Inhibited by Man-made Molecule

Photo: Hay fever

Some allergic reactions, e.g. to pollen, can
become very acute and even life threatening,
making highly potent, rapidly acting interven-
tions necessary; © panthermedia.net/Bernd
Leitner

The new inhibitor disarms IgE antibodies, pivotal players in acute allergies, by detaching the antibody from its partner in crime, a molecule called FcR. "It would be an incredible intervention if you could rapidly disconnect IgE antibodies in the midst of an acute allergic response," said Ted Jardetzky, PhD, professor of structural biology and senior investigator for the study. It turns out the inhibitor used by the team does just that.

A myriad of allergens, ranging from ragweed pollen to bee venom to peanuts, can set off IgE antibodies, resulting in allergic reactions within seconds. The new inhibitor destroys the complex that tethers IgE to the cells responsible for the reaction, called mast cells. Severing this connection would be the holy grail of IgE-targeted allergy treatment.

Dissociation of this IgE-FcR interaction is a sought-after goal of allergy treatment for a good reason: IgE-coated mast cells are grenades of histamine, and re-encountering the allergen is equivalent to pulling out the clip. When an allergen makes a return visit, it binds to the pre-loaded IgE on the mast cell surface, triggering the release of inflammatory mediators — including histamine — that promote the allergic response. As allergy sufferers are well aware, these nasty reactions can occur within a matter of seconds. In a severe allergic response, sudden anaphylactic shock and death can be the result.

The key to actively disabling the allergic response lies in the separation of IgE from the FcRs on the surface of mast cells. While simply blocking IgE binding is helpful for some allergy sufferers, when it comes to the rapid quenching of an acute allergic response, "what you'd really like to do is get rid of it," said Jardetzky. Along with scientists at the University of Bern, his team discovered that an engineered protein inhibitor called DARPin E2-79 stripped IgE from the mast cell receptor. Using this inhibitor, "an interaction that normally lasts for hours or days in terms of its stability is stripped off in a matter of seconds," said Jardetzky.

DARPin E2-79 is one of a family of engineered inhibitors containing protein-binding regions called ankryin repeats. While Jardetzky's group was using structural biology and biophysical approaches to probe the weak spots in the IgE-FcR interaction, scientists at the University of Bern were tinkering with DARPins that dampened IgE's disastrous effects. The collaboration of the two groups resulted in the characterization of DARPin E2-79, an inhibitor that goes beyond mere blockade to actively disassemble the IgE-FcR power couple.

MEDICA.de; Source: Stanford University School of Medicine