ArticlePloS one2014
Affinity improvement of a therapeutic antibody by structure-based computational design: generation of electrostatic interactions in the transition state stabilizes the antibody-antigen complex.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed.
- Computational methods in physical virology: a critical perspective across lengths and timescales.FEMS microbiology reviews · 2026Review
- intDesc-AbMut: A Tool for Describing and Understanding How Antibody Mutations Impact Their Environmental Interactions.Computational and structural biotechnology journal · 2026Article
- Antibody Affinity Maturation by Computational Design.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Molecular mechanistic insights into the OX40-OX40L complex from biophysical and computational analyses.Protein science : a publication of the Protein Society · 2026Article
- Biophysics of SARS-CoV-2 spike protein's receptor-binding domain interaction with ACE2 and neutralizing antibodies: from computation to functional insights.Biophysical reviews · 2025Review
- Enabling the immune escaped etesevimab fully-armed against SARS-CoV-2 Omicron subvariants including KP.2.hLife · 2025Article
- From immune evasion to broadFrontiers in immunology · 2025Article
- Computational electrostatic engineering of nanobodies for enhanced SARS-CoV-2 receptor binding domain recognition.Frontiers in molecular biosciences · 2025Article
- High-throughput analysis system of interaction kinetics for data-driven antibody design.Scientific reports · 2023Article
- In Vitro Affinity Maturation of Nanobodies against Mpox Virus A29 Protein Based on Computer-Aided Design.Molecules (Basel, Switzerland) · 2023Article
- Arginine cluster introduction on framework region in anti-lysozyme antibody improved association rate constant by changing conformational diversity of CDR loops.Protein science : a publication of the Protein Society · 2023Article
- The validation of artificial anti-monkeypox antibodies by in silico and experimental approaches.Immunity, inflammation and disease · 2023Article
- How can we discover developable antibody-based biotherapeutics?Frontiers in molecular biosciences · 2023Review
- Analytical Method for Experimental Validation of Computer-Designed Antibody.Methods in molecular biology (Clifton, N.J.) · 2023Article
- Structure-Based Affinity Maturation of Antibody Based on Double-Point Mutations.Methods in molecular biology (Clifton, N.J.) · 2023Article
- In Silico Maturation of a Nanomolar Antibody against the Human CXCR2.Biomolecules · 2022Article
- RosettaSurf-A surface-centric computational design approach.PLoS computational biology · 2022Article
- Delicate balance among thermal stability, binding affinity, and conformational space explored by single-domain VScientific reports · 2021Article
- IsAb: a computational protocol for antibody design.Briefings in bioinformatics · 2021Article
- Article
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Authors and funding
9 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The optimization of antibodies is a desirable goal towards the development of better therapeutic strategies. The antibody 11K2 was previously developed as a therapeutic tool for inflammatory diseases, and displays very high affinity (4.6 pM) for its antigen the chemokine MCP-1 (monocyte chemo-attractant protein-1). We have employed a virtual library of mutations of 11K2 to identify antibody variants of potentially higher affinity, and to establish benchmarks in the engineering of a mature therapeutic antibody. The most promising candidates identified in the virtual screening were examined by surface plasmon resonance to validate the computational predictions, and to characterize their binding affinity and key thermodynamic properties in detail. Only mutations in the light-chain of the antibody are effective at enhancing its affinity for the antigen in vitro, suggesting that the interaction surface of the heavy-chain (dominated by the hot-spot residue Phe101) is not amenable to optimization. The single-mutation with the highest affinity is L-N31R (4.6-fold higher affinity than wild-type antibody). Importantly, all the single-mutations showing increase affinity incorporate a charged residue (Arg, Asp, or Glu). The characterization of the relevant thermodynamic parameters clarifies the energetic mechanism. Essentially, the formation of new electrostatic interactions early in the binding reaction coordinate (transition state or earlier) benefits the durability of the antibody-antigen complex. The combination of in silico calculations and thermodynamic analysis is an effective strategy to improve the affinity of a matured therapeutic antibody.
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