Carbon P. Dubbs Professor in Chemical Engineering and Biological Engineering
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"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. 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 served as an Associate Director of MIT’s Koch Institute until 2017. 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 fitness landscape. 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.
Momin N, Mehta NK, Bennett NR, Ma L, Palmeri JR, Chinn MM, Lutz EA, Kang B, Irvine DJ, Spranger S, Wittrup KD. Anchoring of intratumorally administered cytokines to collagen safely potentiates systemic cancer immunotherapy. Sci Transl Med. 2019 Jun 26;11(498). pii: eaaw2614. doi: 10.1126/scitranslmed.aaw2614. PMID: 31243150
Kauke MJ, Tisdale AW, Kelly RL, Braun CJ, Hemann MT, Wittrup KD. A Raf-Competitive K-Ras Binder Can Fail to Functionally Antagonize Signaling. Mol Cancer Ther. 2018 Aug;17(8):1773-1780. doi: 10.1158/1535-7163.MCT-17-0645. Epub 2018 May 2. PMID: 29720559
Green DJ, O'Steen S, Lin Y, Comstock ML, Kenoyer AL, Hamlin DK, Wilbur DS, Fisher DR, Nartea M, Hylarides MD, Gopal AK, Gooley TA, Orozco JJ, Till BG, Orcutt KD, Wittrup KD, Press OW. CD38-bispecific antibody pretargeted radioimmunotherapy for multiple myeloma and other B-cell malignancies. Blood. 2018 Feb 8;131(6):611-620. doi: 10.1182/blood-2017-09-807610. Epub 2017 Nov 20. PMID: 29158362
Kwan BH, Zhu EF, Tzeng A, Sugito HR, Eltahir AA, Ma B, Delaney MK, Murphy PA, Kauke MJ, Angelini A, Momin N, Mehta NK, Maragh AM, Hynes RO, Dranoff G, Cochran JR, Wittrup KD.Integrin-targeted cancer immunotherapy elicits protective adaptive immune responses. J Exp Med. 2017 Jun 5;214(6):1679-1690. doi: 10.1084/jem.20160831. Epub 2017 May 4. PMID: 28473400
Jain T, Sun T, Durand S, Hall A, Houston NR, Nett JH, Sharkey B, Bobrowicz B, Caffry I, Yu Y, Cao Y, Lynaugh H, Brown M, Baruah H, Gray LT, Krauland EM, Xu Y, Vásquez M, Wittrup KD. Biophysical properties of the clinical-stage antibody landscape. Proc Natl Acad Sci U S A. 2017 Jan 31;114(5):944-949. doi: 10.1073/pnas.1616408114. Epub 2017 Jan 17. PMID: 28096333
Tzeng A, Kauke MJ, Zhu EF, Moynihan KD, Opel CF, Yang NJ, Mehta N, Kelly RL, Szeto GL, Overwijk WW, Irvine DJ, Wittrup KD. Temporally Programmed CD8α+ DC Activation Enhances Combination Cancer Immunotherapy. Cell Rep. 2016 Dec 6;17(10):2503-2511. doi: 10.1016/j.celrep.2016.11.020. PMID: 27926855
Moynihan KD, Opel CF, Szeto GL, Tzeng A, Zhu EF, Engreitz JM, Williams RT, Rakhra K, Zhang MH, Rothschilds AM, Kumari S, Kelly RL, Kwan BH, Abraham W, Hu K, Mehta NK, Kauke MJ, Suh H, Cochran JR, Lauffenburger DA, Wittrup KD, Irvine DJ. Eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses. Nat Med. 2016 Dec;22(12):1402-1410. doi: 10.1038/nm.4200. Epub 2016 Oct 24. PMID: 27775706
Maass KF, Kulkarni C, Betts AM, Wittrup KD. Determination of Cellular Processing Rates for a Trastuzumab-Maytansinoid Antibody-Drug Conjugate (ADC) Highlights Key Parameters for ADC Design. AAPS J. 2016 May;18(3):635-46. doi: 10.1208/s12248-016-9892-3. Epub 2016 Feb 24. PMID: 26912181
Zhu EF, Gai SA, Opel CF, Kwan BH, Surana R, Mihm MC, Kauke MJ, Moynihan KD, Angelini A, Williams RT, Stephan MT, Kim JS, Yaffe MB, Irvine DJ, Weiner LM, Dranoff G, Wittrup KD. Synergistic innate and adaptive immune response to combination immunotherapy with anti-tumor antigen antibodies and extended serum half-life IL-2. Cancer Cell. 2015 Apr 13;27(4):489-501. doi: 10.1016/j.ccell.2015.03.004. PMID: 25873172
Tzeng A, Kwan BH, Opel CF, Navaratna T, Wittrup KD. Antigen specificity can be irrelevant to immunocytokine efficacy and biodistribution. Proc Natl Acad Sci U S A. 2015 Mar 17;112(11):3320-5. doi: 10.1073/pnas.1416159112. Epub 2015 Mar 2. PMID: 25733854