Radiation-Triggered Payload Release Enhances Bispecific Antibody Efficacy

Therapeutic antibody-drug conjugates (ADC) have demonstrated efficacy in cancer therapy, but adverse effects due to off-target tissue uptake and payload activity pose challenges. To address these concerns, we engineered radiation-amplified ADCs (RAMP-ADC) that release active drug payloads only upon spatially localized exposure to ionizing radiation. To further improve tumor targeting, RAMP-ADCs were developed using the bispecific antibody amivantamab, which binds to both EGFR and MET receptors, carrying either the microtubule-destabilizing monomethyl auristatin E or the topoisomerase 1 inhibitor exatecan as payloads. The constructs enhanced cytotoxic efficacy up to 2,100-fold and improved the selectivity of tumor payload delivery by up to 760-fold while minimizing systemic toxicity. RAMP-ADC treatment combined with radiation blocked colony formation in cell lines that were resistant to either radiation or amivantamab individually. RAMP-ADCs effectively blocked tumor growth in a mouse xenograft model and extended survival, whereas the bispecific antibody had little effect alone. This approach to achieve localized delivery of drug payloads has potential therapeutic value for other bispecific antibodies currently in development. SIGNIFICANCE: Radiation amplified antibody-drug conjugates use EGFR- and MET-targeted amivantamab to deliver cytotoxic payloads to tumors and minimize off-target toxicity by chemically uncaging payload activity with ionizing radiation.