Antibody Format and Drug Release Rate Determine the Therapeutic Activity of Noninternalizing Antibody-Drug Conjugates.
Antibody Format and Drug Release Rate Determine the Therapeutic Activity of Noninternalizing Antibody-Drug Conjugates.
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DOI：
10.1158/1535-7163.mct-15-0480
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发表时间：
2015-11
影响因子：
5.7
通讯作者：
Neri D
中科院分区：
文献类型：
--
作者：
Gébleux R;Wulhfard S;Casi G;Neri D
抗体-药物结合物(ADC)是一类很有前途的抗癌药物，传统上依赖于使用能够在肿瘤细胞中选择性内化的抗体。我们最近已经证明，非内在化抗体通过二硫键连接物与细胞毒药物偶联，可以在肿瘤细胞外环境中切割，也可以显示出强大的治疗活性。在这里，我们比较了两种抗体-药物结合物的肿瘤靶向性，药物释放速率和治疗性能，基于美坦辛DM1硫醇药物和F8抗体，针对纤维连接蛋白的选择性剪接的EDA结构域。抗体以免疫球蛋白形式或小免疫蛋白形式使用。在这两种情况下，DM1与未配对的半胱氨酸残基偶联，药物抗体比为2。在生物分布研究中，SIP(F8)-SS-DM1在肿瘤中蓄积，并比IgG(F8)-SS-DM1更快地从循环中清除。然而，基于免疫球蛋白形式的ADC在以后的时间点表现出更高的肿瘤摄取率(例如，静脉注射后24小时，33%IA/g对8%IA/g)。在小鼠血浆中，令人惊讶的是，与SIP形式相比，Ig形式的ADC产物更稳定(在37°C时，半衰期分别为48h和3h)，揭示了一种控制基于二硫化物的药物释放速率的新机制。对免疫活性小鼠F9肿瘤的治疗实验表明，无论是在等摩尔基础上还是在相同毫克剂量下，SIP(F8)-SS-DM1比免疫球蛋白(F8)-SS-DM1更有效。
The development of antibody-drug conjugates (ADCs), a promising class of anti-cancer agents, has traditionally relied on the use of antibodies capable of selective internalization in tumor cells. We have recently shown that also non-internalizing 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 antibody-drug conjugates, based on the maytansinoid DM1 thiol drug and on the F8 antibody, directed against the alternatively-spliced 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 h after intravenous administration). In mouse plasma, surprisingly, the ADC products in IgG format were substantially more stable compared to the SIP format (half-lives > 48 h and < 3 h at 37 °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.