Targeted ADAM17 blocker directed to CD16 (TAB16) augments NK cell proliferation and cytotoxicity 3752

Abstract Description NK cells are cytotoxic innate lymphocytes that mediate tumor cell killing and are an attractive cell therapy for cancer. The Fc receptor CD16 on human NK cells is cleaved from the cell surface by the membrane protease ADAM17 upon their activation. We have reported that Medi-1, a fully human IgG1 mAb that blocks ADAM17 function is engaged by CD16 and blocks its cleavage, inducing and prolonging CD16 signaling, which synergizes with IL-15 stimulation to enhance NK cell proliferation. Because ADAM17 is broadly expressed and has numerous substrates, on-target off-NK cell effects by Medi-1 are a concern. To address this, we developed TAB16, a novel dual-targeting antibody that links Medi-1 scFv with an anti-CD16 camelid VHH. Our data shows that TAB16 prevents the cleavage of ADAM17 substrates selectively on NK cells. Moreover, IL-15 in combination with TAB16 results in enhanced NK cell proliferation. Real-time cytotoxicity assays show TAB16 augments NK cell-mediated killing of tumor cells with sustained cytotoxic function and reduced cellular exhaustion compared to IL-15 alone. These findings reveal that TAB16 offers a targeted approach to block ADAM17 function and enhance NK cell proliferation and anti-tumor function. Funding Sources NIH R01CA203348 Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)