A MICA/B GAALIE-mutant antibody elicits potent natural killer cell-driven immunity in solid and hematologic...

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.