An Enzymatically Cleavable Tripeptide Linker for Maximizing the Therapeutic Index of Antibody-Drug Conjugates.
An Enzymatically Cleavable Tripeptide Linker for Maximizing the Therapeutic Index of Antibody-Drug Conjugates.
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DOI：
10.1158/1535-7163.mct-22-0362
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发表时间：
2022-09-06
影响因子：
5.7
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中科院分区：
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缬氨酸-瓜氨酸是一种蛋白酶可切割的接头，常用于许多药物递送系统，包括用于癌症治疗的抗体-药物缀合物（ADC）。然而，其次优的体内稳定性可引起各种不良反应，如中性粒细胞减少症和肝毒性，导致给药延迟或治疗中止。在这里，我们报告了谷氨酸-甘氨酸-瓜氨酸（EGCit）接头有可能解决这一临床问题，而不会影响无痕药物释放和ADC治疗效果的能力。我们证明，我们的EGCit ADC抵抗中性粒细胞蛋白酶介导的降解和备件分化人类中性粒细胞。值得注意的是，我们的抗HER 2 ADC在80 mg kg-1下在健康小鼠中几乎没有显示血液和肝脏毒性的迹象。相比之下，在相同剂量水平下，FDA批准的抗HER 2 ADC Kadcyla®和Enhertu®显示血清丙氨酸转氨酶和天冬氨酸转氨酶的水平增加以及肝组织中的形态学变化。与Kadcyla®和Enhertu®相比，我们的EGCit缀合物在多种异种移植肿瘤模型中也发挥更大的抗肿瘤功效。这种接头技术可以大大拓宽ADC和其他药物递送剂的治疗窗口，为临床提供具有改善的疗效和安全性的选择。
Valine-citrulline is a protease-cleavable linker commonly used in many drug delivery systems, including antibody-drug conjugates (ADCs) for cancer therapy. However, its suboptimal in vivo stability can cause various adverse effects such as neutropenia and hepatotoxicity, leading to dose delays or treatment discontinuation. Here, we report that glutamic acid-glycine-citrulline (EGCit) linkers have the potential to solve this clinical issue without compromising the ability of traceless drug release and ADC therapeutic efficacy. We demonstrate that our EGCit ADC resists neutrophil protease-mediated degradation and spares differentiating human neutrophils. Notably, our anti-HER2 ADC show almost no sign of blood and liver toxicity in healthy mice at 80 mg kg–1. In contrast, at the same dose level, the FDA-approved anti-HER2 ADCs Kadcyla® and Enhertu® show increased levels of serum alanine aminotransferase and aspartate transaminase and morphological changes in liver tissues. Our EGCit conjugates also exert greater antitumor efficacy in multiple xenograft tumor models compared to Kadcyla® and Enhertu®. This linker technology could substantially broaden the therapeutic windows of ADCs and other drug delivery agents, providing clinical options with improved efficacy and safety.