Optimizing Cryptic Peptide Immunogenicity for HLA-A*2402 Cancer Therapy
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Solution Overview
Problem
Current cancer immunotherapy approaches using immunodominant peptides have shown disappointing results due to self-tolerance issues, while cryptic peptides, with low MHC I affinity, are non-immunogenic and thus ineffective, necessitating a method to enhance their immunogenicity specifically for HLA-A*2402 phenotype, which is common in 27% of the population, particularly in Japanese and Asian individuals.
Innovation Solution
A method is developed to identify and optimize HLA-A*2402-restricted cryptic peptides by selecting peptides with specific amino acid sequences and modifying them to increase immunogenicity, involving substitution of N-terminal and C-terminal residues, tested in HLA-A*2402 transgenic mice to ensure cross-reactivity and immunogenicity, resulting in optimized peptides that can trigger an immune response against tumor antigens.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If immunodominant peptides are used for cancer immunotherapy, then the immune response is strong, but self-tolerance prevents effective tumor immunity
Solution Approach 1:
The patent inverts the conventional approach by using cryptic peptides (low MHC affinity, non-immunogenic) instead of immunodominant peptides. These cryptic peptides are modified to create optimized peptides that can overcome self-tolerance while maintaining the ability to induce tumor-specific immune responses, thereby resolving the contradiction between strong immune response and self-tolerance limitations
2Reliability
If cryptic peptides are used for immunotherapy, then self-tolerance is avoided, but low MHC I affinity makes them non-immunogenic
Solution Approach 1:
The patent applies parameter changes by modifying amino acid residues at secondary anchor positions of cryptic peptides while preserving primary anchor residues. This increases the MHC I binding affinity and immunogenicity of cryptic peptides without compromising their ability to overcome self-tolerance, thus resolving the contradiction between avoiding self-tolerance and achieving sufficient MHC affinity
3Quantity of substance
If amino acid substitutions are made to enhance MHC I affinity, then immunogenicity increases, but antigenicity may be lost
Solution Approach 1:
The patent applies local quality by making targeted amino acid substitutions only at secondary anchor positions (positions other than 2 and 9) while preserving the primary anchor residues and the antigenic determinant. This localized modification enhances MHC I binding affinity and immunogenicity while maintaining cross-reactivity with native peptides, resolving the contradiction between enhanced immunogenicity and preserved antigenicity
Data Source
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AI summary
The present invention pertains to methods for identifying a HLA-A* 2402- restricted cryptic epitope in an antigen, and for increasing its immunogenicity, in order to obtain HLA-A*2402-restricted epitopes able to trigger an immune response against HLA- A*2402-restricted cryptic epitopes. Isolated peptides consisting of cryptic or optimized HLA- A*2402-restricted epitopes are provided.