三种双特异性抗体对小鼠类风湿关节炎模型的治疗效果  

Therapeutic efficacy of three bispecific antibodies on rheumatoid arthritis mice models

作　　者：李清萃 韩晓辉[1] 周兵[1] 王文飞[1] 任桂萍[1] 孙翠羽[1] 吴强[1] 于引航[1] 徐黎明 王秋颖 齐剑英 魏雨泉[1] 曹宏伟[5] 韩俊岩[6] 李德山[1] 

机构地区：[1]东北农业大学生命科学学院,黑龙江哈尔滨150030 [2]中国水产研究院黑龙江水产研究所,黑龙江哈尔滨150030 [3]哈药集团生物工程有限公司,黑龙江哈尔滨150025 [4]黑龙江庆丰源生物工程技术有限责任公司,黑龙江大庆163300 [5]黑龙江八一农垦大学,黑龙江大庆163300 [6]齐齐哈尔医学院,黑龙江齐齐哈尔161000

出　　处：《药学学报》2014年第3期322-328,共7页Acta Pharmaceutica Sinica

基　　金：黑龙江省发改委项目(黑发改项目[2011]1570号);黑龙江省教育厅科学技术研究项目(12521z004);哈尔滨市科技创新人才研究专项资金项目(2012RFXXS034);黑龙江省高校科技成果产业化前期研发培育项目(1252CGZH29);黑龙江省博士后科研启动基金(LBH-Q09162);国家自然基金东北农业大学生物学理科基地科研训练及科研能力提高项目(J1210069/J0106);国家自然基金青年基金(31200121/C010802);国家自然科学基金-东北农业大学生物学理科基地科研训练及科研能力提高项目(J1210069-31)

摘　　要：为获得治疗类风湿关节炎(rheumatoid arthritis,RA)的先导药物,本研究比较了3种双特异性抗体(BsAB-1、BsAB-2和BsAB-3)对Ⅱ型胶原(CII)诱导的RA(CIA)模型小鼠的治疗效果。首先用ELISA法比较了3种二价抗体同时与两种抗原的结合能力,结果显示,3种抗体均能同时结合两种抗原,BsAB-1结合抗原的能力优于其他两种抗体(P<0.01)。用鸡CII建立CIA模型,用纯化的抗体对CIA模型小鼠进行治疗,每2天给药1次,治疗29天。治疗结束后与CIA模型对照组相比,各治疗组小鼠踝关节肿胀、皮肤紧绷、后足皮肤表面充血等临床症状明显减轻,其中BsAB-1治疗后足趾肿胀不明显,基本恢复正常。采用ELISA法检测了各组小鼠血清中CII抗体,real-time PCR法检测了脾脏中细胞因子IL-2、IL-1β、IL-17A和TNF-α的表达水平。与CIA模型对照组相比,所有抗体治疗组都能明显降低血清中CII抗体水平、脾脏中IL-2、IL-1β、IL-17A和TNF-α的表达量,且BsAB-1治疗效果最佳,与另外两种抗体比较有显著差异(P<0.01)。因此,3种二价抗体对CIA模型小鼠都有治疗效果,BsAB-1的治疗效果要优于另外两种抗体,是优选的先导药物。In order to obtain the lead compound for treatment of rheumatoid arthritis （RA）, in this study, therapeutic efficacy of three bispecific antibodies （BsAB-1, BsAB-2 and BsAB-3） against both hIL-1β and hIL-17 were compared on CIA model mice. First, by ELISA method we compared the binding capacity of the three bispecific antibodies to the two antigens. The results showed that all three antibodies could simultaneously bind both antigens, among these antibodies, BsAB-1 was superior over BsAB-2 and BsAB-3. CIA model was established with chicken type II collagen （CII） and developed RA-like symptoms such as ankle swelling, skin tight, hind foot skin hyperemia. The CIA mice were treated with three antibodies once every two days for total of 29 days. Compared with the CIA model mice, the RA-like symptoms of the antibody treated-mice significantly relieved, while the BsAB-I treated-mice were almost recovered. CII antibody level in the serum and cytokines （IL-2, IL-1β, IL-17A and TNF-α） expression in the spleen were examined. Compared with the CIA model mice, all three antibodies could significantly reduce CII antibody and cytokine expression levels. BsAB-1 antibody was more potent than BsAB-2 and BsAB-3. In summary, BsAB-1 is superior over BsAB-2 and BsAB-3 in amelioration of RA symptoms and regulation of CII antibody production and pro-inflammatory cytokine expression, therefore, BsAB-1 can be chosen as a lead compound for further development of drug candidate for treatment of RA.

关 键 词：双特异抗体 类风湿关节炎 II型胶原 IL-1Β IL-17A 

分 类 号：R965[医药卫生—药理学]