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目的:对食蟹猴重复给予重组人-鼠嵌合抗CD20单克隆抗体IBI301,考察与参照药的非临床安全性相似性,并为临床设计人用剂量及临床毒副反应的监测提供参考依据。方法:食蟹猴分4组:溶媒对照组、IBI301低剂量组(30 mg·kg~(-1))、高剂量组(90 mg·kg~(-1))和对照品利妥昔单抗组。每组8只动物,雌雄各半。静脉注射给药,每周给药1次,共给药4次。实验期间观察动物的临床症状、注射部位刺激性,进行体重、摄食量、体温、心电、血压、尿检查、眼科学、血液学、血清生化检查,进行外周血和淋巴结CD20~+/CD40~+细胞测定,剖检后进行脏器称重、大体和组织病理学检查。结果:低、高剂量IBI301引起食蟹猴外周血和淋巴结B淋巴细胞显著减少或消失,同时组织病理学检查显示低、高剂量IBI301引起脾脏白髓淋巴细胞数目减少、腹股沟淋巴结和肠系膜淋巴结皮质淋巴滤泡数目减少,恢复期结束时上述改变有一定程度的恢复。IBI301 90 mg·kg~(-1)引起食蟹猴血清Ig G水平可逆性升高。IBI301对其他检测指标均未见明显影响。结论:食蟹猴重复静脉注射IBI301 30和90 mg·kg~(-1),除观察到与药效作用相关的改变及引起可逆性的血清Ig G水平升高外,未见其他明显的毒性作用;同剂量IBI301与利妥昔单抗的作用类似。
OBJECTIVE: To repeat the non-clinical safety of recombinant human-mouse chimeric anti-CD20 monoclonal antibody IBI301 in cynomolgus monkeys and to provide a reference for clinical design of human dosage and clinical toxicity monitoring . Methods: Cynomolgus monkeys were divided into 4 groups: vehicle control group, IBI301 low dose group (30 mg · kg -1), high dose group (90 mg · kg -1) and rituximab Anti-group. Eight animals in each group, half male and half female. Intravenous injection, administered once a week, administered a total of 4 times. During the experiment, we observed the clinical symptoms of the animals and the irritation of the injection site. The body weight, food intake, body temperature, ECG, blood pressure, urinalysis, ophthalmology, hematology and serum biochemistry were observed. + Cell determination, necropsy after organ weighing, general and histopathological examination. Results: Low and high doses of IBI301 caused a significant decrease or disappearance of B lymphocytes in peripheral blood and lymph nodes of cynomolgus monkey. Histopathological examination showed that low and high dose of IBI301 caused a decrease in the number of lymphocytes in spleen and white pulp, as well as in inguinal and mesenteric lymph nodes The number of follicles was reduced, and some of the above changes were restored at the end of the recovery period. IBI301 90 mg · kg -1 induced a reversible increase of serum Ig G level in cynomolgus monkeys. IBI301 has no obvious effect on other test indexes. CONCLUSION: Repeated intravenous injection of IBI301 30 and 90 mg · kg -1 in cynomolgus monkeys, except for the observed changes associated with pharmacodynamic effects and the elevated serum Ig G levels causing reversible effects, showed no other significant toxicity Role; the same dose of IBI301 and rituximab similar effect.