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

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)