Chickens TAPBPR Chimeras for Broad HLA Ligand Exchange
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Solution Overview
Problem
Current ligand exchange technologies are limited in their ability to efficiently exchange peptides on HLA molecules, particularly for non-classical MHC molecules like MR1, and are restricted to specific HLA supertypes, hindering the generation of peptide:HLA tetramers and antigen-presenting cell systems for T cell stimulation.
Innovation Solution
The use of an ortholog of the molecular chaperone TAPBPR from Gallus gallus enables the exchange of peptides on HLA molecules of diverse peptide-binding specificities, interacting with multiple classical and non-classical MHC molecules, including MR1, to promote ligand exchange in vitro and on the cell surface.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If human TAPBPR is used for ligand exchange, then exchange efficiency on certain HLA supertypes is improved, but applicability is limited to specific HLA supertypes only
Solution Approach 1:
The patent applies universality by evolving human TAPBPR into a chimeric protein that can interact with multiple HLA supertypes (A, B, C, and non-classical MHC molecules like MR1, HLA-E, HLA-G). The chimeric TAPBPR achieves broad-spectrum ligand exchange capability across diverse HLA molecules, transforming a specialized enzyme into a universal tool for peptide:MHC library generation and T cell stimulation assays.
2Ease of operation
If conventional ligand exchange methods are used, then simplicity of procedure is maintained, but ability to exchange peptides on non-classical MHC molecules like MR1 is insufficient
Solution Approach 1:
The patent applies parameter changes by modifying the TAPBPR protein structure through chimera construction, altering its binding specificity parameters to recognize non-classical MHC molecules like MR1, HLA-E, and HLA-G in addition to classical HLA molecules. This structural parameter modification enables the enzyme to catalyze ligand exchange on a broader range of MHC molecules while preserving the overall exchange mechanism.
3Adaptability or versatility
If chimeric TAPBPR is used for broad HLA coverage, then applicability across multiple supertypes is improved, but protein structure complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the TAPBPR protein into functional domains and recombining them from different species to create a chimeric structure. The chimeric TAPBPR contains segments from human TAPBPR combined with regions from other species that confer binding specificity for diverse HLA supertypes. This modular segmentation allows the protein to achieve broad specificity while maintaining structured organization of functional domains.
Data Source
AI summary
This invention relates to ligand exchange proteins comprising the luminal domain of TAP-binding protein-related (TAPBPR), which functions as a MHC class I ligand-exchange catalyst when presented to mammalian cells either as a soluble extracellular protein or as a membrane bound cell surface protein. This may be useful in modulating immune responses, including for example loading immunogenic ligand onto tumors or other disease cells to induce their recognition by T cells. Ligand-exchange proteins and methods for their use are provided. The invention further relates to an approach for generating conditional peptide ligands for a range of disease-related MHC-I allotypes. The present invention relates to chicken and human TAPBPRs and tapasins as well as orthologs thereof, derivatives thereof, and any mutants thereof as well as any combinations thereof. The present invention also relates to placeholder conditional ligands for ligand-exchange reactions across multiple HLA allotypes.