Background extracellular Nicotinamide phosphoribosyltrasferase (eNAMPT) is a cytokine with paracrine and autocrine effects on different cell types. Importantly, eNAMPT levels are increased in patients suffering of Inflammatory Bowel Diseases (IBD). Biologic drugs have been found effective in many IBD patients; however, a large proportion of patients with severe disease fail to achieve remission due to lack of drug response, loss of response, drug intolerance, or severe side effects that require cessation of therapy. Therefore, there is a clinical need for predictive response biomarkers as well as for new therapeutic strategies. Methods First, we investigated the expression of NAMPT in biopsies, in stools and the secretion of eNAMPT in serum in four cohorts of IBD patients. Second, we investigated if circulating eNAMPT levels correlate with the clinical response to biologics (infliximab, adalimumab, ustekinumab, vedolizumab). Clinical response is defined as a reduction of >2 points in HBI (for CD) and in pMAYO (for UC) from baseline. Third, we have developed a monoclonal anti-eNAMPT antibody and we have evaluated its preclinical efficacy in acute and chronic preclinical models of IBD. Results We have determined the levels of circulating eNAMPT in three cohorts of patients that were not controlled by DMARDs and were treated with infliximab (IFX, cohort 1 and 3) or adalimumab (ADA, cohort 2). Notably, we confirmed a pronounced variability through the cohorts, identifying a group of patients with eNAMPT serum levels comparable with healthy adult populations and a group that showed elevated levels of eNAMPT. Performing a ROC curve analysis, a cutoff of 4.5 ng/ml can be extrapolated to discriminate these two populations. Noteworthy, 100% patients with levels of eNAMPT below 4.5 ng/ml were responsive to infliximab/adalimumab. In contrast, anti-TNF therapy failed either at 14 or 22 weeks in some patients with high circulating levels of eNAMPT, indicating that high systemic eNAMPT might be associated with an increased risk of resistance to anti-TNF therapy. Notably, we found also that eNAMPT levels in stools of IBD patients are elevated compared to healthy subjects. Then, we have developed and validated a candidate monoclonal antibody (called C269) which bind to eNAMPT, block is cytokine activity and reduces IBD symptoms, immune infiltrate and fibrosis in DSS and DNBS models. Conclusion Our data demonstrate that eNAMPT serum levels correlate with the clinical response to anti-TNF therapies suggesting that eNAMPT is not a simple by- stander of IBD, and that local and serum eNAMPT could be define as a biomarker to define the responsiveness to biologics. Notably, its neutralization might be a pharmacological strategy worth investigating.

中文翻译：

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P169 循环 eNAMPT 预测 IBD 患者的抗 TNF 反应：抗 eNAMPT 抗体治疗中的可能地位

背景细胞外烟酰胺磷酸核糖基转移酶（eNAMPT）是一种对不同细胞类型具有旁分泌和自分泌作用的细胞因子。重要的是，患有炎症性肠病 (IBD) 的患者的 eNAMPT 水平会升高。生物药物已被发现对许多 IBD 患者有效；然而，很大一部分重症患者由于缺乏药物反应、失去反应、药物不耐受或需要停止治疗的严重副作用而未能获得缓解。因此，临床需要预测反应生物标志物以及新的治疗策略。方法 首先，我们研究了四组 IBD 患者的活检组织、粪便中 NAMPT 的表达以及血清中 eNAMPT 的分泌。其次，我们研究了循环 eNAMPT 水平是否与生物制剂（英夫利昔单抗、阿达木单抗、乌特克单抗、维多珠单抗）的临床反应相关。临床反应定义为HBI(对于CD)和pMAYO(对于UC)相对于基线降低≥2个点。第三，我们开发了一种单克隆抗eNAMPT抗体，并评估了其在IBD急性和慢性临床前模型中的临床前疗效。结果 我们确定了三组未接受 DMARD 控制且接受英夫利昔单抗（IFX，队列 1 和 3）或阿达木单抗（ADA，队列 2）治疗的患者的循环 eNAMPT 水平。值得注意的是，我们通过队列确认了显着的变异性，确定了一组 eNAMPT 血清水平与健康成年人群相当的患者和一组 eNAMPT 水平升高的患者。执行 ROC 曲线分析，可以推断出 4.5 ng/ml 的截止值来区分这两个群体。值得注意的是，100% eNAMPT 水平低于 4.5 ng/ml 的患者对英夫利昔单抗/阿达木单抗有反应。相比之下，在一些 eNAMPT 循环水平较高的患者中，抗 TNF 治疗在 14 周或 22 周时失败，这表明高全身性 eNAMPT 可能与抗 TNF 治疗耐药风险增加相关。值得注意的是，我们还发现 IBD 患者粪便中的 eNAMPT 水平高于健康受试者。然后，我们开发并验证了一种候选单克隆抗体（称为 C269），它与 eNAMPT 结合，阻断细胞因子活性，并在 DSS 和 DNBS 模型中减少 IBD 症状、免疫浸润和纤维化。结论 我们的数据表明，eNAMPT 血清水平与抗 TNF 治疗的临床反应相关，表明 eNAMPT 不是 IBD 的简单旁观者，并且局部和血清 eNAMPT 可以定义为定义对生物制剂反应性的生物标志物。值得注意的是，它的中和可能是一种值得研究的药理学策略。