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US-20260125448-A1 - PEPTIDES AND ENGINEERED T CELL RECEPTORS TARGETING MAGE-A4 ANTIGEN AND METHODS OF USE

US20260125448A1US 20260125448 A1US20260125448 A1US 20260125448A1US-20260125448-A1

Abstract

This disclosure provides for engineered T cell Receptors (TCRs), cells comprising the TCRs, and methods of making and using the TCRs. The current disclosure relates to TCRs that specifically recognize epitope(s) from tumor antigen MAGE-A4. Accordingly, aspects of the disclosure relate to an engineered T-cell Receptors (TCRs), nucleic acids encoding the TCRs, and cells comprising the nucleic acids and TCRs. Also provided are compositions comprising the cells, nucleic acids, or engineered TCRs of the disclosure, methods of making the cells and methods of using the embodiments of the disclosure for therapeutic treatments.

Inventors

  • Cassian Yee
  • Ke Pan

Assignees

  • BOARD OF REGENTS, THE UNIVERSITY OF TEXAS SYSTEM

Dates

Publication Date
20260507
Application Date
20221024

Claims (20)

  1. 1 . A polypeptide comprising an antigen binding variable region comprising a CDR3 comprising an amino acid sequence with at least 80% sequence identity to SEQ ID NO:8.
  2. 2 . The polypeptide of claim 1 , wherein the CDR3 comprises the amino acid sequence of SEQ ID NO:8.
  3. 3 . The polypeptide of claim 1 or 2 , wherein the variable region comprises a CDR1, CDR2, and/or CDR3.
  4. 4 . The polypeptide of claim 3 , wherein the variable region comprises a CDR1 with at least 80% sequence identity to SEQ ID NO:6.
  5. 5 . The polypeptide of claim 3 or 4 , wherein the variable region comprises a CDR2 with at least 80% sequence identity to SEQ ID NO:7.
  6. 6 . The polypeptide of claim 4 or 5 , wherein the variable region comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:6 and/or a CDR2 comprising the amino acid sequence of SEQ ID NO:7.
  7. 7 . The polypeptide of any one of claims 1-6 , wherein the variable region comprises an amino acid sequence with at least 70% sequence identity to SEQ ID NO:4.
  8. 8 . The polypeptide of claim 7 , wherein the variable region comprises the amino acid sequence of SEQ ID NO:4.
  9. 9 . The polypeptide of any one of claims 1-8 , wherein the polypeptide comprises a T cell receptor alpha (TCR-a) variable region.
  10. 10 . The polypeptide of claim 9 , wherein the polypeptide comprises a TCR-a variable and constant region.
  11. 11 . The polypeptide of any one of claims 1-10 , wherein the polypeptide further comprises a signal peptide.
  12. 12 . The polypeptide of claim 11 , wherein the signal peptide comprises an amino acid sequence with at least 80% identity to SEQ ID NO:5.
  13. 13 . The polypeptide of claim 12 , wherein the signal peptide comprises an amino acid sequence of SEQ ID NO:5.
  14. 14 . A polypeptide comprising an antigen binding variable region comprising a CDR3 comprising an amino acid sequence with at least 80% sequence identity to SEQ ID NO:14.
  15. 15 . The polypeptide of claim 14 , wherein the CDR3 comprises the amino acid sequence of SEQ ID NO:14.
  16. 16 . The polypeptide of claim 14 or 15 , wherein the variable region comprises a CDR1, CDR2, and/or CDR3.
  17. 17 . The polypeptide of claim 16 , wherein the variable region comprises a CDR1 with at least 80% sequence identity to SEQ ID NO:12.
  18. 18 . The polypeptide of claim 16 or 17 , wherein the variable region comprises a CDR2 with at least 80% sequence identity to SEQ ID NO:13.
  19. 19 . The polypeptide of claim 17 or 18 , wherein the variable region comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:12 and/or a CDR2 comprising the amino acid sequence of SEQ ID NO:13.
  20. 20 . The polypeptide of any one of claims 14-19 , wherein the variable region comprises an amino acid sequence with at least 70% sequence identity to SEQ ID NO:10.

Description

This application claims priority of U.S. Provisional Patent Application No. 63/271,368, filed Oct. 25, 2021 and U.S. Provisional Patent Application No. 63/279,527, filed Nov. 15, 2021, both of which are hereby incorporated by reference in their entirety. BACKGROUND OF THE INVENTION The application contains a Sequence Listing prepared in compliance with ST.26 format and is hereby incorporated by reference in its entirety. Said Sequence Listing, created on Oct. 21, 2022 is named MDAC1320WO.xml and is 24,914 bytes in size. II. Field of the Invention This invention relates to the field of cancer therapy. III. Background Adoptive T-cell therapy is one potentially powerful treatment for cancer that genetically modifies natural T cells to make them tumor-specific and to improve their ability to destroy tumor cells. The genetically modified T cells are able to express chimeric antigen receptors (CARs) or T-cell receptors (TCRs), showing impressive results in multiple clinical trials. TCR-engineered T (TCR-T) cells have shown great promise against tumors. The potency of TCRs relies on their interaction with peptide-major histocompatibility complex (pMHC), complexes formed by peptide bound to MHC. Intracellular antigens are cut up into peptide chains and displayed by MHC molecules to form pMHCs. Cytoplasmic proteins to be expressed by class I MHC proteins, most of which are defective ribosomal translation products, are cleaved into peptide chains by proteolysis. These peptides are then bound to class I MHC proteins, which are expressed on all nucleated cells' cell surface. Some cells, called antigen-presenting cells (APCs), express class II MHC proteins. They internalize foreign material proteins by endocytosis and cleave them into peptide chains to bind with class II MHC proteins T-cell receptors from T cells, which must be matched to human leukocyte antigen (HLA) alleles of patients, recognize these pMHCs and cause the killing of cancer cells. (Human class I MHC protein is expressed from 3 gene regions: HLA-A, HLA-B, and HLA-C, and human class II MHC protein is also expressed from 3 gene regions: HLA-DR, HLA-DP, and HLA-DQ.) There is a need for the engineering of TCRs that are directed to cancer-specific antigens and useful for the treatment of cancer. SUMMARY OF THE INVENTION This disclosure provides for peptides useful for vaccination and other applications, engineered T cell Receptors (TCRs), cells comprising the peptides and TCRs, and methods of making and using the peptides and TCRs. The current disclosure relates to TCRs that specifically recognize a HLA-A2 restricted epitope from cancer testis (CT) antigen MAGE-A4 having the amino acid sequence KVLEHVVRV (SEQ ID NO:15). Accordingly, aspects of the disclosure relate to a polypeptide comprising an antigen binding variable region comprising a CDR3 comprising an amino acid sequence with at least 80% sequence identity to SEQ ID NO:8. Other aspects relate to a polypeptide comprising an antigen binding variable region comprising a CDR3 comprising an amino acid sequence with at least 80% sequence identity to SEQ ID NO:14. The disclosure also provides for T-cell receptors (TCR) and engineered TCRs, such as a TCR comprising a TCR-a polypeptide and a TCR-b polypeptide, wherein the TCR-a polypeptide comprises a CDR3 comprising an amino acid sequence with at least 80% sequence identity to SEQ ID NO:8 and the TCR-b polypeptide comprises a CDR3 comprising an amino acid sequence with at least 80% sequence identity to SEQ ID NO:14. The TCR-a polypeptide may comprise a CDR3 comprising an amino acid sequence having or having at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% (or any derivable range therein) sequence identity to SEQ ID NO:8 and the TCR-b polypeptide may comprise a CDR3 comprising an amino acid sequence having or having at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% (or any derivable range therein) sequence identity to SEQ ID NO:14. The TCR-a polypeptide may comprise a CDR3 comprising the amino acid sequence of SEQ ID NO:8 and the TCR-b polypeptide may comprise a CDR3 comprising the amino acid sequence of SEQ ID NO:14. Further aspects relate to a fusion protein comprising a TCR of the disclosure and a CD3 binding region. The CD3 binding region may comprise a CD3-specific fragment antigen binding (Fab), single chain variable fragment (scFv), single domain antibody, or single chain antibody. Exemplary CD3-specific fragment antigen binding (Fab) are known in the art. For example, US20180222981, which is herein incorporated by reference, discloses variable regions that bind specifically to CD3, which may be used in aspects of this disclosure. Anti-CD3 antibodies and variable regions are disclosed in US20180117152,