The goal of this study was to demonstrate that the combination of patient immune profiling and testing in a humanized mouse model of ulcerative colitis (UC) may lead to patient stratification for treatment with oxelumab. First, immunological profiles of UC patients and non-UC donors were analyzed for CD4+ T cells expressing OX40 (CD134) and CD14+ monocytes expressing OX40L (CD252) by flow cytometric analysis. A significant difference was observed between both groups for CD14+ OX40L+ (UC: n=11, 85.44±21.17; mean±sd, non-UC: n=5, 30.7±34.92; p=0.02), no significant difference was detected for CD4+ OX40+. CD14+ OX40L+ monocytes correlated significantly with TH1 and TH2 cells. Secondly, NOD/Scid IL2-Rgamma null mice were reconstituted with peripheral blood mononuclear cells from UC donors exhibiting elevated levels of OX40L, and the efficacy of oxelumab was compared to that of adalimumab. Read out were the clinical, colon, andhistological scores, and serum levels of IL-6, IL-1ß and glutamic acid. Treatment with oxelumab or adalimumab resulted in significantly reduced clinical, colon, and histological scores, reduced serum levels of IL-6 and reduced frequencies of splenic human effector memory T cells and switched B cells. Comparison of efficacy of adalimumab and oxelumab by orthogonal partial least square discrimination analysis revealed that oxelumab was slightly superior to adalimumab, however, elevated serum levels of glutamic acid suggested ongoing inflammation. These results suggest that oxelumab addresses the pro-inflammatory arm of inflammation while promoting the remodeling arm and that patients exhibiting elevated levels of OX40L may benefit from treatment with oxelumab. Keywords: Ulcerative colitis, NOD/Scid IL2-Rγ^null, NSG, anti-CD252 antibodies, oxelumab, inflammatory bowel disease.

中文翻译：

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基于用外周血单核细胞重组的 NOD/Scid IL-2Rγnull 小鼠，在溃疡性结肠炎小鼠模型中对 oxelumab 和 adalimumab 进行头对头研究。

本研究的目的是证明在溃疡性结肠炎 (UC) 的人源化小鼠模型中结合患者免疫分析和测试可能会导致患者分层以接受奥塞鲁单抗治疗。首先，通过流式细胞术分析 UC 患者和非 UC 供体的免疫学特征，分析表达 OX40 (CD134) 的 CD4+ T 细胞和表达 OX40L (CD252) 的 CD14+ 单核细胞。CD14+ OX40L+ 两组间存在显着差异（UC：n=11, 85.44±21.17；平均值±sd，非 UC：n=5, 30.7±34.92；p=0.02），CD4+ 未检测到显着差异OX40+。CD14+ OX40L+ 单核细胞与 TH1 和 TH2 细胞显着相关。其次，用来自 UC 供体的外周血单核细胞重建 NOD/Scid IL2-Rgamma 缺失小鼠，显示 OX40L 水平升高，并且将奥塞鲁单抗的疗效与阿达木单抗的疗效进行了比较。读出的是临床、结肠和组织学评分，以及 IL-6、IL-1β 和谷氨酸的血清水平。奥塞鲁单抗或阿达木单抗治疗可显着降低临床、结肠和组织学评分，降低血清 IL-6 水平，并降低脾脏人类效应记忆 T 细胞和转换 B 细胞的频率。通过正交偏最小二乘判别分析比较阿达木单抗和奥克塞尔单抗的疗效显示奥克单抗略优于阿达木单抗，但血清谷氨酸水平升高表明炎症持续存在。这些结果表明，oxelumab 在促进重塑臂的同时解决了炎症的促炎臂，并且 OX40L 水平升高的患者可能会从 oxelumab 治疗中受益。关键词：溃疡性结肠炎，NOD/Scid IL2-Rγ^null , NSG, 抗 CD252 抗体, oxelumab, 炎症性肠病。