Assessing the manufacturability and critical quality attribute profiles of anti-IL-8 immunoglobulin G mutant variants

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Armstrong, Georgina Bethany and Burley, Glenn A. and Lewis, William and Rattray, Zahra (2024) Assessing the manufacturability and critical quality attribute profiles of anti-IL-8 immunoglobulin G mutant variants. Molecular Pharmaceutics, 21 (12). 6423–6432. ISSN 1543-8384 (https://doi.org/10.1021/acs.molpharmaceut.4c01010)

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Abstract

Early-phase manufacturability assessment of high-concentration therapeutic monoclonal antibodies (mAbs) involves screening of process-related risks impacting their translation into the clinic. Manufacturing a mAb at scale relies on cost-effective and robust approaches to derisk manufacturability parameters, such as viscosity, conformational stability, aggregation, and process-related impurities. Using a panel of model anti-IL-8 IgG1 mutants, we investigate upstream and downstream processability, phase behavior, and process-related impurities. We correlate trends in the biophysical properties of mAbs with their cell growth, expression, filtration flux, solubility, and post-translational modifications. We find significant trends in increased relative free light chain expression with heavy chain mutants and detect a requirement for adjusted operation pH for cation exchange polishing steps with charge-altering variants. Moreover, trends between phase stability and high-concentration viscosity were observed. We also investigated unique correlations between increased glycosylation and biophysical behavior. Further in-depth analysis and modeling are required to elucidate the impact of the mAb sequence on the metabolism of the expression system, solubility limits, and alternative gelation models as future directions.

ORCID iDs

Armstrong, Georgina Bethany ORCID logoORCID: https://orcid.org/0009-0007-3846-0554, Burley, Glenn A., Lewis, William and Rattray, Zahra ORCID logoORCID: https://orcid.org/0000-0002-8371-8549;
CORE (COnnecting REpositories)