Properties and pharmacokinetics of two humanized antibodies specific for L-selectin
| Autor: | Shauna H. Yuan, Jennifer Melrose, Paul R. Hinton, Nicholas F. Landolfi, Jennifer H Tan, Man Sung Co, Corine Klingbeil, Vladimir Vexler, Max Vasquez, Jon O. Nagy, Linda Roark, Ellen L. Berg, Cary L. Queen |
|---|---|
| Rok vydání: | 1999 |
| Předmět: |
medicine.drug_class
Immunology High endothelial venules Molecular Sequence Data Antibody Affinity Immunoglobulin Variable Region Cross Reactions Monoclonal antibody Protein Engineering Transfection Flow cytometry chemistry.chemical_compound Mice Pharmacokinetics Species Specificity Antibody Specificity medicine Cell Adhesion Leukocytes Animals Humans Amino Acid Sequence Cloning Molecular L-Selectin medicine.diagnostic_test biology Chemistry Immunogenicity Antibodies Monoclonal Molecular biology Macaca mulatta Recombinant Proteins Sialyl-Lewis X Liposomes biology.protein L-selectin Immunoglobulin Light Chains Antibody Endothelium Lymphatic Immunoglobulin Heavy Chains |
| Zdroj: | Immunotechnology : an international journal of immunological engineering. 4(3-4) |
| ISSN: | 1380-2933 |
| Popis: | 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. Study design: 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. |
| Databáze: | OpenAIRE |
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