دورية أكاديمية
A novel IgE-neutralizing antibody for the treatment of severe uncontrolled asthma.
| العنوان: | A novel IgE-neutralizing antibody for the treatment of severe uncontrolled asthma. |
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| المؤلفون: | Cohen ES; MedImmune Ltd; Cambridge, UK., Dobson CL; MedImmune Ltd; Cambridge, UK., Käck H; 2 AstraZeneca R&D; Mölndal, Sweden., Wang B; MedImmune LLC; Hayward, CA USA., Sims DA; MedImmune PLC; Gaithersburg, MD USA., Lloyd CO; MedImmune Ltd; Cambridge, UK., England E; MedImmune Ltd; Cambridge, UK., Rees DG; MedImmune Ltd; Cambridge, UK., Guo H; 2 AstraZeneca R&D; Mölndal, Sweden., Karagiannis SN; 5 Cutaneous Medicine and Immunotherapy Unit; St. John's Institute of Dermatology; Division of Genetics and Molecular Medicine; King's College London School of Medicine & NIHR Biomedical Research Centre at Guy's and St. Thomas's Hospitals and King's College London; Guy's Hospital; King's College London; London, UK., O'Brien S; MedImmune Ltd; Cambridge, UK., Persdotter S; 2 AstraZeneca R&D; Mölndal, Sweden., Ekdahl H; Labjoy; Lund, Sweeden., Butler R; MedImmune Ltd; Cambridge, UK., Keyes F; MedImmune Ltd; Cambridge, UK., Oakley S; MedImmune Ltd; Cambridge, UK., Carlsson M; 2 AstraZeneca R&D; Mölndal, Sweden., Briend E; MedImmune Ltd; Cambridge, UK., Wilkinson T; MedImmune Ltd; Cambridge, UK., Anderson IK; Johnson & Johnson Innovation; London, UK., Monk PD; Synairgen Research Ltd; Southampton General Hospital; Southampton, UK., von Wachenfeldt K; 9 Truly Translational Sweden AB; Lund, Sweden., Eriksson PO; Spago Imaging AB; Lund, Sweden., Gould HJ; Randall Division of Cell and Molecular Biophysics; Division of Asthma, Allergy and Lung Biology; MRC and Asthma UK Centre for Allergic Mechanisms of Asthma; King's College London; London, UK., Vaughan TJ; MedImmune Ltd; Cambridge, UK., May RD; MedImmune Ltd; Cambridge, UK. |
| المصدر: | MAbs [MAbs] 2014 May-Jun; Vol. 6 (3), pp. 756-64. Date of Electronic Publication: 2014 Feb 28. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Taylor & Francis Country of Publication: United States NLM ID: 101479829 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1942-0870 (Electronic) Linking ISSN: 19420862 NLM ISO Abbreviation: MAbs Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2015- : Philadelphia, PA : Taylor & Francis Original Publication: Austin, TX : Landes Bioscience |
| مواضيع طبية MeSH: | Antibodies, Anti-Idiotypic/*immunology , Antibodies, Anti-Idiotypic/*therapeutic use , Antibodies, Neutralizing/*immunology , Antibodies, Neutralizing/*therapeutic use , Asthma/*immunology , Asthma/*therapy , Immunoglobulin E/*immunology, Adolescent ; Adult ; Aged ; Antibodies, Anti-Idiotypic/genetics ; Antibodies, Monoclonal, Humanized/therapeutic use ; Antibodies, Neutralizing/genetics ; Antibody Affinity ; Antibody Specificity ; Antigen-Antibody Complex/chemistry ; Antigen-Antibody Complex/immunology ; Antigen-Antibody Reactions ; Binding Sites ; Cohort Studies ; Humans ; Immunoglobulin E/chemistry ; Immunoglobulin E/metabolism ; Immunoglobulin G/genetics ; Immunoglobulin G/immunology ; Immunoglobulin G/therapeutic use ; Middle Aged ; Models, Molecular ; Omalizumab ; Peptide Library ; Receptors, IgE/metabolism ; Young Adult |
| مستخلص: | The critical role played by IgE in allergic asthma is well-documented and clinically precedented, but some patients in whom IgE neutralization may still offer clinical benefit are excluded from treatment with the existing anti-IgE therapy, omalizumab, due to high total IgE levels or body mass. In this study, we sought to generate a novel high affinity anti-IgE antibody (MEDI4212) with potential to treat a broad severe asthma patient population. Analysis of body mass, total and allergen-specific IgE levels in a cohort of severe asthmatics was used to support the rationale for development of a high affinity IgE-targeted antibody therapeutic. Phage display technology was used to generate a human IgG1 lead antibody, MEDI4212, which was characterized in vitro using binding, signaling and functional assay systems. Protein crystallography was used to determine the details of the interaction between MEDI4212 and IgE. MEDI4212 bound human IgE with an affinity of 1.95 pM and was shown to target critical residues in the IgE Cε3 domain critical for interaction with FcεRI. MEDI4212 potently inhibited responses through FcεRI and also prevented the binding of IgE to CD23. When used ex vivo at identical concentration, MEDI4212 depleted free-IgE from human sera to levels ~1 log lower than omalizumab. Our results thus indicate that MEDI4212 is a novel, high affinity antibody that binds specifically to IgE and prevents IgE binding to its receptors. MEDI4212 effectively depleted free-IgE from human sera ex vivo to a level (1 IU/mL) anticipated to provide optimal IgE suppression in severe asthma patients. |
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| معلومات مُعتمدة: | G1000758 United Kingdom MRC_ Medical Research Council; G1100090 United Kingdom MRC_ Medical Research Council |
| فهرسة مساهمة: | Keywords: IgE; MEDI4212; allergen-specific IgE; anti-IgE; antibody therapeutic; asthma; monoclonal antibody; severe asthma |
| المشرفين على المادة: | 0 (Antibodies, Anti-Idiotypic) 0 (Antibodies, Monoclonal, Humanized) 0 (Antibodies, Neutralizing) 0 (Antigen-Antibody Complex) 0 (Immunoglobulin G) 0 (Peptide Library) 0 (Receptors, IgE) 0 (anti-IgE antibodies) 2P471X1Z11 (Omalizumab) 37341-29-0 (Immunoglobulin E) |
| تواريخ الأحداث: | Date Created: 20140304 Date Completed: 20150512 Latest Revision: 20220129 |
| رمز التحديث: | 20221213 |
| مُعرف محوري في PubMed: | PMC7098617 |
| DOI: | 10.4161/mabs.28394 |
| PMID: | 24583620 |
| قاعدة البيانات: | MEDLINE |
PDF full text from Publisher | تدمد: | 1942-0870 |
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| DOI: | 10.4161/mabs.28394 |