Editors' ChoiceALLERGY

Driving a Wedge into Acute Allergic Responses

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Science Translational Medicine  05 Dec 2012:
Vol. 4, Issue 163, pp. 163ec219
DOI: 10.1126/scitranslmed.3005421

Acute allergic or asthmatic reactions can develop with terrifying swiftness, as exemplified by the life-threatening anaphylaxis that can occur in individuals with severe peanut allergies. The hair trigger for these processes is constructed from immunoglobulin E (IgE) antibodies against the allergen and Fc receptors (FcR) found on the surface of mast cells. IgE antibodies are initially produced in a circulating form during early encounters with an allergen but are then mopped up by mast cells’ FcRs, remaining on the cell surface in an extremely stable form for prolonged periods, thus priming the mast cell for future encounters with the allergen. When the same allergen is encountered again, the mast cell rapidly responds by dumping its cargo of histamine and other inflammatory mediators into tissues—and anaphylaxis ensues. A therapeutic capable of stripping the mast cell of the IgE would disarm this hair trigger, but developing one has been challenging owing to the subnanomolar affinity that IgE has for the FcR. In instances such as this one in which protein-protein interactions are preformed and extremely stable, conventional competitive inhibitors often fail. What is needed is a strategy for stripping away IgE from its stable interaction with the mast cell. Now, Kim and co-workers have developed a protein capable of prying these two agents apart.

The protein, DARPin E2_79, works not through competitive inhibition but by a process known as facilitated dissociation. Using surface plasmon resonance (SPR), they observed that DARPin E2_79 could stimulate rapid dissociation of FcR and IgE. Using SPR and COPASI software, which models complex biological processes and networks, the authors concluded that E2_79 was a disruptive inhibitor, first binding to but not dissociating the IgE_FcR complex and then actively disrupting the interface between the two proteins.

The work has substantial translational potential in a number of respects. Currently, an antibody-to-IgE therapeutic exists for the treatment of severe allergic asthma (omalizumab), but this competitive inhibitor cannot disrupt preformed IgE/FcR complexes, so it is not useful for stopping acute allergic episodes. In a more general sense, the authors note that macromolecular therapeutics such as the new disruptive inhibitor may represent an untapped strategy in biopharmaceutical development.

B. Kim et al., Accelerated disassembly of IgE–receptor complexes by a disruptive macromolecular inhibitor. Nature 491, 613–617 (2012). [Full Text]

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