Characterizing the original anti-C5 function-blocking antibody, BB5.1, for species specificity, mode of action and interactions with C5.,Immunology

当前位置： X-MOL 学术 › Immunology › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Characterizing the original anti-C5 function-blocking antibody, BB5.1, for species specificity, mode of action and interactions with C5.
Immunology ( IF 4.9 ) Pub Date : 2020-06-17 , DOI: 10.1111/imm.13228
Wioleta M Zelek ₁ , Georgina E Menzies ₂ , Andrea Brancale ₃ , Brigitta Stockinger ₄ , Bryan Paul Morgan _{1,

2}

Affiliation

The implication of complement in multiple diseases over the last 20 years has fuelled interest in developing anti‐complement drugs. To date, the focus has been on C5; blocking cleavage of C5 prevents formation of two pro‐inflammatory activities, C5a anaphylatoxin and membrane attack complex. The concept of C5 blockade to inhibit inflammation dates back 30 years to the description of BB5.1, an anti‐C5 blocking monoclonal antibody raised in C5‐deficient mice. This antibody proved an invaluable tool to demonstrate complement involvement in mouse disease models and catalysed enthusiasm for anti‐complement drug development, culminating in the anti‐human C5 monoclonal antibody eculizumab, the most successful anti‐complement drug to date, already in clinical use for several rare diseases. Despite its key role in providing proof‐of‐concept for C5 blockade, the mechanism of BB5.1 inhibition remains poorly understood. Here, we characterized BB5.1 cross‐species inhibition, C5 binding affinity and chain specificity. BB5.1 efficiently inhibited C5 in mouse serum but not in human or other rodent sera; it prevented C5 cleavage and C5a generation. BB5.1 bound the C5 α‐chain with high affinity and slow off‐rate. BB5.1 complementarity‐determining regions were obtained and docking algorithms were used to predict the likely binding interface on mouse C5.

中文翻译：

表征原始抗 C5 功能阻断抗体 BB5.1 的物种特异性、作用模式以及与 C5 的相互作用。

过去 20 年来，补体在多种疾病中的作用激发了人们对开发抗补体药物的兴趣。迄今为止，焦点一直集中在 C5；阻断 C5 的裂解可防止两种促炎活性的形成：C5a 过敏毒素和膜攻击复合物。通过阻断 C5 来抑制炎症的概念可以追溯到 30 年前 BB5.1 的描述，BB5.1 是一种在 C5 缺陷小鼠中产生的抗 C5 阻断单克隆抗体。该抗体被证明是证明补体参与小鼠疾病模型的宝贵工具，并激发了抗补体药物开发的热情，最终产生了抗人 C5 单克隆抗体依库丽单抗，这是迄今为止最成功的抗补体药物，已在临床使用几种罕见疾病。尽管它在为 C5 阻断提供概念验证方面发挥着关键作用，但 BB5.1 抑制的机制仍然知之甚少。在这里，我们表征了 BB5.1 跨物种抑制、C5 结合亲和力和链特异性。 BB5.1 可有效抑制小鼠血清中的 C5，但不能抑制人类或其他啮齿动物血清中的 C5；它阻止了 C5 裂解和 C5a 生成。 BB5.1 以高亲和力和慢解离速率结合 C5 α链。获得了 BB5.1 互补决定区，并使用对接算法来预测小鼠 C5 上可能的结合界面。

更新日期：2020-06-17

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文本刊介绍/投稿指南11