ANTIBODY-DIRECTED ENZYME PRODRUG THERAPY (ADEPT)
ANTIBODY-DIRECTED ENZYME PRODRUG THERAPY (ADEPT)
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DOI：
10.1042/bst0180750
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发表时间：
1990-10-01
影响因子：
3.9
通讯作者：
BAGSHAWE, KD
中科院分区：
文献类型：
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作者：
BAGSHAWE, KD
杂交瘤技术的出现允许生产单克隆抗体[11]将抗体用于癌症治疗的可能性从梦想状态提升到实用性。被动施用的抗体作为细胞毒性的补体依赖性试剂本身的有限能力已经被探索，并且兴趣开始集中在它们作为将细胞毒性细胞引导至靶位点的手段121和作为细胞杀伤剂的载体。作为载体，抗体已经与药物131、生物毒素141和放射性同位素151缀合。药物或毒素向肿瘤群体中高比例细胞的有效递送受到可连接至抗体载体的药物或毒素分子的数量的限制。以及靶抗原表达的异质性。异源性抗原表达在淋巴瘤中可能最不明显，但在癌中是一个实质性障碍，特别是那些低分化的癌。放射性标记的抗体具有交叉效应杀死未标记的旁观者细胞的潜力。但是...无论是作为完整抗体还是作为Fab'或flab'）片段使用，它们都具有药代动力学特征，这导致递送到正常和恶性组织的总辐射剂量的不利比率151。仍然存在较小的放射性标记的抗原结合片段和放射增敏剂可以克服这些限制的可能性161。而需要药物或毒素内化的系统需要膜结合的靶标，除非药物通过不稳定的连接与抗体偶联，否则放射性标记的抗体可以针对分泌的抗原以及膜结合的抗原。在这两种情况下，肿瘤环境中的抗原密度可能是关键的。在从天然代谢物171中获得毒性产物或在肿瘤环境中产生关键代谢物的剥夺状态18）的背景下，抗体也已经与酶偶联。同样重要的是，潜在的抗癌药物被认为在肿瘤部位过量存在的酶激活。
The advent of hybridoma technology allowing the production of monoclonal antibodies [11 lifted the possible use of antibodies for cancer therapy from the dream state into practicality. The limited capacity of passively administered antibodies as cytotoxic, complement-dependent agents in their own right had already been explored, and interest began to focus on them as a means of directing cytotoxic cells to target sites 121 and as vectors for cell-killing agents. As vectors, antibodies have been conjugated to drugs 131, biotoxins 141 and to radioisotopes 151. The effective delivery of drugs or toxins to a high proportion of cells in the tumour population is limitcd by the number of drug or toxin molecules that can be attached to the antibody vector. and by heterogeneity in the expression of the target antigen. Heterogeneity in antigen expression is perhaps least apparent in the lymphomas, but is a substantial obstacle in the carcinomas, cspecially those that arc poorly differentiated. Radiolabelled antibodies have the potential to kill unmarked bystander cells in a cross-firc effect. but. whether used as intact antibody or as Fab’or flab’), fragment, they have pharmacokinetic characteristics which result in unfavourable ratios for the summated radiation dose delivered to normal and malignant tissues 151. There remains the possibility that smaller radiolabelled antigen-binding fragments and radiosensitisers can overcome these limitations 161. Whereas systems that require the internalization of the drug or toxin require a membrane bound target, unless the drug is coupled to the antibody by a labile linkage, radiolabelled antibodies can be directed at secreted antigens as well as those that are membrane bound. In both cases antigen density in the tumour environment may be critical. Antibodies have also been coupled to enzymes in the context of deriving toxic products from natural metabolites 171 or of creating a state of deprivation of a key metabolite in the tumour environment 18). It is also relevant that latent anticancer drugs were made so as to bc activated by enzymes presumed to be present in excess at tumour sites 191.