title: Inhibition of ErbB3 by a monoclonal antibody that locks the extracellular domain in an inactive configuration.
abstract: ErbB3 (HER3) is a member of the EGF receptor (EGFR) family of receptor tyrosine kinases, which, unlike the other three family members, contains a pseudo kinase in place of a tyrosine kinase domain. In cancer, ErbB3 activation is driven by a ligand-dependent mechanism through the formation of heterodimers with EGFR, ErbB2, or ErbB4 or via a ligand-independent process through heterodimerization with ErbB2 overexpressed in breast tumors or other cancers. Here we describe the crystal structure of the Fab fragment of an antagonistic monoclonal antibody KTN3379, currently in clinical development in human cancer patients, in complex with the ErbB3 extracellular domain. The structure reveals a unique allosteric mechanism for inhibition of ligand-dependent or ligand-independent ErbB3-driven cancers by binding to an epitope that locks ErbB3 in an inactive conformation. Given the similarities in the mechanism of ErbB receptor family activation, these findings could facilitate structure-based design of antibodies that inhibit EGFR and ErbB4 by an allosteric mechanism.
authors.affiliation: Department of Pharmacology, Yale School of Medicine, New Haven, CT 06520;
authors.forename: Sangwon
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, Yale School of Medicine, New Haven, CT 06520;
authors.forename: Etienne B
authors.initials: EB
authors.lastname: Greenlee
authors.affiliation: Department of Pharmacology, Yale School of Medicine, New Haven, CT 06520;
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Amick
authors.affiliation: Kolltan Pharmaceuticals, Inc., New Haven, CT 06511.
authors.forename: Gwenda F
authors.initials: GF
authors.lastname: Ligon
authors.affiliation: Kolltan Pharmaceuticals, Inc., New Haven, CT 06511.
authors.forename: Jay S
authors.initials: JS
authors.lastname: Lillquist
authors.affiliation: Kolltan Pharmaceuticals, Inc., New Haven, CT 06511.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Natoli
authors.affiliation: Kolltan Pharmaceuticals, Inc., New Haven, CT 06511.
authors.forename: Yaron
authors.initials: Y
authors.lastname: Hadari
authors.affiliation: Kolltan Pharmaceuticals, Inc., New Haven, CT 06511.
authors.forename: Diego
authors.initials: D
authors.lastname: Alvarado
authors.affiliation: Department of Pharmacology, Yale School of Medicine, New Haven, CT 06520; Joseph.Schlessinger@Yale.edu.
authors.forename: Joseph
authors.initials: J
authors.lastname: Schlessinger
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000494:pharmacology*; D003461:Crystallography; D004797:Enzyme-Linked Immunosorbent Assay; D005110:Extracellular Space; D005434:Flow Cytometry; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors* / Q000737:chemistry*
chemical_list: D000911:Antibodies, Monoclonal; C581292:ERBB3 protein, human; D020893:Receptor, ErbB-3
keywords: cancer; cell signaling; crystal structure; surface receptor; therapeutic antibodies