Codon-optimized nucleic acids for CHO cell protein expression
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Solution Overview
Problem
There is a need for efficient recombinant production methods for recombinant proteins like ocrelizumab in mammalian cell lines, particularly in industrially relevant Chinese hamster ovary (CHO) cells, due to challenges in protein translation caused by differences in codon usage bias.
Innovation Solution
The development of codon-optimized nucleic acids for the expression of anti-CD20 antibodies in CHO cells, specifically optimizing the light and heavy chain complementarity-determining regions (CDRs) and variable regions to align with the codon usage preferences of CHO cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If standard nucleic acid sequences are used for recombinant protein production in CHO cells, then the production process is simple, but protein expression levels are low due to codon usage bias differences
Solution Approach 1:
The patent applies parameter changes by optimizing the nucleic acid sequence through codon optimization. The coding sequence is redesigned to match the codon usage preferences of CHO cells, changing specific nucleotide parameters while maintaining the same amino acid sequence. This resolves the contradiction by improving protein expression levels (productivity) through targeted sequence parameter modification without fundamentally changing the protein structure or expression system complexity.
2Productivity
If codon-optimized nucleic acids are used, then protein expression levels improve significantly, but the nucleic acid sequence design becomes more complex
Solution Approach 1:
The patent uses parameter changes to optimize codon usage patterns in the nucleic acid sequence. By systematically adjusting nucleotide choices at the codon level to match CHO cell preferences, the method achieves 3-fold to 9-fold titer improvements while following established optimization algorithms that balance complexity and effectiveness.
Solution Approach 2:
The patent applies preliminary action through pre-optimization of the coding sequence before expression in CHO cells. The nucleic acid sequence is designed and optimized in advance to match the host cell's codon usage bias, ensuring high protein expression levels are achieved from the start of production without requiring subsequent complex modifications.
3Productivity
If wild-type nucleic acid sequences are used, then the genetic code remains simple, but translation efficiency is reduced due to codon usage bias
Solution Approach 1:
The patent modifies the nucleic acid sequence parameters to optimize translation efficiency. By changing codon choices to match CHO cell usage patterns, the system improves both translation efficiency and reliability simultaneously, as the optimized sequence ensures more accurate and efficient protein synthesis while maintaining fidelity to the original protein sequence.
Data Source
AI summary
The present invention relates to recombinant proteins that have been codon optimized for recombinant expression.