Antigen-Binding TCR Constructs for HLA-Polymorphic Repertoires
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Solution Overview
Problem
The challenge in understanding T cell specificities in cancer, particularly in solid tumors, is exacerbated by TCR diversity and human leukocyte antigen (HLA) allele polymorphism, limiting the analysis of diverse TCR repertoires and hindering the identification of tumor-infiltrating T cells' specificities.
Innovation Solution
The development of novel polypeptide constructs, such as T cell receptors (TCRs) and antibodies, with specific binding affinity for antigens, combined with bioinformatics tools like GLIPH2, enables the identification and analysis of T cell specificities, particularly in lung cancer, by inferring shared tumor antigens and their HLA contexts, and utilizing yeast display libraries for antigen discovery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If next-generation sequencing technologies are used to sequence large numbers of TCR, then sequencing cost and accessibility are improved, but the ability to analyze diverse TCR repertoires in the context of highly polymorphic HLA alleles deteriorates due to the absence of analytical tools
Solution Approach 1:
The patent segments the complex TCR repertoire analysis problem into manageable components by grouping TCR sequences based on shared CDR3 beta sequence motifs. This segmentation allows sequences to be organized into specificity groups that can be analyzed collectively, making the analysis of large diverse repertoires tractable despite HLA polymorphism
Solution Approach 2:
The patent introduces CDR3 beta sequence motifs as an intermediary element that mediates between the diverse TCR sequences and their antigen specificities. By identifying and using these conserved motifs within CDR3 beta regions, the method creates a bridge that allows analysis of TCR specificities without requiring direct knowledge of every possible TCR-antigen-HLA interaction
2Loss of information
If TCR diversity and HLA allele polymorphism are taken into account to understand T cell specificities, then understanding of T cell function is improved, but the complexity of analyzing diverse TCR repertoires increases
Solution Approach 1:
The patent changes the analytical parameter from examining individual TCR sequences to examining CDR3 beta sequence motifs. This parameter change simplifies the analysis by focusing on conserved regions that are more likely to determine antigen specificity, thereby reducing the complexity of analyzing diverse TCR repertoires while maintaining understanding of T cell specificities
3Reliability
If polypeptide constructs with high binding affinity for specific antigens are developed, then therapeutic efficacy is improved, but the complexity of identifying and analyzing target antigens increases
Solution Approach 1:
The patent applies universality by developing a methodology that can identify multiple tumor-associated antigens across different cancer types using the same CDR3 beta motif analysis approach. This universal method simplifies antigen identification by providing a single analytical framework that works across diverse TCR repertoires and antigen targets
Data Source
AI summary
The present disclosure relates generally to polypeptide constructs, and particularly relate to T-cell receptor (TCR) constructs having binding affinity for a specific cognate antigen. The disclosure also provides compositions and methods useful for producing such constructs as well as methods for the diagnosis, prevention, and/or treatment of conditions associated with cells expressing the cognate antigen recognized by the polypeptide constructs.