肿瘤坏死因子-α单克隆抗体注射剂在中国健康成年志愿者中抗药抗体产生及其影响因素分析

Anti-drug antibodies of tumor necrosis factor alpha monoclonal antibody injection in Chinese healthy adult volunteers and analysis its influence factors

目的研究肿瘤坏死因子-α(TNF-α)单克隆抗体药物在中国健康成年受试者中抗药抗体(ADA)产生的比率,分析其影响因素。方法按随机、平行、双盲、对照的研究方法设计,3项试验共计纳入164例中国健康成年志愿者。试验1:56例中国健康成年受试者随机分成A、B、C、D、E、F组,其中A组6例,其他每组10例,分别予以单次腹部皮下注射10,20,35,50,65,75 mg的试验药物L00653;试验2:60例中国健康成年志愿者随机分成6个剂量组,每组10例,分别予以单次腹部皮下注射5,15,30,50,75,100 mg的试验药物L02151。试验3:48例中国健康成年志愿者随机分成4组,每组12例,组内按1∶1对照以静脉滴注方式分别给予试验药物L00048或原研药。用配体结合分析法检测ADA水平。结果 164例受试者全部完成试验。试验1:A、B、C、D、E、F组的阳性率分别为17.00%,20.00%,40.00%,30.00%,0,30.00%,组间ADA阳性率与给药剂量比较差异均无统计学意义(均P>0.05)。试验2:5,15,30,50,75,100 mg剂量组的阳性率分别为100.00%,100.00%,100.00%,100.00%,100.00%,70.00%,组间ADA阳性率与给药剂量比较差异均无统计学意义(均P>0.05)。试验3:仅2例ADA检测阳性。结论 TNF-α单克隆抗体药物在人体内ADA的产生与单抗自身来源和结构有关,与药物剂量无密切关系。

Objective To study the ratio of anti - drug antibody （ADA） produced by tumor necrosis factor alpha （TNF -α） monoelonal antibody in Chinese healthy adult volunteers, and to analyze its influencing factors. Methods This is a parallel, randomized, double - blind, con- trolled study. Three sets of test totally included 164 cases of Chinese healthy adult volunteers. Trial one：56 cases of Chinese healthy adult volunteers were randomized into six groups, given 10, 20, 35, 50, 65, 75 mg of L00653 test drugs in abdominal subcutaneous injection way. Trial two：64 cases of Chinese healthy adult volunteers were divided into six groups, given 5, 15, 30, 50, 75, 100 mg of the test drug L02151 by abdominal subcutaneous injection. Trial three： 48 cases of Chinese healthy adult volunteers were randomized into four groups, The volunteers in each group were given E0（0）O and primary research drugs by intravenous infusion according to 1：1 proportion as controlled trials. The levels of ADA were measured by ligand binding assay （LBA）. Results A total of 164 healthy volunteers were performed in the study. Trail one ： The positive rates of A, B, C, D, E, F groups were 17.00%, 20. 00%, 40. 00%, 30. 00%, 0, 30. 00%, respectively. There was no significant difference between ADA positive rate and administration dose （P 〉0. 05） ; Trail two：The positive rates of 5, 15,30, 50,75 and 100 mg groups were 100. 00%, 1000. 00%, 100. 00%, 100.00%, 100. 00%, 70. 00%, respectively. There was no significant difference in ADA positive rate between the groups and the dose of Administration （ P 〉 0. 05 ） ; Trail three ： Only two cases of ADA appeared. Conclusion The ADA produced in the body by TNF - α monoclonal antibody drug was asso- ciated with its source and structure, but without close relationship with drug doses. The research could be used to TNF -α monoelonal antibody drug research, providing experimental basis for clinical safe use.