Research abstract
Letter abstract
Nature Biotechnology 25, 1171 - 1176 (2007)
Published online: 23 September 2007 | doi:10.1038/nbt1336
Computational design of antibody-affinity improvement beyond in vivo maturation
Shaun M Lippow1,4, K Dane Wittrup1,2 & Bruce Tidor2,3
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 potency1, 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.
- Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
- Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
- Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
- Present address: Codon Devices, Inc., One Kendall Square, Building 300, Cambridge, Massachusetts 02139, USA.
Correspondence to: K Dane Wittrup1,2 e-mail: wittrup@mit.edu
Correspondence to: Bruce Tidor2,3 e-mail: tidor@mit.edu
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