Impact of cathepsin B-sensitive triggers and hydrophilic linkers on in vitro efficacy of novel site-specific antibody-drug conjugates

Organic & Biomolecular Chemistry
Francesca BrydenNicolas Joubert

Abstract

Herein we describe the synthesis and evaluation of four novel HER2-targeting, cathepsin B-sensitive antibody-drug conjugates bearing a monomethylauristatin E (MMAE) cytotoxic payload, constructed via the conjugation of cleavable linkers to trastuzumab using a site-specific bioconjugation methodology. These linkers vary by both cleavable trigger motif and hydrophilicity, containing one of two cathepsin B sensitive dipeptides (Val-Cit and Val-Ala), and engendered with either hydrophilic or hydrophobic character via application of a PEG12 spacer. Through evaluation of physical properties, in vitro cytotoxicity, and receptor affinity of the resulting antibody-drug conjugates (ADCs), we have demonstrated that while both dipeptide triggers are effective, the increased hydrophobicity of the Val-Ala pair limits its utility within this type of linker. In addition, while PEGylation augments linker hydrophilicity, this change does not translate to more favourable ADC hydrophilicity or potency. While all described structures demonstrated excellent and similar in vitro cytotoxicity, the ADC with the ValCitPABMMAE linker shows the most promising combination of in vitro potency, structural homogeneity, and hydrophilicity, warranting further e...Continue Reading

References

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Citations

Jan 7, 2020·Médecine sciences : M/S·Alain BeckNicolas Joubert
Jul 2, 2020·Organic & Biomolecular Chemistry·Andrew J CounsellDavid R Spring
Aug 29, 2019·Organic & Biomolecular Chemistry·Kanwen YangPradeep K Dhal
Sep 18, 2020·Pharmaceuticals·Nicolas JoubertCaroline Denevault-Sabourin
Dec 9, 2020·Chemical Society Reviews·Stephen J WalshDavid R Spring
Mar 19, 2021·Chemical Society Reviews·Yufei XueNicolas Hans Voelcker
Jun 3, 2021·Pharmaceuticals·Vesela KostovaAndras Kotschy

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