High Affinity TCRs for Merkel Cell Polyomavirus T Antigen
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Solution Overview
Problem
Current treatments for Merkel cell carcinoma, particularly those targeting Merkel cell polyomavirus (MCPyV), face challenges such as limited availability of high-affinity MCPyV-specific T cells, variability in T cell avidity, and inefficiencies in expanding antigen-specific T cell populations, leading to suboptimal clinical responses.
Innovation Solution
Development of high-affinity T cell receptors (TCRs) specific for MCPyV T antigen peptides that can bind with high avidity to MCPyV T antigen:HLA complexes, enabling enhanced antigen-specific T cell responses and improved treatment outcomes, including the use of genetically engineered T cells expressing these TCRs for adoptive immunotherapy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If high-affinity TCRs are developed for MCPyV T antigen, then antigen-specific T cell response efficiency is improved, but the complexity of T cell engineering increases
Solution Approach 1:
The patent modifies the TCR structure by engineering mutations in the CDR3 regions of the TCRα and TCRβ chains to enhance binding affinity to the MCPyV T antigen peptide-MHC complex. This parameter change in the molecular structure directly improves the productivity of antigen-specific T cell responses while managing the complexity through targeted mutagenesis rather than comprehensive redesign
Solution Approach 2:
The patent uses naturally occurring TCR sequences from patients or donors as templates and creates engineered variants by copying and modifying specific CDR3 regions. This approach leverages the natural affinity maturation that has already occurred in the patient's immune system, then amplifies and optimizes those sequences through molecular engineering to achieve high-affinity binding
2Reliability
If TCR affinity is increased to improve CTL avidity, then anti-tumor efficacy is improved, but the difficulty of identifying suitable T cell clones increases
Solution Approach 1:
The patent performs preliminary screening and sequencing of TCRα and TCRβ gene pairs from multiple donors or patients before actual T cell therapy development. By pre-identifying and characterizing TCR sequences with potential for high affinity, the process reduces the difficulty of later clone identification and selection, allowing systematic evaluation of TCR binding characteristics before committing to clinical development
Solution Approach 2:
The patent employs iterative screening and characterization of TCR clones, using feedback from binding affinity measurements and functional assays to guide the selection and further engineering of superior clones. This feedback loop allows systematic improvement of TCR affinity while managing the identification process through data-driven selection rather than random screening
Data Source
AI summary
The present disclosure provides binding proteins and TCRs with high affinity and specificity against Merkel cell polyomavirus T antigen epitopes or peptides, T cells expressing such high affinity Merkel cell polyomavirus T antigen specific TCRs, nucleic acids encoding the same, and compositions for use in treating Merkel cell carcinoma.