Engineering Antibodies into Targeted Chimeras: From Recognition Modules to Programmable Degraders

Abstract

ABSTRACT Targeted chimeras have reshaped therapeutic design by converting target recognition into active degradation. As one of the most clinically established therapeutic modalities, antibodies provide high affinity and specificity to the protein of interest. Antibody‐associated targeted chimeras (AbTACs) are emerging as an important class of biologic degraders for targeted protein elimination, particularly of extracellular and membrane‐associated proteins. AbTACs offer a strategy to extend its recognition capacity beyond target binding by coupling defined degradation pathway. In these systems, antibody‐derived binders serve as programmable recognition modules, while conjugated ligands, encoded domains, recruited receptors, or nanoparticle scaffolds determine the target's intracellular fate. This review discusses the conceptual evolution of AbTACs and classifies current platforms according to scaffold architecture and engineering strategies, which link target binding to intracellular routing and subsequent clearance. Furthermore, it highlights the design principles and translational barriers that will guide the development of next‐generation antibody‐associated degraders.