A Plug‐and‐Play Platform for Customizing Multivalent Degraders and Degrader‐Drug Conjugates

ABSTRACT Traditional targeted protein degradation (TPD) strategies are largely ineffective against membrane proteins, which constitute over 60% of drug targets. To address this, we develop a modular “plug‐and‐play” UPTAB (Ultrahigh‐affinity Protein pairs fused to Targeting Binders) platform for TPD. The platform leverages orthogonal ultrahigh‐affinity Im/CL protein pairs to assemble complexes between lysosomal trafficking receptor (LTR)‐binding modules and protein of interest (POI)‐binding modules. Three UPTAB configurations were engineered: Type‐I (mono‐targeted), Type‐II (dual‐targeted), and Type‐III (tri‐targeted). In vitro, Type‐I UPTAB achieved near‐complete degradation of EGFR and PD‐L1 across multiple cancer cell lines, with optimal linker length critical for maximal activity. Type‐II and Type‐III UPTAB enabled simultaneous degradation of EGFR/c‐MET, EGFR/PD‐L1, and EGFR/c‐MET/HER2. In a breast cancer xenograft model, Type‐I UPTAB demonstrated approximately 80% tumor growth inhibition, reduced EGFR levels in tumors, and significantly extended survival. Furthermore, we developed degrader‐drug conjugates (DDCs) by site‐specific conjugation of the cytotoxic payload MMAE to UPTAB modules, which retained degradation capacity while exhibiting substantially enhanced anti‐proliferative activity across diverse cancer cell lines. The UPTAB platform combines modular multivalent design, high degradation efficiency, and excellent bioconjugation capability, offering a versatile tool for membrane protein‐targeted degradation and a potential strategy for developing next‐generation cancer therapeutics.