MAGE-A4 T Cell Receptors for Rapid High-Avidity Tumor Targeting
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Solution Overview
Problem
Current adoptive cell therapy (ACT) for cancer treatment is hindered by the difficulty and time-consuming process of isolating and characterizing tumor-specific T cells, often resulting in low-avidity T cells, limiting its broad clinical application.
Innovation Solution
Development of isolated T cell receptors (TCRs) specifically targeting the MAGE-A4 antigen, which are highly specific for the HLA-A2 bound form of the MAGE-A4 peptide, allowing for rapid generation of tumor-reactive T lymphocytes with defined antigen specificity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If adoptive cell therapy uses patient-derived lymphocytes expanded ex vivo, then tumor-specific T cells can be generated, but the process is time-consuming and often yields low-avidity T cells
Solution Approach 1:
The patent extracts only the essential functional element (TCR) from the complex T cell generation process. Instead of isolating and expanding entire T cell populations, the invention uses pre-characterized TCR sequences to rapidly generate tumor-specific T lymphocytes through genetic transfer, eliminating the time-consuming isolation and characterization steps while maintaining high avidity
Solution Approach 2:
The patent performs preliminary characterization and selection of high-avidity TCRs in vitro before clinical application. By pre-identifying and validating TCR sequences that specifically recognize tumor antigens with high affinity, the invention eliminates the need for time-consuming in-vivo selection processes and ensures high avidity T cell generation from the start
2Adaptability or versatility
If custom isolation and characterization of tumor-specific T cells is performed for each patient, then patient-specific tumor response can be achieved, but the process becomes difficult and time-consuming
Solution Approach 1:
The patent creates a library of pre-characterized TCR sequences that can be copied and transferred to patients' T cells. Instead of performing custom isolation for each patient, the invention uses a standardized approach where pre-validated TCR sequences are transferred via viral vectors, maintaining patient-specific tumor targeting while dramatically simplifying the process
Solution Approach 2:
The patent develops a universal platform for TCR transfer that can be applied across different patients and tumor types. The same basic approach of viral-mediated TCR transfer can be used for various cancer indications, with only the specific TCR sequence needing to be changed, thereby reducing overall process complexity while maintaining adaptability
3Reliability
If T cell therapy targets non-mutated tumor antigens, then specificity against tumor can be improved, but autologous T cell responses often fail to trigger effectively
Solution Approach 1:
The patent uses TCR transfer as an intermediary mechanism to bridge the gap between tumor antigen recognition and T cell activation. By introducing exogenous TCRs that specifically recognize tumor antigens into patient T cells, the invention enables effective anti-tumor responses against non-mutated antigens that would otherwise fail to trigger autologous responses, while maintaining tumor specificity through the designed TCR-antigen interaction
Data Source
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AI summary
The present invention relates to an isolated T cell receptor (TCR) specific for MAGE-A4 and a polypeptide comprising a functional portion of the TCR Further implicated are a multivalent TCR complex, a nucleic acid encoding a TCR, a cell expressing the TCR and a pharmaceutical composition comprising the TCR. The invention also refers to the TCR for use as a medicament, in particular to the TCR for use in the treatment of cancer.