Quantitative Analysis of Therapeutic Antibody Interactions with Fcγ Receptors Using High-Speed Atomic Force Microscopy.

IF 1.7 4区 医学 Q3 PHARMACOLOGY & PHARMACY
Biological & pharmaceutical bulletin Pub Date : 2024-01-31 Epub Date: 2023-12-22 DOI:10.1248/bpb.b23-00751
Saeko Yanaka, Hiroki Watanabe, Rina Yogo, Mesayamas Kongsema, Sachiko Kondo, Hirokazu Yagi, Takayuki Uchihashi, Koichi Kato
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引用次数: 0

Abstract

This study employed high-speed atomic force microscopy to quantitatively analyze the interactions between therapeutic antibodies and Fcγ receptors (FcγRs). Antibodies are essential components of the immune system and are integral to biopharmaceuticals. The focus of this study was on immunoglobulin G molecules, which are crucial for antigen binding via the Fab segments and cytotoxic functions through their Fc portions. We conducted real-time, label-free observations of the interactions of rituximab and mogamulizumab with the recombinant FcγRIIIa and FcγRIIa. The dwell times of FcγR binding were measured at the single-molecule level, which revealed an extended interaction duration of mogamulizumab with FcγRIIIa compared with that of rituximab. This is linked to enhanced antibody-dependent cellular cytotoxicity that is attributed to the absence of the core fucosylation of Fc-linked N-glycan. This study also emphasizes the crucial role of the Fab segments in the interaction with FcγRIIa as well as that with FcγRIIIa. This approach provided quantitative insight into therapeutic antibody interactions and exemplified kinetic proofreading, where cellular discrimination relies on ligand residence times. Observing the dwell times of antibodies on the effector molecules has emerged as a robust indicator of therapeutic antibody efficacy. Ultimately, these findings pave the way for the development of refined therapeutic antibodies with tailored interactions with specific FcγRs. This research contributes to the advancement of biopharmaceutical antibody design and optimizing antibody-based treatments for enhanced efficacy and precision.

利用高速原子力显微镜定量分析治疗性抗体与 Fcγ 受体之间的相互作用。
这项研究利用高速原子力显微镜定量分析了治疗性抗体与 Fcγ 受体(FcγRs)之间的相互作用。抗体是免疫系统的重要组成部分,也是生物制药不可或缺的组成部分。本研究的重点是免疫球蛋白 G 分子,它通过 Fab 片段与抗原结合,并通过 Fc 部分发挥细胞毒性功能。我们对利妥昔单抗和莫干单抗与重组 FcγRIIIa 和 FcγRIIa 的相互作用进行了实时、无标记观察。在单分子水平上测量了 FcγR 结合的停留时间,结果显示,与利妥昔单抗相比,莫干珠单抗与 FcγRIIIa 的相互作用持续时间更长。这与抗体依赖性细胞毒性的增强有关,而细胞毒性的增强则归因于 Fc 链接的 N-聚糖的核心岩藻糖基化的缺失。这项研究还强调了 Fab 片段在与 FcγRIIa 以及 FcγRIIIa 的相互作用中的关键作用。这种方法提供了对治疗性抗体相互作用的定量洞察力,并体现了动力学校对(kinetic proofreading),即细胞识别依赖于配体的停留时间。观察抗体在效应分子上的停留时间已成为治疗性抗体疗效的可靠指标。最终,这些发现为开发能与特定 FcγR 发生定制化相互作用的精制治疗性抗体铺平了道路。这项研究有助于推动生物制药抗体的设计,优化基于抗体的治疗,以提高疗效和精确性。
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
CiteScore
3.50
自引率
5.00%
发文量
247
审稿时长
2 months
期刊介绍: Biological and Pharmaceutical Bulletin (Biol. Pharm. Bull.) began publication in 1978 as the Journal of Pharmacobio-Dynamics. It covers various biological topics in the pharmaceutical and health sciences. A fourth Society journal, the Journal of Health Science, was merged with Biol. Pharm. Bull. in 2012. The main aim of the Society’s journals is to advance the pharmaceutical sciences with research reports, information exchange, and high-quality discussion. The average review time for articles submitted to the journals is around one month for first decision. The complete texts of all of the Society’s journals can be freely accessed through J-STAGE. The Society’s editorial committee hopes that the content of its journals will be useful to your research, and also invites you to submit your own work to the journals.
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