Development of aPolypeptide-Based Platform to ConstructAntibody-Drug Conjugates with High Potency

Abstract Antibody-drug conjugates (ADCs) represent an emerging pharmaceutical category that leverages antibodies to facilitate drug delivery to target cells. A key challenge for ADCs is increasing the drug-antibody ratio (DAR) to improve efficacy without compromising their properties, such as pharmacokinetics. Here, we present a novel polypeptide-based platform that substantially increases the DAR of antibody-payload ADCs while minimally compromising the ADCs’ inherent characteristics. A polypeptide-based antibody-drug conjugate lead (polypeptide ADC 6c), capable of achieving a DAR of up to 61, was synthesized using the versatile click reaction method based on our polypeptide-based platform. 6c could efficiently recognize antigens, be subsequently endocytosed, and achieve subnanomolar activity at the cellular level. Moreover, 6c exhibited excellent pharmacokinetic parameters and potent antitumor efficacy in mice. Collectively, this study provides and characterizes a highly variable polypeptide backbone platform that can be used to efficiently develop innovative ADCs with high payloads for the treatment of various cancers