Enzyme therapy for Fabry disease: Neutralizing antibodies toward agalsidase alpha and beta
Enzyme therapy for Fabry disease: Neutralizing antibodies toward agalsidase alpha and beta
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DOI：
10.1111/j.1523-1755.2004.00924.x
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发表时间：
2004-10-01
影响因子：
19.6
通讯作者：
Aerts, JMFG
中科院分区：
文献类型：
--
作者：
Linthorst, GE;Hollak, CEM;Aerts, JMFG
背景法布里病是一种X-连锁遗传性疾病，其由α-半乳糖苷酶A（α-Gal A）缺乏引起的溶酶体神经酰胺三己糖苷（CTH）过度储存引起。两种重组酶制剂已被批准作为治疗方式。我们研究了治疗患者中α-半乳糖苷A抗体的出现和性质。在静脉注射重组酶（rh-alpha-Gal A）的前6至12个月期间，研究了18名成年法布里病患者（2名女性）的抗体形成。女性患者在酶治疗后未产生可检测量的抗体。用半乳糖苷酶α或β治疗6个月后，11/16例男性患者显示出高滴度的免疫球蛋白G（IgG）抗体，其在体外与两种重组酶发生类似的交叉反应。抗rh-alpha-Gal A IgG在体外中和rh-alpha-Gal A活性达65%至95%。在输注rh-Gal A期间，形成循环酶-抗体复合物，这些复合物被外周血中的白细胞摄取。治疗6个月后，所有IgG阴性患者均显示出显著的尿CTH降低（P < 0.01）（1890 +/- 797至603 +/- 291 nmol CTH/24小时尿液），与IgG阳性患者相比（平均从2535 +/- 988增加到2723 +/- 1212），提示循环抗体对肾小管CTH清除的负面影响。在接受治疗的法布里病患者中，经常会出现具有体内中和能力的抗体。这些抗体的完全交叉反应性表明，从一种重组蛋白转换为另一种重组蛋白不太可能阻止免疫应答和相关效应。对α-Gal A抗体的临床意义的进一步研究是必要的。
Background. Fabry disease is an X-linked inherited disorder that is caused by excessive lysosomal globotriaosylceramide (CTH) storage due to a deficiency in alpha-galactosidase A (alpha-Gal A). Two recombinant enzyme preparations have been approved as treatment modality. We studied emergence and properties of alpha-Gal A antibodies in treated patients.Methods. During the first 6 to 12 months of intravenous administration of recombinant enzymes (rh-alpha-Gal A) formation of antibodies was studied in 18 adult Fabry patients (two females).Results. The female patients did not develop detectable amounts of antibodies following enzyme therapy. After 6 months of treatment with either agalsidase alpha or beta, 11/16 male patients showed high titers of immunoglobulin G (IgG) antibodies that cross-react in vitro similarly with both recombinant enzymes. The anti-rh-alpha-Gal A IgG neutralizes rh-alpha-Gal A activity in vitro for 65% to 95%. During infusion with rh-Gal A, circulating enzyme-antibody complexes are formed and these complexes are taken up by leukocytes in the peripheral blood. After 6 months of treatment all IgG-negative patients showed a significant (P < 0.01) reduction of urinary CTH (1890 +/- 797 to 603 +/- 291 nmol CTH/24hr urine), compared to IgG-positive patients (mean increase from 2535 +/- 988 to 2723 +/- 1212), suggesting a negative effect of circulating antibodies on renal tubular CTH clearance.Conclusion. Emergence of antibodies with in vivo neutralizing capacities is frequently encountered in treated Fabry disease patients. Complete cross-reactivity of these antibodies suggests that it is unlikely that switching from one to the other recombinant protein prevents the immune response and related effects. Further studies on the clinical implications of alpha-Gal A antibodies are essential.