| Structural highlights
Publication Abstract from PubMed
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 Cepsilon3 domain critical for interaction with FcepsilonRI. MEDI4212 potently inhibited responses through FcepsilonRI 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.
A novel IgE-neutralizing antibody for the treatment of severe uncontrolled asthma.,Cohen ES, Dobson CL, Kack H, Wang B, Sims DA, Lloyd CO, England E, Rees DG, Guo H, Karagiannis SN, O'Brien S, Persdotter S, Ekdahl H, Butler R, Keyes F, Oakley S, Carlsson M, Briend E, Wilkinson T, Anderson IK, Monk PD, von Wachenfeldt K, Eriksson PO, Gould HJ, Vaughan TJ, May RD MAbs. 2014 May-Jun;6(3):756-64. doi: 10.4161/mabs.28394. Epub 2014 Feb 28. PMID:24583620[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Cohen ES, Dobson CL, Kack H, Wang B, Sims DA, Lloyd CO, England E, Rees DG, Guo H, Karagiannis SN, O'Brien S, Persdotter S, Ekdahl H, Butler R, Keyes F, Oakley S, Carlsson M, Briend E, Wilkinson T, Anderson IK, Monk PD, von Wachenfeldt K, Eriksson PO, Gould HJ, Vaughan TJ, May RD. A novel IgE-neutralizing antibody for the treatment of severe uncontrolled asthma. MAbs. 2014 May-Jun;6(3):756-64. doi: 10.4161/mabs.28394. Epub 2014 Feb 28. PMID:24583620 doi:https://dx.doi.org/10.4161/mabs.28394
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