Background

Activation of the classical and lectin pathway of complement may contribute to tissue damage and organ dysfunction of antibody-mediated diseases and ischemia-reperfusion conditions. Complement factors are being considered as targets for therapeutic intervention.

Objective

We sought to characterize ARGX-117, a humanized inhibitory monoclonal antibody against complement C2.

Methods

The mode-of-action and binding characteristics of ARGX-117 were investigated in detail. Furthermore, its efficacy was analyzed in in vitro complement cytotoxicity assays. Finally, a pharmacokinetic/pharmacodynamic study was conducted in cynomolgus monkeys.

Results

Through binding to the Sushi-2 domain of C2, ARGX-117 prevents the formation of the C3 proconvertase and inhibits classical and lectin pathway activation upstream of C3 activation. As ARGX-117 does not inhibit the alternative pathway, it is expected not to affect the antimicrobial activity of this complement pathway. ARGX-117 prevents complement-mediated cytotoxicity in in vitro models for autoimmune hemolytic anemia and antibody-mediated rejection of organ transplants. ARGX-117 exhibits pH- and calcium-dependent target binding and is Fc-engineered to increase affinity at acidic pH to the neonatal Fc receptor, and to reduce effector functions. In cynomolgus monkeys, ARGX-117 dose-dependently reduces free C2 levels and classical pathway activity. A 2-dose regimen of 80 and 20 mg/kg separated by a week, resulted in profound reduction of classical pathway activity lasting for at least 7 weeks.

Conclusions

ARGX-117 is a promising new complement inhibitor that is uniquely positioned to target both the classical and lectin pathways while leaving the alternative pathway intact.

中文翻译：

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ARGX-117，一种靶向 C2 的治疗性补体抑制抗体

背景

补体的经典和凝集素途径的激活可能导致抗体介导的疾病和缺血再灌注条件的组织损伤和器官功能障碍。补体因子被认为是治疗干预的目标。

客观的

我们试图表征 ARGX-117，一种针对补体 C2 的人源化抑制性单克隆抗体。

方法

详细研究了 ARGX-117 的作用模式和结合特性。此外，在体外补体细胞毒性试验中分析了其功效。最后，在食蟹猴中进行了药代动力学/药效学研究。

结果

通过与 C2 的 Sushi-2 结构域结合，ARGX-117 阻止 C3 转化酶原的形成并抑制 C3 激活上游的经典和凝集素途径激活。由于 ARGX-117 不抑制旁路途径，因此预计不会影响该补体途径的抗菌活性。ARGX-117在体外防止补体介导的细胞毒性自身免疫性溶血性贫血和抗体介导的器官移植排斥模型。ARGX-117 表现出 pH 和钙依赖性靶标结合，并且经过 Fc 工程化以增加酸性 pH 下对新生儿 Fc 受体的亲和力，并降低效应子功能。在食蟹猴中，ARGX-117 剂量依赖性地降低游离 C2 水平和经典途径活性。80 和 20 mg/kg 的 2 剂量方案相隔一周，导致经典途径活性的显着降低持续至少 7 周。

结论

ARGX-117 是一种很有前途的新型补体抑制剂，其独特的定位是针对经典和凝集素途径，同时保持替代途径完整。