Joyce K Hwang, Marina Tuyishime, Daniel J Marston, Hongbing Yang, Daniel Wrapp, Dapeng Li, Simon Brackenridge, McKenzie Frazier, Nicholas P Levering, Richard Scearce, Brianna Rhodes, Caitlin Harris, Max Quastel, Anyway Brenda Kapingidza, Anna E Kliszczak, Jacob Gater, Persephone Borrow, Guido Ferrari, Geraldine M Gillespie, Andrew J McMichael, Barton F Haynes, Mihai L Azoitei
A major natural killer (NK) cell and CD8+ T cell checkpoint is mediated by the inhibitory receptor NKG2A/CD94 and its ligand, human leukocyte antigen E (HLA-E) complexed with nine-amino acid HLA-Ia leader sequence-derived peptides termed VL9 (HLA-E-VL9). Here, we used structure-based design and high-throughput library screening to generate high-affinity antibodies that block NKG2A/CD94 interactions. These antibodies enabled direct NK and CD8+ T cell cytotoxicity and mediated NK cell antibody-dependent cellular cytotoxicity (ADCC). Anti-HLA-E-VL9 antibodies enhanced human NK cell line NK-92 killing of HLA-E-VL9+ human tumors in mice, demonstrating checkpoint inhibition activity in vivo. Moreover, HLA-E-VL9 was found to be expressed on primary human CD4+ T cells infected with HIV in vitro, and its engagement by HLA-E-VL9 antibodies drove elimination of infected cells by NK cell-mediated ADCC. HLA-E-VL9 antibodies also enhanced the killing of HIV-infected cells by NKG2A/CD94+ CD8+ T cells targeting an HIV Rev-derived epitope that complexes with HLA-E. Therefore, anti-HLA-E-VL9 antibodies represent a candidate therapeutic approach to eliminating pathogenic target cells by enhancing both NK cell and CD8+ T cell function and by promoting ADCC.