Modified Bacteriophage G3p Polypeptides for Reduced Immunogenicity
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Solution Overview
Problem
The systemic administration of polypeptides comprising the N1-N2 region of filamentous bacteriophage g3p for treating amyloid-related diseases is hindered by potential immunogenic responses due to T-cell epitopes, which can trigger immune reactions and reduce their therapeutic efficacy.
Innovation Solution
Modification of the N1-N2 amino acid sequence with specific amino acid substitutions to reduce immunogenicity while maintaining the ability to bind and disaggregate amyloid, including fusion proteins with a human immunoglobulin Fc region and pharmaceutical compositions for administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type g3p polypeptides are administered systemically to treat amyloid-related diseases, then therapeutic efficacy is achieved through amyloid binding and disaggregation, but immunogenic responses are triggered due to T-cell epitopes
Solution Approach 1:
The patent identifies and removes specific T-cell epitopes (harmful components) from the g3p polypeptide sequence while retaining the amyloid-binding functional regions. This extraction approach eliminates the immunogenic trigger without compromising therapeutic efficacy.
Solution Approach 2:
The patent applies localized amino acid substitutions specifically at T-cell epitope regions while leaving the amyloid-binding domains unchanged. This local modification strategy reduces immunogenicity precisely where needed without affecting the overall therapeutic function.
2Object-affected harmful factors
If amino acid substitutions are made to reduce immunogenicity, then immune response is reduced, but there is a risk of compromising amyloid-binding ability
Solution Approach 1:
The patent divides the g3p polypeptide into distinct functional segments: T-cell epitope regions (to be modified) and amyloid-binding regions (to be preserved). This segmentation allows independent optimization of each region's properties.
Solution Approach 2:
The patent systematically varies amino acid parameters (charge, hydrophobicity, size) at epitope positions to find substitutions that reduce immunogenicity while maintaining structural integrity and binding function of the overall polypeptide.
Data Source
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AI summary
The invention relates to polypeptides that comprise a portion of filamentous bacteriophage gene 3 protein (g3p) sufficient to bind to and/or disaggregate amyloid, e.g., the N1-N2 portion of g3p and mutants and fragments thereof, wherein that g3p amino acid sequence has been modified through amino acid substitution to be substantially less immunogenic than the corresponding wild-type g3p amino acid sequence when used in vivo. The polypeptides of the invention retain their ability bind to and/or disaggregate amyloid. The invention relates furthermore to the use of these variant g3p- polypeptides in the treatment and/or prevention of diseases associated with misfolding or aggregation of amyloid.