TW202235440A - Antibodies targeting a complex comprising non-classical hla-i and neoantigen and their methods of use - Google Patents

Abstract

Provided herein are antibodies that selectively bind to complex comprising a non-classical HLA-I (e.g. HLA-E) and a neoantigen having variable heavy chain domains (VH), variable light chain domains (VL), and complementarity determining regions (CDRs) as disclosed herein, as well as methods and uses thereof.

Description

Antibodies targeting complexes comprising atypical HLA-I and neoantigens and methods of use thereof

In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a light chain variable domain (VL) comprising at least the amino acid sequence set forth in SEQ ID NO: 7 80% identical amino acid sequence. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a light chain variable domain (VL) comprising at least the amino acid sequence set forth in SEQ ID NO: 7 90% identical amino acid sequence. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a light chain variable domain (VL) comprising at least the amino acid sequence set forth in SEQ ID NO: 7 95% identical amino acid sequence. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a light chain variable domain (VL) comprising at least the amino acid sequence set forth in SEQ ID NO: 7 99% identical amino acid sequence. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a light chain variable domain (VL) comprising the amino acid sequence 100 of SEQ ID NO: 7 % consistent amino acid sequence. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amine that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 8 amino acid sequence. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amine that is at least 90% identical to the amino acid sequence set forth in SEQ ID NO: 8 amino acid sequence. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amine that is at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 8 amino acid sequence. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amine that is at least 99% identical to the amino acid sequence set forth in SEQ ID NO: 8 amino acid sequence. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising amine groups 100% identical to the amino acid sequence set forth in SEQ ID NO: 8 acid sequence. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof selectively binds to a complex comprising HLA-E and a neoantigen. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof has no binding affinity for HLA-E alone. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof has no binding affinity for a neoantigen alone. In some embodiments, neoantigens are expressed by cells that are proficient in the antigen processing machinery (APM). In some embodiments, neoantigens are expressed by cells proficient in TAP1/2. In some embodiments, the neoantigen comprises, consists essentially of, or consists of a sequence according to SEQ ID NO: 18 (VMAPRTLFL). In some embodiments, the HLA-E is HLA-E*0101 or HLA-E*0103. In some embodiments, the antibody selectively binds to a complex comprising: (a) HLA-E*0101 and a neoantigen; (b) HLA-E*0103 and a neoantigen; or (c) HLA-E* 0101 and neoantigens, and HLA-E*0103 and neoantigens. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof is a murine antibody, a chimeric antibody, a camelid antibody, a humanized antibody, or a human antibody. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof is a TCR-like antibody. In some embodiments, monoclonal antibodies or antigen-binding fragments thereof are multispecific antibodies. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof is a bispecific antibody. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof is a bispecific T cell engager (BiTE). In some embodiments, the BiTE binds to the CD3 protein associated with the T cell receptor (TCR). In some embodiments, the BiTE further comprises a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 15. In some embodiments, the BiTE further comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 16. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof is a multifunctional antibody. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof further comprises a binding therapeutic moiety. In some embodiments, selective binding of the antibody to a complex comprising HLA-E and a neoantigen induces an immune response in the cell. In some embodiments, the immune response comprises activation of (i) NK cells, (ii) T cells, or (iii) NK cells and T cells. In some embodiments, the T cells are CD4+ T cells or CD8+ T cells. In some embodiments, the immune response comprises activation of cytotoxic T cells (CTL). In some embodiments, the cell is a cancer cell.

In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a heavy chain variable domain (VH) comprising at least the amino acid sequence set forth in SEQ ID NO: 8 80% identical amino acid sequence. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a heavy chain variable domain (VH) comprising at least the amino acid sequence set forth in SEQ ID NO: 8 90% identical amino acid sequence. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a heavy chain variable domain (VH) comprising at least the amino acid sequence set forth in SEQ ID NO: 8 95% identical amino acid sequence. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a heavy chain variable domain (VH) comprising at least the amino acid sequence set forth in SEQ ID NO: 8 99% identical amino acid sequence. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a heavy chain variable domain (VH) comprising the amino acid sequence 100 of SEQ ID NO: 8 % consistent amino acid sequence. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amine that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 7 amino acid sequence. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amine that is at least 90% identical to the amino acid sequence set forth in SEQ ID NO: 7 amino acid sequence. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amine that is at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 7 amino acid sequence. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amine that is at least 99% identical to the amino acid sequence set forth in SEQ ID NO: 7 amino acid sequence. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising amine groups 100% identical to the amino acid sequence set forth in SEQ ID NO: 7 acid sequence. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof selectively binds to a complex comprising HLA-E and a neoantigen. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof has no binding affinity for HLA-E alone. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof has no binding affinity for a neoantigen alone. In some embodiments, neoantigens are expressed by cells that are proficient in the antigen processing machinery (APM). In some embodiments, neoantigens are expressed by cells proficient in TAP1/2. In some embodiments, the neoantigen comprises, consists essentially of, or consists of a sequence according to SEQ ID NO: 18 (VMAPRTLFL). In some embodiments, the HLA-E is HLA-E*0101 or HLA-E*0103. In some embodiments, the antibody selectively binds to a complex comprising: (a) HLA-E*0101 and a neoantigen; (b) HLA-E*0103 and a neoantigen; or (c) HLA-E*0101 and neoantigens, as well as HLA-E*0103 and neoantigens. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof is a murine antibody, a chimeric antibody, a camelid antibody, a humanized antibody, or a human antibody. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof is a TCR-like antibody. In some embodiments, monoclonal antibodies or antigen-binding fragments thereof are multispecific antibodies. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof is a bispecific antibody. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof is a bispecific T cell engager (BiTE). In some embodiments, the BiTE binds to the CD3 protein associated with the T cell receptor (TCR). In some embodiments, the BiTE further comprises a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 15. In some embodiments, the BiTE further comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 16. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof is a multifunctional antibody. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof further comprises a binding therapeutic moiety. In some embodiments, selective binding of the antibody to a complex comprising HLA-E and a neoantigen induces an immune response in the cell. In some embodiments, the immune response comprises activation of (i) NK cells, (ii) T cells, or (iii) NK cells and T cells. In some embodiments, the T cells are CD4+ T cells or CD8+ T cells. In some embodiments, the immune response comprises activation of cytotoxic T cells (CTL). In some embodiments, the cell is a cancer cell.

In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a light chain complementarity determining region (CDR) having at least one of the amino acid sequences set forth in SEQ ID NO: 1-3 One with at least 80% identical amino acid sequence. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a light chain complementarity determining region (CDR) having at least one of the amino acid sequences set forth in SEQ ID NO: 1-3 One with at least 90% identical amino acid sequence. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a light chain complementarity determining region (CDR) having at least one of the amino acid sequences set forth in SEQ ID NO: 1-3 One with at least 95% identical amino acid sequence. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a light chain complementarity determining region (CDR) having at least one of the amino acid sequences set forth in SEQ ID NO: 1-3 One is at least 99% identical to the amino acid sequence. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a light chain complementarity determining region (CDR) having at least one of the amino acid sequences set forth in SEQ ID NO: 1-3 A 100% identical amino acid sequence. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region (CDR) having at least 80% the same amino acid sequence as at least one of SEQ ID NO: 4-6 consensus amino acid sequence. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region (CDR) having at least 90% the same amino acid sequence as at least one of SEQ ID NOs: 4-6 consensus amino acid sequence. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region (CDR) having at least 95% the same amino acid sequence as at least one of SEQ ID NOs: 4-6 consensus amino acid sequence. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region (CDR) having at least 99% the same amino acid sequence as at least one of SEQ ID NOs: 4-6 consensus amino acid sequence. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region (CDR) that is 100% identical to at least one of the amino acid sequences set forth in SEQ ID NO: 4-6 amino acid sequence. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amine that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 7 amino acid sequence. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amine that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 8 amino acid sequence. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof selectively binds to a complex comprising HLA-E and a neoantigen. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof has no binding affinity for HLA-E alone. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof has no binding affinity for a neoantigen alone. In some embodiments, neoantigens are expressed by cells that are proficient in the antigen processing machinery (APM). In some embodiments, neoantigens are expressed by cells proficient in TAP1/2. In some embodiments, the neoantigen comprises, consists essentially of, or consists of a sequence according to SEQ ID NO: 18 (VMAPRTLFL). In some embodiments, the HLA-E is HLA-E*0101 or HLA-E*0103. In some embodiments, the antibody selectively binds to a complex comprising: HLA-E*0101 and a neoantigen; HLA-E*0103 and a neoantigen; or HLA-E*0101 and a neoantigen, and HLA-E* 0103 and neoantigens. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof is a murine antibody, a chimeric antibody, a camelid antibody, a humanized antibody, or a human antibody. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof is a TCR-like antibody. In some embodiments, monoclonal antibodies or antigen-binding fragments thereof are multispecific antibodies. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof is a bispecific antibody. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof is a bispecific T cell engager (BiTE). In some embodiments, the BiTE binds to the CD3 protein associated with the T cell receptor (TCR). In some embodiments, the BiTE further comprises a light chain complementarity determining region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences set forth in SEQ ID NOs: 9-11 . In some embodiments, the BiTE further comprises a heavy chain complementarity determining region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences set forth in SEQ ID NOs: 12-14 . In some embodiments, the BiTE further comprises a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 15. In some embodiments, the BiTE further comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 16. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof is a multifunctional antibody. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof further comprises a binding therapeutic moiety. In some embodiments, selective binding of the antibody to a complex comprising HLA-E and a neoantigen induces an immune response in the cell. In some embodiments, the immune response comprises activation of (i) NK cells, (ii) T cells, or (iii) NK cells and T cells. In some embodiments, the T cells are CD4+ T cells or CD8+ T cells. In some embodiments, the immune response comprises activation of cytotoxic T cells (CTL). In some embodiments, the cell is a cancer cell.

In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a heavy chain complementarity determining region (CDR) having at least one of the amino acid sequences set forth in SEQ ID NO: 4-6 One with at least 80% identical amino acid sequence. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a heavy chain complementarity determining region (CDR) having at least one of the amino acid sequences set forth in SEQ ID NO: 4-6 One with at least 90% identical amino acid sequence. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a heavy chain complementarity determining region (CDR) having at least one of the amino acid sequences set forth in SEQ ID NO: 4-6 One with at least 95% identical amino acid sequence. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a heavy chain complementarity determining region (CDR) having at least one of the amino acid sequences set forth in SEQ ID NO: 4-6 One is at least 99% identical to the amino acid sequence. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a heavy chain complementarity determining region (CDR) having at least one of the amino acid sequences set forth in SEQ ID NO: 4-6 A 100% identical amino acid sequence. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain complementarity determining region (CDR) having at least 80% the same amino acid sequence as at least one of SEQ ID NO: 1-3 consensus amino acid sequence. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain complementarity determining region (CDR) having at least 90% the same amino acid sequence as at least one of SEQ ID NO: 1-3 consensus amino acid sequence. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain complementarity determining region (CDR) having at least 95% the same amino acid sequence as at least one of SEQ ID NO: 1-3 consensus amino acid sequence. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain complementarity determining region (CDR) having at least 99% the same amino acid sequence as at least one of SEQ ID NO: 1-3 consensus amino acid sequence. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain complementarity determining region (CDR) that is 100% identical to at least one of the amino acid sequences set forth in SEQ ID NO: 1-3 amino acid sequence. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amine that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 8 amino acid sequence. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amine that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 7 amino acid sequence. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof selectively binds to a complex comprising HLA-E and a neoantigen. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof has no binding affinity for HLA-E alone. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof has no binding affinity for a neoantigen alone. In some embodiments, neoantigens are expressed by cells that are proficient in the antigen processing machinery (APM). In some embodiments, neoantigens are expressed by cells proficient in TAP1/2. In some embodiments, the neoantigen comprises, consists essentially of, or consists of a sequence according to SEQ ID NO: 18 (VMAPRTLFL). In some embodiments, the HLA-E is HLA-E*0101 or HLA-E*0103. In some embodiments, the antibody selectively binds to a complex comprising: (a) HLA-E*0101 and a neoantigen; (b) HLA-E*0103 and a neoantigen; or (c) HLA-E* 0101 and neoantigens, and HLA-E*0103 and neoantigens. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof is a murine antibody, a chimeric antibody, a camelid antibody, a humanized antibody, or a human antibody. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof is a TCR-like antibody. In some embodiments, monoclonal antibodies or antigen-binding fragments thereof are multispecific antibodies. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof is a bispecific antibody. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof is a bispecific T cell engager (BiTE). In some embodiments, the BiTE binds to the CD3 protein associated with the T cell receptor (TCR). In some embodiments, the BiTE further comprises a light chain complementarity determining region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences set forth in SEQ ID NOs: 9-11 . In some embodiments, the BiTE further comprises a heavy chain complementarity determining region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences set forth in SEQ ID NOs: 12-14 . In some embodiments, the BiTE further comprises a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 15. In some embodiments, the BiTE further comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 16. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof is a multifunctional antibody. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof further comprises a binding therapeutic moiety. In some embodiments, selective binding of the antibody to a complex comprising HLA-E and a neoantigen induces an immune response in the cell. In some embodiments, the immune response comprises activation of (i) NK cells, (ii) T cells, or (iii) NK cells and T cells. In some embodiments, the cells are CD4+ T cells or CD8+ T cells. In some embodiments, the immune response comprises activation of cytotoxic T cells (CTL). In some embodiments, the cell is a cancer cell.

In certain embodiments, disclosed herein are bispecific antibodies or antigen-binding fragments thereof comprising: a light chain complementarity determining region (CDR) having the same amino acid sequence as shown in SEQ ID NO: 1-3 At least one of the amino acid sequences is at least 80% identical; or a heavy chain complementarity determining region (CDR), the CDR has at least 80% of at least one of the amino acid sequences shown in SEQ ID NO: 4-6 an identical amino acid sequence; and a light chain complementarity determining region (CDR), the CDR having an amino acid sequence at least 80% identical to at least one of the amino acid sequences set forth in SEQ ID NO: 9-11; or a heavy chain complementarity determining region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences set forth in SEQ ID NO: 12-14. In some embodiments, the bispecific antibody comprises: (a) a light chain variable domain (VL), the VL comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 7; Or a heavy chain variable domain (VH), the VH comprising an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 8; and (b) a light chain variable domain (VL), the VL comprises an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 15; or a heavy chain variable domain (VH) comprising the amino acid sequence shown in SEQ ID NO: 16 An amino acid sequence with at least 80% identity. In certain embodiments, disclosed herein are bispecific antibodies or antigen-binding fragments thereof comprising: a light chain complementarity determining region (CDR) having the same amino acid sequence as shown in SEQ ID NO: 1-3 an amino acid sequence that is at least 80% identical to at least one of them; and a heavy chain complementarity determining region (CDR) having at least 80% identity to at least one of the amino acid sequences shown in SEQ ID NO: 4-6 an identical amino acid sequence; and a light chain complementarity determining region (CDR), the CDR having an amino acid sequence at least 80% identical to at least one of the amino acid sequences set forth in SEQ ID NO: 9-11; and a heavy chain complementarity determining region (CDR), the CDR having an amino acid sequence at least 80% identical to at least one of the amino acid sequences shown in SEQ ID NO: 12-14. In some embodiments, the bispecific antibody comprises: (a) a light chain variable domain (VL), the VL comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 7; and a heavy chain variable domain (VH), the VH comprising an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 8; and (b) a light chain variable domain (VL), the VL comprises an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 15; and a heavy chain variable domain (VH) comprising the amino acid set forth in SEQ ID NO: 16 An amino acid sequence with at least 80% identity. In some embodiments, the bispecific antibody binds selectively to a complex comprising HLA-E and a neoantigen. In some embodiments, the bispecific antibody has no binding affinity for HLA-E alone. In some embodiments, the bispecific antibody has no binding affinity for a neoantigen alone. In some embodiments, neoantigens are expressed by cells that are proficient in the antigen processing machinery (APM). In some embodiments, neoantigens are expressed by cells proficient in TAP1/2. In some embodiments, the neoantigen comprises, consists essentially of, or consists of a sequence according to SEQ ID NO: 18 (VMAPRTLFL). In some embodiments, the HLA-E is HLA-E*0101 or HLA-E*0103. In some embodiments, the antibody selectively binds to a complex comprising: HLA-E*0101 and a neoantigen; HLA-E*0103 and a neoantigen; or HLA-E*0101 and a neoantigen, and HLA-E* 0103 and neoantigens. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof is a murine antibody, a chimeric antibody, a camelid antibody, a humanized antibody, or a human antibody. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof is a bispecific T cell engager (BiTE). In some embodiments, the BiTE binds to the CD3 protein associated with the T cell receptor (TCR). In some embodiments, the monoclonal antibody or antigen-binding fragment thereof is a multifunctional antibody. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof further comprises a binding therapeutic moiety. In some embodiments, selective binding of the antibody to a complex comprising HLA-E and a neoantigen induces an immune response in the cell. In some embodiments, the immune response comprises activation of (i) NK cells, (ii) T cells, or (iii) NK cells and T cells. In some embodiments, the T cells are CD4+ T cells or CD8+ T cells. In some embodiments, the immune response comprises activation of cytotoxic T cells (CTL). In some embodiments, the cell is a cancer cell.

In certain embodiments, disclosed herein are pharmaceutical compositions comprising: (a) a monoclonal antibody or antigen-binding fragment thereof as disclosed herein, or a bispecific antibody or antigen-binding fragment thereof as disclosed herein; and (b) A pharmaceutically acceptable carrier or excipient.

In certain embodiments, disclosed herein are methods of treating cancer in an individual in need thereof comprising administering to the individual an effective amount of a monoclonal antibody or antigen-binding fragment thereof comprising a light chain complementarity determining region (CDR), the The CDRs have an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences set forth in SEQ ID NO: 1-3. In certain embodiments, disclosed herein are methods of treating cancer in an individual in need thereof comprising administering to the individual an effective amount of a monoclonal antibody or antigen-binding fragment thereof comprising a heavy chain complementarity determining region (CDR), the The CDRs have an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences set forth in SEQ ID NO: 4-6. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises (a) a light chain complementarity determining region (CDR), which has at least one of the amino acid sequences shown in SEQ ID NO: 1-3 an amino acid sequence of at least 80% identity; and (b) a heavy chain complementarity determining region (CDR) having at least 80% identity with at least one of the amino acid sequences set forth in SEQ ID NO: 4-6 amino acid sequence. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises (a) a light chain complementarity determining region (CDR), which has at least one of the amino acid sequences shown in SEQ ID NO: 1-3 an amino acid sequence that is at least 90% identical; and (b) a heavy chain complementarity determining region (CDR) having at least 90% identity with at least one of the amino acid sequences set forth in SEQ ID NO: 4-6 amino acid sequence. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises (a) a light chain complementarity determining region (CDR), which has at least one of the amino acid sequences shown in SEQ ID NO: 1-3 an amino acid sequence that is at least 95% identical; and (b) a heavy chain complementarity determining region (CDR) having at least 95% identity with at least one of the amino acid sequences set forth in SEQ ID NO: 4-6 amino acid sequence. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises (a) a light chain complementarity determining region (CDR), which has at least one of the amino acid sequences shown in SEQ ID NO: 1-3 an amino acid sequence that is at least 99% identical; and (b) a heavy chain complementarity determining region (CDR) having at least 99% identity with at least one of the amino acid sequences shown in SEQ ID NO: 4-6 amino acid sequence. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises (a) a light chain complementarity determining region (CDR), which has at least one of the amino acid sequences shown in SEQ ID NO: 1-3 100% identical amino acid sequence; and (b) a heavy chain complementarity determining region (CDR) having an amine 100% identical to at least one of the amino acid sequences shown in SEQ ID NO: 4-6 amino acid sequence. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amine that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 7 amino acid sequence. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amine that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 8 amino acid sequence. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof selectively binds to a complex comprising HLA-E and a neoantigen. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof has no binding affinity for HLA-E alone. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof has no binding affinity for a neoantigen alone. In some embodiments, neoantigens are expressed by cells that are proficient in the antigen processing machinery (APM). In some embodiments, neoantigens are expressed by cells proficient in TAP1/2. In some embodiments, the neoantigen comprises, consists essentially of, or consists of a sequence according to SEQ ID NO: 18 (VMAPRTLFL). In some embodiments, the HLA-E is HLA-E*0101 or HLA-E*0103. In some embodiments, the antibody selectively binds to a complex comprising: HLA-E*0101 and a neoantigen; HLA-E*0103 and a neoantigen; or HLA-E*0101 and a neoantigen, and HLA-E* 0103 and neoantigens. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof is a murine antibody, a chimeric antibody, a camelid antibody, a humanized antibody, or a human antibody. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof is a TCR-like antibody. In some embodiments, monoclonal antibodies or antigen-binding fragments thereof are multispecific antibodies. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof is a bispecific antibody. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof is a bispecific T cell engager (BiTE). In some embodiments, the BiTE binds to the CD3 protein associated with the T cell receptor (TCR). In some embodiments, the BiTE further comprises a light chain complementarity determining region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences set forth in SEQ ID NOs: 9-11 . In some embodiments, the BiTE further comprises a heavy chain complementarity determining region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences set forth in SEQ ID NOs: 12-14 . In some embodiments, the BiTE further comprises a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 15. In some embodiments, the BiTE further comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 16. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof is a multifunctional antibody. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof further comprises a binding therapeutic moiety. In some embodiments, selective binding of the antibody to a complex comprising HLA-E and a neoantigen induces an immune response in the cell. In some embodiments, the immune response comprises activation of (i) NK cells, (ii) T cells, or (iii) NK cells and T cells. In some embodiments, the T cells are CD4+ T cells or CD8+ T cells. In some embodiments, the immune response comprises activation of cytotoxic T cells (CTL). In some embodiments, the cancer is breast cancer, renal cancer, lung cancer, ovarian cancer, colorectal cancer, pancreatic cancer, choriocarcinoma, non-small cell lung cancer (NSCLC), gastric cancer, cervical cancer, or head and neck cancer. In some embodiments, the cancer is myeloma, leukemia or lymphoma. In some embodiments, the cancer is acute myeloid leukemia (AML), multiple myeloma, or myelodysplastic syndrome. In some embodiments, the cancer is a B cell malignancy. In some embodiments, the cancer is mantle cell lymphoma.

In certain embodiments, disclosed herein are methods of treating cancer in an individual in need thereof, the method comprising administering to the individual an effective amount of a bispecific antibody or antigen-binding fragment thereof comprising: a light chain complementarity determining region (CDR) , the CDR has an amino acid sequence at least 80% identical to at least one of the amino acid sequences shown in SEQ ID NO: 1-3; or a heavy chain complementarity determining region (CDR), the CDR has an amino acid sequence identical to that of SEQ ID NO: at least one of the amino acid sequences shown in 4-6 is at least 80% identical to the amino acid sequence; and the light chain complementarity determining region (CDR), the CDR has the same as shown in SEQ ID NO: 9-11 An amino acid sequence that is at least 80% identical to at least one of the amino acid sequences; or a heavy chain complementarity determining region (CDR), which has one of the amino acid sequences shown in SEQ ID NO: 12-14 At least one of the amino acid sequences is at least 80% identical. In some embodiments, the bispecific antibody comprises: a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 7; or a heavy chain Variable domain (VH), the VH comprises an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 8; and a light chain variable domain (VL), the VL comprises the same amino acid sequence as SEQ ID NO: : an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 15; or a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 16 amino acid sequence. In certain embodiments, disclosed herein are methods of treating cancer in an individual in need thereof, the method comprising administering to the individual an effective amount of a bispecific antibody or antigen-binding fragment thereof comprising: a light chain complementarity determining region (CDR) , the CDR has an amino acid sequence at least 80% identical to at least one of the amino acid sequences shown in SEQ ID NO: 1-3; and a heavy chain complementarity determining region (CDR), the CDR has an amino acid sequence identical to that of SEQ ID NO: at least one of the amino acid sequences shown in 4-6 is at least 80% identical to the amino acid sequence; and the light chain complementarity determining region (CDR), the CDR has the same as shown in SEQ ID NO: 9-11 an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences; and a heavy chain complementarity determining region (CDR) having one of the amino acid sequences shown in SEQ ID NO: 12-14 At least one of the amino acid sequences is at least 80% identical. In some embodiments, the bispecific antibody comprises: a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 7; and a heavy chain Variable domain (VH), the VH comprises an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 8; and a light chain variable domain (VL), the VL comprises the same amino acid sequence as SEQ ID NO: : an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 15; and a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 16 amino acid sequence. In some embodiments, the bispecific antibody or antigen-binding fragment thereof selectively binds to a complex comprising HLA-E and a neoantigen. In some embodiments, the bispecific antibody or antigen-binding fragment thereof has no binding affinity for HLA-E alone. In some embodiments, the bispecific antibody or antigen-binding fragment thereof has no binding affinity for a neoantigen alone. In some embodiments, neoantigens are expressed by cells that are proficient in the antigen processing machinery (APM). In some embodiments, neoantigens are expressed by cells proficient in TAP1/2. In some embodiments, the neoantigen comprises, consists essentially of, or consists of a sequence according to SEQ ID NO: 18 (VMAPRTLFL). In some embodiments, the HLA-E is HLA-E*0101 or HLA-E*0103. In some embodiments, the bispecific antibody selectively binds to a complex comprising: HLA-E*0101 and a neoantigen; HLA-E*0103 and a neoantigen; or HLA-E*0101 and a neoantigen, and HLA -E*0103 and neoantigens. In some embodiments, the bispecific antibody or antigen-binding fragment thereof is a murine, chimeric, camelid, humanized, or human antibody. In some embodiments, the bispecific antibody or antigen-binding fragment thereof is a TCR-like antibody. In some embodiments, the bispecific antibody or antigen-binding fragment thereof is a bispecific T cell engager (BiTE). In some embodiments, the BiTE binds to the CD3 protein associated with the T cell receptor (TCR). In some embodiments, the bispecific antibody or antigen-binding fragment thereof is a multifunctional antibody. In some embodiments, the bispecific antibody or antigen-binding fragment thereof further comprises a binding therapeutic moiety. In some embodiments, selective binding of the antibody to a complex comprising HLA-E and a neoantigen induces an immune response in the cell. In some embodiments, the immune response comprises activation of (i) NK cells, (ii) T cells, or (iii) NK cells and T cells. In some embodiments, the T cells are CD4+ T cells or CD8+ T cells. In some embodiments, the immune response comprises activation of cytotoxic T cells (CTL). In some embodiments, bispecific antibodies are administered in a therapeutically effective amount. In some embodiments, the cancer is breast cancer, renal cancer, lung cancer, ovarian cancer, colorectal cancer, pancreatic cancer, choriocarcinoma, non-small cell lung cancer (NSCLC), gastric cancer, cervical cancer, or head and neck cancer. In some embodiments, the cancer is myeloma, leukemia or lymphoma. In some embodiments, the cancer is acute myeloid leukemia (AML), multiple myeloma, or myelodysplastic syndrome. In some embodiments, the cancer is a B cell malignancy. In some embodiments, the cancer is mantle cell lymphoma.

In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a light chain (LC) comprising an amine group that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 19 acid sequence. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a light chain (LC) comprising an amine group that is at least 90% identical to the amino acid sequence set forth in SEQ ID NO: 19 acid sequence. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a light chain (LC) comprising an amine group that is at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 19 acid sequence. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a light chain (LC) comprising an amine group that is at least 99% identical to the amino acid sequence set forth in SEQ ID NO: 19 acid sequence. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a light chain (LC) comprising amino acids 100% identical to the amino acid sequence set forth in SEQ ID NO: 19 sequence. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain (HC) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 20. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain (HC) comprising an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO: 20. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain (HC) comprising an amino acid sequence at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 20. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain (HC) comprising an amino acid sequence at least 99% identical to the amino acid sequence set forth in SEQ ID NO: 20. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain (HC) comprising an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 20.

In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain (HC) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 21. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain (HC) comprising an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO: 21. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain (HC) comprising an amino acid sequence at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 21. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain (HC) comprising an amino acid sequence at least 99% identical to the amino acid sequence set forth in SEQ ID NO: 21. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain (HC) comprising an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 21.

In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a light chain (LC) comprising an amine group that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 22 acid sequence. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a light chain (LC) comprising an amine group that is at least 90% identical to the amino acid sequence set forth in SEQ ID NO: 22 acid sequence. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a light chain (LC) comprising an amine group that is at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 22 acid sequence. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a light chain (LC) comprising an amine group that is at least 99% identical to the amino acid sequence set forth in SEQ ID NO: 22 acid sequence. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a light chain (LC) comprising amino acids 100% identical to the amino acid sequence set forth in SEQ ID NO: 22 sequence. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain (HC) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 23. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain (HC) comprising an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO: 23. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain (HC) comprising an amino acid sequence at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 23. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain (HC) comprising an amino acid sequence at least 99% identical to the amino acid sequence set forth in SEQ ID NO: 23. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain (HC) comprising an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 23.

In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a heavy chain (HC) comprising an amine group that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 20 acid sequence. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a heavy chain (HC) comprising an amine group that is at least 90% identical to the amino acid sequence set forth in SEQ ID NO: 20 acid sequence. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a heavy chain (HC) comprising an amine group that is at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 20 acid sequence. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a heavy chain (HC) comprising an amine group that is at least 99% identical to the amino acid sequence set forth in SEQ ID NO: 20 acid sequence. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a heavy chain (HC) comprising amino acids 100% identical to the amino acid sequence set forth in SEQ ID NO: 20 sequence. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a heavy chain (HC) comprising an amine group that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 21 acid sequence. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a heavy chain (HC) comprising an amine group that is at least 90% identical to the amino acid sequence set forth in SEQ ID NO: 21 acid sequence. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a heavy chain (HC) comprising an amine group that is at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 21 acid sequence. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a heavy chain (HC) comprising an amine group that is at least 99% identical to the amino acid sequence set forth in SEQ ID NO: 21 acid sequence. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a heavy chain (HC) comprising amino acids 100% identical to the amino acid sequence set forth in SEQ ID NO: 21 sequence. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain (LC) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 19. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain (LC) comprising an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO: 19. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain (LC) comprising an amino acid sequence at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 19. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain (LC) comprising an amino acid sequence at least 99% identical to the amino acid sequence set forth in SEQ ID NO: 19. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain (LC) comprising an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 19.

In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a heavy chain (HC) comprising an amine group that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 23 acid sequence. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a heavy chain (HC) comprising an amine group that is at least 90% identical to the amino acid sequence set forth in SEQ ID NO: 23 acid sequence. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a heavy chain (HC) comprising an amine group that is at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 23 acid sequence. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a heavy chain (HC) comprising an amine group that is at least 99% identical to the amino acid sequence set forth in SEQ ID NO: 23 acid sequence. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a heavy chain (HC) comprising amino acids 100% identical to the amino acid sequence set forth in SEQ ID NO: 23 sequence. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain (LC) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 22. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain (LC) comprising an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO: 22. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain (LC) comprising an amino acid sequence at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 22. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain (LC) comprising an amino acid sequence at least 99% identical to the amino acid sequence set forth in SEQ ID NO: 22. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain (LC) comprising an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO: 22. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof selectively binds to a complex comprising HLA-E and a neoantigen. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof has no binding affinity for HLA-E alone. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof has no binding affinity for a neoantigen alone. In some embodiments, neoantigens are expressed by cells that are proficient in the antigen processing machinery (APM). In some embodiments, neoantigens are expressed by cells proficient in TAP1/2. In some embodiments, the neoantigen comprises, consists essentially of, or consists of a sequence according to SEQ ID NO: 18 (VMAPRTLFL). In some embodiments, the HLA-E is HLA-E*0101 or HLA-E*0103. In some embodiments, the antibody selectively binds to a complex comprising: (a) HLA-E*0101 and a neoantigen; (b) HLA-E*0103 and a neoantigen; or (c) HLA-E* 0101 and neoantigens, and HLA-E*0103 and neoantigens. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof is a murine antibody, a chimeric antibody, a camelid antibody, a humanized antibody, or a human antibody. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof is a TCR-like antibody. In some embodiments, monoclonal antibodies or antigen-binding fragments thereof are multispecific antibodies. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof is a bispecific antibody. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof is a bispecific T cell engager (BiTE). In some embodiments, the BiTE binds to the CD3 protein associated with the T cell receptor (TCR). In some embodiments, the BiTE further comprises a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 15. In some embodiments, the BiTE further comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 16. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof is a multifunctional antibody. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof further comprises a binding therapeutic moiety. In some embodiments, selective binding of the antibody to a complex comprising HLA-E and a neoantigen induces an immune response in the cell. In some embodiments, the immune response comprises activation of (i) NK cells, (ii) T cells, or (iii) NK cells and T cells. In some embodiments, the T cells are CD4+ T cells or CD8+ T cells. In some embodiments, the immune response comprises activation of cytotoxic T cells (CTL). In some embodiments, the cell is a cancer cell.

Related applications

This application claims U.S. Patent Application No. 17/199,258 filed March 11, 2021 (now pending) and U.S. Provisional Patent Application No. 63/032,886 filed June 1, 2020 (now pending) , each of which is incorporated herein by reference in its entirety for all purposes.

In certain embodiments, disclosed herein are antibodies comprising at least one heavy chain comprising a heavy chain variable domain (VH) and at least one light chain comprising a light chain variable domain (VL). Each VH and VL contains three complementarity determining regions (CDRs). In some embodiments, the antibody is a bispecific antibody. In some embodiments, the bispecific antibody is a bispecific T cell engager (BiTE). In some embodiments, the bispecific antibody binds to the CD3 protein associated with the T cell receptor (TCR). In certain embodiments, further disclosed herein are methods of treating cancer by administering antibodies that selectively bind to complexes comprising atypical HLA-I (eg, HLA-E) and neoantigens. In some embodiments, antibodies that selectively bind to complexes comprising atypical HLA-I (eg, HLA-E) and neoantigens modulate immune responses against cancer cells, thereby treating cancer. In some embodiments, the antibody is a bispecific antibody.

Traditional methods of treating cancer include surgery, radiation, chemotherapy and hormone therapy. However, such therapies themselves have not been proven effective. The development of alternative treatments for the prevention and/or treatment of cancer is of paramount importance. Recently, immunotherapy and gene therapy approaches using antibodies and T-lymphocytes have emerged as novel and promising approaches to treating cancer.

Major histocompatibility complex (MHC) molecules designated human leukocyte antigens (HLA) in the human body play a key role in the body's recognition of disease and the resulting immune response to cancer and invading antigens. The HLA gene family is divided into two subgroups, namely HLA class I (HLA-I) and HLA class II (HLA-II), wherein HLA-I is further divided into typical HLA-I and atypical HLA-I. Each HLA molecule forms a complex with one of the peptides inside the cell. On cancer cells, some peptide/HLA complexes are uniquely presented, which enable the immune system to recognize and kill these cells. Cells decorated with these unique peptide/HLA complexes are recognized and killed by cytotoxic T cells (CTLs). Cancer cells show down-regulation of classic HLA-I expression but up-regulation of atypical HLA AI expression (eg, HLA-E). Thus, the uniquely presented atypical HLA-I-peptide complex upregulated on cancer cells is a novel target for the development of novel immunotherapies for the treatment of cancer. specific term

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter that is claimed. The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

As used herein, the singular forms "a" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an antibody" includes a plurality of antibodies and reference to "an antibody" includes antibodies, etc. in some embodiments.

As used herein, unless the context clearly dictates otherwise, all values or numerical ranges include all integers within such ranges or fractions or integers or ranges encompassing such ranges and values within the ranges. Thus, for example, reference to the range 90-100% includes 91%, 92%, 93%, 94%, 95%, 95%, 97%, etc., as well as 91.1%, 91.2%, 91.3%, 91.4%, 91.5% %, etc., 92.1%, 92.2%, 92.3%, 92.4%, 92.5%, etc., and so on. In another example, reference to a range of 1-5,000 times includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 times, etc., and 1.1, 1.2, 1.3, 1.4, 1.5 times, etc., 2.1, 2.2, 2.3, 2.4, 2.5 times, etc., and so on.

As used herein, a number "about" refers to a range including the number and the range from 10% below the number to 10% above the number. A range of "about" means 10% below the lower end of the range up to 10% above the upper end of the range.

As used herein, the term "MHC" refers to the major histocompatibility complex, which is a group of loci that designate the major histocompatibility antigens. The term "HLA" as used herein refers to human leukocyte antigens, which are histocompatibility antigens found in the human body. As used herein, "HLA" is the human form of "MHC" and the terms are used interchangeably.

As used herein, "antibody" refers to a glycoprotein that exhibits binding specificity for a particular antigen. An antibody herein also includes an "antigen-binding portion" or fragment of an antibody that is capable of binding to an antigen. The term includes, but is not limited to, polyclonal, monoclonal, monospecific, multispecific (such as bispecific antibodies), native, humanized, human, chimeric, synthetic, recombinant, hybrid, mutated, grafted antibody fragments (such as A portion of a full-length antibody, typically its antigen-binding or variable region, such as Fab, Fab'; F(ab')2 and Fv fragments, and antibodies produced in vitro, so long as it exhibits the desired biological activity. The term also includes Single-chain antibodies, such as single-chain Fv (sFv or scFv) antibodies, in which the variable heavy and variable light chains are linked together (directly or via a peptide linker) to form a continuous polypeptide.

As used herein, "CDR" refers to an immunoglobulin (Ig) hypervariable domain. CDRs are defined in any suitable way. In some embodiments, the CDRs may be defined according to any of the Chothia numbering scheme, the Kabat numbering scheme, a combination of Kabat and Chothia, AbM definitions, Contact definitions, and/or combinations of Kabat, Chothia, AbM, and/or Contact definitions; and can produce different results.

As used herein, the term "selectively binds" in the context of any binding agent (such as an antibody) refers to specifically binding to an antigen or epitope (such as with high affinity) and not significantly binding to other unrelated antigens or epitopes the binding agent.

As used herein, the terms "neoantigen" or "neopeptide" are used interchangeably and refer to a peptide that is differentially expressed by diseased or stressed cells (eg, cancer cells) as compared to healthy cells.

The terms "recipient," "individual/subject," "host," and "patient" are used interchangeably herein, and, in some instances, refer to any mammalian individual in need of diagnosis, treatment, or therapy, particularly In other words, human beings. None of these terms require medical supervision.

As used herein, the terms "treatment/treating" and similar terms refer, in some instances, to administering an agent or performing a procedure for the purpose of obtaining an effect. The effect may be prophylactic in terms of completely or partially preventing the disease or its symptoms, and/or may be therapeutic in terms of achieving a partial or complete cure of the disease and/or disease symptoms. As used herein, "treatment" may include treatment of a disease or condition (such as cancer) in mammals, especially humans, and includes: (a) preventing disease or disease symptoms in individuals who may be susceptible to the disease but have not been diagnosed with it (including, for example, diseases that may be associated with or caused by the primary disease); (b) inhibit the disease, that is, arrest its development; and (c) alleviate the disease, that is, the disease regress. Treatment may refer to any marker of success in treating or ameliorating or preventing cancer, including any objective or subjective parameter, such as elimination; remission; attenuation of symptoms or making the disease condition more tolerable to the patient; slowing the rate of degeneration or regression; Or make the final point of denaturation lower and weaker. Treatment or amelioration of symptoms is based on one or more objective or subjective parameters; including physician examination results. Accordingly, the term "treating" includes administering a compound or agent of the invention to prevent or delay, alleviate or arrest or inhibit the development of a symptom or condition associated with a disease such as cancer. The term "therapeutic effect" refers to the alleviation, elimination or prevention of disease, disease symptoms or side effects of disease in a subject.

In some instances, a "therapeutically effective amount" means an amount sufficient to effect treatment of a disease when administered to a subject to treat that disease.

"Percent identity (%)" refers to the degree to which two sequences (nucleotides or amino acids) have the same residue at the same position when aligned. For example, "the amino acid sequence has X% identity to SEQ ID NO: Y" means the % identity of the amino acid sequence to SEQ ID NO: Y and is specified for X% of the residues in the amino acid sequence The base is consistent with the sequence residues disclosed in SEQ ID NO: Y. Generally, computer programs are used to perform such calculations. Exemplary programs for comparing and aligning pairs of sequences include ALIGN (Myers and Miller, 1988), FASTA (Pearson and Lipman, 1988; Pearson, 1990), and gapped BLAST (Altschul et al., 1997), BLASTP, BLASTN, or GCG (Devereux et al., 1984). Major histocompatibility complex ( MHC ) or human leukocyte antigen ( HLA )

The major histocompatibility complex (MHC), also known in humans as human leukocyte antigen (HLA), is a glycoprotein expressed on the surface of nucleated cells that acts as a protein body by providing insight into the state of cellular health Scan the wafer. It sequentially samples peptides from normal host cell proteins, cancer cells, inflammatory cells, and bacterial, viral, and parasite-infected cells, and presents short peptides on the cell surface for recognition by T lymphocytes. Presented peptides may also be derived from out-of-frame proteins or from sequences embedded in introns, or from proteins whose translation initiates at codons other than the conventional methionine codon ATG.

There are two classes of MHC in mice and humans, MHC I and MHC II. MHC I includes typical and atypical MHC I subgroups. Classic MHC I or HLA - I

Typical MHC I molecules include human HLA-A, HLA-B and HLA-C and mouse H-2-K, H-2-D, H-2-B and H-2-L. Typical MHC I molecules are highly polymorphic, with more than 2,735 HLA-A alleles, 3,455 HLA-B alleles and 2,259 HLA-C alleles. Canonical MHC I is expressed on the surface of all nucleated cells and presents peptides to CD8 T lymphocytes. 30% of the protein in the cellular machinery is rapidly degraded and is the main substrate for typical MHC I antigen presentation.

For peptides to be presented by canonical MHC I molecules, the protein is first processed via the well-known processing pathway (ubiquitin-proteasome system) that degrades the protein in the proteasome and transports it in a transport-associated protein (TAP)-dependent manner to Begins in the endoplasmic reticulum (ER) and ends with peptide loading into the HLA peptide binding pocket. Proteins that contribute to conventional processing pathways are collectively referred to as the antigen processing machinery (APM) and include the proteasome, TAP complex, TAP-associated protein (tapasin), endoplasmic reticulum aminopeptidase (ERAAP), binding immunoglobulin protein ( BiP), calcium-linked chaperone and calreticulin. Cells lacking the proteasome subunit, TAP1/2, ErP57, or calreticulin have reduced numbers of canonical MHC I molecules on their surface. Atypical MHC I or HLA - I

Atypical MHC I molecules include HLA-E, HLA-F, and HLA-G, and have limited polymorphisms. It plays a role in the regulation of innate and adaptive immune responses. Atypical MHC I molecules present peptides produced by both conventional and alternative processing pathways in healthy and disease states, and represent a novel set of markers for targeting in disease states such as cancer. HLA-E

Atypical MHC class I molecules, HLA-E is non-polymorphic. In nature, 13 HLA-E alleles have been identified with only two functional variants, namely HLAE*0101 and HLA-E*0103. The difference between HLA-E*0101 (HLA-E ^107R ) and *0103 (HLA-E ^107G ) is a single amino acid difference at position 107 outside the peptide binding pocket. Similar to typical MHC I molecules, HLA-E is expressed in all nucleated cells, however, expression is usually low. Expression of HLA-E molecules in cells and tissues generally increases during stress and disease. Thus, HLA-E is differentially expressed on stressed or diseased cells (eg, cancer cells) compared to healthy cells.

In healthy cells, HLA-E presents peptides derived from canonical MHC molecules and atypical HLA-G molecules to inhibit or stimulate the activity of NK cells and CD8 T cell subsets through the engagement receptor CD94/NKG2. Depending on the specific peptide presented by HLA-E, the HLA-E complex engages CD94/NKG2A or CD94/NKG2C to inhibit or activate NK cells and CD8 T cell subsets, respectively.

Another signal peptide that has the same characteristics as the signal peptide produced by the canonical HLA-I molecule is the signal peptide produced by the atypical HLA-G. HLA-G expression is strictly regulated under normal physiological conditions, and limited expression is found in a relatively small number of tissues and cells in the body. HLA-G plays a key role as an immune tolerance molecule and its expression is observed in cancer tissues/cells. Furthermore, the signal peptide from HLA-G is processed by the well-known antigen processing pathway and delivered to the endoplasmic reticulum by the peptide transporter TAP. In some embodiments, the signal peptide is VMAPRTLFL (SEQ ID NO: 18).

of cancer cells HLA - E. Expression and Peptide Presentation

Cells lacking one or more components of APM load peptides into MHC class I molecules via an alternative processing pathway independent of the conventional APM-dependent processing pathway. Cells lacking APM not only have a reduced number of canonical MHC I molecules on their surface, but also display an increased cell surface density of HLA-E molecules and an increased repertoire of presented peptides. Alternative processing pathways are constitutively turned on and peptides are produced in both healthy and diseased cells. However, these peptides are not presented by healthy cells; instead, they are only presented in diseased or stressed cells. Thus, the distinct peptide repertoire produced by APM-deficient cells, also known as "T-cell epitopes associated with impaired peptide processing (TEIPP)", represents a novel target specific to cancer cells and represents a therapeutic development in cancer therapy. ideal target.

Under a stressed or diseased state (eg, cancer), stressed or diseased cells (eg, cancer cells) differentially express complexes comprising HLA-E and peptides derived from atypical HLA-G molecules. Complexes comprising HLA-E and peptides derived from atypical HLA-G molecules are differentially expressed on stressed or diseased cells compared to healthy cells. Targeting this complex induces an immune response against cells expressing the complex. MHC II or HLA-II

MHC II molecules include human HLA-DM, HLA-DO, HLA-DP, HLA-DQ, and HLA-DR, and include mouse H-2 IA and H-2 IE. MHC II expression is more limited to B cells, dendritic cells, macrophages, activated T cells, and thymic epithelial cells, and MHC II molecules present peptides to CD4 lymphocytes. Antibodies targeting complexes containing atypical HLA - I ( such as HLA - E ) and neoantigens

In certain embodiments, disclosed herein are antibodies that target complexes comprising atypical HLA-I (eg, HLA-E) and neoantigens. In some embodiments, an antibody comprises at least one heavy chain comprising a heavy chain variable domain (VH) and at least one light chain comprising a light chain variable domain (VL). Each VH and VL contains three complementarity determining regions (CDRs). The amino acid sequences of VH and VL and CDR determine the antigen-binding specificity and antigen-binding strength of the antibody. The amino acid sequences of the VH and VL and CDRs are summarized in Table 1. Table 1. Antibodies _ Human monoclonal antibody sequences that bind complexes containing HLA - E and canonical HLA signal peptides (ABX -0010 , 0011 , 0030 , 0012 ) sequence SEQ ID NO: light chain CDR1 QSISSY 1 light chain CDR2 AAS 2 light chain CDR3 QQAAAYPSL 3 heavy chain CDR1 GFTFSSYA 4 heavy chain CDR2 IAYGGGAT 5 heavy chain CDR3 AKGLSNFDY 6 light chain variable domain DIQMTQSPSSLSASSVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAAAYPSLFGQGTKVEIK 7 heavy chain variable domain EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSTIAYGGGATAYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGLSNFDYWGQGTLVTVSS 8 Light chain ( human kappa) DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFLTISSLQPEDFATYYCQQAAAYPSLFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLGSKADYEVECKQGLSS 19 Heavy Chain ( Human IgG1) EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSTIAYGGGATAYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGLSNFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 20 Heavy chain ( human IgG1) enhances FcγR binding to DLE mutations (Ser239Asp/Ala330Leu/Ile332Glu) EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSTIAYGGGATAYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGLSNFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPLPEEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK twenty one light chain ( mouse kappa) DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFLTISSLQPEDFATYYCQQAAAYPSLFGQGTKVEIKRADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSSPNTDQDSKDSTYSMSSTLTLTKDEYERKHNSYTC twenty two Heavy chain ( mouse IgG1) EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSTIAYGGGATAYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGLSNFDYWGQGTLVTVSSAKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVPSSPRPSETVTCNVAHPASSTKVDKKIVPRDCGCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPEVQFSWFVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFPAPIEKTISKTKGRPKAPQVYTIPPPKEQMAKDKVSLTCMITDFFPEDITVEWQWNGQPAENYKNTQPIMNTNGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPGK twenty three CD3 binding mouse monoclonal antibody sequence light chain CDR1 TGAVTTSNY 9 light chain CDR2 GTN 10 light chain CDR3 ALWYSNLWV 11 heavy chain CDR1 GFTFNTYA 12 heavy chain CDR2 IRSKYNNYAT 13 heavy chain CDR3 VRHGNFGNSYVSWFAY 14 light chain variable domain QAVVTQESALTTSPGETVTLTCRSSTGAVTTSNYANWVQEKPDHLFTGLIGGTNKRAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFCALWYSNLWVFGGGTKLTVL 15 heavy chain variable domain EVQLVESGGGLVQPKGSLKLSCAASGFTFNTYAMNWVRQAPGKGLEWVARIRSKYNNYATYYADSVKDRFTISRDDSQSILYLQMNNLKTEDTAMYYCVRHGNFGNSYVSWFAYWGQGTLVTVSS 16

In some embodiments, the antibody selectively binds to a complex comprising atypical HLA-I (eg, HLA-E) and neoantigens. In some embodiments, the antibody has no binding affinity for atypical HLA-I alone. In some embodiments, the antibody has no binding affinity for a neoantigen alone. In some embodiments, the antibody has no binding affinity for a complex comprising atypical HLA-I and a non-related neoantigen.

In some embodiments, neoantigens are expressed by cells that are proficient in the antigen processing machinery (APM). In some embodiments, neoantigens are expressed by cells proficient in TAP1/2. In some embodiments, the neoantigen comprises, consists essentially of, or consists of a sequence according to SEQ ID NO: 18 (VMAPRTLFL).

In some embodiments, the atypical HLA-I is HLA-E, HLA-F, HLA-G or HLA-H. In some embodiments, the atypical HLA-I is HLA-E. In some embodiments, the HLA-E is HLA-E*0101. In some embodiments, the HLA-E is HLA-E*0103.

In some embodiments, the antibody selectively binds to a complex comprising HLA-E and a neoantigen. In some embodiments, the antibody selectively binds to a complex comprising HLA-E*0101 and a neoantigen. In some embodiments, the antibody selectively binds to a complex comprising HLA-E*0103 and a neoantigen. In some embodiments, the antibody selectively binds to a complex comprising HLA-E*0101 and a neoantigen, and binds to a complex comprising HLA-E*0103 and a neoantigen. In some embodiments, the complex comprises HLA-E and a neoantigen according to SEQ ID NO: 18 (VMAPRTLFL).

In some embodiments, the antibody is a murine antibody. In some embodiments, the antibody is a chimeric antibody. In some embodiments, the antibody is a camelid antibody. In some embodiments, the antibody is a humanized antibody. In some embodiments, the antibodies are human antibodies.

In some embodiments, the antibody is a TCR-like antibody. In some embodiments, the antibody is a single domain antibody. In some embodiments, the single domain antibody is a camelid single domain antibody.

In some embodiments, the antibody is a multispecific antibody. In some embodiments, the antibody is a bispecific antibody. In some embodiments, the antibody is a bispecific T cell engager (BiTE). In some embodiments, the BiTE binds to the CD3 protein associated with the T cell receptor (TCR). In some embodiments, the BiTE binds to the CD3ε protein associated with the T cell receptor (TCR). In some embodiments, the antibody is a multifunctional antibody.

In some embodiments, the antibody further comprises a binding therapeutic moiety. Therapeutic moieties include, but are not limited to, cytotoxins, chemotherapeutic drugs, immunosuppressants, and radioisotopes. A cytotoxin or cytotoxic agent includes any agent that is detrimental to (eg, kills) a cell. Examples include, but are not limited to, paclitaxel, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide ), tenoposide, vincristine, vinblastine, coichicin, doxorubicin, daunorubicin, dihydroxyanthraxine Dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine , tetracaine, lidocaine, propranolol, puromycin and their analogs or homologues. Suitable chemotherapeutic agents include, but are not limited to, antimetabolites (e.g. methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, fludarabine, 5-fluorouracil, dacarbazine (decarbazine, hydroxyurea, azathioprine, gemcitabine, and cladribin), alkylating agents (eg, nitrogen mustard, thiotepa, chlorambucil, melphalan, Carmustine (BSNU) and lomustine (CCNU), cyclophosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, and cis-di Platinum(II) chloride (DDP) cisplatin), anthracyclines (such as daunorubicin (protodaunorubicin) and cranberry), antibiotics (such as dactinomycin (proactinomycin), Bleomycin, mithramycin, and ankomycin (AMC)) and antimitotic agents (eg, vincristine, vinblastine, docetaxel, paclitaxel and vinorelbin). Suitable radioisotopes include, but are not limited to, iodine-131, yttrium-90, or indium-111. Other examples of therapeutic moieties are proteins or polypeptides having the desired biological activity. Such proteins may include, for example, enzymatically active toxins or active fragments thereof, such as abrin, ricin A, Pseudomonas exotoxin, or diphtheria toxin; proteins, such as tumor necrosis factor or interferon-gamma; or biological Response modifiers such as lymphoid mediators, interleukin-1 (IL-1), interleukin-2 (IL-2), interleukin-6 (IL-6), granulocyte macrophage colony stimulating factor ( GM-CSF), granule colony stimulating factor (G-CSF) or other growth factors.

In some embodiments, selective binding of antibodies to complexes comprising atypical HLA-I (eg, HLA-E) and neoantigens induces an immune response. In some embodiments, the immune response comprises activation of NK cells. In some embodiments, selective binding of the antibody to a TCR-associated CD3 protein induces an immune response. In some embodiments, the immune response comprises activation of T cells. In some embodiments, the T cells are CD8+ T cells. In some embodiments, the immune response comprises activation of cytotoxic T cells (CTL). In some embodiments, the cell is a cancer cell. Antibody variable domains ( VL and VH )

Disclosed herein are antibodies that selectively bind to complexes comprising HLA-E and neoantigens, the antibodies having a light chain comprising a light chain variable domain (VL). In some embodiments, the antibody comprises a light chain variable domain (VL) having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:7. In some embodiments, the VL has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity. In some embodiments, the VL has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 7.

Further disclosed herein are antibodies that selectively bind to complexes comprising HLA-E and neoantigens, the antibodies having heavy chains comprising heavy chain variable domains (VH). In some embodiments, the antibody comprises a heavy chain variable domain (VH) having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:8. In some embodiments, the VH has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity. In some embodiments, the VH has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 8.

Also disclosed herein are antibodies that selectively bind to a complex comprising HLA-E and a neoantigen, the antibodies comprising a light chain variable domain (VL) and a heavy chain variable domain (VH). In some embodiments, an antibody comprises a light chain variable domain (VL) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO: 7, and a heavy chain variable domain (VH), the VH has an amino acid sequence that is at least about 70% identical to the amino acid sequence shown in SEQ ID NO: 8. In some embodiments, the VL has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequence, and the VH has the same amino acid sequence as SEQ ID NO: The amino acid sequence shown in 8 is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92% %, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequences. In some embodiments, VL has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO: 7, and VH has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO: 8 amino acid sequence. Antibody heavy and light chains

Disclosed herein are antibodies that selectively bind to complexes comprising HLA-E and neoantigens, the antibodies having light chains (LC). In some embodiments, the antibody comprises a light chain (LC) having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO: 19. In some embodiments, the LC has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity. In some embodiments, the LC has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 19.

Further disclosed herein are antibodies that selectively bind to complexes comprising HLA-E and neoantigens, the antibodies having heavy chains (HC). In some embodiments, the antibody comprises an HC having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO: 20. In some embodiments, the HC has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity. In some embodiments, the HC has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 20.

Also disclosed herein are antibodies that selectively bind to complexes comprising HLA-E and neoantigens, the antibodies comprising a light chain (LC) and a heavy chain (HC). In some embodiments, the antibody comprises an LC having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO: 19, and an HC having an amino acid sequence identical to that set forth in SEQ ID NO: 20 The amino acid sequences shown are amino acid sequences that are at least about 70% identical. In some embodiments, the LC has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequence, and HC has the same amino acid sequence as SEQ ID NO: The amino acid sequence shown in 20 is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92% %, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequences. In some embodiments, LC has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO: 19, and HC has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO: 20 amino acid sequence.

Further disclosed herein are antibodies that selectively bind to complexes comprising HLA-E and neoantigens, the antibodies having heavy chains (HC). In some embodiments, the antibody comprises an HC having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO: 21. In some embodiments, the HC has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity. In some embodiments, the HC has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 21.

Also disclosed herein are antibodies that selectively bind to complexes comprising HLA-E and neoantigens, the antibodies comprising a light chain (LC) and a heavy chain (HC). In some embodiments, the antibody comprises an LC having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO: 19, and an HC having an amino acid sequence set forth in SEQ ID NO: 21 The amino acid sequences shown are amino acid sequences that are at least about 70% identical. In some embodiments, the LC has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequence, and HC has the same amino acid sequence as SEQ ID NO: The amino acid sequence shown in 21 is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92% %, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequences. In some embodiments, LC has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO: 19, and HC has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO: 21 amino acid sequence.

Disclosed herein are antibodies that selectively bind to complexes comprising HLA-E and neoantigens, the antibodies having light chains (LC). In some embodiments, the antibody comprises a light chain (LC) having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO: 22. In some embodiments, the LC has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity. In some embodiments, the LC has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 22.

Further disclosed herein are antibodies that selectively bind to complexes comprising HLA-E and neoantigens, the antibodies having heavy chains (HC). In some embodiments, the antibody comprises an HC having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO: 23. In some embodiments, the HC has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity. In some embodiments, the HC has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 23.

Also disclosed herein are antibodies that selectively bind to complexes comprising HLA-E and neoantigens, the antibodies comprising a light chain (LC) and a heavy chain (HC). In some embodiments, the antibody comprises an LC having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO: 22, and an HC having an amino acid sequence identical to that set forth in SEQ ID NO: 23 The amino acid sequences shown are amino acid sequences that are at least about 70% identical. In some embodiments, the LC has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequence, and HC has the same amino acid sequence as SEQ ID NO: The amino acid sequence shown in 23 is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92% %, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequences. In some embodiments, LC has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO: 22, and HC has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO: 23 amino acid sequence. Antibody Complementarity Determining Regions ( CDR )

Disclosed herein are antibodies that selectively bind to complexes comprising HLA-E and neoantigens, the antibodies having light chains comprising light chain complementarity determining regions (CDRs). In some embodiments, the antibody comprises a light chain CDR sequence having an amino acid sequence that is at least about 70% identical to at least one of the amino acid sequences set forth in SEQ ID NOs: 1-3. In some embodiments, the antibody comprises a light chain CDR sequence having at least about 75%, 80%, 81%, 82%, 83% of at least one of the amino acid sequences set forth in SEQ ID NO: 1-3 %, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% agree amino acid sequence. In some embodiments, the antibody comprises a light chain CDR sequence that has an amino acid sequence that is 100% identical to at least one of the amino acid sequences set forth in SEQ ID NO: 1-3.

Further disclosed herein are antibodies that selectively bind to complexes comprising HLA-E and neoantigens, the antibodies having heavy chains comprising heavy chain complementarity determining regions (CDRs). In some embodiments, the antibody comprises a heavy chain CDR sequence having an amino acid sequence that is at least about 70% identical to at least one of the amino acid sequences set forth in SEQ ID NOs: 4-6. In some embodiments, the antibody comprises a heavy chain CDR sequence having at least about 75%, 80%, 81%, 82%, 83% of at least one of the amino acid sequences set forth in SEQ ID NO: 4-6 %, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% agree amino acid sequence. In some embodiments, the antibody comprises a heavy chain CDR sequence that has an amino acid sequence that is 100% identical to at least one of the amino acid sequences set forth in SEQ ID NOs: 4-6.

Also disclosed herein are antibodies that selectively bind to complexes comprising HLA-E and neoantigens, the antibodies comprising light chain complementarity determining regions (CDRs) and heavy chain complementarity determining regions (CDRs). In some embodiments, the antibody comprises a light chain CDR sequence having an amino acid sequence at least about 70% identical to at least one of the amino acid sequences set forth in SEQ ID NO: 1-3, and a heavy chain CDR A sequence having an amino acid sequence that is at least about 70% identical to at least one of the amino acid sequences set forth in SEQ ID NO: 4-6. In some embodiments, the antibody comprises a light chain CDR sequence having at least about 75%, 80%, 81%, 82%, 83% of at least one of the amino acid sequences set forth in SEQ ID NO: 1-3 %, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% agree The amino acid sequence of the amino acid sequence, and the heavy chain CDR sequence, it has at least about 75%, 80%, 81%, 82%, 83% of at least one of the amino acid sequences shown in SEQ ID NO: 4-6 , 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% consistent amino acid sequence. In some embodiments, the antibody comprises a light chain CDR sequence having an amino acid sequence that is 100% identical to at least one of the amino acid sequences set forth in SEQ ID NO: 1-3, and a heavy chain CDR sequence, It has an amino acid sequence that is 100% identical to at least one of the amino acid sequences shown in SEQ ID NO: 4-6.

In some embodiments, the antibody that selectively binds to a complex comprising HLA-E and a neoantigen comprises at least one of the following: an amino acid sequence that is at least about 70 times the amino acid sequence set forth in SEQ ID NO: 1 % Consistent light chain CDR1, amino acid sequence and at least about 70% identical light chain CDR2 and amino acid sequence with the amino acid sequence shown in SEQ ID NO: 2 and the amino acid sequence shown in SEQ ID NO: 3 The light chain CDR3s are at least about 70% identical in sequence. In some embodiments, the antibody comprises at least one of the following light chains: an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83% identical to the amino acid sequence set forth in SEQ ID NO: 1 , 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% consistent Light chain CDR1; the amino acid sequence is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical light chain CDR2; and amino acid sequence and SEQ ID NO : The amino acid sequence shown in 3 is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical light chain CDR3. In some embodiments, the antibody comprises at least one of the following: a light chain CDR1 whose amino acid sequence is 100% identical to the amino acid sequence shown in SEQ ID NO: 1, an amino acid sequence identical to that of SEQ ID NO: 2 The light chain CDR2 whose amino acid sequence is 100% identical as shown, and the light chain CDR3 whose amino acid sequence is 100% identical to the amino acid sequence shown in SEQ ID NO:3.

In some embodiments, the antibody that selectively binds to a complex comprising HLA-E and a neoantigen comprises at least one of the following: an amino acid sequence at least about 70% identical to that set forth in SEQ ID NO: 4 Heavy chain CDR1, heavy chain CDR2 having an amino acid sequence at least about 70% identical to the list set forth in SEQ ID NO: 5, heavy chain having an amino acid sequence at least about 70% identical to the list set forth in SEQ ID NO: 6 CDR3. In some embodiments, the antibody comprises at least one of the following: an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84% of the amino acid sequence set forth in SEQ ID NO: 4 %, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical heavy chain CDR1; the amino acid sequence is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88% of the amino acid sequence shown in SEQ ID NO: 5 , 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical heavy chain CDR2; amino acid sequence and SEQ ID NO: 6 The amino acid sequence shown is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical heavy chain CDR3. In some embodiments, the antibody comprises at least one of the following: a heavy chain CDR1 whose amino acid sequence is 100% identical to the amino acid sequence shown in SEQ ID NO: 4, an amino acid sequence identical to SEQ ID NO: 5 The heavy chain CDR2 whose amino acid sequence is 100% identical, and the heavy chain CDR3 whose amino acid sequence is 100% identical to the amino acid sequence shown in SEQ ID NO:6.

In some embodiments, the antibody that selectively binds to a complex comprising HLA-E and a neoantigen comprises at least one of the following: an amino acid sequence that is at least about 70 times the amino acid sequence set forth in SEQ ID NO: 1 % identical light chain CDR1, the amino acid sequence is at least about 70% identical to the amino acid sequence shown in SEQ ID NO: 2, and the light chain CDR2, the amino acid sequence is at least about 70% identical to the amino acid sequence shown in SEQ ID NO: 3 A light chain CDR3 whose sequence is at least about 70% identical, an amino acid sequence that is at least about 70% identical to the amino acid sequence shown in SEQ ID NO: 4, and a heavy chain CDR1 whose amino acid sequence is at least about 70% identical to the amino acid sequence shown in SEQ ID NO: 5 A heavy chain CDR2 whose amino acid sequence is at least about 70% identical, and a heavy chain CDR3 whose amino acid sequence is at least about 70% identical to the amino acid sequence shown in SEQ ID NO: 6. In some embodiments, the antibody comprises at least one of the following: an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84% of the amino acid sequence set forth in SEQ ID NO: 1 %, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical light chains CDR1; the amino acid sequence is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88% of the amino acid sequence shown in SEQ ID NO: 2 , 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical light chain CDR2; amino acid sequence and SEQ ID NO: 3 The amino acid sequence shown is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the light chain CDR3; the amino acid sequence is at least about 75%, 80% identical to the amino acid sequence shown in SEQ ID NO: 4 , 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97 %, 98% or 99% identical heavy chain CDR1; the amino acid sequence is at least about 75%, 80%, 81%, 82%, 83%, 84%, or the amino acid sequence shown in SEQ ID NO: 5 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical heavy chain CDR2; and an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical heavy chain CDR3. In some embodiments, the antibody comprises at least one of the following: a light chain CDR1 whose amino acid sequence is 100% identical to the amino acid sequence shown in SEQ ID NO: 1, an amino acid sequence identical to that of SEQ ID NO: 2 The light chain CDR2 whose amino acid sequence is 100% consistent, the light chain CDR3 whose amino acid sequence is 100% consistent with the amino acid sequence shown in SEQ ID NO: 3, the amino acid sequence and SEQ ID NO: 4 The amino acid sequence shown is 100% identical to the heavy chain CDR1, the amino acid sequence is 100% identical to the amino acid sequence shown in SEQ ID NO: 5, and the heavy chain CDR2 and the amino acid sequence are 100% identical to SEQ ID NO: 6 The amino acid sequences shown are 100% identical to the heavy chain CDR3. bispecific antibody

In some embodiments, the antibodies disclosed herein are bispecific antibodies. In some embodiments, the bispecific antibody is a bispecific T cell engager (BiTE). In some embodiments, the BiTE binds to the CD3 protein associated with the T cell receptor (TCR). In some embodiments, the BiTE binds to the CD3ε protein associated with the T cell receptor (TCR).

In some embodiments, the BiTE comprises an anti-CD3 antibody or fragment thereof, such as UCHT1, OKT3, F6A, L2K, muromonab, otelixizumab, teplizumab, Visilizumab, CD3-12, MEM-57, 4D10A6, CD3D, or TR66.

In some embodiments, the bispecific antibody comprises (a) a light chain variable domain (VL), the VL comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth in SEQ ID NO: 7; or A heavy chain variable domain (VH), the VH comprising an amino acid sequence at least 70% identical to the amino acid sequence shown in SEQ ID NO: 8; and (b) a light chain variable domain (VL), the VL Comprising an amino acid sequence at least 70% identical to the amino acid sequence shown in SEQ ID NO: 15; or a heavy chain variable domain (VH), the VH comprising the amino acid sequence shown in SEQ ID NO: 16 At least 70% identical amino acid sequence.

In some embodiments, the bispecific antibody comprises (a) a light chain variable domain (VL) comprising at least 75%, 80%, 81%, 82% of the amino acid sequence set forth in SEQ ID NO: 7 %, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical amino acid sequence; or heavy chain variable domain (VH), the VH comprises at least 75%, 80%, 81%, 82%, 83% of the amino acid sequence shown in SEQ ID NO: 8 , 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% consistent Amino acid sequence; and (b) light chain variable domain (VL), the VL comprises at least 75%, 80%, 81%, 82%, 83%, and the amino acid sequence shown in SEQ ID NO: 15 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amines amino acid sequence; or heavy chain variable domain (VH), the VH comprises at least 75%, 80%, 81%, 82%, 83%, 84%, 85% of the amino acid sequence shown in SEQ ID NO: 16 %, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequences.

In some embodiments, the bispecific antibody comprises (a) a light chain variable domain (VL) comprising an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 7; or a heavy chain variable domain (VL) comprising: chain variable domain (VH), the VH comprising an amino acid sequence 100% identical to the amino acid sequence shown in SEQ ID NO: 8; and (b) a light chain variable domain (VL), the VL comprising an amino acid sequence identical to An amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 15; or a heavy chain variable domain (VH), the VH comprising 100% identical to the amino acid sequence shown in SEQ ID NO: 16 amino acid sequence.

In some embodiments, the bispecific antibody comprises (a) a light chain variable domain (VL), the VL comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth in SEQ ID NO: 7; and A heavy chain variable domain (VH), the VH comprising an amino acid sequence at least 70% identical to the amino acid sequence shown in SEQ ID NO: 8; and (b) a light chain variable domain (VL), the VL Comprising an amino acid sequence at least 70% identical to the amino acid sequence shown in SEQ ID NO: 15; and a heavy chain variable domain (VH), the VH comprising the amino acid sequence shown in SEQ ID NO: 16 At least 70% identical amino acid sequence.

In some embodiments, the bispecific antibody comprises (a) a light chain variable domain (VL) comprising at least 75%, 80%, 81%, 82% of the amino acid sequence set forth in SEQ ID NO: 7 %, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical amino acid sequence; and a heavy chain variable domain (VH), the VH comprising at least 75%, 80%, 81%, 82%, 83% of the amino acid sequence shown in SEQ ID NO: 8 , 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% consistent Amino acid sequence; and (b) light chain variable domain (VL), the VL comprises at least 75%, 80%, 81%, 82%, 83%, and the amino acid sequence shown in SEQ ID NO: 15 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amines amino acid sequence; and heavy chain variable domain (VH), the VH comprises at least 75%, 80%, 81%, 82%, 83%, 84%, 85% of the amino acid sequence shown in SEQ ID NO: 16 %, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequences.

In some embodiments, the bispecific antibody comprises: (a) a light chain (LC) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth in SEQ ID NO: 19; or a heavy chain (HC), the HC comprises an amino acid sequence at least 70% identical to the amino acid sequence shown in SEQ ID NO: 20; and (b) a light chain variable domain (VL), the VL comprising the same amino acid sequence as SEQ ID NO : an amino acid sequence that is at least 70% identical to the amino acid sequence shown in SEQ ID NO: 15; or a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 70% identical to the amino acid sequence shown in SEQ ID NO: 16 amino acid sequence.

In some embodiments, the bispecific antibody comprises (a) a light chain (LC) comprising at least 75%, 80%, 81%, 82%, 83% of the amino acid sequence set forth in SEQ ID NO: 19 %, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% agree or the heavy chain (HC), the HC comprises at least 75%, 80%, 81%, 82%, 83%, 84%, 85% of the amino acid sequence shown in SEQ ID NO: 20 , 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequences; and (b) light chain variable domain (VL), the VL comprises at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity; or Chain variable domain (VH), the VH comprises at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87% of the amino acid sequence shown in SEQ ID NO: 16 %, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequences.

In some embodiments, the bispecific antibody comprises: (a) a light chain (LC) comprising an amino acid sequence 100% identical to the amino acid sequence shown in SEQ ID NO: 19; or a heavy chain ( HC), the HC comprises an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 20; and (b) a light chain variable domain (VL), the VL comprising the same amino acid sequence as SEQ ID NO: 15 An amino acid sequence that is 100% identical to the amino acid sequence shown; or a heavy chain variable domain (VH) comprising an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 16 .

In some embodiments, the bispecific antibody comprises: (a) a light chain (LC) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth in SEQ ID NO: 19; or a heavy chain (HC), the HC comprises an amino acid sequence at least 70% identical to the amino acid sequence shown in SEQ ID NO: 21; and (b) a light chain variable domain (VL), the VL comprising the same amino acid sequence as SEQ ID NO : an amino acid sequence that is at least 70% identical to the amino acid sequence shown in SEQ ID NO: 15; or a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 70% identical to the amino acid sequence shown in SEQ ID NO: 16 amino acid sequence.

In some embodiments, the bispecific antibody comprises (a) a light chain (LC) comprising at least 75%, 80%, 81%, 82%, 83% of the amino acid sequence set forth in SEQ ID NO: 19 %, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% agree or the heavy chain (HC), the HC comprises at least 75%, 80%, 81%, 82%, 83%, 84%, 85% of the amino acid sequence shown in SEQ ID NO: 21 , 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequences; and (b) light chain variable domain (VL), the VL comprises at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity; or Chain variable domain (VH), the VH comprises at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87% of the amino acid sequence shown in SEQ ID NO: 16 %, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequences.

In some embodiments, the bispecific antibody comprises: (a) a light chain (LC) comprising an amino acid sequence 100% identical to the amino acid sequence shown in SEQ ID NO: 19; or a heavy chain ( HC), the HC comprises an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 21; and (b) a light chain variable domain (VL), the VL comprising the same amino acid sequence as SEQ ID NO: 15 An amino acid sequence that is 100% identical to the amino acid sequence shown; or a heavy chain variable domain (VH) comprising an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 16 .

In some embodiments, the bispecific antibody comprises: (a) a light chain (LC) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth in SEQ ID NO: 22; or a heavy chain (HC), the HC comprises an amino acid sequence at least 70% identical to the amino acid sequence shown in SEQ ID NO: 23; and (b) a light chain variable domain (VL), the VL comprising the same amino acid sequence as SEQ ID NO: : an amino acid sequence that is at least 70% identical to the amino acid sequence shown in SEQ ID NO: 15; or a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 70% identical to the amino acid sequence shown in SEQ ID NO: 16 amino acid sequence.

In some embodiments, the bispecific antibody comprises (a) a light chain (LC) comprising at least 75%, 80%, 81%, 82%, 83% of the amino acid sequence set forth in SEQ ID NO: 22 %, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% agree or the heavy chain (HC), the HC comprises at least 75%, 80%, 81%, 82%, 83%, 84%, 85% of the amino acid sequence shown in SEQ ID NO: 23 , 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequences; and (b) light chain variable domain (VL), the VL comprises at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity; or Chain variable domain (VH), the VH comprises at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87% of the amino acid sequence shown in SEQ ID NO: 16 %, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequences.

In some embodiments, the bispecific antibody comprises: (a) a light chain (LC) comprising an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 22; or a heavy chain ( HC), the HC comprises an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 23; and (b) a light chain variable domain (VL), the VL comprising the same amino acid sequence as SEQ ID NO: 15 An amino acid sequence that is 100% identical to the amino acid sequence shown; or a heavy chain variable domain (VH) comprising an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 16 .

In some embodiments, the bispecific antibody comprises (a) a light chain variable domain (VL), the VL comprising an amino acid sequence 100% identical to the amino acid sequence shown in SEQ ID NO: 7; and a heavy chain variable domain (VH), the VH comprising an amino acid sequence 100% identical to the amino acid sequence shown in SEQ ID NO: 8; and (b) a light chain variable domain (VL), the VL comprising an amino acid sequence identical to An amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 15; and a heavy chain variable domain (VH), the VH comprising 100% identical to the amino acid sequence shown in SEQ ID NO: 16 amino acid sequence.

In some embodiments, the bispecific antibody comprises (a) a light chain complementarity determining region (CDR) having at least 70% identity to at least one of the amino acid sequences set forth in SEQ ID NO: 1-3 or a heavy chain complementarity determining region (CDR), which has an amino acid sequence that is at least 70% identical to at least one of the amino acid sequences shown in SEQ ID NO: 4-6; and (b) a light chain complementarity determining region (CDR) having an amino acid sequence at least 70% identical to at least one of the amino acid sequences shown in SEQ ID NO: 9-11; or a heavy chain complementarity determining region A region (CDR) having an amino acid sequence that is at least 70% identical to at least one of the amino acid sequences set forth in SEQ ID NO: 12-14.

In some embodiments, the bispecific antibody comprises (a) a light chain complementarity determining region (CDR) having at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96% , 97%, 98% or 99% identical amino acid sequence; or a heavy chain complementarity determining region (CDR), the CDR has at least one of the amino acid sequences shown in SEQ ID NO: 4-6 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95% , 96%, 97%, 98% or 99% identical amino acid sequence; and (b) light chain complementarity determining region (CDR), the CDR has the amino acid sequence shown in SEQ ID NO: 9-11 At least one of at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93% , 94%, 95%, 96%, 97%, 98% or 99% identical amino acid sequence; or heavy chain complementarity determining region (CDR), the CDR has the amine shown in SEQ ID NO: 12-14 At least one of the amino acid sequences is at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92% , 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequences.

In some embodiments, the bispecific antibody comprises (a) a light chain complementarity determining region (CDR) that is 100% identical to at least one of the amino acid sequences set forth in SEQ ID NO: 1-3 Amino acid sequence; or a heavy chain complementarity determining region (CDR), the CDR has an amino acid sequence that is 100% identical to at least one of the amino acid sequences shown in SEQ ID NO: 4-6; and (b ) a light chain complementarity determining region (CDR), which has an amino acid sequence that is 100% identical to at least one of the amino acid sequences shown in SEQ ID NO: 9-11; or a heavy chain complementarity determining region (CDR ), the CDR has an amino acid sequence that is 100% identical to at least one of the amino acid sequences shown in SEQ ID NO: 12-14.

In some embodiments, the bispecific antibody comprises (a) a light chain complementarity determining region (CDR) having at least 70% identity to at least one of the amino acid sequences set forth in SEQ ID NO: 1-3 and the heavy chain complementarity determining region (CDR), the CDR has an amino acid sequence that is at least 70% identical to at least one of the amino acid sequences shown in SEQ ID NO: 4-6; and (b) a light chain complementarity determining region (CDR) having an amino acid sequence at least 70% identical to at least one of the amino acid sequences shown in SEQ ID NO: 9-11; and a heavy chain complementarity determining region A region (CDR) having an amino acid sequence that is at least 70% identical to at least one of the amino acid sequences set forth in SEQ ID NO: 12-14.

In some embodiments, the bispecific antibody comprises (a) a light chain complementarity determining region (CDR) having at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96% , 97%, 98% or 99% identical amino acid sequence; and a heavy chain complementarity determining region (CDR), the CDR has at least one of the amino acid sequences shown in SEQ ID NO: 4-6 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95% , 96%, 97%, 98% or 99% identical amino acid sequence; and (b) light chain complementarity determining region (CDR), the CDR has the amino acid sequence shown in SEQ ID NO: 9-11 At least one of at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93% , 94%, 95%, 96%, 97%, 98% or 99% identical amino acid sequence; and heavy chain complementarity determining region (CDR), the CDR has the amine shown in SEQ ID NO: 12-14 At least one of the amino acid sequences is at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92% , 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequences.

In some embodiments, the bispecific antibody comprises (a) a light chain complementarity determining region (CDR) that is 100% identical to at least one of the amino acid sequences set forth in SEQ ID NO: 1-3 an amino acid sequence; and a heavy chain complementarity determining region (CDR) having an amino acid sequence that is 100% identical to at least one of the amino acid sequences shown in SEQ ID NO: 4-6; and (b ) a light chain complementarity determining region (CDR), which has an amino acid sequence that is 100% identical to at least one of the amino acid sequences shown in SEQ ID NO: 9-11; and a heavy chain complementarity determining region (CDR ), the CDR has an amino acid sequence that is 100% identical to at least one of the amino acid sequences shown in SEQ ID NO: 12-14. treatment method

Provided herein are methods of treating cancer in an individual in need thereof comprising administering an antibody that selectively binds to a complex comprising atypical HLA-I (eg, HLA-E) and a neoantigen as disclosed herein.

In some embodiments, the antibody selectively binds to a complex comprising atypical HLA-I (eg, HLA-E) and neoantigens. In some embodiments, the antibody has no binding affinity for atypical HLA-I alone. In some embodiments, the antibody has no binding affinity for a neoantigen alone. In some embodiments, the antibody has no binding affinity for a complex comprising atypical HLA-I and a non-related neoantigen.

In some embodiments, neoantigens are expressed by cells that are proficient in the antigen processing machinery (APM). In some embodiments, neoantigens are expressed by cells proficient in TAP1/2. In some embodiments, the neoantigen comprises, consists essentially of, or consists of a sequence according to SEQ ID NO: 18 (VMAPRTLFL).

In some embodiments, the atypical HLA-I is HLA-E, HLA-F, HLA-G or HLA-H. In some embodiments, the atypical HLA-I is HLA-E. In some embodiments, the HLA-E is HLA-E*0101. In some embodiments, the HLA-E is HLA-E*0103.

In some embodiments, the antibody selectively binds to a complex comprising HLA-E and a neoantigen. In some embodiments, the antibody selectively binds to a complex comprising HLA-E*0101 and a neoantigen. In some embodiments, the antibody selectively binds to a complex comprising HLA-E*0103 and a neoantigen. In some embodiments, the antibody selectively binds to a complex comprising HLA-E*0101 and a neoantigen, and binds to a complex comprising HLA-E*0103 and a neoantigen. In some embodiments, the complex comprises HLA-E and a neoantigen according to SEQ ID NO: 18 (VMAPRTLFL).

In some embodiments, the antibody comprises a light chain (LC) having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO: 19. In some embodiments, the LC has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity. In some embodiments, the LC has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 19.

In some embodiments, the antibody comprises a heavy chain (HC) having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO: 20. In some embodiments, the HC has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity. In some embodiments, the HC has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 20.

In some embodiments, the antibody comprises a light chain (LC) having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO: 19, and a heavy chain (HC) that Has an amino acid sequence that is at least about 70% identical to the amino acid sequence shown in SEQ ID NO: 20. In some embodiments, the LC has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequence, and HC has the same amino acid sequence as SEQ ID NO: The amino acid sequence shown in 20 is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92% %, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequences. In some embodiments, LC has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO: 19, and HC has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO: 20 amino acid sequence.

In some embodiments, the antibody comprises a heavy chain (HC) having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO: 21. In some embodiments, the HC has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity. In some embodiments, the HC has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 21.

In some embodiments, the antibody comprises a light chain (LC) having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO: 19, and a heavy chain (HC) that Has an amino acid sequence that is at least about 70% identical to the amino acid sequence shown in SEQ ID NO: 21. In some embodiments, the LC has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequence, and HC has the same amino acid sequence as SEQ ID NO: The amino acid sequence shown in 21 is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92% %, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequences. In some embodiments, LC has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO: 19, and HC has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO: 21 amino acid sequence.

In some embodiments, the antibody comprises a light chain having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO: 22. In some embodiments, the LC has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity. In some embodiments, the LC has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 22.

In some embodiments, the antibody comprises a heavy chain (HC) having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO: 23. In some embodiments, the HC has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity. In some embodiments, the HC has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 23.

In some embodiments, the antibody comprises a light chain (LC) having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO: 22, and a heavy chain (HC) that Has an amino acid sequence that is at least about 70% identical to the amino acid sequence shown in SEQ ID NO: 23. In some embodiments, the LC has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequence, and HC has the same amino acid sequence as SEQ ID NO: The amino acid sequence shown in 23 is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92% %, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequences. In some embodiments, the LC has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO: 22, and the HC has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO: 23 amino acid sequence.

In some embodiments, the antibody comprises a light chain variable domain (VL) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:7. In some embodiments, the VL has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity. In some embodiments, the VL has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 7.

In some embodiments, the antibody comprises a heavy chain variable domain (VH) having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:8. In some embodiments, the VH has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity. In some embodiments, the VH has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 8.

In some embodiments, the antibody comprises a light chain variable domain (VL) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO: 7 and a heavy chain variable domain (VH), the VH has an amino acid sequence that is at least about 70% identical to the amino acid sequence shown in SEQ ID NO: 8. In some embodiments, the VL has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequence, and the VH has the same amino acid sequence as SEQ ID NO: The amino acid sequence shown in 8 is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92% %, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequences. In some embodiments, VL has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO: 7, and VH has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO: 8 amino acid sequence.

In some embodiments, the antibody comprises a light chain CDR sequence having an amino acid sequence that is at least about 70% identical to at least one of the amino acid sequences set forth in SEQ ID NOs: 1-3. In some embodiments, the antibody comprises a light chain CDR sequence having at least about 75%, 80%, 81%, 82%, 83% of at least one of the amino acid sequences set forth in SEQ ID NO: 1-3 %, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% agree amino acid sequence. In some embodiments, the antibody comprises a light chain CDR sequence that has an amino acid sequence that is 100% identical to at least one of the amino acid sequences set forth in SEQ ID NO: 1-3.

In some embodiments, the antibody comprises a heavy chain CDR sequence having an amino acid sequence that is at least about 70% identical to at least one of the amino acid sequences set forth in SEQ ID NOs: 4-6. In some embodiments, the antibody comprises a heavy chain CDR sequence having at least about 75%, 80%, 81%, 82%, 83% of at least one of the amino acid sequences set forth in SEQ ID NO: 4-6 %, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% agree amino acid sequence. In some embodiments, the antibody comprises a heavy chain CDR sequence that has an amino acid sequence that is 100% identical to at least one of the amino acid sequences set forth in SEQ ID NOs: 4-6.

In some embodiments, the antibody comprises a light chain CDR sequence having an amino acid sequence at least about 70% identical to at least one of the amino acid sequences set forth in SEQ ID NO: 1-3, and a heavy chain CDR A sequence having an amino acid sequence that is at least about 70% identical to at least one of the amino acid sequences set forth in SEQ ID NO: 4-6. In some embodiments, the antibody comprises a light chain CDR sequence having at least about 75%, 80%, 81%, 82%, 83% of at least one of the amino acid sequences set forth in SEQ ID NO: 1-3 %, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% agree The amino acid sequence of the amino acid sequence, and the heavy chain CDR sequence, it has at least about 75%, 80%, 81%, 82%, 83% of at least one of the amino acid sequences shown in SEQ ID NO: 4-6 , 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% consistent amino acid sequence. In some embodiments, the antibody comprises a light chain CDR sequence having an amino acid sequence that is 100% identical to at least one of the amino acid sequences set forth in SEQ ID NO: 1-3, and a heavy chain CDR sequence, It has an amino acid sequence that is 100% identical to at least one of the amino acid sequences shown in SEQ ID NO: 4-6.

In some embodiments, the antibody comprises HLA-E and a neoantigen comprising at least one of: a light chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO: 1, A light chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO: 2, and an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO: 3 light chain CDR3. In some embodiments, the antibody comprises at least one of the following light chains: an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83% identical to the amino acid sequence set forth in SEQ ID NO: 1 , 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% consistent Light chain CDR1; the amino acid sequence is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical light chain CDR2; and amino acid sequence and SEQ ID NO : The amino acid sequence shown in 3 is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical light chain CDR3. In some embodiments, the antibody comprises at least one of the following: a light chain CDR1 whose amino acid sequence is 100% identical to the amino acid sequence shown in SEQ ID NO: 1, an amino acid sequence identical to that of SEQ ID NO: 2 The light chain CDR2 whose amino acid sequence is 100% identical as shown, and the light chain CDR3 whose amino acid sequence is 100% identical to the amino acid sequence shown in SEQ ID NO:3.

In some embodiments, the antibody comprises HLA-E and a neoantigen comprising at least one of: a heavy chain CDR1 having an amino acid sequence at least about 70% identical to that set forth in SEQ ID NO: 4, amino acids A heavy chain CDR2 whose sequence is at least about 70% identical to that set forth in SEQ ID NO:5, and a heavy chain CDR3 whose amino acid sequence is at least about 70% identical to that set forth in SEQ ID NO:6. In some embodiments, the antibody comprises at least one of the following: an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84% of the amino acid sequence set forth in SEQ ID NO: 4 %, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical heavy chain CDR1; the amino acid sequence is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88% of the amino acid sequence shown in SEQ ID NO: 5 , 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical heavy chain CDR2; amino acid sequence and SEQ ID NO: 6 The amino acid sequence shown is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical heavy chain CDR3. In some embodiments, the antibody comprises at least one of the following: a heavy chain CDR1 whose amino acid sequence is 100% identical to the amino acid sequence shown in SEQ ID NO: 4, an amino acid sequence identical to SEQ ID NO: 5 The heavy chain CDR2 whose amino acid sequence is 100% identical, and the heavy chain CDR3 whose amino acid sequence is 100% identical to the amino acid sequence shown in SEQ ID NO:6.

In some embodiments, the antibody comprises HLA-E and a neoantigen comprising at least one of: a light chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO: 1, A light chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO: 2, an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO: 3 The light chain CDR3, the amino acid sequence is at least about 70% identical to the amino acid sequence shown in SEQ ID NO: 4, the heavy chain CDR1, the amino acid sequence is at least about 70% identical to the amino acid sequence shown in SEQ ID NO: 5 A heavy chain CDR2 that is 70% identical, and a heavy chain CDR3 that has an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:6. In some embodiments, the antibody comprises at least one of the following: an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84% of the amino acid sequence set forth in SEQ ID NO: 1 %, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical light chains CDR1; the amino acid sequence is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88% of the amino acid sequence shown in SEQ ID NO: 2 , 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical light chain CDR2; amino acid sequence and SEQ ID NO: 3 The amino acid sequence shown is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the light chain CDR3; the amino acid sequence is at least about 75%, 80% identical to the amino acid sequence shown in SEQ ID NO: 4 , 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97 %, 98% or 99% identical heavy chain CDR1; the amino acid sequence is at least about 75%, 80%, 81%, 82%, 83%, 84%, or the amino acid sequence shown in SEQ ID NO: 5 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical heavy chain CDR2; and an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical heavy chain CDR3. In some embodiments, the antibody comprises at least one of the following: a light chain CDR1 whose amino acid sequence is 100% identical to the amino acid sequence shown in SEQ ID NO: 1, an amino acid sequence identical to that of SEQ ID NO: 2 The light chain CDR2 whose amino acid sequence is 100% consistent, the light chain CDR3 whose amino acid sequence is 100% consistent with the amino acid sequence shown in SEQ ID NO: 3, the amino acid sequence and SEQ ID NO: 4 The amino acid sequence shown is 100% identical to the heavy chain CDR1, the amino acid sequence is 100% identical to the amino acid sequence shown in SEQ ID NO: 5, and the heavy chain CDR2 and the amino acid sequence are 100% identical to SEQ ID NO: 6 The amino acid sequences shown are 100% identical to the heavy chain CDR3.

In some embodiments, the antibody is a bispecific antibody. In some embodiments, the bispecific antibody comprises (a) a light chain variable domain (VL), the VL comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth in SEQ ID NO: 7; or A heavy chain variable domain (VH), the VH comprising an amino acid sequence at least 70% identical to the amino acid sequence shown in SEQ ID NO: 8; and (b) a light chain variable domain (VL), the VL Comprising an amino acid sequence at least 70% identical to the amino acid sequence shown in SEQ ID NO: 15; or a heavy chain variable domain (VH), the VH comprising the amino acid sequence shown in SEQ ID NO: 16 At least 70% identical amino acid sequence.

In some embodiments, the bispecific antibody comprises (a) a light chain variable domain (VL) comprising at least 75%, 80%, 81%, 82% of the amino acid sequence set forth in SEQ ID NO: 7 %, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical amino acid sequence; or heavy chain variable domain (VH), the VH comprises at least 75%, 80%, 81%, 82%, 83% of the amino acid sequence shown in SEQ ID NO: 8 , 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% consistent Amino acid sequence; and (b) light chain variable domain (VL), the VL comprises at least 75%, 80%, 81%, 82%, 83%, and the amino acid sequence shown in SEQ ID NO: 15 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amines amino acid sequence; or heavy chain variable domain (VH), the VH comprises at least 75%, 80%, 81%, 82%, 83%, 84%, 85% of the amino acid sequence shown in SEQ ID NO: 16 %, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequences.

In some embodiments, the bispecific antibody comprises (a) a light chain variable domain (VL) comprising an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 7; or a heavy chain variable domain (VL) comprising: chain variable domain (VH), the VH comprising an amino acid sequence 100% identical to the amino acid sequence shown in SEQ ID NO: 8; and (b) a light chain variable domain (VL), the VL comprising an amino acid sequence identical to An amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 15; or a heavy chain variable domain (VH), the VH comprising 100% identical to the amino acid sequence shown in SEQ ID NO: 16 amino acid sequence.

In some embodiments, the bispecific antibody comprises (a) a light chain variable domain (VL), the VL comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth in SEQ ID NO: 7; and A heavy chain variable domain (VH), the VH comprising an amino acid sequence at least 70% identical to the amino acid sequence shown in SEQ ID NO: 8; and (b) a light chain variable domain (VL), the VL Comprising an amino acid sequence at least 70% identical to the amino acid sequence shown in SEQ ID NO: 15; and a heavy chain variable domain (VH), the VH comprising the amino acid sequence shown in SEQ ID NO: 16 At least 70% identical amino acid sequence.

In some embodiments, the bispecific antibody comprises (a) a light chain variable domain (VL) comprising at least 75%, 80%, 81%, 82% of the amino acid sequence set forth in SEQ ID NO: 7 %, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical amino acid sequence; and a heavy chain variable domain (VH), the VH comprising at least 75%, 80%, 81%, 82%, 83% of the amino acid sequence shown in SEQ ID NO: 8 , 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% consistent Amino acid sequence; and (b) light chain variable domain (VL), the VL comprises at least 75%, 80%, 81%, 82%, 83%, and the amino acid sequence shown in SEQ ID NO: 15 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amines amino acid sequence; and heavy chain variable domain (VH), the VH comprises at least 75%, 80%, 81%, 82%, 83%, 84%, 85% of the amino acid sequence shown in SEQ ID NO: 16 %, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequences.

In some embodiments, the bispecific antibody comprises (a) a light chain variable domain (VL), the VL comprising an amino acid sequence 100% identical to the amino acid sequence shown in SEQ ID NO: 7; and a heavy chain variable domain (VH), the VH comprising an amino acid sequence 100% identical to the amino acid sequence shown in SEQ ID NO: 8; and (b) a light chain variable domain (VL), the VL comprising an amino acid sequence identical to An amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 15; and a heavy chain variable domain (VH), the VH comprising 100% identical to the amino acid sequence shown in SEQ ID NO: 16 amino acid sequence.

In some embodiments, the bispecific antibody comprises: (a) a light chain (LC) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth in SEQ ID NO: 19; or a heavy chain (HC), the HC comprises an amino acid sequence at least 70% identical to the amino acid sequence shown in SEQ ID NO: 20; and (b) a light chain variable domain (VL), the VL comprising the same amino acid sequence as SEQ ID NO : an amino acid sequence that is at least 70% identical to the amino acid sequence shown in SEQ ID NO: 15; or a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 70% identical to the amino acid sequence shown in SEQ ID NO: 16 amino acid sequence.

In some embodiments, the bispecific antibody comprises (a) a light chain (LC) comprising at least 75%, 80%, 81%, 82%, 83% of the amino acid sequence set forth in SEQ ID NO: 19 %, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% agree or the heavy chain (HC), the HC comprises at least 75%, 80%, 81%, 82%, 83%, 84%, 85% of the amino acid sequence shown in SEQ ID NO: 20 , 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequences; and (b) light chain variable domain (VL), the VL comprises at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity; or Chain variable domain (VH), the VH comprises at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87% of the amino acid sequence shown in SEQ ID NO: 16 %, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequences.

In some embodiments, the bispecific antibody comprises: (a) a light chain (LC) comprising an amino acid sequence 100% identical to the amino acid sequence shown in SEQ ID NO: 19; or a heavy chain ( HC), the HC comprises an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 20; and (b) a light chain variable domain (VL), the VL comprising the same amino acid sequence as SEQ ID NO: 15 An amino acid sequence that is 100% identical to the amino acid sequence shown; or a heavy chain variable domain (VH) comprising an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 16 .

In some embodiments, the bispecific antibody comprises: (a) a light chain (LC) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth in SEQ ID NO: 19; or a heavy chain (HC), the HC comprises an amino acid sequence at least 70% identical to the amino acid sequence shown in SEQ ID NO: 21; and (b) a light chain variable domain (VL), the VL comprising the same amino acid sequence as SEQ ID NO : an amino acid sequence that is at least 70% identical to the amino acid sequence shown in SEQ ID NO: 15; or a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 70% identical to the amino acid sequence shown in SEQ ID NO: 16 amino acid sequence.

In some embodiments, the bispecific antibody comprises (a) a light chain (LC) comprising at least 75%, 80%, 81%, 82%, 83% of the amino acid sequence set forth in SEQ ID NO: 19 %, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% agree or the heavy chain (HC), the HC comprises at least 75%, 80%, 81%, 82%, 83%, 84%, 85% of the amino acid sequence shown in SEQ ID NO: 21 , 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequences; and (b) light chain variable domain (VL), the VL comprises at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity; or Chain variable domain (VH), the VH comprises at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87% of the amino acid sequence shown in SEQ ID NO: 16 %, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequences.

In some embodiments, the bispecific antibody comprises: (a) a light chain (LC) comprising an amino acid sequence 100% identical to the amino acid sequence shown in SEQ ID NO: 19; or a heavy chain ( HC), the HC comprises an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 21; and (b) a light chain variable domain (VL), the VL comprising the same amino acid sequence as SEQ ID NO: 15 An amino acid sequence that is 100% identical to the amino acid sequence shown; or a heavy chain variable domain (VH) comprising an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 16 .

In some embodiments, the bispecific antibody comprises: (a) a light chain (LC) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth in SEQ ID NO: 22; or a heavy chain (HC), the HC comprises an amino acid sequence at least 70% identical to the amino acid sequence shown in SEQ ID NO: 23; and (b) a light chain variable domain (VL), the VL comprising the same amino acid sequence as SEQ ID NO: : an amino acid sequence that is at least 70% identical to the amino acid sequence shown in SEQ ID NO: 15; or a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 70% identical to the amino acid sequence shown in SEQ ID NO: 16 amino acid sequence.

In some embodiments, the bispecific antibody comprises (a) a light chain (LC) comprising at least 75%, 80%, 81%, 82%, 83% of the amino acid sequence set forth in SEQ ID NO: 22 %, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% agree or the heavy chain (HC), the HC comprises at least 75%, 80%, 81%, 82%, 83%, 84%, 85% of the amino acid sequence shown in SEQ ID NO: 23 , 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequences; and (b) light chain variable domain (VL), the VL comprises at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity; or Chain variable domain (VH), the VH comprises at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87% of the amino acid sequence shown in SEQ ID NO: 16 %, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequences.

In some embodiments, the bispecific antibody comprises: (a) a light chain (LC) comprising an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 22; or a heavy chain ( HC), the HC comprises an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 23; and (b) a light chain variable domain (VL), the VL comprising the same amino acid sequence as SEQ ID NO: 15 An amino acid sequence that is 100% identical to the amino acid sequence shown; or a heavy chain variable domain (VH) comprising an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 16 .

In some embodiments, the bispecific antibody comprises: (a) a light chain complementarity determining region (CDR) having at least 70% the same amino acid sequence as at least one of SEQ ID NO: 1-3 a consensus amino acid sequence; or a heavy chain complementarity determining region (CDR) having an amino acid sequence that is at least 70% identical to at least one of the amino acid sequences set forth in SEQ ID NO: 4-6; and (b) a light chain complementarity determining region (CDR) having an amino acid sequence at least 70% identical to at least one of the amino acid sequences shown in SEQ ID NO: 9-11; or a heavy chain complementary A determining region (CDR) having an amino acid sequence that is at least 70% identical to at least one of the amino acid sequences shown in SEQ ID NO: 12-14.

In some embodiments, the bispecific antibody comprises (a) a light chain complementarity determining region (CDR) having at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96% , 97%, 98% or 99% identical amino acid sequence; or a heavy chain complementarity determining region (CDR), the CDR has at least one of the amino acid sequences shown in SEQ ID NO: 4-6 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95% , 96%, 97%, 98% or 99% identical amino acid sequence; and (b) light chain complementarity determining region (CDR), the CDR has the amino acid sequence shown in SEQ ID NO: 9-11 At least one of at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93% , 94%, 95%, 96%, 97%, 98% or 99% identical amino acid sequence; or heavy chain complementarity determining region (CDR), the CDR has the amine shown in SEQ ID NO: 12-14 At least one of the amino acid sequences is at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92% , 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequences.

In some embodiments, the bispecific antibody comprises (a) a light chain complementarity determining region (CDR) that is 100% identical to at least one of the amino acid sequences set forth in SEQ ID NO: 1-3 Amino acid sequence; or a heavy chain complementarity determining region (CDR), the CDR has an amino acid sequence that is 100% identical to at least one of the amino acid sequences shown in SEQ ID NO: 4-6; and (b ) a light chain complementarity determining region (CDR), which has an amino acid sequence that is 100% identical to at least one of the amino acid sequences shown in SEQ ID NO: 9-11; or a heavy chain complementarity determining region (CDR ), the CDR has an amino acid sequence that is 100% identical to at least one of the amino acid sequences shown in SEQ ID NO: 12-14.

In some embodiments, the bispecific antibody comprises (a) a light chain complementarity determining region (CDR) having at least 70% identity to at least one of the amino acid sequences set forth in SEQ ID NO: 1-3 and the heavy chain complementarity determining region (CDR), the CDR has an amino acid sequence that is at least 70% identical to at least one of the amino acid sequences shown in SEQ ID NO: 4-6; and (b) a light chain complementarity determining region (CDR) having an amino acid sequence at least 70% identical to at least one of the amino acid sequences shown in SEQ ID NO: 9-11; and a heavy chain complementarity determining region A region (CDR) having an amino acid sequence that is at least 70% identical to at least one of the amino acid sequences set forth in SEQ ID NO: 12-14.

In some embodiments, the bispecific antibody comprises (a) a light chain complementarity determining region (CDR) having at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96% , 97%, 98% or 99% identical amino acid sequence; and a heavy chain complementarity determining region (CDR), the CDR has at least one of the amino acid sequences shown in SEQ ID NO: 4-6 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95% , 96%, 97%, 98% or 99% identical amino acid sequence; and (b) light chain complementarity determining region (CDR), the CDR has the amino acid sequence shown in SEQ ID NO: 9-11 At least one of at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93% , 94%, 95%, 96%, 97%, 98% or 99% identical amino acid sequence; and heavy chain complementarity determining region (CDR), the CDR has the amine shown in SEQ ID NO: 12-14 At least one of the amino acid sequences is at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92% , 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequences.

In some embodiments, the bispecific antibody comprises (a) a light chain complementarity determining region (CDR) that is 100% identical to at least one of the amino acid sequences set forth in SEQ ID NO: 1-3 an amino acid sequence; and a heavy chain complementarity determining region (CDR) having an amino acid sequence that is 100% identical to at least one of the amino acid sequences shown in SEQ ID NO: 4-6; and (b ) a light chain complementarity determining region (CDR), which has an amino acid sequence that is 100% identical to at least one of the amino acid sequences shown in SEQ ID NO: 9-11; and a heavy chain complementarity determining region (CDR ), the CDR has an amino acid sequence that is 100% identical to at least one of the amino acid sequences shown in SEQ ID NO: 12-14.

In some embodiments, the antibody is a murine antibody. In some embodiments, the antibody is a chimeric antibody. In some embodiments, the antibody is a camelid antibody. In some embodiments, the antibody is a humanized antibody. In some embodiments, the antibodies are human antibodies.

In some embodiments, the antibody is a TCR-like antibody. In some embodiments, the antibody is a single domain antibody. In some embodiments, the single domain antibody is a camelid single domain antibody.

In some embodiments, the antibodies are multispecific antibodies. In some embodiments, the antibody is a bispecific antibody. In some embodiments, the antibody is a bispecific T cell engager (BiTE). In some embodiments, the BiTE binds to the CD3 protein associated with the T cell receptor (TCR). In some embodiments, the BiTE binds to the CD3ε protein associated with the T cell receptor (TCR). In some embodiments, the antibody is a multifunctional antibody.

In some embodiments, the antibody further comprises a binding therapeutic moiety. Therapeutic moieties include, but are not limited to, cytotoxins, chemotherapeutic drugs, immunosuppressants, and radioisotopes. A cytotoxin or cytotoxic agent includes any agent that is detrimental to (eg, kills) a cell. Examples include, but are not limited to, paclitaxel, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide ), tenoposide, vincristine, vinbiastine, coichicin, doxorubicin, daunorubicin, dihydroxyanthraxin Dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine , tetracaine, lidocaine, propranolol, puromycin and their analogs or homologues. Suitable chemotherapeutic agents include, but are not limited to, antimetabolites (e.g. methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, fludarabine, 5-fluorouracil, dacarbazine (decarbazine, hydroxyurea, azathioprine, gemcitabine, and cladribin), alkylating agents (eg, nitrogen mustard, thiotepa, chlorambucil, melphalan, Carmustine (BSNU) and lomustine (CCNU), cyclophosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, and cis-di Platinum(II) chloride (DDP) cisplatin), anthracyclines (such as daunorubicin (protodaunorubicin) and cranberry), antibiotics (such as dactinomycin (proactinomycin), Bleomycin, mithramycin, and ankomycin (AMC)) and antimitotic agents (eg, vincristine, vinblastine, docetaxel, paclitaxel and vinorelbin). Suitable radioisotopes include, but are not limited to, iodine-131, yttrium-90, or indium-111. Other examples of therapeutic moieties are proteins or polypeptides having the desired biological activity. Such proteins may include, for example, enzymatically active toxins or active fragments thereof, such as abrin, ricin A, Pseudomonas exotoxin, or diphtheria toxin; proteins, such as tumor necrosis factor or interferon-gamma; or biological Response modifiers such as lymphoid mediators, interleukin-1 (IL-1), interleukin-2 (IL-2), interleukin-6 (IL-6), granulocyte macrophage colony stimulating factor ( GM-CSF), granule colony stimulating factor (G-CSF) or other growth factors.

In some embodiments, selective binding of antibodies to complexes comprising atypical HLA-I (eg, HLA-E) and neoantigens induces an immune response. In some embodiments, the immune response comprises activation of NK cells. In some embodiments, selective binding of the antibody to a TCR-associated CD3 protein induces an immune response. In some embodiments, the immune response comprises activation of T cells. In some embodiments, the T cells are CD8+ T cells. In some embodiments, the immune response comprises activation of cytotoxic T cells (CTL).

In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is kidney cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is choriocarcinoma. In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is cervical cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is myeloma. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is acute myeloid leukemia (AML). In some embodiments, the cancer is multiple myeloma. In some embodiments, the cancer is myelodysplastic syndrome. In some embodiments, the cancer is a B cell malignancy. In some embodiments, the cancer is mantle cell lymphoma.

In some embodiments, the cancer cells differentially express neoantigens. In some embodiments, the cancer cells differentially express HLA-E. In some embodiments, the cancer cells differentially express complexes comprising HLA-E and neoantigens.

Any suitable route of administration is contemplated for use with the methods disclosed herein. In some embodiments, the antibody is administered by intravenous administration. In some embodiments, the antibody is administered by subcutaneous administration. In some embodiments, the antibody is administered locally. In some embodiments, the antibody is administered systemically (eg, intravenously, intramuscularly, subcutaneously, intradermally, orally, intranasally, sublingually). In some embodiments, antibodies are formulated as ointments, lotions, or emulsions. In some embodiments, antibodies are formulated as solutions. In some embodiments, antibodies are formulated for topical, oral, buccal, or nasal administration.

In some embodiments, the individual is monitored prior to administration of the antibody. Identify symptoms and assess their severity. Antibodies as described herein are administered alone or in combination with additional therapies, single or multiple administrations over time, as discussed herein or known to those skilled in the art. In some embodiments, individuals are monitored to determine the efficacy of treatment regimens. In some embodiments, the treatment regimen is modified in response to preliminary treatment results such that the dose or frequency of treatment, or both, is altered to achieve a desired level of individual response based on symptom relief, side effect relief, or a combination of symptom relief and side effect relief . pharmaceutical composition

Also disclosed herein are pharmaceutical compositions comprising (a) antibodies that selectively bind to complexes comprising atypical HLA-I (eg, HLA-E) and neoantigens as disclosed herein, and (b) pharmaceutically acceptable acceptable carrier or excipient.

In some embodiments, the antibody comprises a light chain (LC) having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO: 19. In some embodiments, the LC has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity. In some embodiments, the LC has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 19.

In some embodiments, the antibody comprises a heavy chain (HC) having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO: 20. In some embodiments, the HC has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity. In some embodiments, the HC has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 20.

In some embodiments, the antibody comprises a light chain (LC) having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO: 19, and a heavy chain (HC) that Has an amino acid sequence that is at least about 70% identical to the amino acid sequence shown in SEQ ID NO: 20. In some embodiments, the LC has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequence, and HC has the same amino acid sequence as SEQ ID NO: The amino acid sequence shown in 20 is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92% %, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequences. In some embodiments, LC has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO: 19, and HC has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO: 20 amino acid sequence.

In some embodiments, the antibody comprises a heavy chain (HC) having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO: 21. In some embodiments, the HC has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity. In some embodiments, the HC has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 21.

In some embodiments, the antibody comprises a light chain (LC) having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO: 19, and a heavy chain (HC) that Has an amino acid sequence that is at least about 70% identical to the amino acid sequence shown in SEQ ID NO: 21. In some embodiments, the LC has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequence, and HC has the same amino acid sequence as SEQ ID NO: The amino acid sequence shown in 21 is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92% %, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequences. In some embodiments, LC has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO: 19, and HC has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO: 21 amino acid sequence.

In some embodiments, the antibody comprises a light chain having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO: 22. In some embodiments, the LC has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity. In some embodiments, the LC has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 22.

In some embodiments, the antibody comprises a heavy chain (HC) having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO: 23. In some embodiments, the HC has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity. In some embodiments, the HC has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 23.

In some embodiments, the antibody comprises a light chain (LC) having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO: 22, and a heavy chain (HC) that Has an amino acid sequence that is at least about 70% identical to the amino acid sequence shown in SEQ ID NO: 23. In some embodiments, the LC has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequence, and HC has the same amino acid sequence as SEQ ID NO: The amino acid sequence shown in 23 is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92% %, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequences. In some embodiments, LC has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO: 22, and HC has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO: 23 amino acid sequence.

In some embodiments, the antibody comprises a light chain variable domain (VL) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:7. In some embodiments, the VL has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity. In some embodiments, the VL has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 7.

In some embodiments, the antibody comprises a heavy chain variable domain (VH) having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:8. In some embodiments, the VH has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity. In some embodiments, the VH has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 8.

In some embodiments, the antibody comprises a light chain variable domain (VL) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO: 7, and a heavy chain variable domain (VL). A domain (VH) having an amino acid sequence at least about 70% identical to the amino acid sequence shown in SEQ ID NO: 8. In some embodiments, the VL has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequence, and the VH has the same amino acid sequence as SEQ ID NO: The amino acid sequence shown in 8 is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92% %, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequences. In some embodiments, VL has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO: 7, and VH has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO: 8 amino acid sequence.

In some embodiments, the antibody comprises a light chain CDR sequence having an amino acid sequence that is at least about 70% identical to at least one of the amino acid sequences set forth in SEQ ID NOs: 1-3. In some embodiments, the antibody comprises a light chain CDR sequence having at least about 75%, 80%, 81%, 82%, 83% of at least one of the amino acid sequences set forth in SEQ ID NO: 1-3 %, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% agree amino acid sequence. In some embodiments, the antibody comprises a light chain CDR sequence that has an amino acid sequence that is 100% identical to at least one of the amino acid sequences set forth in SEQ ID NO: 1-3.

In some embodiments, the antibody comprises a heavy chain CDR sequence having an amino acid sequence that is at least about 70% identical to at least one of the amino acid sequences set forth in SEQ ID NOs: 4-6. In some embodiments, the antibody comprises a heavy chain CDR sequence having at least about 75%, 80%, 81%, 82%, 83% of at least one of the amino acid sequences set forth in SEQ ID NO: 4-6 %, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% agree amino acid sequence. In some embodiments, the antibody comprises a heavy chain CDR sequence that has an amino acid sequence that is 100% identical to at least one of the amino acid sequences set forth in SEQ ID NOs: 4-6.

In some embodiments, the antibody comprises a light chain CDR sequence having an amino acid sequence at least about 70% identical to at least one of the amino acid sequences set forth in SEQ ID NO: 1-3, and a heavy chain CDR A sequence having an amino acid sequence that is at least about 70% identical to at least one of the amino acid sequences set forth in SEQ ID NO: 4-6. In some embodiments, the antibody comprises a light chain CDR sequence having at least about 75%, 80%, 81%, 82%, 83% of at least one of the amino acid sequences set forth in SEQ ID NO: 1-3 %, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% agree The amino acid sequence of the amino acid sequence, and the heavy chain CDR sequence, it has at least one of the amino acid sequences shown in SEQ ID NO: 4-6 about 75%, 80%, 81%, 82%, 83% , 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% consistent amino acid sequence. In some embodiments, the antibody comprises a light chain CDR sequence having an amino acid sequence that is 100% identical to at least one of the amino acid sequences set forth in SEQ ID NO: 1-3, and a heavy chain CDR sequence, It has an amino acid sequence that is 100% identical to at least one of the amino acid sequences shown in SEQ ID NO: 4-6.

In some embodiments, the antibody comprises HLA-E and a neoantigen comprising at least one of: a light chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO: 1, A light chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO: 2 and an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO: 3 Light chain CDR3. In some embodiments, the antibody comprises at least one of the following light chains: an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83% identical to the amino acid sequence set forth in SEQ ID NO: 1 , 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% consistent Light chain CDR1; the amino acid sequence is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical light chain CDR2; and amino acid sequence and SEQ ID NO : The amino acid sequence shown in 3 is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical light chain CDR3. In some embodiments, the antibody comprises at least one of the following: a light chain CDR1 whose amino acid sequence is 100% identical to the amino acid sequence shown in SEQ ID NO: 1, an amino acid sequence identical to that of SEQ ID NO: 2 The light chain CDR2 whose amino acid sequence is 100% identical as shown, and the light chain CDR3 whose amino acid sequence is 100% identical to the amino acid sequence shown in SEQ ID NO:3.

In some embodiments, the antibody comprises HLA-E and a neoantigen comprising at least one of: a heavy chain CDR1 having an amino acid sequence at least about 70% identical to that set forth in SEQ ID NO: 4, amino acids A heavy chain CDR2 whose sequence is at least about 70% identical to that set forth in SEQ ID NO:5, and a heavy chain CDR3 whose amino acid sequence is at least about 70% identical to that set forth in SEQ ID NO:6. In some embodiments, the antibody comprises at least one of the following: an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84% of the amino acid sequence set forth in SEQ ID NO: 4 %, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical heavy chain CDR1; the amino acid sequence is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88% of the amino acid sequence shown in SEQ ID NO: 5 , 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical heavy chain CDR2; amino acid sequence and SEQ ID NO: 6 The amino acid sequence shown is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical heavy chain CDR3. In some embodiments, the antibody comprises at least one of the following: a heavy chain CDR1 whose amino acid sequence is 100% identical to the amino acid sequence shown in SEQ ID NO: 4, an amino acid sequence identical to that of SEQ ID NO: 5 The heavy chain CDR2 whose amino acid sequence is 100% identical, and the heavy chain CDR3 whose amino acid sequence is 100% identical to the amino acid sequence shown in SEQ ID NO:6.

In some embodiments, the antibody comprises HLA-E and a neoantigen comprising at least one of: a light chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO: 1, A light chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO: 2, an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO: 3 The light chain CDR3, the amino acid sequence is at least about 70% identical to the amino acid sequence shown in SEQ ID NO: 4, the heavy chain CDR1, the amino acid sequence is at least about 70% identical to the amino acid sequence shown in SEQ ID NO: 5 A heavy chain CDR2 that is 70% identical, and a heavy chain CDR3 that has an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:6. In some embodiments, the antibody comprises at least one of the following: an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84% of the amino acid sequence set forth in SEQ ID NO: 1 %, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical light chains CDR1; the amino acid sequence is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88% of the amino acid sequence shown in SEQ ID NO: 2 , 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical light chain CDR2; amino acid sequence and SEQ ID NO: 3 The amino acid sequence shown is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the light chain CDR3; the amino acid sequence is at least about 75%, 80% identical to the amino acid sequence shown in SEQ ID NO: 4 , 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97 %, 98% or 99% identical heavy chain CDR1; the amino acid sequence is at least about 75%, 80%, 81%, 82%, 83%, 84%, or the amino acid sequence shown in SEQ ID NO: 5 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical heavy chain CDR2; and an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical heavy chain CDR3. In some embodiments, the antibody comprises at least one of the following: a light chain CDR1 whose amino acid sequence is 100% identical to the amino acid sequence shown in SEQ ID NO: 1, an amino acid sequence identical to that of SEQ ID NO: 2 The light chain CDR2 whose amino acid sequence is 100% consistent, the light chain CDR3 whose amino acid sequence is 100% consistent with the amino acid sequence shown in SEQ ID NO: 3, the amino acid sequence and SEQ ID NO: 4 The amino acid sequence shown is 100% identical to the heavy chain CDR1, the amino acid sequence is 100% identical to the amino acid sequence shown in SEQ ID NO: 5, and the heavy chain CDR2 and the amino acid sequence are 100% identical to SEQ ID NO: 6 The amino acid sequences shown are 100% identical to the heavy chain CDR3.

In some embodiments, the antibody is a bispecific antibody. In some embodiments, the bispecific antibody comprises (a) a light chain variable domain (VL), the VL comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth in SEQ ID NO: 7; or A heavy chain variable domain (VH), the VH comprising an amino acid sequence at least 70% identical to the amino acid sequence shown in SEQ ID NO: 8; and (b) a light chain variable domain (VL), the VL Comprising an amino acid sequence at least 70% identical to the amino acid sequence shown in SEQ ID NO: 15; or a heavy chain variable domain (VH), the VH comprising the amino acid sequence shown in SEQ ID NO: 16 At least 70% identical amino acid sequence.

In some embodiments, the bispecific antibody comprises (a) a light chain variable domain (VL) comprising at least 75%, 80%, 81%, 82% of the amino acid sequence set forth in SEQ ID NO: 7 %, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical amino acid sequence; or heavy chain variable domain (VH), the VH comprises at least 75%, 80%, 81%, 82%, 83% of the amino acid sequence shown in SEQ ID NO: 8 , 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% consistent Amino acid sequence; and (b) light chain variable domain (VL), the VL comprises at least 75%, 80%, 81%, 82%, 83%, and the amino acid sequence shown in SEQ ID NO: 15 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amines amino acid sequence; or heavy chain variable domain (VH), the VH comprises at least 75%, 80%, 81%, 82%, 83%, 84%, 85% of the amino acid sequence shown in SEQ ID NO: 16 %, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequences.

In some embodiments, the bispecific antibody comprises (a) a light chain variable domain (VL), the VL comprising an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 7; or a heavy chain variable domain (VH), the VH comprising an amino acid sequence 100% identical to the amino acid sequence shown in SEQ ID NO: 8; and (b) a light chain variable domain (VL), the VL comprising an amino acid sequence identical to An amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 15; or a heavy chain variable domain (VH), the VH comprising 100% identical to the amino acid sequence shown in SEQ ID NO: 16 amino acid sequence.

In some embodiments, the bispecific antibody comprises (a) a light chain variable domain (VL), the VL comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth in SEQ ID NO: 7; and A heavy chain variable domain (VH), the VH comprising an amino acid sequence at least 70% identical to the amino acid sequence shown in SEQ ID NO: 8; and (b) a light chain variable domain (VL), the VL Comprising an amino acid sequence at least 70% identical to the amino acid sequence shown in SEQ ID NO: 15; and a heavy chain variable domain (VH), the VH comprising the amino acid sequence shown in SEQ ID NO: 16 At least 70% identical amino acid sequence.

In some embodiments, the bispecific antibody comprises (a) a light chain variable domain (VL) comprising at least 75%, 80%, 81%, 82% of the amino acid sequence set forth in SEQ ID NO: 7 %, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical amino acid sequence; and a heavy chain variable domain (VH), the VH comprising at least 75%, 80%, 81%, 82%, 83% of the amino acid sequence shown in SEQ ID NO: 8 , 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% consistent Amino acid sequence; and (b) light chain variable domain (VL), the VL comprises at least 75%, 80%, 81%, 82%, 83%, and the amino acid sequence shown in SEQ ID NO: 15 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amines amino acid sequence; and heavy chain variable domain (VH), the VH comprises at least 75%, 80%, 81%, 82%, 83%, 84%, 85% of the amino acid sequence shown in SEQ ID NO: 16 %, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequences.

In some embodiments, the bispecific antibody comprises (a) a light chain variable domain (VL), the VL comprising an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 7; and a heavy chain variable domain (VH), the VH comprising an amino acid sequence 100% identical to the amino acid sequence shown in SEQ ID NO: 8; and (b) a light chain variable domain (VL), the VL comprising an amino acid sequence identical to An amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 15; and a heavy chain variable domain (VH), the VH comprising 100% identical to the amino acid sequence shown in SEQ ID NO: 16 amino acid sequence.

In some embodiments, the bispecific antibody comprises: (a) a light chain (LC) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth in SEQ ID NO: 19; or a heavy chain (HC), the HC comprises an amino acid sequence at least 70% identical to the amino acid sequence shown in SEQ ID NO: 20; and (b) a light chain variable domain (VL), the VL comprising the same amino acid sequence as SEQ ID NO: : an amino acid sequence that is at least 70% identical to the amino acid sequence shown in SEQ ID NO: 15; or a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 70% identical to the amino acid sequence shown in SEQ ID NO: 16 amino acid sequence.

In some embodiments, the bispecific antibody comprises (a) a light chain (LC) comprising at least 75%, 80%, 81%, 82%, 83% of the amino acid sequence set forth in SEQ ID NO: 19 %, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% agree or the heavy chain (HC), the HC comprises at least 75%, 80%, 81%, 82%, 83%, 84%, 85% of the amino acid sequence shown in SEQ ID NO: 20 , 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequences; and (b) light chain variable domain (VL), the VL comprises at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity; or Chain variable domain (VH), the VH comprises at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87% of the amino acid sequence shown in SEQ ID NO: 16 %, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequences.

In some embodiments, the bispecific antibody comprises: (a) a light chain (LC) comprising an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 19; or a heavy chain ( HC), the HC comprises an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 20; and (b) a light chain variable domain (VL), the VL comprising the same amino acid sequence as SEQ ID NO: 15 An amino acid sequence that is 100% identical to the amino acid sequence shown; or a heavy chain variable domain (VH) comprising an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 16 .

In some embodiments, the bispecific antibody comprises: (a) a light chain (LC) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth in SEQ ID NO: 19; or a heavy chain (HC), the HC comprises an amino acid sequence at least 70% identical to the amino acid sequence shown in SEQ ID NO: 21; and (b) a light chain variable domain (VL), the VL comprising the same amino acid sequence as SEQ ID NO : an amino acid sequence that is at least 70% identical to the amino acid sequence shown in SEQ ID NO: 15; or a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 70% identical to the amino acid sequence shown in SEQ ID NO: 16 amino acid sequence.

In some embodiments, the bispecific antibody comprises (a) a light chain (LC) comprising at least 75%, 80%, 81%, 82%, 83% of the amino acid sequence set forth in SEQ ID NO: 19 %, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% agree or the heavy chain (HC), the HC comprises at least 75%, 80%, 81%, 82%, 83%, 84%, 85% of the amino acid sequence shown in SEQ ID NO: 21 , 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequences; and (b) light chain variable domain (VL), the VL comprises at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity; or Chain variable domain (VH), the VH comprises at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87% of the amino acid sequence shown in SEQ ID NO: 16 %, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequences.

In some embodiments, the bispecific antibody comprises: (a) a light chain (LC) comprising an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 19; or a heavy chain ( HC), the HC comprises an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 21; and (b) a light chain variable domain (VL), the VL comprising the same amino acid sequence as SEQ ID NO: 15 An amino acid sequence that is 100% identical to the amino acid sequence shown; or a heavy chain variable domain (VH) comprising an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 16 .

In some embodiments, the bispecific antibody comprises: (a) a light chain (LC) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth in SEQ ID NO: 22; or a heavy chain (HC), the HC comprises an amino acid sequence at least 70% identical to the amino acid sequence shown in SEQ ID NO: 23; and (b) a light chain variable domain (VL), the VL comprising the same amino acid sequence as SEQ ID NO : an amino acid sequence that is at least 70% identical to the amino acid sequence shown in SEQ ID NO: 15; or a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 70% identical to the amino acid sequence shown in SEQ ID NO: 16 amino acid sequence.

In some embodiments, the bispecific antibody comprises (a) a light chain (LC) comprising at least 75%, 80%, 81%, 82%, 83% of the amino acid sequence set forth in SEQ ID NO: 22 %, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% agree or the heavy chain (HC), the HC comprises at least 75%, 80%, 81%, 82%, 83%, 84%, 85% of the amino acid sequence shown in SEQ ID NO: 23 , 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequences; and (b) light chain variable domain (VL), the VL comprises at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity; or Chain variable domain (VH), the VH comprises at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87% of the amino acid sequence shown in SEQ ID NO: 16 %, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical amino acid sequences.

In some embodiments, the bispecific antibody comprises (a) a light chain (LC) comprising an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 22; or a heavy chain (HC ), the HC comprises an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 23; and (b) a light chain variable domain (VL), the VL comprising the same as SEQ ID NO: 15 An amino acid sequence that is 100% identical to the amino acid sequence shown; or a heavy chain variable domain (VH), the VH comprising an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 16.

In some embodiments, the bispecific antibody comprises (a) a light chain complementarity determining region (CDR) having at least 70% identity to at least one of the amino acid sequences set forth in SEQ ID NO: 1-3 or a heavy chain complementarity determining region (CDR), which has an amino acid sequence that is at least 70% identical to at least one of the amino acid sequences shown in SEQ ID NO: 4-6; and (b) a light chain complementarity determining region (CDR) having an amino acid sequence at least 70% identical to at least one of the amino acid sequences shown in SEQ ID NO: 9-11; or a heavy chain complementarity determining region A region (CDR) having an amino acid sequence that is at least 70% identical to at least one of the amino acid sequences set forth in SEQ ID NO: 12-14.

In some embodiments, the bispecific antibody comprises (a) a light chain complementarity determining region (CDR) having at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96% , 97%, 98% or 99% identical amino acid sequence; or the heavy chain complementarity determining region (CDR), the CDR has at least 75%, 80% of the amino acid sequence shown in SEQ ID NO: 4-6 , 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97 %, 98% or 99% identical amino acid sequence; and (b) light chain complementarity determining region (CDR), the CDR has at least one of the amino acid sequences shown in SEQ ID NO: 9-11 At least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95% %, 96%, 97%, 98% or 99% identical amino acid sequence; or heavy chain complementarity determining region (CDR), the CDR has one of the amino acid sequences shown in SEQ ID NO: 12-14 At least one of at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94 %, 95%, 96%, 97%, 98% or 99% identical amino acid sequences.

In some embodiments, the bispecific antibody comprises (a) a light chain complementarity determining region (CDR) that is 100% identical to at least one of the amino acid sequences set forth in SEQ ID NO: 1-3 Amino acid sequence; or a heavy chain complementarity determining region (CDR), the CDR has an amino acid sequence that is 100% identical to at least one of the amino acid sequences shown in SEQ ID NO: 4-6; and (b ) a light chain complementarity determining region (CDR), which has an amino acid sequence that is 100% identical to at least one of the amino acid sequences shown in SEQ ID NO: 9-11; or a heavy chain complementarity determining region (CDR ), the CDR has an amino acid sequence that is 100% identical to at least one of the amino acid sequences shown in SEQ ID NO: 12-14.

In some embodiments, the antibody comprises (a) a light chain complementarity determining region (CDR) having an amine group that is at least 70% identical to at least one of the amino acid sequences set forth in SEQ ID NO: 1-3 an acid sequence; and a heavy chain complementarity determining region (CDR), the CDR has an amino acid sequence that is at least 70% identical to at least one of the amino acid sequences shown in SEQ ID NO: 4-6; and (b) a light chain complementarity determining region (CDR) having an amino acid sequence at least 70% identical to at least one of the amino acid sequences shown in SEQ ID NO: 9-11; and a heavy chain complementarity determining region (CDR ), the CDR has an amino acid sequence that is at least 70% identical to at least one of the amino acid sequences shown in SEQ ID NO: 12-14.

In some embodiments, the bispecific antibody comprises (a) a light chain complementarity determining region (CDR) having at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96% , 97%, 98% or 99% identical amino acid sequence; and heavy chain complementarity determining region (CDR), the CDR has at least 75%, 80% of the amino acid sequence shown in SEQ ID NO: 4-6 , 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97 %, 98% or 99% identical amino acid sequence; and (b) light chain complementarity determining region (CDR), the CDR has at least one of the amino acid sequences shown in SEQ ID NO: 9-11 At least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95% %, 96%, 97%, 98% or 99% identical amino acid sequence; and a heavy chain complementarity determining region (CDR), the CDR has one of the amino acid sequences shown in SEQ ID NO: 12-14 At least one of at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94 %, 95%, 96%, 97%, 98% or 99% identical amino acid sequences.

In some embodiments, the bispecific antibody comprises (a) a light chain complementarity determining region (CDR) that is 100% identical to at least one of the amino acid sequences set forth in SEQ ID NO: 1-3 an amino acid sequence; and a heavy chain complementarity determining region (CDR) having an amino acid sequence that is 100% identical to at least one of the amino acid sequences shown in SEQ ID NO: 4-6; and (b ) a light chain complementarity determining region (CDR), which has an amino acid sequence that is 100% identical to at least one of the amino acid sequences shown in SEQ ID NO: 9-11; and a heavy chain complementarity determining region (CDR ), the CDR has an amino acid sequence that is 100% identical to at least one of the amino acid sequences shown in SEQ ID NO: 12-14.

In some embodiments, excipients used with the compositions disclosed herein include maleic acid, tartaric acid, lactic acid, citric acid, acetic acid, sodium bicarbonate, sodium phosphate, histidine, glycine, chloride Sodium Chloride, Potassium Chloride, Calcium Chloride, Zinc Chloride, Water, Dextrose, N-Methylpyrrolidone, Dimethylsulfone, N,N-Dimethylacetamide, Ethanol, Propylene Glycol, Polymer Ethylene glycol, diethylene glycol monoethyl ether and surfactant polyoxyethylene-sorbitan monooleate.

In some embodiments, the compositions further comprise additional therapeutic agents. In some embodiments, the therapeutic agent is a chemotherapeutic agent. Chemotherapeutic agents may include, inter alia, cytotoxic agents, antimetabolites (e.g. folic acid antagonists, purine analogs, pyrimidine analogs, etc.), topoisomerase inhibitors (e.g. camptothecin derivatives, anthraquinones, anthracyclines, mycin, epipodophyllotoxin, quinoline alkaloids, etc.), antimicrotubule agents (such as taxanes, vinca alkaloids), protein synthesis inhibitors (such as harringtonine, camptothecin derivatives, quinoline Alkaloids), alkylating agents (such as alkylsulfonates, ethyleneimines, nitrogen mustards, nitrosoureas, platinum derivatives, triazenes, etc.), alkaloids, terpenoids and kinase inhibitors.

In some embodiments, the antibody and therapeutic agent are in the same formulation. In some embodiments, the antibody and therapeutic agent are in different formulations. In some embodiments, the antibodies described herein are used prior to administration of other therapeutic agents. In some embodiments, the antibodies described herein are used concurrently with the administration of other therapeutic agents. In some embodiments, an antibody described herein is used after administration of another therapeutic agent.

A pharmaceutical formulation is made compatible with a particular route of local, regional or systemic administration or delivery. Accordingly, pharmaceutical formulations include carriers, diluents or excipients suitable for administration by a particular route. Specific non-limiting examples of routes of administration of the compositions herein are parenteral, e.g., intravenous, intraarterial, intradermal, intramuscular, subcutaneous, intrapleural, transdermal (topical), transmucosal, intracranial, spinal Intraocular, intraocular, rectal, oral (digestive), mucosal administration, and any other formulation suitable for a method of treatment or administration regimen.

Solutions or suspensions for parenteral administration include: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycol, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or paraben methyl hydroxybenzoate; antioxidants, such as ascorbic acid or sodium bisulfate; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetate, citrate, or phosphate; and tonicity modifiers, such as sodium chloride or Dextrose. In some embodiments, the pH is adjusted with acids or bases such as hydrochloric acid or sodium hydroxide.

Pharmaceutical formulations for injection include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In some embodiments, the carrier is a solvent or dispersion medium containing, for example, water, ethanol, polyol (eg, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), or a suitable mixture thereof. In some embodiments, fluidity is maintained, for example, by using a coating such as lecithin, by maintaining the desired particle size in the case of dispersions, and by using surfactants. Antibacterial and antifungal agents include, for example, parabens, chlorobutanol, phenol, ascorbic acid, and thimerosal. Isotonic agents, such as sugars; polyols, such as mannitol or sorbitol; or in some embodiments, sodium chloride are included in the composition. Agents which delay the absorption of the injectable compositions, for example, aluminum monostearate or gelatin, which prolong the absorption of the injectable compositions, are also included in some instances.

Sterile injectable formulations are prepared by incorporating the active composition in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above. Generally, dispersions are prepared by incorporating the active composition into a sterile vehicle that contains the basic dispersion medium and any other ingredients. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation include, for example, vacuum drying and freeze-drying, which yield a powder of the active ingredient plus any additional desired ingredient from a previously prepared solution thereof.

For transmucosal or transdermal administration, penetrants appropriate to the barrier to penetration are used in the formulation. Such penetrants are known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. In some embodiments, transmucosal administration is via the use of nasal sprays, inhalation devices (eg, inhalers), or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, creams or patches.

In some embodiments, pharmaceutical formulations are prepared with carriers that will protect against rapid elimination from the body, such as a controlled release formulation or a time delay material, such as glyceryl monostearate or glyceryl stearate. In some embodiments, the formulations are also delivered using articles such as implants and microencapsulated delivery systems for local, regional or systemic delivery or controlled or sustained release. example

The following examples are given for the purpose of illustrating various embodiments of the invention and are not intended to limit the invention in any way. The inventive examples and methods described herein are representative of presently preferred embodiments, are illustrative and are not intended as limitations on the scope of the invention. Variations therein and other uses, as defined by the scope of the claims, will occur to those skilled in the art to be encompassed within the spirit of the invention. Example 1. Production of Antibodies

R4 clone 1 (R4c1) was first isolated from a semisynthetic human antibody phage library. Briefly, this is done as follows. The human scFv antibody phage display library (1.42×10 ⁹ clones) (HuScL2 phage library) constructed by Creative Biolabs was used to screen the HLA-G signal peptide/HLA-E*0103 complex (ABI-V-0025; VMAPRTLFL). Briefly, five internal peptide/HLA-A2*0201 complexes (ABI-AV-007-Biot, ABI-AV-0010-Biot, ABI-AV-0014-Biot, ABI-AV-0019 and ABI-AB -0030-Biot) for depletion and pre-blocking, followed by enrichment with 50 µg of ABI-V-0025. The enrichment factor of the phage library was 2.73×10 ⁶ (phage input: 5×10 ¹¹ , phage output: 1.83×10 ⁵ ). This process was repeated for the ^second round of biopanning with an enrichment factor of 4.03 x 102. The third round of biopanning was repeated, but depleted using 20 µg of the complex mixture (enrichment factor 2.31 x ¹⁰² ). For the fourth round of biopanning, 50 µg ABI-V-0018 was used for depletion and pre-blocking, followed by 50 µg ABI-V-0025 for enrichment (enrichment factor 44). From the phage output of the fourth round of biopanning, 40 clones were selected and sequenced, revealing a unique sequence. This clonal line is called R4 clonal line 1 (R4c1) ( Fig. 1A - Fig. 1B ). To determine the affinity of the R4c1 antibody, it was diluted in 0.1% BSA, 0.1% Tween20 PBS dilution/wash buffer and immobilized at 20 μg/ml on a ForteBio Octet protein A biosensor tip for 50 seconds. Tips were then washed for 50 seconds in dilution/wash buffer. Antibody binding association was measured over a 150 second time course using six concentrations of typical 0025-E 01:03 monomer complexes (serial dilutions starting at 100 μg/ml in dilution/wash buffer), followed by Dissociate (dilution/wash buffer) for 150 sec ( Figure 1C ). The equilibrium dissociation constant (KD) of clonal R4 (clonal 1) was determined to be 411 nM ( Figure 1D ).

Affinity Maturation of R4c1 : Cycle 2 : To increase the binding affinity of cloned R4c1 to V-0025, R4c1 scFv constructs were selected into yeast vectors to generate a library of R4c1 mutants by changing two amino acids in the CDRH3 region. Briefly, yeast display libraries generated used EBY100 yeast competent cells prepared by incubation in 100 mM lithium acetate (LiAc, Sigma) plus 10 mM dithiothreitol (DTT, Sigma) in transformation. Yeast/2 mm colorimetric tubes (BioRad) were prepared using a GenePulser (BioRad) at 60 OD in 10 mM LiAc for electroporation with 1 scFv clone and 100 ng pYES3 (ThermoFisher) altered to include Aga2 after the GAL1 promoter and The scFv is followed by a Flag (DYKDDDDK) epitope tag. To determine the number of transformants, 100 µL of 1/10, 1/100, and 1/1000 dilutions of transformed yeast were spread on glucose plates and subtracted for tryptophan and uracil (D-UT, Teknova). After 2 days of incubation at 30°C, the transformation efficiency was calculated. Random inbred lines were then picked to analyze insertion diversity by PCR. Yeast were grown in CM broth with glucose minus tryptophan and uracil (D-UT, Teknova) at 30°C with shaking at 200 rpm. scFv surface induction was achieved by growing yeast for at least 20 hours in CM broth with galactose minus tryptophan and uracil (G-UT, Teknova), supplemented with 0.1% raffinose ( Sigma) (GR-UT).

After first blocking with 2% BSA/PBS 0.05% tween (blocking buffer), yeast were stained for 30 minutes to 1 hour at room temperature with rotation. Yeast is then incubated with biotin-labeled peptide/HLA complex monomers on ice for 30 minutes to 90 minutes, depending on the monomer concentration. Secondary labeling was achieved with Streptaivdin PE (ThermoFisher) and DYKDDDDK epitope tag Alexa Fluor 488 (R&D Systems) for 30 minutes on ice. Samples were acquired using a LSR II flow cytometer (BD Biosciences) or CytoFLEX S (Beckmen Coulter). Data were prepared using Flowjo software version 10 or FACSDiva (BD Biosciences).

Screening was achieved by magnetization-activated cell sorting (MACS) or fluorescence-activated cell sorting (FACS), using at least ten-fold coverage of the library size. For MACS screening, yeast are first blocked with 2% BSA/PBS 0.05% tween (blocking buffer) for 30 minutes to 1 hour at room temperature with rotation. Biotin-labeled peptide/HLA complex monomers were then incubated at 1 µM for 30 minutes on ice. Secondary labeling was achieved using streptavidin microbeads (Miltenyi Biotec). The labeled yeast was poured onto a MACS column on a MACS separator (Miltenyi Biotec). Yeast bound to the column was collected and considered as an enriched population. For FACS screening, yeast were prepared as described in the flow cytometry section. Samples were sorted using a FACS Aria II (BD Bioscience). Treat sorted yeast as an enriched population.

Unique scFv clones were identified by plating. After two days at 30°C, individual colonies were picked and analyzed by PCR. Full-length human IgGl of selected clones were produced in Expi293F (ThermoFisher) cells. Briefly, antibody variable regions were subcloned into mammalian expression vectors with matching human kappa light chain constant regions (pFUSE2ss-CLIg-hK, Invivogen) and human IgG1 constant regions (pFUSEss-CHIg-hG1, Invivogen )sequence. The vector was transfected at a 2:3 light chain:heavy chain ratio. Antibodies were purified with protein A resin (Genscript) and confirmed by electrophoresis under reducing and non-reducing conditions.

Use 1 µM V-0025 for the first round of selection. Gating was based on parental (R4c1) binding; the parental pair V-0025 exhibited 0.11%, while the cycle 2 pool exhibited 1.66%, indicating the presence of higher affinity binders ( Figure 2A ). The second round of sorting used 10OnM V-0025. The cycle 2 pool showed 0.23% binding, while the parent showed 0%; no binding was observed with the negative control (V-0018) ( FIG. 2B ). In the third round of sorting using 1OnM V-0025, 1.05% binding was observed ( Figure 2C ). The final round of sorting incorporated Koff; briefly, V-0025 was incubated at 100 nM for 30 minutes, followed by incubation with the full-length hIgG1 version of R4c1 (R4c1-IgG1 ). 500 nM R4c1-IgG1 was added at various time points as an antibody sink. Therefore, a final round of sorting was performed using Koff pressure to select the top pure lines ( Fig. 2D ). To identify unique clonal lines, individual colonies were picked and sequenced (n=48). Ten unique clonal lines were identified ( Table 2 ) and binding affinities were compared to the parental clonal lines. Among the unique inbreds, six inbreds showed at least 100-fold greater V-0025 binding than the parent ( FIG. 3A - FIG. 3D ). One clonal line (clonal line R2A_1), in addition to having increased binding affinity, also exhibited excellent selectivity and was selected for additional analysis ( FIG. 3E - FIG. 3G ). Table 2. Unique clonal lines and sequence modifications index name CDRH3 1 Parents XXXXXXXX 2 R2A_1 X L X N XXX 3 R2A_3 X H X T XXX 4 R2A_8 X H X A XXX 5 R2B_1 X H X N XXX 6 R2B_3 X H X R XXX 7 R2B_8 X H X W XXX 8 oR2A_1 X Y X T XXX 9 oR2A_2 X V XXXXX 10 oR2A_3 X L X S XXX 11 R3A2 X H X V XXX

Characterization of Clonal R2A_1 : Clonal R2A_1 was converted from scFv to full-length hIgG1 to test by ELISA and perform cell staining. Based on ELISA data, the affinity was measured at about 20 nM (data not shown), which represents a more than 10-fold increase in affinity compared to the parental pure line R4c1. To check antibody stability, binding was compared after storage of antibodies at 37°C for 72 hours. As shown in Figure 4 , the binding of R2A_1 to A549-B4 cells was severely impaired when the antibody was stored at 37°C for 72 hours.

Stabilization of pure R2A_1 : In order to improve the stability of R2A_1, some changes were made to the amino acids in the framework regions of VH and VL. For VL, CDRL2 was modified to match its germline (IGKV1-39). This also removes N-linked glycosylation sites. For VH, in framework region 1, Gln5 was changed to match the germline (Leu5). Also in framework region 1, Met18 was changed to match the germline (Leu18). The stable pure line is called R4c1 H1-L1. The scFv sequences were inserted into yeast for display and compared to the parent (R2A_1). Despite some loss of affinity, there was no change in specificity (data not shown).

In order to generate antibodies with greater affinity and broader specificity, a yeast display library was generated based on R4c1-H1-L1, and four amino acid mutations were introduced in the CDRL3 region, meaning that 44% of the CDRL3 sequence could potentially Changes from parent. As shown in Figure 5A (R0), although there was a selection group with greater binding to the target than the parent, very few inbred lines exhibited binding to the target. Sorting was performed using 10 nM target (R1 output), where gating was performed to select only inbred lines with greater binding affinity than the parent ( Figure 6A ). The R1 repertoire was examined for binding to the target and a substantial increase in the number of inbred lines binding with increased affinity compared to the parent was observed ( Figure 5A , R1). To select for affinity-enhanced clones, the R1 pool was subjected to Koff stress. Briefly, libraries were incubated with 10 nM target. After washing, 1 µM of the parental clone in the full-length IgGl format was added over 15 to 120 minutes to serve as an antibody pool. Any yeast that still showed binding to the target indicated a greater Koff compared to the parental clone. As shown in Figure 5B , yeast clones were observed to maintain target binding even after 120 minutes in the antibody pool. To select these highly improved clones, a final sort (R2 output) was performed using Koff with 10 nM target and 1 µM parental clone-IgG1 as antibody pool for 45 minutes, where sort gating was performed to collect only clones with the highest affinity ( FIG. 6B ). After sorting, individual clones were isolated and sequenced (n=60). Twelve unique clones were found ( Table 3 ) and were examined for binding to the target at 1 and 0.1 nM ( Figure 7 ). The clonal line with the highest binding to the target was selected for additional testing (clonal line R2-C02) ( Figure 7 black arrow). Table 3. Unique Pure Lines pure line CDRL3 Appearance % Parents XXXXXXXXXX R2-B04 FXXXGXXXQ 6.25 R2-A01 XCXXXXXGL 6.25 R2-C02 XXXXAXXSL 6.25 R2-B02 XXXXAXXSY 6.25 R2-A03 XXXXCXXMF 6.25 R2-C03 XXXXSXXQF 6.25 R2-A09 XXXXSXXQW 6.25 R2-A07 XXXXXFWEX 12.5 R2-A06 XXXXXXFSP 25 R2-C12 XXXXXXCL 6.25 R2-B12 XXXXXXXXQF 6.25 R2-A02 XXXXXXXXSL 6.25 Example 2. Characterization of top clones by ELISA , FACS and label-free techniques

The top clone identified from yeast display was made hIgG1 and tested for specificity and affinity. R2-C02 exhibited high affinity and fine specificity (data not shown). R2-C02 was designated ABX0011 (or ABX-11), and was produced in CHO cells using a 1-L transient transfection protocol, followed by purification by protein A affinity chromatography. Reduced (representing two bands for heavy and light chains) and non-reduced (single band at approximately 150 kD) by SDS-PAGE ( FIG. 8A ) and a single peak observed by size exclusion chromatography ( FIG. 8B ) to determine sample purity. ABX0011 was first tested against a broad range of peptide/HLA complexes. As shown in Figure 9A , the HLA-E clone 3D12 bound to all HLA-E complexes, including peptide null HLA-E. However, ABX0011 only recognizes atypical HLA, the HLA-G signal peptide/HLA-E complex and does not recognize a closely related signal peptide from canonical HLA ( FIG. 9B ). Furthermore, it does not recognize any other peptide/HLA-E complexes or any peptide/HLA-A2 complexes. For ELISA runs, high-purity HLA-E 01:03 and HLA-A2 02:01 monomeric complexes (in 0.1% BSA, 0.1% Tween20, PBS dilution/wash buffer) were prepared at 0.25 μg/ml at room temperature diluted) were immobilized on neutravidin-coated microarray plates for one hour. Plates were then washed 5 times in dilution/wash buffer. Antibodies diluted to 1 μg/ml in dilution/wash buffer were incubated for one hour at room temperature, and plates were then washed 5 times in dilution/wash buffer. Anti-mouse and anti-human HRP conjugates were diluted 1:5000 in Dilution/Wash Buffer and incubated for 30 minutes at room temperature, followed by 5 washes in Dilution/Wash Buffer. TMB substrate was added to the plate wells and incubated at 50 μl/well for 15 minutes. 1 N HCl stop solution was added at 50 μl/well and the plate was read at absorbance at 450 nm.

In order to determine whether ABX0011 recognizes the canonical HLA I signal peptide presented by two different phenotypes of HLA-E, namely HLA-E 01:03 and HLA-E 01:01, each single peptide was used in the ELISA as described above. body complex. No difference in binding to the HLA-G signal peptide was observed among the two HLA-E alleles, HLA-E*0101 and *0103 ( FIG. 9B ).

Affinity Determination of ABX0011 : The binding affinity of ABX0011 was determined using a label-free technique (Resonant Sensors, Inc., ResoSens Instruments). The dissociation equilibrium constant (KD) was found to be 7.9 nM or more than 50-fold improvement compared to the R4c1 clone ( FIG. 1D , FIG. 9C ). The method used to determine the affinity is as follows. Thermofisher Capture Select™ Biotin Anti-IgG-Fc (Hu) (diluted in PBS buffer) was immobilized at 5 μg/ml on Neutravidin-coated Bionetic label-free microarray plates until binding equilibrated. Plates were subsequently washed 3 times with 0.1% BSA, 0.1% Tween20, PBS dilution/wash buffer. ABX0011 (5 μg/ml in dilution/wash buffer) was captured by anti-IgG-Fc until binding reached equilibrium. Plates were then washed 3 times in dilution/wash buffer. V-0025 HLA-E 01:03 monomer complexes (serial dilutions starting at 5 μg/ml in dilution/wash buffer) were added to the wells and allowed to incubate for 20 minutes to determine binding association and then dissociate immediately (Dilution/Wash Buffer) approximately 25 minutes. Binding affinities were calculated using Tracedrawer kinetic analysis software.

ABX0011 detection sensitivity can be observed by ELISA. Briefly, V-0025 HLA-E 01:03 monomer complexes (serial dilutions starting at 2 μg/ml in 0.1% BSA, 0.1% Tween20, PBS buffer) were immobilized in neutral Avidin-coated microarray plates were plated for one hour. Plates were then washed 5 times in dilution/wash buffer. Antibodies were diluted to 1 μg/ml in dilution/wash buffer and incubated for one hour at room temperature, and then washed 5 times in dilution/wash buffer. Anti-mouse and anti-human HRP conjugates were diluted 1:5000 in dilution/wash buffer and incubated for 30 minutes at room temperature, and then washed 5 times in dilution/wash buffer. TMB substrate was incubated for 15 minutes at 50 μl/well. 1 N HCl stop solution was added at 50 μl/well and the plate was read at 450 nm. In Figure 9D , ABX0011 and HLA-E bound at 1 μg/mL and were tested against titration of antigen V-0025. Similarly, in Figure 9E , V-0025 bound at 0.25 μg/mL and was tested for titration of ABX0011 and HLA-E using an ELISA protocol similar to that described for Figure 9A . To check stability, ABX0011 was kept at 37°C for 7 to 14 days, followed by examination of ABX0011 stored at 4°C. ABX0011 was incubated at 37°C for 7 and 14 days and diluted to 1 μg/ml in mouse serum (4°C control was prepared in serum at the time of testing) and added to complexes with immobilized HLA-E 01:03 monomer wells and run in an ELISA as described above. As shown in Figure 9F , binding did not change, indicating good stability of ABX0011.

To further characterize specificity, K562 cells transfected to express HLA-E were first peptide-pulsed with V-0025 peptide and then tested for binding to HLA-E and ABX0011. As shown in Figure 9G , V-0025 peptide-pulsed cells displayed a load based on an increase in HLA-E expression compared to no peptide (unpulsed). ABX0011 displayed specificity for HLA-G loaded on HLA-E and did not bind to unpulsed cells ( FIG. 9G ). K562 cells transfected to express HLA-E were then pulsed with all canonical HLA signal peptides, atypical HLA signal peptides, and two other HLA-E binding peptides, namely V-0038 and P-0550. All peptide-pulsed cells displayed loading based on an increase in HLA-E expression compared to no peptide (unpulsed) ( Fig. 9H ) . Again, ABX0011 (as exemplified by ABX0012) only recognized the V-0025 peptide in HLA-E expressing K562 cells ( FIG. 9I ) . Background staining was approximately 500 antibody molecules/cell. To further assess the fine binding specificity of ABX0011, HLA-E expressing K562 cells were peptide-pulsed with 20 μg/ml V-0025, V-0034, V-0044, V-0046, P-0550 or left unpulsed, and This was followed by staining with various concentrations of ABX0011 ranging from 10 to <0.001 μg/ml. Again, when used at a concentration of 10 μg/ml, ABX0011 only showed selectivity for the V-0025 peptide, and only two closely related peptides, V-0044 and V-0046, were barely detected ( FIG. 9J ) .

Alanine scanning based on the peptide sequence of V-0025 (HLA-G signal peptide) indicated that the binding of ABX0011 to the peptide/HLA-E complex is mainly dependent on the amino acid at position 8, with amino acids at positions 2, 7 and Nine are less dependent, but still critical contacts ( Fig. 9K ). Overall, these results indicate that ABX0011 exhibits selectivity for atypical HLA-G peptide signal sequences with high affinity and stability. Example 3. ABX0011 selectively binds to target-positive cancer cell lines

To determine specificity, binding of ABX0011 was tested in various tumor cell lines, human peripheral blood mononuclear spheres (huPBMC) and primary human umbilical vascular endothelial cells (huVEC). Since HLA-E is known to be highly expressed in normal placental trophoblasts, the choriocarcinoma trophoblast cell line JEG-3 was used as a positive control for HLA-E and ABX0011 binding ( FIG. 10A ). To confirm the restriction of ABX0011 to the HLA-E/peptide complex, binding was tested in JEG-3 lacking HLA-E (JEG-3 Eko). As shown in Figure 10A , middle panel, HLA-E and ABX0011 could not bind to JEG-3 Eko cells. To confirm that the HLA-G signal peptide is dependent on Tap1/2 expression, ABX0011 was used to stain Tap-1 knockout JEG3 cells (JEG-3 Tap-1ko). As shown in Figure 10A , lower panel, there is still some HLA-E expression in the absence of Tap-1, however, ABX0011 exhibits no binding, indicating that it only recognizes the HLA-G signal peptide processed through the conventional pathway. Specificity was similarly demonstrated using huPBMC and huVEC cells. Human PBMC, especially B cells and NK cells express high levels of HLA-E ( FIG. 10B ) . In contrast, healthy huPBMCs do not express HLA-G and thus huPBMCs lack binding to ABX0011 ( FIG. 10B ) . In addition, huVECs expressed high levels of HLA-E after overnight treatment with IFN-γ. However, ABX0011 (as exemplified by ABX0010) did not bind to huVEC in the absence or presence of IFN-γ treatment ( FIG. 10C ) .

HLA-E is known to increase in various types of cancer. Therefore, HLA-E expression and ABX0011 binding of several cancer cell lines were analyzed. Since HLA-E is upregulated when cells are stressed or stimulated, binding was observed in unstimulated and IFNy-stimulated cells. Figure 11A illustrates two cell lines (THP-1 and OCI-AML3) that express HLA-E and HLA-G and bind ABX0011 in the absence of stimulation, and express HLA-E and do not express HLA-G and do not bind ABX0011 A cell line (KG-1). Additionally, binding of AML cell lines to ABX0011 (as exemplified by ABX-0012) showed good selectivity for ABX0011 using a range of concentrations (10 to <0.001 μg/ml) ( FIG. 11B ) . These results indicate that ABX0011 can be used to target AML cancers as well as other cancers expressing both HLA-E and HLA-G. K562 cells expressing HLA-E and mutant JEG3 cell lines were obtained from (Thorbald van Hall; Leiden University Medical Center). In some cases, cells required overnight stimulation with IFNγ (10 ng/ml) to induce HLA-E expression.

For all cell binding studies (except ABX0012, ABX0011 with mouse IgG1), cells were incubated at room temperature with anti-human CD16 (clonal KD1), anti-human CD32 (clonal AT10) and anti-human CD64 (clonal 10.1) (Bio-Rad ) or blocked with human TruStain FcX (BioLegend) for 5-10 minutes, followed by 1 µg/mL of ABX0011 or hIgG1 (clone QA16A12, BioLegend) or AF647-labeled ABX0011 or hIgG1 at 4°C with HLA-E Use 100µL of PE or PE-Cy7 (clonal 3D12, BioLegend) for surface staining for 30 minutes. Cells were then washed with staining buffer (PBS with 2 mM EDTA) followed by secondary staining with a mixture including goat anti-human/AF647 (Jackson ImmunoResearch) and zombie/aqua viability dye (BioLegend). Cells were incubated in 100 µL for 30 min at 4°C. Cells were washed twice with staining buffer and fixed using fluorofix (BioLegend). Samples were acquired using a LSR II flow cytometer (BD Biosciences) or CytoFLEX S (Beckmen Coulter). Data were prepared using Flowjo software version 10 (BD Biosciences). Example 4. ABX0011 induces NK -mediated antibody-dependent cellular cytotoxicity ( ADCC ) of target cells

The primary goal of these studies was to determine the ability of ABX0011 to induce NK cell-mediated ADCC of target cells. To test the ability of ABX0011 to induce ADCC, primary human NK cells were co-cultured with various tumor target cells in the presence of ABX0011. Healthy volunteer blood lines were obtained from Carter BloodCare. PBMCs were isolated by density-gradient centrifugation using Ficoll-Paque PLUS (GE Healthcare) or Lymphoprep (StemCell Technologies). Natural killer (NK) cells were purified using the EasySep Human NK Cell Enrichment Kit (StemCell Technologies).

As shown in Figure 12A , after co-cultivating NK cells with peptide-pulsed K562.E cells for four hours, ABX0011 was able to significantly increase the killing of K562.E cells in a dose-dependent manner compared to the isotype control ( Figure 12A ), and upregulates NK CD107a expression ( FIG. 12B ), and more specifically induces an increase in CD107a expression on NKG2A+ NK cells ( FIG. 12C ) . Similar results were also found when using THP-1 cells ( FIG. 12D ). These results indicate that ABX0011 can be used to promote tumor cytotoxicity by inducing NK cell ADCC activity. Example 5. Generation of bispecific antibodies capable of retargeting T cells to lyse tumor target cells

ABX0030 is constructed as a bispecific antibody capable of activating CD3+ T cells to kill tumor cells. ABX0030 was made into a Fab-Fc-scFv construct containing ABX0011 (Fab) conjugated to a single chain (scFv) of clonal SP34 (mouse anti-human CD3e) on an aglycosylated (N297D mutated) human IgG1 backbone . A 20 amino acid linker (GKPGSGKPGSGKPGSGKPGS) was used to covalently link the ABX0011 Fab to the SP34 scFv. ABX0030 was produced in transiently transfected CHO cells and purified on a protein A affinity column. ABX0030 was run on a reducing SDS-PAGE gel and displayed two bands expected at the expected MW (25 kD for ABX0011 light chain and ~55 kD for ABX0030 without light chain) ( FIG. 13A ). More than 91% of ABX0030 migrated as a single peak on the analytical SEC-HPLC column ( Figure 13B ).

The binding affinity of ABX0030 was determined using a label-free assay (ResoSens Instruments, Resonant Sensors, Inc). Briefly, V-0025 HLA-E 01:03 monomer complexes (diluted in 0.1% BSA, 0.1% Tween20, PBS buffer) were immobilized at 5 μg/ml on neutravidin-coated Bionetic label-free microarray plate until binding reaches equilibrium. Plates were then washed 3 times in dilution/wash buffer. ABX0030 (serial dilutions starting at 10 μg/ml in dilution/wash buffer) were assessed for association for approximately 20 minutes, followed by assessments for dissociation (dilute/wash buffer) for approximately 15 minutes. Binding affinities were calculated using Tracedrawer kinetic analysis software. The results showed a dissociation equilibrium constant of 8.97 nM ( FIG. 14 ).

Binding properties of ABX0030 : First, confirm the binding of ABX0030 to target tumor cells. As shown in Figure 15 , ABX0030 bound to V-0025 peptide-pulsed K562 cells expressing HLA-E similarly to the parental line (ABX0011). This binding was restricted by HLA-E, as HLA-E negative parental K562 cells did not exhibit binding to ABX0030 ( FIG. 15 ). Binding to T cells in peripheral blood mononuclear spheres (PBMCs) was used to confirm the anti-CD3 arm ( FIG. 16 ). The K562 cell line was obtained from ATCC. The K562 cell line expressing HLA-E cells was obtained from (Dr. Thorbald van Hall, Leiden University Medical Center, Netherlands). Cells were cultured according to the supplier's recommendations. For cell binding, cells were blocked at room temperature with anti-human CD16 (clonal KD1), anti-human CD32 (clonal AT10), and anti-human CD64 (clonal 10.1) (Bio-Rad) or with human TruStain FcX (BioLegend). 10 min, followed by surface staining with 1 µg/mL of unlabeled antibody or antibody labeled with AF647 and HLA-E/PE-Cy7 (clone 3D12, BioLegend) in 50-100 µL at 4°C for 30 min. Cells were then washed with staining buffer (PBS with 2 mM EDTA) followed by a cocktail consisting of goat anti-human or goat anti-mouse/AF647 (if unlabeled antibody was used, Jackson ImmunoResearch) and zombie/aqua viability dye (BioLegend) Secondary staining. Cells were incubated in 50 µL for 30 min at 4°C. Cells were washed twice with staining buffer and fixed using fluorofix (BioLegend). Samples were acquired using CytoFLEX S (Beckmen Coulter). Data were prepared using FlowJo software version 10 (BD Biosciences).

ABX0030 Enhances Target-Specific Cytotoxicity of Primary CTLs : To assess the activity of ABX0030, primary human CTLs were co-cultured with K562 (HLA-E positive) or V-0025 peptide-pulsed K562.E and titrated with ABX0030. As shown in Figure 17A , ABX0030 induced dose-dependent cytotoxicity in a target-specific manner; unpulsed K562.E cells were unaffected. In addition, ABX0030 did not induce CD25 expression (48 hours) ( FIG. 17B ) and IFNγ expression (48 hours) ( FIG. 17C ) in CD8+ T cells cultured with target-negative K562.E cells.

These results were confirmed using THP-1 cells (ABX0011 binding data are shown in Figure 11A ). After 48 hours of co-culture, ABX030 induced cytotoxicity in a dose-dependent manner ( FIG. 18A ). ABX0030 was also able to induce CD8+ T cell activation as shown by the dose-dependent induction of CD25, CD107a, perforin and IFNγ ( FIG. 18B - FIG. 18E ). These results indicate that ABX0030 enhances the lysis of tumor cells by CD8+ T cells in a target-specific manner.

For in vitro T cell activation assays, blood lines from healthy volunteers were obtained from Carter BloodCare (Arlington, TX). PBMCs were isolated by density-gradient centrifugation using Ficoll-Paque PLUS (GE Healthcare) or Lymphoprep (StemCell Technologies). CD8+ T cells were purified using the EasySep Human CD8+ T Cell Enrichment Kit (StemCell Technologies). The enriched human CD8+ T cells (CTL) were rested overnight at 1×10 ⁶ /mL. Target cells were labeled with CFSE (ThemoFisher) and added to resting CTL at a ratio of 10:1 (E:T). CD3/CD28 stimulation (ImmunoCult Human CD3/CD28 T Cell Activator, StemCell Technologies) was used as a positive control. During the last 4 hours of incubation, monensin and anti-human CD107a/BV421 (BioLegend) were added to all wells. Cells were harvested after 24 to 48 hours. Cells were stained with anti-human CD8/APC (BioLegend), anti-human CD25/PE-Cy7 (Tonbo) and Zombie/Aqua viability marker (BioLegend). For intracellular staining, cells were fixed and permeabilized using BD cytofix/cytoperm solution (BD), and stained with anti-human perforin/PerCP-Cy5.5 (BioLEgend) and anti-human IFNγ/PE-Dazzle 594 (BioLegend). Samples were acquired using CytoFLEX S (Beckmen Coulter). Data were prepared using FlowJo software version 10 (BD Biosciences). Table 4. List of peptide / HLA complexes peptide family peptide identification sequence HLA complex genetic origin Typical HLA V-0021 VMAPRTLIL HLA-E HLA-C HLA-Cw*01, -Cw*03, -Cw*04, -Cw*05, -Cw*06, -Cw*08, -Cw*12, -Cw*14, -Cw*16 and - Cw*17:02 V-0034 VMAPRT LVL HLA-E HLA-A*02, -A*23, -A*24, -A*25, -A*26, -A*34:02, -A*34:06, -A*43, -A*66 and -A*69 V-0035 VTAPRTLLL HLA-E HLA-B*13, -B*18, -B*27, -B*37, -B*40, -B*44, -B*47, -B*54, B*55 -B*56, - B*59, -B*82 and B*83 V-0037 IMAPRT LVL HLA-E HLA-A*34:01 V-0040 VMAPQALLL HLA-E HLA-Cw*17:01, Cw*17:03 and -Cw*17:05 V-0041 VMAPRALL HLA-E HLA-Cw*06:17, -Cw*07 and -Cw*18 V-0042 VMAPRTLLLL HLA-E HLA-A*01, -A*03, -A*11, -A*29, -A*30, A*31, -A*32, -A*33, -A*36, and A*74, HLA-Cw02 and Cw*15 V-0043 VMAPRTTLL HLA-E HLA-Cw*08:09 V-0044 VMAPRTVLL HLA-E HLA-B*07, -B*08, -B*14, -B*38, -B*39, -B*42, -B*48, -B*67, -B*73 and -B*81 V-0045 VMPPRTLLL HLA-E HLA-A*80 V-0046 VTAPRTVLL HLA-E HLA-B*15, -B35, -B*40, -B*41, -B*44:18, -B*45, -B*46 -B*49, -B*50, -B*51, -B*52, -B*53, -B*57, -B*58 and -B*78 Atypical HLA V-0025 VMAPRTLFL HLA-E HLA-G additional V-0038 QMRPVSRVL HLA-E Hsp60 P-0550 RAARLPPLL HLA-E PODXL2 Example 6 ABX0012 does not bind to peripheral immune cells

To test the binding of ABX0012 to immune cells, immune cells were purified, cultured, stained and evaluated by flow cytometry as described below. human primary cells

Healthy volunteer blood lines were obtained from Carter BloodCare. PBMCs were isolated by density-gradient centrifugation using Ficoll-Paque PLUS (GE Healthcare) or Lymphoprep (StemCell Technologies). Total T cells were purified using the EasySep Human T Cell Isolation Kit (StemCell Technologies). Natural killer (NK) cells were purified using the EasySep Human NK Cell Enrichment Kit (StemCell Technologies). Neutrophils were purified using the EasySep Direct Human Neutrophil Isolation Kit (StemCell Technologies). Eosinophils were purified using the EasySep Direct Human Eosinophil Isolation Kit (StemCell Technologies). Dendritic cells (DC) were purified using the EasySep Human Pan-DC Pre-Enrichment Kit (StemCell Technologies). Mononuclear spheres (MO) were purified using the EasySep Human Monocyte Isolation Kit or the EasySep Human Monocyte Enrichment Kit (without CD16 depletion) (both from StemCell Technologies). Platelets were enriched during PBMC processing by collecting the supernatant after washing the PBMC after density-gradient separation. Cord blood and healthy bone marrow lines were obtained from StemExpress. Cord blood PBMCs were isolated by density-gradient centrifugation using Ficoll-Paque PLUS (GE Healthcare) or Lymphoprep (StemCell Technologies). AML patient PBMCs were collected and stained by Champions Oncology and analyzed by flow cytometry in-house.

Upon overnight stimulation with IFNγ, PBMC were cultured at ¹ x 106 cells/ml in supplemented with 1% penicillin-streptomycin, HEPES buffer, 2 mM L-glutamine, 1% non-essential amino acids, acetone Sodium phosphate and 10% fetal bovine serum (Millipore Sigma) in RPMI-640 medium (ATCC). IFNγ was given at 10 μg/mL and compared to PBMC without IFNγ. cell line

HT-1376, SKBR3, SU.86.86, RPMI-8226, THP-1, OVCAR3, LNCaP, NCI-H1355, COLO205, PANC-1, HCT-116, A549 and JEG-3 cell lines were obtained from ATCC. NCC-STC-K140 and RCC-10RGB cell lines were obtained from Sekisui XenoTech. The SNU-899 cell line was obtained from the Korea Cell Line Bank. The OCI-AML3 cell line was obtained from DSMZ. JEG-3 HLA-E ^KO and Tap1 ^KO cells and OCI-AML3 HLA-E ^KO lines were obtained from Professor Throbald van Hall according to MTA. Some cells required overnight stimulation with IFNγ to induce HLA-E expression. macrophage differentiation

Macrophages were generated by culturing monocytes in Immunocult-SF macrophage medium supplemented with 5 μg/mL MCSF (StemCell Technologies). Additional medium was added on day 4. M0 macrophages were activated on day 6 with LPS (10 ng/mL) and M1 with IFNγ (50 ng/mL) or M2a with IL-4 (10 ng/mL). After 2 days of activation, M1 and M2a macrophages were collected. For dissociation, accutase was used for M1 macrophages and 2.5 mM EDTA was used for M2a macrophages. flow cytometry

ABX0012, mIgG1 and MEM-E/02 were labeled with AlexaFluor 647 (AF647) using SiteClick Antibody Azido Modification Kit and Click-iT AF647 sDIBO Alkyne Antibody Labeling Kit (Thermo Fisher Scientific).

For cell binding using unlabeled antibodies, use 1 to 5 µg/mL ABX0012, ABX0011, mouse isotype IgG1 (MOPC-21, BioLegend), human isotype IgG1 (QA16A12, BioLegend), 3D12 in 100 µL at 4°C (BioLegend) or MEM-E/02 (BioRad) to stain cells for 30 minutes. Cells were then washed with staining buffer (PBS with 2 mM EDTA), followed by a mixture of goat anti-human/AF647 (Jackson ImmunoResearch) or goat anti-mouse/AF647 (Thermo Fisher Scientific) and zombie/aqua viability dye (BioLegend). Liquid secondary staining. Cells were incubated in 100 µL for 30 min at 4°C. Cells were washed twice with staining buffer and harvested in 100 μL of staining buffer. For cell binding using labeled antibodies, cells were incubated with antibody staining mix in 100 µL for 30 min at 4°C, then washed twice with staining buffer and harvested in 100 µL staining buffer. If cells were not available on the day of staining, they were fixed with 100 μL of FluoroFix buffer (BioLegend). Samples were acquired using CytoFLEX S (Beckmen Coulter). Data were prepared using Flowjo software version 10 (BD Biosciences).

Anti-HLA-E(3D12)/PE-Cy7, Anti-CD3(HIT3a)/APC-Cy7, Anti-CD3(SK7)/APC-Cy7, Anti-CD4(RPA-T4)/PerCP-Cy5.5, Anti-CD8(RPT -T8)/BV605, Anti-CD14(M5E2)/FITC, Anti-CD16(3G8)/PacificBlue, Anti-CD19(HIB19)/FITC, Anti-CD20(2H7)/BV421, Anti-CD33(WM53)/BV650, Anti-CD34(561 )/AF700, anti-CD45(HI30)/FITC, anti-CD56 (5.1H11)/AF700, anti-lineage mix/FITC and anti-Siglec-8(7C9)/PE were purchased from BioLegend. Anti-CD56(B159)/PE-CF594 was purchased from BD BioScience. Anti-CD3 (HIT3a)/FITC and anti-CD4 (OKT4)/PE were purchased from Tonbo Biosciences. Anti-HLA-G (MEM-G/09)/PE was purchased from Thermo Fisher Scientific.

Because immune cells are known to express HLA-E, it was tested for binding to ABX0012. While all immune cells expressed HLA-E, none displayed HLA-G expression or ABX0012 binding ( Figure 19 ). Since HLA-E can be upregulated when cells are stressed or stimulated, ABX0012 binding in PBMCs was tested with and without IFNγ stimulation. While the HLA-E clone 3D12 did exhibit a slight increase in binding upon stimulation, only the HLA-E clone MEM-E/02 was upregulated, which recognizes no change in binding to HLA-E ABX0012 in the absence of peptide or B2M ( Figure 20 ) . This data indicates that ABX0012 should not have off-target activity on immune cells. Example 7 ABX0012 binding requires HLA - E and typical HLA - G expression

In order to identify cell lines that bind to ABX0012, the expression of HLA-E and HLA-G of various cell lines was analyzed. Several cell lines were identified ( FIG. 21 ) and stimulation with IFNγ increased ABX0012 binding ( FIG. 22 ). HLA-E selectivity was confirmed by testing cell lines expressing HLA-G but not HLA-E ( FIG. 23 ) and cell lines expressing HLA-E but not HLA-G ( FIG. 24A ). This selectivity was not altered by stimulating cells with IFNγ ( FIG. 24B ). Of note, these FACS data were used to emphasize that cells lacking HLA-E were not stained by ABX0011/12. These data do not represent all tumor cells of that cancer type. These are shown only to highlight the selectivity of ABX0012. Additional selectivity of ABX0012 for the HLA-E complex was confirmed by testing isogenic cell lines. As shown in Figure 25A , middle panel, HLA-E and ABX0012 could not bind to JEG-3 E ^ko cells. To confirm that ABX0012 only recognizes HLA-G peptide/HLA-E complexes that require TAP expression, binding was tested in Tap-1 knockout JEG-3 cells (JEG-3 Tap-1 ^ko ). As shown in Figure 25A , right panel, there is still some HLA-E expression in the absence of Tap-1, however, ABX0012 exhibits no binding, indicating that it only recognizes peptides processed via the canonical pathway (HLA-G). Similar results were observed with OCI-AML3 lacking HLA-E ( FIG. 25B ). Example 8 ABX0012 Binding to Acute Myelogenous Leukemia ( AML ) Bone Marrow Blasts in Blood

Based on the binding of ABX0012 to AML cell lines THP-1 and OCI-AML3, the binding of ABX012 to PBMC of AML patients was tested. As shown in Figure 26 , AML PBMCs had a significantly greater percentage of ABX0012 positive cells compared to healthy PBMCs. To ensure that the hematopoietic stem and precursor cell populations are not stained by ABX0012, healthy bone marrow and cord blood were tested. Healthy bone marrow and cord blood exhibited similar levels of ABX0012 to healthy PBMC ( FIG. 26 ). Although the levels of ABX0012 in healthy bone marrow and cord blood were not significantly lower than in AML PBMC, this was a result of the small number of donors. This data indicates that AML may be an indication for ABX0012 therapy. Example 9 Validation of staining protocol using frozen cell blocks

To analyze tissue samples for immunohistochemical (IHC) staining, frozen cell blocks were tested for IHC staining. Human frozen tissue (tumor and normal adjacent tissue (NAT)) blocks were purchased from ProteoGenex (Inglewood, CA) and embedded in OCT compound. Samples were sectioned using a microtome-cryostat and mounted on glass slides. Immunohistochemical (IHC) staining was performed by NovoVita Histopath Laboratory, LLC. (Cambridge, MA). Briefly, frozen tissue slides were air-dried for 20 minutes and then wet-loaded onto a Ventana XT discovery ultra instrument (Ventana Medical Systems, Tucson, AZ). Slides were then rinsed with IX Ventana Reaction Buffer (Catalog #950-300) and subsequently treated with the peroxidase inhibitor CM (Ventana) for 12 minutes to block endogenous peroxidases. After rinsing with 1× Ventana reaction buffer, slides were warmed to 37°C and incubated with 2.25 μg/ml primary antibody (anti-HLA-E (MEM-E/02, AbCam), mouse IgG1 isotype control or AB0012) Incubate together for 60 minutes. Slides were rinsed 3 times with Ventana Reaction Buffer and incubated with FineFix Working Solution (Milestone, Kalamazoo, MI, Cat# 70147WG) for 4 minutes (post-fixation step), and rinsed 3 times. Discovery anti-mouse HQ (Ventana, Cat# 760-4814) was applied to the slides for 24 minutes and washed 3 times with Ventana reaction buffer. One drop of DISC anti-HQ HRP (Ventana, cat# 760-4820) was applied to the slide, incubated for 24 minutes and washed 3 times with Ventana reaction buffer. Subsequently, one drop of Discovery ChromoMap DAB kit (Ventana, cat. no. 760-159) and one drop of CM H2O2 (Ventana) were applied to the slide, incubated for 8 minutes, and then washed 3 times with Ventana reaction buffer. A drop of copper CM (Ventana) was then applied to the slide, incubated for 4 minutes, followed by 3 washes with Ventana reaction buffer, followed by a drop of hematoxylin (contrast stain) applied to the slide for 12 minutes. After rinsing (2x) with Ventana Reaction Buffer, one drop of Bluing Reagent (after contrast staining) was applied and 8 minutes later the slides were rinsed 2x with Ventana Reaction Buffer. Slides were then removed from the Ventana XT, washed with dish detergent and treated with alcohol and xylene to dehydrate. Cover slips were added to the slides and the slides were read on the Discovery Ultra instrument.

K562 cells or HLA- E Cell block of transfected K562 cells (K562.E), K562.E pulsed with 20 μg/ml V-0025 (VMPRTLFL) peptide for 2 hours ( FIG. 27 ). Images show that ABX0012 strongly stains K562.E+V-0025 peptide-pulsed cells (3+++ out of 3) and does not stain (-) K562 cells. These data demonstrate that ABX0012 binds selectively to cells presenting HLA-E/V-0025 and validate the immunohistochemical (IHC) staining protocol. Example 10 staining positive control tissue

Fresh frozen human placenta tissue was used as a positive control for ABX0012. Trophoblast cells are well known to express HLA-E and HLA-G, and therefore ABX0012 staining is expected in placental tissue. In Figure 28 , ABX0012 exhibited strong (2++ to 3+++) staining of trophoblast cells in placental tissue and indicated the presence of HLA-E+ canonical leader peptides on the surface of trophoblast cells. Example 11 ABX0012 staining of head and neck tumor tissue

Figure 29 is a representative image of ABX0012 stained frozen tumor tissue collected from a head and neck patient. Figure 29A left panel shows strong tumor cell staining by anti-HLA-E antibody (clone MEM-E/02). The same panel shows the staining of the stromal area with the MEM-E/02 antibody. The right panel shows ABX0012 antibody staining of tumor tissue. Tumor stroma showed strong staining (3+++), while tumor cells showed weak to moderate staining. The image indicates that the target, HLA-E+ leader atypical HLA-G (VMAPRTLFL), is present in tumor tissue from a patient with head and neck cancer. Figure 29B shows images of normal adjacent tissue (NAT) stained with MEM-E/02 (left panel) and ABX0012 (right panel). Note that NAT epithelial cells were positive for HLA-E (left panel), however, absence of ABX0012 staining indicated lack of HLA-E/VMAPRTLFL peptide complex in NAT epithelial cells (right panel). Example 12 ABX0012 staining of colon adenocarcinoma tumor tissue

Representative images showing fresh-frozen human colon adenocarcinoma tissue stained with anti-HLA-E (left; 10× magnification) or ABX-0012 (right; 10× magnification). Figure 30 shows HLA-E expression in tumor and stromal regions (top 1.4× magnification and bottom 14.4×, left), and in tumor (2++) and stromal (3+++) regions that can be detected by ABX0012 Detected HLA-E/VMAPRTLFL peptide complex (top 1.4× magnification and bottom 14.4×, right). Example 13 ABX0012 staining of lung squamous carcinoma tissue

Representative images show fresh-frozen lung squamous carcinoma tissue stained with anti-HLA-E (left; top 10× magnification) or ABX0012 (right; 10× magnification). Figure 31A shows tumor and stroma stained with anti-HLA-E antibody (2++) or ABX0012 (1+ to 2++), indicating HLA-E and HLA-E/VMAPRTLFL peptide complex expression in lung cancer, respectively. Figure 3 IB shows that ABX0012 does not stain normal adjacent lung tissue, indicating that HLA-E loaded with VMAPRTLFL peptide is not present in normal lung tissue.

While preferred embodiments of the present invention have been shown and described herein, it will be understood by those skilled in the art that these embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments described herein may be employed. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

The novel features of the invention are set forth in detail in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description which sets forth illustrative embodiments utilizing the principles of the invention and the accompanying drawings in which:

Figures 1A - 1D illustrate the identification and affinity characterization of clonal R4 clonal 1 (R4c1 ) relative to V-0025. ( FIG. 1A ) phage and ( FIG. 1B ) single strain soluble ELISA. Antigen was 1 μg/ml. ( FIG. 1C ) Binding affinity sensor map and ( FIG. 1D ) kinetic data.

Figures 2A - 2D are illustrative overviews of sorting schematics for isolation of affinity matured clones from R4c1. Figures 2A - 2C illustrate cell sorting diagrams showing rounds of sorting for the first round of affinity maturation. The "asterisk" indicates the sorted group. For R4 sorting ( FIG. 2D ), Koff was used with 10 nM of V-0025 and 1 μM of R4c1-IgG1 as antibody pool at various time points.

Figures 3A - 3G illustrate clonal lines identified from affinity maturation of R4c1. Figures 3A - 3D illustrate binding profiles to 100 nM of target antigen (V-0025). Figures 3E - 3G illustrate the binding profile of clonal R2A_1 to 10 nM of the target (V-0025) and to 100 nM of additional peptide/HLA-E antigen.

Figure 4 illustrates the binding of R2A_1 to A549-B4 cells.

Figures 5A - 5B illustrate the isolation method for improving clones by affinity maturation of the CDRL3 region of R2A_1. Figure 5A illustrates the binding of the parental clone (R4 clone 1) and the initial affinity matured pool (R0) and first round sorted pool (R1) to the target (V-0025). Figure 5B illustrates the Koff of the R1 affinity maturation pool. Target (V-0025) was maintained at 10nM and R2A_1-hIgG1 was maintained as an antibody pool at 1µM for 15 min to 90 min.

Figures 6A - 6B illustrate a schematic diagram of sorting to isolate clones with greater binding affinity than the parent. Cell sorting diagrams showing ( FIG. 6A ) round 1 and ( FIG. 6B ) round 2 of affinity maturation. Asterisks indicate sorted groups. For R2 sorting, Koff was used with 10 nM of V-0025 for 45 minutes using 1 μM of R2A_1-IgG1 as an antibody pool.

Figure 7 illustrates identification of clonal lines from affinity maturation of the CDRL3 region of R2A_1 and binding profile to 1 nM and 0.1 nM of V-0025. Arrows indicate top pure lines.

Figures 8A - 8B illustrate the QC data used to generate ABX0011.

Figures 9A - 9K illustrate the binding specificity, affinity and stability of ABX0011. Antigen specificity of HLA-E (clonal 3D12) and ( FIG. 9B ) ABX0011 by ELISA ( FIG. 9A ) . For ELISA analysis, antibody was used at 1 mg/ml and HLA-E/peptide antigen was used at 0.5 mg/ml. The monovalent affinity of ABX0011 to target V-0025 was determined using a ResoSens label-free instrument (Resonant Sensors, Inc. Arlington, TX) ( FIG. 9C ) . The limit of detection of ABX0011 compared to the cloned 3D12 was assessed by ELISA ( Fig. 9D & E ) . ABX0011 and HLA-E were used at 1 µg/mL, while V-0025 was titrated from 1 µg/mL to 0.001 µg/mL ( Panel ( D ) . Figure 9E shows that target V-0025 was used at 0.25 µg/mL, while ABX0011 and HLA-E was titrated from 2 µg/mL to 3.8 pg/mL (3.8×10 ^{- 6} µg/mL). The thermal stability of ABX0011 was assessed by ELISA ( Fig. 9F ) . The antibody was incubated in mouse serum at 37°C After 7 to 14 days, the combination of ABX0011 and HLA-E/VMAPRTLFL was evaluated. The selectivity of the binding of clonal 3D12 and ABX0011 to K562.E cells without pulse and peptide pulse ( Figure 9G ). K562.E cells were treated with 20mM Peptides were pulsed for 2 hours followed by antibody staining at 1 µg/mL. Further assessment of ABX0011 binding selectivity was performed using ABX0012 (ABX0011 with mouse IgG1) with related and unrelated peptides. HLA-E ( Fig. 9H ) and ABX0012 ( Fig. 9I ) Staining of K562.E cells pulsed with peptides and without pulses. K562.E pulsed with target V-0025 peptide to determine the detection limit of ABX0011 ( Fig. 9J ) . The control is K562.E cells without pulses and Parental K562 (lack of HLA-E expression) and K562.E cells pulsed with irrelevant peptides (V-0034, V-0044, V-0046 and P-0550). K562.E cells were subjected to epitope localization of ABX0011 ( FIG. 9K ) .

Figure 10A - Figure 10C exemplifies the binding specificity of ABX0011 to cell lines expressing HLA-E and HLA-G ( Figure 10A ) , and no association with human peripheral blood mononuclear spheres (huPBMC) and primary HLA-G-deficient cells was observed. Binding of human umbilical cord vascular endothelial cells (huVEC) ( Figure 10B and Figure 10C ). Antibody binding studies were performed at 1 µg/mL. ( FIG. 10A ) Binding to IFNγ-stimulated JEG3 wild type (WT, upper panel), E ^ko (middle panel) and Tap-1 ^ko (lower panel). ( FIG. 10B ) Binding to huPBMCs and ( FIG. 10C ) huVECs.

11A - 11B illustrate binding to AML cell lines expressing both HLA - E and HLA-G (THP-1 and OCI-AML3) or only HLA-E (KG-1). AML cells were stained with 3D12 (HLA-E), MEM-G/09 (HLA-G) and W632 (pan-HLA I) antibodies at 1 μg/ml ( FIG. 11A ). ABX0012 (ABX0011 with mouse IgG1) was titrated (10 to 0.004 mg/mL) and binding to target positive AML cell lines was observed ( FIG. 11B ) .

Figures 12A - 12D illustrate ABX0011-mediated NK cytotoxicity against tumor cell lines expressing the target. NK cells were co-cultured with V-0025 peptide-pulsed K562.E cells or THP-1 cells with isotype control (hlgG1). The frequencies of CD107a-positive NK cells and CD107a-positive NKG2A+ NK cells are shown ( FIG. 12A and FIG. 12B ) . The frequencies of dead target cells (K562.E) and THP-1 cells are shown in Figure 12C and Figure 12D , respectively.

Figures 13A - 13B illustrate QC data used to generate ABX0030, a bispecific T cell engager containing the _VL and _VH domains of ABX0011 covalently linked to an anti-CD3 scFv fragment.

Figure 14 illustrates affinity analysis of ABX0030.

Figure 15 illustrates that binding of ABX0030 to K562.E cells is peptide specific. Only K562.E cells pulsed with the V-0025 target peptide stained with ABX0030 in a dose-dependent manner. Control cells, parental K562 and K562.E without peptide were not stained with ABX0030.

Figure 16 is an exemplary histogram illustrating that ABX0030 stains human CD3+ cells and does not stain CD3 neg cells. PBMCs stained with GAH-APC conjugate and anti-CD3 (clone SK7) (bottom left histogram). PBMCs stained with anti-CD4 and GAH-APC conjugate (upper left histogram). CD3+ cells stained with ABX0030+GAH-APC conjugate (no SK7 Ab) (top right histogram). Double staining with anti-CD-4-PE and ABX0030+GAH-APC conjugate (top right histogram). Note that this figure represents two CD3+ cell populations of CD4+ and CD8+ T cells. Double staining of CD3+ cells with ABX0030 and clonal SK7-PE (lower right histogram).

Figures 17A - 17C illustrate the efficacy of ABX0030 in specifically activating CD8+ T cells and redirecting T cell lysis of target positive cells. Figure 17A shows the specific redirection of T cell lysis by ABX0030 of K562.E cells pulsed with V-0025 target peptide. Some lytic activity in K562.E (unpulsed) cells was observed when ABX0030 was used at 10,000 pM (the highest concentration). CD25 and CD107a expression of CD8+ T cells were also quantified to determine whether ABX0030 can non-specifically activate T cells. ( FIG. 17B and FIG. 17C ) ABX0030 exhibited minimal activation of CD8+ T cells in the presence of K562.E unpulsed cells (no target).

Figures 18A - 18E illustrate the potent activity of ABX0030 redirecting CD8+ T cell lysis of THP-1 cells. Figure 18A shows the dose-dependent effect (10000 to 80 pM) of ABX0030 redirecting CD8+ T cell lysis of THP-1 cells. ABX0030 activates CD8+ T cells in the presence of THP-1 cells. Figure 18B shows the dose-dependent effect of ABX0030 on the frequency of CD25+ CD8+ T cells. Additional markers demonstrating the effect of ABX0030 on CD8+ T cells in the presence of THP-1 cells were the increased frequency of CD107+ CD8+ T cells ( FIG. 18C ) , and the increase in the frequency of perforin ( FIG. 18D ) and IFNγ ( FIG. 18E ) positive CD8+ T cells. increase in frequency.

Figures 19A - 19B illustrate that peripheral immune cells do not bind ABX0012. Test total PBMC, enriched or purified cells for HLA-E, HLA-G or ABX0012 expression. Gray indicates isotype staining and black lines indicate antibody staining. Platelet staining is representative of 2 donors. B cell staining is representative of 6 donors. T cell and NK cell staining is representative of 10 donors. Neutrophil and eosinophil staining are representative of 7 donors. DC staining is representative of 4 donors. Mononuclear staining is representative of 4 donors. Macrophage staining is representative of 10 donors. N/T means not tested.

Figures 20A - 20B illustrate that stimulation of PBMCs with IFNγ does not induce ABX0012 binding. PBMC were stimulated overnight with ( FIG. 20B ) or without ( FIG. 20A ) IFNγ and tested for expression of HLA-E (clonal 3D12), denatured HLA-E (clonal MEM-e/02) or ABX0023. Gray indicates isotype staining and black lines indicate antibody staining. Staining is representative of 2 donors.

Figure 21 exemplifies that HLA-E positive HLA-G positive cell lines exhibit ABX0012 binding without stimulation. Staining with ABX0012 (mouse Fc) or ABX0011 (human Fc) largely depends on cell line Fc receptor expression. Gray indicates isotype staining and black lines indicate antibody staining.

Figure 22 exemplifies that cell lines exhibiting ABX0012 binding in the absence of stimulation exhibit increased ABX0012 binding in the presence of IFNγ stimulation. Cells were stimulated with IFNγ for 24 hours. Staining with ABX0012 (mouse Fc) or ABX0011 (human Fc) largely depends on cell line Fc receptor expression. Gray indicates isotype staining and black lines indicate antibody staining.

Figure 23 illustrates that HLA-E null cell lines do not exhibit ABX0011 binding. Staining was performed using ABX0011 (human Fc). Gray indicates isotype staining and black lines indicate antibody staining.

Figures 24A - 24B illustrate that HLA-G null cell lines do not exhibit ABX0012 binding. Cells were ( FIG. 24A ) unstimulated or ( FIG. 24B ) stimulated with IFNγ for 24 hours. Gray indicates isotype staining and black lines indicate antibody staining. N/T means not tested.

Figures 25A - 25B illustrate that ABX0012 binding requires HLA-E and Tap1 peptide processing. ( FIG. 25A ) JEG3 cells were stimulated with IFNγ for 24 hours before staining. ( FIG. 25B ) OCI-AML3 cells were unstimulated. Staining was performed using ABX0012 (mouse Fc) or ABX0011 (human Fc). Gray indicates isotype staining and black lines indicate antibody staining. N/T means not tested.

Figure 26 exemplifies AML PBMC binding to ABX0012. ABX0012 binding was tested on CD45dim cells in healthy PBMC (n=6), AML PBMC (n=18), cord blood (n=3) and healthy bone marrow (n=3). The percent binding was calculated as the percent binding of ABX0012 minus the percent binding of the mouse IgGl isotype control. **p=0.0074.

Figure 27 exemplifies ABX-0012 staining of K562.E cells pulsed with specific peptides. K562 and K562.HLA-E+V-0025 (VMAPRTLFL) peptide-pulsed cells were pelleted, treated with OCI compound and snap-frozen to prepare frozen cell blocks for immunohistochemistry. ABX-0012 antibody (1.95 μg/ml) was used to stain K562.E+V-0025 and K562 cells. Upper panel demonstrates positive ABX-0012 staining, while control cells (lower panel) are not stained. The results of these studies validate the use of ABX-0012 to stain frozen tissue sections.

Figure 28 exemplifies positive ABX-0012 staining of human placental tissue and specifically trophoblast cells.

Figures 29A and 29B illustrate cryosection samples of head and neck tumors and normal adjacent tissue (NAT). Figure 29A shows (left) staining with anti-HLA-E antibody (2.25 μg/ml) and (right) staining with ABX0012 antibody (1.95 μg/ml). Figure 29B shows (left) NAT staining with anti-HLA-E antibody but not ABX-0012 antibody (right).

Figure 30 illustrates frozen section samples of colon adenocarcinoma and NAT. Left panel shows staining with anti-HLA-E antibody (2.25 μg/ml) and right panel shows staining with ABX0012 antibody (1.95 μg/ml).

Figures 31A - 31B illustrate cryosection samples of lung squamous cell carcinoma and NAT. Figure 31A shows (left panel) staining with anti-HLA-E antibody (2.25 μg/ml) and (right panel) staining with ABX0012 antibody (1.95 μg/ml). Figure 3 IB does not show ABX-0012 staining of normal adjacent lung tissue.

Claims (302)

A monoclonal antibody or an antigen-binding fragment thereof comprising a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 7 . A monoclonal antibody or an antigen-binding fragment thereof comprising a light chain variable domain (VL) comprising an amino acid sequence at least 90% identical to the amino acid sequence shown in SEQ ID NO: 7 . A monoclonal antibody or an antigen-binding fragment thereof comprising a light chain variable domain (VL) comprising an amino acid sequence at least 95% identical to the amino acid sequence shown in SEQ ID NO: 7 . A monoclonal antibody or an antigen-binding fragment thereof comprising a light chain variable domain (VL) comprising an amino acid sequence at least 99% identical to the amino acid sequence shown in SEQ ID NO: 7 . A monoclonal antibody or an antigen-binding fragment thereof, comprising a light chain variable domain (VL), the light chain variable domain comprising an amino acid sequence 100% identical to the amino acid sequence shown in SEQ ID NO: 7. The monoclonal antibody according to any one of claims 1 to 5, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a heavy chain variable domain (VH), and the heavy chain variable domain comprises a sequence shown in SEQ ID NO: 8 An amino acid sequence that is at least 80% identical to the amino acid sequence. The monoclonal antibody according to any one of claims 1 to 5, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a heavy chain variable domain (VH), and the heavy chain variable domain comprises a sequence shown in SEQ ID NO: 8 An amino acid sequence that is at least 90% identical to the amino acid sequence. The monoclonal antibody according to any one of claims 1 to 5, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a heavy chain variable domain (VH), and the heavy chain variable domain comprises a sequence shown in SEQ ID NO: 8 An amino acid sequence that is at least 95% identical to the amino acid sequence. The monoclonal antibody according to any one of claims 1 to 5, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a heavy chain variable domain (VH), and the heavy chain variable domain comprises a sequence shown in SEQ ID NO: 8 An amino acid sequence that is at least 99% identical to the amino acid sequence. The monoclonal antibody according to any one of claims 1 to 5, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a heavy chain variable domain (VH), and the heavy chain variable domain comprises a sequence shown in SEQ ID NO: 8 Amino acid sequence with 100% identical amino acid sequence. The monoclonal antibody according to any one of claims 1 to 10, wherein the monoclonal antibody or an antigen-binding fragment thereof selectively binds to a complex comprising HLA-E and a neoantigen. The monoclonal antibody according to any one of claims 1 to 11, wherein the monoclonal antibody or antigen-binding fragment thereof has no binding affinity for the HLA-E alone. The monoclonal antibody according to any one of claims 1 to 12, wherein the monoclonal antibody or antigen-binding fragment thereof has no binding affinity for the neoantigen alone. The monoclonal antibody according to any one of claims 1 to 13, wherein the neoantigen is expressed by cells proficient in antigen processing mechanism (APM). The monoclonal antibody according to claim 14, wherein the neoantigen is expressed by cells proficient in TAP1/2. The monoclonal antibody according to any one of claims 1 to 15, wherein the neoantigen comprises, consists essentially of, or consists of the sequence according to SEQ ID NO: 18 (VMAPRTLFL). The monoclonal antibody according to any one of claims 1 to 16, wherein the HLA-E is HLA-E*0101 or HLA-E*0103. The monoclonal antibody according to claim 17, wherein the antibody selectively binds to a complex comprising: (a) the HLA-E*0101 and the neoantigen; (b) the HLA-E*0103 and the neoantigen; or (c) the HLA-E*0101 and the neoantigen, and the HLA-E*0103 and the neoantigen. The monoclonal antibody according to any one of claims 1 to 18, wherein the monoclonal antibody or an antigen-binding fragment thereof is a murine antibody, a chimeric antibody, a camelid antibody, a humanized antibody or a human antibody. The monoclonal antibody according to any one of claims 1 to 19, wherein the monoclonal antibody or an antigen-binding fragment thereof is a TCR-like antibody. The monoclonal antibody according to any one of claims 1 to 20, wherein the monoclonal antibody or an antigen-binding fragment thereof is a multispecific antibody. The monoclonal antibody according to any one of claims 1 to 21, wherein the monoclonal antibody or an antigen-binding fragment thereof is a bispecific antibody. The monoclonal antibody according to any one of claims 1 to 22, wherein the monoclonal antibody or an antigen-binding fragment thereof is a bispecific T cell engager (BiTE). The monoclonal antibody according to claim 23, wherein the BiTE binds to the CD3 protein associated with T cell receptor (TCR). The monoclonal antibody according to any one of claims 23 to 24, wherein the BiTE further comprises a light chain variable domain (VL), and the light chain variable domain comprises at least the amino acid sequence shown in SEQ ID NO: 15 80% identical amino acid sequence. The monoclonal antibody according to any one of claims 23 to 25, wherein the BiTE further comprises a heavy chain variable domain (VH), and the heavy chain variable domain comprises at least the amino acid sequence shown in SEQ ID NO: 16 80% identical amino acid sequence. The monoclonal antibody according to any one of claims 1 to 26, wherein the monoclonal antibody or an antigen-binding fragment thereof is a multifunctional antibody. The monoclonal antibody according to any one of claims 1 to 27, wherein the monoclonal antibody or an antigen-binding fragment thereof further comprises a binding therapeutic moiety. The monoclonal antibody according to any one of claims 1 to 28, wherein selective binding of the antibody to the complex comprising the HLA-E and the neoantigen induces an immune response in cells. The monoclonal antibody according to claim 29, wherein the immune response comprises activation of (i) NK cells, (ii) T cells or (iii) NK cells and T cells. The monoclonal antibody according to claim 30, wherein the T cells are CD4+ T cells or CD8+ T cells. The monoclonal antibody according to claim 30, wherein the immune response comprises activation of cytotoxic T cells (CTL). The monoclonal antibody according to claim 29, wherein the cell is a cancer cell. A monoclonal antibody or an antigen-binding fragment thereof comprising a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 8 . A monoclonal antibody or an antigen-binding fragment thereof comprising a heavy chain variable domain (VH) comprising an amino acid sequence at least 90% identical to the amino acid sequence shown in SEQ ID NO: 8 . A monoclonal antibody or an antigen-binding fragment thereof comprising a heavy chain variable domain (VH) comprising an amino acid sequence at least 95% identical to the amino acid sequence shown in SEQ ID NO: 8 . A monoclonal antibody or an antigen-binding fragment thereof comprising a heavy chain variable domain (VH) comprising an amino acid sequence at least 99% identical to the amino acid sequence shown in SEQ ID NO: 8 . A monoclonal antibody or an antigen-binding fragment thereof, comprising a heavy chain variable domain (VH), the heavy chain variable domain comprising an amino acid sequence 100% identical to the amino acid sequence shown in SEQ ID NO: 8. The monoclonal antibody according to any one of claims 34 to 38, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a light chain variable domain (VL), and the light chain variable domain comprises a sequence shown in SEQ ID NO: 7 An amino acid sequence that is at least 80% identical to the amino acid sequence. The monoclonal antibody according to any one of claims 34 to 38, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a light chain variable domain (VL), and the light chain variable domain comprises a sequence shown in SEQ ID NO: 7 An amino acid sequence that is at least 90% identical to the amino acid sequence. The monoclonal antibody according to any one of claims 34 to 38, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a light chain variable domain (VL), and the light chain variable domain comprises a sequence shown in SEQ ID NO: 7 An amino acid sequence that is at least 95% identical to the amino acid sequence. The monoclonal antibody according to any one of claims 34 to 38, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a light chain variable domain (VL), and the light chain variable domain comprises a sequence shown in SEQ ID NO: 7 An amino acid sequence that is at least 99% identical to the amino acid sequence. The monoclonal antibody according to any one of claims 34 to 38, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a light chain variable domain (VL), and the light chain variable domain comprises a sequence shown in SEQ ID NO: 7 Amino acid sequence with 100% identical amino acid sequence. The monoclonal antibody according to any one of claims 34 to 43, wherein the monoclonal antibody or an antigen-binding fragment thereof selectively binds to a complex comprising HLA-E and a neoantigen. The monoclonal antibody according to any one of claims 34 to 44, wherein the monoclonal antibody or an antigen-binding fragment thereof has no binding affinity for the HLA-E alone. The monoclonal antibody according to any one of claims 34 to 45, wherein the monoclonal antibody or antigen-binding fragment thereof has no binding affinity for the neoantigen alone. The monoclonal antibody according to any one of claims 34 to 46, wherein the neoantigen is expressed by cells proficient in antigen processing mechanism (APM). The monoclonal antibody according to claim 47, wherein the neoantigen is expressed by cells proficient in TAP1/2. The monoclonal antibody according to any one of claims 34 to 48, wherein the neoantigen comprises, consists essentially of, or consists of the sequence according to SEQ ID NO: 18 (VMAPRTLFL). The monoclonal antibody according to any one of claims 34 to 49, wherein the HLA-E is HLA-E*0101 or HLA-E*0103. The monoclonal antibody according to claim 50, wherein the antibody selectively binds to a complex comprising: (a) the HLA-E*0101 and the neoantigen; (b) the HLA-E*0103 and the neoantigen; or (c) the HLA-E*0101 and the neoantigen, and the HLA-E*0103 and the neoantigen. The monoclonal antibody according to any one of claims 34 to 51, wherein the monoclonal antibody or the antigen-binding fragment thereof is a murine antibody, a chimeric antibody, a camelid antibody, a humanized antibody or a human antibody. The monoclonal antibody according to any one of claims 34 to 52, wherein the monoclonal antibody or an antigen-binding fragment thereof is a TCR-like antibody. The monoclonal antibody according to any one of claims 34 to 53, wherein the monoclonal antibody or an antigen-binding fragment thereof is a multispecific antibody. The monoclonal antibody according to any one of claims 34 to 54, wherein the monoclonal antibody or an antigen-binding fragment thereof is a bispecific antibody. The monoclonal antibody according to any one of claims 34 to 55, wherein the monoclonal antibody or an antigen-binding fragment thereof is a bispecific T cell engager (BiTE). The monoclonal antibody according to claim 56, wherein the BiTE binds to the CD3 protein associated with T cell receptor (TCR). The monoclonal antibody according to any one of claims 56 to 57, wherein the BiTE further comprises a light chain variable domain (VL), and the light chain variable domain comprises at least the amino acid sequence shown in SEQ ID NO: 15 80% identical amino acid sequence. The monoclonal antibody according to any one of claims 56 to 58, wherein the BiTE further comprises a heavy chain variable domain (VH), and the heavy chain variable domain comprises at least the amino acid sequence shown in SEQ ID NO: 16 80% identical amino acid sequence. The monoclonal antibody according to any one of claims 34 to 59, wherein the monoclonal antibody or an antigen-binding fragment thereof is a multifunctional antibody. The monoclonal antibody according to any one of claims 34 to 60, wherein the monoclonal antibody or an antigen-binding fragment thereof further comprises a binding therapeutic moiety. The monoclonal antibody according to any one of claims 34 to 61, wherein selective binding of the antibody to the complex comprising the HLA-E and the neoantigen induces an immune response in cells. The monoclonal antibody according to claim 62, wherein the immune response comprises activation of (i) NK cells, (ii) T cells or (iii) NK cells and T cells. The monoclonal antibody according to claim 63, wherein the T cells are CD4+ T cells or CD8+ T cells. The monoclonal antibody according to claim 62, wherein the immune response comprises activation of cytotoxic T cells (CTL). The monoclonal antibody according to claim 62, wherein the cell is a cancer cell. A monoclonal antibody or antigen-binding fragment thereof comprising a light chain complementarity determining region (CDR) having an amine at least 80% identical to at least one of the amino acid sequences set forth in SEQ ID NO: 1-3 amino acid sequence. A monoclonal antibody or antigen-binding fragment thereof comprising a light chain complementarity determining region (CDR) having an amine at least 90% identical to at least one of the amino acid sequences set forth in SEQ ID NO: 1-3 amino acid sequence. A monoclonal antibody or antigen-binding fragment thereof comprising a light chain complementarity determining region (CDR) having an amine at least 95% identical to at least one of the amino acid sequences set forth in SEQ ID NO: 1-3 amino acid sequence. A monoclonal antibody or antigen-binding fragment thereof comprising a light chain complementarity determining region (CDR) having an amine at least 99% identical to at least one of the amino acid sequences set forth in SEQ ID NO: 1-3 amino acid sequence. A monoclonal antibody or antigen-binding fragment thereof comprising a light chain complementarity determining region (CDR) having an amine group that is 100% identical to at least one of the amino acid sequences shown in SEQ ID NO: 1-3 acid sequence. The monoclonal antibody according to any one of claims 67 to 71, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a heavy chain complementarity determining region (CDR), and the CDR has the amine shown in SEQ ID NO: 4-6 Amino acid sequences that are at least 80% identical to at least one of the amino acid sequences. The monoclonal antibody according to any one of claims 67 to 71, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a heavy chain complementarity determining region (CDR), and the CDR has the amine shown in SEQ ID NO: 4-6 Amino acid sequences that are at least 90% identical to at least one of the amino acid sequences. The monoclonal antibody according to any one of claims 67 to 71, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a heavy chain complementarity determining region (CDR), and the CDR has the amine shown in SEQ ID NO: 4-6 Amino acid sequences that are at least 95% identical to at least one of the amino acid sequences. The monoclonal antibody according to any one of claims 67 to 71, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a heavy chain complementarity determining region (CDR), and the CDR has the amine shown in SEQ ID NO: 4-6 Amino acid sequences that are at least 99% identical to at least one of the amino acid sequences. The monoclonal antibody according to any one of claims 67 to 71, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a heavy chain complementarity determining region (CDR), and the CDR has the amine shown in SEQ ID NO: 4-6 Amino acid sequences that are 100% identical to at least one of the amino acid sequences. The monoclonal antibody according to any one of claims 67 to 76, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a light chain variable domain (VL), and the light chain variable domain comprises a sequence shown in SEQ ID NO: 7 An amino acid sequence that is at least 80% identical to the amino acid sequence. The monoclonal antibody according to any one of claims 67 to 77, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a heavy chain variable domain (VH), and the heavy chain variable domain comprises a sequence shown in SEQ ID NO: 8 An amino acid sequence that is at least 80% identical to the amino acid sequence. The monoclonal antibody according to any one of claims 67 to 78, wherein the monoclonal antibody or an antigen-binding fragment thereof selectively binds to a complex comprising HLA-E and a neoantigen. The monoclonal antibody according to any one of claims 67 to 79, wherein the monoclonal antibody or an antigen-binding fragment thereof has no binding affinity for the HLA-E alone. The monoclonal antibody according to any one of claims 67 to 80, wherein the monoclonal antibody or antigen-binding fragment thereof has no binding affinity for the neoantigen alone. The monoclonal antibody according to any one of claims 67 to 81, wherein the neoantigen is expressed by cells proficient in antigen processing mechanism (APM). The monoclonal antibody according to claim 82, wherein the neoantigen is expressed by cells proficient in TAP1/2. The monoclonal antibody according to any one of claims 67 to 83, wherein the neoantigen comprises, consists essentially of, or consists of the sequence according to SEQ ID NO: 18 (VMAPRTLFL). The monoclonal antibody according to any one of claims 67 to 84, wherein the HLA-E is HLA-E*0101 or HLA-E*0103. The monoclonal antibody according to claim 85, wherein the antibody selectively binds to a complex comprising: (a) the HLA-E*0101 and the neoantigen; (b) the HLA-E*0103 and the neoantigen; or (c) the HLA-E*0101 and the neoantigen, and the HLA-E*0103 and the neoantigen. The monoclonal antibody according to any one of claims 67 to 86, wherein the monoclonal antibody or an antigen-binding fragment thereof is a murine antibody, a chimeric antibody, a camelid antibody, a humanized antibody or a human antibody. The monoclonal antibody according to any one of claims 67 to 87, wherein the monoclonal antibody or an antigen-binding fragment thereof is a TCR-like antibody. The monoclonal antibody according to any one of claims 67 to 88, wherein the monoclonal antibody or an antigen-binding fragment thereof is a multispecific antibody. The monoclonal antibody according to any one of claims 67 to 89, wherein the monoclonal antibody or an antigen-binding fragment thereof is a bispecific antibody. The monoclonal antibody according to any one of claims 67 to 90, wherein the monoclonal antibody or an antigen-binding fragment thereof is a bispecific T cell engager (BiTE). The monoclonal antibody according to claim 91, wherein the BiTE binds to the CD3 protein associated with T cell receptor (TCR). The monoclonal antibody according to any one of claims 91 to 92, wherein the BiTE further comprises a light chain complementarity determining region (CDR), and the CDR has at least one of the amino acid sequences shown in SEQ ID NO: 9-11 One with at least 80% identical amino acid sequence. The monoclonal antibody according to any one of claims 91 to 93, wherein the BiTE further comprises a heavy chain complementarity determining region (CDR), and the CDR has at least one of the amino acid sequences shown in SEQ ID NO: 12-14 One with at least 80% identical amino acid sequence. The monoclonal antibody according to any one of claims 91 to 94, wherein the BiTE further comprises a light chain variable domain (VL), and the light chain variable domain comprises at least the amino acid sequence shown in SEQ ID NO: 15 80% identical amino acid sequence. The monoclonal antibody according to any one of claims 91 to 95, wherein the BiTE further comprises a heavy chain variable domain (VH), and the heavy chain variable domain comprises at least the amino acid sequence shown in SEQ ID NO: 16 80% identical amino acid sequence. The monoclonal antibody according to any one of claims 67 to 96, wherein the monoclonal antibody or an antigen-binding fragment thereof is a multifunctional antibody. The monoclonal antibody according to any one of claims 67 to 97, wherein the monoclonal antibody or an antigen-binding fragment thereof further comprises a binding therapeutic moiety. The monoclonal antibody according to any one of claims 67 to 98, wherein selective binding of the antibody to the complex comprising the HLA-E and the neoantigen induces an immune response in cells. The monoclonal antibody according to claim 99, wherein the immune response comprises activation of (i) NK cells, (ii) T cells or (iii) NK cells and T cells. The monoclonal antibody according to claim 100, wherein the T cells are CD4+ T cells or CD8+ T cells. The monoclonal antibody according to claim 99, wherein the immune response comprises activation of cytotoxic T cells (CTL). The monoclonal antibody according to claim 99, wherein the cell is a cancer cell. A monoclonal antibody or antigen-binding fragment thereof comprising a heavy chain complementarity determining region (CDR) having an amine at least 80% identical to at least one of the amino acid sequences set forth in SEQ ID NO: 4-6 amino acid sequence. A monoclonal antibody or antigen-binding fragment thereof comprising a heavy chain complementarity determining region (CDR) having an amine at least 90% identical to at least one of the amino acid sequences set forth in SEQ ID NO: 4-6 amino acid sequence. A monoclonal antibody or antigen-binding fragment thereof comprising a heavy chain complementarity determining region (CDR) having an amine at least 95% identical to at least one of the amino acid sequences set forth in SEQ ID NO: 4-6 amino acid sequence. A monoclonal antibody or antigen-binding fragment thereof comprising a heavy chain complementarity determining region (CDR) having an amine at least 99% identical to at least one of the amino acid sequences set forth in SEQ ID NO: 4-6 amino acid sequence. A monoclonal antibody or an antigen-binding fragment thereof comprising a heavy chain complementarity determining region (CDR) having an amine group that is 100% identical to at least one of the amino acid sequences shown in SEQ ID NO: 4-6 acid sequence. The monoclonal antibody according to any one of claims 104 to 108, wherein the monoclonal antibody or antigen-binding fragment comprises a light chain complementarity determining region (CDR), and the CDR has the amine group shown in SEQ ID NO: 1-3 Amino acid sequences that are at least 80% identical to at least one of the acid sequences. The monoclonal antibody according to any one of claims 104 to 108, wherein the monoclonal antibody or antigen-binding fragment comprises a light chain complementarity determining region (CDR), and the CDR has the amine group shown in SEQ ID NO: 1-3 Amino acid sequences that are at least 90% identical to at least one of the acid sequences. The monoclonal antibody according to any one of claims 104 to 108, wherein the monoclonal antibody or antigen-binding fragment comprises a light chain complementarity determining region (CDR), and the CDR has the amine group shown in SEQ ID NO: 1-3 Amino acid sequences that are at least 95% identical to at least one of the acid sequences. The monoclonal antibody according to any one of claims 104 to 108, wherein the monoclonal antibody or antigen-binding fragment comprises a light chain complementarity determining region (CDR), and the CDR has the amine group shown in SEQ ID NO: 1-3 Amino acid sequences that are at least 99% identical to at least one of the acid sequences. The monoclonal antibody according to any one of claims 104 to 108, wherein the monoclonal antibody or antigen-binding fragment comprises a light chain complementarity determining region (CDR), and the CDR has the amine group shown in SEQ ID NO: 1-3 Amino acid sequences that are 100% identical to at least one of the acid sequences. The monoclonal antibody according to any one of claims 104 to 113, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a heavy chain variable domain (VH), and the heavy chain variable domain comprises a sequence shown in SEQ ID NO: 8 An amino acid sequence that is at least 80% identical to the amino acid sequence. The monoclonal antibody according to any one of claims 104 to 114, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a light chain variable domain (VL), and the light chain variable domain comprises a sequence shown in SEQ ID NO: 7 An amino acid sequence that is at least 80% identical to the amino acid sequence. The monoclonal antibody according to any one of claims 104 to 115, wherein the monoclonal antibody or an antigen-binding fragment thereof selectively binds to a complex comprising HLA-E and a neoantigen. The monoclonal antibody according to any one of claims 104 to 116, wherein the monoclonal antibody or antigen-binding fragment thereof has no binding affinity for the HLA-E alone. The monoclonal antibody according to any one of claims 104 to 117, wherein the monoclonal antibody or antigen-binding fragment thereof has no binding affinity for the neoantigen alone. The monoclonal antibody according to any one of claims 104 to 118, wherein the neoantigen is expressed by cells proficient in antigen processing mechanism (APM). The monoclonal antibody according to claim 119, wherein the neoantigen is expressed by cells proficient in TAP1/2. The monoclonal antibody according to any one of claims 104 to 120, wherein the neoantigen comprises, consists essentially of, or consists of the sequence according to SEQ ID NO: 18 (VMAPRTLFL). The monoclonal antibody according to any one of claims 104 to 121, wherein the HLA-E is HLA-E*0101 or HLA-E*0103. The monoclonal antibody according to claim 122, wherein the antibody selectively binds to a complex comprising: (a) the HLA-E*0101 and the neoantigen; (b) the HLA-E*0103 and the neoantigen; or (c) the HLA-E*0101 and the neoantigen, and the HLA-E*0103 and the neoantigen. The monoclonal antibody according to any one of claims 104 to 123, wherein the monoclonal antibody or the antigen-binding fragment thereof is a murine antibody, a chimeric antibody, a camelid antibody, a humanized antibody or a human antibody. The monoclonal antibody according to any one of claims 104 to 124, wherein the monoclonal antibody or an antigen-binding fragment thereof is a TCR-like antibody. The monoclonal antibody according to any one of claims 104 to 125, wherein the monoclonal antibody or an antigen-binding fragment thereof is a multispecific antibody. The monoclonal antibody according to any one of claims 104 to 126, wherein the monoclonal antibody or an antigen-binding fragment thereof is a bispecific antibody. The monoclonal antibody according to any one of claims 104 to 127, wherein the monoclonal antibody or an antigen-binding fragment thereof is a bispecific T cell engager (BiTE). The monoclonal antibody according to claim 128, wherein the BiTE binds to the CD3 protein associated with T cell receptor (TCR). The monoclonal antibody according to any one of claims 128 to 129, wherein the BiTE further comprises a light chain complementarity determining region (CDR), and the CDR has at least one of the amino acid sequences shown in SEQ ID NO: 9-11 One with at least 80% identical amino acid sequence. The monoclonal antibody according to any one of claims 128 to 130, wherein the BiTE further comprises a heavy chain complementarity determining region (CDR), and the CDR has at least one of the amino acid sequences shown in SEQ ID NO: 12-14 One with at least 80% identical amino acid sequence. The monoclonal antibody according to any one of claims 128 to 131, wherein the BiTE further comprises a light chain variable domain (VL), and the light chain variable domain comprises at least the amino acid sequence shown in SEQ ID NO: 15 80% identical amino acid sequence. The monoclonal antibody according to any one of claims 128 to 132, wherein the BiTE further comprises a heavy chain variable domain (VH), and the heavy chain variable domain comprises at least the amino acid sequence shown in SEQ ID NO: 16 80% identical amino acid sequence. The monoclonal antibody according to any one of claims 104 to 133, wherein the monoclonal antibody or an antigen-binding fragment thereof is a multifunctional antibody. The monoclonal antibody according to any one of claims 104 to 134, wherein the monoclonal antibody or an antigen-binding fragment thereof further comprises a binding therapeutic moiety. The monoclonal antibody according to any one of claims 104 to 135, wherein selective binding of the antibody to the complex comprising the HLA-E and the neoantigen induces an immune response in cells. The monoclonal antibody according to claim 136, wherein the immune response comprises activation of (i) NK cells, (ii) T cells or (iii) NK cells and T cells. The monoclonal antibody according to claim 137, wherein the T cells are CD4+ T cells or CD8+ T cells. The monoclonal antibody according to claim 136, wherein the immune response comprises activation of cytotoxic T cells (CTL). The monoclonal antibody according to claim 136, wherein the cell is a cancer cell. A bispecific antibody or antigen-binding fragment thereof comprising: (a) a light chain complementarity determining region (CDR) having an amino acid sequence at least 80% identical to at least one of the amino acid sequences shown in SEQ ID NO: 1-3; or a heavy chain complementarity determining region A region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences shown in SEQ ID NO: 4-6; and (b) a light chain complementarity determining region (CDR) having an amino acid sequence at least 80% identical to at least one of the amino acid sequences shown in SEQ ID NO: 9-11; or a heavy chain complementarity determining region A region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences set forth in SEQ ID NO: 12-14. The bispecific antibody according to claim 141, wherein the bispecific antibody comprises: (a) a light chain variable domain (VL), the VL comprising an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 7; or a heavy chain variable domain (VH), the VH comprising an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 8; and (b) a light chain variable domain (VL), the VL comprising an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 15; or a heavy chain variable domain (VH), the VH Comprising an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 16. A bispecific antibody or antigen-binding fragment thereof comprising: (a) a light chain complementarity determining region (CDR) having an amino acid sequence at least 80% identical to at least one of the amino acid sequences shown in SEQ ID NO: 1-3; and a heavy chain complementarity determining region A region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences shown in SEQ ID NO: 4-6; and (b) a light chain complementarity determining region (CDR) having an amino acid sequence at least 80% identical to at least one of the amino acid sequences shown in SEQ ID NO: 9-11; and a heavy chain complementarity determining region A region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences set forth in SEQ ID NO: 12-14. The bispecific antibody according to claim 143, wherein the bispecific antibody comprises: (a) a light chain variable domain (VL), the VL comprising an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 7; and a heavy chain variable domain (VH), the VH comprising an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 8; and (b) a light chain variable domain (VL), the VL comprising an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 15; and a heavy chain variable domain (VH), the VH Comprising an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 16. The bispecific antibody according to any one of claims 141 to 144, wherein the bispecific antibody selectively binds to a complex comprising HLA-E and a neoantigen. The bispecific antibody according to any one of claims 141 to 145, wherein the bispecific antibody has no binding affinity for the HLA-E alone. The bispecific antibody according to any one of claims 141 to 146, wherein the bispecific antibody has no binding affinity for the neoantigen alone. The bispecific antibody according to any one of claims 141 to 147, wherein the neoantigen is expressed by cells proficient in antigen processing mechanism (APM). The bispecific antibody according to claim 148, wherein the neoantigen is expressed by cells proficient in TAP1/2. The bispecific antibody according to any one of claims 141 to 149, wherein the neoantigen comprises, consists essentially of, or consists of the sequence according to SEQ ID NO: 18 (VMAPRTLFL). The bispecific antibody according to any one of claims 141 to 150, wherein the HLA-E is HLA-E*0101 or HLA-E*0103. The bispecific antibody according to claim 151, wherein the antibody selectively binds to a complex comprising: (a) the HLA-E*0101 and the neoantigen; (b) the HLA-E*0103 and the neoantigen; or (c) the HLA-E*0101 and the neoantigen, and the HLA-E*0103 and the neoantigen. The bispecific antibody according to any one of claims 141 to 152, wherein the monoclonal antibody or the antigen-binding fragment thereof is a murine antibody, a chimeric antibody, a camelid antibody, a humanized antibody or a human antibody. The bispecific antibody according to any one of claims 104 to 153, wherein the monoclonal antibody or antigen-binding fragment thereof is a bispecific T cell engager (BiTE). The bispecific antibody according to claim 154, wherein the BiTE binds to the CD3 protein associated with T cell receptor (TCR). The bispecific antibody according to any one of claims 141 to 155, wherein the monoclonal antibody or antigen-binding fragment thereof is a multifunctional antibody. The bispecific antibody according to any one of claims 141 to 156, wherein the monoclonal antibody or antigen-binding fragment thereof further comprises a binding therapeutic moiety. The bispecific antibody according to any one of claims 141 to 157, wherein selective binding of the antibody to the complex comprising the HLA-E and the neoantigen induces an immune response in cells. The bispecific antibody according to claim 158, wherein the immune response comprises activation of (i) NK cells, (ii) T cells or (iii) NK cells and T cells. The bispecific antibody according to claim 159, wherein the T cells are CD4+ T cells or CD8+ T cells. The bispecific antibody according to claim 158, wherein the immune response comprises activation of cytotoxic T cells (CTL). The bispecific antibody according to claim 158, wherein the cell is a cancer cell. A pharmaceutical composition comprising: (a) the monoclonal antibody or its antigen-binding fragment according to any one of claims 1 to 140, or the bispecific antibody or its antigen according to any one of claims 141 to 162 a binding fragment; and (b) a pharmaceutically acceptable carrier or excipient. A method of treating cancer in an individual in need thereof, the method comprising administering to the individual an effective amount of a monoclonal antibody or antigen-binding fragment thereof comprising a light chain complementarity determining region (CDR) having the same sequence as SEQ ID NO: An amino acid sequence that is at least 80% identical to at least one of the amino acid sequences shown in 1-3. A method of treating cancer in an individual in need thereof, the method comprising administering to the individual an effective amount of a monoclonal antibody or an antigen-binding fragment thereof comprising a heavy chain complementarity determining region (CDR) having the same sequence as SEQ ID NO: An amino acid sequence that is at least 80% identical to at least one of the amino acid sequences shown in 4-6. The method according to claim 164 or 165, wherein the monoclonal antibody or its antigen-binding fragment comprises (a) a light chain complementarity determining region (CDR), and the CDR has the amino acid sequence shown in SEQ ID NO: 1-3 At least one of them has an amino acid sequence that is at least 80% identical; and (b) a heavy chain complementarity determining region (CDR), which has at least one of the amino acid sequences shown in SEQ ID NO: 4-6 or at least 80% identical amino acid sequences. The method according to any one of claims 164 to 166, wherein the monoclonal antibody or its antigen-binding fragment comprises (a) a light chain complementarity determining region (CDR), and the CDR has the same expression as shown in SEQ ID NO: 1-3 an amino acid sequence that is at least 90% identical to at least one of the amino acid sequences; and (b) a heavy chain complementarity determining region (CDR) having the amino acid sequence shown in SEQ ID NO: 4-6 At least one of them has at least 90% identical amino acid sequence. The method according to any one of claims 164 to 167, wherein the monoclonal antibody or its antigen-binding fragment comprises (a) a light chain complementarity determining region (CDR), which has the same expression as shown in SEQ ID NO: 1-3 an amino acid sequence that is at least 95% identical to at least one of the amino acid sequences; and (b) a heavy chain complementarity determining region (CDR) having the amino acid sequence shown in SEQ ID NO: 4-6 At least one of them has at least 95% identical amino acid sequence. The method according to any one of claims 164 to 168, wherein the monoclonal antibody or its antigen-binding fragment comprises (a) a light chain complementarity determining region (CDR), which has the same expression as shown in SEQ ID NO: 1-3 an amino acid sequence that is at least 99% identical to at least one of the amino acid sequences; and (b) a heavy chain complementarity determining region (CDR) having the amino acid sequence shown in SEQ ID NO: 4-6 At least one of them has at least 99% identical amino acid sequence. The method according to any one of claims 164 to 169, wherein the monoclonal antibody or its antigen-binding fragment comprises (a) a light chain complementarity determining region (CDR), which has the same expression as shown in SEQ ID NO: 1-3 An amino acid sequence that is 100% identical to at least one of the amino acid sequences; and (b) a heavy chain complementarity determining region (CDR), which has the same amino acid sequence as shown in SEQ ID NO: 4-6 100% identical amino acid sequence of at least one of them. The method according to any one of claims 164 to 170, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL), and the light chain variable domain comprises the amine shown in SEQ ID NO: 7 An amino acid sequence with at least 80% identity. The method according to any one of claims 164 to 171, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a heavy chain variable domain (VH), and the heavy chain variable domain comprises the amine shown in SEQ ID NO: 8 An amino acid sequence with at least 80% identity. The method according to any one of claims 164 to 172, wherein the monoclonal antibody or antigen-binding fragment thereof selectively binds to a complex comprising HLA-E and a neoantigen. The method according to any one of claims 164 to 173, wherein the monoclonal antibody or antigen-binding fragment thereof has no binding affinity for the HLA-E alone. The method according to any one of claims 164 to 174, wherein the monoclonal antibody or antigen-binding fragment thereof has no binding affinity for the neoantigen alone. The method according to any one of claims 164 to 175, wherein the neoantigen is expressed by cells proficient in antigen processing machinery (APM). The method of claim 176, wherein the neoantigen is expressed by cells proficient in TAP1/2. The method according to any one of claims 164 to 177, wherein the neoantigen comprises, consists essentially of, or consists of a sequence according to SEQ ID NO: 18 (VMAPRTLFL). The method according to any one of claims 164 to 178, wherein the HLA-E is HLA-E*0101 or HLA-E*0103. The method of claim 179, wherein the antibody selectively binds to a complex comprising: (a) the HLA-E*0101 and the neoantigen; (b) the HLA-E*0103 and the neoantigen; or (c) the HLA-E*0101 and the neoantigen, and the HLA-E*0103 and the neoantigen. The method according to any one of claims 164 to 180, wherein the monoclonal antibody or the antigen-binding fragment thereof is a murine antibody, a chimeric antibody, a camelid antibody, a humanized antibody or a human antibody. The method according to any one of claims 164 to 181, wherein the monoclonal antibody or antigen-binding fragment thereof is a TCR-like antibody. The method according to any one of claims 164 to 182, wherein the monoclonal antibody or antigen-binding fragment thereof is a multispecific antibody. The method according to any one of claims 164 to 183, wherein the monoclonal antibody or antigen-binding fragment thereof is a bispecific antibody. The method according to any one of claims 164 to 184, wherein the monoclonal antibody or antigen-binding fragment thereof is a bispecific T cell engager (BiTE). The method of claim 185, wherein the BiTE binds to a CD3 protein associated with a T cell receptor (TCR). The method according to any one of claims 185 to 186, wherein the BiTE further comprises a light chain complementarity determining region (CDR), and the CDR has at least one of the amino acid sequences shown in SEQ ID NO: 9-11 At least 80% identical amino acid sequence. The method according to any one of claims 185 to 187, wherein the BiTE further comprises a heavy chain complementarity determining region (CDR), and the CDR has at least one of the amino acid sequences shown in SEQ ID NO: 12-14 At least 80% identical amino acid sequence. The method according to any one of claims 185 to 188, wherein the BiTE further comprises a light chain variable domain (VL) comprising amino acids at least 80% identical to the amino acid sequence shown in SEQ ID NO: 15 sequence. The method according to any one of claims 185 to 189, wherein the BiTE further comprises a heavy chain variable domain (VH) comprising amino acids at least 80% identical to the amino acid sequence shown in SEQ ID NO: 16 sequence. The method according to any one of claims 164 to 190, wherein the monoclonal antibody or antigen-binding fragment thereof is a multifunctional antibody. The method according to any one of claims 164 to 191, wherein the monoclonal antibody or antigen-binding fragment thereof further comprises a binding therapeutic moiety. The method of any one of claims 164 to 192, wherein selective binding of the antibody to the complex comprising the HLA-E and the neoantigen induces an immune response in cells. The method according to claim 193, wherein the immune response comprises activation of (i) NK cells, (ii) T cells or (iii) NK cells and T cells. The method according to claim 194, wherein the T cells are CD4+ T cells or CD8+ T cells. The method of claim 193, wherein the immune response comprises activation of cytotoxic T cells (CTL). The method according to any one of claims 164 to 196, wherein the cancer is breast cancer, kidney cancer, lung cancer, ovarian cancer, colorectal cancer, pancreatic cancer, choriocarcinoma, non-small cell lung cancer (NSCLC), gastric cancer, Cervical or head and neck cancer. The method of any one of claims 164 to 196, wherein the cancer is myeloma, leukemia or lymphoma. The method of any one of claims 164 to 196, wherein the cancer is acute myeloid leukemia (AML), multiple myeloma, or myelodysplastic syndrome. The method of any one of claims 164 to 196, wherein the cancer is a B cell malignancy. The method of any one of claims 164 to 196, wherein the cancer is mantle cell lymphoma. A method of treating cancer in an individual in need thereof, the method comprising administering to the individual an effective amount of a bispecific antibody or antigen-binding fragment thereof, comprising: (a) a light chain complementarity determining region (CDR) having an amino acid sequence at least 80% identical to at least one of the amino acid sequences shown in SEQ ID NO: 1-3; or a heavy chain complementarity determining region A region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences shown in SEQ ID NO: 4-6; and (b) a light chain complementarity determining region (CDR) having an amino acid sequence at least 80% identical to at least one of the amino acid sequences shown in SEQ ID NO: 9-11; or a heavy chain complementarity determining region A region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences set forth in SEQ ID NO: 12-14. The method of claim item 199, wherein the bispecific antibody comprises: (a) a light chain variable domain (VL), the VL comprising an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 7; or a heavy chain variable domain (VH), the VH comprising an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 8; and (b) a light chain variable domain (VL), the VL comprising an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 15; or a heavy chain variable domain (VH), the VH Comprising an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 16. A method of treating cancer in an individual in need thereof, the method comprising administering to the individual an effective amount of a bispecific antibody or antigen-binding fragment thereof, comprising: (a) a light chain complementarity determining region (CDR) having an amino acid sequence at least 80% identical to at least one of the amino acid sequences shown in SEQ ID NO: 1-3; and a heavy chain complementarity determining region A region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences shown in SEQ ID NO: 4-6; and (b) a light chain complementarity determining region (CDR) having an amino acid sequence at least 80% identical to at least one of the amino acid sequences shown in SEQ ID NO: 9-11; and a heavy chain complementarity determining region A region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences set forth in SEQ ID NO: 12-14. The method of claim 204, wherein the bispecific antibody comprises: (a) a light chain variable domain (VL), the VL comprising an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 7; and a heavy chain variable domain (VH), the VH comprising an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 8; and (b) a light chain variable domain (VL), the VL comprising an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 15; and a heavy chain variable domain (VH), the VH Comprising an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 16. The method according to any one of claims 202 to 205, wherein the bispecific antibody or antigen-binding fragment thereof selectively binds to a complex comprising HLA-E and a neoantigen. The method according to any one of claims 202 to 206, wherein the bispecific antibody or antigen-binding fragment thereof has no binding affinity for the HLA-E alone. The method according to any one of claims 202 to 207, wherein the bispecific antibody or antigen-binding fragment thereof does not have binding affinity for the neoantigen alone. The method of any one of claims 202 to 208, wherein the neoantigen is expressed by cells proficient in antigen processing machinery (APM). The method of claim 209, wherein the neoantigen is expressed by cells proficient in TAP1/2. The method according to any one of claims 202 to 210, wherein the neoantigen comprises, consists essentially of, or consists of a sequence according to SEQ ID NO: 18 (VMAPRTLFL). The method according to any one of claims 202 to 211, wherein the HLA-E is HLA-E*0101 or HLA-E*0103. The method of claim 212, wherein the bispecific antibody selectively binds to a complex comprising: (a) the HLA-E*0101 and the neoantigen; (b) the HLA-E*0103 and the neoantigen; or (c) the HLA-E*0101 and the neoantigen, and the HLA-E*0103 and the neoantigen. The method according to any one of claims 202 to 213, wherein the bispecific antibody or antigen-binding fragment thereof is a murine antibody, a chimeric antibody, a camelid antibody, a humanized antibody or a human antibody. The method according to any one of claims 202 to 214, wherein the bispecific antibody or antigen-binding fragment thereof is a TCR-like antibody. The method according to any one of claims 202 to 215, wherein the bispecific antibody or antigen-binding fragment thereof is a bispecific T cell engager (BiTE). The method of claim 216, wherein the BiTE binds to a CD3 protein associated with a T cell receptor (TCR). The method according to any one of claims 202 to 217, wherein the bispecific antibody or antigen-binding fragment thereof is a multifunctional antibody. The method of any one of claims 202 to 218, wherein the bispecific antibody or antigen-binding fragment thereof further comprises a binding therapeutic moiety. The method of any one of claims 202 to 219, wherein selective binding of the antibody to the complex comprising the HLA-E and the neoantigen induces an immune response in cells. The method of claim 220, wherein the immune response comprises activation of (i) NK cells, (ii) T cells or (iii) NK cells and T cells. The method according to claim 221, wherein the T cells are CD4+ T cells or CD8+ T cells. The method of claim 221, wherein the immune response comprises activation of cytotoxic T cells (CTL). The method of any one of claims 202 to 223, wherein the bispecific antibody is administered in a therapeutically effective amount. The method according to any one of claims 202 to 224, wherein the cancer is breast cancer, kidney cancer, lung cancer, ovarian cancer, colorectal cancer, pancreatic cancer, choriocarcinoma, non-small cell lung cancer (NSCLC), gastric cancer, Cervical or head and neck cancer. The method of any one of claims 202 to 224, wherein the cancer is myeloma, leukemia or lymphoma. The method of any one of claims 202 to 224, wherein the cancer is acute myeloid leukemia (AML), multiple myeloma, or myelodysplastic syndrome. The method of any one of claims 202 to 224, wherein the cancer is a B cell malignancy. The method of any one of claims 202 to 224, wherein the cancer is mantle cell lymphoma. A monoclonal antibody or an antigen-binding fragment thereof comprising a light chain (LC) comprising an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 19. A monoclonal antibody or antigen-binding fragment thereof comprising a light chain (LC) comprising an amino acid sequence at least 90% identical to the amino acid sequence shown in SEQ ID NO: 19. A monoclonal antibody or an antigen-binding fragment thereof comprising a light chain (LC) comprising an amino acid sequence at least 95% identical to the amino acid sequence shown in SEQ ID NO: 19. A monoclonal antibody or an antigen-binding fragment thereof comprising a light chain (LC) comprising an amino acid sequence at least 99% identical to the amino acid sequence shown in SEQ ID NO: 19. A monoclonal antibody or an antigen-binding fragment thereof comprising a light chain (LC) comprising an amino acid sequence 100% identical to the amino acid sequence shown in SEQ ID NO: 19. The monoclonal antibody according to any one of claims 230 to 234, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a heavy chain (HC), and the heavy chain comprises at least the amino acid sequence shown in SEQ ID NO: 20 80% identical amino acid sequence. The monoclonal antibody according to any one of claims 230 to 234, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a heavy chain (HC), and the heavy chain comprises at least the amino acid sequence shown in SEQ ID NO: 20 90% identical amino acid sequence. The monoclonal antibody according to any one of claims 230 to 234, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a heavy chain (HC), and the heavy chain comprises at least the amino acid sequence shown in SEQ ID NO: 20 95% identical amino acid sequence. The monoclonal antibody according to any one of claims 230 to 234, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a heavy chain (HC), and the heavy chain comprises at least the amino acid sequence shown in SEQ ID NO: 20 99% identical amino acid sequence. The monoclonal antibody according to any one of claims 230 to 234, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a heavy chain (HC), and the heavy chain comprises the amino acid sequence 100 shown in SEQ ID NO: 20 % consistent amino acid sequence. The monoclonal antibody according to any one of claims 230 to 234, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a heavy chain (HC), and the heavy chain comprises at least the amino acid sequence shown in SEQ ID NO: 21 80% identical amino acid sequence. The monoclonal antibody according to any one of claims 230 to 234, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a heavy chain (HC), and the heavy chain comprises at least the amino acid sequence shown in SEQ ID NO: 21 90% identical amino acid sequence. The monoclonal antibody according to any one of claims 230 to 234, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a heavy chain (HC), and the heavy chain comprises at least the amino acid sequence shown in SEQ ID NO: 21 95% identical amino acid sequence. The monoclonal antibody according to any one of claims 230 to 234, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a heavy chain (HC), and the heavy chain comprises at least the amino acid sequence shown in SEQ ID NO: 21 99% identical amino acid sequence. The monoclonal antibody according to any one of claims 230 to 234, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a heavy chain (HC), and the heavy chain comprises the amino acid sequence 100 shown in SEQ ID NO: 21 % consistent amino acid sequence. A monoclonal antibody or an antigen-binding fragment thereof comprising a light chain (LC) comprising an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 22. A monoclonal antibody or an antigen-binding fragment thereof comprising a light chain (LC) comprising an amino acid sequence at least 90% identical to the amino acid sequence shown in SEQ ID NO: 22. A monoclonal antibody or an antigen-binding fragment thereof comprising a light chain (LC) comprising an amino acid sequence at least 95% identical to the amino acid sequence shown in SEQ ID NO: 22. A monoclonal antibody or an antigen-binding fragment thereof comprising a light chain (LC) comprising an amino acid sequence at least 99% identical to the amino acid sequence shown in SEQ ID NO: 22. A monoclonal antibody or an antigen-binding fragment thereof comprising a light chain (LC) comprising an amino acid sequence 100% identical to the amino acid sequence shown in SEQ ID NO: 22. The monoclonal antibody according to any one of claims 245 to 249, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a heavy chain (HC), and the heavy chain comprises at least the amino acid sequence shown in SEQ ID NO: 23 80% identical amino acid sequence. The monoclonal antibody according to any one of claims 245 to 249, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a heavy chain (HC), and the heavy chain comprises at least the amino acid sequence shown in SEQ ID NO: 23 90% identical amino acid sequence. The monoclonal antibody according to any one of claims 245 to 249, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a heavy chain (HC), and the heavy chain comprises at least the amino acid sequence shown in SEQ ID NO: 23 95% identical amino acid sequence. The monoclonal antibody according to any one of claims 245 to 249, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a heavy chain (HC), and the heavy chain comprises at least the amino acid sequence shown in SEQ ID NO: 23 99% identical amino acid sequence. The monoclonal antibody according to any one of claims 245 to 249, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a heavy chain (HC), and the heavy chain comprises the amino acid sequence 100 shown in SEQ ID NO: 23 % consistent amino acid sequence. A monoclonal antibody or an antigen-binding fragment thereof comprising a heavy chain (HC) comprising an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 20. A monoclonal antibody or an antigen-binding fragment thereof comprising a heavy chain (HC) comprising an amino acid sequence at least 90% identical to the amino acid sequence shown in SEQ ID NO: 20. A monoclonal antibody or an antigen-binding fragment thereof comprising a heavy chain (HC) comprising an amino acid sequence at least 95% identical to the amino acid sequence shown in SEQ ID NO: 20. A monoclonal antibody or an antigen-binding fragment thereof comprising a heavy chain (HC) comprising an amino acid sequence at least 99% identical to the amino acid sequence shown in SEQ ID NO: 20. A monoclonal antibody or an antigen-binding fragment thereof comprising a heavy chain (HC) comprising an amino acid sequence 100% identical to the amino acid sequence shown in SEQ ID NO: 20. A monoclonal antibody or an antigen-binding fragment thereof comprising a heavy chain (HC) comprising an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 21. A monoclonal antibody or an antigen-binding fragment thereof comprising a heavy chain (HC) comprising an amino acid sequence at least 90% identical to the amino acid sequence shown in SEQ ID NO: 21. A monoclonal antibody or an antigen-binding fragment thereof comprising a heavy chain (HC) comprising an amino acid sequence at least 95% identical to the amino acid sequence shown in SEQ ID NO: 21. A monoclonal antibody or an antigen-binding fragment thereof comprising a heavy chain (HC) comprising an amino acid sequence at least 99% identical to the amino acid sequence shown in SEQ ID NO: 21. A monoclonal antibody or an antigen-binding fragment thereof comprising a heavy chain (HC) comprising an amino acid sequence 100% identical to the amino acid sequence shown in SEQ ID NO: 21. The monoclonal antibody according to any one of claims 255 to 264, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a light chain (LC), and the light chain comprises at least the amino acid sequence shown in SEQ ID NO: 19 80% identical amino acid sequence. The monoclonal antibody according to any one of claims 255 to 264, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a light chain (LC), and the light chain comprises at least the amino acid sequence shown in SEQ ID NO: 19 90% identical amino acid sequence. The monoclonal antibody according to any one of claims 255 to 264, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a light chain (LC), and the light chain comprises at least the amino acid sequence shown in SEQ ID NO: 19 95% identical amino acid sequence. The monoclonal antibody according to any one of claims 255 to 264, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a light chain (LC), and the light chain comprises at least the amino acid sequence shown in SEQ ID NO: 19 99% identical amino acid sequence. The monoclonal antibody according to any one of claims 255 to 264, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a light chain (LC), and the light chain comprises the amino acid sequence 100 shown in SEQ ID NO: 19 % consistent amino acid sequence. A monoclonal antibody or an antigen-binding fragment thereof comprising a heavy chain (HC) comprising an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 23. A monoclonal antibody or an antigen-binding fragment thereof comprising a heavy chain (HC) comprising an amino acid sequence at least 90% identical to the amino acid sequence shown in SEQ ID NO: 23. A monoclonal antibody or an antigen-binding fragment thereof comprising a heavy chain (HC) comprising an amino acid sequence at least 95% identical to the amino acid sequence shown in SEQ ID NO: 23. A monoclonal antibody or an antigen-binding fragment thereof comprising a heavy chain (HC) comprising an amino acid sequence at least 99% identical to the amino acid sequence shown in SEQ ID NO: 23. A monoclonal antibody or an antigen-binding fragment thereof comprising a heavy chain (HC) comprising an amino acid sequence 100% identical to the amino acid sequence shown in SEQ ID NO: 23. The monoclonal antibody according to any one of claims 270 to 274, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a light chain (LC), and the light chain comprises at least the amino acid sequence shown in SEQ ID NO: 22 80% identical amino acid sequence. The monoclonal antibody according to any one of claims 270 to 274, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a light chain (LC), and the light chain comprises at least the amino acid sequence shown in SEQ ID NO: 22 90% identical amino acid sequence. The monoclonal antibody according to any one of claims 270 to 274, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a light chain (LC), and the light chain comprises at least the amino acid sequence shown in SEQ ID NO: 22 95% identical amino acid sequence. The monoclonal antibody according to any one of claims 270 to 274, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a light chain (LC), and the light chain comprises at least the amino acid sequence shown in SEQ ID NO: 22 99% identical amino acid sequence. The monoclonal antibody according to any one of claims 270 to 274, wherein the monoclonal antibody or an antigen-binding fragment thereof comprises a light chain (LC), and the light chain comprises the amino acid sequence 100 shown in SEQ ID NO: 22 % consistent amino acid sequence. The monoclonal antibody according to any one of claims 230 to 279, wherein the monoclonal antibody or an antigen-binding fragment thereof selectively binds to a complex comprising HLA-E and a neoantigen. The monoclonal antibody according to any one of claims 230 to 280, wherein the monoclonal antibody or antigen-binding fragment thereof does not have binding affinity for the HLA-E alone. The monoclonal antibody according to any one of claims 230 to 281, wherein the monoclonal antibody or antigen-binding fragment thereof has no binding affinity for the neoantigen alone. The monoclonal antibody according to any one of claims 230 to 282, wherein the neoantigen is expressed by cells proficient in antigen processing mechanism (APM). The monoclonal antibody according to claim 283, wherein the neoantigen is expressed by cells proficient in TAP1/2. The monoclonal antibody according to any one of claims 230 to 284, wherein the neoantigen comprises, consists essentially of, or consists of the sequence according to SEQ ID NO: 18 (VMAPRTLFL). The monoclonal antibody according to any one of claims 230 to 284, wherein the HLA-E is HLA-E*0101 or HLA-E*0103. The monoclonal antibody according to claim 286, wherein the antibody selectively binds to a complex comprising: (a) the HLA-E*0101 and the neoantigen; (b) the HLA-E*0103 and the neoantigen; or (c) the HLA-E*0101 and the neoantigen, and the HLA-E*0103 and the neoantigen. The monoclonal antibody according to any one of claims 230 to 287, wherein the monoclonal antibody or the antigen-binding fragment thereof is a murine antibody, a chimeric antibody, a camelid antibody, a humanized antibody or a human antibody. The monoclonal antibody according to any one of claims 230 to 288, wherein the monoclonal antibody or an antigen-binding fragment thereof is a TCR-like antibody. The monoclonal antibody according to any one of claims 230 to 289, wherein the monoclonal antibody or an antigen-binding fragment thereof is a multispecific antibody. The monoclonal antibody according to any one of claims 230 to 290, wherein the monoclonal antibody or an antigen-binding fragment thereof is a bispecific antibody. The monoclonal antibody according to any one of claims 230 to 291, wherein the monoclonal antibody or an antigen-binding fragment thereof is a bispecific T cell engager (BiTE). The monoclonal antibody according to claim 292, wherein the BiTE binds to the CD3 protein associated with T cell receptor (TCR). The monoclonal antibody according to any one of claims 292 to 293, wherein the BiTE further comprises a light chain variable domain (VL), and the light chain variable domain comprises at least the amino acid sequence shown in SEQ ID NO: 15 80% identical amino acid sequence. The monoclonal antibody according to any one of claims 292 to 293, wherein the BiTE further comprises a heavy chain variable domain (VH), and the heavy chain variable domain comprises at least the amino acid sequence shown in SEQ ID NO: 16 80% identical amino acid sequence. The monoclonal antibody according to any one of claims 280 to 295, wherein the monoclonal antibody or an antigen-binding fragment thereof is a multifunctional antibody. The monoclonal antibody according to any one of claims 280 to 296, wherein the monoclonal antibody or an antigen-binding fragment thereof further comprises a binding therapeutic moiety. The monoclonal antibody according to any one of claims 280 to 297, wherein selective binding of the antibody to the complex comprising the HLA-E and the neoantigen induces an immune response in cells. The monoclonal antibody according to claim 298, wherein the immune response comprises activation of (i) NK cells, (ii) T cells or (iii) NK cells and T cells. The monoclonal antibody according to claim 299, wherein the T cells are CD4+ T cells or CD8+ T cells. The monoclonal antibody according to claim 300, wherein the immune response comprises activation of cytotoxic T cells (CTL). The monoclonal antibody according to claim 298, wherein the cells are cancer cells.

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