T CELL RECEPTORS
The present invention relates to T cell receptors (TCRs) which bind the HLA-A2 restricted FMNKFIYEI (158-166) SEQ ID NO: 1 peptide epitope derived from a Fetoprotein (AFP). Certain preferred TCRs of the invention demonstrate excellent binding characteristics and specificity profiles for this AFP epitope. T cell receptors of the invention may comprise at least one TCR alpha chain variable domain and/or at least one TCR beta chain variable domain, the alpha chain variable domain which may comprise an amino acid sequence that has at least 90% identity to the sequence of amino acid residues 1-112 of SEQ ID NO: 2, and/or the beta chain variable domain which may comprise an amino acid sequence that has at least 90% identity to the sequence of amino acid residues 1-112 of SEQ ID NO: 3.
1 . A method for treating a patient comprising:
administering to the patient a non-naturally occurring and/or purified and/or engineered T cell receptor (TCR) having the property of binding to FMNKFIYEI (SEQ ID NO: 1) HLA-A2 complex and comprising:
at least one TCR alpha chain variable domain and at least one TCR beta chain variable domain,
wherein the alpha chain variable domain comprises at least one of the following sets of CDR sequences:
CDR1
DRGSQA
residues 27 to 32 of SEQ ID NO: 6
CDR2
IYSNGD
residues 50 to 55 of SEQ ID NO: 6
CDR3
AVNSDS
residues 90 to 101 of SEQ ID NO: 6
GYALNF
or
CDR1
DRGSQS
residues 27 to 32 of SEQ ID NO: 7
CDR2
IYSNGD
residues 50 to 55 of SEQ ID NO: 7
CDR3
AVNSDS
residues 90 to 101 of SEQ ID NO: 7
SYALNF
or
CDR1
DRGSQS
residues 27 to 32 of SEQ ID NO: 8
CDR2
IYSNGD
residues 50 to 55 of SEQ ID NO: 8
CDR3
AVNSDS
residues 90 to 101 of SEQ ID NO: 8
GVALNF
or
CDR1
DRGSQA
residues 27 to 32 of SEQ ID NO: 9
CDR2
IYSNGD
residues 50 to 55 of SEQ ID NO: 9
CDR3
AVNSDS
residues 90 to 101 of SEQ ID NO: 9
GVALNF
or
CDR1
DRGSQS
residues 27 to 32 of SEQ ID NO: 10
CDR2
IYSNGD
residues 50 to 55 of SEQ ID NO: 10
CDR3
AVNSQS
residues 90 to 101 of SEQ ID NO: 10
GYALNF
or
CDR1
DRGSQS
residues 27 to 32 of SEQ ID NO: 11
CDR2
IYSNGD
residues 50 to 55 of SEQ ID NO: 11
CDR3
AVNSQS
residues 90 to 101 of SEQ ID NO: 11
GYSLNF
or
CDR1
DRGSQS
residues 27 to 32 of SEQ ID NO: 12
CDR2
IYSNGD
residues 50 to 55 of SEQ ID NO: 12
CDR3
AVNSQS
residues 90 to 101 of SEQ ID NO: 12
SYALNF
or
CDR1
DRGSQA
residues 27 to 32 of SEQ ID NO: 13
CDR2
IYSNGD
residues 50 to 55 of SEQ ID NO: 13
CDR3
AVNSQS
residues 90 to 101 of SEQ ID NO: 13
GYALNF
or
CDR1
DRGSQS
residues 27 to 32 of SEQ ID NO: 14
CDR2
IYSNGD
residues 50 to 55 of SEQ ID NO: 14
CDR3
AVNSQS
residues 90 to 101 of SEQ ID NO: 14
GVALNF
or
CDR1
DRGSQS
residues 27 to 32 of SEQ ID NO: 15
CDR2
IYSNGD
residues 50 to 55 of SEQ ID NO: 15
CDR3
AVNSQN
residues 90 to 101 of SEQ ID NO: 15
GYALNF
or
CDR1
DRGSFS
residues 27 to 32 of SEQ ID NO: 16
CDR2
IYSNGD
residues 50 to 55 of SEQ ID NO: 16
CDR3
AVNSDS
residues 90 to 101 of SEQ ID NO: 16
GYALNF
or
CDR1
DRGSYS
residues 27 to 32 of SEQ ID NO: 17
CDR2
IYSNGD
residues 50 to 55 of SEQ ID NO: 17
CDR3
AVNSDS
residues 90 to 101 of SEQ ID NO: 17
GYALNF
or
CDR1
DRGSYS
residues 27 to 32 of SEQ ID NO: 18
CDR2
IYSNGD
residues 50 to 55 of SEQ ID NO: 18
CDR3
AVNSDS
residues 90 to 101 of SEQ ID NO: 18
SYALNF
or
CDR1
DRGSYS
residues 27 to 32 of SEQ ID NO: 19
CDR2
IYSNGD
residues 50 to 55 of SEQ ID NO: 19
CDR3
AVNSDS
residues 90 to 101 of SEQ ID NO: 19
GVALNF
or
CDR1
DRGSYS
residues 27 to 32 of SEQ ID NO: 20
CDR2
IYSNGD
residues 50 to 55 of SEQ ID NO: 20
CDR3
AVNSQS
residues 90 to 101 of SEQ ID NO: 20
GYALNF
and the wherein the beta chain variable domain comprises the following set of CDR sequences:
CDR1
SGDLS
residues 27 to 31 of SEQ ID NO: 5
CDR2
YYNGEE
residues 49 to 54 of SEQ ID NO: 5
CDR3
ASSLGGES
residues 92 to 102 of SEQ ID NO: 5
EQF
2 . The method of claim 1 wherein the treating is treating cancer.
3 . The method of claim 2 wherein the treating cancer is treating hepatocellular carcinoma.
4 . The method of claim 1 wherein the treating comprises treating hepatocellular carcinoma.
5 . The method of claim 1 wherein the treating comprises adoptive therapy.
6 . A method for treating a patient comprising:
administering to the patient a non-naturally occurring and/or purified and/or engineered T cell receptor (TCR) having the property of binding to FMNKFIYEI (SEQ ID NO: 1) HLA-A2 complex and comprising:
at least one TCR alpha chain variable domain wherein the at least one alpha chain variable domain comprises an amino acid sequence that has at least 90% identity to the sequences of amino acid residues 1-112 of SEQ ID NO: 2; and
at least one TCR beta chain variable domain, wherein the at least one beta chain variable domain comprises an amino acid sequence that has at least 90% identity to the sequences of amino acid residues 1-112 of SEQ ID NO: 3.
7 . The method of claim 6 wherein the treating is treating cancer.
8 . The method of claim 7 wherein the treating cancer is treating hepatocellular carcinoma.
9 . The method of claim 6 wherein the treating comprises treating hepatocellular carcinoma.
10 . The method of claim 6 wherein the treating comprises adoptive therapy.
11 . The method of claim 6 , wherein the alpha chain variable domain includes a mutation in one or more of the amino acids corresponding to 31Q, 32S, 94D, 95S, 96G, 97Y and 98A.
12 . The method of claim 6 , wherein the alpha chain variable domain includes at least one of the following mutations:
Residue no.
31Q
F
Y
32S
A
94D
Q
95S
N
96G
S
97Y
V
98A
S
13 . The method of claim 6 , wherein the alpha chain variable domain comprises an amino acid sequence having at least 90% identity to residues 1-112 of any one of SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19 and SEQ ID NO: 20.
14 . The method of claim 6 , wherein the alpha chain variable domain comprises Q1 to H112 of SEQ ID NO: 11, SEQ ID NO: 12 or 13 and/or the beta chain variable domain comprise D1 to T112 of SEQ ID NO: 3.
15 . The method of claim 6 , wherein the alpha chain variable domain comprises amino acid resides 1-112 of SEQ ID NO: 2, and the beta chain variable domain comprises amino acid residues 1-112 of SEQ ID NO: 3.
16 . The method of claim 6 wherein the TCR comprises an alpha chain TRAC constant domain sequence and/or a beta chain TRBC1 or TRBC2 constant domain sequence.
17 . The method of claim 16 wherein the alpha and/or beta chain constant domain sequence(s) are modified by truncation or substitution to delete the native disulfide bond between Cys4 of exon 2 of TRAC and Cys2 of exon 2 of TRBC1 or TRBC2.
18 . The method of claim 16 , wherein the alpha and/or beta chain constant domain sequence(s) are modified by substitution of cysteine residues for Thr 48 of TRAC and Ser 57 of TRBC1 or TRBC2, the cysteines forming a disulfide bond between the alpha and beta constant domains of the TCR.
19 . The method of claim 6 wherein the TCR is in single chain format of the type Vα-L-Vβ, Vβ-L-Vα, Vα-Cα-L-Vβ, Vα-L-Vβ-Cβ or Vα-Cα-L-Vβ-Cβ wherein Vα and VP are TCR α and β variable regions respectively, Cα and Cβ are TCR α and β constant regions respectively, and L is a linker sequence.
20 . The method of claim 6 wherein the TCR comprises an alpha-beta heterodimer and/or is associated with a detectable label, a therapeutic agent or a PK modifying moiety.