Characterization of immune response in Cross-Reactive Immunological Material (CRIM)-positive infantile Pompe disease patients treated with enzyme replacement therapy

Abstract

Enzyme replacement therapy (ERT) with rhGAA has improved clinical outcomes in infantile Pompe disease (IPD). A subset of CRIM-positive IPD patients develop high and sustained antibody titers (HSAT; ≥51,200) and/or sustained intermediate titer (SIT; ≥12,800 and <51,200), similar to CRIM-negative patients. To date there has been no systematic study to analyze the extent of IgG antibody response in CRIM-positive IPD. Such data would be critical and could serve as a comparator group for potential immune modulation approaches. A retrospective analysis of the dataset from the original rhGAA clinical trials final reports was conducted. CRIM-positive patients who received ERT monotherapy and had >6 months of antibody titer data available, were included in the study. Patients were classified based on their longitudinal antibody titers into HSAT, SIT, and low titer (LT; <12,800) groups. Of the 37 patients that met inclusion criteria, five (13%), seven (19%), and 25 (68%) developed HSAT, SIT, and LT, respectively. Median peak titers were 204,800 (51,200-409,600), 25,600 (12,800-51,200), and 800 (200-12,800) for HSAT, SIT, and LT groups, respectively. Median last titers were 102,400 (51,200-409,600), 1600 (200-25,600), and 400 (0-12,800) at median time since ERT initiation of 94 weeks (64-155 weeks), 104 weeks (86-144 weeks), and 130 weeks (38-182 weeks) for HSAT, SIT, and LT groups, respectively. 32% (12/37) of CRIM-positive IPD patients developed HSAT/SIT which may lead to limited ERT response and clinical decline. Further Studies are needed to identify CRIM-positive IPD patients at risk of developing HSAT/SIT, especially with the addition of Pompe disease to the newborn screening.

Keywords: AIMS, Alberta infant motor scale; Anti-rhGAA Ig antibodies; Antidrug antibodies; CI-MPR, Cation-independent mannose 6-phosphate receptor; CRIM, Cross-reactive immunological material; EOW, Every other week; ERT, Enzyme replacement therapy; Enzyme replacement therapy; GAA, Acid α-glucosidase; GAA, Gene encoding acid α-glucosidase; Glc4, Glucose tetrasaccharide; Glycogen storage disease type II; HLA, Human leukocyte antigen; HSAT, High and sustained antibody titers; IPD, Infantile Pompe disease; IgG, Immunoglobulin G; LT, Low titers; LVMI, Left ventricular mass index; MHC, Major histocompatibility complex; Neuromuscular disease; Pompe disease; RUSP, Recommended universal screening panel; SIT, Sustained intermediate titers; iTEM, Individualized T-cell epitope measure; rhGAA, Recombinant human acid α-glucosidase.

Fig. 1

Frequency of GAA variants in HSAT, SIT, and LT groups. HSAT, high and sustained antibody titer; SIT, sustained intermediate titer; LT, low titer.

Fig. 2

Comparison of left ventricular mass index in HSAT + SIT group versus LT group. ERT, enzyme replacement therapy; HSAT, high and sustained titer; SIT, sustained intermediate titer; LT, low titer; LVMI, left ventricular mass index.