HER2-Targeting Affibody Equipped with Albumin-Binding Small Molecules for Radiotheranostics

Abstract HER2-targeting affibody radioprobes are often limited by rapid systemic clearance and excessive renal accumulation. Herein, we develop a modular chemical strategy to optimize the pharmacokinetic properties of affibodies through conjugation of small-molecule albumin-binding motifs (ABMs). Enabled by our selective S-glycosylation approach, ABMs were introduced via a sugar-based linker, allowing systematic modulation of probe behavior. Evaluation of sugar-modified variants revealed that sugar structure plays a critical role in regulating in vivo distribution, with the GalNAc-modified probe [68Ga]Ga-5c exhibiting favorable tumor-to-background contrast in PET/CT imaging. Further incorporation of ABMs afforded GalNAc-IPBA-functionalized affibody [177Lu]Lu-10a, which achieved an 17-fold extension of circulation half-life, reduced renal accumulation, and maintained efficient tumor targeting. Therapeutically, [177Lu]Lu-10a induced 86.25% tumor growth inhibition with minimal systemic toxicity. This study provides a modular strategy for overcoming pharmacokinetic limitations of affibody-based radiotheranostics.