Fc Protein Formulation with Low Ionic Strength Buffers
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Solution Overview
Problem
Engineered protein constructs with an Fc domain in aqueous solutions are prone to instability and degradation due to physical and chemical processes, especially at higher temperatures, making it challenging to maintain stability over the intended shelf-life, even under refrigeration, and requiring pH optimization with buffering capacity.
Innovation Solution
Aqueous solution compositions with engineered protein constructs comprising an Fc domain, minimal buffer concentrations (0-10 mM) at pH 4.0-8.5, and low ionic strength (<20 mM), using uncharged tonicity modifiers like sucrose, and optional neutral amino acids to minimize pH fluctuations and ion impact.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional buffer concentrations and ionic strengths are used in aqueous formulations, then pH stability is improved, but protein construct stability deteriorates due to aggregation and degradation
Solution Approach 1:
The invention changes the formulation parameters by using minimal buffer concentrations (0-10 mM) and low ionic strength (<20 mM), which is opposite to conventional formulations that use higher concentrations. This parameter change resolves the contradiction by finding an optimal balance where sufficient pH control is achieved without causing protein aggregation or degradation.
Solution Approach 2:
The invention introduces uncharged tonicity modifiers (such as sucrose, mannitol, or sorbitol) as intermediary substances that provide tonicity control without contributing to ionic strength. These mediators allow the formulation to maintain osmotic balance while keeping ionic strength low, thus preventing protein degradation while still providing adequate pH stability.
2Reliability
If buffer concentration is increased to maintain pH stability, then pH control is improved, but ionic strength increases causing protein aggregation and degradation
Solution Approach 1:
The invention segments the functional roles in the formulation by separating pH control (achieved with minimal buffers at optimized concentrations) from tonicity control (achieved with uncharged tonicity modifiers). This segmentation allows each component to perform its function without the harmful side effects of high ionic strength, thus preventing protein aggregation while maintaining pH stability.
Solution Approach 2:
Uncharged tonicity modifiers serve as intermediary substances that provide tonicity control without increasing ionic strength. By using these intermediaries, the formulation achieves adequate pH control with minimal buffers while avoiding the harmful effects of high ionic strength that would otherwise be necessary to maintain tonicity.
3Stability of the object's composition
If refrigeration is used to maintain protein stability, then degradation rates are reduced, but storage convenience and patient accessibility deteriorate
Solution Approach 1:
The invention changes the formulation parameters (minimal buffers, low ionic strength, uncharged tonicity modifiers) to achieve enhanced protein stability that allows the product to be stored at elevated temperatures (2-8°C or even at room temperature) without significant degradation. This parameter change resolves the contradiction by enabling stable storage under more convenient temperature conditions.
Solution Approach 2:
The formulation is designed with preliminary stabilization features (optimized pH, minimal ionic strength, protective tonicity modifiers) that preemptively protect the protein from degradation during storage. This preliminary protection allows the product to maintain stability without requiring strict refrigeration, thus improving storage convenience and patient accessibility.
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 compositions achieve improved stability and reduced degradation of engineered protein constructs, maintaining clarity and low impurity levels even at elevated temperatures, extending shelf-life and storage stability.
Implementation Method 1
substances having at least one ionisable group with a pKa in the range of about 3.0 to about 9.5 and which pKa is within 2 pH units of the pH of the composition
Implementation Method 2
an uncharged tonicity modifier wherein the buffers are present in the composition at a total concentration in the range of about 0 mM to about 10 mM; and wherein the total ionic strength of the composition excluding the contribution of the engineered protein construct is less than 20 mM
Data Source
AI summary
There is provided inter alia an aqueous solution composition of pH in the range of about 4.0 to about 8.5 comprising: —an engineered protein construct comprising an Fc domain; —optionally one or more buffers being substances having at least one ionisable group with a pKa in the range of about 3.0 to about 9.5 and which pKa is within 2 pH units of the pH of the composition; —optionally one or more neutral amino acids; and—an uncharged tonicity modifier; wherein the buffers are present in the composition at a total concentration in the range of about 0 mM to about 10 mM; and wherein the total ionic strength of the composition excluding the contribution of the engineered protein construct is less than 20 mM.