Impact of anti-PEG IgM antibodies on the pharmacokinetics of pegylated asparaginase preparations in mice.
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 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.
medac Gesellschaft für klinische Spezialpräparate mbH, Theaterstr. 6, 22880 Wedel, Germany. Electronic address: s.poppenborg@medac.de.
Sabine M
SM
Poppenborg
celares GmbH, Robert-Rössle-Straße 10, Geb. D80, 13125 Berlin, Germany. Electronic address: j.wittmann@celares.com.
Julia
J
Wittmann
Experimental and Clinical Research Center, Charité University Medicine Berlin, and Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str. 10, 13125 Berlin, Germany. Electronic address: Wolfgang.Walther@epo-berlin.com.
Wolfgang
W
Walther
medac Gesellschaft für klinische Spezialpräparate mbH, Theaterstr. 6, 22880 Wedel, Germany. Electronic address: g.brandenburg@medac.de.
Gunda
G
Brandenburg
celares GmbH, Robert-Rössle-Straße 10, Geb. D80, 13125 Berlin, Germany. Electronic address: r.kraehmer@celares.com.
Ralf
R
Krähmer
medac Gesellschaft für klinische Spezialpräparate mbH, Theaterstr. 6, 22880 Wedel, Germany. Electronic address: j.baumgart@medac.de.
Joachim
J
Baumgart
celares GmbH, Robert-Rössle-Straße 10, Geb. D80, 13125 Berlin, Germany. Electronic address: f.leenders@celares.com.
Frank
F
Leenders
D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000276:immunology / Q000493:pharmacokinetics; D001215:Asparaginase / Q000037:antagonists & inhibitors / Q000097:blood / Q000276:immunology / Q000493:pharmacokinetics; D005260:Female; D007074:Immunoglobulin G / Q000097:blood* / Q000276:immunology; D007075:Immunoglobulin M / Q000097:blood* / Q000276:immunology; D051379:Mice; D011092:Polyethylene Glycols / Q000493:pharmacokinetics; D011994:Recombinant Proteins / Q000097:blood / Q000276:immunology / Q000493:pharmacokinetics
D000970:Antineoplastic Agents; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; C042705:pegaspargase; D001215:Asparaginase
Anti-PEG antibodies; Immunogenicity; Mouse; PEGylation; Pharmacokinetics; l-asparaginase