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目的评价注射用重组人B淋巴细胞刺激因子受体-抗体融合蛋白(RCT-18)在恒河猴体内的安全性。方法将恒河猴随机分为4组:低、中、高剂量RCT-18组和对照组,每组8只,低、中、高剂量RCT-18组分别经皮下注射4.6、16.1、57.5 mg/(kg.次)RCT-18,对照组经皮下注射0.7 ml/(kg.次)0.9%氯化钠注射液,每3 d上午同一时间给药1次,共给药91次。每天上午观察记录恒河猴的一般体征,每周常规监测体温1次,并在第1、2、3、13、14、15、28、29和30次给药前、给药后0.5、1、2、4和24 h增加测量动物体温次数。给药0.5、1.5、3、4.5、6、7.5、9个月(停药次日)及停药48 d(恢复期结束),分别对心电图、眼科、血液学、血液生化学、尿常规、血清抗RCT-18抗体、外周血单个核细胞(PBMC)分类计数、血清免疫球蛋白水平(IgG、IgA和IgM)等各项指标进行检查。给药3、6、9个月和恢复期结束,每组各解剖2只猴,进行脏器大体观察,计算脏器系数,并进行组织病理学观察。结果临床反应主要表现为给药后的体温升高;血液学指标出现具有一定剂量-反应关系的单核细胞(monocyte,MONO)数和网织红细胞(reticulocyte,RETIC)升高或网织红细胞平均体积(mean reticulocyte volume,MCVr)降低;3个剂量RCT-18组恒河猴的脏器重量和脏器系数与同期对照组相比,均无明显变化,且未见明显的脏器大体病变;3个剂量RCT-18组均出现无明显剂量相关但可逆的脾小结和淋巴滤泡萎缩;在整个试验期内未检测出血清中的抗RCT-18抗体;3个剂量组外周血淋巴细胞中IgD+细胞(成熟B淋巴细胞)比率均略有下降,但与对照组相比,差异无统计学意义(P>0.05);血清IgG、IgA和IgM从给药0.5～1.5个月后开始明显下降,恢复期结束时,除了中剂量的IgA水平,其他3个剂量RCT-18组的IgG、IgA和IgM水平均出现不同程度的回升。结论 RCT-18对恒河猴具有明显的但可恢复的免疫抑制作用。
Objective To evaluate the safety of injectable recombinant human B lymphocyte stimulating factor receptor-antibody fusion protein (RCT-18) in rhesus monkeys. Methods Rhesus macaques were randomly divided into 4 groups: low, middle and high dose RCT-18 group and control group, with 8 rats in each group. The low, medium and high dose RCT-18 groups were subcutaneously injected with 4.6, 16.1 and 57.5 mg / (kg. times) of RCT-18. The control group was injected subcutaneously with 0.7 ml / (kg) 0.9% sodium chloride injection every 3 days in the morning at the same time for a total of 91 times. Every morning, the general signs of rhesus monkeys were observed and recorded. The body temperature was routinely monitored once a week for 1, 2, 3, 13, 14, 15, 28, 29 and 30 before administration, 2, 4 and 24 h increased the number of animal body temperature measurement. Administration of 0.5,1.5,3,4.5,6,7.5,9 months (the day after drug withdrawal) and withdrawal of 48 days (the end of convalescence), electrocardiogram, ophthalmology, hematology, blood biochemistry, urine routine, Serum anti-RCT-18 antibody, peripheral blood mononuclear cells (PBMC) classification and count, serum immunoglobulin levels (IgG, IgA and IgM) and other indicators were examined. Administration for 3, 6, and 9 months and the end of convalescence, 2 monkeys were dissected in each group, gross observation of organ, calculation of organ coefficient and histopathological observation. Results The clinical response was mainly manifested as the increase of body temperature after administration. The number of monocytes (MONO) and reticulocyte (RETIC) with a dose-response relationship hematological index increased or the average number of reticulocytes Compared with the control group, there was no significant change in organ weight and organ coefficient of rhesus monkeys in 3 doses of RCT-18 group, and no obvious pathological changes of organs were observed. There was no significant dose-related but reversible splenic nodules and lymphatic follicular atrophy in the 3 doses of RCT-18 group; no anti-RCT-18 antibodies in serum were detected during the entire test period; in the 3 dose groups of peripheral blood lymphocytes (P> 0.05). Serum IgG, IgA and IgM levels decreased significantly from 0.5 to 1.5 months after administration At the end of convalescence, besides the middle dose of IgA, the levels of IgG, IgA and IgM in RCT-18 of other three doses all showed different degrees of recovery. Conclusion RCT-18 has obvious but recoverable immunosuppressive effect on rhesus monkeys.