Nonclinical safety, pharmacokinetics, and pharmacodynamics of atacicept
Nonclinical safety, pharmacokinetics, and pharmacodynamics of atacicept
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DOI：
10.1093/toxsci/kfn105
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发表时间：
2008-09-01
影响因子：
3.8
通讯作者：
Ponce, Rafael
中科院分区：
文献类型：
--
作者：
Carbonatto, Michela;Yu, Ping;Ponce, Rafael
Atacicept是人免疫球蛋白（IG）G（1）Fc和人跨膜激活因子和钙调节剂及cyclophylin配体相互作用受体的胞外结构域的可溶性重组融合蛋白，作为B淋巴细胞刺激因子和增殖诱导配体的拮抗剂。在此，我们确定了阿塞西普在小鼠和食蟹猴中的非临床安全性、药代动力学和药效学。皮下atacicept治疗（食蟹猴每周两次，小鼠每周三次）通常安全且耐受性良好，每隔一天给药高达10 mg/kg，持续39周或给药高达80 mg/kg，持续4周。以1 mg/kg剂量皮下注射（sc）atacicept，小鼠和猴的生物利用度分别为76%和92%，平均血清t（1/2）分别为44和179 h。与预期的作用机制雅阁，重复给予阿塞西普使血清IgG浓度降低高达50%，IgM浓度降低> 99%，循环成熟B细胞浓度降低高达60%。这些效应与剂量相关，但在25周的随访期内确定可逆。显微镜下，脾脏滤泡边缘区和淋巴结生发中心周围的外套膜中的B细胞数量减少。这些数据证实了atacicept的临床前安全性和药理活性，并支持其临床开发。
Atacicept, a soluble recombinant fusion protein of the human immunoglobulin (Ig) G(1) Fc and the extracellular domain of the human transmembrane activator and calcium modulator and cyclophylin ligand interactor receptor, acts as an antagonist of both B lymphocyte stimulator and a proliferating-inducing ligand. Here we determined the nonclinical safety, pharmacokinetics and pharmacodynamics of atacicept in mice and cynomolgus monkeys. Subcutaneous atacicept treatment (twice weekly in cynomolgus monkeys, three times weekly in mice) was generally safe and well tolerated safe and well tolerated with dosing up to 10 mg/kg every other day for up to 39 weeks or up to 80 mg/kg when dosed for 4 weeks. At a dose of 1 mg/kg subcutaneous (sc) bioavailability of atacicept in mice and monkeys was 76 and 92%, with a mean serum t(1/2) of 44 and 179 h, respectively. In accord with its anticipated mechanism of action, repeated administration of atacicept decreased serum IgG concentrations up to 50%, IgM concentrations > 99%, and circulating mature B-cell concentrations up to 60%. These effects were dose-related but reversible, as determined in a 25-week follow-up period. Microscopically, B cells numbers were reduced in the follicular marginal zone of the spleen and the mantle surrounding germinal centers of the lymph nodes. These data confirm the preclinical safety and the pharmacological activity of atacicept and support its clinical development.