Modified HLA-Binding Pocket for Stronger Tumor Epitope Presentation

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Solution Overview

Problem

Existing cancer immunotherapies face limitations due to weak T cell responses elicited by tumor-associated epitopes derived from self-antigens, which are traditionally addressed through laborious and low-throughput methods like generating heteroclitic peptides to enhance HLA binding.

Innovation Solution

Modifying the HLA-binding pocket of HLA molecules on antigen-presenting cells to increase the binding affinity and immunogenicity of antigens, thereby enhancing the immune response.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If heteroclitic peptides are generated to enhance HLA binding, then binding affinity is improved, but the process becomes laborious and low-throughput

Engineering Contradiction:

Improvebinding affinityVSAvoidthroughput

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The invention modifies amino acid residues in the HLA-binding pocket (specifically positions 79-83) to change the binding parameters and enhance affinity for tumor-associated epitopes, thereby improving reliability while maintaining high throughput through systematic residue modification approaches

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention focuses modifications specifically on the HLA-binding pocket region (amino acid residues 79-83) rather than the entire HLA molecule or peptide, concentrating the quality enhancement locally where it most impacts binding affinity while preserving overall molecular function

Inventive Principle:

Principle #3Local quality

2Adaptability or versatility

If tumor-associated epitopes are used as antigens, then T cell targeting is achieved, but immunogenicity is weak

Engineering Contradiction:

ImproveT cell targetingVSAvoidimmunogenicity

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The invention changes the amino acid composition of the HLA-binding pocket to optimize the interaction parameters between HLA and tumor-associated epitopes, thereby enhancing the immunogenicity parameter while maintaining the ability to present tumor-specific antigens to T cells

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS20250367292A1HLA superagonists and uses thereof

Publication Date: 2025.12.04 UNIV HEALTH NETWORK

AI summary

The present disclosure is directed to methods of modifying an HLA-binding pocket in an HLA molecule in a subject. Some aspects are directed to HLA molecules comprising a modified HLA-binding pocket, where the HLA molecule has increased affinity for a peptide, e.g., an antigen. Other aspects are directed to compositions comprising the same and methods of using the same.