PDPN antibodies bind to specific epitopes on the PDPN glycoprotein, which is upregulated in cancers such as glioma, squamous cell carcinoma, mesothelioma, and melanoma . Key functional domains targeted include:
PLAG domains: Critical for PDPN-CLEC-2 interaction, which mediates platelet aggregation and metastasis .
Cytoplasmic tail: Associates with ERM proteins to regulate cytoskeletal dynamics and cell motility .
Therapeutic PDPN antibodies primarily aim to disrupt PDPN-CLEC-2 signaling, induce antibody-dependent cellular cytotoxicity (ADCC), or block immunosuppressive pathways in the tumor microenvironment .
PDPN antibodies exert antitumor effects through:
Neutralization of PDPN-CLEC-2 interaction: Prevents platelet activation, reducing metastasis-promoting factors like TGF-β .
ADCC/CDC activation: Humanized antibodies (e.g., humLpMab-23-f) enhance immune effector cell-mediated tumor lysis .
Immune checkpoint modulation: PDPN inhibition on T cells reduces exhaustion and boosts antitumor immunity .
Biomarker potential: PDPN overexpression correlates with poor prognosis in lung, breast, and pancreatic cancers .
Therapeutic targeting:
Normal tissue expression: PDPN is critical in lung alveoli, lymphatic endothelium, and kidney podocytes, raising toxicity concerns .
Epitope variability: Cancer-specific antibodies (e.g., PMab-117) require rigorous validation to avoid off-target effects .