Modified POTE Peptides for MHC Class I Binding
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Solution Overview
Problem
Current cancer treatments, such as chemotherapy and radiotherapy, often have toxic side effects and are not effective for advanced or metastatic cancer, highlighting the need for novel systemic approaches that are specific and less toxic, while existing cancer immunotherapy strategies face challenges in optimizing CTL responses due to tolerization of high-affinity epitopes.
Innovation Solution
Development of immunogenic POTE polypeptides, including modified versions, that bind to MHC class I molecules, specifically designed to induce an immune response against POTE-expressing tumor cells by enhancing their binding affinity, which are administered to elicit a therapeutic immune response in subjects with cancers like breast, prostate, ovarian, lung, and pancreatic cancer.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If natural CTL epitopes are used for cancer immunotherapy, then the treatment targets tumor cells, but the CTL repertoire against high-affinity epitopes becomes tolerized, reducing efficacy
Solution Approach 1:
The patent modifies the amino acid sequence of POTE epitopes by introducing conservative amino acid substitutions at specific positions to alter MHC binding affinity. This parameter change in the epitope sequence enables the creation of immunogenic peptides that overcome tolerization while maintaining tumor specificity, thereby resolving the contradiction between targeting tumor cells and avoiding CTL tolerization.
2Reliability
If chemotherapy and radiotherapy are used to treat cancer, then tumor cells are killed, but toxic side effects are produced affecting normal cells
Solution Approach 1:
The patent extracts and utilizes a specific tumor-associated antigen (POTE) that is selectively expressed in cancer cells but not in normal cells. By focusing the immune response on this specific antigen through engineered epitopes, the therapy achieves cancer cell targeting without the broad toxic effects of conventional chemotherapy and radiotherapy, thus resolving the contradiction between treatment effectiveness and reduction of harmful side effects.
3Reliability
If existing cancer immunotherapy strategies are used, then CTLs are induced to kill tumor cells, but the binding affinity of peptides to MHC molecules is insufficient, limiting CTL activation
Solution Approach 1:
The patent systematically modifies the amino acid sequence of POTE epitopes by introducing conservative substitutions at specific positions to optimize MHC binding affinity. This parameter optimization ensures strong peptide-MHC interactions that effectively activate CTLs, resolving the contradiction between achieving adequate CTL activation and maintaining sufficient peptide-MHC binding strength.
Data Source
AI summary
POTE has recently been identified as a tumor antigen expressed in a variety of human cancers, including colon, ovarian, breast, prostate, lung and pancreatic cancer. Described herein are immunogenic POTE polypeptides, including modified POTE polypeptides, that bind MHC class I molecules. The immunogenic POTE polypeptides are capable of inducing an immune response against POTE-expressing tumor cells. Thus, provided herein is a method of eliciting an immune response in a subject, such as a subject having a type of cancer that expresses POTE.