Elastin-like Peptide Fusion for Therapeutic Protein Stability
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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 elastin-like peptides (ELPs) conjugated with therapeutic proteins, such as GLP-1 receptor agonists, insulin, or Factor VII/VIIa, which enhance stability, solubility, bioavailability, and half-life through reversible inverse phase transitions and specific coupling methods.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If therapeutic proteins or peptides are used in their native state, then therapeutic activity is maintained, but serum stability and half-life are short
Solution Approach 1:
The patent creates a composite structure by fusing the therapeutic protein or peptide with an elastin-like peptide (ELP) component. This composite fusion protein combines the therapeutic activity of the original molecule with the stability and half-life extending properties of the ELP component, resolving the contradiction between maintaining therapeutic activity and extending serum half-life.
Solution Approach 2:
The elastin-like peptide component acts as an intermediary that mediates between the therapeutic protein and the serum environment. The ELP component provides the necessary stability and half-life extension while allowing the therapeutic protein to maintain its biological activity, effectively serving as a bridge that reconciles the conflicting requirements.
2Duration of action of moving object
If PEG is conjugated to extend half-life, then serum stability is improved, but therapeutic activity is substantially reduced or destroyed
Solution Approach 1:
The patent changes the chemical and physical parameters of the therapeutic protein by fusing it with an elastin-like peptide component rather than conjugating PEG. This parameter change involves using a peptide-based fusion strategy with specific amino acid sequences (Val-Pro-Gly-X-Gly repeats) that provide half-life extension through different mechanisms than PEG, thereby maintaining therapeutic activity while achieving the desired pharmacokinetic improvements.
3Reliability
If therapeutic proteins are formulated in aqueous solutions, then bioavailability is improved, but stability is extremely labile
Solution Approach 1:
The elastin-like peptide component forms a composite structure with the therapeutic protein that inherently provides both solubility and stability in aqueous solutions. The ELP component's amphiphilic nature and specific sequence composition create a stable soluble complex that maintains therapeutic activity while protecting against degradation, resolving the contradiction between stability and ease of formulation.
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 ELP-conjugated therapeutic agents demonstrate improved stability, persistence, and biological action, allowing for extended circulation and enhanced therapeutic effects in treating conditions like diabetes and bleeding disorders with reduced frequency of administration.
Implementation Method 1
In some embodiments, the ELP components may undergo a reversible inverse phase transition, which may impart additional practical and/or therapeutic advantages.
Data Source
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AI summary
The present invention provides therapeutic agents and compositions comprising elastin-like peptides(ELPs) and therapeutic protein is a GLP-1 receptor agonist, 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 persistence in the body, solubility, and bioavailability.