Dose selection and confirmation are critical tasks in the development of therapeutic antibodies. These tasks could become particularly challenging in the absence of robust pharmacodynamics biomarkers or at very flat dose-response curves. Although much knowledge has been acquired in the past decade, it remains uncertain which factors are relevant and how to select doses more rationally. In this study, we developed a quantitative metric, Therapeutic Exposure Affinity Ratio (TEAR), to retrospectively evaluate up to 60 approved antibodies and their therapeutic doses (TDs), and systematically assessed the factors that are relevant to antibody TDs and dose selection patterns. This metric supported us to analyze many factors that are beyond antibody pharmacokinetics and target binding affinity. Our results challenged the traditional perceptions about the importance of target turnovers and target anatomical locations in the selection of TDs, highlighted the relevance of an overlooked factor, antibody mechanisms of action. Overall, this study provided insights into antibody dose selection and confirmation in the development of therapeutic antibodies.

中文翻译：

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影响抗体治疗剂量的定量建模因素

剂量选择和确认是开发治疗性抗体的关键任务。在缺乏可靠的药效学生物标记物或剂量反应曲线非常平坦的情况下，这些任务可能会变得特别具有挑战性。尽管在过去十年中已经获得了很多知识，但仍不确定哪些因素相关以及如何更合理地选择剂量。在这项研究中，我们开发了一种量化指标，即治疗暴露亲和力比（TEAR），以回顾性评估多达60种已批准的抗体及其治疗剂量（TDs），并系统地评估与抗体TDs和剂量选择模式有关的因素。该指标支持我们分析抗体药物动力学和靶标结合亲和力以外的许多因素。我们的结果挑战了传统的观念，即在选择TD时靶标转换和靶标解剖位置的重要性，强调了被忽视的因素抗体作用机制的相关性。总的来说，这项研究为治疗性抗体的开发中抗体剂量的选择和确认提供了见识。