Early determination of potential critical quality attributes of therapeutic antibodies in developability studies through surface plasmon resonance-based relative binding activity assessment.

IF 5.6 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
mAbs Pub Date : 2024-01-01 Epub Date: 2024-07-02 DOI:10.1080/19420862.2024.2374607
Shuai Wang, Yanqiu Wang, Zhenzhen Li, Ye Hong, Zhaohui Wang, Jiteng Fan, Qiong Wang, Yuanjie Ge, Xiaofeng Zhao, Guangcun Cheng, Changyan Chen, Yadan Wu, Yayuan Fu
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Abstract

Precise measurement of the binding activity changes of therapeutic antibodies is important to determine the potential critical quality attributes (CQAs) in developability assessment at the early stage of antibody development. Here, we report a surface plasmon resonance (SPR)-based relative binding activity method, which incorporates both binding affinity and binding response and allows us to determine relative binding activity of antibodies with high accuracy and precision. We applied the SPR-based relative binding activity method in multiple forced degradation studies of antibody developability assessment. The current developability assessment strategy provided comprehensive, precise characterization of antibody binding activity in the stability studies, enabling us to perform correlation analysis and establish the structure-function relationship between relative binding activity and quality attributes. The impact of a given quality attribute on binding activity could be confidently determined without isolating antibody variants. We identified several potential CQAs, including Asp isomerization, Asn deamidation, and fragmentation. Some potential CQAs affected binding affinity of antibody and resulted in a reduction of binding activity. Certain potential CQAs impaired antibody binding to antigen and led to a loss of binding activity. A few potential CQAs could influence both binding affinity and binding response and cause a substantial decrease in antibody binding activity. Specifically, we identified low abundance Asn33 deamidation in the light chain complementarity-determining region as a potential CQA, in which all the stressed antibody samples showed Asn33 deamidation abundances ranging from 4.2% to 27.5% and a mild binding affinity change from 1.76 nM to 2.16 nM.

通过基于表面等离子共振的相对结合活性评估,在可开发性研究中及早确定治疗性抗体的潜在关键质量属性。
精确测量治疗性抗体的结合活性变化对于确定抗体开发早期可开发性评估中潜在的关键质量属性(CQA)非常重要。在这里,我们报告了一种基于表面等离子体共振(SPR)的相对结合活性方法,该方法结合了结合亲和力和结合反应,能高精度地测定抗体的相对结合活性。我们将基于 SPR 的相对结合活性方法应用于抗体可开发性评估的多项强制降解研究中。目前的可发展性评估策略在稳定性研究中提供了全面、精确的抗体结合活性表征,使我们能够进行相关性分析,建立相对结合活性与质量属性之间的结构-功能关系。在不分离抗体变体的情况下,就能确定特定质量属性对结合活性的影响。我们确定了几种潜在的 CQA,包括 Asp 异构化、Asn 脱酰胺化和破碎化。一些潜在的 CQA 影响了抗体的结合亲和力,导致结合活性降低。某些潜在的 CQAs 会影响抗体与抗原的结合,导致结合活性下降。少数潜在的 CQAs 可同时影响结合亲和力和结合反应,并导致抗体结合活性大幅降低。具体来说,我们发现轻链互补性决定区的低丰度 Asn33 去氨基化是一种潜在的 CQA,所有受试抗体样品的 Asn33 去氨基化丰度从 4.2% 到 27.5%不等,结合亲和力从 1.76 nM 轻度变化到 2.16 nM。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
mAbs
mAbs 工程技术-仪器仪表
CiteScore
10.70
自引率
11.30%
发文量
77
审稿时长
6-12 weeks
期刊介绍: mAbs is a multi-disciplinary journal dedicated to the art and science of antibody research and development. The journal has a strong scientific and medical focus, but also strives to serve a broader readership. The articles are thus of interest to scientists, clinical researchers, and physicians, as well as the wider mAb community, including our readers involved in technology transfer, legal issues, investment, strategic planning and the regulation of therapeutics.
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