Computational design of antibody-affinity improvement beyond in vivo maturation.

@article{citeulike:1696204, abstract = {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.}, address = {[1] Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA. [2] Present address: Codon Devices, Inc., One Kendall Square, Building 300, Cambridge, Massachusetts 02139, USA.}, author = {Lippow, Shaun M M. and Wittrup, K Dane D. and Tidor, Bruce }, citeulike-article-id = {1696204}, doi = {10.1038/nbt1336}, issn = {1087-0156}, journal = {Nat Biotechnol}, keywords = {design, interaction, invivo, structure}, month = {September}, posted-at = {2007-10-11 16:58:25}, priority = {3}, title = {Computational design of antibody-affinity improvement beyond in vivo maturation.}, url = {http://dx.doi.org/10.1038/nbt1336}, year = {2007} }

TY - JOUR ID - citeulike:1696204 L3 - citeulike-article-id:1696204 TI - Computational design of antibody-affinity improvement beyond in vivo maturation. JF - Nat Biotechnol AD - [1] Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA. [2] Present address: Codon Devices, Inc., One Kendall Square, Building 300, Cambridge, Massachusetts 02139, USA. SN - 1087-0156 N2 - 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. KW - design KW - interaction KW - invivo KW - structure AU - Lippow, Shaun M AU - Wittrup, K Dane AU - Tidor, Bruce PY - 2007/09/23/ UR - http://dx.doi.org/10.1038/nbt1336 ER -