specific T-cell is made by transferring a gene to the subject, wherein the gene encodes the TCR of claim 1 .
6. The method of claim 5 , wherein the disease associated with EBV is EBV-positive Hodgkin's Lymphoma, EBV-positive Burkitt Lymphoma, EBV-positive nasopharyngeal carcinoma, or an EBV-positive post-transplant lymphoproliferative disorder (PTLD).