Development of a novel antibody drug conjugate for the treatment of pancreatic adenocarcinoma
Gromisch, Christopher Marr
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Pancreatic ductal adenocarcinoma (PDAC) is the most lethal common cancer in the United States: in 2017 there will be around 54,000 new cases and 43,000 patient deaths. (SEER, 2017) The high mortality of PDAC is related to late disease presentation and aggressiveness; nearly 52% of patients present with metastatic disease at the time of diagnosis. (SEER, 2017) Current treatments have marginal improvements on survival, with the most efficacious treatment, gemcitabine and nab-paclitaxel, having a median survival of 12.2 months. (Wu 2018) Failure of current PDAC treatments is attributed to the inefficacy of systemic chemotherapeutics and the development of resistance. (Rahib, 2014) The Dual Endothelin1/Signal PeptideVEGF receptor (DEspR), represents a promising therapeutic target for the treatment of PDAC: it is a highly expressed, specific tumor antigen, which is involved in tumor vasculogenesis and cancer stem cell (CSC) survival. DEspR is a developmentally crucial receptor, responsible for early angiogenesis and neural crest migration, with minimal expression in normal adult tissue. In vitro and in vivo studies of anti-DEspR therapy in PDAC have shown efficacy in decreasing CSC survival, tumor angiogenesis, and improving overall survival in xenograft models of PDAC, with anti-DEspR therapy being a promising candidate for clinical use. Furthermore, anti-DEspR therapy seems to augment chemotherapeutic therapy in vitro and in vivo, suggesting that a DEspR-targeted antibody drug conjugate (ADC) would be highly effective. ADCs are a re-emerging drug class with significant promise. Initial failures of ADCs in clinic were related to poor antigen specificity and failures in drug conjugation chemistry to minimally impact the antibody. To develop our ADC, I have developed a novel method of site-specific conjugation that relies on a novel method of supramolecular assembly. My system employs two specific protein sequences that do not self-interact, and tightly assemble through coulombic and hydrophobic interactions, allowing site-specific, stoichiometric self-assembly. To facilitate stable drug delivery, I have synthesized a novel enzymatically cleavable tyrosine-clickable linker, which prevents drug release prior to tumor delivery. Both further investigation into the efficacy of anti-DEspR therapy, and the development of a stoichiometric, site-specific, stable method for drug loading will provide an advancement in anti-cancer therapy.
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