Design of therapeutic proteins with enhanced stability. Export

@article{chennamsetty:09, abstract = {Therapeutic proteins such as antibodies constitute the most rapidly growing class of pharmaceuticals for use in diverse clinical settings including cancer, chronic inflammatory diseases, kidney transplantation, cardiovascular medicine, and infectious diseases. Unfortunately, they tend to aggregate when stored under the concentrated conditions required in their usage. Aggregation leads to a decrease in antibody activity and could elicit an immunological response. Using full antibody atomistic molecular dynamics simulations, we identify the antibody regions prone to aggregation by using a technology that we developed called spatial aggregation propensity (SAP). SAP identifies the location and size of these aggregation prone regions, and allows us to perform target mutations of those regions to engineer antibodies for stability. We apply this method to therapeutic antibodies and demonstrate the significantly enhanced stability of our mutants compared with the wild type. The technology described here could be used to incorporate developability in a rational way during the screening of antibodies in the discovery phase for several diseases.}, author = {Chennamsetty, Naresh and Voynov, Vladimir and Kayser, Veysel and Helk, Bernhard and Trout, Bernhardt L.}, citeulike-article-id = {5094586}, citeulike-linkout-0 = {http://dx.doi.org/10.1073/pnas.0904191106}, citeulike-linkout-1 = {http://www.pnas.org/content/0904191106v1/.abstract}, citeulike-linkout-2 = {http://www.pnas.org/content/0904191106v1/.full.pdf}, citeulike-linkout-3 = {http://view.ncbi.nlm.nih.gov/pubmed/19571001}, citeulike-linkout-4 = {http://www.hubmed.org/display.cgi?uids=19571001}, day = {21}, doi = {10.1073/pnas.0904191106}, issn = {1091-6490}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, keywords = {hydrophobicity, proteins, stability}, month = {July}, number = {29}, pages = {11937--11942}, posted-at = {2009-07-09 06:23:39}, priority = {2}, title = {Design of therapeutic proteins with enhanced stability.}, url = {http://dx.doi.org/10.1073/pnas.0904191106}, volume = {106}, year = {2009} }

TY - JOUR ID - chennamsetty:09 L3 - citeulike-article-id:5094586 N2 - Therapeutic proteins such as antibodies constitute the most rapidly growing class of pharmaceuticals for use in diverse clinical settings including cancer, chronic inflammatory diseases, kidney transplantation, cardiovascular medicine, and infectious diseases. Unfortunately, they tend to aggregate when stored under the concentrated conditions required in their usage. Aggregation leads to a decrease in antibody activity and could elicit an immunological response. Using full antibody atomistic molecular dynamics simulations, we identify the antibody regions prone to aggregation by using a technology that we developed called spatial aggregation propensity (SAP). SAP identifies the location and size of these aggregation prone regions, and allows us to perform target mutations of those regions to engineer antibodies for stability. We apply this method to therapeutic antibodies and demonstrate the significantly enhanced stability of our mutants compared with the wild type. The technology described here could be used to incorporate developability in a rational way during the screening of antibodies in the discovery phase for several diseases. IS - 29 JF - Proceedings of the National Academy of Sciences of the United States of America SN - 1091-6490 EP - 11942 TI - Design of therapeutic proteins with enhanced stability. VL - 106 SP - 11937 KW - hydrophobicity KW - proteins KW - stability AU - Chennamsetty, Naresh AU - Voynov, Vladimir AU - Kayser, Veysel AU - Helk, Bernhard AU - Trout, Bernhardt PY - 2009/07/21/ UR - http://dx.doi.org/10.1073/pnas.0904191106 ER -