researchIn the Wittrup lab, we are interested in developing design principles for effective cancer biopharmaceuticals. We are particularly interested in cancer immunotherapy, the process of provoking a therapeutic immune response against tumors. Most of our projects include the following elements:

  • Simple mass action models of drug distribution and action at whole-organism, tissue, and subcellular resolution. Disciplined mathematical formulation of a hypothesized mechanism of action is a critical component of the design cycle.
    • Wittrup KD, Thurber GM, Schmidt MM, Rhoden JJ. Practical theoretic guidance for the design of tumor-targeting agents. Methods Enzymol. 2012;503:255-68. [Pubmed]
    • Rao, BM, Lauffenburger, DA, Wittrup KD. Integrating cell-level kinetic modeling into the design of engineered protein therapeutics. Nature Biotechnology, 23(2):191-4, 2005. [PubMed, Journal]
  • Synthesis of novel molecular entities by protein engineering. A core tool for the lab is yeast surface display, which enables directed evolution of binding affinity & specificity, expression, and stability. Multispecific topologies are often employed to bring a variety of functions to bear in the therapeutic strategy.
    • 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. [Pubmed , Journal]
    • Van Deventer JA, Wittrup KD. Yeast surface display for antibody isolation: library construction, library screening, and affinity maturation. Methods Mol Biol. 2014;1131:151-81. [Pubmed]
  • Testing in predictive mouse tumor models. The expression in vivo veritas reflects our perspective that only in an animal with an intact immune system can one obtain immunotherapeutic insights with some chance of translating to clinical practice.
    • Spangler JB, Manzari MT, Rosalia EK, Chen TF, Wittrup KD. Triepitopic antibody fusions inhibit cetuximab-resistant BRAF- and KRAS-mutant tumors via EGFR signal repression. J Mol Biol. 2012 Sep 28;422(4):532-44. [Pubmed]
    • Orcutt KD, Rhoden JJ, Ruiz-Yi B, Frangioni JV, Wittrup KD. Effect of small-molecule-binding affinity on tumor uptake in vivo: a systematic study using a pretargeted bispecific antibody. Mol Cancer Ther. 2012 Jun;11(6):1365-72. Epub 2012 Apr 5. [Pubmed]
    • Rhoden JJ, Wittrup KD. Dose dependence of intratumoral perivascular distribution of monoclonal antibodies. J Pharm Sci. 2012 Feb;101(2):860-7. Epub 2011 Nov 4. [Pubmed]
  • Closing the loop. It is of course often the case that our animal experiments fail to be consistent with the original therapeutic hypothesis. This provides a critical learning opportunity as we then initiate another round trip through the design cycle.