CD8+ T Cell Epitope Splicing for Improved Antigen Presentation

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Current methods for identifying and optimizing peptide sequences for T cell recognition, particularly in cancer and viral infections, are limited in efficiently generating immunogenic antigen peptides and enhancing proteasomal cleavage for improved antigen presentation.

Innovation Solution

The development of methods and compositions for identifying and modifying peptide sequences through proteasome-catalyzed peptide splicing (PCPS) to enhance proteasomal digestion and presentation to CD8+ T cells, including the use of specific peptides derived from cancer and viral proteins, and the creation of databases for de novo sequencing of spliced peptides.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If traditional peptide identification methods are used, then the process is simple and straightforward, but the ability to identify immunogenic antigen peptides and enhance proteasomal cleavage is limited

Engineering Contradiction:

Improveidentification efficiency of immunogenic peptide epitopesVSAvoidcomplexity of proteasome-catalyzed peptide splicing methods

Core Design Contradiction:

ProductivityVSDevice complexity

Solution Approach 1:

The patent performs preliminary proteasome-catalyzed peptide splicing (PCPS) reactions before TAP transport and MHC class I loading. By pre-processing antigens through PCPS to generate spliced peptides that are then loaded onto MHC class I molecules, the method enhances the presentation of immunogenic epitopes while maintaining a manageable experimental workflow

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent introduces proteasomes as intermediary enzymes that catalyze peptide splicing reactions. These proteasomes process antigens into spliced peptides that serve as intermediates between the original antigen and the final T cell epitope presentation on MHC class I molecules, enabling enhanced identification of immunogenic peptides

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If peptide sequences are optimized for proteasomal digestion, then antigen presentation to T cells is enhanced, but the peptide sequence modification process becomes more complex

Engineering Contradiction:

Improveantigen presentation efficiency to CD8+ T cellsVSAvoidease of peptide sequence modification

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent modifies peptide sequences by changing specific amino acid parameters to optimize proteasomal recognition and cleavage efficiency. By adjusting sequence parameters such as cleavage site motifs and amino acid composition, the method enhances proteasomal digestion and subsequent antigen presentation while providing a systematic approach to peptide optimization

Inventive Principle:

Principle #35Parameter changes

3Adaptability or versatility

If proteasome-catalyzed peptide splicing is utilized, then the source of peptides for MHC class I presentation is expanded, but the analysis and identification of spliced peptides becomes more difficult

Engineering Contradiction:

Improvediversity of peptide sources for CD8+ T cell recognitionVSAvoiddifficulty of identifying spliced peptide sequences

Core Design Contradiction:

Adaptability or versatilityVSDifficulty of detecting and measuring

Solution Approach 1:

The patent employs mass spectrometry-based proteomics to analyze peptides generated from PCPS reactions. By using computational algorithms that compare observed peptide masses and sequences against predicted spliced peptide databases, the method provides feedback to identify which spliced peptides are actually generated and presented, facilitating the detection and characterization of novel epitopes

Inventive Principle:

Principle #23Feedback

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

This approach enables the rapid identification and optimization of immunogenic peptide epitopes, leading to enhanced T cell responses and improved vaccine efficacy against cancer and viral infections, as demonstrated by increased survival rates in glioblastoma models.

Implementation Method 1

PCPS can be initiated at proteasomal active sites by catalytic threonine residues that perform nucleophilic attack on carbonyl groups within an unfolded polypeptide chain

Methodology Applied

Scientific EffectProteasome-catalyzed peptide splicing (PCPS): Enzyme

Implementation Method 2

catalytic threonine residues that perform nucleophilic attack on carbonyl groups within an unfolded polypeptide chain

Methodology Applied

Scientific EffectNucleophilic attack: Chemical Bonding

Implementation Method 3

A subset of oligopeptides generated by proteasomes are translocated from the cytoplasm into the endoplasmic reticulum (ER) by the transporter associated with antigen presentation (TAP)

Methodology Applied

Scientific EffectTransporter associated with antigen presentation (TAP):