VIII. Antibody-mediated inhibition of enzyme replacement therapy - relevance of dose?

I. Project title

Antibody-mediated inhibition of enzyme replacement therapy - relevance of dose?

Determination of Fabry disease patients’ specific anti-drug antibody status against recombinant alpha-galactosidase A and impact on biomarker levels

II. Principle investigator

Univ.-Prof. Dr. Dr. med. Eva Brand, phone: 0049251-8348746, mail:

Dr. rer. nat. Malte Lenders, phone: 0049251-8348104, mail:

University Hospital Münster, Internal Medicine D, Albert-Schweitzer-Campus 1, Building A1, 48149 Muenster, Germany,

III. Project duration

28 months

IV. Background

Fabry disease (FD; OMIM #301500) is an X-linked (Xq22.1) inborn error of glycosphingolipid catabolism resulting from deficient alpha-galactosidase A activity (GLA; 300644) due to mutations mainly in the GLA coding region. While former studies reported the incidence of FD to reach 1:40,000 to 1:120,000 [Meikle et al.1999, Desnick et al. 2001], a recent newborn screening study in males revealed that the GLA mutation rate was ≈1:3,100 [Spada et al. 2006]. FD-specific manifestations result from the differential systemic accumulation of globotriaoslyceramide (Gb3 or GL-3) in the cellular lysosomes [Zarate et al. 2008]. Onset of first symptoms (acroparesthesia, angiokeratoma, abdominal pain, cornea verticillata and hypo- or hyperhidrosis) in affected hemizygous males with low or absent enzymatic GLA activity starts in early childhood. The persistent accumulation of Gb3/GL-3 in cells of different tissues leads to an early onset of stroke, heart or renal failure, and cardiac arrhythmia leading to a severely reduced life expectancy.

Enzyme replacement therapy (ERT) with recombinant alpha-galactosidase A (i.e agalsidase-alfa/-beta) has been shown to be effective in reducing intracellular Gb3 and lyso-Gb3 levels resulting in an improvement of clinical outcomes. However, intravenous infusion of recombinant ERT may cause antibody formation with neutralizing effects on ERT especially in male FD patients. A positive antibody status is associated with an impaired therapeutic effect on Gb3 reduction and consequently impaired clinical outcome of affected patients (Linthorst et al. 2004; Rombach et al. 2012; Lenders et al. 2016).

V. Project rationale

So far only small patient groups have been analyzed for antibody-mediated ERT inhibition and limited data about the capacity to trigger drug-neutralizing antibody production in humans receiving agalsidase-alfa or agalsidase-beta infusions are available. To date, it is unclear if neutralizing properties of antibodies against agalsidase-alfa are similar to those against agalsidase-beta (and vice versa).  In addition, the clinical impact of a supersaturation of ADA titers is unclear. Furthermore, it remains elusive if a dose escalation to supersaturate ADA titers might also trigger further antibody production. However, recent studies demonstrate that even in patients with ADAs the total dose of infused enzyme has a beneficial effect on the biochemical response (i.e. lyso-Gb3) (Arends et al. 2018), which is probably due to the supersaturation of ADAs in affected patients (Lenders et al. 2018).

The project rationale is to determine the neutralizing ADA status in ERT-treated male Fabry patients from several Fabry centers in Germany in order to

  1. identify affected patients at risk,

  2. analyze if the individual infused ERT dose is sufficient to supersaturate ADA titers,

  3. analyze if neutralizing properties of antibodies against agalsidase-alfa are similar to those against agalsidase-beta (and vice versa)

  4. analyze if an approved dose escalation (switch from agalsidase-alfa (0.2 mg/kg) to agalsidase-beta (the dosage of agalsidase-beta will be the recommended dose of 1 mg/kg BW according to the SmPC) triggers further ADA formation,

  5. analyze the effect of neutralizing antibodies on plasma lyso-Gb3 levels, as a marker for the biochemical response.

VI. References

Arends M, Biegstraaten M, Wanner C, Sirrs S, Mehta A, Elliott PM, Oder D, Watkinson OT, Bichet DG, Khan A, Iwanochko M, Vaz FM, van Kuilenburg ABP, West ML, Hughes DA, Hollak CEM. Agalsidase alfa versus agalsidase beta for the treatment of Fabry disease: an international cohort study. J Med Genet. 2018 Feb 7. pii: jmedgenet-2017-104863

Desnick RJ, Ioannou YA, Eng CM. Alpha-galactosidase A deficiency: Fabry disease. In: The metabolic bases of inherited disease, 8th edition. New York: McGraw-Hill, 2001: 3733-3774.

Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA. 1999, 281: 249-254.

Lenders M, Stypmann J, Duning T, Schmitz B, Brand SM, Brand E. Serum-mediated inhibition of enzyme replacement therapy in Fabry disease. J Am Soc Nephrol. 2016, 27:256-264

Lenders M, Schmitz B, Brand SM, Foell D, Brand E. Characterization of drug-neutralizing antibodies in patients with Fabry disease during infusion. J Allergy Clin Immunol. 2018, 141: 2289-2292.e7

Linthorst GE, Hollak CE, Donker-Koopman WE, Strijland A, Aerts JM. Enzyme therapy for Fabry disease: neutralizing antibodies towards agalsidase alpha and beta. Kidney Int. 2004, 66:1589-1595.

Rombach SM, Aerts JM, Poorthuis BJ, Groener JE, Donker-Koopman W, Hendriks E, Mirzaian M, Kuiper S, Wijburg FA, Hollak CE, Linthorst GE. Long-term effect of antibodies against infused alpha-galactosidase A in Fabry disease on plasma and urinary (lyso)Gb3 reduction and treatment outcome. PLoS One. 2012, 7:e47805.

Spada M, Pagliardini S, Yasuda M, Tukel T, Thiagarajan G, Sakuraba H, Ponzone A, Desnick RJ: High incidence of later-onset Fabry disease revealed by newborn screening. Am J Hum Genet. 2006;79: 31-40.

Zarate YA, Hopkin RJ. Fabry’s disease. Lancet. 2008; 372: 1427-1435.

VII. Funding

This project is funded by Sanofi-Aventis Deutschland GmbH.