Description:

Cytokines constitute a large class of secreted proteins that signal through membrane-embedded 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 cytokine-targeted 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.