Factor IX FcRn Fusion Protein Formulation for Hemophilia B
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Solution Overview
Problem
Current treatments for hemophilia B, caused by Factor IX deficiency, are limited by the short half-life of recombinant Factor IX (rFIX) products, requiring frequent dosing and having lower incremental recovery compared to plasma-derived Factor IX, leading to inadequate prolonged protection from bleeding.
Innovation Solution
A pharmaceutical composition comprising a Factor IX polypeptide fused with an FcRn Binding Partner (rFIXFBP) combined with sucrose, mannitol, sodium chloride, L-histidine, and polysorbate, which provides long-acting Factor IX activity, allowing for less frequent dosing and improved stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If recombinant Factor IX (rFIX) is used for treating hemophilia B, then the treatment can be produced without infectious agents, but the half-life is short requiring frequent dosing
Solution Approach 1:
The patent combines Factor IX with an FcRn binding partner (such as IgG Fc region) to create a fusion protein. This merging allows the Factor IX to utilize the FcRn recycling pathway, thereby extending its half-life while maintaining the safety benefits of recombinant production
Solution Approach 2:
The patent modifies the molecular parameters of Factor IX by changing its structure to include an FcRn binding domain. This structural parameter change enables the protein to interact with the FcRn receptor, fundamentally altering its pharmacokinetic profile and extending its circulation time in the body
2Reliability
If plasma-derived Factor IX (pdFIX) is purified from plasma, then active Factor IX can be obtained, but the purification process is very difficult due to low concentration
Solution Approach 1:
The patent extracts the FcRn binding capability from immunoglobulins and combines it with Factor IX. This allows the use of established FcRn binding properties to solve the pharmacokinetic limitations of Factor IX without requiring complex purification from plasma
Solution Approach 2:
The patent copies the successful pharmacokinetic properties of IgG (which has long half-life due to FcRn binding) and applies them to Factor IX through fusion. This copying of the Fc region's recycling mechanism provides a simplified production approach compared to plasma purification
3Ease of manufacture
If recombinant Factor IX (rFIX) is administered, then Factor IX activity is provided, but the incremental recovery is lower compared to pdFIX requiring higher doses
Solution Approach 1:
By merging Factor IX with the FcRn binding partner, the fusion protein achieves both the manufacturing advantages of recombinant technology and the superior pharmacokinetic properties (including incremental recovery) associated with FcRn-mediated recycling
Solution Approach 2:
The patent changes the pharmacokinetic parameters of Factor IX by introducing FcRn binding capability, which improves incremental recovery and reduces the dosage required to achieve therapeutic effects
4Reliability
If current rFIX products are used, then Factor IX replacement is achieved, but prolonged protection from bleeding is not provided
Solution Approach 1:
The FcRn binding partner acts as an intermediary that mediates the interaction between Factor IX and the FcRn receptor. This intermediary mechanism enables the recycling and protection of Factor IX from degradation, thereby extending its duration of action and providing prolonged protection from bleeding
Solution Approach 2:
The patent fundamentally changes the pharmacokinetic parameters of Factor IX by enabling FcRn binding, which transforms the protein's half-life from hours to days, thereby providing the prolonged protection from bleeding that current therapies cannot achieve
Data Source
AI summary
The present invention provides formulations comprising a Factor IX—FcRn Binding Partner (FIXFBP) polypeptide, and methods of administering FIXFBP.