The D3-GPC2-PBD ADC is Potently Efficacious Against Neuroblastoma and SCLC Via Engagement of a Conformational GPC2 Epitope

The signaling co-receptor heparan sulfate proteoglycan GPC2 is a MYCN-activated, differentially-expressed cell surface oncoprotein and candidate immunotherapeutic target in neuroblastoma. Here we build on GPC2’s attributes as a robust target for immune-based therapies by finding it is highly expressed on the most clinically aggressive human neuroblastomas and small cell lung cancers (SCLCs), with highly enriched expression in the tumor stem cell compartment. A GPC2 directed antibody-drug conjugate (ADC; D3-GPC2-PBD) induces robust and durable tumor regressions in a panel of neuroblastoma and SCLC preclinical models with diverse oncogenic drivers via induction of DNA damage and apoptosis, as well as potent bystander cell killing. Finally, we illustrate that this ADC binds a tumor specific, conformation dependent epitope of the core human and murine GPC2 proteins explaining its tumor specificity and therapeutic tolerability. These studies provide the preclinical data to support the clinical translation of ADCs targeting GPC2.