Next-Generation Multi-Engager Complexes Linking Natural Killer Cells to Tumor Cells and Targeting the Proteolytic Checkpoint ADAM17.

Natural killer (NK) cells are innate lymphocytes capable of killing transformed cells without prior sensitization through direct cytolytic activity and, in an antigen-specific manner, by antibody-dependent cellular cytotoxicity (ADCC). Human NK cells mediate ADCC exclusively via the IgG Fc receptor CD16 (FcγRIIIA), triggering degranulation and cytokine production. Multi-engager complexes, such as BiKEs, TriKEs, TetraKEs, ANKETs, and ICEs, have been developed to link CD16 to tumor antigens. However, CD16 expression can be rapidly downregulated upon NK cell activation by the proteolytic checkpoint, a disintegrin and metalloproteinase-17 (ADAM17). ADAM17 induction in NK cells occurs in response to various stimuli, including the potent activating receptor CD16 and cytokine signaling. CD16 downregulation is further exacerbated within the tumor microenvironment, significantly diminishing ADCC potency by tumor-infiltrating NK cells. Moreover, ADAM17 expression and function are upregulated in various solid tumors, leading to the release of NK cell ligands and tumor-promoting factors. Consequently, developing strategies to inhibit ADAM17 to enhance NK cell function and suppress tumor cell growth is paramount to multi-engager efficacy. This review provides an overview of NK cell biology and the role of ADAM17 in regulating NK cell function and tumor cell growth. We examine the current landscape of NK cell multi-engager complexes in clinical development and discuss emerging strategies for incorporating an ADAM17-blocking component to optimize therapeutic outcomes.