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

Abstract

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, Fc{epsilon}RI, 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 Fc{epsilon}RI, 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 Fc{epsilon}RI. Guided by our research team, Claude pursued a biparatopic molecule that pairs a disruptor arm, which displaces IgE from Fc{epsilon}RI, 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.