在肿瘤学中，首次人体研究（FIH）的设计（例如3+3剂量递增设计）通常不能提供足够的样本量来确定对疗效的剂量-反应关系。本研究旨在评估单克隆抗体（mAb）清除作为疗效生物标志物的可行性，以便于在癌症类型和药物靶标中发现潜在的有效剂量。我们在Drugs @ FDA网站、欧洲药品管理局网站和PubMed上进行了电子搜索，以确定肿瘤学中已批准mAbs的FIH试验报告。提取了不同剂量水平的mAbs的清除、半衰期和总体反应率（ORR）数据。本研究包括25种已批准的mAbs。由于FIH研究中样本大小较小，因此我们在ORR方面没有发现明显的剂量反应。然而，我们发现不同肿瘤/药物靶标之间的mAb清除与ORR之间存在明显的负相关，以及一个明显的负剂量-清除关系，在高剂量水平时清除值降低并达到饱和。已批准的mAb剂量（1-25 mg/kg）约为饱和剂量的2倍（1-10 mg/kg）。批准剂量下的相关清除值在不同癌症和药物靶标之间有所不同（0.17-1.56 L/day），但在疾病/药物靶标内趋于相似。针对B细胞淋巴瘤的抗CD20 mAb表现出较高的清除（约1 L/day），而其他癌症和靶标（例如抗PD-1的0.3 L/day）则较低。mAb的清除可以作为潜在的抗肿瘤活性生物标志物，因为清除随着ORR的增加而减少。我们的研究结果提供了重要的洞见，可以指导FIH肿瘤学研究中mAb的剂量选择，并了解不同癌症和药物靶标的目标清除值，以实现预期的疗效。©2023年该作者，独家许可Springer Nature Switzerland AG使用。

The designs of first-in-human (FIH) studies in oncology (e.g., 3 + 3 dose escalation design) usually do not provide a sufficient sample size to determine the dose-response relationship for efficacy. This study aimed to assess the feasibility of using monoclonal antibody (mAb) clearance as a biomarker for efficacy to facilitate the identification of potentially efficacious doses across cancer types and drug targets.We performed electronic searches of the Drugs@FDA website, the European Medicines Agency website, and PubMed to identify reports of FIH trials of approved mAbs in oncology. The clearance, half-life, and overall response rate (ORR) data for the mAbs at different dose levels were extracted.Twenty-five approved mAbs were included in this study. As expected, due to the small sample sizes in FIH studies, there was no clear dose-response for ORR. However, we found a clear negative association between mAb clearance and ORR across tumors/drug targets, and a clear negative dose-clearance relationship, with clearance decreasing and saturated at high dose levels. The approved mAb doses (1-25 mg/kg) are approximately 2-fold the saturation doses (1-10 mg/kg). The associated clearance values at the approved doses vary across different cancers and drug targets (0.17-1.56 L/day), while tend to be similar within a disease/drug target. Anti-CD20 mAbs for B-cell lymphomas show a higher clearance (~ 1 L/day) than other cancers and targets (e.g., ~ 0.3 L/day for anti-PD-1).Clearance of mAbs can be a tumor/drug target-agnostic biomarker for potential anti-tumor activity as clearance decreases with increasing ORR. Our findings shed important insights into target clearance values that may lead to desired efficacy for different cancers and drug targets, which can be used to guide dose selection for the future development of mAbs during FIH oncology studies.© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.