PTC Read-Through Compounds Induce Neoantigen Expression
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Solution Overview
Problem
Current cancer therapies face limitations in inducing a potent immune response against cancer cells due to the scarcity of robust tumor neoantigens, as cancer cells often evade detection by expressing weak or no antigens, and existing methods struggle to translate premature termination codon-containing mRNAs into proteins, which could serve as potent neoantigens.
Innovation Solution
The approach involves administering compounds that promote premature termination codon read-through and inhibit nonsense-mediated decay (NMD) in mRNAs, allowing the translation of frameshift or nonsense mutation-containing mRNAs into proteins, thereby inducing the expression of neoantigens on cancer cells' surfaces, and combining this with immune checkpoint inhibitors to enhance the immune response.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional cancer vaccines use weakly immunogenic antigens expressed on tumor cells, then an immune response can be temporarily induced, but the response is weak and only temporarily delays disease progression
Solution Approach 1:
The invention changes the parameter of antigen immunogenicity by inducing the expression of neoantigens with high immunogenicity through PTC read-through and NMD inhibition, transforming weakly immunogenic tumor antigens into strongly immunogenic neoantigens that elicit potent immune responses
Solution Approach 2:
The invention uses compounds that promote PTC read-through and inhibit NMD as intermediaries to enable the translation of mutant mRNAs into neoantigens, which then serve as mediators to trigger strong immune responses against cancer cells
2Reliability
If cancer cells do not express foreign antigens, then they evade immune detection, but this also means conventional vaccines cannot effectively target them
Solution Approach 1:
The invention performs preliminary action by administering PTC read-through promoters and NMD inhibitors before immune recognition can occur, enabling cancer cells to express neoantigens in advance so that the immune system can recognize and attack them
Solution Approach 2:
The invention changes the parameter of antigen availability by inducing neoantigen expression through PTC read-through and NMD inhibition, transforming cancer cells from antigen-negative to antigen-positive states that are recognizable by the immune system
Data Source
AI summary
Provided herein, inter alia, are compositions and methods for generating a immune response in an individual and/or inducing the expression of neoantigens on the surface of abnormal (such as proliferative) cells via promotion of premature termination codon (PTC) read-through and inhibition of nonsense-mediated decay (NMD) of messenger RNAs (mRNAs) bearing PTCs.