XTEN Fusion Proteins for Stability and Half-Life
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Solution Overview
Problem
Biologically active proteins are often labile and have short shelf-lives when formulated in aqueous solutions, and they can exhibit limited solubility or aggregation during recombinant production, requiring complex solubilization and refolding procedures.
Innovation Solution
The use of extended recombinant polypeptides (XTENs) as fusion partners linked to biologically active proteins (BPs) to enhance pharmacokinetic properties, solubility, and stability, while maintaining or enhancing therapeutic activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If biologically active proteins are formulated in aqueous solutions, then they maintain therapeutic activity, but they exhibit short shelf-lives and lability
Solution Approach 1:
The patent creates fusion proteins by combining the biologically active protein with XTEN polypeptide, forming a composite molecular structure. The XTEN component provides stability and extended circulation properties while the BP component retains therapeutic activity, resolving the contradiction between maintaining activity and extending shelf-life
Solution Approach 2:
The patent modifies the molecular weight and hydrodynamic radius parameters of the protein by fusing it with XTEN polypeptide. This parameter change extends the protein's circulation half-life and improves pharmacokinetic properties without compromising therapeutic activity
2Reliability
If complex solubilization and refolding procedures are used during recombinant production, then solubility issues are addressed, but manufacturing complexity increases
Solution Approach 1:
The XTEN polypeptide is designed with inherent solubility-enhancing properties that prevent aggregation during recombinant production. By incorporating XTEN into the fusion protein construct before expression, the patent eliminates the need for subsequent complex solubilization and refolding procedures
Solution Approach 2:
The XTEN polypeptide acts as a solubility-enhancing intermediary between the recombinant production system and the biologically active protein. It prevents aggregation and facilitates proper folding without requiring additional processing steps
3Duration of action of stationary object
If chemical conjugation of polymers to proteins is performed, then pharmacokinetic properties are enhanced, but product heterogeneity increases and manufacturing complexity increases
Solution Approach 1:
The patent merges the BP and XTEN components into a single fusion protein expressed as one homogeneous polypeptide chain. This eliminates the need for separate chemical conjugation steps and produces a uniform product with consistent pharmacokinetic properties
Solution Approach 2:
The patent replaces chemical conjugation methods with recombinant DNA technology. Instead of using chemical reagents to attach polymers to proteins, the fusion protein is produced through genetic engineering, resulting in a homogeneous product without the need for complex separation and purification steps
Data Source
AI summary
The present invention relates to compositions comprising biologically active proteins linked to extended recombinant polypeptide (XTEN), isolated nucleic acids encoding the compositions and vectors and host cells containing the same, and methods of using such compositions in treatment of glucose-related diseases, metabolic diseases, coagulation disorders, and growth hormone-related disorders and conditions.