A comparative study of the developability of full-length antibodies, fragments, and bispecific formats reveals higher stability risks for engineered constructs.

IF 5.6 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
mAbs Pub Date : 2024-01-01 Epub Date: 2024-10-04 DOI:10.1080/19420862.2024.2403156
Itzel Condado-Morales, Fabian Dingfelder, Isabel Waibel, Oliver M Turnbull, Bhargav Patel, Zheng Cao, Jais Rose Bjelke, Susanne Nedergaard Grell, Anja Bennet, Alissa M Hummer, Matthew I J Raybould, Charlotte M Deane, Thomas Egebjerg, Nikolai Lorenzen, Paolo Arosio
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引用次数: 0

Abstract

Engineered antibody formats, such as antibody fragments and bispecifics, have the potential to offer improved therapeutic efficacy compared to traditional full-length monoclonal antibodies (mAbs). However, the translation of these non-natural molecules into successful therapeutics can be hampered by developability challenges. Here, we systematically analyzed 64 different antibody constructs targeting Tumor Necrosis Factor (TNF) which cover 8 distinct molecular format families, encompassing full-length antibodies, various types of single chain variable fragments, and bispecifics. We measured 15 biophysical properties related to activity, manufacturing, and stability, scoring variants with a flag-based risk approach and a recent in silico developability profiler. Our comparative assessment revealed that overall developability is higher for the natural full-length antibody format. Bispecific antibodies, antibodies with scFv fragments at the C-terminus of the light chain, and single-chain Fv antibody fragments (scFvs) have intermediate developability properties, while more complicated formats, such as scFv- scFv, bispecific mAbs with one Fab exchanged with a scFv, and diabody formats are collectively more challenging. In particular, our study highlights the propensity for fragmentation and aggregation, both in bulk and at interfaces, for many current engineered formats.

对全长抗体、片段抗体和双特异性抗体的可开发性进行比较研究后发现,工程构建物的稳定性风险更高。
与传统的全长单克隆抗体(mAbs)相比,抗体片段和双特异性抗体等工程抗体形式有可能提高疗效。然而,将这些非天然分子转化为成功的疗法可能会受到可开发性挑战的阻碍。在这里,我们系统分析了 64 种不同的靶向肿瘤坏死因子(TNF)的抗体构建物,它们涵盖了 8 个不同的分子形式家族,包括全长抗体、各种类型的单链可变片段和双特异性抗体。我们测量了与活性、制造和稳定性相关的 15 项生物物理特性,并采用基于标志的风险方法和最新的硅学可开发性剖析器对变体进行了评分。我们的比较评估显示,天然全长抗体形式的总体可开发性更高。双特异性抗体、轻链 C 端带有 scFv 片段的抗体和单链 Fv 抗体片段(scFvs)的可开发性处于中等水平,而更复杂的形式,如 scFv- scFv、一个 Fab 与一个 scFv 交换的双特异性 mAbs 和二抗体形式则总体上更具挑战性。特别是,我们的研究强调了目前许多工程格式在体积和界面上的破碎和聚集倾向。
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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