T cell receptor and its application

Abstract

The present invention relates to the field of cancer immunotherapy. Specifically, the application relates in some aspects to binding molecules, such as complexes capable of specifically binding to major histocompatibility complex (MHC) molecules and AFP peptides. The present invention relates to T cell receptors (TCRs) that bind or recognize such peptide epitopes, including their antigen binding domains. The application further relates to engineered cells comprising such binding molecules, such as TCR dual antibody proteins or TCRs, and their use in cancer immunotherapy.

Claims

1. A T cell receptor comprising an α chain and a β chain, characterized in that The α and β chains contain the following complementarity determining regions: 1) The amino acid sequence of CDR1 on the α chain is shown in SEQ ID NO: 10, the amino acid sequence of CDR2 on the α chain is shown in SEQ ID NO: 2, and the amino acid sequence of CDR3 on the α chain is shown in SEQ ID NO: 3; The amino acid sequence of CDR1 on the β chain is shown in SEQ ID NO: 4, the amino acid sequence of CDR2 on the β chain is shown in SEQ ID NO: 5, and the amino acid sequence of CDR3 on the β chain is shown in SEQ ID NO: 6; or 2) the amino acid sequence of CDR1 on the α chain is shown in SEQ ID NO: 7, the amino acid sequence of CDR2 on the α chain is shown in SEQ ID NO: 2, and the amino acid sequence of CDR3 on the α chain is shown in SEQ ID NO: 13; The amino acid sequence of CDR1 on the β chain is shown in SEQ ID NO: 17, the amino acid sequence of CDR2 on the β chain is shown in SEQ ID NO: 5, and the amino acid sequence of CDR3 on the β chain is shown in SEQ ID NO:

6.

2. The T cell receptor according to claim 1, characterized in that The T cell receptor recognizes HLA-A restricted AFP 158-166 The epitope peptide has an amino acid sequence as shown in SEQ ID NO:

19.

3. The T cell receptor according to claim 2, characterized in that The HLA typing is HLA-A, and the HLA-A is HLA-A*0203, HLA-A*0201, HLA-A*0206 or HLA-A*0207.

4. A nucleic acid molecule encoding the T cell receptor according to any one of claims 1 to 3.

5. An engineered immune cell, characterized in that: Expressing the T cell receptor according to any one of claims 1 to 3.

6. The engineered immune cell according to claim 5, wherein: The T cell receptor is introduced into immune cells by viral vector or non-viral vector transduction, CRISPR / Cas9 system, transposon system or mRNA transfection to obtain engineered immune cells; the engineered immune cells include T cells or NK cells.

7. A TCR dual antibody protein, characterized in that: The TCR dual antibody protein is composed of an antibody targeting a receptor molecule on the cell membrane surface of an immune cell and the extracellular domain of the T cell receptor according to any one of claims 1 to 3, and binds to both immune cells and tumor cells at the same time; The immune cells include T cells or NK cells; The antibodies to the immune cell membrane surface receptor molecules include scFv or Fab antibody fragments.

8. The TCR dual antibody protein according to claim 7, characterized in that: The immune cell cell membrane surface receptor molecules are CD3, CD4, CD8, CD16a and / or NKG2D.

9. The TCR dual antibody protein according to claim 7, characterized in that: The extracellular domain of the T cell receptor recognizes and binds to antigens on tumor cells.

10. A TCR dual-antibody mRNA preparation, characterized in that: The TCR dual antibody protein according to any one of claims 7 to 9 is expressed in vivo using mRNA technology.

11. Use of the T cell receptor according to any one of claims 1 to 3, the nucleic acid molecule according to claim 4, the engineered immune cell according to any one of claims 5 to 6, the TCR dual antibody protein according to any one of claims 7 to 9, or the TCR dual antibody mRNA preparation according to claim 10 in the preparation of a drug for treating liver cancer.

12. The use according to claim 11, characterized in that The drug includes a TCR protein drug; The TCR protein drug is prepared from a multispecific T cell complex, and the multispecific T cell complex is prepared from the T cell receptor according to any one of claims 1 to 3; and wherein the multispecific T cell complex comprises a TCR bispecific antibody, a TCR trispecific antibody, or a TCR tetraspecific antibody; Or the multispecific T cell complex includes a T cell receptor, a TCR bispecific antibody, a TCR trispecific antibody or a TCR tetraspecific antibody, connected to a complex formed by a nuclear drug, a toxin, a fluorescein and an antibody fragment.

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