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

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 that our TOP1i ADCs exhibit robust cytotoxicity against various cell lines, exert bystander activity, and elicit exquisite efficacy. We believe that this novel linker technology is now poised to be incorporated into next-generation ADCs for a variety of applications.