Nishi Yoshisuke
Laboratory of Life Science & Biomolecular Engineering, Japan Tobacco, Inc, Yokohama, Japan.
Curr Pharm Des. 2003;9(26):2113-30. doi: 10.2174/1381612033454063.
Clinically useful prodrug activation systems for cancer therapy can be applied in combination with the exogenous activating enzymes, by which masked prodrugs are able to unmask to exert cytotoxic effects on the target tumors. In essence, designing prodrugs not to be degenerated or activated by the endogenous enzymes is needed. Prodrug activation systems are to be delivered to the tumor site by delivery tools, including antibodies, genes, viral vectors and synthetic polymers, directed to the target tumors. Highly selective accumulation of the prodrug activation system at the tumor site is critically important for the efficacy of the prodrug activations. Genetic engineering of antibodies have made it possible to create a bispecific antibody and its derivatives, which are of special value to the functional antibodies with one arm to direct the target tumor tissues, and another to recruit the effector cells or molecules that can effectively kill the tumor cells. The technology has further opened the window for catalytic antibodies as a prodrug activating system. Catalytic antibodies have two distinct advantages over the enzymes: First, they can be selected to catalyze the reaction that is not catalyzed by the endogenous enzymes. Second, in order to minimize immunogenicity, humanization is applicable to catalytic antibodies. In viewing the concept and experimental data with a few clinical trials of recent approaches of prodrug activation systems, their potential utility in clinical oncology is further discussed.
临床上用于癌症治疗的有用前药激活系统可与外源性激活酶联合应用，通过这种方式，被掩盖的前药能够解除掩盖，对靶肿瘤发挥细胞毒性作用。本质上，需要设计出不会被内源性酶降解或激活的前药。前药激活系统要通过包括抗体、基因、病毒载体和合成聚合物等递送工具递送至肿瘤部位，这些递送工具靶向靶肿瘤。前药激活系统在肿瘤部位的高度选择性积累对于前药激活的疗效至关重要。抗体的基因工程使得制造双特异性抗体及其衍生物成为可能，这对于具有一个臂靶向靶肿瘤组织、另一个臂募集可有效杀死肿瘤细胞的效应细胞或分子的功能性抗体具有特殊价值。该技术进一步为作为前药激活系统的催化抗体打开了窗口。催化抗体相对于酶具有两个明显优势：第一，它们可以被选择来催化内源性酶不催化的反应。第二，为了使免疫原性最小化，催化抗体可进行人源化。结合前药激活系统近期方法的一些临床试验的概念和实验数据，进一步讨论了它们在临床肿瘤学中的潜在效用。
