Chirally Controlled CpG Oligonucleotides for TLR9 Activity Tuning
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Solution Overview
Problem
Existing oligonucleotides, including those with CpG region motifs, face challenges in achieving optimal immunomodulatory activity, stability, and effectiveness due to uncontrolled stereochemistry and chemical modifications, leading to variable TLR9 agonist and antagonist activities.
Innovation Solution
Development of chirally controlled oligonucleotide compositions with predetermined stereochemistry and chemical modifications, particularly in internucleotidic linkages, to enhance or reduce TLR9-related activities, stability, and delivery properties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If oligonucleotides with uncontrolled stereochemistry are used, then manufacturing is simpler and less costly, but immunomodulatory activity and stability are reduced
Solution Approach 1:
The patent applies parameter changes by controlling the stereochemistry of internucleotidic linkages (changing from uncontrolled to controlled R/S configuration) to improve immunomodulatory activity. This involves specifying particular stereochemical configurations at phosphorus atoms in the oligonucleotide backbone to enhance TLR9 agonist or antagonist activities while maintaining manufacturability through defined synthesis protocols.
2Stability of the object's composition
If chemical modifications are made to enhance stability, then oligonucleotide stability improves, but immunomodulatory activity may be reduced
Solution Approach 1:
The patent applies local quality by making specific chemical modifications at particular positions within the oligonucleotide sequence rather than uniform modifications throughout. This allows stability-enhancing modifications (such as phosphorothioate linkages or sugar modifications) to be placed strategically while preserving immunomodulatory activity at critical regions, particularly around CpG motifs.
Solution Approach 2:
The patent employs composite materials by combining different types of chemical modifications within a single oligonucleotide structure. This includes integrating phosphorothioate linkages, modified sugars, and base modifications in specific patterns to achieve both enhanced stability and maintained or improved immunomodulatory activity through synergistic effects.
3Ease of operation
If lipid conjugation is added to improve delivery, then delivery and pharmacokinetics improve, but molecular complexity increases
Solution Approach 1:
The patent applies the intermediary principle by using lipid conjugates as mediator molecules that facilitate the delivery of oligonucleotides to target cells. The lipid portion acts as a carrier that enhances cellular uptake and pharmacokinetic properties, while the oligonucleotide portion retains its immunomodulatory function, creating a hybrid molecule that combines benefits of both components.
Data Source
AI summary
The present disclosure pertains to the recognition that immune responses mediated by CpG oligonucleotides can be affected by the stereochemistry of modified internucleotidic linkages such as phosphorothioates. In some embodiments, the present disclosure relates to chirally controlled CpG oligonucleotide compositions comprising CpG oligonucleotides comprising multiple modified internucleotidic linkages such as phosphorothioate linkages, wherein the oligonucleotides comprise one or more CpG region motifs having defined stereochemistry patterns of chiral internucleotidic linkages. In some embodiments, CpG oligonucleotides comprising one or more CpG region motifs are capable of agonizing an immune response. In some embodiments, CpG oligonucleotides comprising one or more CpG region motifs are antagonistic. Methods for making and using chirally controlled CpG oligonucleotide compositions are also described. In some embodiments, no immune modulation is desired, and the present disclosure provides methods of identifying chirally controlled oligonucleotide compositions which have decreased immune modulation.