Accelerated Dissociation of Ige Receptor Complexes

IgE antibodies bind the high affinity IgE Fc receptor (Fc?RI), found primarily on mast cells and basophils, andtrigger inflammatory cascades of the allergic response. Potent inhibitors of IgE:Fc?RI binding have beenidentified and an anti-IgE therapeutic antibody (omalizumab) is used to treat severe allergic asthma.Omalizumab is also being used experimentally for the treatment of food allergies. However, improvedtherapeutics are needed for the treatment of allergies. With current anti-IgE therapy, IgE remains bound toreceptors on mast cells in peripheral tissues for months, maintaining these cells in a sensitized state andhighlighting the high affinity and low turnover of the preformed IgE receptor complexes. Our studies of anti-IgEDARPin inhibitors have revealed that these inhibitors can rapidly dissociate IgE:Fc?RI complexes, with thepotential for greater therapeutic efficacy than the current anti-IgE therapy. We refer to these inhibitors as?disruptive? since they are able to accelerate the dissociation of preformed receptor complexes. Our resultswith the DARPins demonstrate that macromolecular inhibitors can accelerate the dissociation of receptorcomplexes and raises the possibility that other macromolecules, such as antibodies, can be found that havesimilar activity. The ability to disrupt preformed receptor complexes represents a previously unappreciatedpotential function for macromolecular inhibitors in general and raises the possibility of developing novelresearch tools and biological therapeutics. In this proposal, we are exploring multiple approaches to betterunderstanding the mechanism of the disruptive DARPin inhibitors and how to improve their activities further.Since these synthetic proteins are not likely to replace current anti-IgE therapy, as they may induce immuneresponses in humans, we also propose to indentify an anti-IgE antibody that exhibits similar disruptive inhibitoractivity as the DARPins. The potential overall impact of this proposal is high, given the possibility of improvinganti-IgE antibody therapeutics and also by providing foundational approaches for developing disruptivemacromolecular inhibitors for other receptor-ligand complexes.