Podocalyxin-like protein tumor-restricted glycoepitope (PODXL glycoepitope)

Podocalyxin-like protein (PODXL) is a heavily glycosylated type 1 transmembrane sialomucin and a member of the CD34 family, normally expressed in kidney podocytes and vascular endothelia to regulate cell adhesion and morphology (Hughes et al., 2020). In many cancers, PODXL is upregulated and undergoes aberrant glycosylation, resulting in a tumor-restricted glycoepitope that is absent in healthy tissues (Brassard et al., 2023). This specific glycoform, often identified by the PODO447 antibody, involves a peptide sequence in the mucin domain combined with a core 1 O-glycan, also known as the T-antigen (Snyder et al., 2022). The presence of this glycoepitope is associated with increased tumor cell motility, invasion, and the development of immune cold tumor microenvironments characterized by a lack of infiltrating lymphocytes (Brassard et al., 2023). Because of its high tumor specificity, this glycoepitope is an attractive target for immunotherapies, including antibody-drug conjugates (ADCs) like PODO447-MMAE, which have shown efficacy in preclinical models of ovarian and pancreatic cancer (Hughes et al., 2020). Targeting the glycoepitope rather than the core protein minimizes the risk of off-target toxicity to vital organs like the kidney (Snyder et al., 2022). This target represents a novel class of neo-antigens that exploit cancer-specific post-translational modifications for therapeutic selectivity (Brassard et al., 2023). Clinical development of agents targeting this epitope could provide new options for patients with aggressive, treatment-resistant tumors (Hughes et al., 2020).

Other names

PODO447 epitopeTumor-restricted glycoform of PodocalyxinTumor-associated PODXL glycoepitopePODO447-reactive epitopePodocalyxin-like protein 1 glycoepitope

Antibody-drug conjugate (ADC) mediated delivery of monomethyl auristatin E (MMAE) to induce cell death; Antibody-dependent cellular cytotoxicity (ADCC) via the Fc region of the PODO447 antibody.