Antibody against poly(ethylene glycol) adversely affects PEG‐asparaginase therapy in acute lymphoblastic leukemia patients

Abstract

BACKGROUND. Rapid clearance of poly(ethylene glycol)‐asparaginase (PEG‐ASNase) has been reported for up to one‐third of patients treated for acute lymphoblastic leukemia (ALL), potentially rendering their treatment ineffective. A 25% occurrence of an antibody against PEG (anti‐PEG) was previously reported in healthy blood donors. The objective of the study was to determine whether anti‐PEG was associated with rapid clearance PEG‐ASNase. METHODS. The investigation reanalyzed stored sera from pediatric patients enrolled in the ALL Berlin‐Frankfurt‐Muenster 2000 studies. Twenty‐eight samples were selected to include 15 subjects with undetectable ASNase activity after receiving PEG‐ASNase. Sixteen subjects treated with unmodified ASNase were also included, 8 with low ASNase activity. Sera were tested for anti‐PEG using 2 techniques: 1) serology, by agglutination of PEG‐coated red blood cells; 2) flow cytometry, by analysis of 10 μm PEG beads stained for bound immunoglobulins. RESULTS. Of the 15 sera from PEG‐ASNase‐treated patients with undetectable ASNase activity, anti‐PEG was detected in 9 by serology and in 12 by flow cytometry. Anti‐PEG was detected in 1 PEG‐ASNase‐treated patient with lower ASNase activity (123 U/L). No relation was observed between anti‐PEG and serum ASNase activity for patients treated with unmodified ASNase. CONCLUSIONS. The presence of anti‐PEG was very closely associated with rapid clearance of PEG‐ASNase. Further comprehensive studies are warranted to fully elucidate the effect of anti‐PEG on PEG‐conjugated agents. Screening and monitoring for anti‐PEG may allow identification of patients for whom a modified dosing strategy or use of a non‐PEGylated drug would be appropriate. Cancer 2007. © 2007 American Cancer Society.

Intravenous Administration of Polyethylene Glycol-Coated (PEGylated) Proteins and PEGylated Adenovirus Elicits an Anti-PEG Immunoglobulin M Response

“…A similar response to PEG has been observed in patients receiving intramuscular administration of FDA-approved Oncaspar ® (PEG-asparaginase). 29) In the current study, we showed that a single intravenous injection of PEG-proteins will elicit an anti-PEG IgM response (Fig. 1).…”

Identification and Structural Analysis of an l-Asparaginase Enzyme from Guinea Pig with Putative Tumor Cell Killing Properties

“…A reduced but still present immune intolerance remains because of the foreign origin of these drugs. Furthermore, the enzyme can still be cleared from the blood and an immune reaction elicited because of antibody formation against PEG (11)(12)(13). This suggests that a more human-like enzyme, which would be less immunogenic, could be a superior replacement (14 -16).…”

Therapeutic enzyme deimmunization by combinatorial T-cell epitope removal using neutral drift

“…Masking of immunogenic epitopes via covalent modification with PEG can reduce protein immunogenicity (10), but eventually antigen-specific, and even PEG-specific, antibodies that contribute to therapeutic neutralization may be elicited toward PEGylated proteins (11,12).…”