Impact of Maleimide Disubstitution on Chemical and Biological Characteristics of HER2 Antibody-Drug Conjugates.
Journal
ACS omega
ISSN: 2470-1343
Titre abrégé: ACS Omega
Pays: United States
ID NLM: 101691658
Informations de publication
Date de publication:
28 Jan 2020
28 Jan 2020
Historique:
received:
21
10
2019
accepted:
29
11
2019
entrez:
4
2
2020
pubmed:
6
2
2020
medline:
6
2
2020
Statut:
epublish
Résumé
Antibody-drug conjugates (ADCs) are the spearhead of targeted therapies. According to the technology used, the conjugation of a cytotoxic drug to an antibody can produce suboptimal heterogeneous species, impacting the overall efficacy. Herein, we describe the synthesis of HER2-targeting ADCs with three disulfide rebridging heads, allowing homogeneous and site-specific bioconjugation: dibromomaleimide (DBM), dithiomaleimide (DTM), and hybrid thio-bromomaleimide (TBM) chemical bricks to combine the properties of both previously used heads. The primary purpose of this study was to compare the reactivity of these three chemical bricks in the bioconjugation process. Then, the resulting ADCs were evaluated in terms of physicochemical stability, binding, and biological activity. We have demonstrated that the higher percentage of a drug-to-antibody ratio of 4 was obtained with TBM. Additionally, the reaction time was drastically reduced with TBM in comparison to DTM. The three ADCs showed good binding to HER2 and in vitro cytotoxicity, which validate the TBM structure as an attractive alternative scaffold for rebridging bioconjugation.
Identifiants
pubmed: 32010829
doi: 10.1021/acsomega.9b03510
pmc: PMC6990629
doi:
Types de publication
Journal Article
Langues
eng
Pagination
1557-1565Informations de copyright
Copyright © 2020 American Chemical Society.
Déclaration de conflit d'intérêts
The authors declare no competing financial interest.
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