Lipid Binding Protein Complexes for CDN Delivery
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Solution Overview
Problem
Natural cyclic dinucleotides (CDNs) that activate the STING pathway are highly susceptible to phosphodiesterases, making them unstable for therapeutic use. Synthetic CDN derivatives are more stable but have higher toxicity and are less potent in humans, necessitating new strategies for protection and delivery.
Innovation Solution
The development of lipid binding protein-based complexes, such as Cargomers and HDL-based complexes, that incorporate CDN binding moieties to carry and deliver CDNs. These complexes protect CDNs from degradation and facilitate targeted delivery to target cells, where the CDNs can activate the STING pathway to modulate an immune response.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If natural cyclic dinucleotides (CDNs) are used to activate the STING pathway, then immune response activation is achieved, but stability is poor due to susceptibility to phosphodiesterases
Solution Approach 1:
The patent uses lipid binding protein-based complexes as intermediary carriers to deliver CDNs to target cells. These complexes protect CDNs from phosphodiesterase degradation during circulation while maintaining their ability to activate STING upon cellular uptake, thus resolving the contradiction between stability and biological activity
Solution Approach 2:
The delivery system is segmented into distinct functional components: the lipid binding protein complex serves as the protective carrier, while the CDN remains as the active cargo. This segmentation allows the CDN to be protected during delivery but remain accessible for its immunostimulatory function at the target site
2Stability of the object's composition
If synthetic CDN derivatives are used to improve stability, then resistance to phosphodiesterases increases, but toxicity increases and potency decreases
Solution Approach 1:
Instead of modifying the CDN structure itself (which leads to toxicity), the patent creates a copy/proxy system where the lipid binding protein complex mimics natural lipid carriers. This allows natural, non-toxic CDNs to be delivered with the stability of synthetic derivatives without inheriting their toxic side effects
3Stability of the object's composition
If synthetic CDN derivatives are used to improve stability, then resistance to phosphodiesterases increases, but potency decreases
Solution Approach 1:
The lipid binding protein complex acts as an intermediary delivery vehicle that preserves the high potency of natural CDNs. By protecting the natural CDN structure within the complex, the system maintains the CDN's ability to effectively activate STING and induce type I interferon production, unlike synthetic derivatives that lose potency
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 use of lipid binding protein-based complexes effectively protects CDNs from degradation and ensures targeted delivery, enhancing their stability and potency while minimizing toxicity, thus providing a promising approach for treating diseases associated with the STING pathway.
Implementation Method 1
complexes comprising one or more lipid binding protein molecules (e.g., one or more Apolipoprotein A-I molecules) and one or more CDN binding moieties that bind one or more CDNs and indirectly couple the one or more CDNs to the lipid binding protein molecules
Data Source
AI summary
Lipid binding protein based complexes for carrying cyclic dinucleotides (CDNs) and uses thereof, pharmaceutical compositions comprising the complexes, and methods of making the complexes.