Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang, China.
Drug Discov Today. 2021 Aug;26(8):1980-1990. doi: 10.1016/j.drudis.2021.04.022. Epub 2021 Apr 22.
Factors such as antibody clearance and target affinity can influence antibodies' effective doses for specific indications. However, these factors vary considerably across antibody classes, precluding direct and quantitative comparisons. Here, we apply a dimensionless metric, the therapeutic exposure affinity ratio (TEAR), which normalizes the therapeutic doses by antibody bioavailability, systemic clearance and target-binding property to enable direct and quantitative comparisons of therapeutic doses. Using TEAR, we revisited and dissected the doses of up to 60 approved antibodies. We failed to detect a significant influence of target baselines, turnovers or anatomical locations on antibody therapeutic doses, challenging the traditional perceptions. We highlight the importance of antibodies' modes of action for therapeutic doses and dose selections; antibodies that work through neutralizing soluble targets show higher TEARs than those working through other mechanisms. Overall, our analysis provides insights into the factors that influence antibody doses, and the factors that are crucial for antibodies' pharmacological effects.
抗体清除率和靶点亲和力等因素会影响抗体在特定适应证中的有效剂量。然而,这些因素在不同抗体类别中差异很大,因此无法进行直接和定量的比较。在这里,我们应用了无量纲指标治疗暴露亲和力比(TEAR),通过抗体生物利用度、全身清除率和靶点结合特性对治疗剂量进行归一化,从而实现治疗剂量的直接和定量比较。利用 TEAR,我们重新审视和剖析了多达 60 种已批准抗体的剂量。我们未能发现靶点基线、周转率或解剖位置对抗体治疗剂量有显著影响,这挑战了传统观念。我们强调了抗体作用模式对治疗剂量和剂量选择的重要性;通过中和可溶性靶点发挥作用的抗体比通过其他机制发挥作用的抗体具有更高的 TEAR。总体而言,我们的分析提供了对影响抗体剂量的因素以及对抗体药理作用至关重要的因素的深入了解。