Successful immune tolerance induction to enzyme replacement therapy in CRIM-negative infantile Pompe disease

Abstract

Purpose: Infantile Pompe disease resulting from a deficiency of lysosomal acid α-glucosidase (GAA) requires enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA). Cross-reactive immunologic material negative (CRIM-negative) Pompe patients develop high-titer antibody to the rhGAA and do poorly. We describe successful tolerance induction in CRIM-negative patients.

Methods: Two CRIM-negative patients with preexisting anti-GAA antibodies were treated therapeutically with rituximab, methotrexate, and gammaglobulins. Two additional CRIM-negative patients were treated prophylactically with a short course of rituximab and methotrexate, in parallel with initiating rhGAA.

Results: In both patients treated therapeutically, anti-rhGAA was eliminated after 3 and 19 months. All four patients are immune tolerant to rhGAA, off immune therapy, showing B-cell recovery while continuing to receive ERT at ages 36 and 56 months (therapeutic) and 18 and 35 months (prophylactic). All patients show clinical response to ERT, in stark contrast to the rapid deterioration of their nontolerized CRIM-negative counterparts.

Conclusion: The combination of rituximab with methotrexate ± intravenous gammaglobulins (IVIG) is an option for tolerance induction of CRIM-negative Pompe to ERT when instituted in the naïve setting or following antibody development. It should be considered in other conditions in which antibody response to the therapeutic protein elicits robust antibody response that interferes with product efficacy.

Figure 1. Therapeutic-treated patients with antibody to ERT

Tolerance-induction regimen, with rituximab, methotrexate, and intravenous gammaglobulins (IVIG) showing antibody levels and B-cell percentage for patients treated therapeutically for an established antibody response. Both patients achieved tolerance to ongoing enzyme replacement therapy, and are off immune therapy, with negative antibody titer showing B-cell recovery. (a) Patient 1. (b) Patient 2. ERT, enzyme replacement therapy.

Figure 2. Prophylactic-treated patients

Tolerance-induction regimen, antibody levels, and B-cell percentage for patients treated prophylactically in the naïve setting with rituximab and methotrexate. Both patients are tolerant to ongoing enzyme replacement therapy, off immune therapy with B-cell recovery. (a) Patient 3 with remains with low-titer (1:200) antibody level, similar to CRIM-positive patients. (b) Patient 4 with negative antibody titer.

Figure 3. Change in urinary glucose tetrasaccharide (Glc₄) biomarker concentration on enzyme replacement therapy for the four patients treated by immune therapy

Comparative data for CRIM-negative patients without immune therapy (n = 8, ± SD) are displayed in gray. Mean value of Glc₄ over different time periods (bins) was calculated for each patient, and median value for each bin was used to plot the time point. Upper limit of normal controls is represented by dashed line, which is ≤4.4 mmol/mol CN for more than 1 year of age. Therapeutically treated patient 1 Glc₄ levels (mean ± SD: 31 ± 13 mmol/mol CN, 26 measurements) and patient 2 Glc₄ levels (16 ± 6 mmol/mol CN, 40 measurements) remained lower than those of nontreated CRIM-negative patients. Similarly, prophylactically treated patient 3 Glc₄ levels remained lower than those of nontreated CRIM-negative patients (21, 23 mmol/mol CN). In contrast, patient 4 had levels that were comparable to those of the nontreated CRIM-negative group (50 ± 14 mmol/mol CN, 8 measurements). Note that for patients 3 and 4, last urine samples for Glc₄ were available for later time points than anti-acid α-glucosidase (GAA) antibody measurement depicted in Figure 2.

Figure 4. Long-term changes on brain magnetic resonance imaging (MRI) of patient 1

The images on the left, taken at age 5 months, show normal myelination for age. The images on the right, at age 54 months (4.5 years) show development of T2 prolongation within the deep white matter (white arrows) in the periventricular white matter, centrum semiovale, and external capsule, sparing the subcortical U-fibers (yellow arrow) as well as the internal capsule. I: T2 axial scans at ages (Ia) 5 months and (Ib) 54 months; II: T2 fast low-angle inversion recovery (FLAIR) images; III: T2 coronal scans.