A Self‐Assembled Protein Platform for Plug‐and‐Play Customization of Multivalent Artificial Antibodies and Antibody‐Drug Conjugates

Abstract Modular 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.