IgG Antibody Response to Polyethylene Glycol-modified Adenosine Deaminase in Patients with Adenosine Deaminase Deficiency

Polyethylene glycol (PEG)-modified bovine adenosine deami-nase (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> 5.5 yr. ELISA-detectable anti-ADA IgG appeared in 10 patients, usually between the third and eighth months oftreatment. 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-de-tectable anti-ADA antibodies were directed primarily at bo-vine-specific peptide (rather than PEG-containing) epitopes. Enhanced enzyme clearance, mediated by antibody that di-rectly inhibited native and PEG-modified bovine ADA, and na-tive, but not PEG-modified human ADA, occurred in two pa-tients. 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-at-tachment site "shields " the active site from immune recogni-tion. We conclude that PEG-modification largely prevents the development of high affinity, or high levels of, clearing antibod-ies to bovine ADA, and that PEG-modified human ADA should be further investigated as a possible treatment for ADA defi-ciency. (J. Clin. Invest. 1992. 89:1643-1651.) Key words: ELISA- inhibitory antibody * severe combined immunodefi-ciency disease * enzyme replacement therapy * immune toler-anc