Impact of anti-PEG IgM antibodies on the pharmacokinetics of pegylated asparaginase preparations in mice
| Autor: | Gunda Brandenburg, Joachim Baumgart, Sabine Poppenborg, Julia Wittmann, Ralf Krähmer, Frank Leenders, Wolfgang Walther |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Asparaginase Pharmaceutical Science Antineoplastic Agents macromolecular substances Immunoglobulin G Polyethylene Glycols 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Immune system medicine Animals Pegaspargase biology Chemistry Immunogenicity technology industry and agriculture Antibody titer Recombinant Proteins 030104 developmental biology Immunoglobulin M 030220 oncology & carcinogenesis Immunology biology.protein Female Antibody medicine.drug |
| Zdroj: | European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences. 91 |
| ISSN: | 1879-0720 |
| Popis: | 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 Escherichia colil-asparaginase) - was investigated in immune competent, naive B6D2F1-hybrid mice. To generate anti-PEG antibodies, mice were pre-sensitised by repeated injections of 40kDa 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. |
| Databáze: | OpenAIRE |
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