Serum-Mediated Inhibition of Enzyme Replacement Therapy in Fabry Disease

Abstract

Fabry disease (FD) is a progressive multisystemic disorder, treatable with recombinant enzyme replacement therapy (agalsidase). However, recent studies suggest an endogenous inhibition of agalsidase in patients with FD, as reported for other lysosomal storage diseases. To assess the clinical consequences of serum-mediated agalsidase inhibition in affected patients, we determined the agalsidase inhibition status of 168 patients (68 male) with FD and compared outcomes of inhibition-positive patients with those of inhibition-negative patients. The assessment included clinical events during time on agalsidase, determination of renal and cardiac function, and evaluation of FD-related symptoms. The frequency of serum-mediated agalsidase inhibition was 40% in agalsidase-treated males. Inhibition did not depend on the compound initially used (agalsidase-a or -b). Agalsidase inhibition was associated with higher lysoglobotriaosylceramide levels and worse disease severity scores in patients. Compared with agalsidase inhibition-negative men, agalsidase inhibition-positive men showed greater left ventricular mass (P=0.02) and substantially lower renal function (difference in eGFR of about -30 ml/min per 1.73 m 2 ; P=0.04), which was confirmed by a longitudinal 5-year retrospective analysis. Additionally, affected patients presented more often with FD-typical symptoms, such as diarrhea, fatigue, and neuropathic pain, among others. Therefore, patients with poor clinical outcome on agalsidase should be tested for agalsidase inhibition. Future studies are warranted to determine if affected patients with FD benefit from acute reduction of anti-agalsidase antibodies or long-term immune modulation therapies to suppress agalsidase inhibition and to identify mechanisms that minimize antibody generation against agalsidase.

Reduction of Plasma Globotriaosylsphingosine Levels After Switching from Agalsidase Alfa to Agalsidase Beta as Enzyme Replacement Therapy for Fabry Disease

“…The number of samples that test positive for neutralizing activity and/or inhibition of uptake is dependent on the sensitivity and specificity of the method (Fabrazyme ® Prescribing information, last updated May 2010). Thus, it is not surprising that neutralizing antibody activity results from this study differ from results reported by other groups (Linthorst et al 2004;Lenders et al 2015). Studies have demonstrated that both agalsidase alfa and agalsidase beta are structurally equivalent and, on a milligram basis, induce similar, fully cross-reactive, antibody responses in vivo (Blom et al 2003;Lee et al 2003;Linthorst et al 2004), refuting the suggestion that variation in glycosylation patterns between agalsidase beta and agalsidase alfa may have implications for the long-term safety of ERT (Barbey et al 2008).…”

Plasma lyso-Gb3: a biomarker for monitoring fabry patients during enzyme replacement therapy

“…Some investigators revealed that the elevated plasma lyso-Gb3 level was reduced following ERT and the improvement of some clinical manifestations was associated with it in Fabry patients, suggesting the availability of plasma lyso-Gb3 as an indicator reflecting the efficacy of ERT [3,5,8]. On the other hand, it has been reported that antibodies against recombinant GLAs produced in Fabry patients have a negative impact on the therapeutic effect of the enzymes [9,10]. However, there have been few studies on the relationship between antibodies and plasma lyso-Gb3.…”

Nicotiana benthamiana α-galactosidase A1.1 can functionally complement human α-galactosidase A deficiency associated with Fabry disease

“…Secondly, the elevated circulating lysoGb3, considered to be toxic for podocytes and nociceptive neurons, is not completely corrected by present ERT 30,31 . Finally, a complicating factor with present ERT of FD proves to be the antigenicity of recombinant human α-galactosidase A in the majority of male FD patients that lack any endogenous enzyme (25). In these individuals neutralizing antibodies against therapeutic enzyme develop quickly, resulting in a relapse in the reduction of circulating toxic lysoGb3 (24).…”

“…Unfortunately, most male FD patients lack the α-Gal A protein and consequently develop neutralizing antibodies against the therapeutic recombinant enzymes which might contribute to the noted poor responses to current treatments (24). Indeed, it was recently reported that compared with agalsidase inhibition-negative men, agalsidase inhibition-positive men showed greater left ventricular mass and substantially lower renal function (25). Additionally, these patients presented more often with symptoms such as diarrhea, fatigue, and neuropathic pain.…”