Defining Protective IgGs to Food Allergy

/Abstract Approximately 2% of the population of Western country is affected by peanut allergies. Peanut oral immunotherapy OIT has gained traction in the clinic as therapeutic option. However, successful peanut OIT resulting in tolerance to peanuts, or sustained unresponsiveness, occurs in only 50% of treated individuals. It is not known why peanut oral immunotherapy (OIT) induces tolerance to peanut some peanut-allergic individuals, but not others. There are likely multiple contributing factors, including differences in OIT-induced peanut-specific IgG specificity and affinity, differences in peanut-specific IgG titers, differences in peanut-specific IgE titers, as well as the variable induction of peanut-specific T regulatory cells. However, a systemic characterization of the peanut-specific IgG response to OIT has not been conducted. We profiled peanut-specific IgG from peanut- allergic adults who underwent peanut OIT in PNOIT2 trial. Intriguingly, a signature of peanut-specific IgG was identified in patients that developed sustained unresponsiveness, or tolerance, to peanuts. Our long-term goal is to understand how glycosylation regulates antibody effector functions, enabling therapeutic approaches that modulate antibody glycosylation to tailor effector function accordingly. Our central hypothesis is that allergen- specific IgG generated during successful OIT preferentially bind activating FcγRs. The rationale for these studies is that empirically determining the requirements for IgG that are protective against food allergy will enable the development of novel biologics for food allergies, while extensive characterization of the peanut OIT IgG response will enable identification of biomarkers that predict the outcome of OIT. We will test our central hypothesis by pursuing the following specific aims: 1) Define the IgG signatures from peanut OIT that are associated with OIT outcomes; 2) Determine the requirements for protective IgG during food allergy. Using an approach that combines biophysics, biochemistry cellular and molecular immunology, and glycobiology, we will define the allergen-specific IgG response to OIT from two additional clinical trials and test the IgGs that are identified in functional models of food-mediated anaphylaxis. In addition to enabling discovery of biomarkers successful peanut OIT, these studies will potential outline the requires for IgG that protect from food allergy. Project Number: 1R01AI187292-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Robert Anthony | Institution: MASSACHUSETTS GENERAL HOSPITAL, BOSTON, MA | Award Amount: $806,466 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 IMHA-B (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01AI18729201A1