5ANM

Crystal structure of IgE Fc in complex with a neutralizing antibody

5ANM の概要

• エントリーDOI: 10.2210/pdb5anm/pdb
• 関連するPDBエントリー: 5ANS 5ANT
• 分子名称: IMMUNOGLOBULIN G, IG EPSILON CHAIN C REGION, alpha-D-mannopyranose-(1-3)-alpha-D-mannopyranose-(1-6)-[alpha-D-mannopyranose-(1-3)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total)
• 機能のキーワード: immune system, therapeutic antibody, igg, ige, asthma
• 由来する生物種: HOMO SAPIENS (HUMAN); 詳細
• タンパク質・核酸の鎖数: 9
• 化学式量合計: 228131.06

構造登録者

Cohen, E.S.,Dobson, C.L.,Kack, H.,Wang, B.,Sims, D.A.,Lloyd, C.O.,England, E.,Rees, D.G.,Guo, H.,Karagiannis, S.N.,O'Brien, S.,Persdotter, S.,Ekdahl, H.,Butler, R.,Keyes, F.,Oakley, S.,Carlsson, M.,Briend, E.,Wilkinson, T.,Anderson, I.K.,Monk, P.D.,vonWachenfeldt, K.,Eriksson, P.O.,Gould, H.J.,Vaughan, T.J.,May, R.D. (登録日: 2015-09-07, 公開日: 2015-09-30, 最終更新日: 2024-10-16)

主引用文献

Cohen, E.S.,Dobson, C.L.,Kack, H.,Wang, B.,Sims, D.A.,Lloyd, C.O.,England, E.,Rees, D.G.,Guo, H.,Karagiannis, S.N.,O'Brien, S.,Persdotter, S.,Ekdahl, H.,Butler, R.,Keyes, F.,Oakley, S.,Carlsson, M.,Briend, E.,Wilkinson, T.,Anderson, I.K.,Monk, P.D.,Von Wachenfeldt, K.,Eriksson, P.F.,Gould, H.J.,Vaughan, T.J.,May, R.D.
A Novel Ige-Neutralizing Antibody for the Treatment of Severe Uncontrolled Asthma.
Mabs, 6:756-, 2015

PubMed Abstract: 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.

PubMed: 24583620
DOI: 10.4161/MABS.28394

実験手法

X-RAY DIFFRACTION (2.85 Å)