DARPins against a functional IgE epitope

The monoclonal anti-IgE antibody omalizumab (Xolair®) is mostly used for the treatment of severe allergic asthma. However, the requirement of high doses and suboptimal cost-effectiveness limits the use of the treatment. Here we propose to use a new drug format based on non-immunoglobulin structures, potentially offering increased clinical efficacy while being more cost-effective. For this purpose, DARPins™ (designed ankyrin repeat proteins) against the constant heavy chain region of IgE have been isolated. DARPins were binding to IgE with high specificity and affinities in the low nanomolar range. Selected DARPins antagonized the interaction between IgE and its high-affinity receptor in inhibition assays. Furthermore, anti-IgE DARPins were shown to inhibit proinflammatory mediator release from rat basophilic leukemia cells expressing human high-affinity IgE receptors with higher efficacy than the monoclonal anti-IgE antibody omalizumab. DARPins may thus represent promising future drug candidates for the treatment of allergy.

Research highlights▶ Binders with nanomolar affinities against the IgE heavy chain were selected from DARPin libraries using ribosome display. ▶ Anti-IgE DARPins efficiently inhibit the IgE-FcɛRI interaction. ▶ Anti-IgE DARPins inhibit proinflammatory mediator release. ▶ DARPin E_29 shows higher potency than Omalizumab in vitro.