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Discovery and pre-clinical evaluation of antibodies to the NKG2A inhibitory receptor

View ORCID ProfileDu-San Baek, Ye-Jin Kim, Wei Li, Bernard JC Macatangay, Joshua C. Cyktor, Margaret G. Hines, John W. Mellors, Dimiter S. Dimitrov
doi: https://doi.org/10.1101/2022.05.18.492494
Du-San Baek
1Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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  • For correspondence: dub5@pitt.edu mit666666@pitt.edu
Ye-Jin Kim
1Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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Wei Li
1Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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Bernard JC Macatangay
1Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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Joshua C. Cyktor
1Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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Margaret G. Hines
1Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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John W. Mellors
1Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
2Abound Bio, Pittsburgh, PA, USA
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Dimiter S. Dimitrov
1Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
2Abound Bio, Pittsburgh, PA, USA
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  • For correspondence: dub5@pitt.edu mit666666@pitt.edu
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Abstract

NK and CD8+ T cells are important cells for cytolysis of cancer cells. The tumor microenvironment can upregulate surface expression on these cells of NKG2A, an inhibitory receptor that can dampen immune responses to cancer leading to immune evasion. To block NKG2A-mediated inhibition, we discovered and characterized two fully human antibodies using phage and yeast display that bind to NKG2A. These antibodies are highly specific for human CD94/NKG2A heterodimer complex, displaying no binding to the activating NKG2C receptor. A mutagenesis study revealed that the serine residue at 170 position (S170) of NKG2A is critical for the selectivity of anti-NKG2A antibodies. In vitro cytotoxic assays showed that NKG2A antibody inhibitors activated primary NK cells and promoted ADCC function of specific antibodies that bind to antigens expressed on cancer cells.

Summary heading Fully human antibodies to the NKG2A inhibitory receptor

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 19, 2022.
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Discovery and pre-clinical evaluation of antibodies to the NKG2A inhibitory receptor
Du-San Baek, Ye-Jin Kim, Wei Li, Bernard JC Macatangay, Joshua C. Cyktor, Margaret G. Hines, John W. Mellors, Dimiter S. Dimitrov
bioRxiv 2022.05.18.492494; doi: https://doi.org/10.1101/2022.05.18.492494
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Discovery and pre-clinical evaluation of antibodies to the NKG2A inhibitory receptor
Du-San Baek, Ye-Jin Kim, Wei Li, Bernard JC Macatangay, Joshua C. Cyktor, Margaret G. Hines, John W. Mellors, Dimiter S. Dimitrov
bioRxiv 2022.05.18.492494; doi: https://doi.org/10.1101/2022.05.18.492494

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