IP Library Granted Patent US 10,344,074
Granted Patent B2
US 10,344,074 · App. 15/006,224 · Granted Jul 9, 2019

T cell receptors

Inventors: Peter Molloy (Abingdon, GB); Nicholas Pumphrey (Abingdon, GB)
Assignee: ADAPTIMMUNE LIMITED
C07K14/7051A61K39/0011C12N5/0637A61K38/00C12N2740/15043C12N2799/027
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Quick Facts
Patent No.
US 10,344,074
App. No.
15/006,224
Granted
Jul 9, 2019
Kind
B2
Abstract

The present invention relates to T cell receptors (TCRs) which bind the HLA-A2 restricted FMNKFIYEI (158-166) peptide epitope derived from α 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.

Claims (179)

1. 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

AVNSDSGYALNF

residues 90 to 101 of SEQ ID NO: 6

or

CDR1

DRGSQS

residues 27 to 32 of SEQ ID NO: 7

CDR2

IYSNGD

residues 50 to 55 of SEQ ID NO: 7

CDR3

AVNSDSSYALNF

residues 90 to 101 of SEQ ID NO: 7

or

CDR1

DRGSQS

residues 27 to 32 of SEQ ID NO: 8

CDR2

IYSNGD

residues 50 to 55 of SEQ ID NO: 8

CDR3

AVNSDSGVALNF

residues 90 to 101 of SEQ ID NO: 8

or

CDR1

DRGSQA

residues 27 to 32 of SEQ ID NO: 9

CDR2

IYSNGD

residues 50 to 55 of SEQ ID NO: 9

CDR3

AVNSDSGVALNF

residues 90 to 101 of SEQ ID NO: 9

or

CDR1

DRGSQS

residues 27 to 32 of SEQ ID NO: 10

CDR2

IYSNGD

residues 50 to 55 of SEQ ID NO: 10

CDR3

AVNSQSGYALNF

residues 90 to 101 of SEQ ID NO: 10

or

CDR1

DRGSQS

residues 27 to 32 of SEQ ID NO: 11

CDR2

IYSNGD

residues 50 to 55 of SEQ ID NO: 11

CDR3

AVNSQSGYSLNF

residues 90 to 101 of SEQ ID NO: 11

or

CDR1

DRGSQS

residues 27 to 32 of SEQ ID NO: 12

CDR2

IYSNGD

residues 50 to 55 of SEQ ID NO: 12

CDR3

AVNSQSSYALNF

residues 90 to 101 of SEQ ID NO: 12

or

CDR1

DRGSQA

residues 27 to 32 of SEQ ID NO: 13

CDR2

IYSNGD

residues 50 to 55 of SEQ ID NO: 13

CDR3

AVNSQSGYALNF

residues 90 to 101 of SEQ ID NO: 13

or

CDR1

DRGSQS

residues 27 to 32 of SEQ ID NO: 14

CDR2

IYSNGD

residues 50 to 55 of SEQ ID NO: 14

CDR3

AVNSQSGVALNF

residues 90 to 101 of SEQ ID NO: 14

or

CDR1

DRGSQS

residues 27 to 32 of SEQ ID NO: 15

CDR2

IYSNGD

residues 50 to 55 of SEQ ID NO: 15

CDR3

AVNSQNGYALNF

residues 90 to 101 of SEQ ID NO: 15

or

CDR1

DRGSFS

residues 27 to 32 of SEQ ID NO: 16

CDR2

IYSNGD

residues 50 to 55 of SEQ ID NO: 16

CDR3

AVNSDSGYALNF

residues 90 to 101 of SEQ ID NO: 16

or

CDR1

DRGSYS

residues 27 to 32 of SEQ ID NO: 17

CDR2

IYSNGD

residues 50 to 55 of SEQ ID NO: 17

CDR3

AVNSDSGYALNF

residues 90 to 101 of SEQ ID NO: 17

or

CDR1

DRGSYS

residues 27 to 32 of SEQ ID NO: 18

CDR2

IYSNGD

residues 50 to 55 of SEQ ID NO: 18

CDR3

AVNSDSSYALNF

residues 90 to 101 of SEQ ID NO: 18

or

CDR1

DRGSYS

residues 27 to 32 of SEQ ID NO: 19

CDR2

IYSNGD

residues 50 to 55 of SEQ ID NO: 19

CDR3

AVNSDSGVALNF

residues 90 to 101 of SEQ ID NO: 19

or

CDR1

DRGSYS

residues 27 to 32 of SEQ ID NO: 20

CDR2

IYSNGD

residues 50 to 55 of SEQ ID NO: 20

CDR3

AVNSQSGYALNF

residues 90 to 101 of SEQ ID NO: 20

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

ASSLGGESEQF

residues 92 to 102 of SEQ ID NO: 5.

2. The TCR of claim 1 , wherein the alpha chain variable domain comprises an amino acid sequence of 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.

3. The TCR of claim 1 , wherein the alpha chain variable domain comprises Q1 to H112 of SEQ ID No: 11, SEQ ID No 12 or SEQ ID No 13 or SEQ ID No 14 or SEQ ID No 15 and/or the beta chain variable domain comprises D1 to T112 of SEQ ID No: 3.

4. The TCR of claim 1 , 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.

5. The TCR of claim 1 having an alpha chain TRAC constant domain sequence and/or a beta chain TRBC1 or TRBC2 constant domain sequence.

6. The TCR of claim 5 , 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.

7. The TCR of claim 5 , 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.

8. The TCR of claim 1 , which 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 Vβ 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.

9. The TCR of claim 1 , which is an alpha-beta heterodimer.

10. The TCR of claim 1 associated with a detectable label, a therapeutic agent or a PK modifying moiety.

11. A non-naturally occurring and/or purified and/or engineered nucleic acid encoding the TCR of claim 1 .

12. A non-naturally occurring and/or purified and/or engineered cell, especially a T-cell, presenting a TCR as claimed in claim 1 .

13. A cell harbouring

(a) a TCR expression vector which comprises nucleic acid as claimed in claim 11 encoding in a single open reading frame, or two distinct open reading frames, the alpha chain and the beta chain respectively; or

(b) a first expression vector which comprises nucleic acid encoding the alpha chain of a TCR as claimed in claim 1 , and a second expression vector which comprises nucleic acid encoding the beta chain of a TCR as claimed in claim 1 .

14. A pharmaceutical composition comprising a TCR as claimed in claim 1 , together with one or more pharmaceutically acceptable carriers or excipients.

15. The TCR of claim 1 , wherein the alpha chain variable domain comprising an amino acid sequence that has at least 95% identity to the sequence of amino acid residues 1-112 of SEQ ID No: 2.

16. The TCR of claim 1 , wherein the beta chain variable domain comprising an amino acid sequence that has at least 95% identity to the sequence of amino acid residues 1-112 of SEQ ID No: 3.

17. The TCR of claim 1 , wherein the alpha chain variable domain comprising an amino acid sequence that has at least 95% identity to the sequence of amino acid residues 1-112 of SEQ ID No: 2 and the beta chain variable domain comprising an amino acid sequence that has at least 95% identity to the sequence of amino acid residues 1-112 of SEQ ID No: 3.

Assignments (3)
RELEASE OF SECURITY INTEREST Recorded Jul 31, 2025
From: HERCULES CAPITAL, INC., AS AGENT
To: TCR2 THERAPEUTICS INC.; ADAPTIMMUNE LIMITED
Reel/Frame 072313/0252 →
SECURITY INTEREST Recorded May 14, 2024
From: TCR2 THERAPEUTICS INC.; ADAPTIMMUNE LIMITED
To: HERCULES CAPITAL, INC., AS AGENT
Reel/Frame 067410/0105 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 8, 2018
From: MOLLOY, PETER; PUMPHREY, NICHOLAS
To: ADAPTIMMUNE LIMITED
Reel/Frame 046583/0140 →
Priority Claims (1)
GB 1313377.2 · Jul 26, 2013 · national
Continuity (2)
Continuation In Part PCTGB2014052199 · Jul 18, 2014
Related Publication 20160137715A1 · May 19, 2016