Associate Director, Koch Institute for Integrative Cancer Research
Carbon P. Dubbs Professor of Chemical Engineering and Bioengineering
Ph.D. 1988, California Institute of Technology
"Engineers now have the tools to design biological products and processes at the molecular level. Proteins are of particular therapeutic interest, because proteins mediate most biochemical processes both inside and outside cells. Our laboratory develops protein engineering technology and applies it to the discovery of new biopharmaceuticals. In particular, we use yeast surface display for the directed evolution of protein expression stability, affinity, and specificity. One focus is on the development of anti-cancer drugs, with quantitative studies of cellular-level pharmacokinetics and pharmacodynamics."
Dr. Wittrup is the C.P. Dubbs Professor of Chemical Engineering and Biological Engineering at MIT and Associate Director of MIT’s Koch Institute. In 2012, he was elected to the National Academy of Engineering. He was also elected a Fellow of the American Association for the Advancement of Science in 2011. Dr. Wittrup is co-founder and acting Chief Scientific Officer at Adimab and is a fellow of the American Institute of Biomedical Engineers. He has also served as the J. W. Westwater Professor of Chemical Engineering, Biophysics, and Bioengineering at the University of Illinois at Urbana-Champaign. He previously worked as a postdoctoral research associate in Amgen’s Yeast Molecular Biology Group. He holds a Ph.D. and M.S. in Chemical Engineering from the California Institute of Technology and a B.S. in Chemical Engineering from the University of New Mexico.
Engineers now have the tools to design biological products and processes at the molecular level. Proteins are of particular therapeutic interest, because proteins mediate most biochemical processes both inside and outside cells. The ability to manipulate the strength and specificity of protein binding events provides tremendous leverage for the development of novel biopharmaceuticals. We are developing powerful new tools for protein engineering, and applying them both to particular disease targets and to bettering our understanding of protein structure/function relationships. In the absence of predictive capabilities for protein design, a directed evolution or combinatorial library screening strategy can be effectively applied to alter protein properties in a desired fashion. We apply quantitative engineering analyses of the relevant kinetic and statistical processes to develop optimal search strategies on the protein ìfitness landscape.î In particular, we have developed a method for protein display on the surface of yeast cells that, for example, enabled engineering of a noncovalent protein-ligand bond with a dissociation half-time over one week. We are engineering potential protein biopharmaceuticals in areas where molecular understanding of disease pathology is sufficient to hypothesize particular objective functions to target. For example, antibodies can be used to target cell-killing modalities to cancerous cells, given sufficiently strong and specific binding properties. Growth factors that carry signals between cells do so via particular binding events that, if manipulated to alter intracellular trafficking or signalling outcomes, could alter immune responses in precisely defined ways. Finally, viral and nonviral vectors for gene therapy could be targeted to specific cells and tissues via alteration of an exchangeable antibody recognition module. Altered proteins developed in this work can also provide a potential vehicle for new insights into the mechanisms of protein-ligand binding. We are performing biophysical analyses of the kinetic, thermodynamic, and structural aspects of engineered protein function in order to contribute to an improved understanding of protein binding processes.
Schmidt MM, Wittrup KD. A modeling analysis of the effects of molecular size and binding affinity on tumor targeting. Mol. Cancer Ther., 8(10):2861-71, 2009.
Liu DV, Maier LM, Hafler DA, Wittrup KD. Engineered interleukin-2 antagonists for the inhibition of regulatory T cells. J. Immunother., 32(9):887-94, 2009.
Rakestraw JA, Sazinsky SL, Piatesi A, Antipov E, Wittrup KD. Directed evolution of a secretory leader for the improved expression of heterologous proteins and full-length antibodies in Saccharomyces cerevisiae. Biotechnol Bioeng., 103(6):1192-201, 2009.
Ackerman M, Levary D, Tobon G, Hackel B, Orcutt KD, Wittrup KD. Highly avid magnetic bead capture: An efficient selection method for de nova protein engineering utilizing yeast surface display. Biotechnol Prog., 25(3):774-83, 2009.
Sazinsky SL, Ott RG, Silver NW, Tidor B, Ravetch JV, Wittrup KD. Aglycosylated immunoglobulin G1 variants productively engage activating Fc receptors. Proc. Natl. Acad. Sci., 105:20167-72, 2008.
Hackel BJ, Kapila A, Wittrup KD. Picomolar affinity fibronectin domains engineered utilizing loop length diversity, recursive mutagenesis, and loop shuffling. J Mol Biol., 381(5):159-65, 2008.
Howland SW, Tsuji T, Gnjatic S, Ritter G, Old LJ, Wittrup KD. Inducing efficient cross-priming using antigen-coated yeast particles. J Immunother., 31(7):607-619, 2008.
Thurber GM, Wittrup KD. Quantitative spatiotemporal analysis of antibody fragment diffusion and endocytic consumption in tumor spheroids. Cancer Res., 68(9):3334-41, 2008.
Lippow SM, Wittrup KD, Tidor B. Computational design of antibody-affinity improvement beyond in vivo maturation. Nat. Biotech., 25(10):1171-76, 2007.
Chao G, Lau WL, Hackel BJ, Sazinsky SL, Lippow SM, Wittrup KD. Isolating and engineering human antibodies using yeast surface display. Nat. Protoc., 1(2):755-768, 2007.