Codon-optimized polynucleotides for modulating immune response strength
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Solution Overview
Problem
Current methods for expressing foreign genes in host cells face challenges due to mismatched codon usage patterns, leading to inefficient translation and immune response modulation, as different cell types within an organism have distinct codon usage biases that cannot be predicted by organism-wide averages.
Innovation Solution
The development of a method to rank and replace codons in antigen-encoding polynucleotides with synonymous codons that have higher or lower immune response preferences, as determined experimentally, to optimize immune response quality in mammals, using tables to select codons that enhance or reduce immune response.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If codon composition of antigen-encoding polynucleotide is optimized for host cell translation efficiency, then translation efficiency is improved, but immune response quality is reduced
Solution Approach 1:
The patent applies local quality by differentiating codon optimization strategies for different functional regions of the antigen protein. Critical antigenic epitopes use wild-type or immunogenic codons to maintain immune recognition, while non-critical regions use host-preferred codons to enhance translation efficiency. This localized differentiation resolves the contradiction between translation efficiency and immune response quality.
Solution Approach 2:
The patent inverts the conventional approach by not uniformly optimizing all codons for host preference. Instead, it deliberately retains or introduces rare codons at specific positions to enhance immune recognition. This inversion strategy challenges the assumption that host-preferred codons are always superior, resolving the contradiction by showing that rare codons can be beneficial for immune response quality.
2Ease of manufacture
If organism-wide average codon usage is used for gene expression optimization, then ease of manufacture is improved, but translation efficiency in specific cell types is reduced
Solution Approach 1:
The patent segments the codon optimization process into cell-type-specific strategies. Instead of using a single organism-wide average, it identifies and applies distinct codon usage patterns for different cell types (e.g., dendritic cells, macrophages, B cells). This segmentation resolves the contradiction by enabling tailored optimization for each cell type's translation machinery while maintaining manufacturing feasibility through systematic approaches.
Solution Approach 2:
The patent changes the parameter of codon usage from a fixed organism-wide average to dynamic cell-type-specific values. By adjusting codon preferences based on the specific cell type's tRNA abundance and translation kinetics, the patent achieves both ease of manufacture through systematic optimization and high translation efficiency in target cell types.
3Reliability
If rare codons are present in antigen-encoding polynucleotide, then immune response quality is enhanced, but translation efficiency is reduced
Solution Approach 1:
The patent applies local quality by strategically placing rare codons only at specific positions within the antigen sequence, particularly in regions containing critical epitopes. This localized use of rare codons enhances immune recognition where needed while minimizing the overall impact on translation efficiency. The rare codons are not distributed uniformly but are precisely positioned to maximize immunogenicity.
Solution Approach 2:
The patent employs partial action by using rare codons selectively rather than extensively throughout the entire antigen sequence. Only specific codons at strategically important positions are optimized for immune recognition, while the majority of codons use host-preferred variants to maintain efficient translation. This partial application resolves the contradiction by balancing immune enhancement with translation efficiency.
Data Source
AI summary
The present invention discloses methods and compositions for modulating the quality of an immune response to a target antigen in a mammal, which response results from the expression of a polynucleotide that encodes at least a portion of the target antigen, wherein the quality is modulated by replacing at least one codon of the polynucleotide with a synonymous codon that has a higher or lower preference of usage by the mammal to confer the immune response than the codon it replaces.