دورية أكاديمية
Kinetic approach to pathway attenuation using XOMA 052, a regulatory therapeutic antibody that modulates interleukin-1beta activity.
| العنوان: | Kinetic approach to pathway attenuation using XOMA 052, a regulatory therapeutic antibody that modulates interleukin-1beta activity. |
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| المؤلفون: | Roell MK; Preclinical Research Department, XOMA (US) LLC, Berkeley, CA 94710, USA. roell@xoma.com, Issafras H, Bauer RJ, Michelson KS, Mendoza N, Vanegas SI, Gross LM, Larsen PD, Bedinger DH, Bohmann DJ, Nonet GH, Liu N, Lee SR, Handa M, Kantak SS, Horwitz AH, Hunter JJ, Owyang AM, Mirza AM, Corbin JA, White ML |
| المصدر: | The Journal of biological chemistry [J Biol Chem] 2010 Jul 02; Vol. 285 (27), pp. 20607-14. Date of Electronic Publication: 2010 Apr 21. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology |
| مواضيع طبية MeSH: | Antibodies, Monoclonal/*pharmacology , Interleukin-1beta/*physiology, Antibodies, Monoclonal/therapeutic use ; Antibodies, Monoclonal, Humanized ; Bioengineering ; Fibroblasts/cytology ; Fibroblasts/physiology ; HeLa Cells/drug effects ; HeLa Cells/physiology ; Homeostasis/drug effects ; Homeostasis/physiology ; Humans ; Interleukin-1/physiology ; Interleukin-1beta/drug effects ; Kidney/drug effects ; Kidney/physiology ; Kinetics ; Ligands ; Luciferases/genetics ; Lung/cytology ; Lung/physiology ; NF-kappa B/physiology ; Phosphoproteins/drug effects ; Phosphoproteins/metabolism ; Receptors, Interleukin-1/drug effects ; Receptors, Interleukin-1/physiology ; Recombinant Proteins/pharmacology ; Recombinant Proteins/therapeutic use ; Signal Transduction/drug effects ; Signal Transduction/physiology |
| مستخلص: | Many therapeutic antibodies act as antagonists to competitively block cellular signaling pathways. We describe here an approach for the therapeutic use of monoclonal antibodies based on context-dependent attenuation to reduce pathologically high activity while allowing homeostatic signaling in biologically important pathways. Such attenuation is achieved by modulating the kinetics of a ligand binding to its various receptors and regulatory proteins rather than by complete blockade of signaling pathways. The anti-interleukin-1beta (IL-1beta) antibody XOMA 052 is a potent inhibitor of IL-1beta activity that reduces the affinity of IL-1beta for its signaling receptor and co-receptor but not for its decoy and soluble inhibitory receptors. This mechanism shifts the effective dose response of the cytokine so that the potency of IL-1beta bound by XOMA 052 is 20-100-fold lower than that of IL-1beta in the absence of antibody in a variety of in vitro cell-based assays. We propose that by decreasing potency of IL-1beta while allowing binding to its clearance and inhibitory receptors, XOMA 052 treatment will attenuate IL-1beta activity in concert with endogenous regulatory mechanisms. Furthermore, the ability to bind the decoy receptor may reduce the potential for accumulation of antibody.target complexes. Regulatory antibodies like XOMA 052, which selectively modulate signaling pathways, may represent a new mechanistic class of therapeutic antibodies. |
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| المشرفين على المادة: | 0 (Antibodies, Monoclonal) 0 (Antibodies, Monoclonal, Humanized) 0 (Interleukin-1) 0 (Interleukin-1beta) 0 (Ligands) 0 (NF-kappa B) 0 (Phosphoproteins) 0 (Receptors, Interleukin-1) 0 (Recombinant Proteins) EC 1.13.12.- (Luciferases) QX3JU54GYQ (gevokizumab) |
| تواريخ الأحداث: | Date Created: 20100423 Date Completed: 20100810 Latest Revision: 20211020 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC2898365 |
| DOI: | 10.1074/jbc.M110.115790 |
| PMID: | 20410301 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1083-351X |
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| DOI: | 10.1074/jbc.M110.115790 |