a Antibody Discovery and Protein Engineering, MedImmune Ltd , Cambridge , UK.
b Discovery Sciences, AstraZeneca R&D , Cambridge , UK.
MAbs. 2018 Jan;10(1):104-117. doi: 10.1080/19420862.2017.1384892. Epub 2017 Oct 24.
C5a is a potent anaphylatoxin that modulates inflammation through the C5aR1 and C5aR2 receptors. The molecular interactions between C5a-C5aR1 receptor are well defined, whereas C5a-C5aR2 receptor interactions are poorly understood. Here, we describe the generation of a human antibody, MEDI7814, that neutralizes C5a and C5adesArg binding to the C5aR1 and C5aR2 receptors, without affecting complement-mediated bacterial cell killing. Unlike other anti-C5a mAbs described, this antibody has been shown to inhibit the effects of C5a by blocking C5a binding to both C5aR1 and C5aR2 receptors. The crystal structure of the antibody in complex with human C5a reveals a discontinuous epitope of 22 amino acids. This is the first time the epitope for an antibody that blocks C5aR1 and C5aR2 receptors has been described, and this work provides a basis for molecular studies aimed at further understanding the C5a-C5aR2 receptor interaction. MEDI7814 has therapeutic potential for the treatment of acute inflammatory conditions in which both C5a receptors may mediate inflammation, such as sepsis or renal ischemia-reperfusion injury.
C5a 是一种有效的过敏毒素，通过 C5aR1 和 C5aR2 受体调节炎症。C5a-C5aR1 受体之间的分子相互作用已经得到很好的定义，而 C5a-C5aR2 受体相互作用则知之甚少。在这里，我们描述了一种人源抗体 MEDI7814 的产生，该抗体可以中和 C5a 和 C5adesArg 与 C5aR1 和 C5aR2 受体的结合，而不影响补体介导的细菌细胞杀伤。与其他描述的抗 C5a mAb 不同，该抗体通过阻断 C5a 与 C5aR1 和 C5aR2 受体的结合来抑制 C5a 的作用。该抗体与人类 C5a 复合物的晶体结构揭示了一个 22 个氨基酸的不连续表位。这是首次描述了一种阻断 C5aR1 和 C5aR2 受体的抗体的表位，这项工作为旨在进一步了解 C5a-C5aR2 受体相互作用的分子研究提供了基础。MEDI7814 具有治疗急性炎症性疾病的潜力，在这些疾病中，两种 C5a 受体都可能介导炎症，如败血症或肾缺血再灌注损伤。
