Modified Factor Xa Polypeptides for Bleeding Disorder Treatment
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Solution Overview
Problem
Current therapeutic approaches for bleeding disorders using Factor X (FX) are limited by the safety and efficacy of non-activated zymogen forms, necessitating improved or alternative FX therapeutics that offer enhanced co-factor dependence, resistance to inhibitors, and altered glycosylation properties.
Innovation Solution
Development of modified active Factor Xa polypeptides with specific amino acid substitutions at positions 196 and 332, resulting in increased FVa cofactor dependence, resistance to antithrombin III, and altered glycosylation patterns, which can be isolated and purified for therapeutic use.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If non-activated zymogen form of Factor X is used therapeutically, then safety is improved, but therapeutic efficacy is limited
Solution Approach 1:
The patent applies parameter changes by modifying specific amino acid residues in the Factor X polypeptide sequence. Mutations at positions 196, 202, 211, 214, 217, 219, 327, and 338 alter the protein's properties to achieve both safety and enhanced therapeutic efficacy, resolving the contradiction between using activated vs non-activated forms
2Productivity
If Factor X is activated to FXa form, then therapeutic efficacy is improved, but resistance to inhibitors decreases
Solution Approach 1:
The patent applies local quality by making specific localized mutations at particular amino acid positions (196, 202, 211, 214, 217, 219, 327, 338) rather than global modifications. These targeted local changes confer both activated form efficacy and enhanced resistance to antithrombin III inhibition simultaneously
3Manufacturing precision
If amino acid substitutions are introduced to increase FVa cofactor dependence, then specificity is improved, but manufacturing complexity increases
Solution Approach 1:
The patent uses parameter changes by defining specific amino acid substitutions at predetermined positions to achieve the desired 50-fold increased FVa cofactor dependence. The mutations are designed to create specific biochemical properties while maintaining a relatively simple manufacturing approach through rational protein engineering
Data Source
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AI summary
Modified therapeutic proteins are provided. In particular modified Factor X polypeptides, which includes the Factor X zymogen, Factor Xa and other forms of Factor X, and uses thereof are provided.