Promiscuous HER-2/Neu Epitopes for Broad HLA Coverage
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Solution Overview
Problem
Current cancer immunotherapies and vaccines are limited by the HLA-restriction of peptide epitopes, which confine their applicability to only a small percentage of the population, as they typically form productive peptide-MHC complexes with a small number of HLA alleles, restricting their use to individuals expressing those specific alleles.
Innovation Solution
Identification and utilization of novel promiscuous T cell epitopes within the HER-2/Neu protein sequence, specifically located between amino acids 270-284, which can be presented by at least 25 different HLA-DRB1 alleles, allowing for a universal CD4 T helper cell epitope that can induce a HER-2/Neu-specific immune response across various HLA types, using peptides such as TYNTDTFESMPN, ALVTYNTDTFESMPN, and others, either alone or fused with heterologous polypeptides like GM-CSF.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If conventional peptide epitopes are used in cancer immunotherapies, then T cell recognition of HER-2/Neu can be achieved, but the applicability is limited to only a small percentage of the population due to HLA-restriction
Solution Approach 1:
The patent identifies promiscuous T cell epitopes within the HER-2/Neu protein that can be presented by multiple HLA-DRB1 alleles (at least 25 different alleles). These epitopes, located in the region of amino acids 270-284, serve as universal CD4 T helper cell epitopes that can induce T cell responses across diverse HLA types, making the immunotherapy applicable to a much larger portion of the population while maintaining reliable T cell recognition.
2Reliability
If peptide epitopes are designed to be specific to certain HLA alleles, then T cell response can be reliably induced in HLA-matched individuals, but the therapy cannot be widely applied to the general population
Solution Approach 1:
The patent employs promiscuous epitopes that maintain the ability to bind to and present on at least 25 different HLA-DRB1 alleles. This multi-functionality allows a single epitope design to elicit reliable T cell responses across diverse HLA backgrounds, resolving the contradiction between specificity and versatility by finding epitopes that are both reliably recognized and widely applicable.
3Measurement precision
If HLA-restricted epitopes are used, then immune response can be precisely targeted to specific HLA types, but the scope of clinical trial participation is confined to 20% or less of the general population
Solution Approach 1:
The patent identifies epitopes within the HER-2/Neu protein (amino acids 270-284) that serve as universal markers. These epitopes can be detected and measured across individuals with different HLA types, allowing precise measurement of immune response while expanding the scope of clinical trials to include the general population rather than being confined to a narrow HLA-matched cohort.
Data Source
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AI summary
The present invention relates to the discovery of novel T cell epitopes of the human HER-2/Neu protein that is promiscuous for at least 25 different HLA-DR alleles. The invention also relates to compositions that contain one of the novel epitopes or a fusion peptide of such a epitope and a heterologous polypeptide. Further disclosed herein is the use of the epitopes or their fusion peptides, and compositions containing the epitopes or their fusion peptides.