Cyclic Dinucleotide STING Adjuvants for Cancer Immunotherapy
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Solution Overview
Problem
Current immunologic strategies for treating refractory diseases like cancer are limited by tolerance to targeted antigens, poor trafficking of T cells to tumor sites, and short persistence of induced T cell responses.
Innovation Solution
The use of cyclic purine dinucleotides, such as cyclic-di-AMP and cyclic-di-GMP, which activate the STING pathway to induce type I interferon production, enhancing immune responses when used as adjuvants in vaccines or immunotherapies, particularly in combination with other therapeutic agents like GM-CSF and CTLA-4/PD-1 pathway antagonists.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional immunologic strategies are used to treat refractory diseases, then treatment approaches are limited by tolerance to targeted antigens, but this limits the induction of cytotoxic CD8 T cells of appropriate magnitude and function
Solution Approach 1:
The patent introduces cyclic dinucleotides (CDNs) as intermediary molecules that activate the STING pathway in dendritic cells. These CDNs serve as a mediator between the vaccine antigen and the immune system, bypassing antigen tolerance by triggering innate immune responses through a different recognition pathway (STING) rather than direct T cell recognition of the targeted antigen
Solution Approach 2:
The patent applies preliminary action by activating dendritic cells through STING pathway engagement before they present the targeted antigen to T cells. This preliminary activation of dendritic cells by CDNs creates a primed state that enhances their ability to induce strong cytotoxic T cell responses, overcoming the limiting effect of antigen tolerance
2Reliability
If therapeutic vaccination is used to induce immune response, then antigen-specific T cells can be generated, but poor trafficking of the generated T cells to sites of malignant cells limits effectiveness
Solution Approach 1:
The patent uses cyclic dinucleotides as intermediary molecules that not only activate dendritic cells but also induce the production of chemokines and cytokines. These signaling molecules act as intermediaries that create chemical gradients to guide and accelerate T cell trafficking to tumor sites, solving the problem of poor T cell homing
3Reliability
If therapeutic vaccination is used to induce immune response, then antigen-specific T cells can be generated, but poor persistence of the induced T cell response limits long-term effectiveness
Solution Approach 1:
The patent applies preliminary action by activating dendritic cells through STING pathway engagement before antigen presentation. This preliminary activation creates a more robust and sustained immune environment that supports long-term T cell persistence and memory formation, overcoming the limitation of poor response durability
4Reliability
If STING pathway activation is used to enhance immune response, then type I interferon production is increased, but this requires precise control to avoid excessive inflammation
Solution Approach 1:
The patent employs parameter changes by using modified cyclic dinucleotide structures with varying chemical properties. These structural modifications allow tuning of the STING activation potency and duration, enabling control over type I interferon production levels to achieve therapeutic effect while minimizing excessive inflammation
Solution Approach 2:
The patent uses cyclic dinucleotides as controllable intermediary molecules that can be precisely dosed and structured. These intermediaries provide a regulated interface between the administered vaccine and the STING pathway, allowing controlled activation that produces sufficient type I interferon for therapeutic effect while avoiding harmful excessive inflammation through optimized molecular design and dosing
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
This approach significantly enhances antigen-specific immune responses, improves T cell activation and persistence, and increases the effectiveness of cancer immunotherapy by promoting a balanced Th1/Th2 immune response and activating cytotoxic T cells.
Implementation Method 1
The CDNs cyclic-di-AMP (produced by Listeria monocytogenes) and its analog cyclic-di-GMP (produced by Legionella pneumophila) are recognized by the host cell as a PAMP (Pathogen Associated Molecular Pattern), which bind to the PRR (Pathogen Recognition Receptor) known as STING. STING is an adaptor protein in the cytoplasm of host mammalian cells which activates the TANK binding kinase (TBK1)-IRF3 signaling axis, resulting in the induction of IFN-β and other IRF-3 dependent gene products
Data Source
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AI summary
The present invention provides highly active cyclic-di-nucleotide (CDN) immune stimulators that activate DCs via a recently discovered cytoplasmic receptor known as STING (Stimulator of Interferon Genes). In particular, the CDNs of the present invention are provided in the form of a composition comprising one or more cyclic purine dinucleotides induce STING-dependent type I interferon production, wherein the cyclic purine dinuclotides present in the composition are substantially pure 2', 5', 2', 5' and 2', 5 ',3 ',5' CDNs, and prefereably Rp,Rp stereosiomers thereof.