T-cell modulatory polypeptides for KRAS epitope presentation
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Solution Overview
Problem
Current technologies lack effective methods for modulating T-cell activity and immune responses, particularly in the context of cancer-associated mutations like KRAS.
Innovation Solution
Development of heterodimeric and single-chain T-cell modulatory polypeptides (TMPs) that combine a KRAS peptide with class I HLA polypeptides and immunomodulatory polypeptides, designed to present an epitope to the T-cell receptor and modulate immune responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If conventional methods are used for T-cell modulation, then general immune response can be achieved, but specificity for cancer-associated mutations like KRAS is insufficient
Solution Approach 1:
The T-cell modulatory polypeptide is segmented into distinct functional domains: an MHC class I heavy chain domain for epitope presentation, a beta-2 microglobulin domain for MHC complex stability, and an immunomodulatory domain for T-cell activation. This segmentation allows each domain to independently fulfill its specific function while maintaining overall molecular specificity for cancer-associated mutations
Solution Approach 2:
The polypeptide incorporates local quality variations through the immunomodulatory domain, which contains specific amino acid sequences (e.g., CD80, CD86, or 4-1BBL motifs) that provide localized costimulatory signals. This local functional differentiation enhances the polypeptide's ability to selectively modulate T-cell responses to specific epitopes while maintaining overall structural integrity
2Measurement precision
If T-cell modulation specificity is enhanced through epitope-specific design, then cancer-targeted immune response is improved, but the complexity of polypeptide structure increases
Solution Approach 1:
The patent merges multiple functional components into a single chimeric polypeptide structure: the MHC class I heavy chain, beta-2 microglobulin, and immunomodulatory domain are covalently linked to form one integrated molecule. This merging simplifies production and delivery compared to using separate components, while maintaining the complexity needed for specific epitope recognition and costimulatory signaling
Solution Approach 2:
The polypeptide structure is designed with universal features that allow it to perform multiple functions: the MHC class I framework provides epitope presentation capability, the immunomodulatory domain provides costimulatory signaling, and the overall structure can be adapted to present different cancer-associated epitopes. This multi-functionality reduces the need for multiple separate therapeutic agents
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 TMPs effectively modulate T-cell activity and immune responses, enhancing specificity and selectivity by binding selectively to T cells with cognate costimulatory polypeptides and T-cell receptors specific for the KRAS epitope.
Implementation Method 1
a KRAS peptide that, when bound to major histocompatibility complex (MHC) polypeptides, presents an epitope to a T-cell receptor (TCR)
Implementation Method 2
engagement of costimulatory proteins found on the APC with counterpart costimulatory proteins the T cells. Both signals—epitope/TCR binding and engagement of APC costimulatory proteins with T cell costimulatory proteins—are required to drive T cell specificity and activation or inhibition
Data Source
AI summary
The present disclosure provides T-cell modulatory polypeptides (TMPs) that comprise an immunomodulatory polypeptide, class I HLA polypeptides (a class I HLA heavy chain polypeptide and a β2 microglobulin polypeptide), and a KRAS peptide (e.g., a KRAS peptide comprising a cancer-associated mutation) that presents an epitope to a T-cell receptor. A TMP is useful for modulating the activity of a T cell, and for modulating an immune response in an individual.