Research, Seattle Genetics, Inc., Bothell, Washington.
Translational Science, Seattle Genetics, Inc., Bothell, Washington.
Mol Cancer Ther. 2019 Apr;18(4):780-787. doi: 10.1158/1535-7163.MCT-18-0977. Epub 2019 Mar 1.
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.
为了更好地理解基于抗体的药物的药代动力学-药效学关系，我们在四种小鼠品系中分析了几种嵌合和人源化单克隆抗体或抗体药物偶联物（ADC）的 PK 和疗效。值得注意的是，抗体和 ADC 在 NSG 小鼠的血浆中表现出剂量依赖性的药物处置特征。NSG 小鼠中清除率的增加导致 ADC 的抗肿瘤活性降低。此外，通过比较缺乏 FcγR 结合能力的抗体，我们发现异常清除是由 Fc-FcγR 相互作用介导的。我们还发现 NSG 小鼠的骨髓、脾脏和肝脏中有高比例表达 FcγR 的巨噬细胞，这可能是导致抗体异常分布的原因。总的来说，这些发现表明，抗体和 ADC 的疗效和药代动力学的临床前评估需要考虑小鼠品系诱导的变异。
