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. 2012 Sep;97(9):1320-8.
doi: 10.3324/haematol.2011.058644. Epub 2012 Feb 27.

Hematopoietic stem cell transplantation improves the high incidence of neutralizing allo-antibodies observed in Hurler's syndrome after pharmacological enzyme replacement therapy

Muhammad Ameer Saif  1 , Brian W Bigger, Karen E Brookes, Jean Mercer, Karen L Tylee, Heather J Church, Denise K Bonney, Simon Jones, J Ed Wraith, Robert F Wynn
Affiliations

Hematopoietic stem cell transplantation improves the high incidence of neutralizing allo-antibodies observed in Hurler's syndrome after pharmacological enzyme replacement therapy

Muhammad Ameer Saif et al. Haematologica. 2012 Sep.

Abstract

Background: Mucopolysaccharidosis type I is caused by deficiency of α-L-iduronidase. Currently available treatment options include an allogeneic hematopoietic stem cell transplant and enzyme replacement therapy. Exogenous enzyme therapy appears promising but the benefits may be attenuated, at least in some patients, by the development of an immune response to the delivered enzyme. The incidence and impact of alloimmune responses in these patients remain unknown.

Design and methods: We developed an immunoglobulin G enzyme-linked immunosorbent assay as well as in vitro catalytic enzyme inhibition and cellular uptake inhibition assays and quantified enzyme inhibition by allo-antibodies. We determined the impact of these antibodies in eight patients who received enzyme therapy before and during hematopoietic stem cell transplantation. In addition, 20 patients who had previously received an allogeneic stem cell transplant were tested to evaluate this treatment as an immune tolerance induction mechanism.

Results: High titer immune responses were seen in 87.5% (7/8) patients following exposure to α-L-iduronidase. These patients exhibited catalytic enzyme inhibition (5/8), uptake inhibition of catalytically active enzyme (6/8) or both (4/8). High antibody titers generally preceded elevation of previously described biomarkers of disease progression. The median time to development of immune tolerance was 101 days (range, 26-137) after transplantation. All 20 patients, including those with mixed chimerism (22%), tested 1 year after transplantation were tolerized despite normal enzyme levels.

Conclusions: We found a high incidence of neutralizing antibodies in patients with mucopolysaccharidosis type I treated with enzyme replacement therapy. We also found that allogeneic hematopoietic stem cell transplantation was an effective and rapid immune tolerance induction strategy.

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Figures

Figure 1.
Figure 1.
(A) Longitudinal data demonstrating the immune response in eight patients (1–8) in the longitudinal series from start of ERT to just before HSCT are shown baselined to the time of first starting ERT. All patients raised antibody responses to the enzyme. (B) A western blot for two patients depicting the specificity of the ELISA for IDUA (Aldurazyme). In the absence of antibodies in the pre-ERT sample, there was no antibody binding to IDUA or Myozyme (MZM). After exposure to ERT, the IgG antibodies in the patients’ serum only bound to IDUA and not to MZM. Mkr (Marker) region shows the position of various bands based on their molecular weight (kDa) according to the ladder. (C) Longitudinal data demonstrating the immune response in eight patients (1–8) in the longitudinal series are shown baselined to the time of first HSCT. Antibody titer is presented on the primary vertical axis in a logarithmic scale. Note a rapid decline in antibody titer after HSCT (following approximately 3 months of ERT). Patient 5 rejected his first graft which was followed by an escalation of antibody titers. This immune response resolved after a second transplant on day 328.
Figure 2.
Figure 2.
(A) Catalytic enzyme inhibition in eight patients (1–8) compared to a standard (normal serum) across various enzyme concentrations. (B) Inhibition due to tolerized and non-tolerized serum. Non-tolerized serum taken from a patient (patient 3) on ERT before HSCT with high titer antibodies is compared to tolerized serum taken from the same patient a year after HSCT (with no antibodies) which shows no significant inhibition.
Figure 3.
Figure 3.
(A) Cellular uptake inhibition in all patients (1–8) in the longitudinal series is shown. Patients 6 and 8 showed no cellular uptake inhibition. (B) Tolerized serum (post-transplant with no antibodies) showed no inhibition compared to significant inhibition by non-tolerized serum (prior to transplant) in the same patient.
Figure 4.
Figure 4.
Correlation between biomarkers (DS/CS ratio) and the antibody titers in six patients in the longitudinal series (patients 2–7). The shaded areas represent the period of ERT and black arrows point to the time of HSCT. (A) Patient 2 showed an immediate improvement in the DS/CS ratio after starting ERT which was halted by high titer anti-IDUA antibodies. The biomarker levels improved after the immune response was abrogated. (B) Patient 3 showed minimal improvement in biomarkers despite HSCT and ERT during the high-titer immune response. (C) The improvement in biomarker levels in patient 4 was significant after ERT was commenced; however, this progress was arrested and reversed after the high titer immune response was generated. The biomarkers improved after resolution of the immune response. (D) Patient 5 rejected his first HSCT and had a second successful transplant. The initial improvement in biomarker levels plateaud during the high-titer immune response despite ERT (note a brief period when ERT was interrupted after the first failed HSCT) which improved only after the immune response was completely resolved after the second HSCT. (E) Patient 6 showed a suboptimal response to ERT during the high titer immune response. (F) The DS/CS ratio in patient 7 dropped to a significant level but further follow-up data were not available for the period during the immune response and following the HSCT. Biomarker data are not available for patients 1 and 8.
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