Assessing the Manufacturability and Critical Quality Attribute Profiles of Anti-IL-8 Immunoglobulin G Mutant Variants.

IF 4.5 2区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL
Georgina Bethany Armstrong, Glenn A Burley, William Lewis, Zahra Rattray
{"title":"Assessing the Manufacturability and Critical Quality Attribute Profiles of Anti-IL-8 Immunoglobulin G Mutant Variants.","authors":"Georgina Bethany Armstrong, Glenn A Burley, William Lewis, Zahra Rattray","doi":"10.1021/acs.molpharmaceut.4c01010","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5000,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Pharmaceutics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1021/acs.molpharmaceut.4c01010","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0

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.

评估抗 IL-8 免疫球蛋白 G 突变体的可制造性和关键质量属性特征。
高浓度治疗性单克隆抗体(mAb)的早期可制造性评估包括筛选影响其临床转化的工艺相关风险。大规模制造 mAb 依赖于成本效益高且稳健的方法来降低可制造性参数的风险,如粘度、构象稳定性、聚集和与工艺相关的杂质。我们利用一组抗 IL-8 IgG1 突变体模型,研究了上游和下游的可加工性、相行为以及与加工相关的杂质。我们将 mAbs 的生物物理特性趋势与其细胞生长、表达、过滤通量、溶解度和翻译后修饰相关联。我们发现重链突变体的相对游离轻链表达量有明显增加的趋势,并发现电荷改变变体的阳离子交换抛光步骤需要调整操作 pH 值。此外,我们还观察到了相稳定性和高浓度粘度之间的趋势。我们还研究了糖基化增加与生物物理行为之间的独特关联。还需要进一步深入分析和建模,以阐明 mAb 序列对表达系统新陈代谢的影响、溶解度限制和替代凝胶化模型等未来发展方向。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Molecular Pharmaceutics
Molecular Pharmaceutics 医学-药学
CiteScore
8.00
自引率
6.10%
发文量
391
审稿时长
2 months
期刊介绍: Molecular Pharmaceutics publishes the results of original research that contributes significantly to the molecular mechanistic understanding of drug delivery and drug delivery systems. The journal encourages contributions describing research at the interface of drug discovery and drug development. Scientific areas within the scope of the journal include physical and pharmaceutical chemistry, biochemistry and biophysics, molecular and cellular biology, and polymer and materials science as they relate to drug and drug delivery system efficacy. Mechanistic Drug Delivery and Drug Targeting research on modulating activity and efficacy of a drug or drug product is within the scope of Molecular Pharmaceutics. Theoretical and experimental peer-reviewed research articles, communications, reviews, and perspectives are welcomed.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信