A biparatopic HER2-targeting ADC constructed <i>via</i> site-specific glycan conjugation exhibits superior stability, safety, and efficacy.

ABSTRACT: HER2 is overexpressed in approximately 15-20% of cancers and is associated with aggressive disease progression. We developed JSKN003, a bispecific HER2-targeted antibody-drug conjugate (ADC), through site-specific conjugation technology based on N-glycosylation engineering. JSKN003 maintains a biantennary glycan structure and exhibits superior structural homogeneity, optimized hydrophilicity, and reduced aggregation compared to conventional thiol-maleimide chemistry. In preclinical models JSKN003 demonstrated potent antitumor efficacy, inducing tumor regression in multiple HER2-expressing tumors, such as NCI-N87, BxPC-3, and PDX tumor models. Mechanistically, JSKN003 binds specifically to HER2, undergoes efficient internalization, and traffics to the lysosome, where the payload DXd

SUBMITTER: Xue Q 

PROVIDER: S-EPMC12188319 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature