Antibodies targeting complexes containing non-classical HLA-I and neoantigens, and methods of use thereof

Abstract

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

Description

[Technical field]

[0001] Related Applications This application claims priority to currently pending U.S. patent application Ser. No. 17 / 199,258, filed March 11, 2021, and currently pending U.S. Provisional Patent Application Ser. No. 63 / 032,886, filed June 1, 2020, the entire contents of each of which are incorporated herein by reference for all purposes. Summary of the Invention

[0002] In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO:7. In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising a light chain variable domain (VL) comprising an amino acid sequence at least 90% identical to the amino acid sequence set forth as SEQ ID NO:7. In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising a light chain variable domain (VL) comprising an amino acid sequence at least 95% identical to the amino acid sequence set forth as SEQ ID NO:7. In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising a light chain variable domain (VL) comprising an amino acid sequence at least 99% identical to the amino acid sequence set forth as SEQ ID NO:7. In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising a light chain variable domain (VL) comprising an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:7. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 8. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 90% identical to the amino acid sequence set forth as SEQ ID NO: 8. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 95% identical to the amino acid sequence set forth as SEQ ID NO: 8. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 99% identical to the amino acid sequence set forth as SEQ ID NO: 8.In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:8. 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 the neoantigen alone. In some embodiments, the neoantigen is expressed by antigen processing machinery (APM)-proficient cells. In some embodiments, the neoantigen is expressed by TAP1 / 2-proficient cells. 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 * In some embodiments, the monoclonal antibody is: * 0101 and neoantigens, (b) HLA-E * 0103 and neoantigens, or (c) HLA-E * 0101 and neoantigens and HLA-E *0103 and a neoantigen. 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, the monoclonal antibody or antigen-binding fragment thereof is a multispecific antibody. 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 inducing antibody (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 as 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 as 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 conjugated therapeutic moiety. In some embodiments, selective binding of the monoclonal 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 (CTLs). In some embodiments, the cells are cancer cells.

[0003] In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO:8. In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising a heavy chain variable domain (VH) comprising an amino acid sequence at least 90% identical to the amino acid sequence set forth as SEQ ID NO:8. In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising a heavy chain variable domain (VH) comprising an amino acid sequence at least 95% identical to the amino acid sequence set forth as SEQ ID NO:8. In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising a heavy chain variable domain (VH) comprising an amino acid sequence at least 99% identical to the amino acid sequence set forth as SEQ ID NO:8. In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising a heavy chain variable domain (VH) comprising an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:8. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO:7. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence at least 90% identical to the amino acid sequence set forth as SEQ ID NO:7. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence at least 95% identical to the amino acid sequence set forth as SEQ ID NO:7. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence at least 99% identical to the amino acid sequence set forth as SEQ ID NO:7.In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:7. 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 the neoantigen alone. In some embodiments, the neoantigen is expressed by antigen processing machinery (APM) proficient cells. In some embodiments, the neoantigen is expressed by TAP1 / 2 proficient cells. 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 * In some embodiments, the monoclonal antibody is: * 0101 and neoantigens, (b) HLA-E * 0103 and neoantigens, or (c) HLA-E * 0101 and neoantigens and HLA-E *0103 and a neoantigen. 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, the monoclonal antibody or antigen-binding fragment thereof is a multispecific antibody. 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 inducing antibody (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 as 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 as 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 conjugated therapeutic moiety. In some embodiments, selective binding of the monoclonal 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 (CTLs). In some embodiments, the cells are cancer cells.

[0004] In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising 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 set forth in SEQ ID NOs: 1-3. In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising a light chain complementarity determining region (CDR) having an amino acid sequence at least 90% identical to at least one of the amino acid sequences set forth in SEQ ID NOs: 1-3. In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising a light chain complementarity determining region (CDR) having an amino acid sequence at least 95% identical to at least one of the amino acid sequences set forth in SEQ ID NOs: 1-3. In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising a light chain complementarity determining region (CDR) having an amino acid sequence at least 99% identical to at least one of the amino acid sequences set forth in SEQ ID NOs: 1-3. In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising a light chain complementarity determining region (CDR) having an amino acid sequence 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 90% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 95% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6.In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 99% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region (CDR) having an amino acid sequence 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 7. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 8. 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 the neoantigen alone. In some embodiments, the neoantigen is expressed by antigen processing machinery (APM) proficient cells. In some embodiments, the neoantigen is expressed by TAP1 / 2 proficient cells. 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 * In some embodiments, the monoclonal antibody is HLA-E * 0101 and neoantigens, HLA-E * 0103 and neoantigens, or HLA-E * 0101 and neoantigens and HLA-E *0103 and a neoantigen. 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, the monoclonal antibody or antigen-binding fragment thereof is a multispecific antibody. 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 inducing antibody (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 at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 9-11. In some embodiments, the BiTE further comprises a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 80% identical to at least one of the amino acid sequences set forth as 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 as 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 as 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 conjugated therapeutic moiety. In some embodiments, the selective binding of the monoclonal antibody to a complex comprising HLA-E and a neoantigen induces an immune response in the cells. 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 (CTLs).In some embodiments, the cell is a cancer cell.

[0005] In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 80% identical to at least one of the amino acid sequences set forth in SEQ ID NOs: 4-6. In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 90% identical to at least one of the amino acid sequences set forth in SEQ ID NOs: 4-6. In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 95% identical to at least one of the amino acid sequences set forth in SEQ ID NOs: 4-6. In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 99% identical to at least one of the amino acid sequences set forth in SEQ ID NOs: 4-6. In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising a heavy chain complementarity determining region (CDR) having an amino acid sequence 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6. In some embodiments, the monoclonal antibody or antigen-binding fragment comprises 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 set forth as SEQ ID NOs: 1-3. In some embodiments, the monoclonal antibody or antigen-binding fragment comprises a light chain complementarity determining region (CDR) having an amino acid sequence at least 90% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3. In some embodiments, the monoclonal antibody or antigen-binding fragment comprises a light chain complementarity determining region (CDR) having an amino acid sequence at least 95% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3.In some embodiments, the monoclonal antibody or antigen-binding fragment comprises a light chain complementarity determining region (CDR) having an amino acid sequence at least 99% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3. In some embodiments, the monoclonal antibody or antigen-binding fragment comprises a light chain complementarity determining region (CDR) having an amino acid sequence 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3. In some embodiments, the monoclonal antibody or antigen-binding fragment comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 8. In some embodiments, the monoclonal antibody or antigen-binding fragment comprises a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 7. In some embodiments, the monoclonal antibody or antigen-binding fragment selectively binds to a complex comprising HLA-E and a neoantigen. In some embodiments, the monoclonal antibody or antigen-binding fragment has no binding affinity for HLA-E alone. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof has no binding affinity for the neoantigen alone. In some embodiments, the neoantigen is expressed by antigen processing machinery (APM) proficient cells. In some embodiments, the neoantigen is expressed by TAP1 / 2 proficient cells. 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 * In some embodiments, the monoclonal antibody is: * 0101 and neoantigens, (b) HLA-E * 0103 and neoantigens, or (c) HLA-E * 0101 and neoantigens and HLA-E *0103 and a neoantigen. 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, the monoclonal antibody or antigen-binding fragment thereof is a multispecific antibody. 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 inducing antibody (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 at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 9-11. In some embodiments, the BiTE further comprises a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 80% identical to at least one of the amino acid sequences set forth as 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 as 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 as 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 conjugated therapeutic moiety. In some embodiments, the selective binding of the monoclonal 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 cell is a CD4+ T cell or a CD8+ T cell.In some embodiments, the immune response comprises activation of cytotoxic T cells (CTLs).In some embodiments, the cell is a cancer cell.

[0006] In one embodiment herein, a bispecific antibody or an antigen-binding fragment thereof is disclosed, comprising 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 set forth as SEQ ID NOs: 1 to 3, or a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4 to 6, and 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 set forth as SEQ ID NOs: 9 to 11, or a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 12 to 14. In some embodiments, the bispecific antibody comprises (a) a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO:7, or a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO:8, and (b) a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as 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 set forth as SEQ ID NO:16. In one embodiment herein, a bispecific antibody or an antigen-binding fragment thereof is disclosed, comprising 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 set forth as SEQ ID NOs: 1 to 3, and a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4 to 6, and 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 set forth as SEQ ID NOs: 9 to 11, and a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 12 to 14.In some embodiments, the bispecific antibody comprises (a) a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO:7, and a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO:8, and (b) a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as 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 set forth as SEQ ID NO:16. In some embodiments, the bispecific antibody selectively binds 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 the neoantigen alone. In some embodiments, the neoantigen is expressed by antigen processing machinery (APM) proficient cells. In some embodiments, the neoantigen is expressed by TAP1 / 2 proficient cells. 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 * In some embodiments, the bispecific antibody is * 0101 and neoantigens, HLA-E * 0103 and neoantigens, or HLA-E * 0101 and neoantigens and HLA-E *0103 and a neoantigen. 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-inducing antibody (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 conjugated therapeutic moiety. In some embodiments, the selective binding of the bispecific antibody to a complex comprising HLA-E and a neoantigen induces an immune response in the cells. 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 (CTLs). In some embodiments, the cell is a cancer cell.

[0007] Disclosed in certain embodiments herein is a pharmaceutical composition comprising (a) a monoclonal antibody or antigen-binding fragment thereof disclosed herein, or a bispecific antibody or antigen-binding fragment thereof disclosed herein, and (b) a pharma- ceutically acceptable carrier or excipient.

[0008] Disclosed in certain embodiments herein is 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 an amino acid sequence at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3. Disclosed in certain embodiments herein is 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 heavy chain complementarity determining region (CDR) having an amino acid sequence at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises (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 set forth as SEQ ID NOs: 1-3, and (b) a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises (a) a light chain complementarity determining region (CDR) having an amino acid sequence at least 90% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, and (b) a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 90% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises (a) a light chain complementarity determining region (CDR) having an amino acid sequence at least 95% identical to at least one of the amino acid sequences set forth as SEQ ID NOs:1-3, and (b) a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 95% identical to at least one of the amino acid sequences set forth as SEQ ID NOs:4-6.In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises (a) a light chain complementarity determining region (CDR) having an amino acid sequence at least 99% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, and (b) a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 99% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises (a) a light chain complementarity determining region (CDR) having an amino acid sequence 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, and (b) a heavy chain complementarity determining region (CDR) having an amino acid sequence 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 7. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO:8. 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 the neoantigen alone. In some embodiments, the neoantigen is expressed by antigen processing machinery (APM) proficient cells. In some embodiments, the neoantigen is expressed by TAP1 / 2 proficient cells. 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 *In some embodiments, the monoclonal antibody is HLA-E * 0101 and neoantigens, HLA-E * 0103 and neoantigens, or HLA-E * 0101 and neoantigens and HLA-E *0103 and a neoantigen. 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, the monoclonal antibody or antigen-binding fragment thereof is a multispecific antibody. 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 inducing antibody (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 at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 9-11. In some embodiments, the BiTE further comprises a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 80% identical to at least one of the amino acid sequences set forth as 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 as 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 as 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 conjugated therapeutic moiety. In some embodiments, the selective binding of the monoclonal antibody to a complex comprising HLA-E and a neoantigen induces an immune response in the cells. 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 (CTLs). In some embodiments, the cancer is breast cancer, renal cancer, lung cancer, ovarian cancer, colon 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.

[0009] In certain embodiments herein, a method of treating cancer in an individual in need thereof is disclosed, the method comprising administering to the individual an effective amount of a bispecific antibody or an antigen-binding fragment thereof, the bispecific antibody comprising 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 set forth as SEQ ID NOs: 1-3, or a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, and 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 set forth as SEQ ID NOs: 9-11, or a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 12-14. 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 as SEQ ID NO:7, or a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO:8, and a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO:15, or a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO:16.In certain embodiments herein, a method of treating cancer in an individual in need thereof is disclosed, the method comprising administering to the individual an effective amount of a bispecific antibody or an antigen-binding fragment thereof, the bispecific antibody comprising 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 set forth as SEQ ID NOs: 1-3, and a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, and 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 set forth as SEQ ID NOs: 9-11, and a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 12-14. 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 as SEQ ID NO:7, and a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO:8, and a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as 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 set forth as SEQ ID NO:16. 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 the neoantigen alone. In some embodiments, the neoantigen is expressed by antigen processing machinery (APM) proficient cells. In some embodiments, the neoantigen is expressed by TAP1 / 2 proficient cells. 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 * In some embodiments, the bispecific antibody is * 0101 and neoantigens, HLA-E * 0103 and neoantigens, or HLA-E * 0101 and neoantigens and HLA-E *0103 and a neoantigen. In some embodiments, 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. 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 inducing antibody (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 conjugated therapeutic moiety. In some embodiments, the selective binding of the bispecific antibody to a complex comprising HLA-E and a neoantigen induces an immune response in the cells. 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 includes activation of cytotoxic T cells (CTLs). In some examples, the bispecific antibody is administered in a therapeutically effective amount. In some embodiments, the cancer is breast cancer, kidney cancer, lung cancer, ovarian cancer, colon 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.

[0010] In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising a light chain (LC) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 19. In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising a light chain (LC) comprising an amino acid sequence at least 90% identical to the amino acid sequence set forth as SEQ ID NO: 19. In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising a light chain (LC) comprising an amino acid sequence at least 95% identical to the amino acid sequence set forth as SEQ ID NO: 19. In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising a light chain (LC) comprising an amino acid sequence at least 99% identical to the amino acid sequence set forth as SEQ ID NO: 19. In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising a light chain (LC) comprising an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 19. 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 as 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 as 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 as 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 as 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 100% identical to the amino acid sequence set forth as SEQ ID NO:20.

[0011] 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 as 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 as 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 as 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 as 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 100% identical to the amino acid sequence set forth as SEQ ID NO:21.

[0012] In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising a light chain (LC) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO:22. In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising a light chain (LC) comprising an amino acid sequence at least 90% identical to the amino acid sequence set forth as SEQ ID NO:22. In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising a light chain (LC) comprising an amino acid sequence at least 95% identical to the amino acid sequence set forth as SEQ ID NO:22. In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising a light chain (LC) comprising an amino acid sequence at least 99% identical to the amino acid sequence set forth as SEQ ID NO:22. In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising a light chain (LC) comprising an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:22. 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 as 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 as 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 as 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 as 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 100% identical to the amino acid sequence set forth as SEQ ID NO:23.

[0013] In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising a heavy chain (HC) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO:20. In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising an amino acid sequence at least 90% identical to the amino acid sequence set forth as SEQ ID NO:20. In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising a heavy chain (HC) comprising an amino acid sequence at least 95% identical to the amino acid sequence set forth as SEQ ID NO:20. In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising a heavy chain (HC) comprising an amino acid sequence at least 99% identical to the amino acid sequence set forth as SEQ ID NO:20. In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising a heavy chain (HC) comprising an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:20. In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising a heavy chain (HC) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO:21. In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising an amino acid sequence at least 90% identical to the amino acid sequence set forth as SEQ ID NO:21. In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising a heavy chain (HC) comprising an amino acid sequence at least 95% identical to the amino acid sequence set forth as SEQ ID NO:21. In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising a heavy chain (HC) comprising an amino acid sequence at least 99% identical to the amino acid sequence set forth as SEQ ID NO:21. In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising a heavy chain (HC) comprising an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:21.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 as 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 as 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 as 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 as 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 as SEQ ID NO: 19.

[0014] In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising a heavy chain (HC) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO:23. In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising a heavy chain (HC) comprising an amino acid sequence at least 90% identical to the amino acid sequence set forth as SEQ ID NO:23. In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising a heavy chain (HC) comprising an amino acid sequence at least 95% identical to the amino acid sequence set forth as SEQ ID NO:23. In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising a heavy chain (HC) comprising an amino acid sequence at least 99% identical to the amino acid sequence set forth as SEQ ID NO:23. In certain embodiments herein, a monoclonal antibody or antigen-binding fragment thereof is disclosed, comprising a heavy chain (HC) comprising an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:23. 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 as 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 as 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 as 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 as 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 100% identical to the amino acid sequence set forth as 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 the neoantigen alone. In some embodiments, the neoantigen is expressed by antigen processing machinery (APM) proficient cells. In some embodiments, the neoantigen is expressed by TAP1 / 2 proficient cells. 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 * In some embodiments, the monoclonal antibody is: * 0101 and neoantigens, (b) HLA-E * 0103 and neoantigens, or (c) HLA-E * 0101 and neoantigens and HLA-E *0103 and a neoantigen. 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, the monoclonal antibody or antigen-binding fragment thereof is a multispecific antibody. 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 inducing antibody (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 as 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 as 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 conjugated therapeutic moiety. In some embodiments, selective binding of the monoclonal 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 (CTLs). In some embodiments, the cells are cancer cells. [Brief description of the drawings]

[0015] The novel features of the invention are set forth with particularity in the appended claims. To better understand the features and advantages of the present invention, reference should be made to the following detailed description that sets forth illustrative embodiments in which the principles of the invention are utilized and the accompanying drawings in which:

[0016] [Figure 1A] Figure 1 illustrates the identification and affinity characterization of clone R4 clone 1 (R4c1) against V-0025. (Figure 1A) Phage and (Figure 1B) monoclonal soluble ELISA. Antigen is 1 μg / ml. (Figure 1C) Binding affinity sensorgram and (Figure 1D) kinetic data. [Figure 1B] Figure 1 illustrates the identification and affinity characterization of clone R4 clone 1 (R4c1) against V-0025. (Figure 1A) Phage and (Figure 1B) monoclonal soluble ELISA. Antigen is 1 μg / ml. (Figure 1C) Binding affinity sensorgram and (Figure 1D) kinetic data. [Figure 1C] Figure 1 illustrates the identification and affinity characterization of clone R4 clone 1 (R4c1) against V-0025. (Figure 1A) Phage and (Figure 1B) monoclonal soluble ELISA. Antigen is 1 μg / ml. (Figure 1C) Binding affinity sensorgram and (Figure 1D) kinetic data. [Figure 1D] Figure 1 illustrates the identification and affinity characterization of clone R4 clone 1 (R4c1) against V-0025. (Figure 1A) Phage and (Figure 1B) monoclonal soluble ELISA. Antigen is 1 μg / ml. (Figure 1C) Binding affinity sensorgram and (Figure 1D) kinetic data. [Figure 2A] Figure 2A is an exemplary schematic diagram of a sorting diagram for isolating affinity matured clones from R4c1. Figure 2A illustrates a cell sorting plot showing each round of sorting for the first round of affinity maturation. "Stars" indicate sorted populations. [Figure 2B] FIG. 2B is an exemplary schematic diagram of a sorting diagram for isolating affinity matured clones from R4c1. FIG. 2B illustrates cell sorting plots showing each round of sorting for the first round of affinity maturation. "Stars" indicate sorted populations. [Figure 2C] FIG. 2C is an exemplary schematic diagram of a sorting diagram for isolating affinity matured clones from R4c1. FIG. 2C illustrates cell sorting plots showing each round of sorting for the first round of affinity maturation. "Stars" indicate sorted populations. [Figure 2D] FIG. 2D is an exemplary schematic diagram of a selection scheme for isolating affinity matured clones from R4c1. R4 selection (FIG. 2D) utilized Koff at 10 nM with V-0025 using 1 μM R4c1-IgG1 as antibody sink at various time points. [Figure 3A] Figure 3 illustrates clones identified from affinity maturation of R4c1.Figure 3A illustrates the binding profile to the target antigen (V-0025) at 100 nM. [Figure 3B] Figure 3A illustrates clones identified from affinity maturation of R4c1.Figure 3B illustrates the binding profile to the target antigen (V-0025) at 100 nM. [Figure 3C] Figure 3C illustrates the binding profile to the target antigen (V-0025) at 100 nM of clones identified from affinity maturation of R4c1. [Figure 3D] Figure 3A illustrates clones identified from affinity maturation of R4c1.Figure 3D illustrates the binding profile to the target antigen (V-0025) at 100 nM. [Figure 3E] Figure 3 illustrates clones identified from affinity maturation of R4c1. Figure 3E illustrates the binding profile of clone (R2A_1) to target (V-0025) at 10 nM and additional peptide / HLAe antigen at 100 nM. [Figure 3F] Figure 3 illustrates clones identified from affinity maturation of R4c1. Figure 3F illustrates the binding profile of clone (R2A_1) to target (V-0025) at 10 nM and additional peptide / HLAe antigen at 100 nM. [Figure 3G]Figure 3 illustrates clones identified from affinity maturation of R4c1. Figure 3G illustrates the binding profile of clone (R2A_1) to target (V-0025) at 10 nM and additional peptide / HLAe antigen at 100 nM. [Figure 4] FIG. 1 illustrates R2A_1 binding to A549-B4 cells. [Figure 5A] Figure 5 illustrates the isolation process for clone improvement by affinity maturation of the CDRL3 region of R2A_1. Figure 5A illustrates the binding to target (V-0025) by the parent clone (R4 clone 1), the starting affinity maturation library (R0), and the first round selection library (R1). Target (V-0025) is 10 nM with R2A_1-hIgG1 as antibody sink at 1 μM for 15 min up to 90 min. [Figure 5B] Figure 5A illustrates the isolation process for clone improvement by affinity maturation of the CDRL3 region of R2A_1. Figure 5B illustrates the Koff of the R1 affinity maturation library. Target (V-0025) is 10 nM with R2A_1-hIgG1 as the antibody sink at 1 μM for 15 min up to 90 min. [Figure 6A] Figure 1 illustrates a schematic of selection to isolate clones with higher binding affinity than the parent. Cell sorting plot shows the first round of selection for affinity maturation. Asterisks indicate the sorted population. R2 selection utilized R2A_1-IgG1 at 1 μM for 45 min as antibody sink with V-0025 at Koff 10 nM. [Figure 6B] Figure 1 illustrates a schematic of selection to isolate clones with higher binding affinity than the parent. Cell sorting plot shows the second round of selection for affinity maturation. Asterisks indicate the sorted population. R2 selection utilized R2A_1-IgG1 at 1 μM as antibody sink for 45 min with V-0025 at Koff 10 nM. [Figure 7] FIG. 1 illustrates affinity maturation of the CDRL3 region of R2A_1 and identification of clones from binding profiles to V-0025 at 1 nM and 0.1 nM. Arrows indicate top clones. [Figure 8A] FIG. 1 illustrates QC data for production of ABX0011. [Figure 8B] FIG. 1 illustrates QC data for production of ABX0011. [Figure 9A] Figure 3 illustrates the binding specificity, affinity, and stability of ABX0011. ELISA Specificity for antigen with HLA-E (clone 3D12). In the ELISA assay, the antibody was used at 1 mg / ml and the HLA-E / peptide antigen was used at 0.5 mg / ml. [Figure 9B] Figure 3 illustrates the binding specificity, affinity, and stability of ABX0011. Specificity for antigen by ABX0011. In the ELISA assay, the antibody was used at 1 mg / ml and the HLA-E / peptide antigen was used at 0.5 mg / ml. [Figure 9C] Figure 3 illustrates the binding specificity, affinity, and stability of ABX0011. The monovalent affinity of ABX0011 to target V-0025 was determined using a ResoSens label-free instrument (Resonant Sensors, Inc. Arlington, TX). [Figure 9D] Figure 1 illustrates the binding specificity, affinity, and stability of ABX0011. The detection limit for ABX0011 compared to clone 3D12 was assessed by ELISA. ABX0011 and HLA-E were used at 1 μg / mL, while V-0025 was titrated from 1 μg / mL to 0.001 μg / mL. [Figure 9E] Figure 9 illustrates the binding specificity, affinity, and stability of ABX0011. The detection limit for ABX0011 compared to clone 3D12 was assessed by ELISA. Figure 9E shows that target V-0025 was used at 0.25 μg / mL, while ABX0011 and HLA-E were titrated from 2 μg / mL to 3.8 pg / mL (3.8x10-6 μg / mL). [Figure 9F]Figure 1 illustrates the binding specificity, affinity, and stability of ABX0011. The heat resistance of ABX0011 was assessed by ELISA. ABX0011 binding to HLA-E / VMAPRTLFL was assessed after incubating the antibody in mouse serum at 37°C for 7-14 days. [Figure 9G] Figure 3 illustrates the binding specificity, affinity, and stability of ABX0011. Selectivity of binding of clone 3D12 and ABX0011 to unpulsed and peptide-pulsed K562.E cells. K562.E cells were pulsed with 20 μM peptide for 2 hours followed by staining with 1 μg / mL antibody. Further evaluation of the binding selectivity of ABX0011 was performed using ABX0012 (ABX0011 with mouse IgG1) along with related and irrelevant peptides. [Figure 9H] Figure 2 illustrates the binding specificity, affinity, and stability of ABX0011.HLA-E staining on peptide-pulsed and unpulsed K562.E cells. [Figure 9I] Figure 2 illustrates the binding specificity, affinity, and stability of ABX0011. Staining of ABX0012 on peptide-pulsed and unpulsed K562.E cells. [Figure 9J] Figure 1 illustrates the binding specificity, affinity, and stability of ABX0011. The detection limit for ABX0011 was determined in K562.E pulsed with the target V-0025 peptide. Controls were unpulsed K562.E cells, and parental K562 (lacking HLA-E expression) and K562.E cells pulsed with irrelevant peptides (V-0034, V-0044, V-0046, and P-0550). [Figure 9K] Figure 1 illustrates the binding specificity, affinity, and stability of ABX0011. Epitope mapping for ABX0011 was performed using K562.E cells pulsed with alanine-substituted V-0025 peptide. [Figure 10A]Figure 2 illustrates the binding specificity of ABX0011 to cell lines expressing HLA-E and HLAg. Antibody binding was tested at 1 μg / mL. Binding to IFNγ stimulated JEG3 wild type (WT, top panel), JEG3 Eko (middle panel), and JEG3 Tap-1ko (bottom panel). [Figure 10B] Figure 3 illustrates that no binding was observed to human peripheral blood mononuclear cells (huPBMCs) lacking HLA-G and primary human umbilical vascular endothelial cells (huVECs). Antibody binding was tested at 1 μg / mL. Binding to huPBMCs. [Figure 10C] FIG. 2 illustrates that no binding was observed to human peripheral blood mononuclear cells (huPBMC) lacking HLA-G and primary human umbilical vascular endothelial cells (huVEC). Antibody binding was tested at 1 μg / mL. Binding to huVEC. [Figure 11A] Figure 1 illustrates 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 1ug / ml of antibody using 3D12 (HLA-E), MEMg / 09 (HLA-G), and W632 (pan HLA I). [Figure 11B] Figure 1 illustrates binding to AML cell lines expressing both HLA-E and HLA-G (THP-1 and OCI-AML3) or only HLA-E (KG-1). Binding was observed to target positive AML cell lines with increasing doses (10 to 0.004 mg / ml) of ABX0012 (ABX0011 with mouse IgG1). [Figure 12A] FIG. 2 illustrates that ABX0011 mediated NK cytotoxicity against target-expressing tumor cell lines. NK cells were co-cultured with K562.E cells pulsed with V-0025 peptide or THP-1 cells with isotype control (hIgG1). The frequency of CD107a positive NK cells and CD107a positive NKG2A+ NK cells is shown. [Figure 12B]FIG. 2 illustrates that ABX0011 mediated NK cytotoxicity against target-expressing tumor cell lines. NK cells were co-cultured with K562.E cells pulsed with V-0025 peptide or THP-1 cells with isotype control (hIgG1). The frequency of CD107a positive NK cells and CD107a positive NKG2A+ NK cells is shown. [Figure 12C] FIG. 12C illustrates that ABX0011 mediated NK cytotoxicity against target-expressing tumor cell lines. NK cells were co-cultured with K562.E cells pulsed with V-0025 peptide or THP-1 cells with isotype control (hIgG1). The frequency of killed target cells (K562.E) is shown in FIG. 12C. [Figure 12D] FIG. 12D illustrates that ABX0011 mediated NK cytotoxicity against target-expressing tumor cell lines. NK cells were co-cultured with K562.E cells pulsed with V-0025 peptide or THP-1 cells with isotype control (hIgG1). The frequency of THP-1 cells is shown in FIG. 12D. [Figure 13A] Illustrates the production and QC data for ABX0030, a bispecific T cell inducing antibody containing the VL and VH domains of ABX0011 covalently linked to an anti-CD3 scFv fragment. [Figure 13B] Illustrates the production and QC data for ABX0030, a bispecific T cell inducing antibody containing the VL and VH domains of ABX0011 covalently linked to an anti-CD3 scFv fragment. [Figure 14] FIG. 1 illustrates the affinity analysis of ABX0030. [Figure 15] FIG. 2 illustrates that ABX0030 binding to K562.E cells is peptide specific. Only K562.E cells pulsed with V-0025 targeting peptide were stained with ABX0030 in a dose-dependent manner. Control cells, parental K562 and K562.E without peptide, did not stain with ABX0030. [Figure 16]1 is an exemplary histogram illustrating that ABX0030 stains human CD3+ cells but not CD3neg cells. PBMCs were stained with GAH-APC conjugate and anti-CD3 (clone SK7) (lower left histogram). PBMCs were stained with anti-CD4 and GAH-APC (upper left histogram). CD3+ cells were stained with ABX0030+GAH-APC conjugate (without SK7 Ab) (upper right histogram). Double staining with anti-CD-4-PE and ABX0030+GAH-APC conjugate (upper right histogram). Note that there are two CD3+ cell populations in this panel, representing CD4+ and CD8+ T cells. Double staining of CD3+ cells with ABX0030 and clone SK7-PE (lower right histogram). [Figure 17A] Figure 17 illustrates the performance of ABX0030 to specifically activate CD8+ T cells and redirect T cell lysis of target positive cells. Figure 17A shows specifically redirected T cell lysis of K562.E cells pulsed with V-0025 targeting peptide by ABX0030. When ABX0030 was used at 10,000 pM (highest concentration), some lysis activity was observed in K562.E (unpulsed) cells. CD8+ T cell CD25 and CD107a expression was also quantified to determine whether ABX0030 could non-specifically activate T cells. [Figure 17B] FIG. 1 illustrates the performance of ABX0030 to specifically activate CD8+ T cells and redirect T cell lysis of target positive cells. ABX0030 exhibited minimal activation of CD8+ T cells in the presence of K562.E unpulsed cells (no target). [Figure 17C] FIG. 1 illustrates the performance of ABX0030 to specifically activate CD8+ T cells and redirect T cell lysis of target positive cells. ABX0030 exhibited minimal activation of CD8+ T cells in the presence of K562.E unpulsed cells (no target). [Figure 18A]Figure 18 illustrates the potent activity of ABX0030 to redirect CD8+ T cell lysis of THP-1 cells. Figure 18A shows the dose-dependent effect of ABX0030 (10000 to 80 pM) to redirect CD8+ T cell lysis of THP-1 cells. ABX0030 activated CD8+ T cells in the presence of THP-1 cells. [Figure 18B] Figure 18A illustrates the potent activity of ABX0030 to redirect CD8+ T cell lysis of THP-1 cells. Figure 18B shows the dose-dependent effect of ABX0030 on the frequency of CD25+CD8+ T cells. [Figure 18C] FIG. 1 illustrates the potent activity of ABX0030 to redirect CD8+ T cell lysis of THP-1 cells. An additional marker demonstrating the effect of ABX0030 on CD8+ T cells in the presence of THP-1 cells is the increased frequency of CD107+CD8+ T cells. [Figure 18D] FIG. 1 illustrates the potent activity of ABX0030 to redirect CD8+ T cell lysis of THP-1 cells. An additional marker demonstrating the effect of ABX0030 on CD8+ T cells in the presence of THP-1 cells is the increased frequency of perforin-positive CD8+ T cells. [Figure 18E] FIG. 1 illustrates the potent activity of ABX0030 to redirect CD8+ T cell lysis of THP-1 cells. An additional marker demonstrating the effect of ABX0030 on CD8+ T cells in the presence of THP-1 cells is the increased frequency of IFNγ-positive CD8+ T cells. [Figure 19A] FIG. 1 illustrates that immune cells in the periphery do not bind ABX0012. Total PBMC, enriched or purified cells were tested for HLA-E, HLA-G or ABX0012 expression. Grey represents isotype staining and black lines represent antibody staining. Platelet staining represents 2 donors. B cell staining represents 6 donors. T cell and NK cell staining represents 10 donors. Neutrophil and eosinophil staining represents 7 donors. DC staining represents 4 donors. Monocyte staining represents 4 donors. Macrophage staining represents 10 donors. N / T means not available. [Figure 19B] FIG. 1 illustrates that immune cells in the periphery do not bind ABX0012. Total PBMC, enriched or purified cells were tested for HLA-E, HLA-G or ABX0012 expression. Grey represents isotype staining and black lines represent antibody staining. Platelet staining represents 2 donors. B cell staining represents 6 donors. T cell and NK cell staining represents 10 donors. Neutrophil and eosinophil staining represents 7 donors. DC staining represents 4 donors. Monocyte staining represents 4 donors. Macrophage staining represents 10 donors. N / T means not available. [Figure 20A] FIG. 1 illustrates that stimulation of PBMCs with IFNγ does not induce ABX0012 binding. PBMCs were stained overnight without IFNγ and examined for expression of HLA-E (clone 3D12), denatured-HLA-E (clone MEM-E / 02), or ABX0023. Grey represents isotype staining, black lines represent antibody staining. Staining represents two donors. [Figure 20B] FIG. 1 illustrates that stimulation of PBMCs with IFNγ does not induce ABX0012 binding. PBMCs were stained overnight with IFNγ and examined for expression of HLA-E (clone 3D12), denatured-HLA-E (clone MEM-E / 02), or ABX0023. Grey represents isotype staining, black lines represent antibody staining. Staining represents two donors. [Figure 21] FIG. 1 illustrates that HLA-E positive HLA-G positive cell lines exhibit ABX0012 binding without stimulation. Either ABX0012 (mouse Fc) or ABX0011 (human Fc) were used for staining, depending mainly on cell line Fc receptor expression. Grey represents isotype staining, black line represents antibody staining. [Figure 22]FIG. 1 illustrates that cell lines exhibiting ABX0012 binding without stimulation show increased ABX0012 binding with IFNγ stimulation. Cells were stimulated with IFNγ for 24 hours. Depending primarily on cell line Fc receptor expression, either ABX0012 (mouse Fc) or ABX0011 (human Fc) were used for staining. Grey represents isotype staining and black lines represent antibody staining. [Figure 23] FIG. 1 illustrates that HLA-E-less cell lines do not exhibit ABX0011 binding. ABX0011 (human Fc) was used for staining. Grey represents isotype staining, black line represents antibody staining. [Figure 24A] FIG. 1 illustrates that HLA-G-less cell lines do not exhibit ABX0012 binding. Cells were not stimulated. Grey represents isotype staining, black line represents antibody staining. N / T means not tested. [Figure 24B] FIG. 1 illustrates that HLA-G-negative cell lines do not exhibit ABX0012 binding. Cells were stimulated with IFNγ for 24 hours. Grey represents isotype staining, black line represents antibody staining. N / T means not tested. [Diagram 25] Figure 25 illustrates that ABX0012 binding requires HLA-E and Tap1 peptide treatment. (Figure 25A) JEG3 cells were stimulated with IFNγ for 24 hours prior to staining. (Figure 25B) OCI-AML3 cells were not stimulated. Either ABX0012 (mouse Fc) or ABX0011 (human Fc) was used for staining. Grey represents isotype staining and black line represents antibody staining. N / T means not available. [Figure 26] FIG. 1 illustrates AML PBMC binding to ABX0012. CD45dim cells were examined for ABX0012 binding in healthy PBMC (n=6), AML PBMC (n=18), cord blood (n=3), and healthy bone marrow (n=3). Percentage of binding is calculated as percent of binding by ABX0012 minus percent binding by mouse IgG1 isotype control. **p=0.0074. [Figure 27]Figure 1 illustrates that ABX-0012 stains K562.E cells pulsed with a specific peptide. Frozen cell blocks for immunohistochemistry were prepared by pelleting K562 and K562.HLA-E+V-0025(VMAPRTLFL) peptide-pulsed cells, treating with OCI compound, and flash-frozen. ABX-0012 antibody (1.95ug / ml) was used to stain K562.E+V-0025 and K562 cells. The top panel shows positive ABX-0012 staining, while control cells (bottom panel) are not stained. These findings validate the method of using ABX-0012 to stain frozen tissue sections. [Figure 28] FIG. 1 illustrates positive ABX-0012 staining of human placental tissue, specifically trophoblast cells. [Figure 29A] Figure 29 illustrates frozen section samples of head and neck tumors and normal adjacent tissue (NAT). Figure 29A shows staining with anti-HLA-E antibody (2.25ug / ml) (left) and ABX0012 antibody (1.95ug / ml) (right). [Figure 29B] Figure 29 illustrates frozen section samples of head and neck tumors and normal adjacent tissue (NAT). Figure 29B shows NAT staining with anti-HLA-E antibody (left) but not with ABX-0012 antibody (right). [Diagram 30] Figure 1 illustrates frozen section samples of colon adenocarcinoma and NAT, the left panel shows staining with anti-HLA-E antibody (2.25ug / ml) and the right panel shows staining with ABX0012 antibody (1.95ug / ml). [Figure 31A] Illustrative of frozen section samples of lung squamous cell carcinoma and NAT. Figure 31A shows staining with anti-HLA-E antibody (2.25ug / ml) (left panel) and ABX0012 antibody (1.95ug / ml) (right panel). [Figure 31B] Figure 31A illustrates frozen section samples of lung squamous cell carcinoma and NAT. Figure 31B shows no ABX-0012 staining of normal adjacent lung tissue. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] In certain embodiments herein, an antibody is disclosed that includes at least one heavy chain that includes a heavy chain variable domain (VH) and at least one light chain that includes a light chain variable domain (VL). Each of the VH and VL includes 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 inducing antibody (BiTE). In some embodiments, the bispecific antibody binds to the CD3 protein associated with the T cell receptor (TCR). Further, in certain embodiments herein, a method is disclosed for treating cancer by administering an antibody that selectively binds to a complex that includes a non-classical HLA-I (e.g., HLA-E) and a neoantigen. In some embodiments, the antibody that selectively binds to a complex that includes a non-classical HLA-I (e.g., HLA-E) and a neoantigen treats cancer by modulating the immune response against cancer cells. In some embodiments, the antibody is a bispecific antibody.

[0018] Conventional cancer treatment methods include surgery, radiation therapy, chemotherapy and hormone therapy.However, these treatments have not proven to be effective by themselves.It is important to develop alternative therapies to prevent and / or treat cancer.More recently, immunotherapy using antibodies and T lymphocytes and gene therapy have been found to be new and promising methods for treating cancer.

[0019] Major histocompatibility complex (MHC) molecules, referred to in humans as human leukocyte antigens (HLA), play a key role in the body's disease recognition and therefore immune response to cancer and invading antigens. This HLA gene family is divided into two subgroups, namely HLA class I (HLA-I) and HLA class II (HLA-II), which are further divided into classical HLA-I and non-classical HLA-I. Each HLA molecule forms a complex with one peptide from within the cell. Cancer cells uniquely present a portion of the peptide / HLA complex that allows the immune system to recognize and kill the cancer cells. Cells decorated with such unique peptide / HLA complexes are recognized and killed by cytotoxic T cells (CTLs). Cancer cells show downregulation of classical HLA-I expression but upregulation of non-classical HLA-I expression (e.g., HLA-E). Therefore, non-classical HLA-I-peptide complexes upregulated and uniquely presented on cancer cells are new targets for developing innovative immunotherapies to treat cancer.

[0020] Specific Terms Unless otherwise defined, 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 the foregoing general description and the following detailed description are exemplary and illustrative only and are not intended to limit the scope of any subject matter claimed. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0021] As used herein, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an antibody" includes a plurality of antibodies, in some embodiments reference to "an antibody" includes a plurality of antibodies, and so forth.

[0022] As used herein, all numerical values ​​or ranges of values ​​include whole integers and fractions of numerical values ​​or integers within or encompassing the range unless the context clearly indicates otherwise. Thus, for example, a reference to a range of 90-100% includes 91%, 92%, 93%, 94%, 95%, 95%, 97%, 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. In another example, a reference to a range of 1 to 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, as well as 1.1, 1.2, 1.3, 1.4, 1.5 times, etc., 2.1, 2.2, 2.3, 2.4, 2.5 times, etc.

[0023] As used herein, a number preceded by "about" refers to a range that includes that number, as well as a range that extends from less than 10% to more than 10% of that number. A range preceded by "about" refers to less than 10% at the lower limit of that range to more than 10% at the upper limit of that range.

[0024] As used herein, the term "MHC" refers to the major histocompatibility complex, a set of genetic loci that specify the major histocompatibility antigens. As used herein, the term "HLA" refers to human leukocyte antigens, a histocompatibility antigen found in humans. As used herein, "HLA" is the human form of "MHC" and these terms are used interchangeably.

[0025] As used herein, the term "antibody" refers to a glycoprotein that exhibits binding specificity to a specific antigen. Antibodies herein also include the "antigen-binding portion" of an antibody or fragments thereof capable of binding to an antigen. The term includes, but is not limited to, polyclonal, monoclonal, monospecific, multispecific (e.g., bispecific), natural, humanized, human, chimeric, synthetic, recombinant, cross-linked, mutated, grafted, antibody fragments (e.g., a portion of a full-length antibody, usually its antigen-binding or variable region, e.g., Fab, Fab', F(ab')2, Fv fragments), and in vitro generated antibodies, so long as they exhibit the desired biological activity. The term also includes single chain antibodies, e.g., single chain Fv (sFv or scFv) antibodies, in which the variable heavy chain and the variable light chain are linked together (directly or via a peptide linker) to form a continuous polypeptide.

[0026] As used herein, "CDR" refers to an immunoglobulin (Ig) hypervariable domain. The CDRs may be defined in any suitable manner. 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, the AbM definition, the contact definition, and / or a combination of the Kabat, Chothia, AbM, and / or contact definitions, which may yield different results.

[0027] As used herein, the term "selectively binds" in the context of any binding agent, e.g., an antibody, refers to a binding agent that binds to an antigen or epitope, such as with high affinity, but does not significantly bind to other, unrelated antigens or epitopes.

[0028] As used herein, the terms "neoantigen" or "neopeptide" are used interchangeably and refer to peptides that are differentially expressed by diseased or stressed cells (e.g., cancer cells) compared to healthy cells.

[0029] The terms "recipient," "individual," "subject," "host," and "patient" are used interchangeably herein and refer to any mammalian subject, particularly humans, for whom diagnosis, treatment, or therapy, as the case may be, is desired. None of these terms require the supervision of a medical professional.

[0030] As used herein, terms such as "treatment" and "treating" refer to the administration of an agent or the performance of a procedure, as the case may be, for the purpose of obtaining a certain effect. The effect may be prophylactic, in terms of the complete or partial prevention of a disease or its symptoms, and / or therapeutic, in terms of the achievement of a partial or complete cure of a disease and / or its symptoms. "Treatment," as used herein, may include the treatment of a disease or disorder (e.g., cancer) in a mammal, particularly a human, including (a) preventing the onset of a disease or its symptoms in a subject susceptible to the disease (including, for example, a disease that may be associated with or caused by a primary disease) but not diagnosed as having the disease, (b) inhibiting the disease, i.e., arresting the progression of the disease, and (c) relieving the disease, i.e., causing regression of the disease. Treating may refer to any indicator of successful cancer treatment, amelioration, or prevention, including any objective or subjective parameter, such as reduction, remission, alleviation of symptoms or improved patient tolerance to the disease state, slowing or reducing the rate of degeneration, or reduced debilitation to the end point of degeneration. Treating or monitoring symptoms is based on one or more objective or subjective parameters, including the outcome of a physician's examination. Thus, the term "treating" includes administering a compound or agent of the present invention to prevent or delay, alleviate, or arrest or inhibit the progression of symptoms or illnesses associated with a disease (e.g., cancer). The term "therapeutic effect" refers to the reduction, elimination, or prevention of the disease, disease symptoms, or side effects of the disease in a subject.

[0031] A "therapeutically effective amount" means the amount that, when administered to a subject for treating a disease, is sufficient to effect treatment for the disease, as the case may be.

[0032] "Percent (%) identity" refers to the degree to which two sequences (nucleotides or amino acids) have the same residues at the same position of alignment. For example, "an amino acid sequence is X% identical to SEQ ID NO:Y" refers to the % identity of the amino acid sequence of SEQ ID NO:Y and details that X% of the residues in the amino acid sequence are identical to the residues of the sequence disclosed in SEQ ID NO:Y. Usually, a computer program is used for this calculation. Exemplary programs for comparing and aligning pairs of sequences include ALIGN (Myers and Miller, 1988), FASTA (Pearson and Lipman, 1988; Pearson, 1990), gapped BLAST (Altschul et al., 1997), BLASTP, BLASTN, GCG (Devereux et al., 1984).

[0033] Major histocompatibility complex (MHC) or human leukocyte antigen (HLA) Major histocompatibility complexes (MHC), also called human leukocyte antigens (HLA) in humans, are glycoproteins expressed on the surface of nucleated cells that act as proteomic scanning chips by providing insight into the health of cells. They continuously sample peptides from normal host cell proteins, cancer cells, inflamed cells and cells infected with bacteria, viruses and parasites, and present short peptides on the cell surface for recognition by T lymphocytes. The presented peptides can be derived from proteins that are out of frame, from sequences embedded in introns, or even from proteins that initiate translation at a codon other than the conventional methionine codon, i.e. ATG.

[0034] There are two classes of MHC in mice and humans: MHC I and MHC II. MHC I contains classical and non-classical MHC I subgroups.

[0035] Classical MHC I or HLA-I Classical MHC I molecules include HLA-A, HLA-B, and HLA-C in humans, and H-2-K, H-2-D, H-2-B, and H-2-L in mice. Classical MHC I molecules are highly polymorphic, with over 2,735 alleles for HLA-A, over 3,455 alleles for HLA-B, and over 2,259 alleles for HLA-C. Classical MHC I is expressed on the surface of all nucleated cells and peptides presented to CD8 T lymphocytes. Thirty percent of the proteins in the cellular machinery are rapidly degraded, providing the primary substrate for classical MHC I antigen presentation.

[0036] For a peptide to be presented by classical MHC I molecules, the protein is first processed through the classical processing pathway (ubiquitin-proteasome system), which begins with proteolysis in the proteasome and transporter-associated protein (TAP)-dependent transport of the peptide into the endoplasmic reticulum (ER), culminating in loading of the peptide into the HLA peptide-binding pocket. The proteins that contribute to the classical processing pathway are collectively known as the antigen processing machinery (APM) and include the proteasome, the TAP complex, tapasin, endoplasmic reticulum aminopeptidase (ERAAP), binding immunoglobulin protein (BiP), clanexin, and calreticulin. Cells lacking any of the proteasome subunits, TAP1 / 2, ErP57, or calreticulin, have a reduced number of classical MHC I molecules on their surface.

[0037] Nonclassical MHC I or HLA-I Non-classical MHC I molecules include HLA-E, HLA-F, and HLA-G and have limited polymorphism. They play a role in regulating innate and adaptive immune responses. Non-classical MHC I molecules present peptides generated by both conventional and alternative processing pathways in health and disease states, and represent a novel set of markers for targeting against disease states (e.g., cancer).

[0038] HLA-E HLA-E, a non-classical MHC class I molecule, is non-polymorphic. In fact, 13 HLA-E alleles exist in two functional variants, namely HLAE1 and HLAE2. * 0101 and HLA-E * It has been identified only with 0103. * 0101 (HLA-E107R) and HLA-E * The difference between HLA-E107G and HLA-E107G is one amino acid difference at position 107, which is outside the peptide-binding pocket. However, like classical MHC I molecules, HLA-E is normally expressed on all nucleated cells at lower levels. HLA-E molecule expression in cells and tissues is normally increased during stress and disease. Therefore, HLA-E is differentially expressed on stressed or diseased cells (e.g., cancer cells) compared to healthy cells.

[0039] In healthy tissue, HLA-E presents peptides derived from classical MHC molecules and non-classical HLA-G molecules to suppress or stimulate the activity of subsets of NK cells and CD8 T cells through binding of the receptor CD94 / NKG2. Depending on the particular peptide presented by HLA-E, the HLA-E complex binds either CD94 / NKG2A or CD94 / NKG2C to inhibit or activate subsets of NK cells and CD8 T cells, respectively.

[0040] Another signal peptide with similar characteristics to the signal peptide generated from classical HLA-I molecules is the signal peptide generated from non-classical HLA-G. HLA-G expression under normal physiological conditions is tightly regulated, with limited expression found in a relatively small number of tissues and cells in the body. HLA-G plays an important 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 conventional 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).

[0041] HLA-E expression and peptide presentation in cancer cells

[0042] Cells lacking one or more components of the APM load peptides into MHC class I molecules via an alternative processing pathway that is independent of the APM-dependent classical processing pathway. Cells lacking APM not only show a reduced number of classical MHC I molecules on their surface, but also an increased cell surface density of HLA-E molecules, as well as an increased peptide repertoire. The alternative processing pathway is constitutively open, producing peptides in both healthy and diseased cells. However, these peptides are not presented by healthy cells, but instead only by diseased or stressed cells. Thus, the diverse peptide repertoires generated by cells lacking APM, also known as "T-cell epitopes associated with impaired peptide processing (TEIPP)", represent novel targets unique to cancer cells and ideal targets for therapeutic development in cancer treatment.

[0043] In stressed or diseased conditions (e.g., cancer), stressed or diseased cells (e.g., cancer cells) differentially express a complex that includes HLA-E and a peptide derived from a non-classical HLA-G molecule. The complex that includes HLA-E and a peptide derived from a non-classical HLA-G molecule is differentially expressed on stressed or diseased cells compared to healthy cells. Targeting of this complex induces an immune response against cells expressing the complex.

[0044] MHC II or HLA-II MHC II molecules in humans include HLA-DM, HLA-DO, HLA-DP, HLA-DQ, and HLA-DR, and in mice include H-2 IA and H-2 IE. MHC II expression is further restricted to B cells, dendritic cells, macrophages, activated T cells, and thymic epithelial cells, and MHC II molecules present peptides to CD4 lymphocytes.

[0045] Antibodies targeting complexes containing non-classical HLA-I (e.g., HLA-E) and neoantigens In certain embodiments herein, an antibody is disclosed that targets a complex containing non-classical HLA-I (e.g., HLA-E) and a neoantigen. In some embodiments, the 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 of the VH and VL comprises three complementarity determining regions (CDRs). The amino acid sequences of the VH, VL, and CDRs determine the antigen-binding specificity and antigen-binding strength of the antibody. The amino acid sequences of the VH, VL, and CDRs are summarized in Table 1.

[0046] [Table 1-1]

[0047] [Table 1-2]

[0048] [Table 1-3]

[0049] In some embodiments, the antibody selectively binds to a complex comprising a non-classical HLA-I (e.g., HLA-E) and a neoantigen. In some embodiments, the antibody has no binding affinity for non-classical 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 a non-classical HLA-I and an unrelated neoantigen.

[0050] In some embodiments, the neoantigen is expressed by antigen processing machinery (APM) proficient cells. In some embodiments, the neoantigen is expressed by TAP1 / 2 proficient cells. In some embodiments, the neoantigen comprises, consists essentially of, or consists of a sequence according to SEQ ID NO: 18 (VMAPRTLFL).

[0051] In some embodiments, the non-classical HLA-I is HLA-E, HLA-F, HLA-G, or HLA-H. In some embodiments, the non-classical HLA-I is HLA-E. In some embodiments, the HLA-E is HLA-E * In some embodiments, the HLA-E is HLA-E * The number is 0103.

[0052] 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 and a neoantigen. * In some embodiments, the antibody selectively binds to a complex comprising HLA-E * Complexes containing 0101 and neoantigens, and HLA-E * In some embodiments, the complex comprises HLA-E and a neoantigen according to SEQ ID NO: 18 (VMAPRTLFL).

[0053] 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 antibody is a human antibody.

[0054] 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.

[0055] 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-inducing antibody (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.

[0056] In some embodiments, the antibody further comprises a conjugated therapeutic moiety. Therapeutic moieties include, but are not limited to, cytotoxins, chemotherapeutic drugs, immunosuppressants, and radioisotopes. Cytotoxins or cytotoxic drugs include any agent that is detrimental to (e.g., kills) cells. Examples include, but are not limited to, taxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin and its analogs or homologs. Suitable chemotherapeutic agents include antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, fludarabine, 5-fluorouracil, decarbazine, hydroxyurea, azathioprine, gemcitabine, and cladribine), alkylating agents (e.g., mechlorethamine, thioepa, chlorambucil, melphalan, carmustine (BSNU) and lomustine (CCNU), cyclophosphamide, busulfan, dibromomannitol, , streptozotocin, mitomycin C, and cis-dichlorodiamineplatinum(II) (DDP) cisplatin), anthracyclines (e.g., daunorubicin (formerly daunomycin) and doxorubicin), antibiotics (e.g., dactinomycin (formerly actinomycin), bleomycin, mithramycin, and anthramycin (AMC)), and antimitotics (e.g., vincristine, vinblastine, docetaxel, paclitaxel, and vinorelbine). Suitable radioisotopes include, but are not limited to, iodine-131, yttrium-90, or indium-Ill.Further examples of therapeutic moieties are proteins or polypeptides with 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-γ, or biological response modifiers, such as lymphokines, interleukin-1 (IL-1), interleukin-2 (IL-2), interleukin-6 (IL-6), granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte-colony stimulating factor (G-CSF), or other growth factors.

[0057] In some embodiments, selective binding of the antibody to a complex comprising non-classical HLA-I (e.g., HLA-E) and a neoantigen 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 CD3 protein associated with a TCR 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 (CTLs). In some embodiments, the cell is a cancer cell.

[0058] Antibody variable domains (VL and VH) Disclosed herein is an antibody that selectively binds to a complex comprising HLA-E and a neoantigen, the antibody 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 at least about 70% identical to the amino acid sequence set forth as 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% identical to the amino acid sequence set forth as SEQ ID NO:7. In some embodiments, the VL has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:7.

[0059] Disclosed herein is an antibody that selectively binds to a complex comprising HLA-E and a neoantigen, the antibody having a heavy chain comprising a heavy chain variable domain (VH). In some embodiments, the antibody comprises a heavy chain variable domain (VH) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as 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% identical to the amino acid sequence set forth as SEQ ID NO:8. In some embodiments, the VH has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:8.

[0060] Disclosed herein is an antibody that selectively binds to a complex comprising HLA-E and a neoantigen, the antibody comprising a light chain variable domain (VL) and a heavy chain variable domain (VH). 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 as SEQ ID NO:7, and a heavy chain variable domain (VH) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as 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 to the amino acid sequence set forth as SEQ ID NO:7, and 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% identical to the amino acid sequence set forth as SEQ ID NO:8. In some embodiments, the VL has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:7, and the VH has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:8.

[0061] Antibody Heavy and Light Chains Disclosed herein is an antibody that selectively binds to a complex comprising HLA-E and a neoantigen, the antibody having a light chain (LC). In some embodiments, the antibody comprises a light chain (LC) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as 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% identical to the amino acid sequence set forth as SEQ ID NO: 19. In some embodiments, the LC has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 19.

[0062] Further disclosed herein is an antibody that selectively binds to a complex comprising HLA-E and a neoantigen, the antibody having a heavy chain (HC). In some embodiments, the antibody comprises a HC having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as 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% identical to the amino acid sequence set forth as SEQ ID NO: 20. In some embodiments, the HC has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 20.

[0063] Disclosed herein is an antibody that selectively binds to a complex comprising HLA-E and a neoantigen, the antibody comprising a light chain (LC) and a heavy chain (HC). In some embodiments, the antibody comprises a LC having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 19, and a HC having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 20. In some embodiments, the LC has an amino acid sequence that 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 amino acid sequence set forth as SEQ ID NO:19 and the HC has an amino acid sequence that 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 amino acid sequence set forth as SEQ ID NO:20. In some embodiments, the LC has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:19, and the HC has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:20.

[0064] Further disclosed herein is an antibody that selectively binds to a complex comprising HLA-E and a neoantigen, the antibody having a heavy chain (HC). In some embodiments, the antibody comprises a HC having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as 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% identical to the amino acid sequence set forth as SEQ ID NO:21. In some embodiments, the HC has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:21.

[0065] Disclosed herein is an antibody that selectively binds to a complex comprising HLA-E and a neoantigen, the antibody comprising a light chain (LC) and a heavy chain (HC). In some embodiments, the antibody comprises a LC having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 19, and a HC having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 21. In some embodiments, the LC has an amino acid sequence that 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 amino acid sequence set forth as SEQ ID NO:19 and the HC has an amino acid sequence that 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 amino acid sequence set forth as SEQ ID NO:21. In some embodiments, the LC has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:19, and the HC has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:21.

[0066] Disclosed herein is an antibody that selectively binds to a complex comprising HLA-E and a neoantigen, the antibody having a light chain (LC). In some embodiments, the antibody comprises a light chain (LC) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as 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% identical to the amino acid sequence set forth as SEQ ID NO: 22. In some embodiments, the LC has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 22.

[0067] Further disclosed herein is an antibody that selectively binds to a complex comprising HLA-E and a neoantigen, the antibody having a heavy chain (HC). In some embodiments, the antibody comprises a HC having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as 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% identical to the amino acid sequence set forth as SEQ ID NO: 23. In some embodiments, the HC has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 23.

[0068] Disclosed herein is an antibody that selectively binds to a complex comprising HLA-E and a neoantigen, the antibody comprising a light chain (LC) and a heavy chain (HC). In some embodiments, the antibody comprises a LC having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO:22, and a HC having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as 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 to the amino acid sequence set forth as SEQ ID NO:22 and 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% identical to the amino acid sequence set forth as SEQ ID NO:23. In some embodiments, the LC has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:22, and the HC has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:23.

[0069] Antibody Complementarity Determining Regions (CDRs) Disclosed herein are antibodies that selectively bind to a complex comprising HLA-E and a neoantigen, the antibodies having a light chain comprising a light chain complementarity determining region (CDR). In some embodiments, the antibodies comprise 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 as SEQ ID NOs: 1-3. In some embodiments, the antibodies comprise a light chain CDR sequence having 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 to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3. In some embodiments, the antibodies comprise a light chain CDR sequence having an amino acid sequence 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3.

[0070] Further disclosed herein is an antibody that selectively binds to a complex comprising HLA-E and a neoantigen, the antibody having a heavy chain comprising a heavy chain complementarity determining region (CDR). In some embodiments, the antibody comprises a heavy chain CDR sequence having an amino acid sequence at least about 70% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6. In some embodiments, the antibody comprises a heavy chain CDR sequence having 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 to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6. In some embodiments, the antibody comprises a heavy chain CDR sequence having an amino acid sequence 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6.

[0071] Disclosed herein is an antibody that selectively binds to a complex containing HLA-E and a neoantigen, the antibody comprising a light chain complementarity determining region (CDR) and a heavy chain complementarity determining region (CDR). 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 as SEQ ID NOs: 1-3, and a heavy chain CDR sequence having an amino acid sequence at least about 70% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6. In some embodiments, the antibody comprises a light chain CDR sequence having 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 to at least one of the amino acid sequences set forth as SEQ ID NOs:1-3, and a heavy chain CDR sequence having 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 to at least one of the amino acid sequences set forth as SEQ ID NOs:4-6. 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 as SEQ ID NOs:1-3, and a heavy chain CDR sequence having an amino acid sequence that is at least about 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs:4-6.

[0072] In some embodiments, the antibody selectively binds to a complex comprising HLA-E and a neoantigen, and comprises 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 as 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 as SEQ ID NO:2, and a light chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO:3. In some embodiments, the antibody comprises a light chain CDR1 having 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 to the amino acid sequence set forth as SEQ ID NO:1, a light chain CDR2 having 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 to the amino acid sequence set forth as SEQ ID NO:2, , 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO:3, and at least one light chain CDR3 having 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 to the amino acid sequence set forth as SEQ ID NO:3. In some embodiments, the antibody comprises at least one of a light chain CDR1 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:1, a light chain CDR2 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:2, and a light chain CDR3 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:3.

[0073] In some embodiments, an antibody that selectively binds to a complex comprising HLA-E and a neoantigen comprises at least one of a heavy chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO:4, a heavy chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO:5, and a heavy chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO:6. In some embodiments, the antibody comprises a heavy chain CDR1 having 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 to the amino acid sequence set forth as SEQ ID NO:4, a heavy chain CDR2 having 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 to the amino acid sequence set forth as SEQ ID NO:5, , 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO:6, and at least one heavy chain CDR3 having 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 to the amino acid sequence set forth as SEQ ID NO:6. In some embodiments, the antibody comprises at least one of a heavy chain CDR1 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:4, a heavy chain CDR2 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:5, and a heavy chain CDR3 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:6.

[0074] In some embodiments, an antibody that selectively binds to a complex comprising HLA-E and a neoantigen comprises 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 as 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 as SEQ ID NO:2, a light chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO:3, a heavy chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO:4, a heavy chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO:5, and a heavy chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO:6.In some embodiments, the antibody comprises a light chain CDR1 having 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 to the amino acid sequence set forth as SEQ ID NO:1, a light chain CDR2 having 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 to the amino acid sequence set forth as SEQ ID NO:2, , 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO:3; a heavy chain CDR1 having 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 to the amino acid sequence set forth as SEQ ID NO:4; , 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO:6, and at least one heavy chain CDR3 having 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 to the amino acid sequence set forth as SEQ ID NO:6.In some embodiments, the antibody comprises at least one of a light chain CDR1 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:1, a light chain CDR2 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:2, a light chain CDR3 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:3, a heavy chain CDR1 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:4, a heavy chain CDR2 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:5, and a heavy chain CDR3 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:6.

[0075] bispecific antibody In some embodiments, the antibodies disclosed herein are bispecific antibodies. In some embodiments, the bispecific antibodies are bispecific T cell-inducing antibodies (BiTEs). In some embodiments, the BiTEs bind to the CD3 protein associated with the T cell receptor (TCR). In some embodiments, the BiTEs bind to the CD3ε protein associated with the T cell receptor (TCR).

[0076] 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.

[0077] In some embodiments, the bispecific antibody comprises (a) a light chain variable domain (VL) comprising an amino acid sequence that is at least 70% identical to the amino acid sequence set forth as SEQ ID NO:7, or a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 70% identical to the amino acid sequence set forth as SEQ ID NO:8, and (b) a light chain variable domain (VL) comprising an amino acid sequence that is at least 70% identical to the amino acid sequence set forth as 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 set forth as SEQ ID NO:16.

[0078] In some embodiments, the bispecific antibody comprises (a) a light chain variable domain (VL) comprising an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:7; or a heavy chain variable domain comprising an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:8. and (b) a light chain variable domain (VL) comprising an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:15, or a heavy chain variable domain (VH) comprising an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:16.

[0079] In some embodiments, the bispecific antibody comprises (a) a light chain variable domain (VL) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:7, or a heavy chain variable domain (VH) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:8, and (b) a light chain variable domain (VL) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:15, or a heavy chain variable domain (VH) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:16.

[0080] In some embodiments, the bispecific antibody comprises (a) a light chain variable domain (VL) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO:7, and a heavy chain variable domain (VH) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO:8, and (b) a light chain variable domain (VL) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO:15, and a heavy chain variable domain (VH) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO:16.

[0081] In some embodiments, the bispecific antibody comprises (a) a light chain variable domain (VL) comprising an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:7, and a heavy chain variable domain comprising an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:8. and (b) a light chain variable domain (VL) comprising an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:15, and a heavy chain variable domain (VH) comprising an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:16.

[0082] 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 as SEQ ID NO: 19, or a heavy chain (HC) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO: 20, and (b) a light chain variable domain (VL) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO: 15, or a heavy chain variable domain (VH) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO: 16.

[0083] In some embodiments, the bispecific antibody comprises (a) a light chain (LC) that comprises an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO: 19; or a heavy chain (HC) that comprises an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:20. ) and (b) a light chain variable domain (VL) comprising an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:15, or a heavy chain variable domain (VH) comprising an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:16.

[0084] In some embodiments, the bispecific antibody comprises (a) a light chain (LC) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 19, or a heavy chain (HC) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 20, and (b) a light chain variable domain (VL) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 15, or a heavy chain variable domain (VH) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 16.

[0085] 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 as SEQ ID NO: 19, or a heavy chain (HC) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO: 21, and (b) a light chain variable domain (VL) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO: 15, or a heavy chain variable domain (VH) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO: 16.

[0086] In some embodiments, the bispecific antibody comprises (a) a light chain (LC) that comprises an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO: 19; or a heavy chain (HC) that comprises an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:21. ) and (b) a light chain variable domain (VL) comprising an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:15, or a heavy chain variable domain (VH) comprising an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:16.

[0087] In some embodiments, the bispecific antibody comprises (a) a light chain (LC) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 19, or a heavy chain (HC) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 21, and (b) a light chain variable domain (VL) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 15, or a heavy chain variable domain (VH) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 16.

[0088] 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 as SEQ ID NO: 22, or a heavy chain (HC) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO: 23, and (b) a light chain variable domain (VL) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO: 15, or a heavy chain variable domain (VH) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO: 16.

[0089] In some embodiments, the bispecific antibody comprises (a) a light chain (LC) that comprises an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:22; or a heavy chain (HC) that comprises an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:23. ) and (b) a light chain variable domain (VL) comprising an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:15, or a heavy chain variable domain (VH) comprising an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:16.

[0090] In some embodiments, the bispecific antibody comprises (a) a light chain (LC) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 22, or a heavy chain (HC) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 23, and (b) a light chain variable domain (VL) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 15, or a heavy chain variable domain (VH) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 16.

[0091] In some embodiments, the bispecific antibody comprises (a) a light chain variable domain (VL) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:7, and a heavy chain variable domain (VH) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:8, and (b) a light chain variable domain (VL) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:15, and a heavy chain variable domain (VH) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:16.

[0092] In some embodiments, the bispecific antibody comprises (a) a light chain CDR having an amino acid sequence at least 70% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1 to 3, or a heavy chain CDR having an amino acid sequence at least 70% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4 to 6, and (b) a light chain CDR having an amino acid sequence at least 70% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 9 to 11, or a heavy chain CDR having an amino acid sequence at least 70% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 12 to 14.

[0093] In some embodiments, the bispecific antibody comprises (a) a light chain complementarity determining region (CDR) having an amino acid sequence 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 to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3; or a heavy chain complementarity determining region (CDR) having an amino acid sequence 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 to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6. and (b) a light chain complementarity determining region (CDR) having an amino acid sequence 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 to at least one of the amino acid sequences set forth as SEQ ID NOs: 9 to 11. ), or a heavy chain complementarity determining region (CDR) having an amino acid sequence 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 to at least one of the amino acid sequences set forth as SEQ ID NOs: 12-14.

[0094] In some embodiments, the bispecific antibody comprises (a) a light chain CDR having an amino acid sequence that is 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1 to 3, or a heavy chain CDR having an amino acid sequence that is 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4 to 6, and (b) a light chain CDR having an amino acid sequence that is 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 9 to 11, or a heavy chain CDR having an amino acid sequence that is 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 12 to 14.

[0095] In some embodiments, the bispecific antibody comprises (a) 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 set forth as SEQ ID NOs: 1-3, and a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 70% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 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 set forth as SEQ ID NOs: 9-11, and a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 70% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 12-14.

[0096] In some embodiments, the bispecific antibody comprises (a) a light chain complementarity determining region (CDR) having an amino acid sequence 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 to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, and a heavy chain complementarity determining region (CDR) having an amino acid sequence 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 to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6. and (b) a light chain complementarity determining region (CDR) having an amino acid sequence 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 to at least one of the amino acid sequences set forth as SEQ ID NOs: 9 to 11. ), and heavy chain complementarity determining regions (CDRs) having an amino acid sequence 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 to at least one of the amino acid sequences set forth as SEQ ID NOs: 12-14.

[0097] In some embodiments, the bispecific antibody comprises (a) a light chain complementarity determining region (CDR) having an amino acid sequence that is 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1 to 3, 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 set forth as SEQ ID NOs: 4 to 6, and (b) a light chain complementarity determining region (CDR) having an amino acid sequence that is 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 9 to 11, 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 set forth as SEQ ID NOs: 12 to 14.

[0098] Treatment Provided herein are methods of treating cancer in an individual in need thereof, comprising administration of an antibody that selectively binds to a complex comprising a non-classical HLA-I (e.g., HLA-E) and a neoantigen as disclosed herein.

[0099] In some embodiments, the antibody selectively binds to a complex comprising a non-classical HLA-I (e.g., HLA-E) and a neoantigen. In some embodiments, the antibody has no binding affinity for non-classical 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 a non-classical HLA-I and an unrelated neoantigen.

[0100] In some embodiments, the neoantigen is expressed by antigen processing machinery (APM) proficient cells. In some embodiments, the neoantigen is expressed by TAP1 / 2 proficient cells. In some embodiments, the neoantigen comprises, consists essentially of, or consists of a sequence according to SEQ ID NO: 18 (VMAPRTLFL).

[0101] In some embodiments, the non-classical HLA-I is HLA-E, HLA-F, HLA-G, or HLA-H. In some embodiments, the non-classical HLA-I is HLA-E. In some embodiments, the HLA-E is HLA-E * In some embodiments, the HLA-E is HLA-E * The number is 0103.

[0102] 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 and a neoantigen. *In some embodiments, the antibody selectively binds to a complex comprising HLA-E * Complexes containing 0101 and neoantigens, and HLA-E * In some embodiments, the complex comprises HLA-E and a neoantigen according to SEQ ID NO: 18 (VMAPRTLFL).

[0103] In some embodiments, the antibody comprises a light chain (LC) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as 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% identical to the amino acid sequence set forth as SEQ ID NO: 19. In some embodiments, the LC has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 19.

[0104] In some embodiments, the antibody comprises a heavy chain (HC) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as 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% identical to the amino acid sequence set forth as SEQ ID NO: 20. In some embodiments, the HC has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 20.

[0105] In some embodiments, the antibody comprises a light chain (LC) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 19, and a heavy chain (HC) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 20. In some embodiments, the LC has an amino acid sequence that 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 amino acid sequence set forth as SEQ ID NO:19 and the HC has an amino acid sequence that 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 amino acid sequence set forth as SEQ ID NO:20. In some embodiments, the LC has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:19, and the HC has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:20.

[0106] In some embodiments, the antibody comprises a heavy chain (HC) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as 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% identical to the amino acid sequence set forth as SEQ ID NO: 21. In some embodiments, the HC has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 21.

[0107] In some embodiments, the antibody comprises a light chain (LC) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 19, and a heavy chain (HC) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 21. In some embodiments, the LC has an amino acid sequence that 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 amino acid sequence set forth as SEQ ID NO:19 and the HC has an amino acid sequence that 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 amino acid sequence set forth as SEQ ID NO:21. In some embodiments, the LC has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:19, and the HC has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:21.

[0108] In some embodiments, the antibody comprises a light chain (LC) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as 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% identical to the amino acid sequence set forth as SEQ ID NO: 22. In some embodiments, the LC has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 22.

[0109] In some embodiments, the antibody comprises a heavy chain (HC) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as 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% identical to the amino acid sequence set forth as SEQ ID NO: 23. In some embodiments, the HC has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 23.

[0110] In some embodiments, the antibody comprises a light chain (LC) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO:22, and a heavy chain (HC) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as 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 to the amino acid sequence set forth as SEQ ID NO:22 and 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% identical to the amino acid sequence set forth as SEQ ID NO:23. In some embodiments, the LC has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:22, and the HC has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:23.

[0111] 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 as 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% identical to the amino acid sequence set forth as SEQ ID NO: 7. In some embodiments, the VL has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 7.

[0112] In some embodiments, the antibody comprises a heavy chain variable domain (VH) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as 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% identical to the amino acid sequence set forth as SEQ ID NO: 8. In some embodiments, the VH has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:8.

[0113] 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 as SEQ ID NO:7, and a heavy chain variable domain (VH) having an amino acid sequence at least 70% identical to the amino acid sequence set forth as 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 to the amino acid sequence set forth as SEQ ID NO:7, and 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% identical to the amino acid sequence set forth as SEQ ID NO:8. In some embodiments, the VL has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:7, and the VH has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:8.

[0114] 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 as SEQ ID NOs: 1-3. In some embodiments, the antibody comprises a light chain CDR sequence having 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 to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3. In some embodiments, the antibody comprises a light chain CDR sequence having an amino acid sequence 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3.

[0115] In some embodiments, the antibody comprises a heavy chain CDR sequence having an amino acid sequence at least about 70% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6. In some embodiments, the antibody comprises a heavy chain CDR sequence having 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 to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6. In some embodiments, the antibody comprises a heavy chain CDR sequence having an amino acid sequence 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6.

[0116] 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 as SEQ ID NOs:1-3, and a heavy chain CDR sequence having an amino acid sequence at least about 70% identical to at least one of the amino acid sequences set forth as SEQ ID NOs:4-6. In some embodiments, the antibody comprises a light chain CDR sequence having 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 to at least one of the amino acid sequences set forth as SEQ ID NOs:1-3, and a heavy chain CDR sequence having 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 to at least one of the amino acid sequences set forth as SEQ ID NOs:4-6. 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 as SEQ ID NOs:1-3, and a heavy chain CDR sequence having an amino acid sequence that is at least about 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs:4-6.

[0117] In some embodiments, an antibody comprising HLA-E and a neoantigen comprises 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 as 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 as SEQ ID NO:2, and a light chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO:3. In some embodiments, the antibody comprises a light chain CDR1 having 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 to the amino acid sequence set forth as SEQ ID NO:1, a light chain CDR2 having 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 to the amino acid sequence set forth as SEQ ID NO:2, , 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO:3, and at least one light chain CDR3 having 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 to the amino acid sequence set forth as SEQ ID NO:3. In some embodiments, the antibody comprises at least one of a light chain CDR1 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:1, a light chain CDR2 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:2, and a light chain CDR3 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:3.

[0118] In some embodiments, an antibody comprising HLA-E and a neoantigen comprises at least one of a heavy chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO:4, a heavy chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO:5, and a heavy chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO:6. In some embodiments, the antibody comprises a heavy chain CDR1 having 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 to the amino acid sequence set forth as SEQ ID NO:4, a heavy chain CDR2 having 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 to the amino acid sequence set forth as SEQ ID NO:5, , 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO:6, and at least one heavy chain CDR3 having 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 to the amino acid sequence set forth as SEQ ID NO:6. In some embodiments, the antibody comprises at least one of a heavy chain CDR1 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:4, a heavy chain CDR2 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:5, and a heavy chain CDR3 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:6.

[0119] In some embodiments, the antibody comprising HLA-E and a neoantigen comprises 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 as 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 as SEQ ID NO:2, a light chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO:3, a heavy chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO:4, a heavy chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO:5, and a heavy chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO:6.In some embodiments, the antibody comprises a light chain CDR1 having 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 to the amino acid sequence set forth as SEQ ID NO:1, a light chain CDR2 having 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 to the amino acid sequence set forth as SEQ ID NO:2, , 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO:3; a heavy chain CDR1 having 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 to the amino acid sequence set forth as SEQ ID NO:4; , 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO:6, and at least one heavy chain CDR3 having 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 to the amino acid sequence set forth as SEQ ID NO:6.In some embodiments, the antibody comprises at least one of a light chain CDR1 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:1, a light chain CDR2 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:2, a light chain CDR3 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:3, a heavy chain CDR1 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:4, a heavy chain CDR2 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:5, and a heavy chain CDR3 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:6.

[0120] In some embodiments, the antibody is a bispecific antibody. In some embodiments, the bispecific antibody comprises (a) a light chain variable domain (VL) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO:7, or a heavy chain variable domain (VH) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO:8, and (b) a light chain variable domain (VL) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO:15, or a heavy chain variable domain (VH) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO:16.

[0121] In some embodiments, the bispecific antibody comprises (a) a light chain variable domain (VL) comprising an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:7; or a heavy chain variable domain comprising an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:8. and (b) a light chain variable domain (VL) comprising an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:15, or a heavy chain variable domain (VH) comprising an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:16.

[0122] In some embodiments, the bispecific antibody comprises (a) a light chain variable domain (VL) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:7, or a heavy chain variable domain (VH) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:8, and (b) a light chain variable domain (VL) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:15, or a heavy chain variable domain (VH) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:16.

[0123] In some embodiments, the bispecific antibody comprises (a) a light chain variable domain (VL) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO:7, and a heavy chain variable domain (VH) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO:8, and (b) a light chain variable domain (VL) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO:15, and a heavy chain variable domain (VH) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO:16.

[0124] In some embodiments, the bispecific antibody comprises (a) a light chain variable domain (VL) comprising an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:7, and a heavy chain variable domain comprising an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:8. and (b) a light chain variable domain (VL) comprising an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:15, and a heavy chain variable domain (VH) comprising an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:16.

[0125] In some embodiments, the bispecific antibody comprises (a) a light chain variable domain (VL) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:7, and a heavy chain variable domain (VH) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:8, and (b) a light chain variable domain (VL) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:15, and a heavy chain variable domain (VH) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:16.

[0126] 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 as SEQ ID NO: 19, or a heavy chain (HC) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO: 20, and (b) a light chain variable domain (VL) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO: 15, or a heavy chain variable domain (VH) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO: 16.

[0127] In some embodiments, the bispecific antibody comprises (a) a light chain (LC) that comprises an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO: 19; or a heavy chain (HC) that comprises an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:20. ) and (b) a light chain variable domain (VL) comprising an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:15, or a heavy chain variable domain (VH) comprising an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:16.

[0128] In some embodiments, the bispecific antibody comprises (a) a light chain (LC) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 19, or a heavy chain (HC) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 20, and (b) a light chain variable domain (VL) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 15, or a heavy chain variable domain (VH) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 16.

[0129] 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 as SEQ ID NO: 19, or a heavy chain (HC) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO: 21, and (b) a light chain variable domain (VL) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO: 15, or a heavy chain variable domain (VH) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO: 16.

[0130] In some embodiments, the bispecific antibody comprises (a) a light chain (LC) that comprises an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO: 19; or a heavy chain (HC) that comprises an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:21. ) and (b) a light chain variable domain (VL) comprising an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:15, or a heavy chain variable domain (VH) comprising an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:16.

[0131] In some embodiments, the bispecific antibody comprises (a) a light chain (LC) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 19, or a heavy chain (HC) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 21, and (b) a light chain variable domain (VL) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 15, or a heavy chain variable domain (VH) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 16.

[0132] 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 as SEQ ID NO: 22, or a heavy chain (HC) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO: 23, and (b) a light chain variable domain (VL) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO: 15, or a heavy chain variable domain (VH) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO: 16.

[0133] In some embodiments, the bispecific antibody comprises (a) a light chain (LC) that comprises an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:22; or a heavy chain (HC) that comprises an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:23. ) and (b) a light chain variable domain (VL) comprising an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:15, or a heavy chain variable domain (VH) comprising an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:16.

[0134] In some embodiments, the bispecific antibody comprises (a) a light chain (LC) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 22, or a heavy chain (HC) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 23, and (b) a light chain variable domain (VL) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 15, or a heavy chain variable domain (VH) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 16.

[0135] In some embodiments, the bispecific antibody comprises (a) a light chain CDR having an amino acid sequence at least 70% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1 to 3, or a heavy chain CDR having an amino acid sequence at least 70% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4 to 6, and (b) a light chain CDR having an amino acid sequence at least 70% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 9 to 11, or a heavy chain CDR having an amino acid sequence at least 70% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 12 to 14.

[0136] In some embodiments, the bispecific antibody comprises (a) a light chain complementarity determining region (CDR) having an amino acid sequence 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 to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3; or a heavy chain complementarity determining region (CDR) having an amino acid sequence 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 to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6. and (b) a light chain complementarity determining region (CDR) having an amino acid sequence 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 to at least one of the amino acid sequences set forth as SEQ ID NOs: 9 to 11. ), or a heavy chain complementarity determining region (CDR) having an amino acid sequence 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 to at least one of the amino acid sequences set forth as SEQ ID NOs: 12-14.

[0137] In some embodiments, the bispecific antibody comprises (a) a light chain CDR having an amino acid sequence that is 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1 to 3, or a heavy chain CDR having an amino acid sequence that is 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4 to 6, and (b) a light chain CDR having an amino acid sequence that is 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 9 to 11, or a heavy chain CDR having an amino acid sequence that is 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 12 to 14.

[0138] In some embodiments, the bispecific antibody comprises (a) 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 set forth as SEQ ID NOs: 1-3, and a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 70% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 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 set forth as SEQ ID NOs: 9-11, and a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 70% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 12-14.

[0139] In some embodiments, the bispecific antibody comprises (a) a light chain complementarity determining region (CDR) having an amino acid sequence 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 to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, and a heavy chain complementarity determining region (CDR) having an amino acid sequence 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 to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6. and (b) a light chain complementarity determining region (CDR) having an amino acid sequence 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 to at least one of the amino acid sequences set forth as SEQ ID NOs: 9 to 11. ), and heavy chain complementarity determining regions (CDRs) having an amino acid sequence 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 to at least one of the amino acid sequences set forth as SEQ ID NOs: 12-14.

[0140] In some embodiments, the bispecific antibody comprises (a) a light chain complementarity determining region (CDR) having an amino acid sequence that is 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1 to 3, 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 set forth as SEQ ID NOs: 4 to 6, and (b) a light chain complementarity determining region (CDR) having an amino acid sequence that is 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 9 to 11, 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 set forth as SEQ ID NOs: 12 to 14.

[0141] 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 antibody is a human antibody.

[0142] 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.

[0143] 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-inducing antibody (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.

[0144] In some embodiments, the antibody further comprises a conjugated therapeutic moiety. Therapeutic moieties include, but are not limited to, cytotoxins, chemotherapeutic drugs, immunosuppressants, and radioisotopes. Cytotoxins or cytotoxic drugs include any agent that is harmful to (e.g., kills) cells. Examples include, but are not limited to, taxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicine, doxorubicin, daunorubicin, dihydroxyanthracin dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin and its analogs or homologs. Suitable chemotherapeutic agents include antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, fludarabine, 5-fluorouracil, dacarbazine, hydroxyurea, azathioprine, gemcitabine, and cladribine), alkylating agents (e.g., mechlorethamine, thiotepa, chlorambucil, melphalan, carmustine (BSNU) and lomustine (CCNU), cyclophosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin, and cyclosporine). Suitable radioisotopes include, but are not limited to, cis-dichlorodiamineplatinum(II) (DDP) (cisplatin), anthracyclines (e.g., daunorubicin (formerly daunomycin) and doxorubicin), antibiotics (e.g., dactinomycin (formerly actinomycin), bleomycin, mithramycin, and anthramycin (AMC)), and antimitotics (e.g., vincristine, vinblastine, docetaxel, paclitaxel, and vinorelbine). Suitable radioisotopes include, but are not limited to, iodine-131, yttrium-90, or indium-Ill. A further example of a therapeutic moiety is a protein or polypeptide having a 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-γ, or biological response modifiers, such as lymphokines, interleukin-1 (IL-1), interleukin-2 (IL-2), interleukin-6 (IL-6), granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte-colony stimulating factor (G-CSF), or other growth factors.

[0145] In some embodiments, selective binding of an antibody to a complex comprising a non-classical HLA-I (e.g., HLA-E) and a neoantigen induces an immune response. In some embodiments, the immune response comprises activation of NK cells. In some embodiments, selective binding of an antibody to a CD3 protein associated with a TCR 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 (CTLs).

[0146] In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is renal cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is colon 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.

[0147] In some embodiments, the cancer cells differentially express a neoantigen. In some embodiments, the cancer cells differentially express HLA-E. In some embodiments, the cancer cells differentially express a complex comprising HLA-E and a neoantigen.

[0148] Any suitable route of administration is contemplated for use with the methods disclosed herein. In some embodiments, the antibody is administered intravenously. In some embodiments, the antibody is administered subcutaneously. In some embodiments, the antibody is administered locally. In some embodiments, the antibody is administered systemically (e.g., intravenously, intramuscularly, subcutaneously, intradermally, orally, intranasally, sublingually). In some embodiments, the antibody is formulated as an ointment, lotion, or emulsion. In some embodiments, the antibody is formulated as a solution. In some embodiments, the antibody is formulated for topical, oral, buccal, or intranasal administration.

[0149] In some embodiments, the individual is monitored prior to administration of the antibody. Symptoms are identified and their severity is evaluated. The antibodies described herein are administered alone or in combination with one or more additional treatments over time, as discussed herein or known to those skilled in the art. In some embodiments, the individual is monitored to determine the effectiveness of the treatment regimen. In some embodiments, the treatment regimen is modified according to the preliminary treatment outcome, so that the dosage or frequency of treatment is altered to achieve the desired level of subject response in terms of symptom relief, side effect reduction, or a combination of symptom relief and side effect reduction.

[0150] Pharmaceutical Compositions Also disclosed herein is a pharmaceutical composition comprising (a) an antibody that selectively binds to a complex comprising a non-classical HLA-I (e.g., HLA-E) and a neoantigen as disclosed herein, and (b) a pharma- ceutically acceptable carrier or excipient.

[0151] In some embodiments, the antibody comprises a light chain (LC) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as 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% identical to the amino acid sequence set forth as SEQ ID NO: 19. In some embodiments, the LC has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 19.

[0152] In some embodiments, the antibody comprises a heavy chain (HC) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as 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% identical to the amino acid sequence set forth as SEQ ID NO: 20. In some embodiments, the HC has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 20.

[0153] In some embodiments, the antibody comprises a light chain (LC) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 19, and a heavy chain (HC) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 20. In some embodiments, the LC has an amino acid sequence that 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 amino acid sequence set forth as SEQ ID NO:19 and the HC has an amino acid sequence that 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 amino acid sequence set forth as SEQ ID NO:20. In some embodiments, the LC has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:19, and the HC has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:20.

[0154] In some embodiments, the antibody comprises a heavy chain (HC) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as 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% identical to the amino acid sequence set forth as SEQ ID NO: 21. In some embodiments, the HC has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 21.

[0155] In some embodiments, the antibody comprises a light chain (LC) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 19, and a heavy chain (HC) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 21. In some embodiments, the LC has an amino acid sequence that 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 amino acid sequence set forth as SEQ ID NO:19 and the HC has an amino acid sequence that 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 amino acid sequence set forth as SEQ ID NO:21. In some embodiments, the LC has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:19, and the HC has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:21.

[0156] In some embodiments, the antibody comprises a light chain (LC) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as 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% identical to the amino acid sequence set forth as SEQ ID NO: 22. In some embodiments, the LC has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 22.

[0157] In some embodiments, the antibody comprises a heavy chain (HC) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as 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% identical to the amino acid sequence set forth as SEQ ID NO: 23. In some embodiments, the HC has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 23.

[0158] In some embodiments, the antibody comprises a light chain (LC) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO:22, and a heavy chain (HC) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as 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 to the amino acid sequence set forth as SEQ ID NO:22 and 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% identical to the amino acid sequence set forth as SEQ ID NO:23. In some embodiments, the LC has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:22, and the HC has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:23.

[0159] 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 as 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% identical to the amino acid sequence set forth as SEQ ID NO: 7. In some embodiments, the VL has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 7.

[0160] In some embodiments, the antibody comprises a heavy chain variable domain (VH) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as 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% identical to the amino acid sequence set forth as SEQ ID NO: 8. In some embodiments, the VH has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:8.

[0161] 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 as SEQ ID NO:7, and a heavy chain variable domain (VH) having an amino acid sequence at least 70% identical to the amino acid sequence set forth as 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 to the amino acid sequence set forth as SEQ ID NO:7, and 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% identical to the amino acid sequence set forth as SEQ ID NO:8. In some embodiments, the VL has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:7, and the VH has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:8.

[0162] 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 as SEQ ID NOs: 1-3. In some embodiments, the antibody comprises a light chain CDR sequence having 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 to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3. In some embodiments, the antibody comprises a light chain CDR sequence having an amino acid sequence 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3.

[0163] In some embodiments, the antibody comprises a heavy chain CDR sequence having an amino acid sequence at least about 70% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6. In some embodiments, the antibody comprises a heavy chain CDR sequence having 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 to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6. In some embodiments, the antibody comprises a heavy chain CDR sequence having an amino acid sequence 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6.

[0164] 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 as SEQ ID NOs:1-3, and a heavy chain CDR sequence having an amino acid sequence at least about 70% identical to at least one of the amino acid sequences set forth as SEQ ID NOs:4-6. In some embodiments, the antibody comprises a light chain CDR sequence having 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 to at least one of the amino acid sequences set forth as SEQ ID NOs:1-3, and a heavy chain CDR sequence having 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 to at least one of the amino acid sequences set forth as SEQ ID NOs:4-6. 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 as SEQ ID NOs:1-3, and a heavy chain CDR sequence having an amino acid sequence that is at least about 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs:4-6.

[0165] In some embodiments, an antibody comprising HLA-E and a neoantigen comprises 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 as 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 as SEQ ID NO:2, and a light chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO:3. In some embodiments, the antibody comprises a light chain CDR1 having 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 to the amino acid sequence set forth as SEQ ID NO:1, a light chain CDR2 having 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 to the amino acid sequence set forth as SEQ ID NO:2, , 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO:3, and at least one light chain CDR3 having 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 to the amino acid sequence set forth as SEQ ID NO:3. In some embodiments, the antibody comprises at least one of a light chain CDR1 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:1, a light chain CDR2 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:2, and a light chain CDR3 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:3.

[0166] In some embodiments, an antibody comprising HLA-E and a neoantigen comprises at least one of a heavy chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO:4, a heavy chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO:5, and a heavy chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO:6. In some embodiments, the antibody comprises a heavy chain CDR1 having 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 to the amino acid sequence set forth as SEQ ID NO:4, a heavy chain CDR2 having 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 to the amino acid sequence set forth as SEQ ID NO:5, , 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO:6, and at least one heavy chain CDR3 having 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 to the amino acid sequence set forth as SEQ ID NO:6. In some embodiments, the antibody comprises at least one of a heavy chain CDR1 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:4, a heavy chain CDR2 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:5, and a heavy chain CDR3 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:6.

[0167] In some embodiments, the antibody comprising HLA-E and a neoantigen comprises 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 as 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 as SEQ ID NO:2, a light chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO:3, a heavy chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO:4, a heavy chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO:5, and a heavy chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO:6.In some embodiments, the antibody comprises a light chain CDR1 having 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 to the amino acid sequence set forth as SEQ ID NO:1, a light chain CDR2 having 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 to the amino acid sequence set forth as SEQ ID NO:2, , 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO:3; a heavy chain CDR1 having 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 to the amino acid sequence set forth as SEQ ID NO:4; , 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO:6, and at least one heavy chain CDR3 having 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 to the amino acid sequence set forth as SEQ ID NO:6.In some embodiments, the antibody comprises at least one of a light chain CDR1 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:1, a light chain CDR2 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:2, a light chain CDR3 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:3, a heavy chain CDR1 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:4, a heavy chain CDR2 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:5, and a heavy chain CDR3 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:6.

[0168] In some embodiments, the antibody is a bispecific antibody. In some embodiments, the bispecific antibody comprises (a) a light chain variable domain (VL) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO:7, or a heavy chain variable domain (VH) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO:8, and (b) a light chain variable domain (VL) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO:15, or a heavy chain variable domain (VH) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO:16.

[0169] In some embodiments, the bispecific antibody comprises (a) a light chain variable domain (VL) comprising an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:7; or a heavy chain variable domain comprising an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:8. and (b) a light chain variable domain (VL) comprising an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:15, or a heavy chain variable domain (VH) comprising an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:16.

[0170] In some embodiments, the bispecific antibody comprises (a) a light chain variable domain (VL) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:7, or a heavy chain variable domain (VH) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:8, and (b) a light chain variable domain (VL) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:15, or a heavy chain variable domain (VH) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:16.

[0171] In some embodiments, the bispecific antibody comprises (a) a light chain variable domain (VL) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO:7, and a heavy chain variable domain (VH) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO:8, and (b) a light chain variable domain (VL) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO:15, and a heavy chain variable domain (VH) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO:16.

[0172] In some embodiments, the bispecific antibody comprises (a) a light chain variable domain (VL) comprising an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:7, and a heavy chain variable domain comprising an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:8. and (b) a light chain variable domain (VL) comprising an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:15, and a heavy chain variable domain (VH) comprising an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:16.

[0173] In some embodiments, the bispecific antibody comprises (a) a light chain variable domain (VL) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:7, and a heavy chain variable domain (VH) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:8, and (b) a light chain variable domain (VL) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:15, and a heavy chain variable domain (VH) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:16.

[0174] 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 as SEQ ID NO: 19, or a heavy chain (HC) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO: 20, and (b) a light chain variable domain (VL) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO: 15, or a heavy chain variable domain (VH) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO: 16.

[0175] In some embodiments, the bispecific antibody comprises (a) a light chain (LC) that comprises an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO: 19; or a heavy chain (HC) that comprises an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:20. ) and (b) a light chain variable domain (VL) comprising an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:15, or a heavy chain variable domain (VH) comprising an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:16.

[0176] In some embodiments, the bispecific antibody comprises (a) a light chain (LC) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 19, or a heavy chain (HC) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 20, and (b) a light chain variable domain (VL) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 15, or a heavy chain variable domain (VH) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 16.

[0177] 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 as SEQ ID NO: 19, or a heavy chain (HC) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO: 21, and (b) a light chain variable domain (VL) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO: 15, or a heavy chain variable domain (VH) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO: 16.

[0178] In some embodiments, the bispecific antibody comprises (a) a light chain (LC) that comprises an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO: 19; or a heavy chain (HC) that comprises an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:21. ) and (b) a light chain variable domain (VL) comprising an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:15, or a heavy chain variable domain (VH) comprising an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:16.

[0179] In some embodiments, the bispecific antibody comprises (a) a light chain (LC) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 19, or a heavy chain (HC) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 21, and (b) a light chain variable domain (VL) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 15, or a heavy chain variable domain (VH) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 16.

[0180] 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 as SEQ ID NO: 22, or a heavy chain (HC) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO: 23, and (b) a light chain variable domain (VL) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO: 15, or a heavy chain variable domain (VH) comprising an amino acid sequence at least 70% identical to the amino acid sequence set forth as SEQ ID NO: 16.

[0181] In some embodiments, the bispecific antibody comprises (a) a light chain (LC) that comprises an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:22; or a heavy chain (HC) that comprises an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:23. ) and (b) a light chain variable domain (VL) comprising an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:15, or a heavy chain variable domain (VH) comprising an amino acid sequence 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 to the amino acid sequence set forth as SEQ ID NO:16.

[0182] In some embodiments, the bispecific antibody comprises (a) a light chain (LC) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 22, or a heavy chain (HC) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 23, and (b) a light chain variable domain (VL) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 15, or a heavy chain variable domain (VH) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 16.

[0183] In some embodiments, the bispecific antibody comprises (a) a light chain CDR having an amino acid sequence at least 70% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1 to 3, or a heavy chain CDR having an amino acid sequence at least 70% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4 to 6, and (b) a light chain CDR having an amino acid sequence at least 70% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 9 to 11, or a heavy chain CDR having an amino acid sequence at least 70% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 12 to 14.

[0184] In some embodiments, the bispecific antibody comprises (a) a light chain complementarity determining region (CDR) having an amino acid sequence 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 to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3; or a heavy chain complementarity determining region (CDR) having an amino acid sequence 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 to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6. and (b) a light chain complementarity determining region (CDR) having an amino acid sequence 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 to at least one of the amino acid sequences set forth as SEQ ID NOs: 9 to 11. ), or a heavy chain complementarity determining region (CDR) having an amino acid sequence 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 to at least one of the amino acid sequences set forth as SEQ ID NOs: 12-14.

[0185] In some embodiments, the bispecific antibody comprises (a) a light chain CDR having an amino acid sequence that is 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1 to 3, or a heavy chain CDR having an amino acid sequence that is 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4 to 6, and (b) a light chain CDR having an amino acid sequence that is 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 9 to 11, or a heavy chain CDR having an amino acid sequence that is 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 12 to 14.

[0186] In some embodiments, the bispecific antibody comprises (a) 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 set forth as SEQ ID NOs: 1-3, and a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 70% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 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 set forth as SEQ ID NOs: 9-11, and a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 70% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 12-14.

[0187] In some embodiments, the bispecific antibody comprises (a) a light chain complementarity determining region (CDR) having an amino acid sequence 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 to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, and a heavy chain complementarity determining region (CDR) having an amino acid sequence 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 to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6. and (b) a light chain complementarity determining region (CDR) having an amino acid sequence 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 to at least one of the amino acid sequences set forth as SEQ ID NOs: 9 to 11. ), and heavy chain complementarity determining regions (CDRs) having an amino acid sequence 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 to at least one of the amino acid sequences set forth as SEQ ID NOs: 12-14.

[0188] In some embodiments, the bispecific antibody comprises (a) a light chain complementarity determining region (CDR) having an amino acid sequence that is 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1 to 3, 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 set forth as SEQ ID NOs: 4 to 6, and (b) a light chain complementarity determining region (CDR) having an amino acid sequence that is 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 9 to 11, 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 set forth as SEQ ID NOs: 12 to 14.

[0189] 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, sodium chloride, potassium chloride, calcium chloride, zinc chloride, water, dextrose, N-methylpyrrolidone, dimethylsulfoxide, N,N-dimethylacetamide, ethanol, propylene glycol, polyethylene glycol, diethylene glycol monoethyl ether, and the surfactant polyoxyethylene-sorbitan monooleate.

[0190] In some embodiments, the composition further comprises an additional therapeutic agent. In some embodiments, the therapeutic agent is a chemotherapeutic agent. Chemotherapeutic agents can include, among others, cytotoxic agents, anti-metabolite agents (e.g., antifolates, purine analogs, pyrimidine analogs, etc.), topoisomerase inhibitors (e.g., camptothecin derivatives, anthracenediones, anthracyclines, epipodophyllotoxins, quinoline alkaloids, etc.), microtubule inhibitors (e.g., taxanes, vinca alkaloids), protein synthesis inhibitors (e.g., cephalotaxines, camptothecin derivatives, quinoline alkaloids), alkylating agents (e.g., alkyl sulfonates, ethylenimines, nitrogen mustards, nitrosoureas, platinum derivatives, triazenes, etc.), alkaloids, terpenoids, and kinase inhibitors.

[0191] In some embodiments, the antibody and the therapeutic agent are in the same formulation. In some embodiments, the antibody and the therapeutic agent are in different formulations. In some embodiments, the antibody described herein is used prior to administration of another therapeutic agent. In some embodiments, the antibody described herein is used simultaneously with administration of another therapeutic agent. In some embodiments, the antibody described herein is used after administration of another therapeutic agent.

[0192] Pharmaceutical formulations are made to suit specific local, regional or systemic administration or delivery routes.To this end, pharmaceutical formulations include carriers, diluents or excipients suitable for administration by various routes.Specific non-limiting examples of administration routes for the compositions herein are parenteral, for example, intravenous, intraarterial, intradermal, intramuscular, subcutaneous, intrapleural, transdermal (topical), oral mucosa, intracranial, intramedullary, intraocular, rectal, oral (nutrient), mucosal administration, and any other formulation suitable for treatment method or administration protocol.

[0193] Solutions or suspensions used for parenteral use include sterile diluents such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol, or other synthetic solvents, antibacterial agents such as benzyl alcohol or methylparabens, antioxidants such as ascorbic acid or sodium hydrogen sulfide, chelating agents such as ethylenediaminetetraacetic acid, buffers such as acetates, citrates, or phosphates, and agents for adjusting tonicity such as sodium chloride or dextrose. In some embodiments, the pH is adjusted with acids or bases such as hydrochloric acid or sodium hydroxide.

[0194] Pharmaceutical preparations for injection include sterile aqueous solutions (where water soluble) or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, NJ), or phosphate buffered saline (PBS). In some embodiments, the carrier is a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.), or suitable mixtures thereof. In some embodiments, fluidity is maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Antibacterial and antifungal agents include, for example, parabens, chlorobutanol, phenol, ascorbic acid, and thimerosal. In some embodiments, isotonic agents, for example, sugars, polyalcohols such as mannitol or sorbitol, or sodium chloride, are included in the composition. In some cases, agents which delay absorption are included, for example, aluminum monostearate or gelatin, which prolong absorption of the injectable compositions.

[0195] Sterile injectable preparations are prepared by incorporating the active composition in the required amount in one of the above-mentioned components or their combination in suitable solvent.Generally, dispersion is prepared by incorporating active composition into sterile vehicle that contains basic dispersion medium and all other components.For the case of sterile powder for preparing sterile injectable solution, preparation method includes, for example, vacuum drying or freeze-drying, which obtains the powder of active ingredient with additional desired ingredient from the solution previously prepared.

[0196] For transmucosal and transdermal administration, a penetrant suitable for the barrier to be permeated is 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 achieved by using nasal sprays, inhalation devices (e.g., aspirators), or suppositories. For transdermal administration, the active compound is formulated into salves, ointments, gels, creams, or patches.

[0197] In some embodiments, pharmaceutical formulations are prepared with carriers that 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 further delivered using products such as implants or microencapsulated delivery systems to achieve local, regional, systemic delivery or controlled or sustained release. EXAMPLES

[0198] The following examples are given for the purpose of illustrating various embodiments of the present invention, and are not intended to limit the present invention in any manner. The examples, together with the methods described herein, are representative and representative of preferred embodiments, and are not intended to limit the scope of the present invention. Modifications and other uses encompassed within the spirit of the present invention, as defined by the scope of the claims, will occur to those skilled in the art.

[0199] Example 1. Antibody Generation First, R4 clone 1 (R4c1) was isolated from a semi-synthetic human antibody phage library. Briefly, this was done as follows: A human scFv antibody phage display library (1.42 × 10 9 (HuScL-2 phage library) was used to express the HLA-G signal peptide / HLA-E * Screening was performed against the 0103 complex (ABI-V-0025; VMAPRTLFL). Briefly, five internal peptides / HLA-A2* 30 μg of a mixture of 0201 complexes (ABI-AV-007-Biot, ABI-AV-0010-Biot, ABI-AV-0014-Biot, ABI-AV-0019, and ABI-AB-0030-Biot) were used for depletion and preblocking, followed by enrichment with 50 μg of ABI-V-0025. The enrichment factor of the phage library was 2.73x10 6 (Phage input: 5x10 11 , Phage output: 1.83x10 5 This process was repeated for a second biopanning round, resulting in an enrichment factor of 4.03x10 2 This process was repeated for the third biopanning round, but 20 μg of the complex mixture was used in the depletion (enrichment factor 2.31×10 2 ). In the fourth biopanning, 50 μg of ABI-V-0018 was used for depletion and preblocking followed by enrichment with 50 μg of ABI-V-0025 (enrichment factor 44). From the phage output of the fourth biopanning, 40 clones were picked and sequenced, revealing one unique sequence. This clone was designated R4 clone 1 (R4c1) (Figure 1A-B). To determine the affinity of the R4c1 antibody, it was diluted in 0.1% BSA, 0.1% Tween 20, PBS dilution / wash buffer and immobilized on a ForteBio Octet Protein A biosensor chip at 20 ug / ml for 50 seconds. The chip was subsequently washed in dilution / wash buffer for 50 seconds. Antibody binding association was measured using six concentrations (serial dilutions starting at 100ug / ml in dilution / wash buffer) of standard 0025-E 01:03 monomer complex for 150 seconds followed immediately by dissociation (dilution / wash buffer) for 150 seconds (Figure 1C). The equilibrium dissociation constant (KD) of clone R4 (clone 1) was determined to be 411nM (Figure 1D).

[0200] Affinity maturation of R4c1: Cycle 2: To increase the binding affinity of clone R4c1 to V-0025, the R4c1 scFv construct was cloned into a yeast vector to generate a library of R4c1 mutants by changing two amino acids in the CDRH3 region. Briefly, the yeast display library generated used EBY100 yeast competent cells prepared for transformation by incubation in 100 mM lithium acetate (LiAc, Sigma) plus 10 mM dithiothreitol (DTT, Sigma). Electroporation was achieved using a GenePulser (BioRad) with an OD of 60 prepared yeast cells per 2 mm cuvette (BioRad) in 10 mM LiAc, and 1 μg of scFv clone and 100 ng of pYES3 (ThermoFisher) were modified to contain Aga2 after the GAL1 promoter and Flag (DYKDDDDK) epitope tags after the scFv. To determine the number of transformants, 100 μL of 1 / 10, 1 / 100, and 1 / 1000 dilutions of transformed yeast were propagated on glucose plates minus tryptophan and uracil (D-UT, Teknova). After 2 days of incubation at 30°C, transformation efficiencies were calculated. Clones were then randomly picked by PCR for insertion diversity. Yeast were grown at 30°C in CM broth with glucose minus tryptophan and uracil (D-UT, Teknova) with shaking at 200 rpm. scFv surface induction was achieved by growing yeast in CM broth with galactose minus tryptophan and uracil (g-UT, Teknova) plus 0.1% raffinose (Sigma) (GR-UT) for at least 20 hours.

[0201] Yeast cells were stained after an initial blocking with 2% BSA in PBS 0.05% Tween (blocking buffer) at room temperature for 30 min to 1 h with rotation. Yeast cells were then incubated with biotinylated peptide / HLA complex monomers for 30 min to 90 min on ice depending on the monomer concentration. A second labeling was achieved with Streptaivdin PE (ThermoFisher) and DYKDDDDK epitope tag Alexa Fluor 488 (R&D Systems) for 30 min on ice. Samples were acquired using an LSR II flow cytometer (BD Biosciences) or CytoFLEX S (Beckmen Coulter). Data were prepared using Flowjo software version 10 or FACSDiva (BD Biosciences).

[0202] Screening was accomplished by either magnetic activated cell sorting (MACS) or fluorescence activated cell sorting (FACS) using library sizes with at least 10-fold coverage. For MACS screening, yeast cells were first blocked with 2% BSA in PBS 0.05% Tween (blocking buffer) at room temperature with rotation for 30 min to 1 h. Biotinylated peptide / HLA complex monomers were then incubated at 1 μM for 30 min on ice. A second labeling was achieved using streptavidin microbeads (Miltenyi Biotec). The labeled yeast cells were poured onto a MACS column in a MACS separator (Miltenyi Biotec). Yeast cells bound to the column were collected and confirmed as an enriched population. For FACS screening, yeast cells were prepared as described in the flow cytometry section. Samples were sorted using a FACS Aria II (BD Biosciences). Sorted yeast cells were confirmed as an enriched population.

[0203] Unique scFv clones were identified by plating. After 2 days at 30°C, individual colonies were picked and analyzed by PCR. Full-length human IgG1 from selected clones was produced in Expi293F (ThermoFisher) cells. Briefly, antibody variable regions were subcloned into mammalian expression vectors matching the human kappa light chain constant region (pFUSE2ss-CLIg-hK, Invivogen) and human IgG1 constant region (pFUSEss-CHIg-hG1, Invivogen) sequences. Vectors were transfected at a light to heavy chain ratio of 2:3. Antibodies were purified with protein A resin (Genscript) and electrophoretically characterized under reducing and non-reducing conditions.

[0204] The first round of selection was performed with 1 μM V-0025. Gating was based on binding by the parent (R4c1). The parent exhibited 0.11% to V-0025, whereas the cycle 2 library exhibited 1.66%, indicating the presence of higher affinity binders (Figure 2A). The second round of selection used 100 nM V-0025. 0.23% binding was observed for the cycle 2 library, compared to 0% for the parent, and no binding was observed to the negative control (V-0018) (Figure 2B). The third round of selection used 10 nM V-0025, where 1.05% binding was observed (Figure 2C). The final round of selection incorporated Koff. Briefly, V-0025 was incubated at 100 nM for 30 min, followed by incubation with R4c1 in full-length hIgG1 format (R4c1-IgG1). R4c1-IgG1 was added at 500 nM at various time points to act as an antibody sink. For this reason, a final round of selection was performed using Koff pressure to select top clones (Figure 2D). To identify unique clones, individual colonies were picked and sequenced (n=48). Ten unique clones were identified (Table 2) and the binding affinity was compared to the parental clone. Six of the unique clones were found to have at least 100-fold greater binding to V-0025 compared to the parent (Figures 3A-D). One clone (clone R2A_1), in addition to increased binding affinity, also exhibited superior selectivity and was selected for further analysis (Figures 3E-G).

[0205] [Table 2]

[0206] Characterization of clone R2A_1: Clone R2A_1 was converted from scFv to full-length hIgG1 for testing by ELISA and cell sorting. The affinity was determined to be approximately 20 nM based on ELISA data (data not shown), representing a more than 10-fold increase in affinity compared to the parental clone R4c1. To confirm antibody stability, binding was compared after storing the antibody at 37° C. for 72 hours. As shown in FIG. 4, binding of R2A_1A to 549-B4 cells was significantly impaired when the antibody was stored at 37° C. for 72 hours.

[0207] Stabilization of clone R2A_1: To increase the stability of R2A_1, several modifications were made to amino acids in both VH and VL framework regions. In VL, CDRL2 was modified to match its germline (IGKV1-39). This also removed the N-linked glycosylation site. In VH, in framework region 1, Gln5 was changed to match the germline (Leu5). In framework region 1, Met18 was also changed to match the germline (Leu18). The stable clone is called R4c1 H1-L1. The scFv sequence was inserted into yeast for display and compared to the parent (R2A_1). Some loss in affinity was observed, but no modification in specificity (not shown).

[0208] To generate antibodies with higher affinity and broader specificity, a yeast display library was generated based on R4c1-H1-L1 to introduce four amino acid mutations in the CDRL3 region, meaning that 44% of the CDRL3 sequence could be modified from the parent. As shown in Figure 5A (R0), very few clones showed binding to the target, but there was a selection population with more binding to the target than the parent. Screening was performed using the target at 10 nM (R1 out) and gating was performed only to select clones with greater binding affinity than the parent (Figure 6A). The R1 library was checked for binding to the target and a substantial increase was observed in several clones binding with improved affinity compared to the parent (Figure 5A, R1). To select clones with enhanced affinity, the R1 library was subjected to Koff pressure. Briefly, the library was incubated with 10 nM target. After washing, 1 μM of the parent clone as full-length IgG1 was added for 15-20 min to act as an antibody sink. All yeast clones that still showed binding to the target showed a higher Koff than the parental clone. As shown in Figure 5B, we observed yeast clones that maintained binding to the target in the antibody sink even after 120 min. To select these highly improved clones, a final selection (R2 out) was performed using a Koff of 10 nM target and 1 μM parental clone-IgG1 as antibody sink for 45 min, and a sort gate was performed to collect only the clones with the highest affinity (Figure 6B). After selection, individual clones were isolated and sequenced (n=60). 12 unique clones were found (Table 3) and binding to the target was confirmed at 1 and 0.1 nM (Figure 7). The top binding clone that was the target target was selected for further testing (clone R2-C02) (black arrow in Figure 7).

[0209] [Table 3]

[0210] Example 2. Characterization of top clones by ELISA, FACS, and label-free techniques The top clones identified from yeast display were produced as hIgG1 and tested for specificity and affinity. R2-C02 exhibited high affinity and fine specificity (not shown). R2-C02 was given the designation ABX0011 (or ABX-11) and was produced using a 1-L transient transfection protocol in CHO cells, followed by purification by protein affinity chromatography. Purity of the sample was determined by SDS-PAGE in reduced (two bands representing heavy and light chains) and non-reduced (single band at approximately 150 kD) form (Figure 8A) and by observing a single peak by size-exclusion chromatography (Figure 8B). First, ABX0011 was tested against a broad array of peptide / HLA complexes. As shown in Figure 9A, HLA-E clone 3D12 binds to all HLA-E complexes, including peptide-empty HLA-E. However, ABX0011 only recognized the non-classical HLA, HLA-G signal peptide / HLA-E complex, but not the closely related signal peptide from classical HLA (Figure 9B). Furthermore, neither additional peptide / HLA-E complexes, nor peptide / HLA-A2 complexes were recognized. For ELISA runs, highly pure HLA-E 01:03 and HLA-A2 02:01 monomeric complexes (diluted in 0.1% BSA, 0.1% Tween20, PBS dilution / wash buffer) were immobilized at 0.25ug / ml on neutravidin-coated microarray plates for 1 hour at room temperature. The plates were subsequently washed with 5x dilution / wash buffer. Antibodies diluted to 1ug / ml in dilution / wash buffer were incubated for 1 hour at room temperature, followed by washing the plates with 5x 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 5x washing with dilution / wash buffer. TMB substrate was added to the plate wells and incubated for 15 minutes at 50ul / well. 50ul / well of 1N HCl stop solution was added before reading the plate at 450nm absorbance.

[0211] To determine whether ABX0011 recognized the classical HLA I signal peptide presented by two different phenotypes of HLA-E, namely HLA-E 01:03 and HLA-E 01:01, the respective monomeric complexes were used in the ELISA described above. * 0101 and * No differences in HLA-G signal peptide binding were observed between 0103 and 0103 (Figure 9B).

[0212] Affinity determination for ABX0011: The binding affinity of ABX0011 was determined using label-free technology (Resonant Sensors, Inc., ResoSens instrument). The dissociation equilibrium constant (KD) was found to be 7.9 nM or more than 50-fold improvement over the R4c1 clone (Figure 1D, Figure 9C). The method for determining affinity was as follows: Thermofisher Capture Select™ Biotin anti-IgG-Fc (Hu) (diluted in PBS buffer) was immobilized at 5 μg / ml on a Neutravidin-coated Biotec label-free microarray plate until binding reached equilibrium. The plate was then washed 3x with 0.1% BSA, 0.1% Tween 20, PBS dilution / wash buffer. ABX0011 (5 μg / ml in dilution / wash buffer) was captured by anti-IgG-Fc until binding reached equilibrium. The plate was then washed 3x with dilution / wash buffer. Binding associations were determined by adding V-0025 HLA-E 01:03 monomer complexes (serial dilutions starting at 5 μg / ml in dilution / wash buffer) to wells and incubating for 20 min, immediately followed by dissociation (dilution / wash buffer) for approximately 25 min. Binding affinities were calculated using Tracedrawer kinetic analysis software.

[0213] The detection sensitivity of ABX0011 was observed by ELISA. Briefly, V-0025 HLA-E 01:03 monomer complex (serial dilutions starting from 2 μg / ml in 0.1% BSA, 0.1% Tween20, PBS buffer) was immobilized on neutravidin-coated microarray plates for 1 hour at room temperature. The plates were then washed with 5x dilution / wash buffer. The antibodies were diluted to 1 μg / ml in dilution / wash buffer and incubated for 1 hour at room temperature, followed by washing with 5x 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 washing 5x with dilution / wash buffer. TMB substrate was incubated at 50ul / well for 15 minutes. 50μL / well of 1N HCl stop solution was added and the plates were read at 450nm. In Figure 9D, ABX0011 and HLA-E were conjugated at 1 μg / mL and tested against titration of antigen V-0025. Similarly, in Figure 9E, V-0025 was conjugated at 0.25 μg / mL and tested against titration of ABX0011 and HLA-E using a similar ELISA protocol as described in Figure 9A. To confirm stability, ABX0011 was left at 37°C for 7-14 days, and then ABX0011 stored at 4°C was checked. ABX0011 was diluted to 1 μg / mL in mouse serum incubated at 37°C for 7-14 days (4°C controls were prepared in serum at the time of testing), added to wells with immobilized HLA-E 01:03 monomer complex, and the ELISA described above was performed. As shown in Figure 9F, binding was not modified and good stability of ABX0011 was not observed.

[0214] To further characterize the specificity, we first pulsed K562 cells transfected to express HLA-E with V-0025 peptide and then tested binding to HLA-E and ABX0011. As shown in Figure 9G, cells pulsed with V-0025 peptide showed loading based on increased HLA-E expression compared to no peptide (unpulsed). ABX0011 showed specificity for HLA-G loaded with HLA-E, but no binding was observed to unpulsed cells (Figure 9G). Next, K562 cells transfected to express HLA-E were pulsed with all of the classical HLA signal peptides, the non-classical HLA signal peptides, and two other HLA-E binding peptides, namely V-0038 and P-0550. All peptide-pulsed cells showed loading based on increased HLA-E expression compared to no peptide (unpulsed) (Figure 9H). Again, ABX0011 (exemplified by ABX0012) recognized only the V-0025 peptide in HLA-E expressing K562 cells (Figure 9I). Background staining was approximately 500 antibody molecules / cell. To further evaluate the fine binding specificity of ABX0011, HLA-E expressing K562 cells were pulsed with V-0025, V-0034, V-0044, V-0046, or P-0550 at 20 μg / ml or left unpulsed and stained with ABX0011 at various concentrations ranging from 10 to less than 0.001 μg / ml. Again, ABX0011 exhibited selectivity only for the V-0025 peptide, with minimal detection of only two closely related peptides, V-0044 and V-0046, when used at a concentration of 10 ug / ml (Figure 9J).

[0215] Alanine scans based on the peptide sequence for V-0025 (HLA-G signal peptide) showed that binding of ABX0011 to the peptide / HLA-E complex was primarily dependent on amino acid 8, with consistent large contacts but less dependent on amino acids 2, 7, and 9 (Figure 9K). Overall, these results indicate that ABX0011 exhibits selectivity for nonclassical HLA-G peptide signal sequences with high affinity and stability.

[0216] Example 3. ABX0011 binds with selectivity to target-positive cancer cell lines To confirm specificity, binding of ABX0011 was tested against various tumor cell lines, human peripheral blood mononuclear cells (huPBMCs), and primary human umbilical vascular endothelial cells (huVECs). Because 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 binding by both HLA-E and ABX0011 (Figure 10A). To confirm the restriction of ABX0011 to HLA-E / peptide complexes, binding of JEG-3 lacking HLA-E (JEG-3 Eko) was tested. As shown in the middle panel of Figure 10A, HLA-E and ABX0011 were unable to 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-3Tap-1ko). As shown in the bottom panel of Figure 10A, there is still some expression of HLA-E without Tap-1, but ABX0011 shows no binding, confirming that it only recognizes the HLA-G signal peptide processed via the conventional pathway. Specificity was similarly demonstrated using huPBMC and huVEC cells. Human PBMC, specifically B cells and NK cells, express high levels of HLA-E (Figure 10B). In contrast, healthy huPBMC do not express HLA-G, and therefore huPBMC lack binding to ABX0011 (Figure 10B). In addition, huVEC after O / N treatment with IFN-γ express high levels of HLA-E. However, ABX0011 (exemplified by ABX0010) does not bind to huVECs with or without IFN-γ treatment (Figure 10C).

[0217] HLA-E is known to be increased in several types of cancer. Therefore, several cancer cell lines were analyzed for HLA-E expression and ABX0011 binding. Since HLA-E is upregulated upon cell stress or stimulation, binding was observed in both unstimulated and IFNγ-stimulated cells. Figure 11A illustrates two cell lines (THP-1 and OCI-AML3) that express HLA-E and HLA-G and bind ABX0011 without stimulation, and one cell line (KG-1) that expresses HLA-E but not HLA-G and does not bind ABX0011. Furthermore, binding of ABX0011 (exemplified by ABX-0012) to AML cell lines using a range of concentrations (10 to less than 0.001 μg / ml) revealed good selectivity for ABX0011 (Figure 11B). These results suggest that ABX0011 may be used to target AML cancers as well as other cancers that express both HLA-E and HLA-G. K562 cells expressing HLA-E and mutant JEG3 cells 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.

[0218] For all cell binding studies (except ABX0012, ABX0011 with mouse IgG1), cells were blocked with anti-human CD16 (clone KD1), anti-human CD32 (clone AT10), and anti-human CD64 (clone 10.1) (Bio-Rad) at 1 μg / mL, with Human TruStain FcX (BioLegend) for 5-10 min at room temperature prior to surface staining with ABX0011 or hIgG1 (clone QA16A12, BioLegend) or with AF647-labeled ABX0011 or hIgG1, and with HLA-E in PE or PE-Cy7 (clone 3D12, BioLegend) at 100 μL for 30 min at 4 °C. Cells were then washed with staining buffer (PBS containing 2 mM EDTA) followed by a secondary staining cocktail containing goat anti-human / AF647 (Jackson ImmunoResearch) and zombie / aqua viability stain (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 an LSR II flow cytometer (BD Biosciences) or CytoFLEX S (Beckmen Coulter). Data were prepared using Flowjo software version 10 (BD Biosciences).

[0219] Example 4. ABX0011 induces NK-mediated antibody-dependent cellular cytotoxicity (ADCC) of target cells The primary objective 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. Blood from healthy volunteers was 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).

[0220] As shown in Figure 12A, after 4 hours of co-culture of NK cells with peptide-pulsed K562.E cells, ABX0011 was able to significantly increase the killing of K562.E cells in a dose-dependent manner compared to the isotype control (Figure 12A), upregulate NK CD107a expression (Figure 12B), and more specifically induce an increase in CD107a expression on NKG2A+ NK cells (Figure 12C). Similar results were found using THP-1 cells (Figure 12D). These results indicate that ABX0011 can be used to promote tumor cytotoxicity by inducing NK cell ADCC activity.

[0221] Example 5. Generation of bispecific antibodies capable of redirecting T cells to lyse tumor target cells ABX0030 was constructed as a bispecific antibody capable of activating CD3+ T cells to kill tumor cells. ABX0030 was generated as a Fab-Fc-scFv construct containing ABX0011 (Fab) linked to the single chain (scFv) of clone SP34 (mouse anti-human CD3e) on an aglycosylated (N297D mutation) human IgG1 scaffold. ABX0011 Fab was covalently linked to SP34 scFv using a 20 amino acid linker (GKPGSGKPGSGKPGSGKPGS). ABX0030 was produced in transiently transfected CHO cells and purified on a protein A affinity column. ABX0030 runs on a reducing SDS-PAGE gel and shows the expected two bands at the predicted MW (25 kD for the ABX0011 light chain and approximately 55 kD for ABX0030 without the light chain) (Figure 13A). Greater than 91% of ABX0030 migrates as a single peak on an analytical SEC-HPLC column (Figure 13B).

[0222] A label-free assay (ResoSens instrument, Resonant Sensors, Inc) was used to determine the binding affinity of ABX0030. Briefly, V-0025 HLA-E 01:03 monomer complex (diluted in 0.1% BSA, 0.1% Tween 20, PBS buffer) was immobilized on a Neutravidin-coated Bionetique label-free microarray plate at 5 μg / ml until binding reached equilibrium. The plate was then washed with 3-fold dilution / wash buffer. The binding association of ABX0030 (serial dilutions starting at 10 μg / ml in dilution / wash buffer) was assessed for approximately 20 min, followed immediately by dissociation (dilution / wash buffer) for approximately 15 min. Binding affinity was calculated using Tracedrawer kinetic analysis software. Findings revealed a dissociation equilibrium constant of 8.97 nM (Figure 14).

[0223] ABX0030 binding properties: ABX0030 binding to target tumor cells was first confirmed. As shown in Figure 15, ABX0030 binds to V-0025 peptide-pulsed K562 cells, which express HLA-E similarly to the parent clone (ABX0011). This binding is HLA-E restricted, as the HLA-E negative parent K562 cells show no binding to ABX0030 (Figure 15). Binding to T cells in peripheral blood mononuclear cells (PBMCs) was used to confirm the anti-CD3 arm (Figure 16). The K562 cell line was obtained from ATCC. K562 cells expressing HLA-E cells were 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 with anti-human CD16 (clone KD1), anti-human CD32 (clone AT10), and anti-human CD64 (clone 10.1) (Bio-Rad) at 1 μg / mL, Human TruStain FcX (BioLegend) for 5–10 min at room temperature prior to surface staining with unlabeled antibodies, as well as with HLA-E / PE-Cy7 (clone 3D12, BioLegend) at 50–100 μL for 30 min at 4 °C. Cells were then washed with staining buffer (PBS containing 2 mM EDTA) followed by a secondary staining cocktail containing goat anti-human or goat anti-mouse / AF647 (Jackson ImmunoResearch, if unlabeled antibodies were used) and zombie / aqua viability stain (BioLegend). Cells were incubated in 50 μL for 30 min at 4 °C. Cells were washed twice with staining buffer and fixed with fluorofix (BioLegend). Samples were acquired using a CytoFLEX S (Beckmen Coulter), and data were prepared using Flowjo software version 10 (BD Biosciences).

[0224] ABX0030 enhances target-specific cytotoxicity of primary CTLs. To evaluate the activity of ABX0030, primary human CTLs were co-cultured with either K562 (HLA-E positive) or K562.E pulsed with V-0025 peptide and titrated with ABX0030. As shown in Figure 17A, ABX0030 induced dose-dependent cytotoxicity specifically against the target. Unpulsed K562.E cells were unaffected. Furthermore, ABX0030 does not induce expression of CD25 (48 h) (Figure 17B) and IFNγ (48 h) (Figure 17C) in CD8+ T cells cultured with target-negative K562.E cells.

[0225] These results were confirmed using THP-1 cells (ABX0011 binding data shown in Figure 11A). After 48 hours of co-culture, ABX030 induced cytotoxicity in a dose-dependent manner (Figure 18A). ABX0030 was also able to induce CD8+ T cell activation, as shown by the dose-dependent induction of CD25, CD107a, perforin, and IFNγ (Figures 18B-E). These results indicate that ABX0030 can enhance tumor cell lysis by CD8+ T cells in a target-specific manner.

[0226] To perform in vitro T cell activation assays, blood from healthy volunteers was 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). Enriched human CD8+ T cells (CTLs) were collected at 1x10 6Cells were incubated overnight at 100 / mL. Target cells were labeled with CFSE (ThemoFisher) and incubated CTLs were added 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. Monensin and anti-human CD107a / BV421 (BioLegend) were added to all wells for the final 4 h of incubation. Cells were harvested 24–48 h later. Cells were stained with anti-human CD8 / APC (BioLegend), anti-human CD25 / PE-Cy7 (Tonbo), and Zombie / Aqua viability markers (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-Dazzle594 (BioLegend). Samples were acquired using a CytoFLEX S (Beckmen Coulter). Data were prepared using Flowjo software version 10 (BD Biosciences).

[0227] [Table 4]

[0228] Example 6. ABX0012 does not bind to peripheral immune cells To test binding of ABX0012 to immune cells, immune cells were purified, cultured, stained, and evaluated by flow cytometry as described below.

[0229] Human primary cells Blood from healthy volunteers was 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 (DCs) were purified using the EasySep human pan-DC pre-enrichment kit (StemCell Technologies). Monocytes (MOs) were purified using either 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 PBMCs following density gradient separation. Cord blood and healthy bone marrow were obtained from StemExpress. Cord blood PBMCs were isolated by density gradient centrifugation using Ficoll-Paque PLUS (GE Healthcare) or Lymphoprep (StemCell Technologies). PBMCs from AML patients were collected and stained by Champions Oncology, and flow cytometry analysis was performed in-house.

[0230] For overnight stimulation with IFNγ, PBMCs were cultured at 1 × 10 in RPMI-640 medium (ATCC) (Millipore Sigma) supplemented with 1% penicillin-streptomycin, HEPES buffer, 2 mM L-glutamine, 1% non-essential amino acids, sodium pyruvate, and 10% fetal bovine serum. 6IFNγ was provided at 10 μg / mL and compared with PBMCs without IFNγ.

[0231] 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 cells were obtained from ATCC. NCC-STC-K140 and RCC-10RGB cells were obtained from Sekisui XenoTech. SNU-899 cells were obtained from the Korea Cell Line Bank. OCI-AML3 cells were obtained from DSMZ. JEG-3 HLA-EKO and Tap1 KO cells, and OCI-AML3 HLA-E KO were obtained from Professor Throbald van Hall under the MTA. Some cells required overnight stimulation with IFNγ to induce HLA-E expression.

[0232] Macrophage differentiation Macrophages were generated by culturing monocytes in Immunocult-SF macrophage medium (StemCell Technologies) supplemented with 5 μg / mL M-CSF. Additional medium was added on day 4. On day 6, M0 macrophages were activated with LPS (10 ng / mL) and IFNγ (50 ng / mL) for M1 activation or with IL-4 (10 ng / mL) for M2a activation. After 2 days of activation, M1 and M2a macrophages were harvested. Dissociation was performed using accutase for M1 macrophages and 2.5 mM EDTA for M2a macrophages.

[0233] Flow cytometry ABX0012, mIgG1, and MEM-E / 02 were labeled with AlexaFluor 647 (AF647) using the SiteClick Antibody Azido Modification kit and the Click-iT AF647 sDIBO Alkyne Antibody Labeling Kit (Thermo Fisher Scientific).

[0234] For cell binding with unlabeled antibodies, cells were stained with ABX0012, ABX0011, mouse isotype IgG1 (MOPC-21, BioLegend), human isotype IgG1 (QA16A12, BioLegend), 3D12 (BioLegend), or MEM-E / 02 (BioRad) at 1–5 μg / mL in 100 μL for 30 min at 4 °C. Cells were then washed with staining buffer (PBS containing 2 mM EDTA) followed by a secondary stain cocktail containing goat anti-human / AF647 (Jackson ImmunoResearch) or goat anti-human mouse / AF647 (Thermo Fisher Scientific) and zombie / aqua viability stain (BioLegend). Cells were incubated in 100 μL for 30 min at 4 °C. Cells were washed twice with staining buffer and acquired in 100 μL of staining buffer. For cell binding with labeled antibodies, cells were incubated with antibody staining cocktail in 100 μL for 30 min at 4 °C, followed by washing twice with staining buffer and acquisition in 100 μL of staining buffer. If cells were not available on the same day as staining, cells were fixed with 100 μL of FluoroFix buffer (BioLegend). Samples were acquired using a CytoFLEX S (Beckmen Coulter). Data were prepared using Flowjo software version 10 (BD Biosciences).

[0235] Anti-HLA-E(3D12) / PE-Cy7, anti-CD3(HIT3a) / APC-Cy7, anti-CD3(SK7) / APC-Cy7, anti-CD4(RPA-T4) / PerC P-Cy5.5, anti-CD8 (RPT-T8) / BV605, anti-CD14 (M5E2) / FITC, anti-CD16 (3G8) / PacificBlue, anti-CD19 (HI B19) / FITC, anti-CD20(2H7) / BV421, anti-CD33(WM53) / BV650, anti-CD34(561) / AF700, anti-CD45(HI30) / FITC, anti-CD56(5.1H11) / AF700, anti-lineage cocktail / 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.

[0236] Immune cells were tested for binding to ABX0012 since they are known to express HLA-E. All immune cells expressed HLA-E, but none showed expression of HLA-G or binding by ABX0012 (Figure 19). Since HLA-E can be upregulated upon stress or stimulation of cells, ABX0012 binding was tested in PBMCs with and without IFNγ stimulation. HLA-E clone 3D12 showed a slight increase upon stimulation, but only HLA-E clone MEM-E / 02, which recognizes HLA-E without peptide or B2M, was upregulated. No modification of ABX0012 binding was observed (Figure 20). This data suggests that ABX0011 should not have off-target activity on immune cells.

[0237] Example 7. ABX0012 binding requires expression of HLA-E and classical HLA-G To identify cell lines that bind ABX0012, various cell lines were analyzed for expression of HLA-E and HLA-G. Several cell lines were identified (Figure 21), and ABX0012 binding was increased by IFNγ-stimulation (Figure 22). HLA-E selectivity was confirmed by testing cell lines expressing HLA-G but not HLA-E (Figure 23), and cell lines expressing HLA-E but not HLA-G (Figure 24A). This selectivity was not altered by stimulating the cells with IFNγ (Figure 24B). Note that these FACS data are used to highlight the point that cells lacking HLA-E do not stain with ABX0011 / 12. These data are not representative of all tumor cells of that cancer type. They are presented 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 the middle panel of FIG. 25A, HLA-E and ABX0012 are involved in the JEG-3 E ko To confirm that ABX0012 only recognizes the HLA-G peptide / HLA-E complex that requires TAP expression, we used Tap-1 knockout JEG-3 cells (JEG-3 Tap-1 ko ) binding. As shown in the right panel of Figure 25A, there was still some expression of HLA-E without Tap-1, but ABX0012 showed no binding, confirming that ABX0012 only recognizes peptides processed via the classical pathway (HLA-G). Similar results were observed with OCI-AML3, which lacks HLA-E (Figure 25B).

[0238] Example 8. ABX0012 binds to acute myeloid leukemia (AML) myeloblasts in blood Based on the binding of ABX0012 to AML cell lines, THP-1, and OCI-AML3, PBMCs from AML patients were tested for ABX012 binding. As shown in Figure 26, the percentage of ABX0012 positive cells in AML PBMCs was significantly higher compared to healthy PBMCs. To confirm that hematopoietic stem and progenitor cell populations were not stained with ABX0012, healthy bone marrow and umbilical cord blood were tested. Healthy bone marrow and umbilical cord blood exhibited similar levels of ABX0012 as healthy PBMCs (Figure 26). The levels of ABX0012 in healthy bone marrow and umbilical cord blood were not significantly lower than AML PBMCs, which is a result of the low donor numbers. This data suggests that AML could be an indication for ABX0011 therapy.

[0239] Example 9. Validation of staining protocol using frozen cell blocks To analyze the immunohistochemistry (IHC) staining of tissue samples, IHC staining was tested on frozen cell blocks of human frozen tissue blocks (tumor and normal adjacent tissue (NAT) were purchased from ProteoGenex (Inglewood, CA) and embedded in OCT compound. Samples were sectioned and mounted on slides using a microtome cryostat. Immunohistochemistry (IHC) staining was performed by NovoVita Histopath Laboratory, LLC (Cambridge, MA). Briefly, frozen tissue slides were air-dried for 20 min and then stained with a Ventana XT discovery ultra-instrument (entana Medical The slides were then mounted in a 1x Ventana reaction buffer (Cat. #950-300) and treated with peroxidase inhibitor CM (Ventana) for 12 minutes to block endogenous peroxidase. After rinsing once with Ventana reaction buffer, the slides were warmed to 37°C and incubated with 2.25ug / ml of primary antibody (anti-HLA-E (MEM-E / 02 (AbCam), mouse IgG1 isotype control, or AB0012) for 60 minutes. Slides were rinsed 3 times with Ventana reaction buffer, incubated for 4 minutes with FineFix working solution (Milestone, Kalamazoo, MI, Cat. #70147W) (after the fixation step) and rinsed 3 times. Discovery anti-mouse HQ (Ventana, Cat. #760-4814) was applied to the slides for 24 minutes and rinsed 3 times with Ventana reaction buffer. DISC anti-HQ One drop of HRP (Ventana, Cat. #760-4820) was added to the slide, incubated for 24 hours, and rinsed three times with Ventana reaction buffer. Next, one drop of Discovery ChromoMap DAB kit (Ventana, Cat. #760-159) and one drop of CM H2O2 (Ventana) were added to the slide, incubated for 8 minutes, followed by rinsing three times with Ventana reaction buffer. Then, one drop of copper CM (Ventana) was added to the slide, incubated for 4 minutes, followed by rinsing three times with Ventana reaction buffer, after which one drop of hematoxylin (counterstain) was added to the slide for 12 minutes.After rinsing (2x) with Ventana reaction buffer, a drop of Bluing reagent (after counterstaining) was added and after 8 minutes the slides were rinsed 2x with Ventana reaction buffer. Slides were then removed from the Ventana XT, washed with dishwashing detergent, and treated with alcohol and xylene for dehydration. A coverslip was placed on the slide and the slides were read on a Discovery Ultra instrument.

[0240] ABX0012 was used at 1.95ug / ml, anti-HLA-E (MEM-E / 02) antibody, and mouse IgG1 isotype control antibody at 2.25ug / ml to stain cell blocks of HLA-E (K562.E) transfected K562 cells or K562 cells pulsed with 20ug / ml V-0025 (VMPRTLFL) peptide for 2 hours (Figure 27). Images show that ABX0012 strongly stains (3 out of 3+++) cells pulsed with K562.E+V-0025 peptide but not K562 cells (-). These data show that ABX0012 selectively binds to cells presenting HLA-E / V-0025, validating the immunohistochemistry (IHC) staining protocol.

[0241] Example 10. Staining of positive control tissues Fresh frozen human placental tissue was used as a positive control for ABX0012. Staining with ABX0012 was not novel in placental tissue, as trophoblast cells are known to express HLA-E and HLA-G. In Figure 28, ABX0012 shows strong (2++-3+++) staining for trophoblast cells in placental tissue, demonstrating that the HLA-E+ canonical leader sequence peptide is present on the surface of trophoblast cells.

[0242] Example 11. ABX0012 stains head and neck tumor tissue FIG. 29 shows images of ABX0012 stained frozen tumor tissue collected from the head and neck of a patient. The left panel of FIG. 29A shows strong tumor cell staining with anti-HLA-E antibody (clone MEM-E / 02). The panel shows staining of stromal regions with MEM-E / 02 antibody. The right panel shows ABX0012 antibody staining of tumor tissue. The tumor stroma shows strong staining (3+++) while the tumor cells show weak to moderate staining. The images show that the target HLA-E+ leader sequence non-classical HLA-G (VMAPRTLFL) is present in the tumor tissue from the head and neck of the patient. FIG. 29B shows images of normal adjacent tissue (NAT) stained with MEM-E / 02 (left panel) and ABX0023 (right). Note that NAT epithelium is positive for HLA-E expression (left panel), but the absence of ABX0012 staining indicates the lack of HLA-E / VMAPRTLFL peptide complex in NAT epithelium (right panel).

[0243] Example 12. ABX0012 stained colon adenocarcinoma tumor tissue Representative images showing fresh frozen human colon adenocarcinoma tissue stained with anti-HLA-E (left, 10x magnification) or ABX-0012 (right, 10x magnification). Figure 30 shows HLA-E expression in both tumor and stromal regions (top 1.4x magnification and bottom 14.4x magnification, left), and HLA-E / VMAPRTLFL peptide complexes are detectable by ABX0012 in both tumor (2++) and stromal (3+++) regions (top 1.4x magnification and bottom 14.4x magnification, right).

[0244] Example 13. ABX0012 stains lung squamous cell carcinoma tissue Representative images show fresh frozen lung squamous cell carcinoma tissue stained with anti-HLA-E (top left, 10x magnification) or ABX0012 (right, 10x magnification). Figure 31A shows tumor and stroma staining with both anti-HLA-E antibody (2++) or ABX0012 (1+-2++), respectively, indicating expression of HLA-E and HLA-E / VMAPRTLFL peptide complex in lung cancer. Figure 31B 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.

[0245] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such 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 is understood that various alternatives to the embodiments described herein may be utilized. 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 are covered thereby.

Claims

1. A monoclonal antibody or antigen-binding fragment thereof that selectively binds to a complex containing HLA-E and a peptide having the sequence of SEQ ID NO: 18 (VMAPRTLFL), (a) a light chain variable domain (VL) comprising an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO:7, and a light chain complementarity determining region (CDR) 1 having the amino acid sequence of SEQ ID NO:1, a light chain CDR2 having the amino acid sequence of SEQ ID NO:2, and a light chain CDR3 having the amino acid sequence of SEQ ID NO:3; (b) a heavy chain variable domain (VH) comprising an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO:8, and a heavy chain CDR1 having the amino acid sequence of SEQ ID NO:4, a heavy chain CDR2 having the amino acid sequence of SEQ ID NO:5, and a heavy chain CDR3 having the amino acid sequence of SEQ ID NO:

6. Including, A monoclonal antibody or an antigen-binding fragment thereof.

2. (a) the VL comprises an amino acid sequence that is at least 99% identical to the amino acid sequence of SEQ ID NO:7; (b) the VH comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO:8; The monoclonal antibody or antigen-binding fragment thereof according to claim 1.

3. (a) the VL comprises the amino acid sequence of SEQ ID NO:7; (b) the VH comprises the amino acid sequence of SEQ ID NO:8; A monoclonal antibody or an antigen-binding fragment thereof according to claim 1 or 2.

4. (a) a heavy chain (HC) comprising an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO:21; and (b) a light chain (LC) comprising an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO:

19. The monoclonal antibody or antigen-binding fragment thereof according to any one of claims 1 to 3, comprising:

5. (a) a HC comprising an amino acid sequence that is at least 99% identical to the amino acid sequence of SEQ ID NO:21; and (b) a LC comprising an amino acid sequence that is at least 99% identical to the amino acid sequence of SEQ ID NO: 19; The monoclonal antibody or antigen-binding fragment thereof according to any one of claims 1 to 4, comprising:

6. (a) a HC comprising the amino acid sequence of SEQ ID NO:21; and (b) LC comprising the amino acid sequence of SEQ ID NO: 19 The monoclonal antibody or antigen-binding fragment thereof according to any one of claims 1 to 5, comprising:

7. (a) a HC comprising an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO:20; and (b) a LC comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 19; The monoclonal antibody or antigen-binding fragment thereof according to any one of claims 1 to 3, comprising:

8. (a) a HC comprising an amino acid sequence that is at least 99% identical to the amino acid sequence of SEQ ID NO: 20; and (b) a LC comprising an amino acid sequence that is at least 99% identical to the amino acid sequence of SEQ ID NO: 19; 8. The monoclonal antibody or antigen-binding fragment thereof of claim 1 , comprising:

9. (a) a HC comprising the amino acid sequence of SEQ ID NO: 20; and (b) LC comprising the amino acid sequence of SEQ ID NO: 19 9. The monoclonal antibody or antigen-binding fragment thereof of claim 1 , comprising:

10. A monoclonal antibody or antigen-binding fragment thereof that selectively binds to a complex containing HLA-E and a peptide having the sequence of SEQ ID NO: 18 (VMAPRTLFL), (a) a HC comprising an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 21; and (b) a heavy chain CDR1 having the amino acid sequence of SEQ ID NO:4, a heavy chain CDR2 having the amino acid sequence of SEQ ID NO:5, and a heavy chain CDR3 having the amino acid sequence of SEQ ID NO:6; (c) a LC comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 19; and (d) a light chain CDR1 having the amino acid sequence of SEQ ID NO:1, a light chain CDR2 having the amino acid sequence of SEQ ID NO:2, and a light chain CDR3 having the amino acid sequence of SEQ ID NO:3; A monoclonal antibody or an antigen-binding fragment thereof comprising:

11. A monoclonal antibody or antigen-binding fragment thereof described in claim 10, wherein the HC comprises an amino acid sequence that is at least 99% identical to the amino acid sequence of SEQ ID NO:21, and the LC comprises an amino acid sequence that is at least 99% identical to the amino acid sequence of SEQ ID NO:

19.

12. A monoclonal antibody or an antigen-binding fragment thereof described in claim 10 or 11, wherein the HC comprises the amino acid sequence of SEQ ID NO: 21 and the LC comprises the amino acid sequence of SEQ ID NO:

19.

13. (a) a VL comprising an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO:7; and (b) a VH comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:8; 13. The monoclonal antibody or antigen-binding fragment thereof according to any one of claims 10 to 12, comprising:

14. (a) a VL comprising an amino acid sequence that is at least 99% identical to the amino acid sequence of SEQ ID NO:7; and (b) a VH comprising an amino acid sequence that is at least 99% identical to the amino acid sequence of SEQ ID NO:8; 14. The monoclonal antibody or antigen-binding fragment thereof according to any one of claims 10 to 13, comprising:

15. (a) a VL comprising the amino acid sequence of SEQ ID NO:7, and (b) a VH comprising the amino acid sequence of SEQ ID NO:8; 15. The monoclonal antibody or antigen-binding fragment thereof according to any one of claims 10 to 14, comprising:

16. A monoclonal antibody or antigen-binding fragment thereof that selectively binds to a complex comprising HLA-E and a peptide comprising the sequence of SEQ ID NO:18 (VMAPRTLFL), comprising: (a) a HC comprising an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 20; and (b) a heavy chain CDR1 having the amino acid sequence of SEQ ID NO:4, a heavy chain CDR2 having the amino acid sequence of SEQ ID NO:5, and a heavy chain CDR3 having the amino acid sequence of SEQ ID NO:6; (c) a LC comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 19; and (d) a light chain CDR1 having the amino acid sequence of SEQ ID NO:1, a light chain CDR2 having the amino acid sequence of SEQ ID NO:2, and a light chain CDR3 having the amino acid sequence of SEQ ID NO:

3. A monoclonal antibody or an antigen-binding fragment thereof comprising:

17. A monoclonal antibody or antigen-binding fragment thereof described in claim 16, wherein the HC comprises an amino acid sequence that is at least 99% identical to the amino acid sequence of SEQ ID NO: 20, and the LC comprises an amino acid sequence that is at least 99% identical to the amino acid sequence of SEQ ID NO:

19.

18. A monoclonal antibody or antigen-binding fragment thereof described in claim 16 or 17, wherein the HC comprises the amino acid sequence of SEQ ID NO: 20 and the LC comprises the amino acid sequence of SEQ ID NO:

19.

19. (a) a VL comprising an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO:7; and (b) a VH comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:8; 19. The monoclonal antibody or antigen-binding fragment thereof according to any one of claims 16 to 18, comprising:

20. (a) a VL comprising an amino acid sequence that is at least 99% identical to the amino acid sequence of SEQ ID NO:7; and (b) a VH comprising an amino acid sequence that is at least 99% identical to the amino acid sequence of SEQ ID NO:8; 20. The monoclonal antibody or antigen-binding fragment thereof according to any one of claims 16 to 19, comprising:

21. (a) a VL comprising the amino acid sequence of SEQ ID NO:7, and (b) a VH comprising the amino acid sequence of SEQ ID NO:8; 21. The monoclonal antibody or antigen-binding fragment thereof according to any one of claims 16 to 20, comprising:

22. (a) a first antigen-binding arm that selectively binds to a complex comprising HLA-E and a peptide comprising the sequence of SEQ ID NO: 18 (VMAPRTLFL), (i) a VL comprising an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO:7, and a light chain CDR1 having the amino acid sequence of SEQ ID NO:1, a light chain CDR2 having the amino acid sequence of SEQ ID NO:2, and a light chain CDR3 having the amino acid sequence of SEQ ID NO:3; (ii) a VH comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:8, and a heavy chain CDR1 having the amino acid sequence of SEQ ID NO:4, a heavy chain CDR2 having the amino acid sequence of SEQ ID NO:5, and a heavy chain CDR3 having the amino acid sequence of SEQ ID NO:6; and a first antigen-binding arm comprising: (b) a second antigen-binding arm that specifically binds to the CD3 protein associated with the T cell receptor (TCR); and A bispecific T cell-inducing antibody comprising:

23. (a) a light chain CDR1 having the amino acid sequence of SEQ ID NO:9, a light chain CDR2 having the amino acid sequence of SEQ ID NO:10, and a light chain CDR3 having the amino acid sequence of SEQ ID NO:11, and (b) a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 12, a heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 13, and a heavy chain CDR3 having the amino acid sequence of SEQ ID NO:

14.

23. The bispecific T cell engaging antibody of claim 22, comprising a second antigen binding arm comprising:

24. (a) the VL comprises an amino acid sequence that is at least 99% identical to the amino acid sequence of SEQ ID NO:7; (b) the VH comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO:8; 24. The bispecific T cell inducing antibody of any one of claims 22 to 23, comprising a first antigen-binding arm.

25. (a) the VL comprises the amino acid sequence of SEQ ID NO:7; (b) the VH comprises the amino acid sequence of SEQ ID NO:8; 25. The bispecific T cell inducing antibody of any one of claims 22 to 24, comprising a first antigen-binding arm.

26. (a) a HC comprising an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO:21; and (b) a LC comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 19; 26. The bispecific T cell inducing antibody of any one of claims 22 to 25, comprising a first antigen binding arm comprising:

27. (a) a HC comprising an amino acid sequence that is at least 99% identical to the amino acid sequence of SEQ ID NO:21; and (b) a LC comprising an amino acid sequence that is at least 99% identical to the amino acid sequence of SEQ ID NO: 19; 27. The bispecific T cell inducing antibody of any one of claims 22 to 26, comprising a first antigen binding arm comprising:

28. (a) a HC comprising the amino acid sequence of SEQ ID NO:21; and (b) LC comprising the amino acid sequence of SEQ ID NO: 19 28. The bispecific T cell inducing antibody of any one of claims 22 to 27, comprising a first antigen binding arm comprising:

29. (a) a HC comprising an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO:20; and (b) a LC comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 19; 29. The bispecific T cell inducing antibody of any one of claims 22 to 28, comprising a first antigen binding arm comprising:

30. (a) a HC comprising an amino acid sequence that is at least 99% identical to the amino acid sequence of SEQ ID NO: 20; and (b) a LC comprising an amino acid sequence that is at least 99% identical to the amino acid sequence of SEQ ID NO: 19; 30. The bispecific T cell engaging antibody of any one of claims 22 to 25, or 29, comprising a first antigen binding arm comprising:

31. (a) a HC comprising the amino acid sequence of SEQ ID NO: 20; and (b) LC comprising the amino acid sequence of SEQ ID NO: 19 31. The bispecific T cell inducing antibody of any one of claims 22 to 25, 29, or 30, comprising a first antigen binding arm comprising:

32. (a) a VL comprising the amino acid sequence of SEQ ID NO: 15; and (b) a VH comprising the amino acid sequence of SEQ ID NO: 16; 32. The bispecific T cell inducing antibody of any one of claims 22 to 25, or 29 to 31, comprising a second antigen binding arm comprising:

33. 33. A pharmaceutical composition comprising a monoclonal antibody or antigen-binding fragment thereof according to any one of claims 1 to 21, or a bispecific T cell engaging antibody according to any one of claims 22 to 32, and a pharma- ceutically acceptable carrier or excipient.

34. 33. A pharmaceutical composition for use in the treatment of HLA-E expressing cancer comprising a monoclonal antibody or antigen-binding fragment thereof according to any one of claims 1 to 21, or a bispecific T cell engaging antibody according to any one of claims 22 to 32, and a pharma- ceutical acceptable carrier or excipient.

35. The pharmaceutical composition of claim 34, wherein the HLA-E expressing cancer is breast cancer, kidney cancer, lung cancer, ovarian cancer, colon cancer, pancreatic cancer, choriocarcinoma, non-small cell lung cancer (NSCLC), gastric cancer, cervical cancer, head and neck cancer, leukemia, lymphoma, myeloma, multiple myeloma (MM), acute myeloid leukemia (AML), myelodysplastic syndrome, B cell malignancies, and mantle cell lymphoma.

36. 33. Use of a monoclonal antibody or antigen-binding fragment thereof according to any one of claims 1 to 21, or a bispecific T cell engaging antibody according to any one of claims 22 to 32, in the preparation of a medicament for treating an HLA-E expressing cancer in an individual in need thereof.

37. 37. The use of claim 36, wherein the HLA-E expressing cancer is breast cancer, renal cancer, lung cancer, ovarian cancer, colon cancer, pancreatic cancer, choriocarcinoma, non-small cell lung cancer (NSCLC), gastric cancer, cervical cancer, head and neck cancer, leukemia, lymphoma, myeloma, multiple myeloma (MM), acute myeloid leukemia (AML), myelodysplastic syndrome, B cell malignancies, and mantle cell lymphoma.

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