title: A novel IgE-neutralizing antibody for the treatment of severe uncontrolled asthma.
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.
authors.affiliation: MedImmune Ltd; Cambridge, UK.
authors.forename: E Suzanne
authors.initials: ES
authors.lastname: Cohen
authors.affiliation: MedImmune Ltd; Cambridge, UK.
authors.forename: Claire L
authors.initials: CL
authors.lastname: Dobson
authors.affiliation: 2 AstraZeneca R&D; Mölndal, Sweden.
authors.forename: Helena
authors.initials: H
authors.lastname: Käck
authors.affiliation: MedImmune LLC; Hayward, CA USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.affiliation: MedImmune PLC; Gaithersburg, MD USA.
authors.forename: Dorothy A
authors.initials: DA
authors.lastname: Sims
authors.affiliation: MedImmune Ltd; Cambridge, UK.
authors.forename: Christopher O
authors.initials: CO
authors.lastname: Lloyd
authors.affiliation: MedImmune Ltd; Cambridge, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: England
authors.affiliation: MedImmune Ltd; Cambridge, UK.
authors.forename: D Gareth
authors.initials: DG
authors.lastname: Rees
authors.affiliation: 2 AstraZeneca R&D; Mölndal, Sweden.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Guo
authors.affiliation: 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.
authors.forename: Sophia N
authors.initials: SN
authors.lastname: Karagiannis
authors.affiliation: MedImmune Ltd; Cambridge, UK.
authors.forename: Siobhan
authors.initials: S
authors.lastname: O'Brien
authors.affiliation: 2 AstraZeneca R&D; Mölndal, Sweden.
authors.forename: Sofia
authors.initials: S
authors.lastname: Persdotter
authors.affiliation: Labjoy; Lund, Sweeden.
authors.forename: Helena
authors.initials: H
authors.lastname: Ekdahl
authors.affiliation: MedImmune Ltd; Cambridge, UK.
authors.forename: Robin
authors.initials: R
authors.lastname: Butler
authors.affiliation: MedImmune Ltd; Cambridge, UK.
authors.forename: Feenagh
authors.initials: F
authors.lastname: Keyes
authors.affiliation: MedImmune Ltd; Cambridge, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Oakley
authors.affiliation: 2 AstraZeneca R&D; Mölndal, Sweden.
authors.forename: Mats
authors.initials: M
authors.lastname: Carlsson
authors.affiliation: MedImmune Ltd; Cambridge, UK.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Briend
authors.affiliation: MedImmune Ltd; Cambridge, UK.
authors.forename: Trevor
authors.initials: T
authors.lastname: Wilkinson
authors.affiliation: Johnson & Johnson Innovation; London, UK.
authors.forename: Ian K
authors.initials: IK
authors.lastname: Anderson
authors.affiliation: Synairgen Research Ltd; Southampton General Hospital; Southampton, UK.
authors.forename: Phillip D
authors.initials: PD
authors.lastname: Monk
authors.affiliation: 9 Truly Translational Sweden AB; Lund, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: von Wachenfeldt
authors.affiliation: Spago Imaging AB; Lund, Sweden.
authors.forename: Per-Olof F
authors.initials: PO
authors.lastname: Eriksson
authors.affiliation: 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.
authors.forename: Hannah J
authors.initials: HJ
authors.lastname: Gould
authors.affiliation: MedImmune Ltd; Cambridge, UK.
authors.forename: Tristan J
authors.initials: TJ
authors.lastname: Vaughan
authors.affiliation: MedImmune Ltd; Cambridge, UK.
authors.forename: Richard D
authors.initials: RD
authors.lastname: May
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000888:Antibodies, Anti-Idiotypic / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D057134:Antibodies, Neutralizing / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use*; D000915:Antibody Affinity; D000918:Antibody Specificity; D000936:Antigen-Antibody Complex / Q000737:chemistry / Q000276:immunology; D000937:Antigen-Antibody Reactions; D001249:Asthma / Q000276:immunology* / Q000628:therapy*; D001665:Binding Sites; D015331:Cohort Studies; D006801:Humans; D007073:Immunoglobulin E / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D008875:Middle Aged; D008958:Models, Molecular; D000069444:Omalizumab; D019151:Peptide Library; D017455:Receptors, IgE / Q000378:metabolism; D055815:Young Adult
chemical_list: D000888:Antibodies, Anti-Idiotypic; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; D000936:Antigen-Antibody Complex; D007074:Immunoglobulin G; D019151:Peptide Library; D017455:Receptors, IgE; C026408:anti-IgE antibodies; D000069444:Omalizumab; D007073:Immunoglobulin E
keywords: IgE; MEDI4212; allergen-specific IgE; anti-IgE; antibody therapeutic; asthma; monoclonal antibody; severe asthma