A first insight into the developability of an Immunoglobulin G3 : a combined computational and experimental approach

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Armstrong, Georgina and Lewis, Alan and Shah, Vidhi and Taylor, Paul and Jamieson, Craig J. and Burley, Glenn A. and Lewis, Will and Rattray, Zahra (2024) A first insight into the developability of an Immunoglobulin G3 : a combined computational and experimental approach. ACS Pharmacology & Translational Science, 7 (8). pp. 2439-2451. ISSN 2575-9108 (https://doi.org/10.1021/acsptsci.4c00271)

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Abstract

Immunoglobulin G 3 (IgG3) monoclonal antibodies (mAbs) are high-value scaffolds for developing novel therapies. Despite their wide-ranging therapeutic potential, IgG3 physicochemical properties and developability characteristics remain largely under-characterized. Protein–protein interactions elevate solution viscosity in high-concentration formulations, impacting physicochemical stability, manufacturability, and the injectability of mAbs. Therefore, in this manuscript, the key molecular descriptors and biophysical properties of a model anti-IL-8 IgG1 and its IgG3 ortholog are characterized. A computational and experimental framework was applied to measure molecular descriptors impacting their downstream developability. Findings from this approach underpin a detailed understanding of the molecular characteristics of IgG3 mAbs as potential therapeutic entities. This work is the first report examining the manufacturability of IgG3 for high-concentration mAb formulations. While poorer conformational and colloidal stability and elevated solution viscosity were observed for IgG3, future efforts controlling surface potential through sequence-engineering of solvent-accessible patches can be used to improve biophysical parameters that dictate mAb developability.

ORCID iDs

Armstrong, Georgina ORCID logoORCID: https://orcid.org/0009-0007-3846-0554, Lewis, Alan, Shah, Vidhi, Taylor, Paul, Jamieson, Craig J. ORCID logoORCID: https://orcid.org/0000-0002-6567-8272, Burley, Glenn A., Lewis, Will and Rattray, Zahra ORCID logoORCID: https://orcid.org/0000-0002-8371-8549;
CORE (COnnecting REpositories)