抗体
药代动力学
单克隆抗体
脾脏
药效学
药理学
药品
结合
骨髓
分布(数学)
抗体-药物偶联物
化学
分子生物学
免疫学
医学
生物
数学分析
数学
作者
Fu Li,Michelle Ulrich,Vincent Feng-Sheng Shih,Julia H. Cochran,Joshua H. Hunter,Lori Westendorf,Jason Neale,Dennis R. Benjamin
出处
期刊:Molecular Cancer Therapeutics
[American Association for Cancer Research]
日期:2019-03-01
卷期号:18 (4): 780-787
被引量:39
标识
DOI:10.1158/1535-7163.mct-18-0977
摘要
Abstract To provide a better understanding of the pharmacokinetics–pharmacodynamics relationships of antibody-based drugs, we analyzed several chimeric and humanized monoclonal antibodies or antibody–drug conjugates (ADC) for PK and efficacy among four strains of mice. Notably, antibodies and ADCs displayed a dose-dependent drug disposition profile in the plasma of NSG mice. The increased clearance rate in NSG mice resulted in the reduction of antitumor activity of ADCs. Furthermore, we identified that the abnormal clearance was mediated by Fc–FcγR interaction by comparing antibodies that lack FcγR binding capacity. We also found a high percentage of FcγR-expressing macrophages in the bone marrow, spleen, and liver of NSG mice, which may be responsible for the abnormal distribution of antibodies. Overall, these findings suggest that preclinical evaluation of efficacy and pharmacokinetics of antibodies and ADCs need to consider mouse strain-induced variations.
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