mAbs自身免疫性疾病的潜在治疗抗体.doc

mAbs：自身免疫性疾病的潜在治疗抗体 2014年10月28日讯 /生物谷BIOON/ --通过天然免疫选择和靶向蛋白技术的组合，A * STAR研究者已经制造出一种抗体，能够在人类细胞和小鼠实验模型中有效地阻断与疾病相关的炎症通路。 感染或受伤事件发生后，信号蛋白白细胞介素1β（IL-1β）帮助免疫系统进行快速免疫反击。然而，过量的IL-1β活性可导致有害的炎症，促进疾病状态如各种自身免疫性疾病。IL-1β抑制剂是药物研发的活跃区域??，Cheng-I Wang和同事最近生成IL-1β特异性抗体，这可能是解决炎症性疾病的关键。 哺乳动物免疫系统已经进化能产生抗体，能结合外来分子，并且具有显著的亲和性和特异性。Wang和同事们利用蛋白质工程，获得一个有前途的抗体，被证明能够结合并抑制人类和小鼠的IL-1β。 研究人员集中在抗体的一小部分氨基酸，即可能有助于抗体结合IL-1β的氨基酸，随机置换这些氨基酸位点并产生抗体变体的一个库。通过筛选该抗体变体库，Wang和同事获得性能显着提高的抗体，得到了20?50倍更好亲和力的抗体变体。 这些抗体的最好变体是P2D7，其在抑制IL-1β上比康纳单抗（市售消炎药）更有效。康纳单抗和P2D7绑定相同的蛋白质，但识别相同分子上不同位点。 此外，P2D7结合至小鼠和猴子版本的IL-1β蛋白，并具有高亲和力的，而康纳单抗却没有此功效。研究人员利用小鼠模型显示，P2D7能对抗关节炎和腹膜炎症状，甚至延长了已经注射了人骨髓瘤细胞动物的存活。（生物谷B） 本文系生物谷原创编译整理，欢迎转载！转载请注明来源并附原文链接。谢谢！ doi:10.4161/mabs.28614PMC:PMID: A novel human anti-interleukin-1β neutralizing monoclonal antibody showing in vivo efficacy Goh, A. X. H., Bertin-Maghit, S., Yeo, S. P., Ho, A., Derks, H. et al. The pro-inflammatory cytokine interleukin (IL)-1β is a clinical target in many conditions involving dysregulation of the immune system; therapeutics that block IL-1β have been approved to treat diseases such as rheumatoid arthritis (RA), neonatal onset multisystem inflammatory diseases, cryopyrin-associated periodic syndromes, active systemic juvenile idiopathic arthritis. Here, we report the generation and engineering of a new fully human antibody that binds tightly to IL-1β with a neutralization potency more than 10 times higher than that of the marketed antibody canakinumab. After affinity maturation, the derived antibody shows a 30-fold increased affinity to human IL-1β compared with its parent antibody. This anti-human IL-1β IgG also cross-reacts with mouse and monkey IL-1β, hence facilitating preclinical development. In a number of mouse models, this antibody efficiently reduced or abolished signs of disease associated with IL-1β pathology. Due to its high affinity for the cytokine and its potency both in vitro and in vivo, we propose that this novel fully human anti-IL-1β monoclonal antib