| ATROSAB, a humanized antagonistic anti-tumor necrosis factor receptor one-specific antibody. | |
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MedLine Citation:
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PMID: 20935477 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Tumor necrosis factor (TNF) signals through two membrane receptors, TNFR1 and TNFR2, and TNFR1 is known to be the major pathogenic mediator of chronic and acute inflammatory diseases. Present clinical intervention is based on neutralization of the ligand TNF. Selective inhibition of TNF receptor 1 (TNFR1) provides an alternative opportunity to neutralize the pro-inflammatory activity of TNF while maintaining the advantageous immunological responses mediated by TNFR2, including immune regulation, tissue homeostasis and neuroprotection. We recently humanized a mouse anti-human TNFR1 monoclonal antibody exhibiting TNFR1-neutralizing activity. This humanized antibody has been converted into an IgG1 molecule (ATROSAB) containing a modified Fc region previously demonstrated to have greatly reduced effector functions. Purified ATROSAB, produced in CHO cells, showed strong binding to human and rhesus TNFR1-Fc fusion protein and mouse embryonic fibroblasts transfected with a recombinant TNFR1 fusion protein with an affinity identical to the parental mouse antibody H398. Using chimeric human/mouse TNFR1 molecules, the epitope of ATROSAB was mapped to the N-terminal region (amino acid residues 1-70) comprising the first cysteine-rich domain (CRD1) and the A1 sub-domain of CRD2. In vitro, ATROSAB inhibited typical TNF-mediated responses like apoptosis induction and activation of NFκB-dependent gene expression such as IL-6 and IL-8 production. These findings open the way to further analyze the therapeutic activity of ATROSAB in relevant disease models in non-human primates. |
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Authors:
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Kirstin A Zettlitz; Verena Lorenz; Karlheinz Landauer; Sabine Münkel; Andreas Herrmann; Peter Scheurich; Klaus Pfizenmaier; Roland Kontermann |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-11-01 |
Journal Detail:
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Title: mAbs Volume: 2 ISSN: 1942-0870 ISO Abbreviation: MAbs Publication Date: 2010 Nov-Dec |
Date Detail:
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Created Date: 2010-12-02 Completed Date: 2011-03-22 Revised Date: 2011-11-01 |
Medline Journal Info:
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Nlm Unique ID: 101479829 Medline TA: MAbs Country: United States |
Other Details:
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Languages: eng Pagination: 639-47 Citation Subset: IM |
Affiliation:
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Institut für Zellbiologie und Immunologie, Universität Stuttgart, Stuttgart, Germany. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Sequence Animals Antibodies, Monoclonal / immunology*, pharmacokinetics Antibody Specificity Chromatography, High Pressure Liquid Enzyme-Linked Immunosorbent Assay Epitope Mapping Epitopes Humans Immunoglobulin G / immunology Mice Molecular Sequence Data Protein Structure, Quaternary Receptors, Tumor Necrosis Factor, Type I / antagonists & inhibitors*, immunology |
| Chemical | |
Reg. No./Substance:
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0/Antibodies, Monoclonal; 0/Epitopes; 0/Immunoglobulin G; 0/Receptors, Tumor Necrosis Factor, Type I |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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