Computationally-Driven Redesign of Therapeutic Proteins


Christopher Bailey-Kellogg, Department of Computer Science, Dartmouth College


2017.03.22 16:15-17:30


601 Pao Yue-Kong Library


The protein universe manifests a wide array of functions that may be useful in treating disease. Unfortunately, the human immune system can recognize non-“self” proteins and mount a response decreasing therapeutic efficacy or potentially even producing harmful side effects. To meet this challenge, we have developed a computationally-driven approach that combines models of immunogenicity with models of protein stability and function, optimizing mutagenic variants so as to maintain therapeutic activity while reducing immunogenicity. This talk describes our protein design methodology and presents experimental results from application to therapeutic candidates including lysostaphin, a highly potent but immunogenic anti-staphylococcal enzyme. In contrast to wild-type lysostaphin, our variants maintain low antibody titers and are able to repeatedly rescue humanized mice from challenges with methicillin resistant Staphylococcus aureus (MRSA). This work provides the first controlled demonstration that depletion of T cell epitopes from a biotherapeutic agent leads to a reduced antibody response and consequently enhanced efficacy in an immune competent disease model.


Dr. Chris Bailey-Kellogg is Professor of Computer Science at Dartmouth College, where he is also an adjunct Professor of Chemistry. His lab develops and applies computational methods for experiment optimization and analysis in studies of protein sequence-structure-function relationships. He is currently pursuing computationally-driven development of both protein therapeutics, redesigning non-human proteins so as to render them acceptable to the immune system, as well as vaccines, modeling and engineering immune responses to infection and vaccination. Chris earned a BS/MS with Dr. Sandy Pentland at MIT and a PhD with Dr. Feng Zhao (currently serves as CTO and SVP of Haier) at Ohio State and Xerox PARC, conducted postdoctoral research with Dr. Bruce Donald at Dartmouth College, and started his faculty career at Purdue. Dr. Bailey-Kellogg has published over 70 journal articles, along with numerous refereed conference papers, at the interface of computational and life sciences. He has received a prestigious NSF Career award and Alfred P. Sloan Research Fellowship, along with more than $13 million in grants from the NIH, NSF, and Gates Foundation.