Engineered immunotherapies neutralizing interleukin-22 binding protein

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Inflammatory bowel diseases, including ulcerative colitis and Crohn's disease, are commonly treated with monoclonal antibodies against inflammatory cytokines. However, a large proportion of patients do not respond to such biologics or experience diminishing efficacy over time. Additionally, episodic dosing can exacerbate the production of anti-drug antibodies. Even in responding patients, while anti-cytokine therapies can ameliorate disease symptoms, they often fail to induce adequate intestinal epithelial regeneration. There is therefore a critical unmet need for an alternative therapy for inflammatory bowel disease that generates predictable therapeutic efficacy for broad patient populations by both reducing inflammation and promoting tissue regeneration. Active Immunotherapy, where anti-inflammatory immune responses are generated within the patient using engineered immunogens, is an alternative but nascent strategy that may offer improved therapeutic efficacy. This project aims to design an active immunotherapy against a key mediator of inflammatory bowel disease, IL-22 binding protein (IL-22BP). The cytokine it inhibits, IL-22, is a member of the IL-10 family and plays a central role in regulating the intestinal barrier in healthy tissue and during epithelial regeneration; thus, neutralizing IL-22BP promises to facilitate the pro- regenerative properties of IL-22 for the amelioration of IBD. Active immunotherapies will be designed using innovative supramolecular nanomaterials designed to contain precise quantities of B-cell epitopes raising neutralizing responses against IL-22BP and TNF, along with exogenous T-cell epitopes designed to provide CD4+ T cell help without breaking T-cell tolerance to the native cytokines. Efficacy will be assessed in a murine model of dextran sodium sulfate-induced colitis. If successful, this high risk/high reward project will establish a-proof-of-concept for combinatorial active immunotherapies that are both anti-inflammatory and regenerative in the context of IBD, constituting a first demonstration of this strategy that could have broader application to other inflammatory diseases and cytokines.