Structure-guided design of ultrapotent disruptive IgE inhibitors to rapidly terminate acute allergic reactions.

Pennington, Luke F; Gasser, Pascal; Brigger, Daniel; Guntern, Pascal; Eggel, Alexander; Jardetzky, Theodore S (2021). Structure-guided design of ultrapotent disruptive IgE inhibitors to rapidly terminate acute allergic reactions. Journal of allergy and clinical immunology, 148(4), pp. 1049-1060. Elsevier 10.1016/j.jaci.2021.03.050

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BACKGROUND

Anaphylaxis represents one of the most severe and fatal forms of allergic reactions. Like most other allergies, it is caused by activation of basophils and mast cells by allergen-mediated cross-linking of IgE bound to its high-affinity receptor, FcεRI, on the cell surface. The systemic release of soluble mediators induces an inflammatory cascade, rapidly causing symptoms with peak severity in minutes to hours after allergen exposure. Primary treatment for anaphylaxis consists of immediate intramuscular administration of adrenaline.

OBJECTIVE

While adrenaline alleviates life-threatening symptoms of an anaphylactic reaction, there are currently no disease-modifying interventions available. We sought to develop potent and fast-acting IgE inhibitors with the potential to rapidly terminate acute allergic reactions.

METHODS

Using affinity maturation by yeast display and structure-guided molecular engineering, we generated 3 optimized disruptive IgE inhibitors based on designed ankyrin repeat proteins and assessed their ability to actively remove IgE from allergic effector cells in vitro as well as in vivo in mice.

RESULTS

The engineered IgE inhibitors rapidly dissociate preformed IgE:FcεRI complexes, terminate IgE-mediated signaling in preactivated human blood basophils in vitro, and shut down preinitiated allergic reactions and anaphylaxis in mice in vivo.

CONCLUSIONS

Fast-acting disruptive IgE inhibitors demonstrate the feasibility of developing kinetically optimized inhibitors for the treatment of anaphylaxis and the rapid desensitization of allergic individuals.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Rheumatologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Rheumatologie

04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Rheumatology, Clinical Immunology and Allergology
04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Institute for Immunology [discontinued]

UniBE Contributor:

Gasser, Pascal; Brigger, Daniel; Guntern, Pascal Martin and Eggel, Alexander

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1097-6825

Publisher:

Elsevier

Language:

English

Submitter:

Lee-Anne Brand

Date Deposited:

16 Nov 2021 16:51

Last Modified:

16 Nov 2021 16:56

Publisher DOI:

10.1016/j.jaci.2021.03.050

PubMed ID:

33991582

Uncontrolled Keywords:

Active desensitization DARPins Fc fusion IgE affinity maturation allergies anaphylaxis disruptive IgE inhibitors knobs in holes yeast display

BORIS DOI:

10.48350/161232

URI:

https://boris.unibe.ch/id/eprint/161232

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