vc-MMAE antibody-drug conjugates (ADCs) consist of a monoclonal antibody (mAb) covalently bound with a potent anti-mitotic toxin (MMAE) through a protease-labile valine-citrulline (vc) linker. The objective of this study was to characterize the pharmacokinetics (PK) and explore exposure-response relationships of eight vc-MMAE ADCs, against different targets and for diverse tumor indications, using data from eight first-in-human Phase 1 studies. PK parameters of the three analytes, namely antibody-conjugated MMAE (acMMAE), total antibody, and unconjugated MMAE, were estimated using non-compartmental approaches and compared across the eight vc-MMAE ADCs. Relationships between analytes were assessed by linear regression. Exposure-response relationships were explored with key efficacy (objective response rate) and safety (Grade 2+ peripheral neuropathy) endpoints. PK profiles of acMMAE, total antibody and unconjugated MMAE following the first dose of 2.4 mg/kg were comparable across the eight ADCs; the exposure differences between molecules were small relative to the inter-subject variability. acMMAE exposure was strongly correlated with total antibody exposure for all the eight ADCs, but such correlation was less evident between acMMAE and unconjugated MMAE exposure. For multiple ADCs evaluated, efficacy and safety endpoints appeared to correlate well with acMMAE exposure, but not with unconjugated MMAE over the doses tested. PK of vc-MMAE ADCs was well characterized and demonstrated remarkable similarity at 2.4 mg/kg across the eight ADCs. Results from analyte correlation and exposure-response relationship analyses suggest that measurement of acMMAE analyte alone might be adequate for vc-MMAE ADCs to support the clinical pharmacology strategy used during late-stage clinical development.

中文翻译：

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vc-MMAE抗体-药物偶联物在癌症患者中的临床药理作用：从八项人类第一项1期研究中学习。

vc-MMAE抗体-药物结合物（ADC）由通过蛋白酶不稳定的缬氨酸-瓜氨酸（vc）接头与有效的抗有丝分裂毒素（MMAE）共价结合的单克隆抗体（mAb）组成。这项研究的目的是使用八项人类第一阶段研究的数据来表征八种vc-MMAE ADC的药代动力学（PK），以及针对不同靶点和多种肿瘤适应症的暴露-反应关系。使用非隔离方法估算了三种分析物（即抗体结合的MMAE（acMMAE），总抗体和未结合的MMAE）的PK参数，并在八个vc-MMAE ADC中进行了比较。通过线性回归评估分析物之间的关系。探索了关键的疗效（客观缓解率）和安全性（2+级周围神经病变）终点的暴露-反应关系。在八个ADC中，首次剂量为2.4 mg / kg后，acMMAE，总抗体和未结合的MMAE的PK谱具有可比性；相对于受试者间的变异性，分子之间的暴露差异很小。acMMAE暴露与所有八个ADC的总抗体暴露密切相关，但在acMMAE和未缀合MMAE暴露之间这种相关性不太明显。对于评估的多个ADC，功效和安全性终点似乎与acMMAE暴露有很好的相关性，但与测试剂量下未结合的MMAE却没有相关性。vc-MMAE ADC的PK具有良好的特性，并且在八个ADC中以2.4 mg / kg表现出显着的相似性。