Ectodomain shedding is a proteolytic process occurring at the surface of cells that regulates the density of cell surface receptors and the release of soluble proinflammatory factors. The a disintegrin and metalloprotease-17 (ADAM17), originally referred to as TNFalpha converting enzyme (TACE), is a key protease that mediates ectodomain shedding. ADAM17 is constitutively expressed by leukocytes and its enzymatic activity is very rapidly induced upon their activation by various stimuli.
Human natural killer (NK) cells exclusively recognize tumor-bound antibodies by the receptor CD16a (FcγRIIIa/FCGR3A), and the expression levels of this receptor directly correlate with their killing potency. CD16a expression and NK cell killer function can undergo a marked down-regulation in cancer patients. Thus, blocking CD16a shedding has clinical significance. CD16a shedding is mediated by ADAM17 and we are studying various approaches to block this process in hopes of enhancing cancer cell killing by NK cells and improving the efficacy of therapeutic antibodies used in cancer treatment.
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