Structural understanding of stabilization patterns in engineered bispecific Ig-like antibody molecules.
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.
Jordan
Jacob L
JL
Biogen Idec, Inc., 12 Cambridge Center, Cambridge, Massachusetts 02142, USA.
Arndt
Joseph W
JW
Hanf
Karl
K
Li
Guohui
G
Hall
Janine
J
Demarest
Stephen
S
Huang
Flora
F
Wu
Xiufeng
X
Miller
Brian
B
Glaser
Scott
S
Fernandez
Erik J
EJ
Wang
Deping
D
Lugovskoy
Alexey
A
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
D018033:Antibodies, Bispecific; D007128:Immunoglobulin Fragments; D053259:Lymphotoxin beta Receptor; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C055966:immunoglobulin Fv