HTLV-1 Antigen-Specific TCR Screening for Targeted Cell Therapy
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Solution Overview
Problem
Current treatments for HTLV-1-associated diseases, such as adult T-cell leukemia (ATL), are not sufficiently safe or effective, particularly when combined with transplantation, and there is a need for a more effective treatment approach.
Innovation Solution
A method for screening and expressing T-cell receptors (TCR) with high affinity for HTLV-1-derived antigens, involving TCR repertoire analysis and selection of highly ranked TCRs, which are then expressed in cells to target and cytotoxicity against HTLV-1-infected cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If multidrug chemotherapy and allogeneic stem-cell transplantation are used to treat HTLV-1-associated diseases, then treatment coverage is provided, but treatment safety and effectiveness are insufficient with inevitable relapse and GVHD exacerbation
Solution Approach 1:
The patent extracts and isolates specific T-cell receptors (TCRs) that recognize HTLV-1 Tax antigen from the complex immune system. By identifying and utilizing only the specific TCR types (such as those with CDR3 sequences matching SEQ ID NO: 3 and SEQ ID NO: 8) that target HTLV-1-infected cells, the treatment eliminates the need for broad multidrug chemotherapy and transplantation, thereby avoiding GVHD and relapse while maintaining effectiveness against the virus.
Solution Approach 2:
The patent introduces engineered T-cells expressing specific anti-HTLV-1 TCRs as intermediaries between the patient's immune system and the HTLV-1-infected cells. These modified T-cells serve as a bridge that specifically targets and destroys infected cells without triggering the harmful immune responses (GVHD) associated with allogeneic transplantation, thus resolving the contradiction between effective treatment and treatment safety.
2Ease of operation
If anti-CCR4 antibody monotherapy is used, then treatment is simplified, but GVHD exacerbation and relapse occur
Solution Approach 1:
The patent enables the patient's own T-cells to serve the therapeutic function by engineering them with specific anti-HTLV-1 TCRs. This autologous approach eliminates the need for complex allogeneic transplantation procedures while maintaining treatment effectiveness. The modified patient T-cells naturally target and destroy HTLV-1-infected cells without causing GVHD, thus achieving both treatment simplicity and reliability.
3Measurement precision
If TCR repertoire analysis is performed on sorted HTLV-1 Tax antigen-specific CTLs, then high-affinity TCRs can be identified, but the screening process requires intensive research and analysis
Solution Approach 1:
The patent segments the complex TCR repertoire analysis into manageable steps: (1) sorting HTLV-1 Tax antigen-specific CTLs from patient cells, (2) performing TCR repertoire analysis on the sorted cells, (3) ranking TCR types by frequency, and (4) selecting highly ranked TCRs for further development. This segmentation makes the intensive research process systematic and reproducible, enabling the identification of high-affinity TCRs (such as those with CDR3 sequences in SEQ ID NO: 3 and SEQ ID NO: 8) through a structured approach rather than random screening.
Data Source
AI summary
An object of the present invention is to provide a technique for preventing or treating HTLV-1-associated diseases, such as ATL, a material for use in the technique, a method for screening the material, and the like. The present invention provides a TCR screening method comprising sorting HTLV-1-derived antigen-recognizing cells from cells derived from an HTVL-1 patient and subjecting the HTLV-1-derived antigen-recognizing cells to TCR repertoire analysis, ranking the TCR types in descending order of the number of cells of each TCR type, and selecting a highly ranked TCR. The present invention provides a prophylactic or therapeutic agent for an HTLV-1-associated disease, the agent comprising a TCR comprising specific CDRs that can be obtained by the TCR screening method and cells expressing the TCR.