Mutant Alpha-Galactosidase A ERT With Reduced Immunogenicity
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current enzyme replacement therapies for Fabry disease, such as Fabrazyme and Replagal, induce significant immune responses in patients, leading to neutralizing antibodies and reduced efficacy, necessitating frequent intravenous infusions and high treatment costs.
Innovation Solution
Development of mutant alpha-galactosidase A proteins with specific amino acid changes in antigenic epitopes to reduce immunogenicity while maintaining enzymatic function, thereby minimizing immune reactions and neutralizing antibody production.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If standard enzyme replacement therapy (ERT) with native alpha-galactosidase A is administered, then the therapeutic enzyme replaces the deficient enzyme to treat Fabry disease, but the therapy induces significant immune responses and neutralizing antibodies that reduce efficacy
Solution Approach 1:
The patent applies local quality by making specific amino acid substitutions only in the antigenic epitopes of the alpha-galactosidase A enzyme while preserving the rest of the protein structure. This targeted modification approach (e.g., mutating residues in epitopes like LHWERF at positions 45-50, DCQEEPDSCI at positions 55-64, and others listed in the patent) reduces immunogenicity at specific locations without affecting the overall enzymatic function, thereby resolving the contradiction between maintaining therapeutic efficacy and reducing immune response
Solution Approach 2:
The patent employs parameter changes by altering the amino acid sequence parameters of the alpha-galactosidase A enzyme. Specifically, it introduces point mutations in the antigenic epitopes (changing specific amino acid residues) to modify the immunogenic properties of the enzyme. These parameter changes in the protein sequence reduce the immune response while maintaining the catalytic activity, thus resolving the contradiction between therapeutic effectiveness and immune reactogenicity
2Reliability
If frequent intravenous infusions are administered to maintain therapeutic efficacy, then the enzyme replacement therapy remains effective, but the treatment burden and costs increase significantly
Solution Approach 1:
The patent applies preliminary anti-action by pre-modifying the alpha-galactosidase A enzyme to reduce its immunogenicity before administration. By anticipating and preventing the formation of neutralizing antibodies through epitope mutation, the therapy maintains its efficacy over longer periods without requiring frequent dosing. This preliminary modification approach counteracts the expected immune response that would otherwise necessitate frequent infusions, thereby reducing treatment burden while maintaining therapeutic effectiveness
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The mutant alpha-galactosidase A proteins effectively reduce immune responses, increasing the efficacy of enzyme replacement therapy by decreasing neutralizing antibodies and potentially reducing treatment frequency and costs.
Implementation Method 1
an enzyme that hydrolyses alpha-galactose from glycosphingolipids, in particular globotriaosylceramide (Gb3)
Data Source
AI summary
The present disclosure provides less immunogenic mutant α-galactosidase A protein (α-gal), methods of making and methods of use. The less immunogenic mutant α-gal of the present invention provides a reduced immune response when administered to a subject.