Towards a best-in-class IgE disruptor for food allergy with Claude-enabled antibody design

Food allergy affects an estimated 220–250 million people worldwide, for whom the constant risk of a severe reaction weighs heavily on quality of life. Allergic reactions are triggered by the cross-linking of allergen-specific IgE bound to its high-affinity receptor, FcϵRI, on mast cells and basophils, causing degranulation, inflammation and, in severe cases, anaphylaxis. Omalizumab (Xolair), the sole FDA-approved biologic for food allergy, neutralizes circulating IgE; however, it does not effectively remove IgE from FcϵRI, where it can persist for weeks and where even a small residual amount can sustain sensitivity. Here we describe an agentic computational design campaign with Claude toward a disruptive inhibitor antibody that physically removes bound IgE from FcϵRI. Guided by our research team, Claude pursued a biparatopic molecule that pairs a disruptor arm, which displaces IgE from FcϵRI, with a non-competing anchor arm that holds the molecule on receptor-bound IgE. Of 91 experimentally characterized disruptor designs, 20 showed activity against receptor-bound IgE by competitive bio-layer interferometry, and in a dose-titration assay three variants removed more IgE than omalizumab at therapeutically relevant concentrations (25–400 nM). De novo designs for the anchor arm bound IgE at diverse epitopes with apparent affinities of 3.4–235 nM. These subcomponents provide the starting point for further characterization toward a best-in-class IgE disruptor.