Modified Tumor Antigen Polypeptide for Th Cell Infiltration
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Solution Overview
Problem
Conventional immunization protocols using MHC class I binding peptides fail to achieve sufficient antitumor activity as they do not effectively infiltrate tumor tissues, and inducing tumor-specific Th cells is challenging due to self-tolerance mechanisms that suppress immune responses.
Innovation Solution
A modified molecule of a tumor-specific antigen-derived polypeptide is created with added amino acids to enhance binding to MHC class II molecules, conferring resistance to degrading enzymes, which efficiently presents the antigen to Th cells, promoting their infiltration into tumor tissues and activation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a tumor antigen polypeptide is administered to induce Th cells, then Th cell induction is attempted, but regulatory T cells are induced instead which suppress antitumor immunity
Solution Approach 1:
The patent applies local quality by modifying specific terminal regions (N-terminal and C-terminal) of the tumor antigen polypeptide with amino acid sequences that have distinct functions: the N-terminal modification enhances Th1 cell induction while the C-terminal modification confers protease resistance. This localized modification strategy allows the polypeptide to selectively induce protective Th1 cells while avoiding induction of suppressive regulatory T cells.
Solution Approach 2:
The patent changes the chemical parameters of the polypeptide by adding specific amino acid sequences at the terminals and incorporating non-natural amino acids or chemically modified amino acids. These parameter changes increase protease resistance and enhance the polypeptide's ability to bind MHC class II molecules, thereby improving Th1 cell induction efficiency and preventing regulatory T cell induction.
2Quantity of substance
If conventional immunization protocols use MHC class I binding peptides to induce CTL, then CTL production is achieved, but infiltration into tumor tissues is insufficient
Solution Approach 1:
The patent merges the functions of Th1 cell induction and CTL enhancement by using a modified tumor antigen polypeptide that, when administered with a Th1-inducing adjuvant, simultaneously induces tumor-specific Th1 cells and enhances CTL activity. The Th1 cells secreted cytokines like IFN-γ that promote CTL infiltration into tumor tissues, thereby combining the benefits of both Th1 response and CTL-mediated cytotoxicity.
Solution Approach 2:
The patent introduces Th1 cells as an intermediary that mediates between the administered polypeptide and the CTL infiltration process. The Th1 cells, induced by the modified polypeptide and adjuvant, secrete cytokines that act as mediators to recruit and enhance CTL infiltration into the tumor tissue, thereby solving the infiltration problem.
3Productivity
If amino acid sequences are added to enhance MHC class II binding and protease resistance, then Th cell induction efficiency increases, but molecule complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the polypeptide into functional segments: the core tumor antigen region that maintains immunogenicity, the N-terminal modification segment that enhances Th1 induction, and the C-terminal modification segment that provides protease resistance. This segmented approach allows each region to be optimized independently while maintaining overall functionality.
Solution Approach 2:
The patent creates a composite polypeptide structure by combining the natural tumor antigen sequence with modified amino acid sequences at the terminals. This composite structure integrates the immunogenic properties of the original antigen with the enhanced stability and Th1-inducing capabilities of the modified terminals, achieving high Th cell induction efficiency.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The modified molecule significantly increases the efficiency of Th cell induction and infiltration into tumors, leading to enhanced antitumor immune responses and regression of solid tumors by facilitating the entry of CTLs into tumor tissues.
Implementation Method 1
A modified molecule of a tumor-specific antigen-derived polypeptide that binds an MHC class II molecule
Implementation Method 2
addition of an amino acid sequence...conferring resistance to degrading enzymes
Data Source
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AI summary
The present invention provides a tumor antigen-specific Th-inducing polypeptide capable of efficient antigen presentation, and an antitumor agent using same.