Modified Factor VII Polypeptides for Hemophilia Treatment
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Solution Overview
Problem
Current treatments for hemophilia and bleeding disorders using recombinant Factor VIIa require multiple doses to manage acute bleeding episodes, indicating a need for more efficacious variants with improved therapeutic properties such as increased resistance to inhibitors, enhanced catalytic activity, and improved pharmacokinetic properties.
Innovation Solution
Development of modified Factor VII polypeptides with specific amino acid modifications, including insertions, deletions, and replacements, which provide increased resistance to antithrombin III and tissue factor pathway inhibitor, improved catalytic activity, and enhanced binding to platelet surface and serum albumin, thereby improving therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If multiple doses of recombinant Factor VIIa are administered to manage acute bleeding episodes, then bleeding control is achieved, but treatment complexity and frequency of administration increase
Solution Approach 1:
The patent modifies the amino acid sequence of Factor VII polypeptides by substituting specific residues (e.g., position 286 with basic amino acids like arginine or lysine, position 319 with serine or threonine) to alter the protein's properties. These parameter changes in the molecular structure result in improved resistance to inhibitors and enhanced catalytic activity, allowing for more effective bleeding control with potentially reduced dosing frequency.
2Reliability
If recombinant Factor VIIa is used to treat hemophilia patients with inhibitors, then bleeding episodes are managed, but resistance to inhibitors (antithrombin III and TFPI) is insufficient
Solution Approach 1:
The patent applies parameter changes by modifying specific amino acid positions in the Factor VII polypeptide sequence. The substitution of residue 286 with basic amino acids and residue 319 with polar amino acids alters the protein's interaction with inhibitors, resulting in enhanced resistance to antithrombin III and tissue factor pathway inhibitor while maintaining or improving coagulant activity.
Solution Approach 2:
The patent applies local quality by making targeted amino acid substitutions at specific positions (286 and 319) within the Factor VII polypeptide. These localized modifications confer inhibitor resistance and enhanced catalytic activity without requiring changes throughout the entire protein structure, thus improving therapeutic properties while maintaining overall protein function.
3Reliability
If the amino acid sequence of Factor VII is modified to enhance catalytic activity and inhibitor resistance, then therapeutic efficacy is improved, but deviation from native sequence increases
Solution Approach 1:
The patent applies parameter changes by making targeted amino acid substitutions at specific positions (286 and 319) in the Factor VII polypeptide sequence. These controlled modifications enhance catalytic activity and inhibitor resistance while maintaining sufficient similarity to the native sequence to ensure proper protein folding, stability, and biological function.
Data Source
AI summary
Nucleic acids encoding modified factor VII polypeptides, vectors and cells containing the nucleic acids, uses of the nucleic acids, methods of making the encoded polypeptides, and methods of treatment are provided. The encoded modified FVII polypeptides include Factor VIIa and other forms of Factor VII. Among the encoded modified FVII polypeptides provided are those that have altered activities, typically altered procoagulant activity, including increased procoagulant activities.