OptMAVEn—a new framework for the de novo design of antibody variable region models targeting specific antigen epitopes
Open accessAbstract
Antibody-based therapeutics provides novel and efficacious treatments for a number of diseases. Traditional experimental approaches for designing therapeutic antibodies rely on raising antibodies against a target antigen in an immunized animal or directed evolution of antibodies with low affinity for the desired antigen. However, these methods remain time consuming, cannot target a specific epitope and do not lead to broad design principles informing other studies. Computational design methods can overcome some of these limitations by using biophysics models to rationally select antibody parts that maximize affinity for a target antigen epitope. This has been addressed to some extend by OptCDR for the design of complementary determining regions. Here, we extend this earlier contribution by addressing the de novo design of a model of the entire antibody variable region against a given antigen epitope while safeguarding for immunogenicity (Optimal Method for Antibody Variable region Engineering, OptMAVEn). OptMAVEn simulates in silico the in vivo steps of antibody generation and evolution, and is capable of capturing the critical structural features responsible for affinity maturation of antibodies. In addition, a humanization procedure was developed and incorporated into OptMAVEn to minimize the potential immunogenicity of the designed antibody models. As case studies, OptMAVEn was applied to design models of neutralizing antibodies targeting influenza hemagglutinin and HIV gp120. For both HA and gp120, novel computational antibody models with numerous interactions with their target epitopes were generated. The observed rates of mutations and types of amino acid changes during in silico affinity maturation are consistent with what has been observed during in vivo affinity maturation. The results demonstrate that OptMAVEn can efficiently generate diverse computational antibody models with both optimized binding affinity to antigens and reduced immunogenicity.
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Four methods have been made available for computational antibody design: OptCDR, OptMAVEn, AbDesign and RosettaAntibodyDesign.
“Since then, four methods have been made available: OptCDR [139], OptMAVEn[140], AbDesign [143] and RosettaAntibodyDesign [142].”
From Computational approaches to therapeutic antibody design: established methods and emerging trends (2020) · cites this paper as [140]
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“Since then, four methods have been made available: OptCDR [139], OptMAVEn[140], AbDesign [143] and RosettaAntibodyDesign [142].”
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- Authors
- Li, T., Pantazes, R. J., & Maranas, C. D.
- Affiliations
- Pennsylvania State University (US)
- Corresponding author
- Maranas, Costas D.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-08-25
- Volume
- 9
- Issue
- 8
- Pages
- e105954
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4143332
- OpenAlex
- W1985743545
- Cited by
- 79
- References
- 66
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 8 · 2023: 6 · 2022: 8 · 2021: 7 · 2020: 6 · 2019: 6 · 2018: 12 · 2017: 8 · 2016: 3 · 2015: 4
- FWCI
- 3.90
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- National Science Foundation (1133040)
- Division of Chemical, Bioengineering, Environmental, and Transport Systems
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- de novo antibody design, immunoglobulin variable region, affinity maturation, immunogenicity, humanization, influenza hemagglutinin, HIV gp120, neutralizing antibodies
- MeSH terms
- Antibodies, Antibody Affinity, Epitopes, Antigens, Humans, Immunoglobulin Variable Region, Models, Molecular
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