2′ Fluoro-Modified RNA Immunostimulators for Cancer Therapy
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Solution Overview
Problem
Current RNA therapeutics that activate Pattern Recognition Receptors (PRRs) for anti-cancer applications face challenges due to the short half-life of RNA in vivo and immune evasion by ribose modifications, such as 2′fluoro (2′F) and 2′-O-methyl (2′O-Me) modifications, which reduce their effectiveness in inducing programmed cell death in cancer cells.
Innovation Solution
Development of 5′ triphosphate, 2′ fluoro-modified pyrimidine non-linear single-stranded RNA (ssRNA) or double-stranded RNA (dsRNA) compositions that are at least 17 nucleotides long, with specific secondary structures, which are delivered intracellularly to activate RIG-I and MAVS, inducing apoptosis and cytokine production in cancer cells while avoiding immune activation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of stationary object
If chemical modifications (2′fluoro and 2′-O-methyl) are introduced to increase RNA stability and nuclease resistance, then the half-life of RNA is extended, but the ability to activate RNA-sensing PRRs is inhibited
Solution Approach 1:
The patent applies local quality by introducing 2′fluoro modifications at specific positions (pyrimidine residues at positions 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100) while leaving other positions unmodified or differently modified, creating a heterogeneous modification pattern that maintains PRR recognition capability while providing nuclease resistance
Solution Approach 2:
The patent changes the chemical parameter of the ribose 2′-hydroxyl group to a 2′-fluoro substituent, which fundamentally alters the RNA's properties by providing both enhanced stability through nuclease resistance and maintained ability to activate PRRs, resolving the contradiction between stability and immunogenicity
2Reliability
If conventional RIG-I agonists are used to induce apoptosis in cancer cells, then anti-tumor immunity is enhanced, but the RNA is rapidly degraded by serum nucleases in vivo
Solution Approach 1:
The patent creates a composite RNA structure combining 2′fluoro-modified nucleotides with unmodified or differently modified nucleotides in a specific arrangement, forming a hybrid molecule that exhibits both the immunogenicity of conventional RNAs and the stability of chemically modified RNAs, enabling in vivo persistence and sustained anti-tumor immunity
Data Source
AI summary
Methods of inhibiting the growth of cells or inducing cell death by contacting the cells with or introducing into the cells a composition including a 5′ triphosphate, 2′ fluoro-modified pyrimidine non-linear single stranded RNA at least 17 nucleotides long with a least 3 base pairings or a 5′ triphosphate, 2′ fluoro-modified double stranded RNA at least 17 base pairs long in an amount effective to inhibit cell growth, induce cell death or induce cytokine production by the cells. The methods also include administration of the compositions to a subject. The subject may have a proliferative disorder or infectious disease and administration of the compositions provided herein may treat the disorder or disease.