Tumor specific epitopes on Podocalyxin as a target for ADC and CAR T cell therapy

Podocalyxin (Podxl) is a heavily glycosylated sialomucin type 1 membrane protein that has been shown to be involved in cell adhesion, migration, and polarity. Although Podxl is found on a variety of normal cell types, it is aberrantly expressed in acute myeloid leukemia (AML) blasts, and its presence in breast, colorectal and glial malignancies is correlated with poor clinical outcome. Using the human triple negative breast cancer line MDA-MB-231, we have demonstrated a functional role for Podxl in tumor growth and metastasis in xenografted mice, and have recently developed high affinity antibodies to a tumor-specific post-translational modification of Podxl. Preliminary IHC data suggests that this post-translational modification on Podxl may found in glioblastoma, melanoma, and female reproductive tract tumors, but not on matched normal tissue. Staining intensity in melanoma samples correlates with stage of disease and is strongest in tissues collected from metastatic lesions. Preliminary experiments indicate that expression of this glyco-epitope is increased in myeloid leukemia cells lines by co-culture with bone marrow stromal cells or hypoxia, suggesting that the tumor microenvironment may contribute to the observed reactivity. Our lead antibody, Podo447, binds this tumor-associated glycoform of Podxl with high affinity and induces cytotoxicity in various tumor cell lines as an antibody drug conjugate (ADC), and when expressed as a human IgG1 Fc chimera stimulates antibody dependent cellular cytotoxicity. With its exquisite specificity for malignant tissues, and the number of potential indications, Podo447 is an ideal targeting arm for an antibody drug conjugate or CAR-T enabled therapeutic.