STING Activator dsDNA 5' End Modifications
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Solution Overview
Problem
Current methods fail to effectively activate immune responses in cancer and immune-mediated conditions due to the inability to differentiate between apoptotic/tumorigenic cells and infected cells, which both harbor DNA, leading to evasion of immune activation.
Innovation Solution
Development of STING activators in the form of double-stranded DNA (dsDNA) with modified 5' ends, specifically designed to induce STING signaling, which can stimulate immune responses by activating immune cells and inducing cytokine production.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If DNA from apoptotic or tumorigenic cells is detected, then immune activation occurs, but this leads to lethal autoinflammatory disease due to chronic cytokine production
Solution Approach 1:
The patent applies local quality by modifying specific regions of the dsDNA molecule (5' end modifications, specific nucleotide compositions) to create distinct structural characteristics that allow immune cells to differentiate between therapeutic DNA and self-DNA, thereby activating immune responses only at the desired location without triggering systemic autoinflammation
Solution Approach 2:
The invention segments the DNA detection process by creating highly specific structural requirements for STING activation, where only DNA with precise modifications (5' phosphorothioate linkages, specific nucleotide sequences) can trigger immune responses, while endogenous DNA lacking these specific features remains unrecognized
2Productivity
If tumor cells are engulfed by APCs, then immune response is generated, but tumor cells evade activation to avoid lethal autoinflammatory disease
Solution Approach 1:
The patent applies preliminary action by pre-modifying the dsDNA structure with specific 5' end modifications and nucleotide compositions before administration, ensuring that the DNA is pre-configured to be recognized by STING in a manner that mimics pathogen-associated DNA structures, thereby preemptively overcoming tumor cell evasion mechanisms
Solution Approach 2:
The invention changes physical and chemical parameters of the DNA molecule, including 5' end modifications (phosphorothioate linkages), nucleotide composition (AT-rich or GC-rich sequences), and structural conformation, to create DNA variants that have altered recognition properties by the immune system, enabling specific activation without triggering tolerance
3Quantity of substance
If dsDNA structure is used to stimulate immune response, then STING signaling is induced, but specificity in differentiating between self and non-self DNA is challenged
Solution Approach 1:
The patent introduces dsDNA with specific structural modifications as an intermediary that bridges the gap between self-DNA and pathogen-associated DNA, creating a molecular structure that is recognized by STING as foreign-like (triggering immune responses) while being chemically distinct from endogenous DNA, thereby achieving specific immune activation without cross-reactivity
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 STING activators effectively stimulate immune responses, leading to decreased tumor size and enhanced anti-tumor immunity by activating immune cells and inducing cytokine production, particularly Cxcl10 and type I IFN, thereby addressing the challenge of immune evasion by tumor cells.
Implementation Method 1
the activator induces STING signaling
Data Source
AI summary
The present disclosure relates, in general, to oligonucleotides that stimulate STING (STimulator of Interferon Genes) activity and increase activity of immune cells. The disclosed STING activators (STAVs) are useful in the treatment of cancer and other immune-mediated conditions.