The emergence of cell-based protein arrays to test for polyspecific off-target binding of antibody therapeutics.

IF 5.6 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
mAbs Pub Date : 2024-01-01 Epub Date: 2024-08-24 DOI:10.1080/19420862.2024.2393785
Diana M Norden, Carmen T Navia, Jonathan T Sullivan, Benjamin J Doranz
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引用次数: 0

Abstract

Specificity profiling is a requirement for monoclonal antibodies (mAbs) and antibody-directed biotherapeutics such as CAR-T cells prior to initiating human trials. However, traditional approaches to assess the specificity of mAbs, primarily tissue cross-reactivity studies, have been unreliable, leading to off-target binding going undetected. Here, we review the emergence of cell-based protein arrays as an alternative and improved assessment of mAb specificity. Cell-based protein arrays assess binding across the full human membrane proteome, ~6,000 membrane proteins each individually expressed in their native structural configuration within live or unfixed cells. Our own profiling indicates a surprisingly high off-target rate across the industry, with 33% of lead candidates displaying off-target binding. Moreover, about 20% of therapeutic mAbs in clinical development and currently on the market display off-target binding. Case studies and off-target rates at different phases of biotherapeutic drug approval suggest that off-target binding is likely a major cause of adverse events and drug attrition.

基于细胞的蛋白质阵列用于检测抗体疗法的多特异性脱靶结合。
特异性分析是单克隆抗体(mAbs)和抗体定向生物疗法(如 CAR-T 细胞)在开始人体试验前的一项要求。然而,评估 mAbs 特异性的传统方法(主要是组织交叉反应研究)并不可靠,导致脱靶结合未被发现。在此,我们回顾了基于细胞的蛋白质阵列作为一种替代方法的出现,并对 mAb 特异性评估进行了改进。基于细胞的蛋白质阵列可评估全人类膜蛋白质组的结合情况,约有 6,000 种膜蛋白,每种蛋白都在活细胞或未固定细胞内以其原生结构构型单独表达。我们自己的分析表明,整个行业的脱靶率高得惊人,33% 的先导候选药物显示出脱靶结合。此外,在临床开发和目前上市的治疗用 mAbs 中,约有 20% 显示出脱靶现象。生物治疗药物审批不同阶段的案例研究和脱靶率表明,脱靶结合可能是不良事件和药物损耗的主要原因。
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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