B-domain Truncated Factor VIII Conjugated with Hydrophilic Polymer
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Solution Overview
Problem
Current treatments for Haemophilia A, which involve administering coagulation Factor VIII, require frequent injections due to the short circulatory half-life of the protein, causing inconvenience and pain, especially in children, and existing methods to prolong its half-life result in products that are not homogenous or safe.
Innovation Solution
Development of a B-domain truncated Factor VIII molecule covalently conjugated with a hydrophilic polymer via an O-linked oligosaccharide in the truncated B domain, which is removed upon activation, resulting in a molecule with a modified circulatory half-life and improved safety profile.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If PEGylation of Factor VIII is performed to prolong circulatory half life, then the circulatory half life is improved, but the product homogeneity and safety are worsened
Solution Approach 1:
The invention extracts and removes the problematic B-domain from the Factor VIII molecule, which is the site where PEGylation occurs. By deleting this domain, the patent eliminates the source of heterogeneity and safety issues while preserving the essential A-domain and C-domain functions, thereby achieving prolonged half-life without compromising product quality
Solution Approach 2:
The invention segments the Factor VIII molecule into distinct functional regions (A-domains and C-domains) separated by the removed B-domain. This segmentation allows the remaining domains to maintain their native structure and function while enabling controlled conjugation of hydrophilic polymers at specific engineered sites, ensuring homogeneity and safety
2Duration of action of moving object
If conventional methods are used to produce conjugated Factor VIII molecules, then the circulatory half life is prolonged, but the manufacturing complexity and production difficulty increase
Solution Approach 1:
The invention performs preliminary action by pre-engineering O-linked glycosylation sites in the truncated B-domain during the protein production phase. This allows hydrophilic polymers to be conjugated automatically during cell culture without requiring complex post-translational modification steps, thereby simplifying manufacturing while achieving prolonged half-life
Solution Approach 2:
The invention enables the Factor VIII molecule to self-conjugate with hydrophilic polymers through naturally occurring O-linked glycosylation mechanisms in the truncated B-domain. This self-service approach eliminates the need for external conjugation machinery and complex manufacturing processes, reducing production difficulty while maintaining extended circulatory half-life
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 modified Factor VIII molecule has a significantly prolonged circulatory half-life, reducing the frequency of administration and maintaining safety and homogeneity, while being similar to endogenous activated Factor VIII in function.
Implementation Method 1
a B domain truncated Factor VIII molecule with a modified circulatory half life, said molecule being covalently conjugated with a hydrophilic polymer via an O-linked oligosaccharide in the truncated B domain
Implementation Method 2
wherein Factor VIII activation results in removal of the covalently conjugated side group
Data Source
AI summary
The present invention relates to B-domain truncated Factor VIII molecules with a modified circulatory half life, said molecule being covalently conjugated with a hydrophilic polymer. The invention furthermore relates to methods for obtaining such molecules as well as use of such molecules.