title: A metalloantibody that irreversibly binds a protein antigen.
abstract: Antibody affinity is critically important in therapeutic applications, as well as steady state diagnostic assays. Picomolar affinity antibodies, approaching the association limit of protein-protein interactions, have been discovered for highly potent antigens, but even such high-affinity binders have off-rates sufficient to negate therapeutic efficacy. To cross this affinity threshold, antibodies that tether their targets in a manner other than reversible non-covalent interaction will be required. Here we report the design and construction of an antibody that forms an irreversible complex with a protein antigen in a metal-dependent reaction. The complex resists thermal and chemical denaturation, as well as attempts to remove the coordinating metal ion. Such irreversibly binding antibodies could facilitate the development of next generation "reactive antibody" therapeutics and diagnostics.
authors.affiliation: IntegriGen, Inc., Novato, California 94949, USA.
authors.forename: Kirk
authors.initials: K
authors.lastname: Trisler
authors.forename: Loren L
authors.initials: LL
authors.lastname: Looger
authors.forename: Vikram
authors.initials: V
authors.lastname: Sharma
authors.forename: Martin
authors.initials: M
authors.lastname: Baker
authors.forename: David E
authors.initials: DE
authors.lastname: Benson
authors.forename: Sunia
authors.initials: S
authors.lastname: Trauger
authors.forename: Peter G
authors.initials: PG
authors.lastname: Schultz
authors.forename: Vaughn V
authors.initials: VV
authors.lastname: Smider
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D000915:Antibody Affinity / Q000235:genetics; D000941:Antigens / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D008670:Metals / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000941:Antigens; D008670:Metals; D014409:Tumor Necrosis Factor-alpha