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

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• 作者：Sabine M. Poppenborg^a ; ^{s.poppenborg@medac.de" class="auth_mail" title="E-mail the corresponding author} ; Julia Wittmann^b ; ^{j.wittmann@celares.com" class="auth_mail" title="E-mail the corresponding author} ; Wolfgang Walther^c ; ^{Wolfgang.Walther@epo-berlin.com" class="auth_mail" title="E-mail the corresponding author} ; Gunda Brandenburg^a ; ^{g.brandenburg@medac.de" class="auth_mail" title="E-mail the corresponding author} ; Ralf Krä ; hmer^b ; ^{r.kraehmer@celares.com" class="auth_mail" title="E-mail the corresponding author} ; Joachim Baumgart^a ; ^{j.baumgart@medac.de" class="auth_mail" title="E-mail the corresponding author} ; Frank Leenders^b ; ^{f.leenders@celares.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：ALL ; acute lymphoblastic leukemia ; ASNase ; l-asparaginase ; AUC ; area under the curve ; CL ; total plasma clearance ; ELISA ; enzyme-linked immunosorbent assay ; PD ; pharmacodynamics ; PEG-rASNase ; pegylated recombinant E. colil-Asparaginase ; PEG ; polyethylene glycol ; PK ; pharmacokinetics
• 刊名：European Journal of Pharmaceutical Sciences
• 出版年：2016
• 出版时间：25 August 2016
• 年：2016
• 卷：91
• 期：Complete
• 页码：122-130
• 全文大小：771 K

文摘

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, 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.