Biodistribution of a Radiolabeled Antibody in Mice as an Approach to Evaluating Antibody Pharmacokinetics
Biodistribution of a Radiolabeled Antibody in Mice as an Approach to Evaluating Antibody Pharmacokinetics
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DOI：
10.3390/pharmaceutics10040262
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发表时间：
2018-12-01
期刊：
影响因子：
5.4
通讯作者：
Dadachova, Ekaterina
中科院分区：
文献类型：
--
作者：
Allen, Kevin J. H.;Jiao, Rubin;Dadachova, Ekaterina
(1)背景：单克隆抗体用于治疗多种疾病，包括癌症、自身免疫性疾病和感染性疾病。选择用于进一步临床前开发的抗体候选物的初始步骤之一是确定其在小动物模型中的药代动力学。使用质谱和其他技术来确定这些抗体的命运是费力和昂贵的。在这里，我们描述了一个简单的和高度可重复的方法，利用放射性标记的抗体的药代动力学研究。(2)方法：使用市售的双功能连接剂CHXA "和III-铟放射性核素。将黑色素特异性嵌合抗体A1和同种型匹配的无关对照A2与CHXA“”缀合，然后用In-111放射性标记。在4和24 h时间点在荷黑色素瘤和健康C57 BL/6雌性小鼠中进行生物分布。(3)黑色素结合抗体的生物分布显示在肿瘤中的显著摄取，其随时间增加，并且在健康的含黑色素组织如眼睛的视网膜和黑化皮肤中的摄取非常低。健康组织中的这种生物分布模式与同种型匹配对照抗体的生物分布模式非常接近。(4)结论：生物分布实验使我们能够同时评估两种抗体的药代动力学，并得出关于特异性抗体是否适合进一步开发的结论。
(1) Background: Monoclonal antibodies are used in the treatment of multiple conditions including cancer, autoimmune disorders, and infectious diseases. One of the initial steps in the selection of an antibody candidate for further pre-clinical development is determining its pharmacokinetics in small animal models. The use of mass spectrometry and other techniques to determine the fate of these antibodies is laborious and expensive. Here we describe a straightforward and highly reproducible methodology for utilizing radiolabeled antibodies for pharmacokinetics studies. (2) Methods: Commercially available bifunctional linker CHXA '' and ill-Indium radionuclide were used. A melanin-specific chimeric antibody A1 and an isotype matching irrelevant control A2 were conjugated with the CHXA '', and then radiolabeled with In-111. The biodistribution was performed at 4 and 24 h time points in melanoma tumor-bearing and healthy C57BL/6 female mice. (3) The biodistribution of the melanin-binding antibody showed the significant uptake in the tumor, which increased with time, and very low uptake in healthy melanin-containing tissues such as the retina of the eye and melanized skin. This biodistribution pattern in healthy tissues was very close to that of the isotype matching control antibody. (4) Conclusions: The biodistribution experiment allows us to assess the pharmacokinetics of both antibodies side by side and to make a conclusion regarding the suitability of specific antibodies for further development.