Integral Molecular, Philadelphia, PA, USA.
MAbs. 2024 Jan-Dec;16(1):2393785. doi: 10.1080/19420862.2024.2393785. Epub 2024 Aug 24.
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.
特异性分析是单克隆抗体（mAbs）和抗体导向生物疗法（如 CAR-T 细胞）在进行人体试验之前的必要要求。然而，传统的评估 mAbs 特异性的方法，主要是组织交叉反应研究，一直不可靠，导致潜在的脱靶结合未被发现。在这里，我们回顾了基于细胞的蛋白质阵列作为替代和改进的 mAb 特异性评估方法的出现。基于细胞的蛋白质阵列评估了整个人类膜蛋白质组的结合情况，每个蛋白质都在活细胞或未固定细胞中以其天然结构构象单独表达。我们自己的分析表明，整个行业的脱靶率惊人地高，33%的先导候选药物显示出脱靶结合。此外，目前处于临床开发和市场上的约 20%的治疗性 mAbs 显示出脱靶结合。在生物治疗药物批准的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淘汰的主要原因。
