Liver-targeted allergen immunotherapy rapidly and safely induces antigen-specific tolerance to treat allergic diseases 2256367

Abstract Introduction Allergic diseases are increasing worldwide, with current treatments managing symptoms rather than addressing the underlying immune response. Allergen immunotherapy holds the promise of long-term symptom relief through the development of allergen-specific tolerance; however, its use is hindered by lengthy protocols and debilitating side-effects, with ultimately inconsistent efficacy at preventing allergic disease. Methods To overcome these limitations, we developed LIT, a liver-targeted allergen immunotherapy, to rapidly and safely raise allergen-specific tolerance and provide long-term control of allergic disease without continuous intervention. LIT’s synthetic mannosylation of native allergens prevents antibody-mediated recognition and subsequent life-threatening anaphylaxis upon administration. LIT’s protein engineering prevents sensitization events that occur due to the proteolytic activity of native allergens which limits allergen immunotherapy effectiveness. Results In preclinical models of asthma and food allergies, LIT reduced clinical symptoms in as quick as two therapeutic interventions. LIT induces allergen-specific regulatory T cells in vivo, and these were necessary to mediate LIT’s protections. In allergic asthma, LIT reduced features of allergic disease, including airway eosinophilia, mucus hypersecretion, allergen-specific IgE and airway hyperresponsiveness. Furthermore, LIT provided a year-long control of disease symptoms in the absence of additional intervention. In food allergy, LIT protected mice from fatal food anaphylaxis and reduced clinical and serological features associated with the reaction. Conclusion Altogether, our data provides proof of concept that LIT provides durable control of allergic symptoms by inducing allergen-specific Tregs to control the immunological cause underlying the disease. As such, we propose LIT as a rapid, safe, and effective approach to allergen immunotherapy that holds promise for long-lasting control of allergic diseases and anaphylaxis. Funding Source Chicago Immunoengineering Innovation Center, Alper Fund Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)