A repeated injection of polyethyleneglycol-conjugated recombinant human butyrylcholinesterase elicits immune response in mice
Abstract
Human serum butyrylcholinesterase (Hu BChE) serves as an efficacious bioscavenger of highly toxic organophosphorus (OP) compounds. Since there is a concern that the supply of native Hu BChE may be limited, monomeric and tetrameric forms of recombinant Hu BChE (rHu BChE) were evaluated as replacements and found that they lacked sufficient stability in vivo. However, their in vivo stability could be significantly prolonged by conjugation with polyethyleneglycol-20K (PEG) suggesting that monomeric and tetrameric PEG-rHu BChE could function as bioscavengers. Here, the immunogenicity of PEG-rHu BChE was evaluated in mice following two injections given four weeks apart. In addition to pharmacokinetic parameters, such as mean residence time, maximal concentration, time to reach the maximal concentration, elimination half-life and area under the plasma concentration-time curve extrapolated to infinity, the presence of circulating anti-rHu BChE antibodies was also determined. Although the pharmacokinetic parameters were significantly improved for the first injection of monomeric and tetrameric PEG-rHu BChEs, they were much lower for the second injection. Anti-rHu BChE antibodies were detected in the blood of mice following the first and second enzyme injections and their levels were approximately higher by 5-fold and 2-fold in mice injected with monomeric and tetrameric PEG-rHu BChEs as compared tomore »
- Authors:
-
- Division of Biochemistry, Walter Reed Army Institute of Research, Silver Spring, Maryland, 20910-7500 (United States)
- Publication Date:
- OSTI Identifier:
- 21140967
- Resource Type:
- Journal Article
- Journal Name:
- Toxicology and Applied Pharmacology
- Additional Journal Information:
- Journal Volume: 231; Journal Issue: 3; Other Information: DOI: 10.1016/j.taap.2008.05.016; PII: S0041-008X(08)00240-8; Copyright (c) 2008 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 60 APPLIED LIFE SCIENCES; ANTIBODIES; BLOOD; ENZYMES; HALF-LIFE; IN VIVO; INJECTION; MICE; ORGANIC PHOSPHORUS COMPOUNDS; STABILITY; TOXICITY
Citation Formats
Chilukuri, Nageswararao, Wei, Sun, Parikh, Kalpana, Naik, Ramachandra S, Lin, Tang, Doctor, Bhupendra P, and Saxena, Ashima. A repeated injection of polyethyleneglycol-conjugated recombinant human butyrylcholinesterase elicits immune response in mice. United States: N. p., 2008.
Web. doi:10.1016/j.taap.2008.05.016.
Chilukuri, Nageswararao, Wei, Sun, Parikh, Kalpana, Naik, Ramachandra S, Lin, Tang, Doctor, Bhupendra P, & Saxena, Ashima. A repeated injection of polyethyleneglycol-conjugated recombinant human butyrylcholinesterase elicits immune response in mice. United States. https://doi.org/10.1016/j.taap.2008.05.016
Chilukuri, Nageswararao, Wei, Sun, Parikh, Kalpana, Naik, Ramachandra S, Lin, Tang, Doctor, Bhupendra P, and Saxena, Ashima. 2008.
"A repeated injection of polyethyleneglycol-conjugated recombinant human butyrylcholinesterase elicits immune response in mice". United States. https://doi.org/10.1016/j.taap.2008.05.016.
@article{osti_21140967,
title = {A repeated injection of polyethyleneglycol-conjugated recombinant human butyrylcholinesterase elicits immune response in mice},
author = {Chilukuri, Nageswararao and Wei, Sun and Parikh, Kalpana and Naik, Ramachandra S and Lin, Tang and Doctor, Bhupendra P and Saxena, Ashima},
abstractNote = {Human serum butyrylcholinesterase (Hu BChE) serves as an efficacious bioscavenger of highly toxic organophosphorus (OP) compounds. Since there is a concern that the supply of native Hu BChE may be limited, monomeric and tetrameric forms of recombinant Hu BChE (rHu BChE) were evaluated as replacements and found that they lacked sufficient stability in vivo. However, their in vivo stability could be significantly prolonged by conjugation with polyethyleneglycol-20K (PEG) suggesting that monomeric and tetrameric PEG-rHu BChE could function as bioscavengers. Here, the immunogenicity of PEG-rHu BChE was evaluated in mice following two injections given four weeks apart. In addition to pharmacokinetic parameters, such as mean residence time, maximal concentration, time to reach the maximal concentration, elimination half-life and area under the plasma concentration-time curve extrapolated to infinity, the presence of circulating anti-rHu BChE antibodies was also determined. Although the pharmacokinetic parameters were significantly improved for the first injection of monomeric and tetrameric PEG-rHu BChEs, they were much lower for the second injection. Anti-rHu BChE antibodies were detected in the blood of mice following the first and second enzyme injections and their levels were approximately higher by 5-fold and 2-fold in mice injected with monomeric and tetrameric PEG-rHu BChEs as compared to mice injected with unconjugated enzymes. The findings that the rapid clearance of a repeat injection of PEG-rHu BChEs in mice which coincides with the presence of circulating anti-rHu BChE antibodies suggest that PEG conjugation prolonged the circulatory stability of rHu BChE but failed to eliminate its immunogenicity in mice.},
doi = {10.1016/j.taap.2008.05.016},
url = {https://www.osti.gov/biblio/21140967},
journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 3,
volume = 231,
place = {United States},
year = {Mon Sep 15 00:00:00 EDT 2008},
month = {Mon Sep 15 00:00:00 EDT 2008}
}