FcRn-Binding VHH Polypeptides for Extended Plasma Half-Life
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Solution Overview
Problem
There is a need for FcRn-binding polypeptides with improved plasma half-life to enhance therapeutic efficacy and reduce the frequency and amount of drug administration.
Innovation Solution
Development of polypeptides comprising VHH domains that bind FcRn with specific CDR sequences, including humanized variants, which exhibit high affinity and pH-dependent binding to FcRn, potentially combined with albumin-binding capabilities, to extend plasma half-life.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If conventional therapeutic agents are used, then plasma half-life is short (1-5 days), but this requires frequent and high-dose administration increasing toxicity and cost
Solution Approach 1:
The patent modifies the molecular parameters of the therapeutic agent by fusing it to an FcRn-binding polypeptide. This changes the binding characteristics and recycling pathway of the drug, extending its plasma half-life from conventional 1-5 days to over 15 days, thereby reducing administration frequency and improving therapeutic index
Solution Approach 2:
The FcRn-binding polypeptide acts as an intermediary that mediates between the therapeutic agent and the FcRn receptor. This intermediary component enables the drug to utilize the FcRn recycling pathway, protecting it from degradation and extending its circulation time in the plasma
2Reliability
If FcRn-binding polypeptides are designed with specific CDR sequences, then binding affinity to FcRn is improved, but this increases the complexity of protein engineering and manufacturing
Solution Approach 1:
The patent segments the binding function into distinct CDR (complementarity determining region) sequences within the FcRn-binding polypeptide. By identifying and optimizing specific CDR sequences (such as those contacting residues 25-30, 50-55, and 80-85 of FcRn), the complex binding interface is broken down into manageable segments that can be engineered and manufactured more efficiently
Solution Approach 2:
The patent applies local quality by focusing the binding optimization on specific local regions of the FcRn interface through targeted CDR sequence design. Rather than redesigning the entire protein, only the specific CDR regions responsible for FcRn binding are optimized, reducing overall engineering complexity while maintaining high affinity
3Object-affected harmful factors
If VHH domains are humanized to reduce immunogenicity, then safety profile is improved, but this increases the time required for sequence optimization and validation
Solution Approach 1:
The patent applies the inversion principle by starting with a non-human VHH domain sequence and systematically humanizing it through targeted mutations in the CDR and framework regions. This reverse approach—taking the animal sequence and adapting it to human requirements—allows for controlled optimization of both binding affinity and human compatibility, reducing immunogenicity while maintaining functional activity
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 VHH domains enhance the plasma half-life of therapeutic agents, allowing for precise control of plasma drug concentrations, reducing toxicity, and minimizing the frequency and amount of drug needed.
Implementation Method 1
their ability to recycle from endothelial micropinocytosis through pH dependent binding to the neonatal Fc receptor (FcRn)
Implementation Method 2
at least one VHH domain that binds FcRn comprises a CDR1 sequence selected from SEQ ID NOs: 80-81, a CDR2 sequence selected from SEQ ID NOs: 83-84, and a CDR3 sequence of SEQ ID NO: 85
Data Source
AI summary
Provided herein are VHH-containing polypeptides that bind FcRn. Uses of the VHH-containing polypeptides are also provided.