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Impact of anti-PEG IgM antibodies on the pharmacokinetics of pegylated asparaginase preparations in mice

Item Type:Article
Title:Impact of anti-PEG IgM antibodies on the pharmacokinetics of pegylated asparaginase preparations in mice
Creators Name:Poppenborg, S.M. and Wittmann, J. and Walther, W. and Brandenburg, G. and Kraehmer, R. and Baumgart, J. and Leenders, F.
Abstract:The potential impact of pre-existing anti-PEG antibodies on the asparaginase activity kinetics of two pegylated L-Asparaginase preparations -pegylated recombinant L-Asparaginase (PEG-rASNase MC0609) and pegaspargase (pegylated E. coli L-Asparaginase) - was investigated in immune competent, naïve B6D2F1-hybrid mice. To generate anti-PEG antibodies, mice were pre-sensitised by repeated injections of 40 kDa PEG-Diol without being conjugated to a carrier. Successful PEG-Diol pre-sensitisation was verified by analysis of anti-PEG antibody titers in serum. 88 - 100 % of animals developed PEG-specific anti-PEG IgM antibodies after PEG-Diol pre-sensitisation. All animals positive for anti-PEG IgM antibodies and control animals (without prior PEG-Diol pre-sensitisation) were treated once with PEG-rASNase MC0609 or pegaspargase, and asparaginase enzyme activity levels and immunogenicity of both preparations were analysed. Known serum asparaginase activity profiles were measured after treatment with PEG-rASNase MC0609 or pegaspargase in all treatment groups. No rapid decrease of asparaginase activity was observed - irrespective of successful PEG-Diol pre-sensitisation and presence of acquired anti-drug-IgG and/or anti-PEG IgM antibodies. In conclusion, the pharmacokinetics of pegylated L-asparaginase was unaffected by the presence of pre-existing anti-PEG IgM antibodies in immune competent B6D2F1-hybrid mice Probably the titre or affinity of these anti-PEG IgM antibodies were too low to influence the pharmacokinetics of PEG-rASNase MC0609 or pegaspargase or anti-PEG IgM antibodies bound to PEG-ASNase without neutralising capabilities. Thus, early loss of asparaginase activity as observed in serum of ALL patients is a complex process and cannot be explained solely by the existence of pre-existing anti-PEG antibodies.
Keywords:Anti-Peg Antibodies, L-Asparaginase, Pharmacokinetics, Immunogenicity, PEGylation, Animals, Mice
Source:European Journal of Pharmaceutical Sciences
Publisher:Elsevier (The Netherlands)
Page Range:122-130
Date:25 August 2016
Official Publication:https://doi.org/10.1016/j.ejps.2016.06.007
PubMed:View item in PubMed

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