Elastin-like peptide fusion proteins for serum half-life extension
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Solution Overview
Problem
Therapeutic proteins and peptides are often labile and have short serum stability and half-life, limiting their effectiveness, and existing stabilization methods like PEG conjugation can reduce therapeutic activity.
Innovation Solution
Development of therapeutic agents comprising an elastic peptide component and a therapeutic proteinaceous component, where the elastic peptide provides enhanced stability, solubility, bioavailability, and half-life, and can be covalently coupled with the therapeutic component using chemical coupling or recombinant fusion technology.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of stationary object
If therapeutic proteins are used in their native state, then they exhibit short serum stability and half-life, but they maintain their natural therapeutic activity
Solution Approach 1:
The patent combines therapeutic proteins with elastin-like peptide (ELP) moieties to create fusion proteins. The ELP component provides extended serum half-life through its unique properties (hydrophobic effect, temperature-responsive solubility), while the therapeutic protein component maintains its biological activity. This merging resolves the contradiction by achieving both long circulation time and preserved therapeutic function.
Solution Approach 2:
The invention creates composite protein structures by fusing therapeutic proteins with elastin-like peptide sequences. The composite structure leverages the stability and long circulation characteristics of ELP while incorporating the therapeutic functionality of the protein of interest, thereby extending serum half-life without sacrificing therapeutic activity.
2Duration of action of stationary object
If PEG is conjugated to a proteinaceous molecule, then serum half-life is extended, but therapeutic activity is substantially reduced or destroyed
Solution Approach 1:
The patent uses elastin-like peptides with specific amino acid sequences (rich in glycine, proline, and valine) that exhibit unique physical properties including temperature-responsive solubility and hydrophobic effects. By changing the chemical parameters of the half-life extension strategy from PEG (hydrophilic polymer) to ELP (amphiphilic peptide with specific sequence characteristics), therapeutic activity is preserved while achieving extended serum half-life.
3Stability of the object's composition
If therapeutic proteins are formulated in aqueous solutions, then they are stable for formulation, but they exhibit extreme lability and short serum persistence
Solution Approach 1:
The patent merges therapeutic proteins with elastin-like peptide moieties that provide both formulation stability and extended serum persistence. The ELP component's unique properties (temperature-responsive behavior, hydrophobic effect) enable the fusion protein to remain stable in aqueous formulations while achieving prolonged circulation half-life in vivo.
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 elastic peptide component significantly improves the stability, persistence, and biological action of therapeutic proteins, such as GLP-1 receptor agonists, insulin, and Factor VII/VIIa, leading to extended half-life and improved therapeutic efficacy.
Implementation Method 1
In some embodiments, the elastic peptide is an ELP that undergoes a reversible inverse phase transition, which may impart additional practical and/or therapeutic advantages.
Data Source
AI summary
The present invention provides therapeutic agents and compositions comprising elastic peptides and therapeutic proteins. Such peptides exhibit a flexible, extended conformation. In some embodiments, the therapeutic protein is a GLP-1 receptor agonist (e.g., GLP-1, exendin), insulin, or Factor VII/VIIa, including functional analogs. The present invention further provides encoding polynucleotides, as well as methods of making and using the therapeutic agents. The therapeutic agents have improvements in relation to their use as therapeutics, including, inter alia, one or more of half-life, clearance and/or persistance in the body, solubility, and bioavailability.