Development of a Polypeptide-Based Platform to Construct Antibody-Drug Conjugates with High Potency

IF 8.5 Q1 CHEMISTRY, MULTIDISCIPLINARY

JACS Au Pub Date : 2026-09-28 Epub Date: 2026-08-14 DOI:10.1021/jacsau.6c01025

Ruyao Tang, Fusheng Guo, Jinyi Bai, Xiaoguang Lei

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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

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构建高效抗体-药物偶联物多肽平台的研究

抗体-药物偶联物（adc）是一种新兴的药物类别，它利用抗体促进药物递送到靶细胞。adc面临的一个关键挑战是在不影响其特性（如药代动力学）的情况下提高药物-抗体比（DAR）以提高疗效。在这里，我们提出了一种新的基于多肽的平台，该平台大大增加了抗体有效负载adc的DAR，同时最小限度地损害adc的固有特性。基于我们的多肽平台，利用多功能点击反应方法合成了一种基于多肽的抗体-药物偶联铅（多肽ADC 6c），其DAR高达61。6c能有效识别抗原，随后被内吞，并在细胞水平上达到亚纳摩尔的活性。6c在小鼠体内表现出良好的药动学参数和较强的抗肿瘤作用。总的来说，本研究提供并表征了一个高度可变的多肽主干平台，该平台可用于有效开发具有高有效载荷的创新型adc，用于治疗各种癌症

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