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是有效的过敏毒素，可通过C5aR1和C5aR2受体调节炎症。C5a–C5aR1受体之间的分子相互作用已得到很好的定义，而C5a–C5aR2受体之间的相互作用则知之甚少。在这里，我们描述了人类抗体MEDI7814的产生，该抗体中和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。与所述的其他抗C5a mAb不同，该抗体已显示出通过阻断C5a与C5aR1和C5aR2受体的结合而抑制C5a的作用。与人C5a结合的抗体的晶体结构揭示了22个氨基酸的不连续表位。这是首次描述阻断C5aR1和C5aR2受体的抗体的表位，这项工作为进一步研究C5a–C5aR2受体相互作用的分子研究提供了基础。MEDI7814具有治疗两种C5a受体均可介导炎症的急性炎症的潜能，例如败血症或肾脏缺血再灌注损伤。