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

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 headingFully human antibodies to the NKG2A inhibitory receptor