Structural understanding of stabilization patterns in engineered bispecific Ig-like antibody molecules

Proteins. 2009 Dec;77(4):832-41. doi: 10.1002/prot.22502.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antibodies, Bispecific / chemistry*
  • Antibodies, Bispecific / genetics
  • Computer Simulation
  • Databases, Protein
  • Immunoglobulin Fragments / chemistry
  • Immunoglobulin Fragments / genetics
  • Lymphotoxin beta Receptor / immunology
  • Models, Molecular
  • Molecular Structure
  • Mutagenesis
  • Protein Engineering / methods*
  • Protein Stability
  • Protein Structure, Tertiary
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / immunology
  • Static Electricity
  • Thermodynamics

Substances

  • Antibodies, Bispecific
  • Immunoglobulin Fragments
  • Lymphotoxin beta Receptor
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • immunoglobulin Fv