Truncated VWF Domain Stabilizes FVIII Against Degradation

Solution Overview

Problem

Current methods for stabilizing coagulation factor VIII (FVIII) in therapeutic preparations are inadequate, leading to instability and reduced efficacy, particularly in the absence of albumin or native von Willebrand Factor (VWF).

Innovation Solution

The use of a polypeptide comprising a truncated von Willebrand Factor (VWF) with a molar ratio greater than 20 to FVIII enhances the in vitro stability of FVIII, preventing degradation and maintaining activity during storage and processing.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Stability of the object's composition

If albumin or native VWF is used to stabilize FVIII, then FVIII stability is improved, but formulation complexity and cost increase

Engineering Contradiction:

ImproveFVIII stabilityVSAvoidformulation complexity

Core Design Contradiction:

Stability of the object's compositionVSDevice complexity

Solution Approach 1:

The patent extracts and utilizes only the essential stabilizing domain of VWF (the D3 domain containing amino acids 866-1242) rather than using the complete native VWF protein or albumin. This extracted domain is sufficient to bind and stabilize FVIII, thereby simplifying the formulation while maintaining stability benefits.

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The invention applies local quality by using a specific functional domain (D3 domain) of VWF that has the localized capability to bind FVIII and provide stability. Rather than using the entire VWF protein with multiple functions, only the relevant local region is employed for the stabilization function.

Inventive Principle:

Principle #3Local quality

2Stability of the object's composition

If albumin or native VWF is used to stabilize FVIII, then FVIII stability is improved, but manufacturing cost increases

Engineering Contradiction:

ImproveFVIII stabilityVSAvoidmanufacturing cost

Core Design Contradiction:

Stability of the object's compositionVSEase of manufacture

Solution Approach 1:

The patent extracts and utilizes only the essential stabilizing domain of VWF (the D3 domain containing amino acids 866-1242) rather than using the complete native VWF protein or albumin. This extracted domain is sufficient to bind and stabilize FVIII, thereby simplifying the formulation while maintaining stability benefits.

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The truncated VWF polypeptide serves as a cost-effective stabilizing agent that can be produced recombinantly without the need for complex plasma fractionation processes required for native VWF or albumin. This approach reduces manufacturing costs while achieving the desired stabilization effect.

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

3Device complexity

If FVIII is stored without stabilizing agents, then formulation simplicity is improved, but FVIII activity is lost during storage and processing

Engineering Contradiction:

Improveformulation simplicityVSAvoidFVIII activity retention

Core Design Contradiction:

Device complexityVSReliability

Solution Approach 1:

The truncated VWF polypeptide acts as an intermediary molecule that mediates between FVIII and the storage environment. It binds to FVIII and protects it from degradation during storage and processing, thereby maintaining FVIII activity without requiring complex formulation conditions.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent extracts and utilizes only the essential stabilizing domain of VWF (the D3 domain containing amino acids 866-1242) rather than using the complete native VWF protein or albumin. This extracted domain is sufficient to bind and stabilize FVIII, thereby simplifying the formulation while maintaining stability benefits.

Inventive Principle:

Principle #2Taking out (Extraction)

Data Source

PatentUS20220389082A1A truncated von willebrand factor (VWF) for increasing the in vitro stability of coagulation factor viii

Publication Date: 2022.12.08 CSL BEHRING LENGNAU AG

AI summary

The present invention relates to the use of a polypeptide comprising a truncated von Willebrand Factor (VWF) for increasing the in vitro stability of coagulation factor VIII (FVIII) in a composition comprising said FVIII and said polypeptide, wherein the molar ratio of the polypeptide to the FVIII in the composition is greater than 20.