Multimeric pMHC Polypeptides for Redirecting Antiviral T Cells
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Solution Overview
Problem
Current technologies struggle to effectively redirect a patient's repertoire of antiviral T cells to target and kill cancer cells, particularly in cases where cancer cells evade the immune system through HLA loss, preventing recognition and killing by the patient's own cancer-specific T cells.
Innovation Solution
T-cell modulatory multimeric polypeptides (TMMPs) comprising immunomodulatory, class I HLA, tumor-targeting, and epitope-presenting components that bind to cancer cells, mimicking pathogen-infected cells to activate existing antiviral T cells for targeted cancer cell killing.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If cancer cells lose HLA expression to evade immune recognition, then they gain resistance to T cell killing, but they become vulnerable to alternative immune targeting strategies
Solution Approach 1:
The patent uses HLA molecules as intermediaries to bridge the gap between the tumor-targeting polypeptide and antiviral T cells. The HLA-peptide complex serves as a mediator that translates tumor-specific targeting into T cell recognition, allowing the system to overcome HLA loss by providing exogenous HLA molecules that can still be recognized by T cells while directing them to tumor cells through the tumor-targeting polypeptide component
2Reliability
If existing antiviral T cells are redirected to target cancer cells, then immune response efficacy is enhanced, but the complexity of the multimeric polypeptide structure increases
Solution Approach 1:
The patent merges multiple functional components into a single multimeric polypeptide structure: HLA molecules for T cell recognition, peptide epitopes for TCR binding, tumor-targeting polypeptides for tumor cell specificity, and costimulatory molecules for full T cell activation. This consolidation of multiple immune engagement functions into one molecule achieves reliable cancer cell killing while the modular nature of the design allows for standardized production approaches
Solution Approach 2:
The multimeric polypeptide is designed with universal functionality by incorporating common HLA alleles that can recognize broad epitope patterns, tumor-targeting polypeptides that bind conserved tumor antigens, and costimulatory domains that engage universal T cell costimulatory receptors. This multi-functionality allows a single construct type to address multiple aspects of immune recognition and activation while maintaining manufacturability through standardized molecular designs
Data Source
AI summary
The present disclosure provides T-cell modulatory multimeric polypeptides (TMMPs) that comprise comprise (i) an optional immunomodulatory polypeptide such as a variant IL-2 polypeptide, (ii) class I HLA major histocompatibility complex (MHC) polypeptides (a class I HLA heavy chain polypeptide and a β2 microglobulin polypeptide), (iii) a peptide that presents an epitope to a T-cell receptor, which together with the class I MHC polypeptides forms a peptide-MHC complex (pMHC), (iv) a tumor-targeting polypeptide, and (v) an optional Ig Fc polypeptide or other scaffold. Such TMMP is useful for modulating the activity of a T cell, and for modulating an immune response in an individual, and for “redirecting” a patient's repertoire of antiviral T cells to attack and kill cancer cells.