A humanized anti-osteopontin antibody protects from Concanavalin A induced-liver injury in mice
A humanized anti-osteopontin antibody protects from Concanavalin A induced-liver injury in mice
复制标题
人源化抗骨桥蛋白抗体可保护小鼠免受伴刀豆球蛋白 A 诱导的肝损伤
DOI：
10.1016/j.ejphar.2011.01.041
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发表时间：
2011-04-25
影响因子：
5
通讯作者：
Guo, Yajun
中科院分区：
文献类型：
--
作者：
Fan, Kexing;Zhang, Bo;Guo, Yajun
骨桥蛋白与各种炎症性疾病有关，包括类风湿性关节炎、多发性硬化症、克罗恩病和暴发性肝炎。骨桥蛋白在这些疾病的病理灶中表达增加。在小鼠体内注射中和抗骨桥蛋白抗体，成功地治疗了RA和重型肝炎。然而，啮齿动物抗体在人类中具有高度的免疫原性，因此限制了其临床应用。本文采用基于计算机辅助分子模拟的互补决定区嫁接方法，人源化了鼠抗人骨桥蛋白的单抗23C3。23C3的人源化版本，记为Hu23C3，具有与其亲本抗体相当的亲和力。Hu23C3在体外也能抑制骨桥蛋白诱导的单核细胞迁移。体内实验结果表明，Hu23C3对刀豆蛋白A(ConA)诱导的小鼠肝损伤有明显的保护作用，其机制可能与降低转氨酶活性和改善肝损伤有关。机制研究表明，Hu23C3可抑制T细胞和NKT细胞的浸润，抑制肝脏核因子-kappaB的活化，从而减少肿瘤坏死因子-α和干扰素-γ的产生。因此，我们的数据有力地支持了人源化抗骨桥蛋白抗体Hu23C3可能具有治疗T细胞介导的人类肝炎的潜力。(C)2011爱思唯尔B.V.保留所有权利。
Osteopontin has been implicated in various inflammatory diseases including rheumatoid arthritis, multiple sclerosis, Crohn's disease, and fulminant hepatitis. Increased expression of osteopontin has been detected in pathological foci of these diseases. RA and fulminant hepatitis have been successfully treated by administration of neutralizing anti-osteopontin antibody in mice. However, rodent antibodies are highly immunogenic in humans and therefore limited in their clinical application. Here, a murine monoclonal antibody 23C3 against human osteopontin, was humanized by complementarity-determining region grafting method based on computer-assisted molecular modeling. The humanized version of 23C3, denoted as Hu23C3, was shown to possess affinity comparable to that of its parental antibody. Hu23C3 could also inhibit monocyte migration in response to osteopontin in vitro. Furthermore, in vivo data showed that Hu23C3 significantly protects mice from Concanavalin A (Con A) induced-liver injury in association with the reduction of transaminase activities and improvement of liver injury. Mechanistic studies demonstrated that Hu23C3 inhibited T and NKT cell infiltration, and activation of nuclear factor kappa B (NF-kappa B) in the liver, resulting in reduction of TNF-alpha and IFN-gamma production. Thus, our data strongly support that the humanized anti-osteopontin antibody, Hu23C3, may have a potential for the treatment of T cell mediated-hepatitis in human. (C) 2011 Elsevier B.V. All rights reserved.