Epitopes described in "Redesign of a cross-reactive antibody to dengue virus with broad-spectrum activity and increased in vivo potency."

Article Authors:Kannan Tharakaraman; Luke N Robinson; Andrew Hatas; Yi-Ling Chen; Liu Siyue; S Raguram; V Sasisekharan; Gerald N Wogan; Ram Sasisekharan
Article Title:Redesign of a cross-reactive antibody to dengue virus with broad-spectrum activity and increased in vivo potency.
Reference Detail
Reference ID:1025731
Abstract:Affinity improvement of proteins, including antibodies, by computational chemistry broadly relies on physics-based energy functions coupled with refinement. However, achieving significant enhancement of binding affinity (>10-fold) remains a challenging exercise, particularly for cross-reactive antibodies. We describe here an empirical approach that captures key physicochemical features common to antigen-antibody interfaces to predict protein-protein interaction and mutations that confer increased affinity. We apply this approach to the design of affinity-enhancing mutations in 4E11, a potent cross-reactive neutralizing antibody to dengue virus (DV), without a crystal structure. Combination of predicted mutations led to a 450-fold improvement in affinity to serotype 4 of DV while preserving, or modestly increasing, affinity to serotypes 1-3 of DV. We show that increased affinity resulted in strong in vitro neutralizing activity to all four serotypes, and that the redesigned antibody has potent antiviral activity in a mouse model of DV challenge. Our findings demonstrate an empirical computational chemistry approach for improving protein-protein docking and engineering antibody affinity, which will help accelerate the development of clinically relevant antibodies.
Affiliations:Department of Biological Engineering, Infectious Diseases Interdisciplinary Research Group, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Reference Type:Literature
PubMed ID:23569282
Journal:Proc Natl Acad Sci U S A
Journal Volume:110
Article Pages:E1555-64
Journal ISSN:0027-8424
Article Chemical List:gov.nih.nlm.ncbi.www.jaxb.impl.NameOfSubstanceImpl@7baa354f;gov.nih.nlm.ncbi.www.jaxb.impl.NameOfSubstanceImpl@639214f6;gov.nih.nlm.ncbi.www.jaxb.impl.NameOfSubstanceImpl@b9e558c
Article MeSH List:Animals; Antibodies, Neutralizing(biosynthesis); Antibodies, Viral(biosynthesis); Antibody Affinity(genetics); Binding Sites, Antibody(genetics); Cross Reactions(immunology); Dengue Virus(immunology); Enzyme-Linked Immunosorbent Assay; Epitopes(genetics); Mice; Models, Immunological; Protein Binding; Protein Engineering(methods); Real-Time Polymerase Chain Reaction; Surface Plasmon Resonance
Curation Last Updated:2015-01-18 00:48:10