title: IgG antibody response to polyethylene glycol-modified adenosine deaminase in patients with adenosine deaminase deficiency.
abstract: Polyethylene glycol (PEG)-modified bovine adenosine deaminase (ADA) is used for replacement therapy of severe combined immunodeficiency disease due to inherited ADA deficiency. We monitored IgG anti-ADA antibody in 17 patients treated by intramuscular injections of PEG-ADA for 1 to greater than 5.5 yr. ELISA-detectable anti-ADA IgG appeared in 10 patients, usually between the third and eighth months of treatment. Anti-ADA levels did not correlate with trough plasma ADA activity, which averaged 1.8-5 times normal blood (erythrocyte) ADA activity, depending on dose (15-60 U/kg per wk). ELISA-detectable anti-ADA antibodies were directed primarily at bovine-specific peptide (rather than PEG-containing) epitopes. Enhanced enzyme clearance, mediated by antibody that directly inhibited native and PEG-modified bovine ADA, and native, but not PEG-modified human ADA, occurred in two patients. In one, tolerance was induced; in the second, twice weekly injections of PEG-ADA compensated for accelerated clearance. We speculate that inhibitory antibodies recognize conserved, relatively PEG-free epitope(s) encompassing the active site, and that in human, but not bovine, ADA a PEG-attachment site "shields" the active site from immune recognition. We conclude that PEG-modification largely prevents the development of high affinity, or high levels of clearing antibodies to bovine ADA, and that PEG-modified human ADA should be further investigated as a possible treatment for ADA deficiency.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: S
authors.initials: S
authors.lastname: Chaffee
authors.forename: A
authors.initials: A
authors.lastname: Mary
authors.forename: E R
authors.initials: ER
authors.lastname: Stiehm
authors.forename: D
authors.initials: D
authors.lastname: Girault
authors.forename: A
authors.initials: A
authors.lastname: Fischer
authors.forename: M S
authors.initials: MS
authors.lastname: Hershfield
mesh_terms: D000243:Adenosine Deaminase / Q000737:chemistry / Q000172:deficiency* / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use; D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D000918:Antibody Specificity; D001323:Autoantibodies / Q000276:immunology; D002417:Cattle; D002648:Child; D002675:Child, Preschool; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007223:Infant; D011092:Polyethylene Glycols / Q000737:chemistry; D013045:Species Specificity
chemical_list: D058892:Adenosine Deaminase Inhibitors; D001323:Autoantibodies; D007074:Immunoglobulin G; D011092:Polyethylene Glycols; D000243:Adenosine Deaminase