The DOI matches its Crossref record; 30 of the 30 references it cites were found in a registry or an index.
Computational design of antibody-affinity improvement beyond in vivo maturation
Open accessAbstract
Antibodies are used extensively in diagnostics and as therapeutic agents. Achieving high-affinity binding is important for expanding detection limits, extending dissociation half-times, decreasing drug dosages and increasing drug efficacy. However, antibody-affinity maturation in vivo often fails to produce antibody drugs of the targeted potency, making further affinity maturation in vitro by directed evolution or computational design necessary. Here we present an iterative computational design procedure that focuses on electrostatic binding contributions and single mutants. By combining multiple designed mutations, a tenfold affinity improvement to 52 pM was engineered into the anti-epidermal growth factor receptor drug cetuximab (Erbitux), and a 140-fold improvement in affinity to 30 pM was obtained for the anti-lysozyme model antibody D44.1. The generality of the methods was further demonstrated through identification of known affinity-enhancing mutations in the therapeutic antibody bevacizumab (Avastin) and the model anti-fluorescein antibody 4-4-20. These results demonstrate computational capabilities for enhancing and accelerating the development of protein reagents and therapeutics.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Selected molecules had better affinity for the target, demonstrating that in some scenarios computational approaches alone can be used for affinity maturation.”
From Computational approaches to therapeutic antibody design: established methods and emerging trends (2020) · cites this paper as [181]
In the citing paper
“The seminal work on the subject was published by Lippow and co-workers, who computationally improved the binding of an antibody against its target, starting from an existing structural complex [181].”
From Computational approaches to therapeutic antibody design: established methods and emerging trends (2020) · cites this paper as [181]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
1 retracted
Computational Design of a Biologically Active Enzyme
Dwyer, M. A., Looger, L. L., & Hellinga, H. W. (2004) · Science · doi:10.1126/science.1098432 · Cited by 295
RetractedDesign of a Novel Globular Protein Fold with Atomic-Level Accuracy
Kuhlman, B. A., Dantas, G. A., Ireton, G. C., Varani, G., Stoddard, B. L., & Baker, D. A. (2003) · Science · doi:10.1126/science.1089427 · Cited by 1,666
Presta, L. G., Chen, H., O'Connor, S. J., Chisholm, V., Meng, Y. G., KRUMMEN, L. A., Winkler, M., & Ferrara, N. (1997) · PubMed · Cited by 1,596
De Novo Protein Design: Fully Automated Sequence Selection
Dahiyat, B. I., & Mayo, S. L. (1997) · Science · doi:10.1126/science.278.5335.82 · Cited by 1,156
Directed evolution of antibody fragments with monovalent femtomolar antigen-binding affinity
Boder, E. T., Midelfort, K. S., & Wittrup, K. D. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.170297297 · Cited by 673
Self-citationComputational design of receptor and sensor proteins with novel functions
Looger, L. L., Dwyer, M. A., Smith, J. J., & Hellinga, H. W. (2003) · Nature · doi:10.1038/nature01556 · Cited by 668
Biological effects in vitro of monoclonal antibodies to human epidermal growth factor receptors.
Sato, J. D., Kawamoto, T., Le, A. D., Mendelsohn, J. M., Polikoff, J., & SATO, G. H. (1983) · PubMed · Cited by 458
Chen, Y., Wiesmann, C., Fuh, G., Li, B., Christinger, H. W., McKay, P., de Vos, A. M., & Lowman, H. B. (1999) · Journal of Molecular Biology · doi:10.1006/jmbi.1999.3192 · Cited by 449
Kinetic and affinity limits on antibodies produced during immune responses.
Foote, J., & Eisen, H. N. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.5.1254 · Cited by 375
Computational Thermostabilization of an Enzyme
Korkegian, A., Black, M. E., Baker, D. A., & Stoddard, B. L. (2005) · Science · doi:10.1126/science.1107387 · Cited by 360
Cited by
Sorted by citations
The SWISS-MODEL Repository and associated resources
Kiefer, F., Arnold, K., Künzli, M., Bordoli, L., & Schwede, T. F. (2008) · Nucleic Acids Research · doi:10.1093/nar/gkn750 · Cited by 2,003
Antibody Structure and Function: The Basis for Engineering Therapeutics
Chiu, M. L., Goulet, D. R., Teplyakov, A., & Gilliland, G. L. (2019) · Antibodies · doi:10.3390/antib8040055 · Cited by 711
Chen, Y.-C. (2015) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2014.12.001 · Cited by 611
Beyond natural antibodies: the power of in vitro display technologies
Bradbury, A. M., Sidhu, S. S., Dübel, S., & McCafferty, J. (2011) · Nature Biotechnology · doi:10.1038/nbt.1791 · Cited by 548
Engineering protein-based therapeutics through structural and chemical design
Ebrahimi, S. B., & Samanta, D. (2023) · Nature Communications · doi:10.1038/s41467-023-38039-x · Cited by 405
Metadata
- Authors
- Lippow, S. M., Wittrup, K. D., & Tidor, B.
- Affiliations
- Massachusetts Institute of Technology (US)
- Corresponding author
- Wittrup, K Dane
- Tidor, Bruce
- Venue
- Nature Biotechnology
- Published
- 2007-09-23
- Volume
- 25
- Issue
- 10
- Pages
- 1171-1176
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- PMC
- PMC2803018
- OpenAlex
- W2083028331
- Cited by
- 342
- References
- 30
- Citations by year
- 2026: 9 · 2025: 11 · 2024: 14 · 2023: 17 · 2022: 24 · 2021: 14 · 2020: 22 · 2019: 15 · 2018: 23 · 2017: 18 · 2016: 15 · 2015: 24 · 2014: 23 · 2013: 21 · 2012: 21
- FWCI
- 14.05
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Biotechnology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Science Foundation
- National Institutes of Health
- National Cancer Institute (CA96504, R01CA096504)
- National Institute of General Medical Sciences (GM65418, R56GM065418, R01GM065418)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
- Keywords
- affinity maturation, computational antibody design, point mutations, cetuximab, anti-EGFR monoclonal antibody, bevacizumab, anti-fluorescein antibody, anti-lysozyme antibody, therapeutic antibodies, directed evolution, binding affinity enhancement
- MeSH terms
- Antibodies, Antibody Affinity, Antigens, Genetic Engineering, Models, Biological, Models, Molecular, Muramidase, Mutation, Protein Binding, Protein Conformation, Yeasts, Computer-Aided Design
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
