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首页> 外文期刊>Molecular cancer therapeutics >Antibody Format and Drug Release Rate Determine the Therapeutic Activity of Noninternalizing Antibody-Drug Conjugates
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Antibody Format and Drug Release Rate Determine the Therapeutic Activity of Noninternalizing Antibody-Drug Conjugates

机译：抗体形式和药物释放速率决定了非氮化抗体 - 药物缀合物的治疗活性

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摘要

The development of antibody-drug conjugates (ADC), a promising class of anticancer agents, has traditionally relied on the use of antibodies capable of selective internalization in tumor cells. We have recently shown that also noninternalizing antibodies, coupled to cytotoxic drugs by means of disulfide linkers that can be cleaved in the tumor extracellular environment, can display a potent therapeutic activity. Here, we have compared the tumor-targeting properties, drug release rates, and therapeutic performance of two ADCs, based on the maytansinoid DM1 thiol drug and on the F8 antibody, directed against the alternatively spliced Extra Domain A (EDA) domain of fibronectin. The antibody was used in IgG or in small immune protein (SIP) format. In both cases, DM1 was coupled to unpaired cysteine residues, resulting in a drug-antibody ratio of 2. In biodistribution studies, SIP(F8)-SS-DM1 accumulated in the tumor and cleared from circulation more rapidly than IgG(F8)-SS-DM1. However, the ADC based on the IgG format exhibited a higher tumor uptake at later time points (e.g., 33% IA/g against 8% IA/g at 24 hours after intravenous administration). In mouse plasma, surprisingly, the ADC products in IgG format were substantially more stable compared with the SIP format (half-lives >48 hours and <3 hours at 37 degrees C, respectively), revealing a novel mechanism for the control of disulfide-based drug release rates. Therapy experiments in immunocompetent mice bearing murine F9 tumors revealed that SIP(F8)-SS-DM1 was more efficacious than IgG(F8)-SS-DM1 when the two products were compared either in an equimolar basis or at equal milligram doses. (C) 2015 AACR.
机译：传统上依赖于使用能够在肿瘤细胞中选择性内化的抗体的抗体类抗癌剂的抗体 - 药物缀合物（ADC）的发展。我们最近表明，通过可以在肿瘤细胞外环境中裂解的二硫化物接头偶联到细胞毒性药物的非internalized抗体也可以显示有效的治疗活性。在这里，我们已经比较了基于Maytansinoid DM1硫醇药和F8抗体的两种ADC的肿瘤靶向性质，药物释放速率和治疗性能，以替代的纤维素的额外结构域A（EDA）结构域。抗体以IgG或小免疫蛋白（SIP）形式使用。在这两种情况下，DM1偶联到未配对的半胱氨酸残基，导致药物 - 抗体比为2.在生物分布研究中，SIP（F8）-S-DM1积聚在肿瘤中并从循环中清除比IgG（F8）快速地清除循环 - SS-DM1。然而，基于IgG格式的ADC在稍后的时间点（例如，在静脉内给药后24小时以8％IA / g，在稍后的时间点上表现出更高的肿瘤摄取）。在小鼠等离子体中，令人惊讶的是，与SIP格式相比，IgG格式的ADC产品与37摄氏度分别在37℃下的半衰期> 48小时和<3小时相比，揭示了用于控制二硫化的新机制 - 基于药物释放率。免疫活性小鼠轴承鼠F9肿瘤的治疗实验显示，当在等摩尔基础上或以等毫克剂量比较时，SIP（F8）-S-DM1比IgG（F8）-S-DM1更有效率。 （c）2015年AACR。

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  • 来源
    《Molecular cancer therapeutics》 |2015年第11期|共7页
  • 作者

    Gebleux Remy; Wulhfard Sarah; Casi Giulio; Neri Dario;

  • 作者单位

    Swiss Fed Inst Technol Dept Chem &

    Appl Biosci Inst Pharmaceut Sci Zurich Switzerland;

    Philochem AG Otelfingen Switzerland;

    Philochem AG Otelfingen Switzerland;

    Swiss Fed Inst Technol Dept Chem &

    Appl Biosci Inst Pharmaceut Sci Zurich Switzerland;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 肿瘤学;
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