SAGE1 Peptide-MHC Complexes for Cancer Immunotherapy
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Solution Overview
Problem
Current immunotherapeutic approaches face challenges in accurately targeting tumor cells due to a scarcity of T cells recognizing tumor-associated antigen (TAA)-derived peptides with high affinity, and existing prediction methods generate false positives, making it difficult to identify suitable TAAs for cancer therapy.
Innovation Solution
Development of novel peptides derived from Sarcoma antigen 1 (SAGE1) that form stable complexes with MHC molecules, along with binding moieties that specifically target these peptide-MHC complexes, to create immunotherapeutic reagents for cancer treatment, utilizing RNA expression differences to identify a therapeutic window and employing in silico algorithms and experimental validation for peptide-MHC interaction.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If in silico algorithms are used to predict MHC-presented peptides, then the screening process is accelerated, but the prediction accuracy deteriorates due to high false positive rates
Solution Approach 1:
The invention segments the peptide identification process into two distinct phases: (1) high-throughput in silico algorithm screening to generate candidate peptides, and (2) experimental validation using mass spectrometry and T cell assays to confirm actual MHC presentation. This segmentation allows the benefits of both computational speed and experimental accuracy to be realized in sequence.
Solution Approach 2:
The invention introduces experimental validation methods (mass spectrometry, T cell proliferation assays, ELISPOT assays) as intermediary steps between in silico prediction and therapeutic application. These intermediaries serve as filters to eliminate false positives while preserving true positives, thereby resolving the accuracy-productivity contradiction.
2Reliability
If T cells with high affinity for TAA-derived peptides are sought, then the specificity of tumor targeting is improved, but the availability of such T cells deteriorates due to scarcity in the circulating repertoire
Solution Approach 1:
The invention performs preliminary identification and characterization of optimal TAA targets and their presented peptides before initiating T cell therapy. By pre-validating peptide-MHC complexes through mass spectrometry and in vitro T cell assays, the system ensures that the scarce high-affinity T cells that do exist will be directed against verified, high-value targets, maximizing the utility of limited T cell resources.
Solution Approach 2:
The invention changes the selection parameter from relying on natural circulating T cell frequency to actively selecting and expanding specific T cell clones in vitro that demonstrate high affinity for validated peptide-MHC complexes. This parameter change transforms the limitation of scarcity into an opportunity for customized, high-purity T cell product manufacturing.
3Reliability
If TAAs with high expression in tumor tissue are targeted, then the therapeutic window is improved, but the risk of off-tumor toxicity increases if the TAA is also expressed in normal tissues
Solution Approach 1:
The invention applies local quality by focusing the immune response on the specific peptide epitope presented by MHC molecules rather than the entire TAA protein. Even if the TAA is expressed in both tumor and normal tissues, the immune system is directed against the unique peptide-MHC complex configuration, allowing differentiation between tumor and normal cells based on the specific peptide presentation context.
Solution Approach 2:
The invention performs preliminary validation to confirm that the selected TAA-derived peptide is actually presented on the surface of tumor cells before developing therapeutic reagents. This pre-confirmation ensures that the therapeutic target is genuinely present on tumor cells, minimizing the risk of targeting normal tissues that may express the parent protein but do not present the specific peptide epitope.
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 peptides and binding moieties effectively target tumor cells with a suitable therapeutic window, minimizing off-target toxicity and enhancing the specificity of immune responses, thereby providing an effective cancer treatment strategy.
Implementation Method 1
The peptide binds to the peptide binding groove of the MHC molecule
Implementation Method 2
Recognition of particular peptide-MHC antigens is mediated by a corresponding T cell receptor (TCR)
Data Source
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AI summary
The present invention relates to novel peptides derived from Sarcoma antigen 1 (SAGE1), complexes comprising such peptides bound to recombinant MHC molecules, and cells presenting said peptide in complex with MHC molecules. Also provided by the present invention are binding moieties that bind to the peptides and/or complexes of the invention. Such moieties are useful for the development of immunotherapeutic reagents for the treatment of diseases such as cancer.