Fc-Mediated Anomalous Biodistribution of Therapeutic Antibodies in Immunodeficient Mouse Models.
Fc-Mediated Anomalous Biodistribution of Therapeutic Antibodies in Immunodeficient Mouse Models.
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DOI：
10.1158/0008-5472.can-17-1958
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发表时间：
2018-04-01
期刊：
影响因子：
11.2
通讯作者：
Lewis JS
中科院分区：
文献类型：
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作者：
Sharma SK;Chow A;Monette S;Vivier D;Pourat J;Edwards KJ;Dilling TR;Abdel-Atti D;Zeglis BM;Poirier JT;Lewis JS
开发基于抗体的疗法的关键基准是在人类疾病的临床前小鼠模型中证明功效，其中许多依赖于免疫缺陷小鼠。然而，关于各种免疫缺陷菌株的生物学如何影响这些药物的体内命运，人们知之甚少。在这里，我们使用免疫PET放射性示踪剂制备的人源化，嵌合和鼠单克隆抗体对四个治疗肿瘤学目标，以询问他们的生物分布在四个不同的免疫缺陷小鼠品系的肺，前列腺和卵巢癌异种移植。小鼠宿主的免疫缺陷状态以及抗体的生物来源和糖基化均显著导致治疗性单克隆抗体以Fc受体依赖性方式的异常生物分布。这些发现可能对含Fc的治疗药物的临床前评价具有重要意义，并强调了在抗体药物开发的早期阶段进行生物分布研究的明确需求。
A critical benchmark in the development of antibody-based therapeutics is demonstration of efficacy in preclinical mouse models of human disease, many of which rely on immunodeficient mice. However, relatively little is known about how the biology of various immunodeficient strains impacts the in vivo fate of these drugs. Here we used immunoPET radiotracers prepared from humanized, chimeric and murine monoclonal antibodies against four therapeutic oncologic targets to interrogate their biodistribution in four different strains of immunodeficient mice bearing lung, prostate, and ovarian cancer xenografts. The immunodeficiency status of the mouse host as well as both the biological origin and glycosylation of the antibody contributed significantly to the anomalous biodistribution of therapeutic monoclonal antibodies in an Fc receptor-dependent manner. These findings may have important implications for the preclinical evaluation of Fc-containing therapeutics and highlight a clear need for biodistribution studies in the early stages of antibody drug development.