Hypoallergenic Bet v 1a Mutants Reducing IgE Binding
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Solution Overview
Problem
Current approaches to creating hypoallergenic molecules for treating pollen-food syndrome caused by Bet v 1a cross-reactive allergens are inadequate, as they do not completely eliminate IgE reactivity, and existing mutations in specific regions of the Bet v 1a molecule do not result in a hypoallergenic form with reduced IgE reactivity for all individuals.
Innovation Solution
A hypoallergenic molecule is developed by introducing mutations in the region of amino acids 100 to 125 of Bet v 1a, specifically at position 114, and optionally additional residues like 102 and 120, which significantly reduces IgE reactivity by altering the three-dimensional structure, making it substantially less allergenic compared to the wild-type allergen.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If point mutations are introduced in Bet v 1a at positions 10, 30, 57, 112, 113 and/or 125, then IgE reactivity is decreased for some patients, but not for all patients due to polyclonal nature of IgE responses
Solution Approach 1:
The patent divides the allergen protein into functional regions: the IgE-binding region (amino acids 100-125) and the T-cell epitope region. By selectively mutating only the IgE-binding region while preserving the T-cell epitope region, the invention achieves segment-specific modification that reduces IgE reactivity while maintaining immunostimulatory properties. This segmentation approach allows independent optimization of different functional aspects.
Solution Approach 2:
The invention applies local quality modification by introducing mutations specifically at amino acid positions 100-125 (the IgE-binding region) while leaving the rest of the protein sequence intact. This localized mutation strategy ensures that only the specific region responsible for IgE binding is altered, thereby reducing IgE reactivity without affecting other properties like T-cell recognition and overall protein structure.
2Object-affected harmful factors
If mutations are introduced to reduce IgE reactivity, then hypoallergenic properties are improved, but the three-dimensional structure may be compromised
Solution Approach 1:
The mutations are confined to a specific local region (amino acids 100-125) that is known to be involved in IgE binding, rather than disrupting the overall protein fold. This localized approach allows modification of the surface properties responsible for IgE interaction while preserving the core three-dimensional structure and stability of the allergen molecule.
Solution Approach 2:
The invention changes the amino acid sequence parameters specifically in the region of amino acids 100-125, introducing mutations that alter the chemical properties of this segment. These parameter changes are designed to modify IgE binding affinity while maintaining the overall structural integrity of the protein through conservative substitution choices.
3Reliability
If wild-type Bet v 1a is used, then T-cell epitopes are maintained for immune response, but IgE reactivity causes allergic reactions
Solution Approach 1:
The patent segments the allergen into distinct functional domains: the IgE-binding segment (amino acids 100-125) and the T-cell epitope segment. By mutating only the IgE-binding segment while preserving the T-cell epitope segment, the invention achieves selective modification that eliminates IgE reactivity while maintaining T-cell stimulation capability.
Solution Approach 2:
The invention applies local quality changes to the IgE-binding region (amino acids 100-125) by introducing mutations that specifically reduce IgE binding affinity. The T-cell epitope region remains unchanged, thereby preserving its ability to stimulate immune responses. This localized modification strategy allows independent control of different immune interaction pathways.
Data Source
Figure 1A~1C
Figure 2A~2B
Figure 3~4
AI summary
The present invention relates to a hypoallergenic molecule consisting of Bet v Ia or an allergen having at least 40% identity to Bet v Ia comprising mutations of at least four amino acid residues in the region of amino acids 100 to 125 of Bet v Ia or its corresponding region of the allergen having at least 40% identity to Bet v 1a.