MAGEB2 Peptide-MHC Complexes for Targeted Cancer Immunotherapy
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current immunotherapeutic approaches face challenges in accurately predicting and targeting tumor-associated antigen (TAA)-derived peptides presented by Major Histocompatibility Complex (MHC) molecules on tumor cells, due to limitations in existing prediction algorithms 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 Melanoma-associated antigen B2 (MAGEB2) that form stable complexes with MHC molecules, along with binding moieties such as T cell receptors and antibodies, to specifically target tumor cells while minimizing healthy tissue interaction, utilizing RNA expression data for therapeutic window identification.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If in silico algorithms are used to predict TAA-derived peptides, then peptide identification is accelerated, but prediction accuracy deteriorates due to high false positive rates
Solution Approach 1:
The patent introduces experimental validation methods (mass spectrometry, MHC binding assays, T cell recognition assays) as intermediary steps between computational prediction and therapeutic application. These experimental intermediaries filter false positives from in silico predictions, thereby resolving the contradiction between rapid identification and accurate prediction.
Solution Approach 2:
The patent replaces reliance on purely computational (in silico) methods with experimental (in vitro and in vivo) validation systems. By substituting algorithmic prediction with empirical measurement through mass spectrometry and biological assays, the system achieves both efficiency and accuracy.
2Reliability
If T cells with high affinity for TAA-derived peptides are selected, then tumor targeting specificity is improved, but T cell scarcity worsens due to selection processes in the thymus
Solution Approach 1:
The patent performs preliminary identification and characterization of optimal TAA-derived peptides using in silico algorithms and experimental validation before T cell selection. By pre-screening peptides for high affinity, specificity, and low off-target binding, the system ensures that selected T cells will have high tumor targeting capability while maintaining sufficient availability in the repertoire.
Solution Approach 2:
The patent optimizes multiple parameters including peptide length, amino acid sequence, MHC binding affinity, and T cell receptor affinity to identify peptides that balance high specificity with sufficient T cell frequency. By adjusting these parameters, the system finds optimal targets that resolve the contradiction between specificity and availability.
3Reliability
If TAAs with high expression in tumor tissue are targeted, then therapeutic efficacy is improved, but off-target toxicity worsens due to expression in normal healthy tissues
Solution Approach 1:
The patent applies local quality by selecting TAA-derived peptides that are specifically presented by MHC molecules on tumor cells but not on normal healthy cells. Even when the parent TAA is expressed in both tumor and normal tissues, the peptide-MHC complexes may be selectively presented on tumor cells due to differential processing, trafficking, or MHC expression patterns. This local differentiation at the peptide-MHC level resolves the contradiction between efficacy and safety.
Solution Approach 2:
The patent segments the TAA protein into specific peptide fragments and selects those that are tumor-specific or tumor-enriched in their MHC presentation. By dividing the TAA into discrete peptide epitopes and selecting only those with optimal tumor specificity, the system achieves high therapeutic efficacy while minimizing off-target effects from normal tissue expression.
4Reliability
If peptide-MHC complexes are stabilized for enhanced T cell recognition, then immune response efficacy is improved, but peptide sequence uniqueness deteriorates increasing risk of cross-reactivity
Solution Approach 1:
The patent performs preliminary bioinformatics analysis and experimental validation to identify peptide sequences that simultaneously achieve high MHC binding stability and low sequence homology with non-tumor proteins. By pre-screening for uniqueness before optimizing stability, the system selects peptides that can be stabilized without increasing cross-reactivity risk.
Solution Approach 2:
The patent optimizes peptide parameters including binding affinity to MHC, stability of the peptide-MHC complex, and sequence uniqueness simultaneously. By adjusting amino acid substitutions and deletions to maximize stability while maintaining low homology with normal proteins, the system resolves the contradiction between enhanced immune response and reduced cross-reactivity.
Data Source
Figure 1
Figure 2
Figure 3
AI summary
The present invention relates to novel peptides derived from Melanoma-associated antigen B2 (MAGEB2), 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.