title: DARPins against a functional IgE epitope.
abstract: The monoclonal anti-IgE antibody omalizumab (Xolair is mostly used for the treatment of severe allergic asthma. However, the requirement of high doses and suboptimal cost-effectiveness limits the use of the treatment. Here we propose to use a new drug format based on non-immunoglobulin structures, potentially offering increased clinical efficacy while being more cost-effective. For this purpose, DARPins™ (designed ankyrin repeat proteins) against the constant heavy chain region of IgE have been isolated. DARPins were binding to IgE with high specificity and affinities in the low nanomolar range. Selected DARPins antagonized the interaction between IgE and its high-affinity receptor in inhibition assays. Furthermore, anti-IgE DARPins were shown to inhibit proinflammatory mediator release from rat basophilic leukemia cells expressing human high-affinity IgE receptors with higher efficacy than the monoclonal anti-IgE antibody omalizumab. DARPins may thus represent promising future drug candidates for the treatment of allergy.
authors.affiliation: Institute of Immunology, University of Bern, Inselspital, Sahlihaus 2, 3010 Bern, Switzerland.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Baumann
authors.forename: Alexander
authors.initials: A
authors.lastname: Eggel
authors.forename: Patrick
authors.initials: P
authors.lastname: Amstutz
authors.forename: Beda M
authors.initials: BM
authors.lastname: Stadler
authors.forename: Monique
authors.initials: M
authors.lastname: Vogel
mesh_terms: D000818:Animals; D017089:Ankyrin Repeat / Q000235:genetics; D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000915:Antibody Affinity; D001249:Asthma / Q000188:drug therapy*; D045744:Cell Line, Tumor; D018985:Epitopes, B-Lymphocyte / Q000276:immunology*; D006801:Humans; D007127:Immunoglobulin Constant Regions / Q000235:genetics; D007073:Immunoglobulin E / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000069444:Omalizumab; D011485:Protein Binding; D015202:Protein Engineering; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000627:therapeutic use; D019076:Transgenes / Q000235:genetics
chemical_list: D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C577317:DARPin E2 79; D018985:Epitopes, B-Lymphocyte; D007127:Immunoglobulin Constant Regions; D011993:Recombinant Fusion Proteins; D000069444:Omalizumab; D007073:Immunoglobulin E