Pre-existing antibodies against polyethylene glycol reduce asparaginase activities on first administration of pegylated E. coli asparaginase in children with acute lymphocytic leukemia

Antibodies against polyethylene glycol (PEG) in healthy subjects raise concerns about the efficacy of pegylated drugs. We evaluated the prevalence of antibodies against PEG among patients with acute lymphoblastic leukemia (ALL) prior to and/or immediately after their first dose of pegylated E.coli asparaginase (PEG-ASNase). Serum samples from 701 children (673 with primary ALL, 28 with relapsed ALL) and 188 adults with primary ALL were analyzed for anti-PEG IgG and IgM. Measurements in 58 healthy infants served as a reference to define cut-points for antibody-positive and -negative samples. The prevalence of anti-PEG antibodies in ALL patients prior to the first administration of PEG-ASNase was 13.9% for anti-PEG IgG and 29.1% for anti-PEG IgM. After administration of PEG-ASNase the prevalence of anti-PEG antibodies decreased to 4.2% for anti-PEG IgG and to 4.5% for anti-PEG IgM. Pre-existing anti-PEG antibodies did not inhibit PEGASNase activity but significantly reduced PEG-ASNase activity levels in a concentration-dependent manner. Although pre-existing anti-PEG antibodies were not boosted, pre-existing anti-PEG IgG were significantly associated with first-exposure hypersensitivity reactions (Common Terminology Criteria for Adverse Events grade 2) (P<0.01; Fisher exact test). Two of four patients with pre-existing anti-PEG IgG and first-exposure hypersensitivity reactions were not switched to Erwinia ASNase and continued on PEG-ASNase with sufficient activity (≥100 U/L). In conclusion, pre-existing anti-PEG antibodies were detected in a considerable proportion of patients with ALL and although they did not inhibit PEG-ASNase activity, they were associated with lower serum PEG-ASNase activity levels. Patients with pre-existing antibodies may show mild to moderate signs of hypersensitivity reaction after their first administration PEG-ASNase, which may be successfully addressed by re-challenge.