Factor IX PEG Conjugates with Hydrolyzable Linkage
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Solution Overview
Problem
Current methods for delivering polypeptides and proteins, such as Factor IX, face challenges including short half-life, immunogenicity, and the need for frequent injections due to enzymatic degradation and immune response, which limits their therapeutic efficacy and convenience.
Innovation Solution
Development of conjugates with a releasable linkage, specifically using a water-soluble polymer like polyethylene glycol (PEG) linked to Factor IX via a hydrolyzable carbamate bond, allowing for controlled release of the active agent in vivo without enzymatic dependence, thereby extending half-life and reducing immunogenicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If polypeptides are administered by injection to avoid proteolytic degradation in the stomach, then the active agent reaches systemic circulation, but the half-life is short requiring repeated injections
Solution Approach 1:
The patent changes the molecular weight parameter of the polypeptide by conjugating it to a water-soluble polymer. This parameter change increases the hydrodynamic radius and decreases renal clearance, thereby extending the half-life of the active agent in systemic circulation without requiring repeated injections
Solution Approach 2:
The patent creates a composite structure by conjugating the polypeptide active agent to a water-soluble polymer backbone. This composite material combines the pharmacological activity of the polypeptide with the extended circulation properties of the polymer, resolving the contradiction between reliable delivery and short duration of action
2Reliability
If polypeptides are injected into systemic circulation, then therapeutic effect is achieved, but immune responses are elicited that destroy or neutralize the polypeptide
Solution Approach 1:
The water-soluble polymer acts as an intermediary carrier that shields the immunogenic polypeptide from the immune system. The polymer backbone provides a non-immunogenic scaffold that presents the active agent to target tissues while reducing recognition by the patient's immune system, thereby maintaining therapeutic effect while reducing immunogenicity
Solution Approach 2:
The patent changes the immunogenicity parameter by modifying the molecular structure through polymer conjugation. This structural modification alters the antigenic properties of the polypeptide, reducing its recognition by the immune system while preserving its pharmacological activity
3Duration of action of moving object
If polymer is conjugated to active agent to extend half-life and reduce immunogenicity, then dosing frequency is reduced, but the conjugation may occur at or near sites necessary for pharmacologic activity
Solution Approach 1:
The patent segments the polypeptide structure by identifying and utilizing specific amino acid residues (such as lysine or cysteine) as attachment points for the polymer. This segmentation allows the polymer to be conjugated at strategic locations that minimize interference with the pharmacologically critical regions of the active agent, preserving its activity while extending 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 conjugates demonstrate extended half-life and reduced immunogenicity, leading to less frequent dosing and improved therapeutic efficacy by maintaining pharmacodynamic activity over a longer period.
Implementation Method 1
linked to Factor IX via a hydrolyzable carbamate bond, allowing for controlled release of the active agent in vivo
Data Source
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AI summary
The present invention provides Factor IX moiety-polymer conjugates having a releasable linkage. Methods of making conjugates, methods for administering conjugates, are also provided.