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Transcript
CBE Seminar Dr. Jamie B. Spangler Postdoctoral Fellow Stanford University School of Medicine DATE: January 19, 2017 TIME: 10:00 am Dr. Jamie Spangler obtained a Bachelor of Science LOCATION: Degree in Biomedical Engineering at Johns Hopkins 366 CLB University and went on to conduct her Ph.D. research in Biological Engineering in Professor K. Dane Wittrup’s group at MIT, studying antibody-mediated down-regulation of epidermal growth factor receptor as a new mechanism for cancer therapy. She is currently a postdoctoral fellow in Professor K. Christopher Garcia’s lab in the Molecular & Cellular Physiology and Structural Biology departments at Stanford University School of Medicine. Her work focuses on engineering cytokine systems to therapeutically bias immune homeostasis. Dr. Spangler has been awarded a National Defense Science and Engineering Graduate Fellowship, a Repligen Koch Institute for Integrative Cancer Research Fellowship, and most recently a Leukemia & Lymphoma Society postdoctoral fellowship for her research. Reshaping the Immune Response through Molecular Engineering Cytokines constitute a large class of secreted proteins that signal through membraneembedded receptors to orchestrate all aspects of the immune response. Their critical role in immune regulation has motivated the therapeutic use of cytokines to treat a range of diseases including autoimmune disorders, infectious diseases, and cancer. However, clinical performance has been limited by such challenges as pleiotropy, redundancy, and poor pharmacokinetic properties, which confound efficacy and lead to harmful off-target effects. Recent advances in protein engineering present exciting opportunities to apply molecular design tools to overcome the limitations of naturally occurring cytokines. I will describe two molecular engineering approaches I have pursued toward selectively tuning the immune response to achieve targeted disease therapy: (1) I elucidated the structural mechanisms through which cytokinetargeted antibodies bias immune homeostasis and leveraged crystallographic insights to design enhanced cytokine-directed therapeutic antibodies; and (2) I engineered a novel class of antibody-based agonists that functionally recapitulate cytokine activity by using a single binding site to bridge the interface between two receptors in a heterodimeric signaling complex. Collectively, these efforts offer new insight into the determinants of protein function and construct a molecular blueprint for therapeutically biasing immune activity. Department of Chemical & Biomolecular Engineering