Legumain-Cleavable Top1i Antibody-Drug Conjugates without Self-Immolative Spacers Demonstrate Potent Antitumor Activity.

ABSTRACT: Virtually all antibody-drug conjugates employ a cleavable linker that is attached to a self-immolative spacer element. The linker and self-immolative spacer are widely known to have a dramatic influence on ADC stability, pharmacokinetics, and therapeutic efficacy. In 2021, our group described a highly polar legumain-cleavable linker that could be used to generate highly potent MMAE-based ADCs. Herein, we build on this finding by describing the design of legumain-cleavable ADCs that release a potent topoisomerase-I inhibitor (TOP1i) without the need for a self-immolative spacer. These ADCs employ an α-TROP2 antibody to target various pancreatic cancer lines. We directly compare their potency, stability, efficacy, and pharmacokinetics to an industry-standard deruxtecan comparator. We show th

SUBMITTER: Ojo VT 

PROVIDER: S-EPMC12924678 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature