The advent of targeted therapies has vastly improved cancer diagnostics and treatments over the last three decades, however, cancer still remains the second leading cause of death worldwide. Importantly, the majority of cancer-related deaths are the result of metastatic disease. This highlights the need to identify biomarkers of tumors at high risk of metastasizing, and to generate targeted therapies against them. Previous studies have demonstrated a strong association between high expression of podocalyxin and decreased patient survival, however, little is known about the role of podocalyxin in promoting cancer progression or its potential as a therapeutic target.
Here we perform an in-depth characterization of PODO83, an anti-podocalyxin antibody that we previously demonstrated delays primary tumor growth in murine tumor models. We show that despite its ability to delay primary tumor growth, its primary effect is actually the prevention of metastasis to the lung. We identified the binding epitope of PODO83 on the extracellular juxtamembrane domain of podocalyxin and showed that the antibody recognizes the core podocalyxin protein in both tumors and healthy tissue. Further, using urothelial, breast and ovarian carcinomas tissue microarrays, we present PODO83 as a promising diagnostic tool.
Podocalyxin is normally readily expressed in the vascular endothelia and kidney podocytes, representing a source of concern surrounding the use of podocalyxin-based therapies. Here, we identified a novel tumor-restricted glycoepitope on podocalyxin and generated and characterized an antibody (PODO447) to target it. We found that while unconjugated PODO447 does not exert any inhibitory or toxic effect on tumor cells, when used as the targeting arm in a Vedotin antibody-drug conjugate (ADC), the PODO447-ADC specifically targets cancerous cells and increases the survival in pre-clinical models.
The work presented in this thesis contributes directly to scientific understanding of the role of podocalyxin in tumor growth and metastasis. Further, we provide pre-clinical evidence supporting the furthered development of the novel podocalyxin antibodies PODO83, and PODO447 as diagnostic and targeted immunotherapies, respectively, to be used in the fight against cancer and to improve patient outcome.Medicine, Faculty ofMedical Genetics, Department ofGraduat
