Anti-α-galactosidase A antibody response to agalsidase beta treatment: Data from the Fabry Registry William R. Wilcox a, b, ⁎, Gabor E. Linthorst c , Dominique P. Germain d , Ulla Feldt-Rasmussen e , Stephen Waldek f , Susan M. Richards g , Dana Beitner-Johnson g , Marta Cizmarik g , J. Alexander Cole g , Wytske Kingma g , David G. Warnock h a Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA b Department of Pediatrics, UCLA School of Medicine, Los Angeles, CA, USA c Academic Medical Center, Amsterdam, Netherlands d University of Versailles, Hôpital Raymond Poincaré, Garches, France e National University Hospital, Copenhagen, Denmark f Salford Royal NHS Foundation Trust, Manchester, UK g Genzyme, Cambridge, MA, USA h Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA abstract article info Article history: Received 1 October 2011 Received in revised form 8 December 2011 Accepted 8 December 2011 Available online 14 December 2011 Keywords: Fabry disease Lysosomal storage diseases Alpha-galactosidase Enzyme replacement therapy Glycosphingolipids Antibody formation Agalsidase beta, a form of recombinant human α-galactosidase A (αGAL), is approved for use as enzyme replacement therapy (ERT) for Fabry disease. An immunogenic response against a therapeutic protein could potentially impact its efficacy or safety. The development of anti-αGAL IgG antibodies was evaluated in 571 men and 251 women from the Fabry Registry who were treated with agalsidase beta. Most men developed antibodies (416 of 571, 73%), whereas most women did not (31 of 251, 12%). Women were also significantly more likely to tolerize than men; whereas 18 of 31 women tolerized (58%, 95%CI: 52%–64%), only 47 of 416 men tolerized during the observation period (11%, 95% CI: 8%–15%). Patients who eventually tolerized had lower median peak anti-αGAL IgG antibody titers than patients who remained seropositive at their most recent assessment (400 versus 3200 in men, 200 versus 400 in women, respectively). Patients with nonsense mutations in the GLA gene were more likely to develop anti-αGAL IgG antibodies than patients with mis- sense mutations. Approximately 26% of men (151 of 571) reported infusion-associated reactions (IARs), compared to 11% of women (27 of 251). Men who developed anti-αGAL IgG antibodies were more likely to experience IARs compared to those who remained seronegative. Nine percent of seronegative men and women (34 of 375) reported IARs. The majority of IARs occurred during the first 6 to 12 months of agalsidase beta treatment and decreased over time, in both seroconverted and seronegative patients. © 2012 Elsevier Inc. All rights reserved. 1. Introduction Fabry disease is a rare lysosomal storage disorder caused by a deficiency of the lysosomal enzyme α-galactosidase A (αGAL) and the resulting progressive accumulation of globotriaosylceramide (GL-3) and other glycosphingolipids within various cells and tissues [1,2]. Over time, this accumulation of GL-3 is associated with renal disease progression, cardiovascular disease and strokes [3–8]. Because Fabry disease is X-linked, hemizygous males typically experience the most severe manifestations of Fabry disease [1,2]. However, many heterozygous females also develop substantial signs and symptoms of Fabry disease, including renal failure, cerebrovascular events, and cardiovascular events [4–6,8]. Agalsidase beta, a form of recombinant human αGAL, is approved for use as enzyme replacement therapy (ERT) for treatment of Fabry disease (Fabrazyme®, Genzyme, a Sanofi company, Cambridge, MA). In clinical studies, agalsidase beta was shown to clear microvascular endothelial GL-3 deposits from the kidney, heart, and skin [9,10], and to improve clinical outcomes when initiated before the onset of irreversible organ damage [10,11]. Agalsidase beta is administered via intravenous infusion at the recommended labeled dose of 1.0 mg/kg/2 weeks. Like other thera- peutic proteins [12,13], agalsidase beta can cause immunogenicity [14,15], especially if patients have little or no endogenous enzyme. Anti-αGAL IgG antibodies could potentially impact the safety and efficacy of ERT in certain patients, possibly by altering its biodistri- bution or metabolic clearance [13]. Regular monitoring of serum Molecular Genetics and Metabolism 105 (2012) 443–449 Abbreviations: CI, confidence interval; ERT, enzyme replacement therapy; αGAL, α- galactosidase A; GPS&RM, Genzyme Global Patient Safety & Risk Management; IAR, infusion-associated reaction. ⁎ Corresponding author at: Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. E-mail address: bill.wilcox@cshs.org (W.R. Wilcox). 1096-7192/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.ymgme.2011.12.006 Contents lists available at SciVerse ScienceDirect Molecular Genetics and Metabolism journal homepage: www.elsevier.com/locate/ymgme