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Lactone Stabilization is Not a Necessary Feature for Antibody Conjugates of Camptothecins
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2018-08-01 00:00:00 , DOI: 10.1021/acs.molpharmaceut.8b00477 Uland Y. Lau 1 , Lauren T. Benoit 1 , Nicole S. Stevens 1 , Kim K. Emmerton 1 , Margo Zaval 1 , Julia H. Cochran 1 , Peter D. Senter 1
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2018-08-01 00:00:00 , DOI: 10.1021/acs.molpharmaceut.8b00477 Uland Y. Lau 1 , Lauren T. Benoit 1 , Nicole S. Stevens 1 , Kim K. Emmerton 1 , Margo Zaval 1 , Julia H. Cochran 1 , Peter D. Senter 1
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Camptothecins exist in a pH-dependent equilibrium between the active, closed lactone and the inactive open-carboxylate forms. Several previous reports underscore the need for lactone stabilization in generating improved camptothecins, and indeed, such designs have been incorporated into antibody–drug conjugates containing this drug. Here, we demonstrate that lactone stabilization is not necessary for camptothecin-based ADC efficacy. We synthesized and evaluated camptothecin SN-38 drug linkers that differed with respect to lactone stability and released SN-38 or the hydrolyzed open-lactone form upon cleavage from the antibody carrier. An α-hydroxy lactone-linked SN-38 drug linker preserved the closed-lactone ring structure, while the phenol-linked version allowed conversion between the closed-lactone and open-carboxylate structures. The in vitro cytotoxicity, pharmacokinetic properties, and in vivo efficacy in the L540cy Hodgkin’s lymphoma model of the corresponding ADCs were found to be indistinguishable, leading us to conclude that camptothecin-based antibody–drug conjugates possess pronounced activity regardless of the lactone state of the bound drug. This is most likely a result of ADC processing within acidic intracellular vesicles, delivering camptothecin in its active closed-lactone form.
中文翻译：
内酯稳定不是喜树碱抗体缀合物的必要功能。
喜树碱在活性，封闭的内酯和非活性的开放羧酸盐形式之间以pH依赖的平衡存在。先前的几份报告强调了在生成喜树碱方面需要稳定内酯，实际上，这种设计已被纳入含有这种药物的抗体-药物结合物中。在这里，我们证明内酯稳定对于基于喜树碱的ADC功效不是必需的。我们合成并评估了喜树碱SN-38药物连接子，它们在内酯稳定性方面有所不同，并在从抗体载体上裂解后释放出SN-38或水解的开放内酯形式。α-羟基内酯连接的SN-38药物连接基保留了封闭的内酯环结构，而酚连接的版本则允许封闭的内酯和开放的羧酸酯结构之间进行转化。发现在相应ADC的L540cy霍奇金淋巴瘤模型中的体外细胞毒性，药代动力学特性和体内功效难以区分，这使我们得出结论，基于喜树碱的抗体-药物偶联物具有明显的活性，而与内酯状态无关。结合药物。这很可能是酸性细胞内囊泡中ADC处理的结果，以其活性封闭内酯形式递送喜树碱。
更新日期：2018-08-01
中文翻译：
内酯稳定不是喜树碱抗体缀合物的必要功能。
喜树碱在活性，封闭的内酯和非活性的开放羧酸盐形式之间以pH依赖的平衡存在。先前的几份报告强调了在生成喜树碱方面需要稳定内酯，实际上，这种设计已被纳入含有这种药物的抗体-药物结合物中。在这里，我们证明内酯稳定对于基于喜树碱的ADC功效不是必需的。我们合成并评估了喜树碱SN-38药物连接子，它们在内酯稳定性方面有所不同，并在从抗体载体上裂解后释放出SN-38或水解的开放内酯形式。α-羟基内酯连接的SN-38药物连接基保留了封闭的内酯环结构，而酚连接的版本则允许封闭的内酯和开放的羧酸酯结构之间进行转化。发现在相应ADC的L540cy霍奇金淋巴瘤模型中的体外细胞毒性，药代动力学特性和体内功效难以区分，这使我们得出结论，基于喜树碱的抗体-药物偶联物具有明显的活性，而与内酯状态无关。结合药物。这很可能是酸性细胞内囊泡中ADC处理的结果，以其活性封闭内酯形式递送喜树碱。
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