甘露糖受体与抗体相互作用的解码:高甘露糖 N-聚糖和聚糖配对的重要性。

IF 5.6 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
mAbs Pub Date : 2024-01-01 Epub Date: 2024-09-08 DOI:10.1080/19420862.2024.2400414
Julia Baumeister, Maximilian Meudt, Sybille Ebert, Frank Rosenau, Boris Mizaikoff, Michaela Blech, Kristina M J Aertker, Fabian Higel
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引用次数: 0

摘要

在治疗性单克隆抗体(mAbs)的开发过程中,控制影响药代动力学(PK)和 Fc 效应器功能的 N-糖基化等(关键)质量属性至关重要。以前的报告显示,含有高甘露糖 N-聚糖的 mAbs 能更快地从血液循环中清除,从而缩短半衰期。在细胞培养过程中,mAbs 的高甘露糖 N-聚糖含量会受到细胞系、工艺条件和培养基等因素的影响。此外,mAbs 要么含有一个高甘露糖 N-聚糖(不对称高甘露糖糖对),要么含有两个高甘露糖 N-聚糖(对称高甘露糖糖对)。甘露糖受体(MR,CD206)通过促进其内化和随后的溶酶体降解来加速清除的假设很普遍。然而,MR 与 mAbs 之间的相互作用尚未得到明确证实。本研究旨在研究这种相互作用,首次系统地展示了 MR 与具有高甘露糖 N-聚糖的 mAbs 的 Fc 区的结合。研究人员开发并应用了两种新型分析方法--磁共振表面等离子体共振和磁共振亲和层析来研究磁共振与 mAb 的相互作用。研究发现,这种相互作用取决于高甘露糖含量,但与 mAb 格式或序列无关。然而,不同的糖对与 MR 的结合亲和力各不相同,对称的高甘露糖糖对显示出最强的结合特性。这些发现加强了 MR 介导的 mAb 相互作用的假设,有助于加深对 MR 与 mAb 相互作用的理解,这可能会影响以 IgG 为基础的分子的高甘露糖 mAb 开发策略的关键性,并改善其 PK 图谱。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Decoding the mannose receptor-mAb interaction: the importance of high-mannose N-glycans and glycan-pairing.

During the development process of therapeutic monoclonal antibodies (mAbs), it is crucial to control (critical) quality attributes such as N-glycosylation influencing pharmacokinetics (PK) and Fc effector functions. Previous reports have shown that mAbs containing high-mannose N-glycans are cleared faster from blood circulation, leading to reduced half-lives. The high-mannose N-glycan content of mAbs can be influenced during the cell culture process by factors such as cell lines, process conditions, and media. Furthermore, mAbs have either one high mannose N-glycan (asymmetrical high-mannose glyco-pair) or two high mannose N-glycans (symmetrical high-mannose glyco-pair). The hypothesis that the mannose receptor (MR, CD206) accelerates clearance by facilitating their internalization and subsequent lysosomal degradation is widespread. However, the interaction between MR and mAbs has not been explicitly demonstrated. This study aimed to investigate this interaction, providing the first systematic demonstration of MR binding to the Fc region of mAbs with high-mannose N-glycans. Two novel analytical methods, MR surface plasmon resonance and MR affinity chromatography, were developed and applied to investigate the MR-mAb interaction. The interaction is found to be dependent on high-mannose content, but is independent of the mAb format or sequence. However, different glyco-pairs exhibited varying binding affinities to the MR, with the symmetrical high-mannose glyco-pair showing the strongest binding properties. These findings strengthen the hypothesis for the MR-mediated mAb interaction and contribute to a deeper understanding of the MR-mAb interaction, which could affect the criticality of high-mannose containing mAbs development strategies of IgG-based molecules and improve their PK profiles.

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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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