Hwang et al. engineered high-affinity antibodies against HLA-E–VL9 using structure-based design and high-throughput library screening to block inhibitory NKG2A/CD94 interactions. HLA-E–VL9 mAbs enhanced direct NK cell killing and NK-mediated ADCC against HLA-E–VL9+ tumors in vitro and K562HLA-E–VL9 tumors in vivo. HIV-infected primary CD4+ T cells expressed HLA-E–VL9, and HLA-E–VL9 mAbs mediated NK cell ADCC that selectively eliminated activated or infected CD4+ T cells over resting CD4+ T cells. HLA-E–VL9 blockade also enhanced NKG2A+CD8+ T cell-mediated HIV-specific cytotoxicity.
Contributed by Shishir Pant
ABSTRACT: 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.
Author Info: (1) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. Department of Medicine, Duke University School of Medicine, Durham, NC, USA. (2) Department o
Author Info: (1) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. Department of Medicine, Duke University School of Medicine, Durham, NC, USA. (2) Department of Surgery, Duke University School of Medicine, Durham, NC, USA. (3) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA. (4) Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. Chinese Academy of Medical Sciences Oxford Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. (5) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. Department of Medicine, Duke University School of Medicine, Durham, NC, USA. (6) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. Department of Medicine, Duke University School of Medicine, Durham, NC, USA. (7) Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. (8) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA. (9) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. Department of Medicine, Duke University School of Medicine, Durham, NC, USA. (10) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. Department of Medicine, Duke University School of Medicine, Durham, NC, USA. (11) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA. (12) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA. (13) Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. (14) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. (15) Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. (16) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. Department of Medicine, Duke University School of Medicine, Durham, NC, USA. (17) Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. (18) Department of Surgery, Duke University School of Medicine, Durham, NC, USA. (19) Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. (20) Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. (21) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. Department of Medicine, Duke University School of Medicine, Durham, NC, USA. Department of Integrative Immunobiology, Duke University School of Medicine, Durham, NC, USA. (22) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA.
