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首页> 外文期刊>Drug Design, Development and Therapy >Preclinical pharmacokinetics, interspecies scaling, and pharmacokinetics of a Phase I clinical trial of TTAC-0001, a fully human monoclonal antibody against vascular endothelial growth factor 2
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Preclinical pharmacokinetics, interspecies scaling, and pharmacokinetics of a Phase I clinical trial of TTAC-0001, a fully human monoclonal antibody against vascular endothelial growth factor 2

机译：TTAC-0001的第一阶段临床试验的临床前药代动力学，物种间定标和药代动力学，TTAC-0001是针对血管内皮生长因子2的完全人单克隆抗体

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Background: VEGF is a highly selective mitogen that serves as the central regulator of tumor angiogenesis by mediating endothelial proliferation, permeability, and survival. Tanibirumab (TTAC-0001) is a fully human IgG1 monoclonal antibody derived from a fully human na?ve single-chain variable fragment (ScFv) phage library that was developed to inhibit the effects of VEGF in the treatment of solid tumors, especially those of the brain. Methods: In the present study, we conducted intravenous pharmacokinetic studies of TTAC-0001 in mice, rats, and cynomolgus monkeys. At the doses studied (3 mg/kg, 10 mg/kg, 30 mg/kg), TTAC-0001 exhibited dose proportionality in mice and monkeys. At a dose of ~10 mg/kg, the clearance of TTAC-0001 from serum was 0.017 mL/h in mice, 0.35 mL/h in rats, and 2.19 mL/h in cynomolgus monkeys, and the terminal half-life ranged from 20–30 h among the three species. Pharmacokinetic data in mice, rats, and cynomolgus monkeys were used to predict the pharmacokinetics of TTAC-0001 in humans using allometric scaling. The predicted serum clearance of TTAC-0001 in humans was 102.45 mL/h and the terminal half-life was 27.52 h. Results: The maximum life span-corrected clearance value was 72.92 mL/h. The observed clearance in humans was more similar to the predicted scaled clearance. Conclusion: We investigated the pharmacokinetics of TTAC-0001 in mice, rats, and cynomolgus monkeys after intravenous administration. At the doses studied, TTAC-0001 exhibited dose proportionality in mice and monkeys. The scaled pharmacokinetics of TTAC-0001 reported here was useful for designing first-in-human studies. Allometric scaling in the therapeutic antibody is feasible.
机译：背景：VEGF是一种高度选择性的促分裂原，通过介导内皮细胞的增殖，通透性和存活而充当肿瘤血管生成的主要调节剂。 Tanibirumab（TTAC-0001）是衍生自完全人类幼稚单链可变片段（ScFv）噬菌体库的完全人类IgG1单克隆抗体，被开发来抑制VEGF在治疗实体瘤（尤其是实体瘤）中的作用。大脑。方法：在本研究中，我们进行了TTAC-0001在小鼠，大鼠和食蟹猴中的静脉药代动力学研究。在研究剂量（3 mg / kg，10 mg / kg，30 mg / kg）下，TTAC-0001在小鼠和猴子中表现出剂量比例性。剂量约为10 mg / kg时，小鼠中TTAC-0001与血清的清除率为0.017 mL / h，大鼠中为0.35 mL / h，食蟹猴为2.19 mL / h，终末半衰期为在三个物种中20-30小时。小鼠，大鼠和食蟹猴的药代动力学数据用于通过异速生长定标法预测TTAC-0001在人体内的药代动力学。人体中TTAC-0001的预计血清清除率为102.45 mL / h，终末半衰期为27.52 h。结果：最大使用寿命校正后的清除值为72​​.92 mL / h。在人类中观察到的清除率与预测的清除率更相似。结论：我们研究了静脉内给药后TTAC-0001在小鼠，大鼠和食蟹猴中的药代动力学。在研究的剂量下，TTAC-0001在小鼠和猴子中表现出剂量比例性。此处报道的TTAC-0001的比例药代动力学可用于设计首次人类研究。治疗性抗体中的异构缩放是可行的。

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