title: Structural understanding of stabilization patterns in engineered bispecific Ig-like antibody molecules.
abstract: Bispecific immunoglobulin-like antibodies capable of engaging multiple antigens represent a promising new class of therapeutic agents. Engineering of these molecules requires optimization of the molecular properties of one of the domain components. Here, we present a detailed crystallographic and computational characterization of the stabilization patterns in the lymphotoxin-beta receptor (LTbetaR) binding Fv domain of an anti-LTbetaR/anti-TNF-related apoptosis inducing ligand receptor-2 (TRAIL-R2) bispecific immunoglobulin-like antibody. We further describe a new hierarchical structure-guided approach toward engineering of antibody-like molecules to enhance their thermal and chemical stability.
authors.affiliation: Biogen Idec, Inc., 12 Cambridge Center, Cambridge, Massachusetts 02142, USA.
authors.forename: Jacob L
authors.initials: JL
authors.lastname: Jordan
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Arndt
authors.forename: Karl
authors.initials: K
authors.lastname: Hanf
authors.forename: Guohui
authors.initials: G
authors.lastname: Li
authors.forename: Janine
authors.initials: J
authors.lastname: Hall
authors.forename: Stephen
authors.initials: S
authors.lastname: Demarest
authors.forename: Flora
authors.initials: F
authors.lastname: Huang
authors.forename: Xiufeng
authors.initials: X
authors.lastname: Wu
authors.forename: Brian
authors.initials: B
authors.lastname: Miller
authors.forename: Scott
authors.initials: S
authors.lastname: Glaser
authors.forename: Erik J
authors.initials: EJ
authors.lastname: Fernandez
authors.forename: Deping
authors.initials: D
authors.lastname: Wang
authors.forename: Alexey
authors.initials: A
authors.lastname: Lugovskoy
mesh_terms: D018033:Antibodies, Bispecific / Q000737:chemistry* / Q000235:genetics; D003198:Computer Simulation; D030562:Databases, Protein; D007128:Immunoglobulin Fragments / Q000737:chemistry / Q000235:genetics; D053259:Lymphotoxin beta Receptor / Q000276:immunology; D008958:Models, Molecular; D015394:Molecular Structure; D016296:Mutagenesis; D015202:Protein Engineering / Q000379:methods*; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology; D055672:Static Electricity; D013816:Thermodynamics
chemical_list: D018033:Antibodies, Bispecific; D007128:Immunoglobulin Fragments; D053259:Lymphotoxin beta Receptor; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C055966:immunoglobulin Fv