Radiation-Triggered Payload Release Enhances Bispecific Antibody Efficacy

Area of Science:

• Oncology
• Pharmacology
• Bioconjugation Chemistry

Background:

• Therapeutic antibody-drug conjugates (ADCs) show promise in cancer treatment but face challenges with off-target effects and systemic toxicity.
• Developing targeted drug delivery systems is crucial for enhancing efficacy and reducing adverse events in cancer therapy.

Purpose of the Study:

• To engineer radiation-amplified antibody-drug conjugates (RAMP-ADCs) for localized drug payload release upon exposure to ionizing radiation.
• To enhance tumor targeting and minimize systemic toxicity of antibody-drug conjugates.
• To evaluate the efficacy of RAMP-ADCs utilizing the bispecific antibody amivantamab with different payloads.

Main Methods:

• Development of RAMP-ADCs using the bispecific antibody amivantamab, targeting EGFR and MET receptors.
• Conjugation of payloads monomethyl auristatin E (MMAE) or exatecan to RAMP-ADCs.
• In vitro assessment of cytotoxic efficacy and payload delivery selectivity.
• In vivo evaluation of RAMP-ADC efficacy in a mouse xenograft model.

Main Results:

• RAMP-ADCs demonstrated up to 2,100-fold enhancement in cytotoxic efficacy.
• Improved tumor payload delivery selectivity by up to 760-fold with minimized systemic toxicity.
• RAMP-ADC treatment combined with radiation overcame resistance in cell lines and effectively blocked tumor growth in vivo, extending survival.

Conclusions:

• RAMP-ADCs provide a novel strategy for localized drug delivery, significantly enhancing therapeutic efficacy and selectivity.
• This radiation-triggered activation mechanism offers a promising approach to overcome limitations of conventional ADCs.
• The RAMP-ADC platform holds potential for development with other bispecific antibodies in future cancer therapies.