Fusion Protein Half-Life Extension via Hydrodynamic Radius
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Solution Overview
Problem
Current methods for extending the biological half-life of therapeutic proteins and peptides, such as PEGylation, are costly, immunogenic, and involve complex manufacturing processes, and there is a need for new means to prolong their duration in the body without increasing immunogenicity or manufacturing complexity.
Innovation Solution
A fusion protein comprising a biologically active polypeptide and a half-life extending polypeptide moiety derived from the C-terminal domain of human bile salt-stimulated lipase, which increases the protein's hydrodynamic radius and reduces renal clearance, thereby extending its biological half-life without the drawbacks of existing methods.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of stationary object
If PEGylation is used to extend half-life, then hydrodynamic radius increases and renal clearance decreases, but manufacturing complexity and cost increase
Solution Approach 1:
The invention extracts the half-life extending function from the chemical PEGylation process and transfers it to a genetically encoded peptide sequence (Ala-Glu-Ala-Asp-Asp-Ala). This genetic approach allows the half-life extension to be built into the protein structure itself through recombinant expression, eliminating the need for post-manufacturing chemical modification and thereby reducing manufacturing complexity while maintaining the desired pharmacokinetic properties
Solution Approach 2:
The invention creates a simplified copy of the PEGylation effect using a short, repetitive peptide sequence that mimics the hydrodynamic properties of PEG without requiring actual PEG chemistry. The (AEAADD)n sequence serves as a genetic copy that provides similar half-life extension through its polymeric structure, but can be produced directly through recombinant DNA technology rather than chemical conjugation
2Duration of action of stationary object
If PEGylation is used to extend half-life, then hydrodynamic radius increases, but immunogenicity increases
Solution Approach 1:
The invention changes the chemical composition parameter from foreign PEG polymers to human-derived amino acid sequences. The (AEAADD)n peptide is composed of natural amino acids that are unlikely to trigger immune responses, whereas PEG is a synthetic polymer that has been shown to be immunogenic. This parameter change maintains the hydrodynamic radius effect while eliminating the immunogenicity problem
3Reliability
If frequent dosing is used to maintain therapeutic effect, then therapeutic efficacy is maintained, but patient discomfort and healthcare resource demand increase
Solution Approach 1:
The invention adds a partial sequence ((AEAADD)n, where n=2-80) that is sufficient to achieve the desired half-life extension without adding excessive molecular weight or complexity. This partial addition provides just enough hydrodynamic radius increase to reduce renal clearance and enable less frequent dosing, balancing the need for extended half-life with maintaining ease of administration
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 fusion protein achieves a significant extension of biological half-life, allowing for less frequent administration, reduced immunogenicity, and improved bioavailability, with potential for subcutaneous administration instead of intravenous, and simplified purification processes.
Implementation Method 1
increases the protein's hydrodynamic radius and reduces renal clearance, thereby extending its biological half-life
Data Source
AI summary
A fusion protein is provided, comprising i) a biologically active polypeptide; and ii) a half-life extending polypeptide moiety comprising 2-80 units independently selected the amino acid sequences according to SEQ ID NO: 1: X1-X2-X3-X4-X5-X6-D-X8-X9-X10-X11 (SEQ ID NO: 1) in which, independently: X1 is P or absent; X2 is V or absent; X3 is P or T; X4 is P or T; X5 is T or V; X6 is D, G or T; X8 is A, Q or S; X9 is E, G or K; X10 is A, E P or T; and X11 is A, P or T. The half-life extending polypeptide moiety has a generally unfolded conformation and provides a fusion protein with a large hydrodynamic radius that may avoid renal clearance. As a result, the biological half-life of the fusion protein is increased and the biological effect of the biologically active polypeptide may thus be prolonged.