IgE antibodies bind the high affinity IgE Fc receptor (Fc?RI), found primarily on mast cells and basophils, and trigger inflammatory cascades of the allergic response. Potent inhibitors of IgE:Fc?RI binding have been identified 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, improved therapeutics are needed for the treatment of allergies. With current anti-IgE therapy, IgE remains bound to receptors on mast cells in peripheral tissues for months, maintaining these cells in a sensitized state and highlighting the high affinity and low turnover of the preformed IgE receptor complexes. Our studies of anti-IgE DARPin inhibitors have revealed that these inhibitors can rapidly dissociate IgE:Fc?RI complexes, with the potential 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 results with the DARPins demonstrate that macromolecular inhibitors can accelerate the dissociation of receptor complexes and raises the possibility that other macromolecules, such as antibodies, can be found that have similar activity. The ability to disrupt preformed receptor complexes represents a previously unappreciated potential function for macromolecular inhibitors in general and raises the possibility of developing novel research tools and biological therapeutics. In this proposal, we are exploring multiple approaches to better understanding 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 immune responses in humans, we also propose to indentify an anti-IgE antibody that exhibits similar disruptive inhibitor activity as the DARPins. The potential overall impact of this proposal is high, given the possibility of improving anti-IgE antibody therapeutics and also by providing foundational approaches for developing disruptive macromolecular inhibitors for other receptor-ligand complexes.
This proposal focuses on developing novel approaches to disassembling receptor-ligand complexes, with a specific focus on IgE antibody interactions with its high affinity receptor that are central to most allergic responses. Blocking IgE binding to its receptor provides a universal approach to disabling the allergic response because it does not depend on the specific sensitizing allergen and should work globally to inhibit all IgE- dependent reactions. Currently, an antibody (omalizumab) that blocks this interaction is used to treat severe allergic asthma, and it is being used experimentally for the treatment of food allergies as well. We are pursuing the development of new protein-based inhibitors to block the IgE receptor interaction, based on our discovery that these complexes, which are normally very stable, can be actively torn apart. In animal studies, we have demonstrated that engineered inhibitors with this disruptive activity are more potent than the currently available antibody therapeutic and we propose specific approaches to identifying and engineering new antibodies that should also exhibit this enhanced activity. We anticipate that our novel antibodies could represent a next- generation therapeutic for the treatment of allergies, including the treatment of severe food allergies. In addition, the approaches that we are developing may prove useful for targeting other receptor complexes, where accelerated disassembly could provide potential therapeutic benefit.
|Pennington, Luke F; Tarchevskaya, Svetlana; Brigger, Daniel et al. (2016) Structural basis of omalizumab therapy and omalizumab-mediated IgE exchange. Nat Commun 7:11610|