title: Design of a heterobivalent ligand to inhibit IgE clustering on mast cells.
abstract: We describe the design, synthesis, and characterization of a heterobivalent ligand (HBL) system that competitively inhibits allergen binding to mast cell bound IgE antibody, thereby inhibiting mast cell degranulation. HBLs are composed of a hapten conjugated to a nucleotide analog allowing simultaneous targeting of the antigen-binding site as well the "unconventional nucleotide binding site" on IgE Fab domains. Simultaneous bivalent binding to both sites provides HBLs with over 100-fold enhancement both in avidity for IgE(DNP) (K(d) = 0.33 μM) and in inhibition of allergen binding to IgE(DNP) (IC(50) = 0.45 μM) than the monovalent hapten (K(d)(mono) = 41 μM; IC(50)(mono) = 55.4 μM, respectively). In cellular assays, HBL2 effectively inhibits mast cell degranulation (IC(50) = 15 μM), whereas no inhibition is detected by the monovalent hapten. In conclusion, this study establishes the use of multivalency in a novel HBL design to inhibit mast cell degranulation.
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Handlogten
authors.forename: Tanyel
authors.initials: T
authors.lastname: Kiziltepe
authors.forename: Demetri T
authors.initials: DT
authors.lastname: Moustakas
authors.forename: Başar
authors.initials: B
authors.lastname: Bilgiçer
mesh_terms: D000485:Allergens / Q000737:chemistry; D001666:Binding Sites, Antibody; D015550:Cell Degranulation; D006801:Humans; D007073:Immunoglobulin E / Q000737:chemistry / Q000378:metabolism*; D008024:Ligands; D008407:Mast Cells / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D017455:Receptors, IgE / Q000276:immunology / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D000485:Allergens; D008024:Ligands; D017455:Receptors, IgE; D007073:Immunoglobulin E