Cell Culture Metabolic Shift for High-Titer Lactate Consumption
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Solution Overview
Problem
Existing cell culture methods face limitations in achieving high protein titers due to lactate accumulation, which inhibits cell growth and productivity, particularly in mammalian cell cultures, necessitating improved metabolic strategies for lactate consumption.
Innovation Solution
Culturing cells to achieve a metabolic shift to lactate consumption by maintaining specific viable cell concentrations in seed train cultures, followed by transferring cells to subsequent cultures to optimize lactate consumption and reduce accumulation, thereby enhancing protein production.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If cells are cultured in batch or fed-batch process to produce proteins, then protein production is achieved, but lactate accumulates which inhibits cell growth and productivity
Solution Approach 1:
The patent changes the metabolic state parameter of cells from lactate production to lactate consumption by controlling viable cell concentration thresholds and culture conditions. This parameter change allows cells to shift their metabolic profile, consuming lactate instead of producing it, thereby resolving the contradiction between protein production and lactate accumulation
Solution Approach 2:
The patent converts the harmful effect of lactate accumulation into a beneficial process by inducing cells to consume lactate as a carbon source. The lactate that would normally inhibit cell growth is instead utilized by cells, transforming the harmful waste product into a useful nutrient that supports continued productivity
2Productivity
If viable cell concentration is increased to enhance productivity, then protein titer increases, but lactate accumulation worsens and inhibits further growth
Solution Approach 1:
The patent applies preliminary action by inducing the metabolic shift to lactate consumption during seed train cultures before production cultures. This preliminary metabolic reprogramming ensures that when cells are transferred to production cultures at high viable cell concentrations, they are already equipped with the metabolic capability to consume lactate, preventing the harmful effects before they can occur
3Reliability
If cells are maintained in exponential growth phase for production, then cell health is maintained, but lactate production continues and limits maximum titer
Solution Approach 1:
The patent applies inversion by reversing the conventional metabolic behavior of cells. Instead of allowing cells to produce lactate during exponential growth (the normal behavior), the patent induces cells to consume lactate while maintaining exponential growth. This inverted metabolic approach allows simultaneous achievement of cell health maintenance and reduced lactate production
Data Source
AI summary
Improved methods for large scale production of proteins and/or polypeptides in cell culture is provided. In accordance with the present invention, the method provides for culturing cells that have metabolically shifted. The use of such a method or system allows high levels of protein or polypeptide production and reduces accumulation of unwanted metabolic waste such as lactate. Proteins and polypeptides expressed in accordance with the present invention may be advantageously used in the preparation of pharmaceutical, immunogenic, or other commercial biologic compositions, such as antibodies.