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EP-4737476-A1 - T-CELL RECEPTOR VARIANT AGAINST MKRAS 7-16 G12D

EP4737476A1EP 4737476 A1EP4737476 A1EP 4737476A1EP-4737476-A1

Abstract

The present invention relates to a novel TCR characterized by its CDR3 sequences of the α chain variable region and/or the β chain variable region. The present invention relates to a TCR polypeptide complex and/or a combination comprising a novel TCR characterized by its CDR3 sequences of the α chain variable region and/or the β chain variable region. The present invention further relates to a nucleic acid, a vector as well as a host cell comprising said nucleic acid or said vector. The present invention relates to a method for obtaining said TCR and said chimeric co-stimulatory receptor and to a pharmaceutical or diagnostic composition comprising the abovementioned. The present invention further relates to the abovementioned for use as a medicament or for use in a method of diagnosing, detecting, preventing, and/or treating cancer. Furthermore, the present invention relates to a method of detecting the presence of a cancer in a subject in vitro, by applying within said method the abovementioned, and the use of the abovementioned for generating modified lymphocytes and a kit.

Inventors

  • LONGINOTTI, Giulia
  • MOHR, Anne-Wiebe
  • ALTERAUGE, Marc Dominik
  • BITTMANN, Julia Carola

Assignees

  • Medigene Immunotherapies GmbH

Dates

Publication Date
20260506
Application Date
20240912

Claims (16)

  1. A T-cell receptor (TCR) comprising: i) an α chain Complementarity Determining Region 3 (CDR3) comprising an amino acid sequence having at least 80 % identity to SEQ ID NO: 16 (CAVSRSGNTPLVF); ii) a β chain Complementarity Determining Region 3 (CDR3) comprising an amino acid sequence having at least 80 % identity to SEQ ID NO: 4 (CASSGAGETGELFF); iii) an α chain Complementarity Determining Region 1 (CDR1) comprising an amino acid sequence having at least 80 % identity to SEQ ID NO: 14 (SSVSVY); iv) an α chain Complementarity Determining Region 2 (CDR2) comprising an amino acid sequence having at least 80 % identity to SEQ ID NO: 15 (YLSGSTLV); v) a β chain CDR1 comprising an amino acid sequence having at least 80 % identity to SEQ ID NO: 2 (WNHNN); and vi) a β chain CDR2 comprising an amino acid sequence having at least 80 % identity to SEQ ID NO: 3 (SYGVHD).
  2. The TCR of claim 1, comprising: i) an α chain Complementarity Determining Region 3 (CDR3) comprising an amino acid sequence having SEQ ID NO: 16 (CAVSRSGNTPLVF); and ii) a β chain Complementarity Determining Region 3 (CDR3) comprising an amino acid sequence having SEQ ID NO: 4 (CASSGAGETGELFF); wherein said TCR further comprises the following: a) an α chain Complementarity Determining Region 1 (CDR 1) comprising an amino acid sequence having SEQ ID NO: 14 (SSVSVY); b) an α chain Complementarity Determining Region 2 (CDR2) comprising an amino acid sequence having SEQ ID NO: 15 (YLSGSTLV); c) a β chain CDR1 comprising an amino acid sequence having SEQ ID NO: 2 (WNHNN); and d) a β chain CDR2 comprising an amino acid sequence having SEQ ID NO: 3 (SYGVHD).
  3. The TCR of any one of the preceding claims, comprising: i) an α chain variable region comprising the amino acid sequence of SEQ ID NO: 20, or an amino acid sequence having at least 80 % identity to SEQ ID NO: 20; and/or ii) a β chain variable region comprising the amino acid sequence of SEQ ID NO: 8, or an amino acid sequence having at least 80 % identity to SEQ ID NO: 8.
  4. The TCR of any one of the preceding claims, having antigenic specificity to an epitope presented in the context of a MHC class I molecule, the epitope comprising the amino acid sequence of VVVGADGVGK (SEQ ID NO: 1), or a fragment thereof or a variant thereof comprising one or more (e.g. one or two) conservative amino acid substitutions (preferably corresponding to position(s) 1, 2, 3, 4, 5, 6, 7, 8, 9 and/or 10 of SEQ ID NO: 1).
  5. The TCR of claim 4, wherein the TCR has antigenic specificity for said epitope presented in the context of: iv) an HLA-A molecule, preferably HLA-A*11 molecule; v) an HLA-A*11:01 molecule; and/or vi) at least any one of an HLA-A*11 molecule, preferably HLA-A*11:01, HLA-A*11:02, HLA-A*11:03 and/or HLA-A*11:12.
  6. A nucleic acid and/or vector, preferably expression vector, comprising a nucleotide sequence encoding the TCR of any one of the preceding claims.
  7. A host cell (e.g., isolated and/or recombinant host cell) comprising the TCR of any one of claims 1 to 6 and/or the nucleic acid or vector of claim 6.
  8. A method for obtaining the TCR according to any one of claims 1 to 5, comprising a) incubating the host cell of claim 7 under conditions causing expression of said TCR; and b) purifying said TCR.
  9. A composition and/or kit, preferably a pharmaceutical and/or diagnostic composition, comprising one or more of the following: i) the TCR of any one of claims 1 to 5; ii) the nucleic acid and/or vector of claim 6; and/or iii) the host cell of claim 7; and, optionally, pharmaceutically excipient(s).
  10. The TCR of any one of claims 1 to 5, the nucleic acid and/or vector of claim 6, the host cell of claim 7 and/or the composition of claim 9 for use as a medicament and/or for use in therapy.
  11. A method of detecting the presence of a cancer in a subject in vitro, comprising: (a) contacting a sample obtained from a subject and comprising one or more cells with: i) the TCR of any one of claims 1 to 5; ii) the nucleic acid and/or vector of claim 6; iii) the host cell of claim 7, and/or iv) the composition of claim 9, preferably a pharmaceutical composition; thereby forming a complex, and (b) detecting the complex, wherein detection of the complex is indicative of the presence of the cancer in the subject.
  12. A T-cell receptor (TCR) polypeptide complex and/or a combination comprising: a) a TCR, preferably the TCR of any one of claims 1 to 5; and b) a chimeric co-stimulatory receptor, wherein the TCR comprises: i) an α chain Complementarity Determining Region 3 (CDR3) comprising an amino acid sequence having at least 80 % identity to SEQ ID NO: 16; ii) a β chain Complementarity Determining Region 3 (CDR3) comprising an amino acid sequence having at least 80 % identity to SEQ ID NO: 4; iii) an α chain Complementarity Determining Region 1 (CDR 1) comprising an amino acid sequence having at least 80 % identity to SEQ ID NO: 14 (SSVSVY); iv) an α chain Complementarity Determining Region 2 (CDR2) comprising an amino acid sequence having at least 80 % identity to SEQ ID NO: 15 (YLSGSTLV); v) a β chain CDR1 comprising an amino acid sequence having at least 80 % identity to SEQ ID NO: 2 (WNHNN); and vi) a β chain CDR2 comprising an amino acid sequence having at least 80 % identity to SEQ ID NO: 3 (SYGVHD).
  13. A cell population comprising cells or a cell expressing: a) a TCR, preferably the TCR of any one of claims 1 to 5; and b) a chimeric co-stimulatory receptor, wherein the TCR comprises: i) an α chain Complementarity Determining Region 3 (CDR3) comprising an amino acid sequence having at least 80 % identity to SEQ ID NO: 16; ii) a β chain Complementarity Determining Region 3 (CDR3) comprising an amino acid sequence having at least 80 % identity to SEQ ID NO: 4; iii) an α chain Complementarity Determining Region 1 (CDR1) comprising an amino acid sequence having at least 80 % identity to SEQ ID NO: 14 (SSVSVY); iv) an α chain Complementarity Determining Region 2 (CDR2) comprising an amino acid sequence having at least 80 % identity to SEQ ID NO: 15 (YLSGSTLV); v) a β chain CDR1 comprising an amino acid sequence having at least 80 % identity to SEQ ID NO: 2 (WNHNN); and vi) a β chain CDR2 comprising an amino acid sequence having at least 80 % identity to SEQ ID NO: 3 (SYGVHD).
  14. The complex and/or the combination, and/or the cell population or the cell of any one of the preceding claims, wherein the TCR comprises: i) an α chain variable region comprising the amino acid sequence of SEQ ID NO: 20, or an amino acid sequence having at least 80 % identity to SEQ ID NO: 20; and/or ii) a β chain variable region comprising the amino acid sequence of SEQ ID NO: 8, or an amino acid sequence having at least 80 % identity to SEQ ID NO: 8.
  15. The complex and/or the combination, and/or the cell population or the cell of any one of the preceding claims, wherein the TCR has antigenic specificity to an epitope presented in the context of a MHC class I molecule, the epitope comprising the amino acid sequence of VVVGADGVGK (SEQ ID NO: 1), or a fragment thereof or a variant thereof comprising one or more (e.g. one or two) conservative amino acid substitutions (preferably corresponding to position 1, 2, 3, 4, 5, 6, 7, 8, 9 and/or 10 and/or SEQ ID NO: 1), optionally wherein the TCR has antigenic specificity for said epitope presented in the context of: iv) an HLA-A molecule, preferably HLA-A*11 molecule; v) an HLA-A*11:01 molecule; and/or vi) at least any one of an HLA-A*11 molecule, preferably HLA-A*11:01, HLA-A*11:02, HLA-A*11:03 and/or HLA-A*11:12.
  16. The complex and/or the combination and/or the cell population or the cell of any one of the preceding claims, wherein the chimeric co-stimulatory receptor comprises: i) an extracellular domain comprising a polypeptide derived from PD-1 at its N-terminus (e.g., SEQ ID NO: 28); ii) a transmembrane domain; and/or iii) an intracellular domain comprising a polypeptide derived from 4-1BB at its C-terminus (e.g., SEQ ID NO: 32).

Description

SEQUENCE LISTING This application contains a Sequence Listing in computer readable form, which is incorporated herein by reference. TECHNICAL FIELD OF THE INVENTION The present invention relates to a novel TCR (TCR16) characterized by its CDR1-6 sequences of the α chain variable region and/or the β chain variable region. The present invention further relates to a nucleic acid encoding said TCR, a vector comprising said nucleic acid, as well as a host cell comprising said TCR, said nucleic acid or said vector. The present invention further relates to a method for obtaining said TCR and to a pharmaceutical or diagnostic composition comprising said TCR, said nucleic acid molecule, said vector, and/or said host cell. The present invention further relates to said TCR, said nucleic acid, said vector, said host cell and/or said pharmaceutical composition for use as a medicament, or for use in a method of diagnosing, detecting, preventing, and/or treating cancer. Furthermore, the present invention relates to a method of detecting the presence of a cancer in a subject in vitro, by applying within said method said TCR, said nucleic acid, said vector, said host cell, and/or said pharmaceutical composition and the use of said TCR, said nucleic acid, and/or said vector for generating modified lymphocytes. Finally, the present invention relates to a kit comprising said TCR, said nucleic acid, said vector, said host cell and/or said pharmaceutical or diagnostic composition. The present invention further relates to a TCR polypeptide complex and/or a combination comprising a novel TCR characterized by its CDR sequences of the α chain variable region and/or the β chain variable region. The present invention further relates to a nucleic acid, a vector as well as a host cell comprising said nucleic acid or said vector. The present invention relates to a method for obtaining said TCR and said chimeric co-stimulatory receptor and to a pharmaceutical or diagnostic composition comprising the abovementioned. The present invention further relates to the abovementioned for use as a medicament or for use in a method of diagnosing, detecting, preventing, and/or treating cancer. Furthermore, the present invention relates to a method of detecting the presence of a cancer in a subject in vitro, by applying within said method the abovementioned, and the use of the abovementioned for generating modified lymphocytes and a kit. BACKGROUND OF THE INVENTION T lymphocytes (or T cells) which form a part of the cell mediated immune system play a major role in the eradication of pathogens. T cells develop in the thymus and express T cell receptor molecules on their surface that allow the recognition of peptides presented on human leukocyte antigen (HLA) molecules which are expressed on nucleated cells (antigen presentation). Antigens of pathogens, i.e. foreign antigens presented by HLA molecules will elicit a powerful T cell response whereas self-antigens usually do not lead to a T cell response due to a negative selection of self-antigen specific T cells in the thymus during the development of such T cells. The immune system can thus discriminate between nucleated cells presenting foreign- or self-antigens or self, but aberrant antigens and specifically target and eradicate infected cells via potent cytokine release and cellular cytotoxicity mechanisms of the T cells. The power of the immune system has been recognized as a promising tool for future cancer therapies. In the last decade, research has begun to exploit the unique properties of T cells by using adoptive cell transfer (ACT), which involves the administration of tumor infiltrating lymphocytes (TILs) which are patient-derived, expanded ex vivo. Although ACT has been shown to be a promising treatment for various types of cancer, its broad application as clinical treatment has been hampered by the need for custom isolation and characterization of tumor-specific T cells from each patient - a process that can be difficult and time-consuming but also often fails to yield high-avidity T cells (Xue et al., Clin Exp Immunol. 2005 February; 139(2): 167-172; Schmitt et al., Hum Gene Ther. 2009 November; 20(11): 1240-1248). The genetic transfer of tumor antigen-specific TCRs into primary T cells can overcome some of the current limitations of ACT, as it allows for the rapid generation of tumor-reactive T lymphocytes with defined antigen specificity even in immunocompromised patients. However, the identification of suitable T cell clones bearing TCRs that specifically recognize tumor antigens and exhibit the desired anti-tumor effects in vivo is still the topic of ongoing research. Tumors with Kirsten rat sarcoma (KRAS) mutations have been shown to create a tumor microenvironment (TME) that impairs immune cells in the TME and promotes tumor progression and immune escape. In the presence of KRAS mutations, increased levels of inflammatory cytokines necessary for tumorigenesis and progression have been