Chemistry Weekly Seminar - Moralba Dominguez Garcia, PhD Candidate

Title

Lysine-Lysine-Based Enzymatic Cleavable Linkers for Antibody Drug Conjugates

Abstract

Antibody drug conjugates (ADCs) are a class of hybrid drugs comprised of an antibody and a covalently linked cytotoxic drug. ADCs are a promising cancer treatment due to the high specificity and affinity of antibodies to recognize cancer-associated receptors, delivering a cytotoxic drug into the tumour. Enzymatic cleavable linkers for ADCs allow the drug to be selectively released inside of cancer cells through the catalytic activity of enzymes such as Cathepsin B (CTB), an overexpressed tumour-associated protease in metastatic cancers. However, the linkers currently used have some drawbacks including selectivity, hydrophobicity, and plasma instability, which can result in premature release of drug and cause side effects and reduce their effectiveness. By using a linker that is more selectively hydrolyzed by CTB, the safety and ADC efficacy can be improved. In this research project, Lysine-Lysine-containing linkers were synthesized and conjugated to a fluorophore reporter instead of a drug to evaluate the effect of linker structure on CTB cleavage rates. The results demonstrated higher CTB hydrolysis and selectivity compared to a Valine-Citrulline linker, the most used cleavable linker in ADCs. In silico molecular docking studies were conducted to understand the interaction between linkers and CTB and their relationship with hydrolysis rate values. The Lysine-Lysine, Valine-Citrulline, and non-cleavable linkers (controls) were used to prepare [⁸⁹Zr]Zr-DFO-linker-AR20.5 radioimmunoconjugates to mimic ADC behavior in vivo and target MUC1 in healthy mice and SKOV3 xenograft models. The linker stability and biodistribution were evaluated by positron emission tomography (PET) imaging. The results showed no significant differences in tumour uptake but higher CTB hydrolysis and liver uptake for Lysine-Lysine-containing linkers. Thus, our results suggest that Lysine-Lysine-based linkers have significant potential as enzymatic cleavable linker for ADC.

Date:    Friday, January 13

Time:    1:30 pm

Place:    HLTH GB06