Properties and pharmacokinetics of two humanized antibodies specific for L-selectin.
Immunotechnology
; 4(3-4): 253-66, 1999 Mar.
Article
in En
| MEDLINE
| ID: mdl-10231094
ABSTRACT
BACKGROUND:
The participation of L-selectin in leukocyte recruitment during inflammation has suggested the use of L-selectin inhibitors as potential anti-inflammatory therapeutics. Blocking monoclonal antibodies could serve as such therapeutic agents, particularly if humanized to reduce their immunogenicity and improve their serum half-life.OBJECTIVES:
For this purpose, two mouse monoclonal antibodies, DREG-55 and DREG-200, that block human L-selectin were humanized and characterized. STUDYDESIGN:
The resulting humanized antibodies, HuDREG-55 and HuDREG-200, constructed with human IgG4 constant regions, were evaluated for their specificity, affinity and ability to block L-selectin-dependent adhesion in in vitro assays. Their pharmacokinetic behavior in rhesus monkeys was also studied.RESULTS:
HuDREG-55 and HuDREG-200 were found to retain the specificity and affinity, within 2-fold, of the parent murine antibodies. HuDREG-55 and HuDREG-200 block L-selectin-dependent adhesion of human lymphocytes to high endothelial venules in frozen sections of lymph nodes. In addition, HuDREG-55 and HuDREG-200 are inhibitory in a novel L-selectin-dependent adhesion assay. This assay utilizes flow cytometry to measure binding of polymerized liposomes containing an analog of sialyl Lewis X, sialyl Lewis X glycoliposomes, to peripheral blood neutrophils and lymphocytes. Studying the pharmacokinetics of HuDREG-55 and HuDREG-200 in rhesus monkeys showed terminal elimination half-lives at 12.0 and 20.3 days, respectively.CONCLUSION:
The shorter terminal elimination half-life of HuDREG-55 in rhesus monkeys may be due to the ability of HuDREG-55 but not HuDREG-200 to bind rhesus monkey L-selectin.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
L-Selectin
/
Antibodies, Monoclonal
/
Antibody Affinity
Limits:
Animals
/
Humans
Language:
En
Journal:
Immunotechnology
Journal subject:
BIOLOGIA MOLECULAR
/
BIOQUIMICA
Year:
1999
Document type:
Article
Affiliation country:
Estados Unidos