NPSR1 Peptide MHC Complexes for Tumor Targeting
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Solution Overview
Problem
Current immunotherapeutic approaches for cancer treatment face challenges in accurately identifying tumor-associated antigen (TAA)-derived peptides presented by Major Histocompatibility Complex (MHC) molecules on tumor cells, leading to scarcity of T cells recognizing these peptides with high affinity, and existing prediction methods generate false positives due to incomplete understanding of intracellular processing.
Innovation Solution
Development of novel peptides derived from Neuropeptide S Receptor (NPSR1) that form stable complexes with MHC molecules, along with binding moieties that specifically target these complexes, to enhance T cell recognition and targeting of tumor cells, particularly in colon and oesophageal cancers, utilizing RNA expression differences to define therapeutic windows and avoiding cross-reactivity with normal tissues.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If in silico algorithms are used to predict MHC-presented peptides, then peptide identification is accelerated, but false positives increase due to incomplete understanding of intracellular processing
Solution Approach 1:
The patent combines in silico prediction algorithms with direct experimental data from mass spectrometry analysis of tumor cell surfaces. This integration allows the method to maintain the speed advantage of computational prediction while correcting false positives through experimental validation, specifically by comparing predicted peptides against actually presented peptides identified via MS/MS sequencing of MHC-eluted peptides from tumor cells
Solution Approach 2:
The patent uses an intermediary experimental step (mass spectrometry analysis of MHC-bound peptides directly from tumor cells) to bridge the gap between computational prediction and clinical application. This intermediary validation layer filters out false positives by identifying only those peptides that are actually processed and presented by tumor cells, thereby resolving the reliability issue while preserving productivity
2Reliability
If T cells are selected during thymus maturation, then immune system development is optimized, but scarcity of T cells recognizing TAA-derived peptides with high affinity occurs
Solution Approach 1:
The patent performs preliminary identification of tumor-associated peptides that are actually presented on tumor cell surfaces using mass spectrometry before developing T cell therapies. By pre-identifying the specific peptide-MHC complexes present on tumor cells, the method enables selection or engineering of T cells targeted against these confirmed antigens, overcoming the scarcity issue by focusing on validated targets rather than relying solely on natural T cell repertoire
Solution Approach 2:
The patent changes the selection parameter from relying on natural T cell affinity to actively identifying and selecting T cells or TCRs that recognize specifically identified tumor-presented peptides. By using experimental data to define target peptides and then selecting T cells/TCRs based on their ability to recognize these confirmed antigens, the method overcomes the limitation of natural T cell scarcity while maintaining immune system reliability
3Productivity
If TAAs with high expression in tumor tissue are targeted, then therapy efficacy is improved, but off-tumour on-target toxicity increases due to expression in normal healthy tissues
Solution Approach 1:
The patent applies local quality by identifying peptides that are specifically presented on tumor cell surfaces versus normal tissue cells, even when the source proteins are expressed in both. By analyzing which peptides are actually processed and presented on tumor MHC molecules (using mass spectrometry of tumor-derived MHC peptides), the method identifies tumor-specific presentation patterns that distinguish cancer cells from healthy cells expressing the same proteins, thereby enabling targeted therapy with reduced off-target effects
Solution Approach 2:
The patent inverts the traditional approach by not starting with protein expression data to identify targets, but rather by directly analyzing which peptides are actually presented on tumor cell surfaces. This inversion reveals that peptide presentation, not just protein expression, determines targetability. By selecting targets based on actual tumor surface presentation rather than bulk tissue expression, the method achieves high efficacy while minimizing off-target toxicity against normal tissues that may express the source proteins
4Reliability
If peptide mimics are used to target tumor cells, then T cell recognition is enhanced, but in vivo toxicity increases due to cross-reactivity with normal tissues
Solution Approach 1:
The patent performs preliminary screening to identify peptides that are actually presented on tumor cell surfaces using mass spectrometry before developing T cell therapies. By pre-validating target peptides through experimental detection of tumor-presented peptides, the method ensures that selected T cell targets are specific to tumor antigens and not shared with normal tissues, thereby preventing cross-reactivity and in vivo toxicity while maintaining high T cell recognition affinity
Data Source
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AI summary
The present invention relates to novel peptides derived from Neuropeptide S Receptor (NPSR1), 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.