Factor IX Variants With Half-Life Enhancers for Hemophilia B
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current Factor IX replacement therapies for hemophilia B suffer from short half-life and require frequent high-dose administrations, leading to high costs and potential immune responses.
Innovation Solution
Development of Factor IX variants with specific amino acid substitutions at positions 410 and 338, linked to half-life enhancers via cleavable linkers, enhancing pro-coagulant activity and extending functional half-life.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If Factor IX replacement therapy is administered frequently at high doses, then adequate Factor IX activity levels are maintained, but treatment cost increases and immune responses are triggered
Solution Approach 1:
The patent applies parameter changes by modifying amino acid residues at positions 338 and 410 in the Factor IX sequence. Specifically, substituting position 338 with basic amino acids (arginine, lysine, histidine) and position 410 with hydrophobic amino acids (leucine, isoleucine, valine, phenylalanine, methionine) creates variants with enhanced pro-coagulant activity, allowing reduced dosing frequency and lower total doses while maintaining therapeutic efficacy
Solution Approach 2:
The patent employs preliminary action by pre-modifying the Factor IX molecule through amino acid substitutions before administration. These pre-engineered variants are designed to have inherently higher specific activity, so that when administered, they immediately provide sufficient pro-coagulant effect without requiring frequent high-dose supplementation, thereby preventing immune response activation
2Quantity of substance
If Factor IX polypeptide dose is reduced, then treatment cost decreases, but achieving necessary Factor IX activity levels becomes difficult
Solution Approach 1:
The patent changes the molecular parameters of Factor IX by substituting specific amino acids to enhance its biological activity. The variants with modified positions 338 and 410 exhibit increased pro-coagulant activity per molecule, meaning less total polypeptide mass is required to achieve the same therapeutic effect. This allows reduction in administered quantity while maintaining reliable activity levels
Solution Approach 2:
The patent applies local quality by making targeted modifications at specific locations (positions 338 and 410) within the Factor IX molecule. These localized amino acid substitutions enhance the overall pro-coagulant function of the molecule without requiring changes throughout the entire sequence, thereby improving activity efficiency and reducing the total amount of polypeptide needed
3Stability of the object's composition
If Factor IX half-life is short, then clearance is rapid, but frequent administrations are required increasing treatment burden
Solution Approach 1:
The patent changes the stability parameters of Factor IX through amino acid substitutions at positions 338 and 410. These modifications enhance not only pro-coagulant activity but also in vivo stability and half-life of the molecule. The variants demonstrate prolonged circulation time and sustained activity levels, reducing the frequency of administrations required and decreasing treatment burden
Data Source
AI summary
This invention provides Factor IX variants, molecules comprising the variants, nucleic acids encoding the variants, compositions comprising the variants or the nucleic acids encoding the variants, and their use in methods for the modulation of hemostasis, for example in the prophylaxis or treatment of hemophilia B. The Factor IX variants have improved biological properties relative to other Factor IX variants and/or relative to wild-type Factor IX.