W181 - Antibodies to PODXL as an Approach to Targeting Tumor Stem Cells

Julyanne Brassard, PhD – PDF, School for Biomedical Engineering, U of British Columbia; Michael Hughes, PhD – PDF, School for Biomedical Engineering, U of British Columbia; Janella schwab – student, School for Biomedical Engineering, U of British Columbia; Pamela Dean, PhD – PDF, Department of Cellular and Physiological Sciences, U of British Columbia; Erin Bell – Graduate Student, Department of Cellular and Physiological Sciences, U of British Columbia; Yasmine Lau – student, School for Biomedical Engineering, U of British Columbia; Yicong Li – Technician, School for Biomedical Engineering, U of British Columbia; Diana Canals Hernaez, PhD – PDF, School for Biomedical Engineering, U of British Columbia; Calvin Roskelley, PhD – Professor, Department of Cellular and Physiological Sciences, U of British Columbia

Abstract Text: Podocalyxin (PODXL) is a CD34-related stem cell sialomucin normally expressed by kidney podocytes, vascular endothelia and early hematopoietic progenitors, ESCs and iPSCs. Intriguingly, PODXL is frequently upregulated on a wide range of human cancers and is consistently linked to poor prognosis. Furthermore, we find that inactivation of PODXL in human tumor cell lines cripples their ability to form tumors in xenografted mice, suggesting a functional role in tumor growth and metastasis. Accordingly, we developed several hundred monoclonal antibodies (mAb) to human PODXL as potential immunotherapeutics. One mAb, PODO83, binds to the juxtamembrane domain of PODXL and exhibits a potent ability to block primary tumor growth and development of distal metastases in mice. A second mAb, PODO447, shows exquisite specificity for a tumor glycoform of PODXL but no reactivity with PODXL expressed by any normal human tissue. Intriguingly, evaluation of PODO447 expression on ovarian cancer tumor microarrays suggest that this epitope is selectively expressed by tumors with a "cold" immunophenotype (those lacking infiltrating T and B cells) and thus could be a promising therapeutic for this poor outcome subset of tumors. Although PODO447 lacks an intrinsic ability to block tumor growth, when coupled to toxins as an antibody drug conjugate (ADC) it exhibits dose-dependent tumor cell killing in vitro and in vivo. In summary, we have identified PODXL as a functionally significant molecule expressed by a wide range of poor outcome human tumors and developed two novel PODXL-targeting immunotherapeutic reagents that show promise in preclinical models.