A Novel Family of Acid-Cleavable Linker Based on Cyclic Acetal Motifs for the Production of Antibody-Drug Conjugates with High Potency and Selectivity - DSA-IPHC Accéder directement au contenu
Article Dans Une Revue Bioconjugate Chemistry Année : 2022

A Novel Family of Acid-Cleavable Linker Based on Cyclic Acetal Motifs for the Production of Antibody-Drug Conjugates with High Potency and Selectivity

Résumé

Cleavable linkers have become the subject of intense study in the field of chemical biology, particularly because of their applications in the construction of antibody-drug conjugates (ADC), where they facilitate lysosomal cleavage and liberation of drugs from their carrier protein. Due to lysosomes' acidic nature, acid-labile motifs have attracted much attention, leading to the development of hydrazone and carbonate linkers among several other entities. Continuing our efforts in designing new moieties, we present here a family of cyclic acetals that exhibit excellent plasma stability and acid lability, notably in lysosomes. Incorporated in ADC, they led to potent constructs with picomolar potency in vitro and similar in vivo efficacy as the commercially available ADC Kadcyla in mouse xenograft models.

Domaines

Chimie
Fichier principal
Vignette du fichier
manuscript corrected.pdf (869.51 Ko) Télécharger le fichier
Origine : Fichiers produits par l'(les) auteur(s)

Dates et versions

hal-03783825 , version 1 (22-09-2022)

Identifiants

Citer

Tony Rady, Lorenzo Turelli, Marc Nothisen, Elisabetta Tobaldi, Stéphane Erb, et al.. A Novel Family of Acid-Cleavable Linker Based on Cyclic Acetal Motifs for the Production of Antibody-Drug Conjugates with High Potency and Selectivity. Bioconjugate Chemistry, 2022, ⟨10.1021/acs.bioconjchem.2c00314⟩. ⟨hal-03783825⟩
40 Consultations
318 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More