Antibody mutations favoring pH-dependent binding in solid tumor microenvironments: Insights from large-scale structure-based calculations.
ADAPT
computational antibody engineering
histidine pH-switches
sequence-based method
solid tumor microenvironment
structure-based calculations
Journal
Proteins
ISSN: 1097-0134
Titre abrégé: Proteins
Pays: United States
ID NLM: 8700181
Informations de publication
Date de publication:
08 2022
08 2022
Historique:
revised:
26
02
2022
received:
30
11
2021
accepted:
23
03
2022
pubmed:
1
4
2022
medline:
12
7
2022
entrez:
31
3
2022
Statut:
ppublish
Résumé
Antibody-based therapeutics for treatment of various tumors have grown rapidly in recent years. Unfortunately, safety issues, attributed to off-tumor effects and cytotoxicity, are still a significant concern with the standard of care. Improvements to ensure targeted delivery of antitumor pharmaceuticals are desperately needed. We previously demonstrated that incorporating histidyl pH-switches in an anti-HER2 antibody induced selective antigen binding under acidic pH conditions (MAbs 2020;12:1682866). This led to an improved safety profile due to preferential targeting of the oncoprotein in the acidic solid tumor microenvironment. Following this success, we expanded this approach to a set of over 400 antibody structures complexed with over 100 different human oncoproteins, associated with solid tumors. Calculations suggested that mutations to His of certain residue types, namely Trp, Arg, and Tyr, could be significantly more successful for inducing pH-dependent binding under acidic conditions. Furthermore, 10 positions within the complementarity-determining region were also predicted to exhibit greater successes. Combined, these two accessible metrics could serve as the basis for a sequence-based engineering of pH-selective binding. This approach could be applied to most anticancer antibodies, which lack detailed structural characterization.
Substances chimiques
Antibodies, Monoclonal
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1538-1546Informations de copyright
© 2022 Her Majesty the Queen in Right of Canada. Proteins: Structure, Function, and Bioinformatics © 2022 Wiley Periodicals LLC. Reproduced with the permission of the Minister of Innovation, Science and Industry.
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