Therapeutic Targeting of Cancer-Specific Plectin is a Novel and Potent Antitumor Strategy

Over a decade ago, Kelly et al. pioneered a phage display-based functional proteomic approach to identify cancer-specific plectin (CSP) as an abundant target exclusively expressed on the cell surface of malignant tissue. Since then, CSP-targeting moieties have been leveraged to increase the accumulation of imaging agents and drug delivery systems to tumor tissue in pancreatic, ovarian, and breast cancer models. Moreover, CSP has emerged as a mitigator of malignant hallmarks, with CSP-positive cancer cells demonstrating increased cell migration, invasion, clonogenicity, and elevated stem cell biomarkers compared to CSP-negative cancer cells. However, despite its bioavailability, abundance, and functional importance, few studies have investigated the therapeutic targeting of CSP as a novel cancer strategy. Thus, the overarching goal of this dissertation was to expand and mobilize our understanding of CSP as a high-value drug target in ovarian, bile duct, and pancreatic cancer.

Chapter 1 presents the first comprehensive review of plectin and CSP in cancer, highlighting their clinical utility as a prognostic marker, diagnostic biomarker, and target for imaging and therapeutic modalities. In Chapter 2, we introduce the generation of a first-in-class CSP-targeting monoclonal antibody with potent antitumor activity and with the ability to synergize with first-line cancer therapies in ovarian cancer models. Chapter 3 details the clinical development of CSP targeted therapy by developing a humanized anti-CSP monoclonal antibody that induces robust antitumor effects both as a monotherapy and in combination with gemcitabine in cholangiocarcinoma models. Moreover, we performed a series of toxicokinetic and toxicology studies to demonstrate the excellent safety profile of our CSP-targeting human IgG1 antibody. Chapter 4 describes ongoing efforts interrogating the cell-intrinsic and cell-extrinsic activity induced by our anti-CSP antibody in immunocompetent pancreatic cancer models. Finally, in Chapter 5, we present future research directions, elaborate on the main conclusions from our studies, and highlight the significance of anti-CSP antibody therapy on the future of cancer disease management.

Collectively, this dissertation reveals therapeutic antibody targeting of CSP as a novel breakthrough therapy ready for evaluation in a first-in-human clinical trial. Moreover, CSP-positive cancers, including ovarian, pancreatic, bile duct, lung, and breast cancer, collectively account for over 3 million annual deaths worldwide, underscoring the potential for this dissertation to improve cancer patient survival significantly.