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Title | Targeting immunodominant Bet v 1 epitopes with monoclonal antibodies prevents the birch allergic response. |
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Journal, issue, pages | J Allergy Clin Immunol, Vol. 149, Issue 1, Page 200-211, Year 2022 |
Publish date | Jun 11, 2021 |
Authors | Amanda Atanasio / Matthew C Franklin / Vishal Kamat / Annabel Romero Hernandez / Ashok Badithe / Li-Hong Ben / Jennifer Jones / Joannie Bautista / George D Yancopoulos / William Olson / Andrew J Murphy / Matthew A Sleeman / Jamie M Orengo |
PubMed 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 ...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. |
External links | J Allergy Clin Immunol / PubMed:34126155 |
Methods | EM (single particle) / X-ray diffraction |
Resolution | 3 - 3.71 Å |
Structure data | EMDB-24073, PDB-7mxl: PDB-7n0u: PDB-7n0v: |
Chemicals | ChemComp-SO4: ChemComp-NAG: ChemComp-HOH: |
Source |
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Keywords | ALLERGEN / COMPLEX / ANTIBODY / BIRCH POLLEN ALLERGEN BET V 1 / Birch pollen / allergy / neutralizing antibody / immunotherapy |