Conjugation to 10 kDa Linear PEG Extends Serum Half-Life and Preserves the Receptor-Binding Ability of mmTRAIL with Minimal Stimulation of PEG-Specific Antibodies.
Mol Pharm
; 14(2): 502-512, 2017 02 06.
Article
in En
| MEDLINE
| ID: mdl-28029256
ABSTRACT
The poor in vivo potencies of most therapeutic proteins might be attributed to their short serum half-lives. PEGylation is a well-established method and has been clinically proven to improve pharmacokinetics. mmTRAIL exhibited supercytotoxicity in a variety of tumor cells, but its serum half-life was less than 10 min in mice. Here, mmTRAIL-5K, mmTRAIL-10K, and mmTRAIL-20K were produced by N-terminus-specific PEGylation of mmTRAIL with 5, 10, or 20 kDa mPEG, respectively. The particle sizes of mmTRAIL-5K, mmTRAIL-10K, and mmTRAIL-20K were 9.09 ± 2.76, 12.62 ± 4.05, and 15.68 ± 4.95 nm, which were higher than the threshold (â¼7 nm) of renal clearance. Accordingly, mmTRAIL-5K exhibited a serum half-life of 30 min only 3 times longer than that of mmTRAIL. However, both mmTRAIL-10K and mmTRAIL-20K exhibited similar serum half-lives ranging from 350 to 400 min, indicating that PEGylation with 10 or 20 kDa mPEG significantly improved the pharmacokinetics of mmTRAIL. However, death receptor binding of mmTRAIL-20K was reduced 5- to 8-fold, resulting in a 3-fold reduction of cytotoxicity. Additionally, repeated administration of mmTRAIL-20K elicited both mPEG-specific IgG and IgM antibody responses in rats. In contrast, the receptor binding and cytotoxicity of mmTRAIL-10K were similar to those of mmTRAIL. Repeated administration of mmTRAIL-10K did not obviously stimulate mPEG-specific antibody responses in rats and rhesus monkeys. Of the three PEGylated mmTRAIL analogues, mmTRAIL-10K exerted the greatest tumor suppression in mice bearing human tumor xenografts. These results demonstrated that conjugation of mmTRAIL to 10 kDa mPEG was better than that to 5 or 20 kDa mPEG for enhancing antitumor effects.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Polyethylene Glycols
/
TNF-Related Apoptosis-Inducing Ligand
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Antibodies
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Antineoplastic Agents
Limits:
Animals
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Humans
/
Male
Language:
En
Journal:
Mol Pharm
Journal subject:
BIOLOGIA MOLECULAR
/
FARMACIA
/
FARMACOLOGIA
Year:
2017
Document type:
Article
Affiliation country:
China