TNF Alpha Binding Protein Charge Profile Control
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Solution Overview
Problem
Biosimilars face challenges in achieving identical charge profiles to reference proteins due to differences in manufacturing processes and environmental conditions, which affects their stability, activity, and immunogenicity, requiring methods to enhance biosimilarity while maintaining safety and potency.
Innovation Solution
A cell culture method that adjusts metal ion concentrations and pH levels in the culture medium during the fermentation process to modify the charge profile of TNF α binding proteins, such as adalimumab or etanercept, to align with the reference protein's characteristics, thereby increasing biosimilarity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If standard cell culture conditions are used for producing TNF α binding proteins, then the manufacturing process is simple and cost-effective, but the charge profile of the produced protein differs from the reference protein, reducing biosimilarity
Solution Approach 1:
The patent applies parameter changes by systematically modifying cell culture conditions including metal ion concentrations (Fe, Cu, Zn, Se), pH levels, and temperature to optimize the charge profile of TNF α binding proteins. These parameter adjustments enable precise control over post-translational modifications and protein heterogeneity, achieving biosimilarity to reference proteins while maintaining a feasible manufacturing process
2Manufacturing precision
If metal ion concentrations and pH are adjusted during cell culture to modify charge profile, then biosimilarity to reference protein increases, but the manufacturing process becomes more complex and time-consuming
Solution Approach 1:
The patent implements preliminary action by pre-determining optimal metal ion concentrations and pH levels based on desired charge profile outcomes. The method specifies adding metal ions (Fe, Cu, Zn, Se) at defined concentrations before protein expression begins and maintaining specific pH ranges during culture, allowing the charge profile to be optimized in advance rather than requiring extended culture times for natural optimization
3Manufacturing precision
If cell culture conditions are optimized to match reference protein charge profile, then biosimilarity increases, but the risk of immunogenic reactions may increase due to heterogeneity
Solution Approach 1:
The patent uses parameter changes to control the balance between achieving reference-like charge profiles and minimizing immunogenic heterogeneity. By optimizing metal ion concentrations (particularly Zn and Se) and pH levels within specific ranges, the method achieves charge profile similarity while controlling the extent of post-translational modifications that could lead to immunogenic variants
Solution Approach 2:
The patent implements feedback control by characterizing the charge profile of produced proteins and using this information to adjust subsequent cell culture batches. Through iterative optimization based on measured charge heterogeneity and impurity profiles, the method achieves consistent biosimilarity while maintaining safety by identifying and controlling parameters that minimize immunogenic variants
Data Source
AI summary
The present invention relates to a method of increasing biosimilarity of a TNF α binding protein to a reference TNF α binding protein by modifying the charge profile of the binding protein produced by cell culture in a cell culture medium, by making an adjustment to a cell culture condition The adjustment is an increase in the concentration of a metal ion in the cell culture medium and the adjustment occurs on one or more days during the cell culture method, whereby the adjustment in the cell culture condition results in the modification of the charge profile of the binding protein. The present invention also relates to a biosimilar protein obtainable by such a process.