ASCL2-Derived Peptides for Targeted Cancer Immunotherapy
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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, due to limitations in predicting peptide-MHC presentation and the scarcity of T cells recognizing these peptides with high affinity, leading to potential off-target toxicity.
Innovation Solution
Development of novel peptides derived from Achaete-scute homolog 2 (ASCL2) that form stable complexes with MHC molecules, along with binding moieties such as T cell receptors (TCRs) and antibodies, which specifically target tumor cells by exploiting differences in RNA expression levels to create a therapeutic window, minimizing toxicity to normal tissues.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If in silico algorithms are used to predict peptide-MHC sequences, then the screening process is accelerated, but the prediction accuracy decreases due to high false positive rates
Solution Approach 1:
The patent segments the peptide identification process into two distinct phases: initial high-throughput in silico screening to generate candidate peptides, followed by rigorous experimental validation using mass spectrometry and ELISPOT assays. This segmentation allows the system to leverage the speed of computational methods while compensating for their inaccuracy through targeted experimental verification of only the most promising candidates.
Solution Approach 2:
The patent introduces an intermediary validation layer between computational prediction and therapeutic application. Candidate peptides predicted by in silico algorithms undergo intermediate experimental testing including binding affinity measurements, presentation verification on tumor cells, and immunogenicity assessment. This intermediary step filters out false positives before advancing to clinical development.
2Reliability
If T cells with high affinity for TAA-derived peptides are selected during thymus maturation, then tumor cell detection capability improves, but the circulating T cell repertoire becomes scarce
Solution Approach 1:
The patent performs preliminary identification and characterization of optimal peptide-MHC targets before initiating T cell therapy. By pre-validating peptide binding affinity, tumor cell presentation, and immunogenicity through in vitro and in vivo models, the system ensures that the limited circulating T cells with high affinity for these predetermined targets can be effectively expanded and deployed for therapeutic use.
Solution Approach 2:
The patent changes the selection parameters for T cell therapy by focusing on peptides with specific binding characteristics to MHC molecules. By identifying peptides with optimal binding affinity and stability, the system maximizes the functionality of the scarce high-affinity T cells. Additionally, the patent employs in vitro expansion techniques that maintain the high-affinity binding characteristics while increasing the absolute number of therapeutic T cells.
3Reliability
If TAAs with high expression in tumor tissue are targeted, then therapeutic efficacy improves, but off-tumor toxicity increases due to expression in normal healthy tissue
Solution Approach 1:
The patent applies local quality by selecting peptide targets that exhibit heterogeneous expression patterns across different tissue types. Specifically, the patent identifies peptides from proteins that are highly expressed in specific tumor types but have low or absent expression in normal tissues. This localized expression pattern ensures that immune targeting is confined to tumor sites while sparing healthy organs. The patent also considers spatial expression patterns within tumors to optimize target selection.
Solution Approach 2:
The patent employs partial action by targeting peptides that are moderately to highly expressed in tumor tissue rather than requiring universal high expression. This approach allows sufficient target availability for effective immune recognition while reducing the likelihood of significant normal tissue expression. The patent also uses peptide epitopes that represent only a portion of the full protein, enabling selective targeting of tumor-expressed isoforms or post-translationally modified versions that are absent in normal tissues.
4Object-affected harmful factors
If peptide sequences are made highly specific to avoid peptide mimics, then off-target toxicity decreases, but the difficulty of identifying suitable peptides increases
Solution Approach 1:
The patent uses copying by creating synthetic versions of endogenous peptides for validation purposes. By synthesizing candidate peptides and their potential mimics, the patent enables direct comparison of their binding characteristics and immunogenicity. This copying approach allows the system to identify and eliminate peptides with excessive similarity to self-peptides while maintaining the ability to validate the functionality of selected targets through replicated experimental systems.
Data Source
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AI summary
The present invention relates to novel peptides derived from Achaete-scute homolog 2 (ASCL2), 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.