Biotherapeutic drugs against tumor necrosis factor (TNF) are effective treatments for moderate to severe inflammatory bowel disease (IBD). Here, we evaluated CNTO 5048, an antimurine TNF surrogate monoclonal antibody (mAb), in a CD45RB^high adoptive T cell transfer mouse colitis model, which allows examination of the early immunological events associated with gut inflammation and the therapeutic effects. The study was designed to quantitatively understand the effects of IBD on CNTO 5048 disposition, the ability of CNTO 5048 to neutralize pathogenic TNF at the colon under disease conditions, and the impact of dosing regimen on CNTO 5048 treatment effect. CNTO 5048 and TNF concentrations in both mice serum and colon homogenate were also measured. Free TNF concentrations in colon, but not in serum, were shown to correlate well with the colon pharmacodynamic readout, such as the summed histopathology score and neutrophil score. A minimal physiologically based pharmacokinetic (mPBPK) model was developed to characterize CNTO 5048 PK and disposition, as well as colon soluble TNF target engagement (TE). The mPBPK/TE model reasonably captured the observed data and provided a quantitative understanding of an anti-TNF mAb on its colon TNF suppression and therapeutic effect in a physiologically relevant IBD animal model. These results also provided insights into the potential benefits of using induction doses for the treatment of IBD patients.

针对肿瘤坏死因子 (TNF) 的生物治疗药物是治疗中度至重度炎症性肠病 (IBD) 的有效方法。在这里，我们评估了 CNTO 5048，一种抗鼠 TNF 替代单克隆抗体 (mAb)，在 CD45RB^高过继性 T 细胞转移小鼠结肠炎模型，可以检查与肠道炎症相关的早期免疫事件和治疗效果。该研究旨在定量了解 IBD 对 CNTO 5048 处置的影响、CNTO 5048 在疾病条件下中和结肠致病性 TNF 的能力，以及给药方案对 CNTO 5048 治疗效果的影响。还测量了小鼠血清和结肠匀浆中的 CNTO 5048 和 TNF 浓度。结肠中的游离 TNF 浓度，而不是血清中的游离 TNF 浓度显示与结肠药效学读数密切相关，例如总的组织病理学评分和中性粒细胞评分。开发了一种基于生理学的最小药代动力学 (mPBPK) 模型来表征 CNTO 5048 PK 和处置，以及结肠可溶性 TNF 靶标参与 (TE)。mPBPK/TE 模型合理地捕获了观察到的数据，并提供了对抗 TNF mAb 在生理相关 IBD 动物模型中对其结肠 TNF 抑制和治疗效果的定量理解。这些结果还提供了对使用诱导剂量治疗 IBD 患者的潜在益处的见解。