Modified FIX GLA Domain for Extended Half-Life
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Solution Overview
Problem
Current FIX formulations, such as FIX-Fc, PEGylated FIX, and FIX-Albumin, have short plasma half-lives and low bioavailability, limiting their administration frequency and route, particularly due to unknown reasons related to the FIX molecule itself, and are not effectively extended by fusion with half-life elongation elements like Fc, PEG, or Albumin.
Innovation Solution
Modifying the GLA domain of FIX by deleting or reducing Gla residues, non-covalently binding GLA-domain-recognizing antibodies, or inhibiting Gla-modification to extend plasma half-life and improve bioavailability, allowing for subcutaneous administration and reduced patient burden.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If FIX is fused with Fc, PEG, or Albumin to extend half-life, then the plasma half-life is extended, but the extension is insufficient compared to human IgG and the route of administration remains intravenous only
Solution Approach 1:
The patent extracts and removes the GLA domain from the FIX molecule. This removal eliminates the harmful interaction between Gla residues and endothelial cells, thereby extending plasma half-life sufficiently to enable subcutaneous administration, which was previously impossible due to rapid clearance
Solution Approach 2:
The patent changes the molecular structure parameter by deleting or modifying the GLA domain. This structural change fundamentally alters the pharmacokinetic properties, extending half-life from approximately 18 hours to sufficiently long durations that allow subcutaneous administration and reduce dosing frequency
2Reliability
If FIX is administered intravenously to ensure bioavailability, then therapeutic effect is achieved, but patient burden increases due to frequent injections
Solution Approach 1:
By removing the GLA domain, the patent eliminates the cause of rapid clearance, thereby maintaining reliable bioavailability through subcutaneous administration. This reduces patient burden by eliminating the need for intravenous access and frequent hospital visits
Solution Approach 2:
The patent creates a dynamic dosing regimen where the extended half-life allows flexible administration intervals. Patients can receive treatments less frequently (e.g., once weekly or less), adapting the treatment schedule to reduce burden while maintaining therapeutic efficacy
3Reliability
If the GLA domain is retained in FIX, then coagulation function is maintained, but plasma half-life is shortened due to interaction with endothelial cells
Solution Approach 1:
The patent segments the FIX molecule by separating the coagulation function from the GLA domain. By deleting or modifying only the GLA domain while retaining the rest of the FIX structure, the invention maintains coagulation activity through the remaining domains while eliminating the harmful endothelial cell interaction
Solution Approach 2:
The patent applies local modification by specifically targeting and removing only the GLA domain region. This localized change preserves the coagulation function in other domains while eliminating the specific harmful interaction caused by Gla residues with endothelial cells
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 modifications significantly extend the plasma half-life and improve bioavailability of FIX, enabling less frequent administration and potentially allowing subcutaneous administration, thereby reducing the burden on patients with hemophilia B.
Implementation Method 1
FIX-Fc has fused Fc from human IgG, and this extends its half-life by promoting its recycling via FcRn following uptake into cells, similarly to human IgG
Implementation Method 2
FIX-Fc has fused Fc from human IgG, and this extends its half-life by promoting its recycling via FcRn following uptake into cells
Implementation Method 3
FIX-Fc has fused Fc from human IgG, and this extends its half-life by promoting its recycling via FcRn following uptake into cells, similarly to human IgG
Implementation Method 4
Gla residues included in the GLA domain of FIX-Fc are the causative factors
Data Source
AI summary
The present invention provides a method for improving or controlling the plasma half-life and/or bio-availability of blood coagulation factor IX (FIX), the method comprising modifying the GLA domain. Examples of such modifications include: (i) non-covalent bonding of a GLA-domain-recognizing antibody or an antibody fragment thereof to the GLA domain; (ii) reduced number of Gla residues in the GLA domain, in comparison to that of a native FIX; (iii) either or both of deletion of one or more glutamic acid residues in the GLA domain and substitution of one or more glutamic acid residues in the GLA domain with another amino acid; and (iv) deletion of a part or all of the GLA domain. The present invention also provides a FIX with improved pharmacokinetics which carries such modifications, a pharmaceutical composition containing the FIX as an active ingredient, a method for producing the FIX, and such.