Discovery and preclinical evaluation of monoclonal antibodies and bispecific engagers targeting the NKG2A inhibitory receptor

NK and T cells are key effectors that eliminate cancer cells, but upregulation of the inhibitory receptor NKG2A on these cells attenuates antitumor immune responses. To counteract NKG2A inhibitory signaling, we identified two specific fully human monoclonal anti-NKG2A antibodies that block HLA-E ligand binding. These antibodies activated NK cells and enhanced antibody-dependent cellular cytotoxicity of tumor-targeting IgG1s both in vitro and in vivo. Bispecific engagers (BiNKs), generated by fusing NKG2A antibodies with tumor targeting binders, promoted immune synapse formation and directed cytotoxicity of NK and CD8⁺ T cells toward cancer cells. In a human PBMC-engrafted NSG mouse xenograft lung cancer model, an anti-HER2 × anti-NKG2A BiNK markedly inhibited tumor growth as a monotherapy or in combination with pertuzumab. Cell depletion studies revealed that the BiNK enhanced antitumor activity of both NK and T cells. NKG2A blockade with potent and specific, fully human antibodies and BiNKs show promise for further development as cancer immunotherapeutics.