Pro-cyclic Dinucleotide Linker System for Targeted Drug Release
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Solution Overview
Problem
Current therapies for treating cancers, immunological disorders, and infections face challenges in delivering immunomodulatory effects and cytotoxic agents specifically to targeted sites within the body, leading to reduced efficacy and increased toxicity due to non-specific distribution and poor cellular penetration of cyclic dinucleotides (CDNs).
Innovation Solution
Development of Pro-cyclic dinucleotides (Pro-CDNs) coupled with a linker system that can be metabolized at targeted sites and conjugated with biologically active molecules (BAMs) to enhance immunomodulatory and cytotoxic effects, utilizing enzymatically cleavable linkers to release active compounds specifically within cells or tissues.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If cyclic dinucleotides (CDNs) are administered as immunomodulatory agents, then immune response is activated, but cellular penetration is poor and distribution is non-specific
Solution Approach 1:
The patent introduces a linker system as an intermediary carrier that facilitates cellular penetration of the CDN. The linker system acts as a mediator between the CDN and the cell membrane, enabling the CDN to cross the membrane through transporter proteins while maintaining its immunomodulatory activity upon intracellular release.
Solution Approach 2:
The patent segments the CDN into a pro-drug format where the active CDN is coupled to a linker system that can be metabolically processed. This segmentation allows the CDN to be delivered in a non-active form that can penetrate cells, then converted to its active form inside the cell through enzymatic cleavage of the linker.
2Reliability
If CDNs are delivered systemically, then broad immune activation occurs, but specificity to targeted sites is reduced
Solution Approach 1:
The patent applies local quality by designing the linker system to be selectively activated in specific tissues or cell types through tissue-specific metabolic processes. The linker contains functional groups that are metabolized by enzymes present only in certain locations (e.g., lysosomal enzymes in cancer cells), thereby localizing the CDN activation to the desired target site and reducing off-target effects.
3Productivity
If CDNs are used as cytotoxic agents, then cancer cell killing is achieved, but toxicity to normal cells increases
Solution Approach 1:
The patent applies preliminary action by designing the linker system to be cleaved by specific enzymes that are overexpressed or activated in cancer cells but not in normal cells. The linker contains pro-drug moieties that are metabolically activated only after cellular uptake, ensuring that cytotoxic CDN release is preceded by selective cellular penetration and enzymatic processing that occurs preferentially in malignant cells.
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 Pro-CDN and BAM-CDN conjugates achieve targeted delivery and release of immunomodulatory and cytotoxic agents, maximizing therapeutic effects while minimizing side effects by ensuring specific activation at the target site, thereby improving treatment outcomes for cancers, immunological disorders, and infections.
Implementation Method 1
The linker system comprises a connector which is a spontaneous self-eliminating group able to link with the CDN and the specifier; a specifier which is an enzymatically cleavable unit
Implementation Method 2
The Pro-CDNs of the present invention can be metabolized at a targeted site into CDNs and exert their full immunomodulatory effects at said targeted site
Data Source
AI summary
The present invention provides a Pro-cyclic dinucleotide (Pro-CDN) comprising a STING agonist cyclic dinucleotide which is coupled to a linker system. The Pro-CDNs of the present invention can be metabolized at a targeted site into CDNs and exert their full immunomodulatory effects at said targeted site. The present invention also provides conjugates wherein a Pro-CDN is conjugated to a Biologically Active Molecule (BAM) such as e.g. a cytotoxic molecule, a lipid, a protein, a peptide, a nucleic acid, a sugar or a PRR ligand. The invention provides also methods related to the use of such compounds to perform their activities at their targeted sites, to exert cytotoxic, cytostatic or immunomodulatory effects, to treat or to prevent diseases such as cancers, immunological disorders or infections.