Immune Regulatory Oligonucleotides for Controlled TLR9 Antagonism
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current oligonucleotides used to modulate immune responses through TLR9 either activate or inhibit immune responses excessively, lacking a controlled, dose-dependent mechanism to partially antagonize TLR activity, which is desirable for treating certain diseases.
Innovation Solution
Development of novel immune regulatory oligonucleotide compounds with specific chemical modifications that reduce TLR9-mediated immune responses in a controlled manner by incorporating 2′-substituted nucleotides or nucleotide derivatives as blocking moieties, allowing for dose-dependent antagonism of TLR9 activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If oligonucleotides are used to activate TLR9-mediated immune responses, then immune response activation is improved, but excessive activation occurs leading to lack of controlled modulation
Solution Approach 1:
The patent applies local quality by introducing chemical modifications at specific positions (2′-substituted nucleotides at positions 2, 4, or 6) within the oligonucleotide sequence. These localized modifications create blocking moieties that prevent TLR9 binding at those specific sites, allowing the oligonucleotide to act as a partial antagonist rather than a full agonist, thus achieving controlled immune response modulation.
Solution Approach 2:
The patent employs parameter changes by systematically varying the degree of chemical modification (different substitution patterns, positions, and types of blocking moieties) to create a spectrum of oligonucleotide activities. By changing the parameters of chemical structure and modification extent, the patent achieves dose-dependent antagonism where the immune response can be finely tuned from full activation to partial inhibition.
2Reliability
If oligonucleotides are used to inhibit TLR9-mediated immune responses, then immune response inhibition is improved, but excessive inhibition occurs leading to complete blockade
Solution Approach 1:
The patent applies partial action by using oligonucleotides with one or more (but not complete) blocking moieties. These partially modified oligonucleotides provide intermediate levels of TLR9 antagonism, allowing for controlled inhibition rather than complete blockade. The partial modification enables dose-dependent control where the degree of inhibition can be adjusted by varying the extent of chemical modification.
3Adaptability or versatility
If chemical modifications are introduced to block TLR9 activity, then controlled antagonism is improved, but molecular complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the oligonucleotide into functional domains: unmodified regions that maintain TLR9 agonist activity and modified regions with blocking moieties that provide antagonism. This segmentation allows the molecule to exhibit both agonist and antagonist properties in a controlled manner, achieving dose-dependent modulation without excessive complexity.
Data Source
AI summary
The invention relates to TLR9 antagonist compounds and their therapeutic or prophylactic use. The invention provides novel immune regulatory oligonucleotides and immunomers as antagonist of TLRs and methods of use thereof. These immune regulatory oligonucleotides have unique sequences that suppress, without completely ablating, TLR-mediated signaling in response to a TLR ligand or TLR signaling agonist. The methods may have use in the prevention and treatment of autoimmunity, inflammation, inflammatory bowel disease, lupus, allergy, asthma, infection, sepsis, cancer and immunodeficiency.