title: Structural and functional characterization of an agonistic anti-human EphA2 monoclonal antibody.
abstract: We report here the three-dimensional structure of human ephrin type A receptor 2 (EphA2) bound to the Fab (fragment antigen binding) of an agonistic human antibody (1C1; IgG1/κ). The structure of the corresponding complex was solved at a resolution of 2.5 Å using molecular replacement and constitutes the first reported structure of a human ephrin receptor bound to an antibody. We have also defined the corresponding functional epitope using a mutagenesis-based approach. This study revealed discrete structural features that determine the fine specificity of 1C1 to EphA2. Our data also provided a molecular basis for 1C1 mechanism of action. More precisely, we propose that its agonistic, internalizing properties are the result of ligand mimicry by the third heavy-chain complementarity-determining region of 1C1. Because EphA2 is an important contributor to cancer formation and progression, these findings may have implications for designing the next generation of anti-tumor therapies.
authors.affiliation: Department of Antibody Discovery and Protein Engineering, MedImmune, Gaithersburg, MD 20878, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Peng
authors.forename: Vaheh
authors.initials: V
authors.lastname: Oganesyan
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Damschroder
authors.forename: Herren
authors.initials: H
authors.lastname: Wu
authors.forename: William F
authors.initials: WF
authors.lastname: Dall'Acqua
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D018360:Crystallography, X-Ray; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D007074:Immunoglobulin G / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D007145:Immunoglobulin kappa-Chains / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008956:Models, Chemical; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism; D017433:Protein Structure, Secondary; D036104:Receptor, EphA2 / Q000819:agonists* / Q000276:immunology / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014407:Tumor Cells, Cultured
chemical_list: D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D007145:Immunoglobulin kappa-Chains; D036104:Receptor, EphA2