title: Structural and Physical Basis for Anti-IgE Therapy.
abstract: Omalizumab, an anti-IgE antibody, used to treat severe allergic asthma and chronic idiopathic urticaria, binds to IgE in blood or membrane-bound on B lymphocytes but not to IgE bound to its high (FcεRI) or low (CD23) affinity receptor. Mutagenesis studies indicate overlapping FcεRI and omalizumab-binding sites in the Cε3 domain, but crystallographic studies show FcεRI and CD23-binding sites that are far apart, so how can omalizumab block IgE from binding both receptors? We report a 2.42-Å omalizumab-Fab structure, a docked IgE-Fc/omalizumab-Fab structure consistent with available experimental data, and the free energy contributions of IgE residues to binding omalizumab, CD23, and FcεRI. These results provide a structural and physical basis as to why omalizumab cannot bind receptor-bound IgE and why omalizumab-bound IgE cannot bind to CD23/FcεRI. They reveal the key IgE residues and their roles in binding omalizumab, CD23, and FcεRI.
authors.affiliation: 1] Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan [2] The Genomics Research Center, Academia Sinica 115, Taiwan.
authors.forename: Jon D
authors.initials: JD
authors.lastname: Wright
authors.affiliation: The Genomics Research Center, Academia Sinica 115, Taiwan.
authors.forename: Hsing-Mao
authors.initials: HM
authors.lastname: Chu
authors.affiliation: The Genomics Research Center, Academia Sinica 115, Taiwan.
authors.forename: Chun-Hsiang
authors.initials: CH
authors.lastname: Huang
authors.affiliation: The Genomics Research Center, Academia Sinica 115, Taiwan.
authors.forename: Che
authors.initials: C
authors.lastname: Ma
authors.affiliation: The Genomics Research Center, Academia Sinica 115, Taiwan.
authors.forename: Tse Wen
authors.initials: TW
authors.lastname: Chang
authors.affiliation: 1] Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan [2] Department of Chemistry, National Tsing Hua University, Hsinchu 300, Taiwan.
authors.forename: Carmay
authors.initials: C
authors.lastname: Lim
mesh_terms: D000595:Amino Acid Sequence; D018927:Anti-Asthmatic Agents / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use; D000888:Antibodies, Anti-Idiotypic / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy / Q000276:immunology; D001665:Binding Sites / Q000235:genetics; D018360:Crystallography, X-Ray; D006801:Humans; D007073:Immunoglobulin E / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D009154:Mutation; D000069444:Omalizumab / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D017455:Receptors, IgE / Q000737:chemistry / Q000378:metabolism
chemical_list: D018927:Anti-Asthmatic Agents; D000888:Antibodies, Anti-Idiotypic; D017455:Receptors, IgE; C026408:anti-IgE antibodies; D000069444:Omalizumab; D007073:Immunoglobulin E