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首页> 外文期刊>Clinical and Experimental Immunology: An Official Journal of the British Society for Immunology >Rapid-onset clinical and mechanistic effects of anti-C5aR treatment in the mouse collagen-induced arthritis model
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Rapid-onset clinical and mechanistic effects of anti-C5aR treatment in the mouse collagen-induced arthritis model

机译：抗C5aR治疗在小鼠胶原诱导的关节炎模型中的快速起效的临床和机制作用

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Preclinical evidence supports targeting the C5a receptor (C5aR) in rheumatoid arthritis (RA). To support ongoing clinical development of an anti-C5aR monoclonal antibody, we have investigated for the first time the mechanism of action and the pharmacodynamics of a blocking anti-murine C5aR (anti-mC5aR) surrogate antibody in mouse collagen-induced arthritis (CIA). First, efficacy was demonstrated in a multiple-dose treatment study. Almost complete inhibition of clinical disease progression was obtained, including reduced bone and cartilage destruction in anti-mC5aR-treated mice. Then, the mechanism of action was examined by looking for early effects of anti-mC5aR treatment in single-dose treatment studies. We found that 48h after single-dose treatment with anti-mC5aR, the neutrophil and macrophage infiltration into the paws was already reduced. In addition, several inflammatory markers, including tumour necrosis factor (TNF)-α, interleukin (IL)-6 and IL-17A were reduced locally in the paws, indicating reduction of local inflammation. Furthermore, dose-setting experiments supported a beneficial clinical effect of dosing above the C5aR saturation level. In conclusion, these preclinical data demonstrated rapid onset effects of antibody blockade of C5aR. The data have translational value in supporting the Novo Nordisk clinical trials of an anti-C5aR antibody in rheumatoid arthritis patients, by identifying potential biomarkers of treatment effects as well as by providing information on pharmacodynamics and novel insights into the mechanism of action of monoclonal antibody blockade of C5aR.
机译：临床前证据支持靶向类风湿关节炎（RA）中的C5a受体（C5aR）。为支持抗C5aR单克隆抗体的正在进行的临床开发，我们首次研究了在小鼠胶原蛋白诱发的关节炎（CIA）中阻断性抗鼠C5aR（anti-mC5aR）替代抗体的作用机理和药效学。首先，在多剂量治疗研究中证明了疗效。获得了对临床疾病进展的几乎完全抑制，包括在抗mC5aR治疗的小鼠中减少的骨和软骨破坏。然后，通过在单剂量治疗研究中寻找抗mC5aR治疗的早期作用来检查其作用机理。我们发现，单剂抗mC5aR处理48小时后，中性粒细胞和巨噬细胞向爪中的浸润已经减少。此外，一些炎症标记物，包括肿瘤坏死因子（TNF）-α，白介素（IL）-6和IL-17A，在爪中局部减少，表明局部炎症减少。此外，剂量设定实验支持剂量高于C5aR饱和水平的有益临床效果。总之，这些临床前数据证明了抗体对C5aR的阻断作用起效迅速。数据通过鉴定潜在的治疗作用生物标志物以及提供药效学信息和对单克隆抗体阻断作用机制的新见解，对支持类风湿性关节炎患者抗C5aR抗体的Novo Nordisk临床试验具有翻译价值。 C5aR。

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