Chemically Modified RNA Antitumor Agents for NK Cell Activation
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Solution Overview
Problem
Current antitumor agents are ineffective in activating immune cells, particularly NK cells, to inhibit tumor metastasis effectively, as they lack stability and efficiency in interacting with specific protein targets like ZC3H12D.
Innovation Solution
Development of RNA-based antitumor agents with chemically modified nucleotide units at the 3' and 5' ends, which interact with ZC3H12D protein to activate NK cells, enhancing their stability and ability to inhibit tumor metastasis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antitumor agents are used, then they can be administered to patients, but they fail to effectively activate immune cells and inhibit tumor metastasis due to lack of stability and efficiency in interacting with ZC3H12D protein
Solution Approach 1:
The patent applies parameter changes by introducing specific chemical modifications to the RNA structure, including 2'-O-methyl modifications at positions 1-10 from the 5' end and 2'-O-methyl modifications at positions 1-10 from the 3' end. These parameter changes in the RNA's chemical structure enhance its stability while maintaining its ability to interact with ZC3H12D protein and activate immune cells to inhibit tumor metastasis.
Solution Approach 2:
The patent employs composite materials by creating a hybrid RNA structure that combines modified nucleotide units (2'-O-methyl modifications) with standard nucleotide units. This composite approach provides both enhanced stability from the modified portions and functional activity from the standard portions, resolving the contradiction between stability and anti-metastatic efficacy.
2Reliability
If RNA agents with chemical modifications are used, then in vivo stability is improved, but the complexity of the RNA structure increases
Solution Approach 1:
The patent applies local quality by introducing chemical modifications only at specific local regions of the RNA molecule - specifically at the 5' end (positions 1-10) and 3' end (positions 1-10), rather than throughout the entire molecule. This localized approach enhances stability where most needed while minimizing structural complexity in the functional regions of the RNA.
Solution Approach 2:
The patent uses parameter changes by systematically modifying specific nucleotide positions with 2'-O-methyl groups at defined regions of the RNA molecule. This controlled parameter change approach provides predictable enhancement of in vivo stability without excessive increase in overall structural complexity, as the modifications are limited to specific positions rather than being random or comprehensive.
3Productivity
If RNA agents are designed to interact with ZC3H12D protein, then immune cell activation is enhanced, but the specificity requirements increase
Solution Approach 1:
The patent applies parameter changes by optimizing the RNA sequence composition and chemical modification pattern to achieve optimal interaction with ZC3H12D protein. The specific 2'-O-methyl modifications at defined positions enhance both the stability and the binding affinity to ZC3H12D, thereby improving immune cell activation efficiency while maintaining manufacturable sequence specificity.
Data Source
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AI summary
An antitumor agent containing, as an active ingredient, RNA having a base sequence selected from the group consisting of (1) and (2) below, and having at least one nucleotide unit represented by Formula (1) below in a 3' end region within 20 bases of the 3' end thereof and/or in a 5' end region within 25 bases of the 5' end thereof. (1) A base sequence represented by SEQ ID NO: 2 or a base sequence having 90% or more identity with such sequence (2) A base sequence consisting of between 20 and 200 consecutive nucleotides of the base sequence described in (1) above (In Formula (1), R1 represents a hydroxyl group, a hydroxyl group with a hydrogen atom substituted with an alkyl or alkenyl group, or a halogen atom; R2 represents NHR3 with a linking group, the linking group being a divalent hydrocarbon group with one or more carbon atoms; R3 represents a hydrogen atom, an alkyl group, or an alkenyl group; n is 0 or 1; X1 represents an oxygen atom or sulfur atom; X2 represents OH (or O-) or SH (or S-); and B represents a purine base or a pyrimidine base.)