Intracerebroventricular infusion of monoclonal antibody or its derived Fab fragment against misfolded forms of SOD1 mutant delays mortality in a mouse model of ALS
Intracerebroventricular infusion of monoclonal antibody or its derived Fab fragment against misfolded forms of SOD1 mutant delays mortality in a mouse model of ALS
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DOI：
10.1111/j.1471-4159.2010.06683.x
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发表时间：
2010-06-01
影响因子：
4.7
通讯作者：
Julien, Jean-Pierre
中科院分区：
文献类型：
--
作者：
Gros-Louis, Francois;Soucy, Genevieve;Julien, Jean-Pierre
突变型超氧化物歧化酶1（SOD 1）的分泌途径和毒性的发现提高了使用免疫方法来减少或中和神经系统中有毒SOD 1种类的负担的可能性。在这里，我们测试了一种被动免疫的方法，在G93 A-SOD 1小鼠脑室内输注的单克隆抗体特异性错误折叠形式的SOD 1（mSOD 1）。我们测试了两种单克隆抗体，其结合mSOD 1中的不同表位，并且不结合完整的野生型（WT）SOD 1。一种抗体成功地将脊髓中mSOD 1的水平降低了23%，并与治疗持续时间成比例地延长了G93 A-SOD 1小鼠的寿命。然而，另一种与不同SOD 1表位结合的单克隆抗体未能提供保护，表明并非所有抗SOD 1抗体都适用于免疫治疗。有趣的是，抗SOD 1抗体的可变Fab片段足以在G93 A-SOD 1小鼠中赋予一些保护。Fc区的部分可免除性应为开发具有较小分子大小和低免疫原性的抗体的免疫疗法提供一些优势。从这些结果，我们建议被动免疫策略应被视为治疗家族性肌萎缩侧索硬化症引起的SOD 1突变的潜在途径。
P>The finding of a secretion pathway and toxicity for mutant superoxide dismutase 1 (SOD1) raised up the possibility of using immunization approaches to reduce or neutralize the burden of toxic SOD1 species in the nervous system. Here we tested a passive immunization approach based on intracerebroventricular infusion in G93A-SOD1 mice of monoclonal antibodies specific to misfolded forms of SOD1 (mSOD1). We tested two monoclonal antibodies that bind distinct epitopes in mSOD1 and that do not bind to intact wild-type (WT) SOD1. One antibody succeeded in reducing the level of mSOD1 by 23% in the spinal cord and in prolonging the lifespan of G93A-SOD1 mice in proportion to the duration of treatment. However, another monoclonal antibody binding to a different SOD1 epitope failed to confer protection indicating that not all anti-SOD1 antibodies might be suitable for immunotherapy. Interestingly, the variable Fab fragment of an anti-SOD1 antibody was sufficient to confer some protection in G93A-SOD1 mice. The partial dispensability of Fc region should offer some advantages for development of immunotherapy with antibodies of smaller molecular size and low immunogenicity. From these results, we propose that passive immunization strategies should be considered as potential avenues for treatment of familial amyotrophic lateral sclerosis caused by SOD1 mutations.