Development of ADAM10 Prodomain as a Therapeutic Agent

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DESCRIPTION (provided by applicant): Recent cancer therapies have focused on using biologics to target specific signal transduction pathways implicated in the tumor development or progression. For example, recombinant fusion proteins consisting of the extracellular domain of the immunoregluatory proteins and the constant (Fc) domain of immunoglobulin (IgG) represent a growing class of protein therapeutics with improved plasma half-lives and with the potential for avoiding many of the side effects associated with traditional chemotherapeutic agents. Disintegrin- metalloproteases such as ADAM10 (Kuzbanian) are sheddases involved in the ectodomain cleavage of a variety of cell surface receptors, ligands, adhesion molecules and other signaling molecules. Many ADAM substrates are involved in signaling events that are dysregulated in cancers and/or during tumor progression. Indeed, several recent studies have highlighted the potential of targeting ADAM family members as a new approach for anti-tumor therapies. We have recently demonstrated that bacterially-expressed recombinant ADAM10 prodomain is a potent and specific inhibitor of ADAM10 catalytic activity. Importantly, the recombinant ADAM10 prodomain was capable of inhibiting substrate shedding (e.g. betacellulin (BTC) and HER2) in cell- based assays and could inhibit cell proliferation of human cancer cell lines in vitro. The long-term objective of our research is to understand the biology of ADAM proteases in normal physiology and disease states. The goal of this specific STTR grant proposal is to employ recombinant Fc fusion technology for the development and characterization of an ADAM10 prodomain-Fc fusion protein as a cancer therapeutic agent. PUBLIC HEALTH RELEVANCE: Cancer is the second leading cause of death in the United States with over 500,000 cancer deaths each year. The disintegrin-metalloprotease ADAM10 is required for the activation of several critical signaling pathways (e.g. HER2 signaling) involved in cellular transformation and tumor progression. This grant proposes to develop the ADAM10 prodomain-Fc fusion protein as a novel cancer therapeutic.