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Abstract

Although advances in the field have improved understanding of cancer diagnosis and treatment, the disease still remains one of the leading causes of death globally. While some cancers are susceptible to conventional treatment options, others relapse or metastasize and lead to patient mortality, highlighting the need to identify and target novel biomarkers for improved patient outcomes. One potential target is podocalyxin, a CD34-related sialomucin that is overexpressed in a variety of cancer cell types including breast, lung, and pancreatic cancer. Previous works have confirmed a correlation between high podocalyxin expression and poor patient survival, and our lab has further demonstrated that podocalyxin is implicated in tumor progression and metastasis. Knowing this, our lab has previously developed two podocalyxin-targeting antibodies, PODO83 and PODO447, to effectively target podocalyxin expressing tumors. The PODO83 antibody binds to the core protein of the podocalyxin protein while PODO447 binds a tumor-specific glycoepitope exhibited by podocalyxin-expressing cancers. This project evaluates the therapeutic activity of these antibodies using immune deficient and immune competent mouse models. Here, we demonstrate that PODO83 can operate as an unconjugated monoclonal antibody to effectively block primary tumor growth and peripheral metastases in various human cancers. We use a chimeric human-mouse podocalyxin transgenic mouse model to demonstrate that PODO83 treatment does not induce toxicity in healthy tissue. While the unconjugated PODO447 antibody does not exert any inhibitory or toxic effects on its own, as an antibody-drug conjugate (ADC) PODO447 can be used as a targeting arm in a Vedotin antibody-drug conjugate to eliminate cancer cells. The work presented in this thesis has the potential to improve cancer patient outcomes by providing a novel targeted therapy for podocalyxin-expressing primary tumors and metastasis.