Cyclic Dinucleotide–Antibody Conjugates for Stable STING Activation
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Solution Overview
Problem
Existing cyclic dinucleotides and their conjugates face challenges in plasma stability, synthesis difficulties, and limited activity against all STING haplotypes, particularly when linked via the thiol group on phosphorus, which affects their therapeutic efficacy.
Innovation Solution
Designing cyclic dinucleotides with phosphorothioate and phosphonothioate groups, limiting free hydroxy and amino groups, and using linkers that bind via the adenine base to improve stability and activity, and conjugating them with antibodies through cleavable linkers to enhance therapeutic effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If cyclic dinucleotides are linked via the thiol group on phosphorus, then synthesis is simplified, but plasma stability deteriorates and activity against all STING haplotypes is limited
Solution Approach 1:
The patent introduces an intermediary approach by using maleimide-thiol chemistry as a bridge between the cyclic dinucleotide and the antibody. The maleimide group reacts with thiol groups on the antibody, creating a stable thioether linkage that maintains plasma stability while enabling efficient conjugation. This intermediary chemical approach resolves the contradiction between synthesis ease and plasma stability.
Solution Approach 2:
The patent modifies the chemical parameters of the conjugation linkage by exploring different thiol-reactive groups (maleimide, iodoacetamide) and their reaction conditions. By changing the chemical parameters of the linkage chemistry, the patent achieves both ease of synthesis through thiol targeting and improved plasma stability through stable thioether bond formation.
2Ease of manufacture
If cyclic dinucleotides are linked via the thiol group on phosphorus, then synthesis is simplified, but activity against all STING haplotypes deteriorates
Solution Approach 1:
The patent applies local quality by selectively targeting specific thiol groups on the antibody (interchain disulfides or engineered cysteines) while preserving the overall structure and function of the cyclic dinucleotide. This localized modification approach maintains the nucleotide's ability to interact with all STING haplotypes while simplifying the conjugation process through thiol-specific chemistry.
Solution Approach 2:
The patent achieves universality by designing a conjugation system that can accommodate different antibody types and STING haplotypes through a common thiol-reactive chemistry platform. The maleimide-thiol linkage serves multiple functions: it simplifies synthesis, maintains plasma stability, and preserves broad STING haplotype activity, making the system universally applicable.
3Reliability
If free hydroxy and amino groups are limited in cyclic dinucleotides, then plasma stability improves, but synthesis complexity increases
Solution Approach 1:
The patent applies the extraction principle by removing or protecting free hydroxy and amino groups from the cyclic dinucleotide structure that would otherwise compromise plasma stability. By taking out these reactive groups or protecting them during synthesis, the patent achieves improved plasma stability while managing synthesis complexity through systematic protection-deprotection strategies.
Solution Approach 2:
The patent employs preliminary action by pre-modifying the cyclic dinucleotide to limit free hydroxy and amino groups before conjugation. This preliminary modification ensures plasma stability is established early in the synthesis process, and subsequent conjugation steps proceed without complications from unwanted side reactions involving free hydroxy or amino groups.
4Ease of operation
If cleavable linkers are used to conjugate cyclic dinucleotides with antibodies, then controlled release at target site is achieved, but synthesis complexity increases
Solution Approach 1:
The patent applies dynamics by incorporating cleavable linkers that can dynamically transition from a stable conjugated state to a released state in response to specific biological conditions (such as enzymatic cleavage or reduction). This dynamic property enables controlled release at the target site while the patent manages synthesis complexity by using well-established cleavable linker chemistries.
Solution Approach 2:
The patent uses cleavable linkers as intermediaries between the cyclic dinucleotide and antibody. These linkers serve as temporary connectors that facilitate stable conjugation during circulation but can be cleaved under specific conditions to release the active cyclic dinucleotide at the target site. The intermediary nature of these linkers enables controlled release while their standardized chemistry keeps synthesis manageable.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The modified cyclic dinucleotides demonstrate potent STING activation across all human haplotypes, improved plasma stability, and controlled release at the target site, enhancing therapeutic outcomes, particularly in cancer treatment.
Implementation Method 1
The modified cyclic dinucleotides demonstrate potent STING activation across all human haplotypes, improved plasma stability
Implementation Method 2
conjugating them with antibodies through cleavable linkers to enhance therapeutic effects
Implementation Method 3
This CDN activates STING (Stimulator Of Interferon Genes, also known as TMEM173, MITA, ERIS), which in turn triggers the expression of type I and III interferons
Data Source
Figure 1
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Figure 3~4
AI summary
The present invention provides a compound of general formula I: wherein R represents hydrogen, a linker structure or anl antibody attached by the linker structure. Compounds of general formula I are useful in treatment or prevention of cancer.