Truncated VWF Polypeptide Stabilizes Endogenous FVIII

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Solution Overview

Problem

Current treatments for bleeding disorders caused by deficiencies in blood coagulation Factor VIII, such as hemophilia A, require frequent intravenous administration due to the short plasma half-life of Factor VIII, which is cumbersome and risky, and do not effectively stabilize endogenous Factor VIII levels in conditions like von Willebrand disease.

Innovation Solution

A truncated von Willebrand Factor (VWF) polypeptide with a half-life extending moiety is administered to prolong the in vivo half-life of endogenous Factor VIII, allowing for reduced administration frequency and stabilization of endogenous Factor VIII levels without the need for continuous exogenous FVIII administration.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If intravenous administration of Factor VIII is performed frequently to maintain therapeutic levels, then the coagulation function is maintained, but the treatment becomes cumbersome and increases infection risk

Engineering Contradiction:

Improvecoagulation function maintenanceVSAvoidtreatment convenience

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The invention changes the pharmacokinetic parameters of Factor VIII by fusing it with von Willebrand Factor, thereby extending the half-life from 12-14 hours to a much longer duration. This parameter change allows less frequent administration while maintaining therapeutic efficacy

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates a composite protein structure by fusing Factor VIII with von Willebrand Factor. This composite molecule combines the coagulant activity of FVIII with the stability and long circulation half-life of VWF, resolving the contradiction between maintaining function and reducing administration frequency

Inventive Principle:

Principle #40Composite materials

2Reliability

If intravenous administration is performed frequently to maintain therapeutic levels, then the coagulation function is maintained, but the risk of infection increases

Engineering Contradiction:

Improvecoagulation function maintenanceVSAvoidinfection risk

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

By extending the half-life of Factor VIII through fusion with VWF, the administration frequency is reduced, thereby reducing the cumulative infection risk associated with repeated needle punctures and intravenous access

Inventive Principle:

Principle #35Parameter changes

3Reliability

If exogenous Factor VIII is administered continuously to maintain levels, then the coagulation function is maintained, but the complexity of treatment increases

Engineering Contradiction:

Improvecoagulation function maintenanceVSAvoidtreatment regimen complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The fusion protein of Factor VIII and von Willebrand Factor utilizes the body's endogenous VWF system to maintain FVIII levels. The extended half-life allows the modified protein to self-persist in circulation without requiring continuous external administration, simplifying the treatment regimen

Inventive Principle:

Principle #25Self-service

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 polypeptide significantly increases and stabilizes endogenous Factor VIII levels, enabling prophylactic treatment and reducing the frequency of administration, while potentially reducing the risk of inhibitor formation against FVIII.

Implementation Method 1

the polypeptide is capable of binding to endogenous FVIII

Methodology Applied

Scientific EffectProtein-protein binding:

Implementation Method 2

wherein the terminal half-life of said endogenous FVIII is prolonged in the plasma of said subject

Methodology Applied

Scientific EffectReduced clearance:

Data Source

PatentUS11814421B2Truncated von Willebrand Factor polypeptides for treating hemophilia

Publication Date: 2023.11.14 CSL BEHRING LENGNAU AG

AI summary

The invention pertains to a polypeptide comprising a truncated von Willebrand Factor (VWF) and a half-life extending moiety, for use in the treatment of a blood coagulation disorder, said treatment comprising administering the polypeptide to a subject having a blood coagulation disorder and having endogenous Factor VIII (FVIII), wherein the activity level of endogenous FVIII in said subject before treatment with said polypeptide is reduced relative to the activity level of FVIII in normal human plasma (NHP) provided that the activity level of endogenous FVIII in said subject is at least 0.5% of the activity level of endogenous FVIII in normal human plasma (NHP), wherein the polypeptide is capable of binding to endogenous FVIII and wherein the endogenous FVIII level is increased following administration of said polypeptide.