Targeting immunodominant Bet v 1 epitopes with monoclonal antibodies prevents the birch allergic response - 05/01/22
Abstract |
Background |
Blocking the major cat allergen, Fel d 1, with mAbs was effective in preventing an acute cat allergic response.
Objectives |
This study sought to extend the allergen-specific antibody approach and demonstrate that a combination of mAbs targeting Bet v 1, the immunodominant and most abundant allergenic protein in birch pollen, can prevent the birch allergic response.
Methods |
Bet v 1–specific mAbs, REGN5713, REGN5714, and REGN5715, were isolated using the VelocImmune platform. Surface plasmon resonance, x-ray crystallography, and cryo-electron microscopy determined binding kinetics and structural data. Inhibition of IgE-binding, basophil activation, and mast cell degranulation were assessed via blocking ELISA, flow cytometry, and the passive cutaneous anaphylaxis mouse model.
Results |
REGN5713, REGN5714, and REGN5715 bind with high affinity and noncompetitively to Bet v 1. A cocktail of all 3 antibodies, REGN5713/14/15, blocks IgE binding to Bet v 1 and inhibits Bet v 1– and birch pollen extract–induced basophil activation ex vivo and mast cell degranulation in vivo. Crystal structures of the complex of Bet v 1 with immunoglobulin antigen-binding fragments of REGN5713 or REGN5715 show distinct interaction sites on Bet v 1. Cryo-electron microscopy reveals a planar and roughly symmetrical complex formed by REGN5713/14/15 bound to Bet v 1.
Conclusions |
These data confirm the immunodominance of Bet v 1 in birch allergy and demonstrate blockade of the birch allergic response with REGN5713/14/15. Structural analyses show simultaneous binding of REGN5713, REGN5714, and REGN5715 with substantial areas of Bet v 1 exposed, suggesting that targeting specific epitopes is sufficient to block the allergic response.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : Bet v 1, birch pollen allergy, mAbs, IgE, x-ray crystallography, cryo-electron microscopy
Abbreviations used : AIT, AR, BPE, Cryo-EM, Fab, Fc, Fv, nBet v 1, rBet v 1, OAS, PCA, rCar b 1, SPR
Plan
| This study was funded by Regeneron Pharmaceuticals, Inc. |
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| Disclosure of potential conflict of interest: All authors are current employees of Regeneron Pharmaceuticals, Inc, and hold stock and/or stock options in the company. |
Vol 149 - N° 1
P. 200-211 - janvier 2022 Retour au numéro
Article précédent
- Novel antibody cocktail targeting Bet v 1 rapidly and sustainably treats birch allergy symptoms in a phase 1 study
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