Binding molecules
AssigneeImmunocore Limited
InventorsJakub JAWORSKI, Kate ATKIN, Arnaud TECHINE, Vijaykumar KARUPPIAH, Florence SCHLOSSER, Ana PEREIRA RIBEIRO, Chandramouli CHILLAKURI, Nathaniel LIDDY, Andrew CREESE, Martin EBNER
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Abstract
The present invention relates to binding molecules that comprise T cell receptor (TCR) variable domains and which can bind to a PRAME peptide-HLA complex. In particular, the present invention relates to binding molecules that bind to PYLGQMINL (SEQ ID NO: 1) in complex with HLA-A24. The invention also relates to the use of such molecules for the treatment of malignant diseases.
Claims61
A binding molecule comprising a TCR alpha chain variable domain and a TCR beta chain variable domain, wherein the binding molecule has the property of binding to PYLGQMINL (SEQ ID NO:
- 1) in complex with HLA-A24, wherein each of the alpha chain variable domain and the beta chain variable domain comprises FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4, where FR is a framework region and CDR is a complementarity determining region, wherein
- (a) the binding molecule contacts at least residues P1, Q5, I7 and N8 of the PYLGQMINL (SEQ ID NO:
- 1) peptide when the binding molecule is bound to PYLGQMINL (SEQ ID NO:
- 1) in complex with HLA-A24;
- and/or
- (b) the alpha chain CDR3 comprises the sequence X-X-X-X-P-N/H-R/H-X-X-X-X-X (SEQ ID NO:
- 125),
- the beta chain CDR1 comprises the sequence X-X-X-L/Y-X (SEQ ID NO:
- 126),
- the beta chain CDR2 comprises the sequence X-Y-X-X-X-X (SEQ ID NO:
- 127), and
- the beta chain CDR3 comprises the sequence X-X-X-V/I-W-S-S/I/N-G-X-X-S-A/S-X-X-X-X (SEQ ID NO:
- 128),
- where X is any amino acid.
A binding molecule comprising a TCR alpha chain variable domain and a TCR beta chain variable domain, wherein the binding molecule has the property of binding to PYLGQMINL (SEQ ID NO:
- 1) in complex with HLA-A24, wherein each of the alpha chain variable domain and the beta chain variable domain comprises FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4, where FR is a framework region and CDR is a complementarity determining region, wherein
- (a) the alpha chain CDRs have the following sequences:
- CDR1
- (SEQ ID NO:
- 5)
- SSYSPS,
- CDR2
- (SEQ ID NO:
- 27)
- YIGNVTLV,
- CDR3
- (SEQ ID NO:
- 30)
- VVGAPHHNDKII,
- or with one, two, or three mutations in total across all three alpha chain CDRs, and
- (b) the beta chain CDRs have the following sequences:
- CDR1
- (SEQ ID NO:
- 32)
- SGDYS
- CDR2
- (SEQ ID NO:
- 35)
- YYNAEE
- CDR3
- (SEQ ID NO:
- 41)
- ASSIWSIGGASSGNLS.
- or with one, two, or three mutations in total across all three beta chain CDRs.
A binding molecule comprising a TCR alpha chain variable domain and a TCR beta chain variable domain, wherein the binding molecule has the property of binding to PYLGQMINL (SEQ ID NO:
- 1) in complex with HLA-A24, wherein each of the TCR alpha chain variable domain and the TCR beta chain variable domain comprises FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4, wherein FR is a framework region and CDR is a complementarity determining region, wherein the binding molecule comprises one of the following combinations of alpha chain CDRs and beta chain CDRs:
- (a) alpha chain CDR1, CDR2 and CDR3 amino acid sequences of SSYSPS (SEQ ID NO:
- 5), YTSAATLV (SEQ ID NO:
- 6) and VVSAPNRDDKII (SEQ ID NO:
- 7), respectively, or with one, two, or three mutations in total across all three alpha chain CDRs, and beta chain CDR1, CDR2 and CDR3 amino acid sequences of SGDLS (SEQ ID NO:
- 15), YYNGEE (SEQ ID NO:
- 16) and ASSVWSSGGASAGELF (SEQ ID NO:
- 17), respectively, or with one, two, or three mutations in total across all three beta chain CDRs;
- (b) alpha chain CDR1, CDR2 and CDR3 amino acid sequences of SSYSPS (SEQ ID NO:
- 5), YTSAATLV (SEQ ID NO:
- 6) and VVGAPHRNDKII (SEQ ID NO:
- 23), respectively, or with one, two, or three mutations in total across all three alpha chain CDRs, and
- beta chain CDR1, CDR2 and CDR3 amino acid sequences of SGDLS (SEQ ID NO:
- 15), YYNGEE (SEQ ID NO:
- 16) and ASSVWSSGGASAGELF (SEQ ID NO:
- 17), respectively, or with one, two, or three mutations in total across all three beta chain CDRs;
- (c) alpha chain CDR1, CDR2 and CDR3 amino acid sequences of SSYSPS (SEQ ID NO:
- 5), YIGNDTLV (SEQ ID NO:
- 25) and VVGAPHRNDKII (SEQ ID NO:
- 23), respectively, or with one, two, or three mutations in total across all three alpha chain CDRs, and beta chain CDR1, CDR2 and CDR3 amino acid sequences of SGDYS (SEQ ID NO:
- 32), YYNGEE (SEQ ID NO:
- 16) and ASSVWSNGGASSGNLS (SEQ ID NO:
- 33), respectively, or with one, two, or three mutations in total across all three beta chain CDRs;
- or
- (d) alpha chain CDR1, CDR2 and CDR3 amino acid sequences of SSYSPS (SEQ ID NO:
- 5), YIGNVTLV (SEQ ID NO:
- 27) and VVGAPHRNDKII (SEQ ID NO:
- 23), respectively, or with one, two, or three mutations in total across all three alpha chain CDRs, and
- beta chain CDR1, CDR2 and CDR3 amino acid sequences of SGDYS (SEQ ID NO:
- 32), YYNAEE (SEQ ID NO:
- 35) and ASSVWSIGGASSGNLS (SEQ ID NO:
- 36), respectively, or with one, two, or three mutations in total across all three beta chain CDRs.
Dependencies are inferred from the claim text.