title: Successful immune tolerance induction to enzyme replacement therapy in CRIM-negative infantile Pompe disease.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Pediatric Hematology/Oncology, Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota, USA. yoav.messinger@childrensmn.org
authors.forename: Yoav H
authors.initials: YH
authors.lastname: Messinger
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Mendelsohn
authors.forename: William
authors.initials: W
authors.lastname: Rhead
authors.forename: David
authors.initials: D
authors.lastname: Dimmock
authors.forename: Eli
authors.initials: E
authors.lastname: Hershkovitz
authors.forename: Michael
authors.initials: M
authors.lastname: Champion
authors.forename: Simon A
authors.initials: SA
authors.lastname: Jones
authors.forename: Rebecca
authors.initials: R
authors.lastname: Olson
authors.forename: Amy
authors.initials: A
authors.lastname: White
authors.forename: Cara
authors.initials: C
authors.lastname: Wells
authors.forename: Deeksha
authors.initials: D
authors.lastname: Bali
authors.forename: Laura E
authors.initials: LE
authors.lastname: Case
authors.forename: Sarah P
authors.initials: SP
authors.lastname: Young
authors.forename: Amy S
authors.initials: AS
authors.lastname: Rosenberg
authors.forename: Priya S
authors.initials: PS
authors.lastname: Kishnani
mesh_terms: D000906:Antibodies / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D056947:Enzyme Replacement Therapy / Q000009:adverse effects; D005260:Female; D006009:Glycogen Storage Disease Type II / Q000175:diagnosis / Q000276:immunology* / Q000628:therapy*; D006801:Humans; D007108:Immune Tolerance; D007223:Infant; D007231:Infant, Newborn; D008279:Magnetic Resonance Imaging; D008297:Male; D059906:Neuroimaging; D009844:Oligosaccharides / Q000652:urine; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use; D016896:Treatment Outcome; D000520:alpha-Glucosidases / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use
chemical_list: D000906:Antibodies; D009844:Oligosaccharides; D011994:Recombinant Proteins; C033620:glucose tetrasaccharide; D000520:alpha-Glucosidases