FcRn Binding Polypeptide for Half-Life Extension
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Solution Overview
Problem
Current therapies for modifying pharmacokinetic and pharmacodynamic properties of biomolecules face challenges due to the large size of fusion proteins, which affect tissue penetration and specificity, and often lead to immunoreactivity, necessitating the development of small, high-affinity FcRn binding molecules that do not adversely impact the properties of fused molecules.
Innovation Solution
Development of a neonatal Fc receptor (FcRn) binding polypeptide with a specific amino acid sequence motif that interacts with FcRn, allowing for efficient targeting while maintaining the properties of the fused molecules, and potentially used as a therapeutic agent or in combination treatments.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If fusion proteins are used to modify pharmacokinetic properties, then half-life is extended, but tissue penetration and specificity are reduced
Solution Approach 1:
The invention extracts the essential FcRn binding function from the large Fc domain and albumin, concentrating it into a small peptide motif (approximately 10-20 amino acids). This motif contains the critical binding residues necessary for FcRn interaction while eliminating the bulk of the protein structure, thereby achieving half-life extension without the size penalty of traditional fusion proteins.
Solution Approach 2:
The invention applies local quality by identifying and utilizing only the specific local region of FcRn (the binding site) and matching it with a correspondingly small local motif in the polypeptide. This localized interaction approach allows the small polypeptide to engage FcRn with high affinity at the specific binding interface without requiring the entire Fc domain or albumin structure.
2Duration of action of moving object
If Fc domain or albumin fusion is used to increase half-life, then pharmacokinetic properties are improved, but immunoreactivity increases and specificity decreases
Solution Approach 1:
The invention extracts only the essential FcRn binding residues from the large Fc domain and albumin structures, creating a minimal peptide motif that performs the half-life extension function without the immunogenic epitopes present in the full-length proteins. This extraction eliminates most of the harmful immunoreactivity while preserving the beneficial pharmacokinetic effect.
Solution Approach 2:
The invention uses a small, simple polypeptide motif that is structurally less complex and potentially less immunogenic than Fc domains or albumin. While the motif itself is short-lived in isolation, its function is sustained through continuous recycling via FcRn, achieving durable half-life extension with reduced immunogenic burden.
3Reliability
If large fusion proteins are used for FcRn targeting, then binding affinity is achieved, but tissue penetration is reduced
Solution Approach 1:
The invention extracts the critical binding residues from the large Fc domain and albumin structures, creating a minimal peptide motif (approximately 10-20 amino acids) that retains high affinity for FcRn. This small size enables excellent tissue penetration while the concentrated binding residues maintain reliable binding affinity through optimized interactions with the FcRn binding site.
Solution Approach 2:
The invention changes the size parameter dramatically from thousands of Daltons (Fc domain or albumin) to hundreds of Daltons (small peptide motif), while compensating for the reduced mass through optimized binding residue composition and arrangement. This parameter change enables both small size for tissue penetration and sufficient binding affinity for effective FcRn targeting.
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 FcRn binding polypeptide effectively modifies the pharmacokinetic and pharmacodynamic properties of biomolecules, enhancing their stability and targeting capabilities without compromising tissue penetration or specificity, and can be used as a standalone therapeutic or in combination with other agents.
Implementation Method 1
FcRn is able to bind to serum albumin and immunoglobulin G (IgG) at pH≤6.5 and release them at pH≥7.0
Data Source
AI summary
The present disclosure relates to a class of engineered polypeptides having a binding affinity for the neonatal Fc receptor (in the following referred to as FcRn), and provides an FcRn binding polypeptide comprising the sequence EX2 X3 X4 AX6 X7 EIRWLPNL X16X17 X18 QRX21 AFIX25 X26LX28 X29. The present disclosure also relates to the use of such an FcRn binding polypeptide as an agent for modifying pharmacokinetic and pharmacodynamic properties and as a therapeutic agent.