Engineered regulatory T cell
The present invention relates to an engineered regulatory T cell (Treg) comprising a T cell receptor (TCR) which is capable of specifically binding to a myelin basic protein (MBP) peptide or variant or fragment thereof when the peptide is presented by a major histocompatibility complex (MHC) molecule. The present invention further relates to methods for providing an engineered Treg and to methods and uses of said engineered Treg and vectors and kits of vectors encoding said Treg.
1 . An engineered Treg comprising a T cell receptor (TCR), wherein the TCR comprises an α chain and a β chain,
wherein the α chain of the TCR comprises three CDRs having the following amino acid sequences:
CDR1α-
(SEQ ID NO: 3)
TISGTDY
CDR2α-
(SEQ ID NO: 4)
GLTSN
CDR3α-
(SEQ ID NO: 1)
TVYGGATNKLI;
and
wherein the β chain of the TCR comprises three CDRs having the following amino acid sequences:
CDR1β-
(SEQ ID NO: 5)
DFQATT
CDR2β-
(SEQ ID NO: 6)
SNEGSKA
CDR3β-
(SEQ ID NO: 2)
SARGGSYNSPLH,
wherein the α chain of the TCR comprises a human constant region amino acid sequence having at least 95% sequence identity to SEQ ID NO: 26 and/or the β chain of the TCR comprises a human constant region amino acid sequence having at least 95% sequence identity to SEQ ID NO: 27.
2 . An engineered Treg according to claim 1 , wherein:
(a) the variable region of the α chain of the TCR comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 7; and
(b) the variable region of the β chain of the TCR comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 8.
3 . An engineered Treg according to claim 1 , wherein
the β chain of the TCR comprises a human constant region amino acid sequence which comprises a cysteine residue at the position corresponding to position 22 as shown in SEQ ID NO: 27.
4 . An engineered Treg according to claim 1 , wherein the constant region domains of the α chain and β chain of the TCR each comprise an additional cysteine residue that enables the formation of an extra disulphide bond between the α chain and the β chain.
5 . An engineered Treg according to claim 1 , wherein:
(a) the α chain of the TCR comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 9; and
(b) the β chain of the TCR comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 10.
6 . An engineered Treg according to claim 1 , wherein the Treg is derived from a T cell isolated from a subject.
7 . A pharmaceutical composition comprising an engineered Treg according to claim 1 .
8 . A method for treating multiple sclerosis in an HLADRB1*0401 subject which comprises the step of administering an engineered Treg according to claim 1 to the subject.