A MICA/B GAALIE-mutant antibody elicits potent natural killer cell-driven immunity in solid and hematologic
Ruan Pimenta1, Stefanie Maurer1, Xiaoxuan Zhong1
1Department of Immunology and Immunotherapy, and Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Anti-MICA/B antibodies that inhibit the shedding hold promise for cancer immunotherapy and are in phase 1 clinical trials. Although MICA/B-shedding inhibition promotes natural killer (NK) cell-driven immunity by NKG2D engagement, the Fc enables antibody-dependent cellular cytotoxicity. We, therefore, engineer the Fc of an anti-MICA/B antibody (clone 7C6) through GAALIE mutations that increase the binding affinity to Fc-activating receptors. 7C6-GAALIE inhibits MICA/B shedding and potently triggers NK cell-effector functions against tumor cells. Furthermore, we establish a model of metastatic prostate cancer with which we formally demonstrate that 7C6-GAALIE is superior to 7C6 as wild-type human IgG1 in inhibiting metastases in Fc gamma receptor-humanized mice. In melanoma and leukemia models, 7C6-GAALIE had a therapeutic efficacy more consistent than that with 7C6 as wild-type human IgG1. Therefore, this study establishes the proof of concept of a next-generation anti-MICA/B antibody for cancer immunotherapy through an Fc optimization that enhances the antibody's ability to elicit NK cell-driven immunity.
Anti-MICA/B antibodies that inhibit the shedding hold promise for cancer immunotherapy and are in phase 1 clinical trials. Although MICA/B-shedding inhibition promotes natural killer (NK) cell-driven immunity by NKG2D engagement, the Fc enables antibody-dependent cellular cytotoxicity. We, therefore, engineer the Fc of an anti-MICA/B antibody (clone 7C6) through GAALIE mutations that increase the binding affinity to Fc-activating receptors. 7C6-GAALIE inhibits MICA/B shedding and potently triggers NK cell-effector functions against tumor cells. Furthermore, we establish a model of metastatic prostate cancer with which we formally demonstrate that 7C6-GAALIE is superior to 7C6 as wild-type human IgG1 in inhibiting metastases in Fc gamma receptor-humanized mice. In melanoma and leukemia models, 7C6-GAALIE had a therapeutic efficacy more consistent than that with 7C6 as wild-type human IgG1. Therefore, this study establishes the proof of concept of a next-generation anti-MICA/B antibody for cancer immunotherapy through an Fc optimization that enhances the antibody's ability to elicit NK cell-driven immunity.
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