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In vitro and in silico assessment of the developability of a designed monoclonal antibody library.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Wolf Pérez, Adriana-Michelle 
Andersen, Jonathan Sonne 
Sakhnini, Laila Ismail  ORCID logo  https://orcid.org/0000-0002-1209-3078
Rodriguez-Leon, Ileana  ORCID logo  https://orcid.org/0000-0001-7319-2080

Abstract

Despite major advances in antibody discovery technologies, the successful development of monoclonal antibodies (mAbs) into effective therapeutic and diagnostic agents can often be impeded by developability liabilities, such as poor expression, low solubility, high viscosity and aggregation. Therefore, strategies to predict at the early phases of antibody development the risk of late-stage failure of antibody candidates are highly valuable. In this work, we employ the in silico solubility predictor CamSol to design a library of 17 variants of a humanized mAb predicted to span a broad range of solubility values, and we examine their developability potential with a battery of commonly used in vitro and in silico assays. Our results demonstrate the ability of CamSol to rationally enhance mAb developability, and provide a quantitative comparison of in vitro developability measurements with each other and with more resource-intensive solubility measurements, as well as with in silico predictors that offer a potentially faster and cheaper alternative. We observed a strong correlation between predicted and experimentally determined solubility values, as well as with measurements obtained using a panel of in vitro developability assays that probe non-specific interactions. These results indicate that computational methods have the potential to reduce or eliminate the need of carrying out laborious in vitro quality controls for large numbers of lead candidates. Overall, our study provides support to the emerging view that the implementation of in silico tools in antibody discovery campaigns can ensure rapid and early selection of antibodies with optimal developability potential.

Description

Keywords

biophysical properties, computational predictions, developability assessment, monoclonal antibodies, Antibodies, Monoclonal, Computer Simulation, Drug Development, Drug Discovery, Humans, Solubility, Structure-Activity Relationship

Journal Title

MAbs

Conference Name

Journal ISSN

1942-0862
1942-0870

Volume Title

11

Publisher

Informa UK Limited