Department of Gastroenterology, APHP, Hôpital Saint Louis, INSERM UMRS 1160, Paris Diderot, Sorbonne Paris-Cité University, Paris, France.
Novo Nordisk, Inc., Princeton, New Jersey, USA.
Gut. 2017 Nov;66(11):1918-1925. doi: 10.1136/gutjnl-2016-311824. Epub 2016 Aug 3.
Anti-NKG2D (NNC0142-0002) is an antagonising human immunoglobulin G4 monoclonal antibody that binds to natural killer group 2 member D (NKG2D) receptors, which are expressed by T cells and innate lymphoid cells, and may be linked to mucosal damage in Crohn's disease (CD).
Seventy-eight patients (aged ≥18 and ≤75 years) with CD for ≥3 months, Crohn's Disease Activity Index (CDAI) ≥220 and ≤450 and either C-reactive protein ≥10 mg/L or endoscopic evidence of inflammation, were randomised 1:1 to a single subcutaneous (SC) dose of 2 mg/kg anti-NKG2D or placebo. Primary endpoint was change in CDAI (ΔCDAI) from baseline to week 4. Prespecified significance level was 10% for CDAI endpoints. A futility analysis was instituted due to slow recruitment.
Primary endpoint was not significantly different between anti-NKG2D and placebo (week 4 ΔCDAI=-16); however, there was a significant difference by week 12 (ΔCDAI=-55; p≤0.10). Significant improvements were noted in the non-failure to biologics subgroup (treated with anti-NKG2D (n=28)) from week 1 onward. Greater effects of anti-NKG2D were also observed in patients with baseline CDAI ≥330. Frequencies of adverse events (AEs) were comparable between anti-NKG2D and placebo. Most AEs were mild (49%) or moderate (43%). No antidrug antibodies were observed.
A single SC dose of 2 mg/kg anti-NKG2D did not reduce disease activity at week 4 versus placebo, but the difference was significant at week 12, and effects were evident in key subgroups. These data support further development of anti-NKG2D in IBD.
NCT01203631.
抗 NKG2D（NNC0142-0002）是一种拮抗人免疫球蛋白 G4 单克隆抗体，与 T 细胞和固有淋巴细胞表达的自然杀伤组 2 成员 D（NKG2D）受体结合，可能与克罗恩病（CD）的粘膜损伤有关。
78 例（年龄≥18 岁且≤75 岁）患有 CD 至少 3 个月、克罗恩病活动指数（CDAI）≥220 且≤450 且 C-反应蛋白≥10mg/L 或内镜有炎症证据的患者，按 1:1 随机分为单次皮下（SC）剂量 2mg/kg 抗 NKG2D 或安慰剂。主要终点是从基线到第 4 周时 CDAI 的变化（ΔCDAI）。CDAI 终点的预设显著性水平为 10%。由于招募缓慢，进行了无效性分析。
抗 NKG2D 与安慰剂之间的主要终点无显著差异（第 4 周 ΔCDAI=-16）；然而，第 12 周有显著差异（ΔCDAI=-55；p≤0.10）。在未接受生物制剂治疗的亚组（n=28）中，从第 1 周开始就观察到显著的改善。在基线 CDAI≥330 的患者中，抗 NKG2D 的效果更为明显。抗 NKG2D 和安慰剂的不良反应（AE）发生率相当。大多数 AE 为轻度（49%）或中度（43%）。未观察到抗药物抗体。
与安慰剂相比，单次 SC 剂量 2mg/kg 抗 NKG2D 不能在第 4 周降低疾病活动度，但在第 12 周时差异有统计学意义，且在关键亚组中有效。这些数据支持进一步开发抗 NKG2D 治疗 IBD。
NCT01203631。
