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Sialylation-dependent pharmacokinetics and differential complement pathway inhibition are hallmarks of CR1 activity in vivo.
Biochemical Journal ( IF 4.4 ) Pub Date : 2022-05-13 , DOI: 10.1042/bcj20220054
Sandra Wymann 1 , Marcel Mischnik 2 , David Leong 3 , Subhajit Ghosh 2 , Xiahui Tan 3 , Helen Cao 3 , Benjamin Kuehnemuth 2 , Glenn A Powers 3 , Partho Halder 2 , Mitchell J de Souza 3 , Hannah S James 3 , Vesna Tomasetig 3 , Holger Lind 2 , Paolo Rossato 2 , Catherine M Owczarek 3 , Saw Yen Ow 3 , Steven K Dower 3 , Adriana Baz Morelli 3 , Tony Rowe 3 , Matthew P Hardy 3
Affiliation  

Human Complement Receptor 1 (HuCR1) is a potent membrane-bound regulator of complement both in vitro and in vivo, acting via interaction with its ligands C3b and C4b. Soluble versions of HuCR1 have been described such as TP10, the recombinant full-length extracellular domain, and more recently CSL040, a truncated version lacking the C-terminal long homologous repeat domain D (LHR-D). However, the role of N-linked glycosylation in determining its pharmacokinetic (PK) and pharmacodynamic (PD) properties is only partly understood. We demonstrated a relationship between the asialo-N-glycan levels of CSL040 and its PK/PD properties in rats and non-human primates (NHPs), using recombinant CSL040 preparations with varying asialo-N-glycan levels. The clearance mechanism likely involves the asialoglycoprotein receptor (ASGR), as clearance of CSL040 with a high proportion of asialo-N-glycans was attenuated in vivo by co-administration of rats with asialofetuin, which saturates the ASGR. Biodistribution studies also showed CSL040 localization to the liver following systemic administration. Our studies uncovered differential PD effects by CSL040 on complement pathways, with extended inhibition in both rats and NHPs of the alternative pathway compared with the classical and lectin pathways that were not correlated with its PK profile. Further studies showed that this effect was dose dependent and observed with both CSL040 and the full-length extracellular domain of HuCR1. Taken together, our data suggests that sialylation optimization is an important consideration for developing HuCR1-based therapeutic candidates such as CSL040 with improved PK properties and shows that CSL040 has superior PK/PD responses compared with full-length soluble HuCR1.

中文翻译:

唾液酸化依赖性药代动力学和差异补体途径抑制是体内 CR1 活性的标志。

人补体受体 1 (HuCR1) 是一种有效的体外和体内补体膜结合调节剂,通过与其配体 C3b 和 C4b 的相互作用发挥作用。HuCR1 的可溶版本已被描述,例如 TP10,重组全长胞外结构域,以及最近的 CSL040,一种缺乏 C 末端长同源重复结构域 D (LHR-D) 的截短版本。然而,仅部分了解 N-连接糖基化在确定其药代动力学 (PK) 和药效学 (PD) 特性中的作用。我们使用具有不同去唾液酸-N-聚糖水平的重组 CSL040 制剂证明了 CSL040 的去唾液酸-N-聚糖水平与其在大鼠和非人类灵长类动物 (NHP) 中的 PK/PD 特性之间的关系。清除机制可能涉及去唾液酸糖蛋白受体(ASGR),由于大鼠与去唾液酸胎球蛋白共同给药可在体内减弱具有高比例去唾液酸-N-聚糖的 CSL040 的清除,使 ASGR 饱和。生物分布研究还显示 CSL040 在全身给药后定位于肝脏。我们的研究揭示了 CSL040 对补体途径的不同 PD 影响,与与其 PK 特征不相关的经典途径和凝集素途径相比,替代途径的大鼠和 NHPs 具有延长的抑制作用。进一步的研究表明,这种作用是剂量依赖性的,并且在 CSL040 和 HuCR1 的全长细胞外结构域中都可以观察到。综合起来,
更新日期:2022-04-26
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