The Impact of Conjugation Mode and Site on Tubulysin Antibody-Drug-Conjugate Efficacy and Stability.

ABSTRACT: Antibody-drug conjugates (ADCs) represent a prominent class of biotherapeutics engineered to selectively deliver cytotoxic payloads to tumors, thereby facilitating targeted cell killing. While first-generation ADCs, created by conjugating payloads to surface-accessible lysine or hinge-cysteine residues, have achieved clinical success, several site-specific ADCs with defined drug-to-antibody ratios are currently under clinical investigation. Herein, the efficacy, stability, and pharmacokinetics of ADCs generated by attaching the drug linker to surface-exposed lysine residues, hinge-cysteine residues, and the C'E loop in the CH2 domain (mediated by bacterial transglutaminase) using a tubulysin payload are compared. In N87 xenograft mice, the order of efficacy is C'E loop > hinge-cysteine > l

SUBMITTER: Yamazoe S 

PROVIDER: S-EPMC12368874 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature