Degrader antibody conjugates (DACs) as a next-generation therapeutic approach for selective and potent targeted protein degradation in EGFR-positive cancers

Antibody Drug Conjugates (ADCs) have become an established therapeutic modality in oncology; however, challenges such as payload-associated systemic toxicity and the emergence of resistance to conventional cytotoxic payloads underscore the need for next-generation payload. Degrader Antibody Conjugates (DACs) have recently attracted attention as an alternative strategy that leverages targeted protein degradation rather than traditional toxin-mediated cytotoxicity. In this study, we synthesized a panel of DACs by generating diverse linker-payload (LP) designs engineered for targeted degradation and conjugating them to cetuximab. These DACs were evaluated across multiple cell lines for their degradation potency and anti-proliferative activity. In several EGFR-positive models, specific DAC constructs demonstrated significantly enhanced degradation efficiency relative to the corresponding free payloads, accompanied by improved inhibition of cellular proliferation. In vivo pharmacodynamic studies confirmed selective degradation of the target protein in EGFR-positive tissues, whereas no degradation was detected in EGFR-negative tissues, demonstrating the high specificity of the DAC mechanism. Overall, our findings show that our DAC platform exhibits potent on-target antitumor activity in relevant indications while minimizing off-target toxicity in non-expressing tissues. These results establish a proof-of-concept for DACs as a safer and mechanistically differentiated therapeutic approach warranting further development.