The EphA2 receptor is found at high levels in tumors and low levels in normal tissue and high EphA2 expression in biopsies is a predictor of poor outcome in patients. Drug discovery groups have therefore sought to develop EphA2-based therapies using small molecule, peptide, and nanoparticle-based approaches (1–3). However, until now only EphA2-targeting antibody–drug conjugates (ADC) have entered clinical development. For example, MEDI-547 is an EphA2-targeting ADC that displayed encouraging antitumor activity in preclinical models and progressed to phase I clinical testing in man. Here we describe the development of BT5528, a bicyclic peptide (“Bicycle”) conjugated to the auristatin derivative maleimidocaproyl-monomethyl auristatin E to generate the Bicycle toxin conjugate BT5528. The report compares and contrasts the Pharmacokinetics (PK) characteristics of antibody and Bicycle-based targeting systems and discusses how the PK and payload characteristics of different delivery systems impact the efficacy—toxicity trade off which is key to the development of successful cancer therapies. We show that BT5528 gives rise to rapid update into tumors and fast renal elimination followed by persistent toxin levels in tumors without prolonged exposure of parent drug in the vasculature. This fast in, fast out kinetics gave rise to more favorable toxicology findings in rats and monkeys than were observed with MEDI-547 in preclinical and clinical studies. Graphical Abstract: http://mct.aacrjournals.org/content/molcanther/19/7/1385/F1.large.jpg. Visual Overview

中文翻译：

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使用自行车毒素偶联物 BT5528 进行 MMAE 递送

EphA2 受体在肿瘤中含量高，在正常组织中含量低，活检中 EphA2 的高表达是患者预后不良的预测因素。因此，药物发现小组试图使用基于小分子、肽和纳米颗粒的方法开发基于 EphA2 的疗法 (1-3)。然而，到目前为止，只有 EphA2 靶向抗体-药物偶联物 (ADC) 进入临床开发。例如，MEDI-547 是一种靶向 EphA2 的 ADC，在临床前模型中显示出令人鼓舞的抗肿瘤活性，并已进入人体 I 期临床试验。在这里，我们描述了 BT5528，一种与 auristatin 衍生物马来酰亚胺己酰基-单甲基 auristatin E 偶联的双环肽（“Bicycle”）的开发，以生成 Bicycle 毒素偶联物 BT5528。该报告比较和对比了抗体和基于自行车的靶向系统的药代动力学 (PK) 特征，并讨论了不同递送系统的 PK 和有效载荷特征如何影响疗效 - 毒性权衡，这是成功开发癌症疗法的关键。我们表明 BT5528 可以快速更新为肿瘤和快速肾脏消除，随后肿瘤中的毒素水平持续存在，而不会长时间暴露于脉管系统中的母体药物。这种快进快出动力学在大鼠和猴子中产生了比在临床前和临床研究中观察到的 MEDI-547 更有利的毒理学发现。图形摘要：http://mct.aacrjournals.org/content/molcanther/19/7/1385/F1.large.jpg。视觉概览 我们表明 BT5528 可以快速更新为肿瘤和快速肾脏消除，随后肿瘤中的持续毒素水平不会长时间暴露于脉管系统中的母体药物。这种快进快出动力学在大鼠和猴子中产生了比在临床前和临床研究中观察到的 MEDI-547 更有利的毒理学发现。图形摘要：http://mct.aacrjournals.org/content/molcanther/19/7/1385/F1.large.jpg。视觉概览 我们表明 BT5528 可以快速更新为肿瘤和快速肾脏消除，随后肿瘤中的毒素水平持续存在，而不会长时间暴露于脉管系统中的母体药物。这种快进快出动力学在大鼠和猴子中产生了比在临床前和临床研究中观察到的 MEDI-547 更有利的毒理学发现。图形摘要：http://mct.aacrjournals.org/content/molcanther/19/7/1385/F1.large.jpg。视觉概览