A high affinity monoclonal antibody against HLA-E-VL9 enhances natural killer cell anti-tumor killing

Hwang, J. K.; Marston, D. J.; Wrapp, D.; Li, D.; Tuyishime, M.; Brackenridge, S.; Rhodes, B.; Quastel, M.; Kapingidza, A. B.; Gater, J.; Harner, A.; Wang, Y.; Rountree, W.; Ferrari, G.; Borrow, P.; McMichael, A. J.; Gillespie, G. M.; Haynes, B. F.; Azoitei, M. L.

doi:10.1101/2024.07.08.602401

bioRxiv · 10.1101/2024.07.08.602401

A high affinity monoclonal antibody against HLA-E-VL9 enhances natural killer cell anti-tumor killing

Hwang, J. K.·Marston, D. J.·Wrapp, D.·Li, D.·Tuyishime, M.·Brackenridge, S.·Rhodes, B.·Quastel, M.·Kapingidza, A. B.·Gater, J.·Harner, A.·Wang, Y.·Rountree, W.·Ferrari, G.·Borrow, P.·McMichael, A. J.·Gillespie, G. M.·Haynes, B. F.·Azoitei, M. L.

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Abstract

A major natural killer (NK) cell and CD8+ T cell checkpoint is mediated by the inhibitory receptor NKG2A/CD94 and its ligand, HLA-E complexed with 9 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 antibodies that block NKG2A/CD94 interactions, resulting in direct NK and CD8+ T cell cytotoxicity, and trigger NK cell antibody-dependent cellular cytotoxicity (ADCC). Anti-HLA-E-VL9 antibodies limited HLA-E-VL9+ tumor growth in mice, demonstrating checkpoint inhibition activity in vivo. HLA-E-VL9 was found to be expressed on HIV-infected cells, and its engagement by HLA-E-VL9 antibodies eliminated infected cells by NK-mediated ADCC. HLA-E-VL9 antibodies also enhanced the killing of HIV-infected cells by NKG2A/CD94+ CD8+ T cells targeting a novel HLA-E binding HIV Rev-derived epitope. Therefore, anti-HLA-E-VL9 antibodies represent a novel approach to eliminate pathogenic target cells by enhancing NK and CD8+ T cell function and promoting ADCC.

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Hwang, J. K., Marston, D. J., Wrapp, D., Li, D., Tuyishime, M., Brackenridge, S., Rhodes, B., Quastel, M., Kapingidza, A. B., Gater, J., Harner, A., Wang, Y., Rountree, W., Ferrari, G., Borrow, P., McMichael, A. J., Gillespie, G. M., Haynes, B. F., Azoitei, M. L.. 2024-07-11. A high affinity monoclonal antibody against HLA-E-VL9 enhances natural killer cell anti-tumor killing. https://doi.org/10.1101/2024.07.08.602401

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