Source:http://linkedlifedata.com/resource/pubmed/id/20211615
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
1-3
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| pubmed:dateCreated |
2010-7-30
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| pubmed:abstractText |
Human serum and recombinant butyrylcholinesterase (rHuBChE) are the most advanced prophylactics against organophosphate (OP) toxicity due to nerve agent or insecticide exposure. For ethical reasons, such potential multi-use treatments cannot be tested in humans and will require extensive testing in animal models and the "Animal Rule" 21 (21 CFR 601.90) for regulatory approval. This will involve multiple injections of rHuBChE into heterologous animals, e.g. macaques, rodents with inevitable immunogenicity and subsequent elimination of the enzyme on repeat injections. In order to accurately assess pharmacokinetics, efficacy and safety of a candidate rBChE in an "antibody free" system, a homologous macaque (Ma) model has been developed. In these studies, macaques received single or multiple intravenous injections of native MaBChE as well as unmodified or PEG-conjugated forms of rMaBChE produced in CHO cells. Compared to the poor plasma retention of unmodified rBChE (MRT: <10h), three injections of 1.5-2.3mg/kg of PEG-conjugated tetrameric rBChE resulted in high circulatory stability (MRT: >134h) and lack of immunogenicity similar to native MaBChE. PEG-conjugation of the monomeric rMaBChE form also exhibited pharmacokinetic profiles comparable to the tetrameric form (MRT: >113h). However, despite the increased bioavailability of PEG-rBChE, antigenicity studies using sandwich ELISA showed that while macaque BChE was not immunogenic in macaques, PEGylation of rMaBChE did not prevent binding to anti-BChE antibodies, suggesting PEGylation may not be sufficient to mask non-human epitopes on rBChE. This homologous model can provide necessary preclinical protection data for the use of PEG-rHuBChE in humans and bodes well for a safe and efficacious CHO-derived rHuBChE therapeutic.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antibodies,
http://linkedlifedata.com/resource/pubmed/chemical/Antidotes,
http://linkedlifedata.com/resource/pubmed/chemical/Butyrylcholinesterase,
http://linkedlifedata.com/resource/pubmed/chemical/Organophosphorus Compounds,
http://linkedlifedata.com/resource/pubmed/chemical/Polyethylene Glycols,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Proteins
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| pubmed:status |
MEDLINE
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| pubmed:month |
Sep
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| pubmed:issn |
1872-7786
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| pubmed:author | |
| pubmed:copyrightInfo |
Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.
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| pubmed:issnType |
Electronic
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| pubmed:day |
6
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| pubmed:volume |
187
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
279-86
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| pubmed:meshHeading |
pubmed-meshheading:20211615-Amino Acid Sequence,
pubmed-meshheading:20211615-Animals,
pubmed-meshheading:20211615-Antibodies,
pubmed-meshheading:20211615-Antidotes,
pubmed-meshheading:20211615-Butyrylcholinesterase,
pubmed-meshheading:20211615-CHO Cells,
pubmed-meshheading:20211615-Catalytic Domain,
pubmed-meshheading:20211615-Cloning, Molecular,
pubmed-meshheading:20211615-Cricetinae,
pubmed-meshheading:20211615-Cricetulus,
pubmed-meshheading:20211615-Drug Discovery,
pubmed-meshheading:20211615-Enzyme Stability,
pubmed-meshheading:20211615-Humans,
pubmed-meshheading:20211615-Injections,
pubmed-meshheading:20211615-Macaca,
pubmed-meshheading:20211615-Mice,
pubmed-meshheading:20211615-Models, Animal,
pubmed-meshheading:20211615-Molecular Sequence Data,
pubmed-meshheading:20211615-Organophosphorus Compounds,
pubmed-meshheading:20211615-Polyethylene Glycols,
pubmed-meshheading:20211615-Protein Multimerization,
pubmed-meshheading:20211615-Protein Structure, Quaternary,
pubmed-meshheading:20211615-Recombinant Proteins,
pubmed-meshheading:20211615-Sequence Homology, Amino Acid
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| pubmed:year |
2010
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| pubmed:articleTitle |
Demonstration of in vivo stability and lack of immunogenicity of a polyethyleneglycol-conjugated recombinant CHO-derived butyrylcholinesterase bioscavenger using a homologous macaque model.
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| pubmed:affiliation |
PlantVax Inc., Suite 120, 9430 Key West Avenue, Rockville, MD 20850-6350, USA. yjr@plantvax.com
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| pubmed:publicationType |
Journal Article
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