US Food and Drug Administration, Center for Drug Evaluation and Research, Office of Hematology and Oncology Products, 10903 New Hampshire Ave, Silver Spring, MD, 20903, United States.
US Food and Drug Administration, Center for Drug Evaluation and Research, Office of Hematology and Oncology Products, 10903 New Hampshire Ave, Silver Spring, MD, 20903, United States.
Regul Toxicol Pharmacol. 2019 Oct;107:104429. doi: 10.1016/j.yrtph.2019.104429. Epub 2019 Jul 17.
With a new generation of antibody-drug conjugates (ADCs) that contain a drug-to-antibody ratio (DAR) of 2, the question remains whether advances in technology have resulted in more stable and tumor-specific ADCs. These ADCs are anticipated to cause minimal systemic exposures of payloads, with toxicities being evident mainly at tumor sites. We examined 15 ADCs with PBD-dimer payloads and a DAR of 2 and concluded that dose limiting toxicities in animals and in humans are generally related to the payload. Both the payloads and the ADCs had pro-inflammatory responses causing severe toxicities that were at times of low incidence, making it difficult to assess a cause-effect relationship. Due to their low incidence, single-patient cohorts may not detect these events and such design may not be suitable in first-in-human (FIH) trials. The commonly proposed approach by the sponsors for FIH dose selection was 1/6 highest non-severely toxic dose (HNSTD) in monkeys. This approach resulted in an acceptable balance of safety and efficient dose escalation in phase 1 trials, when using data from repeat-dose toxicology studies and body surface area for scaling. No sponsor used the data generated in rodents or proposed novel approaches for FIH dose selection.
随着新一代抗体药物偶联物（ADC）的出现，其药物抗体比（DAR）达到 2，人们仍然想知道，技术的进步是否带来了更稳定和更具肿瘤特异性的 ADC。这些 ADC 预计会使有效载荷的全身暴露最小化，毒性主要在肿瘤部位显现。我们研究了 15 种含有 PBD-二聚体有效载荷且 DAR 为 2 的 ADC，并得出结论，动物和人体中的剂量限制毒性通常与有效载荷有关。有效载荷和 ADC 均具有促炎反应，导致严重的毒性，有时发生率较低，难以评估因果关系。由于发生率较低，单个患者队列可能无法检测到这些事件，因此这种设计可能不适合首次人体（FIH）试验。发起人通常提议的 FIH 剂量选择方法是猴子中最高非严重毒性剂量（HNSTD）的 1/6。当使用重复剂量毒性研究和体表面积进行缩放时，这种方法在 1 期试验中实现了安全性和高效剂量递增之间的可接受平衡。没有发起人使用啮齿动物产生的数据或提出用于 FIH 剂量选择的新方法。
