title: The impact of antibodies on clinical outcomes in diseases treated with therapeutic protein: lessons learned from infantile Pompe disease.
abstract: OBJECTIVE
  Enzyme replacement therapy with rhGAA (Myozyme®) has lead to improved survival, which is largely attributable to improvements in cardiomyopathy and skeletal muscle function. However, crossreactive immunologic material-negative patients have a poor clinical response to enzyme replacement therapy secondary to high sustained antibody titers. Furthermore, although the majority of crossreactive immunologic material-positive patients tolerize or experience a downtrend in anti-rhGAA antibody titers, antibody response is variable with some crossreactive immunologic material-positive infants also mounting high sustained antibody titers.
  
  
  METHODS
  We retrospectively analyzed 34 infants with Pompe disease: 11 crossreactive immunologic material-negative patients, nine high-titer crossreactive immunologic material-positive patients, and 14 low-titer crossreactive immunologic material-positive patients. Clinical outcome measures were overall survival, ventilator-free survival, left ventricular mass index, Alberta Infant Motor Scale score, and urine Glc(4) levels.
  
  
  RESULTS
  Clinical outcomes in the high-titer crossreactive immunologic material-positive group were poor across all areas evaluated relative to the low-titer crossreactive immunologic material-positive group. For the crossreactive immunologic material-negative and high-titer crossreactive immunologic material-positive groups, no statistically significant differences were observed for any outcome measures, and both patient groups did poorly.
  
  
  CONCLUSIONS
  Our data indicate that, irrespective of crossreactive immunologic material status, patients with infantile Pompe disease with high sustained antibody titer have an attenuated therapeutic response to enzyme replacement therapy. With the advent of immunomodulation therapies, identification of patients at risk for developing high sustained antibody titer is critical.
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Suhrad G
authors.initials: SG
authors.lastname: Banugaria
authors.forename: Sean N
authors.initials: SN
authors.lastname: Prater
authors.forename: Yiu-Ki
authors.initials: YK
authors.lastname: Ng
authors.forename: Joyce A
authors.initials: JA
authors.lastname: Kobori
authors.forename: Richard S
authors.initials: RS
authors.lastname: Finkel
authors.forename: Roger L
authors.initials: RL
authors.lastname: Ladda
authors.forename: Yuan-Tsong
authors.initials: YT
authors.lastname: Chen
authors.forename: Amy S
authors.initials: AS
authors.lastname: Rosenberg
authors.forename: Priya S
authors.initials: PS
authors.lastname: Kishnani
mesh_terms: D000906:Antibodies / Q000097:blood; D057134:Antibodies, Neutralizing / Q000097:blood; D015415:Biomarkers / Q000652:urine; D002658:Developmental Disabilities; D057075:Enzyme Assays; D056947:Enzyme Replacement Therapy; D005260:Female; D006009:Glycogen Storage Disease Type II / Q000188:drug therapy* / Q000401:mortality; D065089:Glycoside Hydrolase Inhibitors; D006352:Heart Ventricles / Q000473:pathology; D006601:Hexoses / Q000652:urine; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D053208:Kaplan-Meier Estimate; D008297:Male; D009929:Organ Size; D000520:alpha-Glucosidases / Q000276:immunology / Q000627:therapeutic use*
chemical_list: D000906:Antibodies; D057134:Antibodies, Neutralizing; D015415:Biomarkers; D065089:Glycoside Hydrolase Inhibitors; D006601:Hexoses; C509951:GAA protein, human; D000520:alpha-Glucosidases