title: Structural basis of omalizumab therapy and omalizumab-mediated IgE exchange.
abstract: Omalizumab is a widely used therapeutic anti-IgE antibody. Here we report the crystal structure of the omalizumab-Fab in complex with an IgE-Fc fragment. This structure reveals the mechanism of omalizumab-mediated inhibition of IgE interactions with both high- and low-affinity IgE receptors, and explains why omalizumab selectively binds free IgE. The structure of the complex also provides mechanistic insight into a class of disruptive IgE inhibitors that accelerate the dissociation of the high-affinity IgE receptor from IgE. We use this structural data to generate a mutant IgE-Fc fragment that is resistant to omalizumab binding. Treatment with this omalizumab-resistant IgE-Fc fragment, in combination with omalizumab, promotes the exchange of cell-bound full-length IgE with omalizumab-resistant IgE-Fc fragments on human basophils. This combination treatment also blocks basophil activation more efficiently than either agent alone, providing a novel approach to probe regulatory mechanisms underlying IgE hypersensitivity with implications for therapeutic interventions.
authors.affiliation: Department of Structural Biology, Stanford University School of Medicine, Stanford, California 94305, USA.|Progam in Immunology, Stanford University School of Medicine, Stanford, California 94305, USA.|Sean N. Parker Center for Allergy Research at Stanford University, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Luke F
authors.identifier: 0000-0002-7947-8714
authors.initials: LF
authors.lastname: Pennington
authors.affiliation: Department of Structural Biology, Stanford University School of Medicine, Stanford, California 94305, USA.|Sean N. Parker Center for Allergy Research at Stanford University, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Tarchevskaya
authors.affiliation: Department of Rheumatology, Immunology and Allergology, University Hospital Bern, Bern 3012, Switzerland.|Department of Clinical Research, University of Bern, Bern 3012, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Brigger
authors.affiliation: Department of Structural Biology, Stanford University School of Medicine, Stanford, California 94305, USA.|Sean N. Parker Center for Allergy Research at Stanford University, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Karthik
authors.initials: K
authors.lastname: Sathiyamoorthy
authors.affiliation: Sean N. Parker Center for Allergy Research at Stanford University, Stanford University School of Medicine, Stanford, California 94305, USA.|Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Michelle T
authors.initials: MT
authors.lastname: Graham
authors.affiliation: Progam in Immunology, Stanford University School of Medicine, Stanford, California 94305, USA.|Sean N. Parker Center for Allergy Research at Stanford University, Stanford University School of Medicine, Stanford, California 94305, USA.|Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Kari Christine
authors.initials: KC
authors.lastname: Nadeau
authors.affiliation: Department of Rheumatology, Immunology and Allergology, University Hospital Bern, Bern 3012, Switzerland.|Department of Clinical Research, University of Bern, Bern 3012, Switzerland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Eggel
authors.affiliation: Department of Structural Biology, Stanford University School of Medicine, Stanford, California 94305, USA.|Progam in Immunology, Stanford University School of Medicine, Stanford, California 94305, USA.|Sean N. Parker Center for Allergy Research at Stanford University, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Theodore S
authors.initials: TS
authors.lastname: Jardetzky
mesh_terms: D000818:Animals; D018926:Anti-Allergic Agents / Q000737:chemistry / Q000494:pharmacology*; D001491:Basophils / Q000187:drug effects; D002460:Cell Line; D004357:Drug Synergism; D006801:Humans; D007073:Immunoglobulin E / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics; D009154:Mutation; D000069444:Omalizumab / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D017455:Receptors, IgE / Q000037:antagonists & inhibitors*
chemical_list: D018926:Anti-Allergic Agents; D017455:Receptors, IgE; D000069444:Omalizumab; D007073:Immunoglobulin E