pH-Dependent HSA-Binding Molecules for Selective Half-Life Extension
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Solution Overview
Problem
Current technologies that use HSA-binding molecules to extend the half-life of therapeutic agents do so by continuous binding to HSA, leading to increased size and potential interference with serum albumin function and tissue penetration, affecting efficacy.
Innovation Solution
Development of pH-dependent HSA-binding molecules that preferentially bind to HSA at acidic pH and do not bind or bind weakly at physiological pH, allowing for the creation of fusion proteins that enhance therapeutic protein half-life without interfering with serum albumin function.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If HSA-binding molecules are used to extend half-life of therapeutic agents, then the duration of action is improved, but the molecular size increases significantly causing steric hindrance and reduced tissue penetration
Solution Approach 1:
The patent applies dynamics by creating pH-dependent binding behavior where the HSA-binding molecule dynamically adjusts its binding affinity based on environmental pH. At acidic pH (endosomes), binding is strong to extend half-life, while at physiological pH (circulation), binding is weak to maintain small effective size and tissue penetration capability.
Solution Approach 2:
The patent changes the binding parameter (affinity) as a function of pH. The equilibrium dissociation constant varies from low values (strong binding) at acidic pH to high values (weak binding) at physiological pH, allowing the system to optimize both half-life extension and tissue penetration under different physiological conditions.
2Duration of action of moving object
If HSA-binding molecules bind continuously to HSA, then the half-life is extended, but the function of serum albumin is interfered with
Solution Approach 1:
The patent applies local quality by creating spatially and conditionally specific binding behavior. The HSA-binding molecule exhibits strong binding only in specific local environments (acidic endosomes) while maintaining weak binding in other environments (physiological circulation), thus extending half-life locally without globally interfering with HSA function.
Solution Approach 2:
The dynamic pH-dependent binding allows the molecule to selectively interact with HSA only under specific conditions (acidic pH in endosomes) rather than continuously, preserving HSA's normal physiological functions in circulation while achieving half-life extension through endosomal recycling.
3Duration of action of moving object
If HSA-binding molecules are used to extend half-life, then the duration of action is improved, but the therapeutic efficacy is reduced due to steric hindrance
Solution Approach 1:
The patent uses dynamic pH-dependent binding to achieve strong HSA association in endosomes (extending half-life) while maintaining weak association in circulation (preserving therapeutic efficacy and tissue penetration), thus resolving the contradiction between duration of action and therapeutic reliability.
Solution Approach 2:
By changing the binding affinity parameter as a function of pH, the system achieves strong binding (low KD) at acidic pH for half-life extension while maintaining weak binding (high KD) at physiological pH for optimal therapeutic efficacy and tissue penetration.
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 pH-dependent HSA-binding molecules maintain therapeutic efficacy by avoiding steric hindrance and improving tissue penetration while extending the half-life of therapeutic agents.
Implementation Method 1
HSA-binding molecules that bind preferentially to HSA at acidic pH with reduced or no binding to HSA at physiological pH
Data Source
AI summary
Provided herein are pH-dependent HSA binding molecules. Fusion proteins comprising pH-dependent HSA binding molecules and a therapeutic protein are also provided. Polynucleotides, vectors, host cells, methods of use, and methods of production are also provided herein.