In 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. We have recently focused on anchoring activating cytokines in tumors, to stimulate an immune response.
- Wittrup KD, Kaufman HL, Schmidt MM, Irvine DJ. Intratumorally anchored cytokine therapy. Expert Opinion in Drug Delivery 19(6):725-732, 2022. [PubMed]
- Santollani L, Wittrup KD. Spatiotemporally programming cytokine immunotherapies through protein engineering. Immunological Reviews, July 2023. [PubMed]
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]
- Momin N, Palmeri JR, Lutz EA, Jailkhani N, Mak H, Tabet A, Chinn MM, Kang BH, Spanoudaki V, Hynes RO, Wittrup KD. Maximizing response to intratumoral immunotherapy in mice by tuning local retention Nature communications, 13(1):109, 2022. [PubMed]
- 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]
- Kang BH, Lax BM, Wittrup KD. Yeast Surface Display for Protein Engineering: Library Generation, Screening, and Affinity Maturation. Methods in Molecular Biology 2491:29-62, 2022. [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.
- Stinson JA, Sheen A, Momin N, Hampel J, Bernstein R, Kamerer R, Fadl-Alla B, Samuelson J, Fink E, Fan TM, Wittrup KD. Collagen-Anchored Interleukin-2 and Interleukin-12 Safely Reprogram the Tumor Microenvironment in Canine Soft-Tissue Sarcomas. Clinical Cancer Research 29(11):2110-2122, 2023. [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]
- Agarwal Y, Milling LE, Chang JYH, Santollani L, Sheen A, Lutz EA, Tabet A, Stinson J, Ni K, Rodrigues KA, Moyer TJ, Melo MB, Irvine DJ, Wittrup KD. Intratumourally injected alum-tethered cytokines elicit potent and safer local and systemic anticancer immunity. Nature Biomedical Engineering 6(2):129-143, 2022 [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.