全人源抗人肿瘤坏死因子α单克隆抗体注射液对食蟹猴的长期毒性试验
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摘要
目的评价全人源抗人肿瘤坏死因子α单克隆抗体(抗-h TNF-αFHMA)注射液对食蟹猴的长期毒性。方法将40只食蟹猴随机分成5组,分别为阴性对照组、阿达木单抗10 mg·kg~(- 1)对照组和抗-h TNF-αFHMA 2,10和50 mg·kg~(- 1)组,经皮下注射每周给药1次,连续给药5次,停药后恢复期4周。实验期间进行临床观察、体质量、体温、心电图、血细胞计数、凝血功能、血液生化、尿液、眼科、免疫指标、脏器及组织病理观察,同时进行血药浓度检测,分析毒代动力学参数。结果实验期间各组食蟹猴的观察、体质量、体温、心电图参数、眼科检查、血细胞计数、凝血功能、血生化、尿液分析、淋巴细胞亚群、细胞因子、血清免疫球蛋白和血清补体等指标均未见与给药相关的具有毒理意义的改变;抗-h TNF-αFHMA和阿达木单抗均可引起食蟹猴体内产生抗药抗体,且具有中和活性。抗-h TNF-αFHMA在体内基本呈线性动力学特征。相同剂量下与阿达木单抗呈现相似的免疫原性和代谢动力学特征。结论抗-h TNF-αFHMA未观察到不良反应的剂量为50 mg·kg~(- 1),相当于临床拟用剂量(0.67 mg·kg~(- 1))的75倍,表明抗-h TNF-αFHMA临床应用安全性较好。
OBJECTIVE To evaluate the long-term toxicity of fully human anti-human tumor necrosis factor-α monoclonal antibody(anti-h TNF-α FHMA)for injection in cynomolgus monkeys. METHODS Forty cynomolgus monkeys were randomly divided into 5 groups(4 males and 4 females in each group):negative control group,adalimumab 10 mg·kg~(- 1)group,anti-h TNF-α FHMA 2,10 and 50 mg·kg~(- 1)groups. Cynomolgus monkeys in each group were injected sc once a week for 5 consecutive times,followed by 4 weeks of recovery. During the test,general clinical observation,body mass,body temperature,electrocardiogram(ECG),hematology,coagulation function,blood biochemistry,urine,ophthalmology,immune index,and pathological changes in organs and tissues were observed. At the same time,plasma drug concentrations were detected and the toxicokinetics parameters were analyzed.RESULTS No significant toxicological changes related to drugs were observed in general clinical observation,body mass,body temperature,ECG,ophthalmic examination,blood cell counts,coagulation function,blood biochemistry,urine analysis,lymphocyte subsets,cytokines,serum immunoglobulin,serum complement. Neutralizing anti-drug antibody(ADA)could be detected in adalimumab group and anti-h TNF-α FHMA groups. Anti-h TNF-α FHMA showed linear dynamic characteristics in cynomolgus monkeys. At the same dose(10 mg·kg~(- 1)),anti-h TNF-α FHMA had similar immunogenicity and kinetics characteristics to adalimumab. CONCLUSION The level of anti-h TNF-α FHMA at which no adverse effect was observed was 50 mg·kg~(- 1),which is equivalent to 75 times clinical dosage of quasi(0.67 mg·kg~(- 1)),which suggests that anti-h TNF-α FHMA be safe in clinical use.
OBJECTIVE To evaluate the long-term toxicity of fully human anti-human tumor necrosis factor-α monoclonal antibody(anti-h TNF-α FHMA)for injection in cynomolgus monkeys. METHODS Forty cynomolgus monkeys were randomly divided into 5 groups(4 males and 4 females in each group):negative control group,adalimumab 10 mg·kg~(- 1)group,anti-h TNF-α FHMA 2,10 and 50 mg·kg~(- 1)groups. Cynomolgus monkeys in each group were injected sc once a week for 5 consecutive times,followed by 4 weeks of recovery. During the test,general clinical observation,body mass,body temperature,electrocardiogram(ECG),hematology,coagulation function,blood biochemistry,urine,ophthalmology,immune index,and pathological changes in organs and tissues were observed. At the same time,plasma drug concentrations were detected and the toxicokinetics parameters were analyzed.RESULTS No significant toxicological changes related to drugs were observed in general clinical observation,body mass,body temperature,ECG,ophthalmic examination,blood cell counts,coagulation function,blood biochemistry,urine analysis,lymphocyte subsets,cytokines,serum immunoglobulin,serum complement. Neutralizing anti-drug antibody(ADA)could be detected in adalimumab group and anti-h TNF-α FHMA groups. Anti-h TNF-α FHMA showed linear dynamic characteristics in cynomolgus monkeys. At the same dose(10 mg·kg~(- 1)),anti-h TNF-α FHMA had similar immunogenicity and kinetics characteristics to adalimumab. CONCLUSION The level of anti-h TNF-α FHMA at which no adverse effect was observed was 50 mg·kg~(- 1),which is equivalent to 75 times clinical dosage of quasi(0.67 mg·kg~(- 1)),which suggests that anti-h TNF-α FHMA be safe in clinical use.
引文
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[2]Tracey D,Klareskog L,Sasso EH,Salfeld JG,Tak PP.Tumor necrosis factor antagonist mechanisms of action:a comprehensive review[J].Pharmacol Ther,2008,117(2):244-279.
[3]Huang F,Yang CH.The present situation of the biological inhibitor treatment of rheumatic diseases[J].Clin Med J(临床药物治疗杂志),2005,3(1):1-8.
[4]Liang LQ,Zhan ZP,Fu D,Ye YJ,Xu HS,Yang XY.Efficacy of etanercept in the treatment of r efractory rheumatoid arthritis[J].J Pract Med(实用医学杂志),2008,24(18):3229-3231.
[5]Zhang W,Shi Q,Wu DH,Bao CD,Yang NP,Li ZG,et al.Efficacy and safety of infliximab in patients with rheumatoid arthritis[J].Natl Med J China(中华医学杂志),2009,89(27):1876-1880.
[6]Breedveld FC,Weisman MH,Kavanaugh AF,Cohen SB,Pavelka K,van Vollenhoven R,et al.The PREMIER study:a multicenter,randomized,double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early,aggressive rheumatoid arthritis who had not had previous methotrexate treatment[J].Arthritis Rheum,2006,54(1):26-37.
[7]Burmester GR,Mariette X,Montecucco C,Monteagudo-Sáez I,Malaise M,Tzioufas AG,et al.Adalimumab alone and in combination with diseasemodifying antirheumatic drugs for the treatment of rheumatoid arthritis in clinical practice:the Research in Active Rheumatoid Arthritis(Re Act)trial[J].Ann Rheum Dis,2007,66(6):732-739.
[8]CFDA.General Principles of Non-Clinical Safety Technical Evaluation about Biological Products for Treatment[S].GPT1-1.2007-01.http://www.cde.org.cn/zdyz.do?method=large Page&id=100
[9]Wang HX,Peng J,Zhang RM,Wang QL.Consideration in non-clinical safety evaluation of monoclonal antibody products[J].Chin J New Drugs(中国新药杂志),2009,18(3):199-201,205.
[10]CFDA.Guideline on Drug Toxicity Test by Repeat Administration[S].[2014-05-13].http://www.cde.org.cn/zdyz.do?method=large Page&id=192