A Self‐Assembled Protein Platform for Plug‐and‐Play Customization of Multivalent Artificial Antibodies and Antibody‐Drug Conjugates
Abstract
AbstractModular assembly of multivalent therapeutics with precise modulation of pharmacokinetic and pharmacological properties remains a critical challenge in drug development. Here, we present ATPlug, a self‐assembling protein platform that integrates three crucial functional modules: a trimerization domain to enhance avidity, a SpyCatcher module for efficient conjugation, and an albumin‐binding domain to optimize pharmacokinetics and tissue selectivity. This rational design facilitates the modular assembly of multivalent artificial antibodies and antibody‐drug conjugates (ADCs), demonstrating remarkable versatility through the successful incorporation of diverse therapeutic modules targeting epidermal growth factor receptor (EGFR), programmed cell death ligand 1 (PD‐L1), and vascular endothelial growth factor (VEGF). The trivalent constructs exhibited up to 30‐fold enhancement in target binding avidity and extended plasma half‐life via endogenous albumin hitchhiking. Notably, the ATPlug‐customized modular ADCs achieved binding affinities of 1.8 nM for EGFR and exhibited selective cytotoxicity toward EGFR‐overexpressing tumor cells, resulting in potent tumor suppression efficacy. This plug‐and‐play strategy provides a framework for next‐generation therapeutics combining customized multivalency with multidrug synergies.
Article Details
Authors (19)
Yuzhe Chen
Yunchuan Huang
Division of Liver Surgery and NHC Key Lab of Transplant Engineering and Immunology Institutes for Systems Genetics Frontiers Science Center for Disease‐Related Molecular Network West China Hospital Sichuan University Chengdu 610041 China
Shisheng Wang
Division of Liver Surgery and NHC Key Lab of Transplant Engineering and Immunology Institutes for Systems Genetics Frontiers Science Center for Disease‐Related Molecular Network West China Hospital Sichuan University Chengdu 610041 China
Xinyuan Wang
Hongyu Lu
Jie Chen
Jing Li
Zhuo Chen
Zhao Li
Tianshan She
Division of Liver Surgery and NHC Key Lab of Transplant Engineering and Immunology Institutes for Systems Genetics Frontiers Science Center for Disease‐Related Molecular Network West China Hospital Sichuan University Chengdu 610041 China
Youmei Jin
Proteomics‐Metabolomics Platform, Core facilities West China Hospital Sichuan University Chengdu 610041 China
Yuanping Gao
Proteomics‐Metabolomics Platform, Core facilities West China Hospital Sichuan University Chengdu 610041 China
Jie Zhang
Lijun Wang
Wenjuan Zeng
Division of Liver Surgery and NHC Key Lab of Transplant Engineering and Immunology Institutes for Systems Genetics Frontiers Science Center for Disease‐Related Molecular Network West China Hospital Sichuan University Chengdu 610041 China
Hong Zhu
School of Life and Health Technology
Ze Tao
Xiaofeng Lu
Hao Yang