Preclinical Development of a Novel, Orally-Administered Anti-Tumour Necrosis Factor Domain Antibody for the Treatment of Inflammatory Bowel Disease.
Preclinical Development of a Novel, Orally-Administered Anti-Tumour Necrosis Factor Domain Antibody for the Treatment of Inflammatory Bowel Disease.
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DOI：
10.1038/s41598-018-23277-7
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发表时间：
2018-03-21
影响因子：
4.6
通讯作者：
West MR
中科院分区：
文献类型：
--
作者：
Crowe JS;Roberts KJ;Carlton TM;Maggiore L;Cubitt MF;Clare S;Harcourt K;Reckless J;MacDonald TT;Ray KP;Vossenkämper A;West MR
肿瘤坏死因子α是炎症性肠病的重要细胞因子。V565是一种新型的抗肿瘤坏死因子α结构域抗体，用于IBD患者的口服治疗，源自骆驼结构域抗体，旨在增强肠道蛋白水解酶的抵抗力。V565的活性在肿瘤坏死因子α-肿瘤坏死因子α受体结合的ELISA以及肿瘤坏死因子α反应的细胞试验中进行了评估，显示了可溶性和膜型肿瘤坏死因子α的中和作用，其效力与阿达利单抗相似。虽然V565对胃酶敏感，但在与胰酶、胰凝乳酶、胰酶以及小鼠小肠、人回肠和粪便上清液长期孵育后，V565仍保持活性。在口服幼稚和DSS结肠炎小鼠中，观察到肠道内容物和粪便中V565浓度较高，免疫染色显示V565在小鼠结肠组织中定位。用酶联免疫吸附试验在结肠炎小鼠给药后的血清中检测到V565，而在幼稚小鼠的血清中没有检测到V565，表明V565穿透了破损的上皮。在体外人类IBD组织培养模型中，V565抑制组织磷蛋白水平和炎性细胞因子生物标记物的产生与英夫利昔单抗相似，当出现在疾病部位时显示出有效性。综上所述，这些研究的结果提供了信心，即口服V565剂量将对黏膜上皮屏障受损的IBD患者具有治疗作用。
TNFα is an important cytokine in inflammatory bowel disease. V565 is a novel anti-TNFα domain antibody developed for oral administration in IBD patients, derived from a llama domain antibody and engineered to enhance intestinal protease resistance. V565 activity was evaluated in TNFα-TNFα receptor-binding ELISAs as well as TNFα responsive cellular assays and demonstrated neutralisation of both soluble and membrane TNFα with potencies similar to those of adalimumab. Although sensitive to pepsin, V565 retained activity after lengthy incubations with trypsin, chymotrypsin, and pancreatin, as well as mouse small intestinal and human ileal and faecal supernatants. In orally dosed naïve and DSS colitis mice, high V565 concentrations were observed in intestinal contents and faeces and immunostaining revealed V565 localisation in mouse colon tissue. V565 was detected by ELISA in post-dose serum of colitis mice, but not naïve mice, demonstrating penetration of disrupted epithelium. In an ex vivo human IBD tissue culture model, V565 inhibition of tissue phosphoprotein levels and production of inflammatory cytokine biomarkers was similar to infliximab, demonstrating efficacy when present at the disease site. Taken together, results of these studies provide confidence that oral V565 dosing will be therapeutic in IBD patients where the mucosal epithelial barrier is compromised.
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影响因子：
15
作者：
Knezevic, Jelena;Langer, Andreas;Rant, Ulrich
通讯作者：
Rant, Ulrich
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
29.4
作者：
Atreya, Raja;Zimmer, Michael;Neurath, Markus F.
通讯作者：
Neurath, Markus F.
影响因子：
8
作者：
Hartman, Deborah S.;Tracey, Daniel E.;Fox, Barbara S.
通讯作者：
Fox, Barbara S.
抗肿瘤坏死因子抗体在炎症性肠病中的作用机理。
影响因子：
4.3
作者：
Billmeier U;Dieterich W;Neurath MF;Atreya R
通讯作者：
Atreya R