Turner C T, Hopwood J J, Brooks D A
Department of Chemical Pathology, Women's and Children's Hospital, North Adelaide, South Australia, Australia.
Mol Genet Metab. 2000 Apr;69(4):277-85. doi: 10.1006/mgme.2000.2979.
Enzyme replacement therapy (ERT) has been developed and trialed for the treatment of human lysosomal storage disorder patients. The viability of ERT for the treatment of these severe multiple pathology disorders has subsequently been established. However, in both animal model studies and human clinical trials, some individuals have been shown to develop an immune response to the replacement protein. This potential complication for treatment has been investigated by the infusion of recombinant human alpha-L-iduronidase (rh-alpha-L-iduronidase) into nonimmune and immunized rats to simulate mucopolysaccharidosis type I ERT in the presence of different levels of antibody. In rats with high antibody titers to rh-alpha-L-iduronidase (titer 1,024,000) there was evidence of altered organ distribution and subcellular targeting when compared to either lower titer immunized rats (titers less than 64,000) or nonimmune rats (titers 512-1024). In addition, hypersensitivity reactions were observed for high titer rats (titer 1,024,000) during rh-alpha-L-iduronidase infusion, but not for the other two treatment groups. A rat with an antibody titer of 64,000 had only minor changes in subcellular targeting and organ distribution when infused with rh-alpha-L-iduronidase. This implied that a high level of antibody was required to effect changes in alpha-L-iduronidase enzyme targeting and distribution. Notably, in the high titer rats, the antibody produced appeared to increase the tissue and subcellular level of rh-alpha-L-iduronidase specific activity. This suggested that antibody production may not always result in an adverse effect on ERT.
酶替代疗法（ERT）已被开发并用于治疗人类溶酶体贮积症患者的试验。随后确定了ERT治疗这些严重多病理疾病的可行性。然而，在动物模型研究和人体临床试验中，一些个体已被证明会对替代蛋白产生免疫反应。通过将重组人α-L-艾杜糖醛酸酶（rh-α-L-艾杜糖醛酸酶）注入未免疫和免疫的大鼠体内，以模拟在不同抗体水平下的I型黏多糖贮积症ERT，对这种潜在的治疗并发症进行了研究。与低滴度免疫大鼠（滴度小于64,000）或未免疫大鼠（滴度512 - 1024）相比，对rh-α-L-艾杜糖醛酸酶抗体滴度高的大鼠（滴度1,024,000）有器官分布改变和亚细胞靶向改变的证据。此外，在注入rh-α-L-艾杜糖醛酸酶期间，高滴度大鼠（滴度1,024,000）出现了过敏反应，但其他两个治疗组未出现。抗体滴度为64,000的大鼠在注入rh-α-L-艾杜糖醛酸酶时，亚细胞靶向和器官分布仅有轻微变化。这意味着需要高水平的抗体才能影响α-L-艾杜糖醛酸酶的靶向和分布变化。值得注意的是，在高滴度大鼠中，产生的抗体似乎增加了rh-α-L-艾杜糖醛酸酶特异性活性的组织和亚细胞水平。这表明抗体产生不一定总是对ERT产生不利影响。
