抗体药物偶联物及其在恶性血液系统肿瘤治疗中的应用

单克隆抗体靶向治疗是目前临床肿瘤治疗的热点。针对抗体分子大而组织穿透性差以及临床使用剂量大、生产成本高的问题,抗体的小型化和高效性设计已成为抗体药物研发的新趋势。近年来,单抗与细胞毒性药物的结合物被称为抗体药物偶联物(antibody-drug conjugates,ADCs),已加入到抗癌药物的行列中,成为新型的抗体药物而受到广泛关注。泛义的ADC通常由抗体、接头(linker)和效应分子等3部分组成。根据效应分子的不同,可将ADC分为化学免疫偶联物、免疫毒素、放射性免疫偶联物等3类。ADC被内化进入细胞后,通过细胞内的化学和酶解作用释放出细胞毒性物质,细胞毒性物质则通过抑制蛋白合成、解聚微管蛋白或断裂双链DNA等作用而对靶细胞产生杀伤作用。近年来,FDA已经批准2种ADC药物上市,有多种处于II～III期临床试验阶段,取得了显著的临床效果,吸引了越来越多的制药企业争相竞逐。本文介绍ADC的过去和现状,结合临床肿瘤应用中的实际问题,探讨其将来的发展趋势。

Antibody-drug conjugates and their application in the treatment of hematological malignancies

Monoclonal antibody-targeted therapy has been a hot spot in current clinical cancer treatment.As current antibody drugs have large molecule sizes leading to poor tissue penetration,and high dosage in clinical application leading to high cost,to overcome the problems,the development of new antibody drugs with miniaturization and high potency has become a new trend.In recent years,the conjugates of monoclonal antibodies and cytotoxins,called antibody-drug conjugates(ADCs),have entered the arsenal of anti-cancer drugs,becoming a new format of antibody drugs and attracting extensive attentions.The ADC molecule usually consists of antibody,linker and effector molecule.According to different effector molecules,ADCs can be divided into three categories as chemo-conjugates,immunotoxins and radio-conjugates.When ADC molecules are internalized into cancer cells,cytotoxins will be released by chemical,enzyme degradation or by action of lysosomal proteases,then kill targeted cells by inhibiting protein synthesis,depolymerizing microtubules or breaking double-strand DNA.Recently,two ADC drugs have been approved by the US FDA and more ADC drug candidates are in clinical phase II or III trials which show significantly clinical effects and attracting much attention and competition of pharmaceutical enterprises.In this review,antibody conjugates in the past and present will be summarized and the future development trends and challenges of this type of antibody drugs will be discussed.