Homocitrullinated T-Cell Epitopes for MHC Cancer Immunotherapy
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Solution Overview
Problem
Existing cancer therapies fail to effectively target intracellular antigens, and existing autoimmune responses driven by extracellular antigens complicate the use of homocitrullinated peptides for immunotherapy.
Innovation Solution
Development of homocitrullinated T cell epitopes with specific binding scores and conformational structures that stimulate T cell responses, particularly for intracellular antigens like vimentin, aldolase, cytokeratin 8, BiP, nucleophosmin, α-enolase, β-catenin, and HSP60, by converting lysine residues to homocitrulline, which can be processed and presented on MHC class I or II molecules to induce anti-tumor immunity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If homocitrullinated peptides are used to target intracellular antigens for cancer immunotherapy, then T cell response is stimulated, but autoimmune responses driven by extracellular antigens complicate the therapy
Solution Approach 1:
The patent applies local quality by creating distinct homocitrullinated peptide variants that target specific intracellular antigens (vimentin, aldolase, cytokeratin 8, BiP, nucleophosmin, α-enolase, β-catenin, HSP60) with different binding scores to MHC class I or II molecules. Each peptide is locally optimized for its specific target antigen and MHC presentation pathway, allowing selective stimulation of anti-tumor T cell responses while avoiding cross-reactivity with extracellular antigens that trigger autoimmune responses.
2Reliability
If lysine residues are converted to homocitrulline to generate unique T cell epitopes, then antigenic properties are altered and T cell response is induced, but the complexity of identifying effective epitopes increases
Solution Approach 1:
The patent employs universality by developing a systematic approach that screens homocitrullinated peptides against multiple MHC class I and II molecules simultaneously. The methodology identifies epitopes with predicted binding scores that can present on different MHC molecules, creating a universal platform for cancer immunotherapy that can be adapted to various patient MHC profiles. This multi-functional screening approach efficiently identifies effective epitopes across multiple targets without requiring separate optimization for each MHC type.
3Reliability
If homocitrullinated peptides are designed with specific binding scores to MHC molecules, then presentation on MHC class I or II is improved, but the difficulty of detecting and measuring effective epitopes increases
Solution Approach 1:
The patent applies preliminary action by using computational algorithms to predict binding scores of homocitrullinated peptides to MHC class I and II molecules before experimental validation. This in silico screening预先 identifies peptides with high predicted binding affinity, allowing researchers to prioritize these candidates for subsequent in vitro and in vivo testing. This preliminary computational assessment significantly reduces the experimental workload and accelerates the identification of effective epitopes with proven MHC presentation capability.
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 homocitrullinated epitopes elicit strong CD4 and CD8 T cell responses, mediating effective tumor therapy by processing and presenting carbamylated proteins on MHC class I or II pathways, even in MHC-negative tumors, and are effective in various cancer types.
Implementation Method 1
MPO is expressed by immune cells including neutrophils, monocytes and macrophages (Eruslanov et al. 2014). Carbamylation has been extensively investigated in the past for its role in renal dysfunction ureamia, and chronic systolic heart failure. However, interest has recently been focused on its role in inflammation and initiation of rheumatoid arthritis (RA) disease (Mydel et al. 2010; Kollipara and Zahedi 2013; Lac et al. 2018; Ospelt et al. 2017).
Implementation Method 2
Lysine can be chemically modified to homocitrulline (Ospelt et al. 2017; Lac et al. 2018) (FIG. 1) in a process known as carbamylation. This reaction occurs when isocyanic acid reacts with the amine (NH2) groups on lysine to yield homocitrulline.
Implementation Method 3
The T cell epitope of the present invention may be a MHC class I or MHC class II epitope, i.e. form a complex with and be presented on a MHC class I or MHC class II molecule.
Implementation Method 4
The inventors have unexpectedly found that it is possible to raise T cell response to epitopes from intracellular antigens expressed within viable MPO negative cells in which the lysine has been replaced by homocitrulline.
Data Source
AI summary
The present invention relates to epitopes containing homocitrulline (Heit) that can be used as targets for cancer immunotherapy. The homocitrullinated T cell epitope has (i) a predicted binding score to MIC class II or class I of <30 using the online IEDB prediction program (http://www.iedb.org/) and (ii) at least 5 consecutive amino acids that form a spiral conformational structure. These modified peptides can be used as vaccines or as targets for T cell receptor (TCR) and adoptive T cell transfer therapies.