VWF-Binding Clotting Factor Chimeras for Longer Half-Life
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Solution Overview
Problem
Current therapeutic proteins, such as clotting factors, have a short half-life, requiring frequent administration, which is inconvenient for patients and necessitates the development of products with extended half-lives.
Innovation Solution
The introduction of isolated single-domain antibodies (sdAbs) directed against the von Willebrand Factor (VWF) D′D3 domain into therapeutic peptides results in a chimeric polypeptide with increased stability and reduced clearance rates, leading to extended half-life.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If clotting factors are administered to treat bleeding disorders, then therapeutic efficacy is achieved, but the short half-life requires frequent administration
Solution Approach 1:
The patent creates a chimera protein that combines clotting factor (FVIII or FVII) with single-domain antibodies (sdAbs) that specifically bind to von Willebrand factor (VWF). This composite structure allows the clotting factor to associate with VWF, which has a longer half-life, thereby extending the circulation time of the therapeutic clotting factor and reducing administration frequency
2Duration of action of moving object
If chemical modification such as PEGylation is applied to extend half-life, then protein stability is improved, but the half-life extension is limited to about 1.5 to 2 hours
Solution Approach 1:
The patent uses von Willebrand factor (VWF) as an intermediary molecule to extend the half-life of clotting factors. The sdAbs act as mediators that bind both the clotting factor and VWF, creating a stable complex. This approach achieves more reliable and significant half-life extension (up to 4.3-fold) compared to direct chemical modification methods
3Duration of action of moving object
If Fc-fusion is used to extend half-life, then clotting factor stability is improved, but the half-life is only extended 1.7 fold compared with ADVATE
Solution Approach 1:
The patent changes the binding parameters and interaction mechanisms by using sdAbs that specifically target the D′D3 domain of VWF. This specific binding interaction creates a more stable complex with extended half-life (up to 4.3-fold extension) compared to the standard Fc-fusion approach, demonstrating superior adaptability in achieving half-life extension
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 chimeric polypeptides exhibit a 1.9-fold increase in half-life compared to wild-type, reducing the frequency of administration and improving therapeutic efficacy.
Implementation Method 1
isolated single-domain antibodies (sdAb) directed against von Willebrand Factor (VWF) D′D3 domain
Data Source
AI summary
The invention relates to isolated single-domain antibodies (sdAb) directed against von Willebrand Factor (VWF) D′D3 domain and chimeric polypeptides comprising thereof such as blood clotting factors and their uses in therapy such as in the prevention and treatment of hemostatic disorders. The invention also relates to a method of extending or increasing half-life of a therapeutic polypeptide comprising a step of adding to the polypeptide sequence of said therapeutic polypeptide at least one sdAb directed against VWF D′D3 domain.