Chronic Administration of Belatacept, a T-cell Costimulatory Signal Blocker, in Cynomolgus Monkeys
Chronic Administration of Belatacept, a T-cell Costimulatory Signal Blocker, in Cynomolgus Monkeys
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DOI：
10.1093/toxsci/kfs081
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发表时间：
2012-05-01
影响因子：
3.8
通讯作者：
Proctor, Stanley J.
中科院分区：
文献类型：
--
作者：
Haggerty, Helen G.;Proctor, Stanley J.
以食蟹猴为研究对象，研究了贝拉塔塞特(LEA29Y)的毒代动力学和毒性特征。在目前的研究中，30只猴子(每个性别每组5只猴子)接受了为期6个月的静脉注射贝拉塔塞特(10、22或50 mg/kg)，每周一次。每性别另外五只猴子接受静脉注射生理盐水，作为对照。全身暴露于贝拉塔塞特的剂量成比例，男女相似。多次给药导致巴拉坦中度蓄积(1.6-1.9倍)。贝拉西普在猴子身上的临床耐受性良好，没有观察到与药物有关的实验室参数变化或靶器官毒性，包括缺乏肾毒性。与药物相关的改变是可逆的，与药理学有关，包括剂量依赖的脾和淋巴结淋巴生发中心的大小和数量轻微/轻度减少，以及血清免疫球蛋白水平轻微下降。在治疗期间，没有检测到针对贝拉泰普的特异性抗体。外周血或脾淋巴细胞亚群没有变化，也没有自身免疫性炎症、感染或恶性肿瘤的迹象，包括癌前病变。在最后一次给药2个月后，免疫接种后对锁孔帽状血蓝蛋白产生了强烈的抗体反应，表明在所有剂量下免疫系统的功能恢复。因此，每周剂量高达50毫克/公斤的治疗6个月的猴子对贝拉塔塞特的耐受性很好，这意味着在肾移植接受者中，比批准的维持剂量增加了20倍。这些发现支持贝拉泰塞的安全性，并证明了贝拉泰塞不会对肾脏造成不良影响。
The toxicokinetics and toxicity profile of belatacept (LEA29Y), which blocks the CD28 costimulation pathway to prevent T-cell activation, were evaluated in cynomolgus monkeys. In the current study, 30 monkeys (five monkeys per sex per group) received an intravenous dose of belatacept (10, 22, or 50 mg/kg) once weekly for 6 months. An additional five monkeys per sex received saline intravenously and served as controls. Systemic exposure to belatacept was dose proportional and similar for both sexes. Multiple dosing resulted in moderate belatacept accumulation (1.6- to 1.9-fold). Belatacept was clinically well tolerated in monkeys, with no drug-related laboratory parameter changes or target organ toxicity observed, including a lack of nephrotoxicity. Drug-related changes, which were reversible and related to the pharmacology, included dose-dependent minimal/mild reduction in the size and number of lymphoid germinal centers of the spleen and lymph nodes and minimal reductions in serum IgG levels. No antibodies specific for belatacept were detected during the treatment period. There were no changes in peripheral blood or splenic lymphocyte subpopulations or indications of autoimmune-like inflammation, infection, or malignancy, including preneoplastic changes. Functional recovery of the immune system was noted at all doses by a robust antibody response to keyhole limpet hemocyanin following immunization 2 months after the last belatacept dose was administered. Thus, belatacept was well tolerated in monkeys treated for 6 months at weekly doses up to 50 mg/kg, which represented a 20-fold increase above exposures achieved by the approved maintenance dose in kidney transplant recipients. These findings support the belatacept safety profile and demonstrate that belatacept does not result in adverse renal effects.