Detection of low affinity TCRs - Isis Project No 71223

Fluorochrome-conjugated peptide-major histocompatibility complex (pMHC) multimers have transformed the study of antigen-specific T cells by enabling their visualization, enumeration, phenotypic characterization and isolation from ex vivo samples by flow cytometry. The affinity thresholds for identifying T cells with pMHC multimers and that required for antigen-specific activation of T cells differ. As a result, not all T cells that respond to a particular pMHC are amenable to detection with this antigen in multimeric form and pMHC multimers are unable to identify all T cells that respond to a particular antigen. This is a problem when using pMHC multimer to identify T cells with low affinity T cell receptors (TCRs) such as those that predominate in anti-tumour or autoimmune responses. Research at Oxford University has developed CD8-enhanced pMHC multimers. These reagents can identify all T cells that respond to a particular antigen and can be utilized at 100X lower concentration and still produce bright staining of anti-viral T cells.

Marketing Opportunity

There is clearly a market for research and diagnostics for these reagents. They can be applied to any MHC class I molecule to enhance CD8 binding. Surface plasmon resonance has been used to confirm that these mutations do not affect the interaction between the TCRs and the pMHC antigens. Mutant antigens have also been shown to have substantial benefits when used in priming anti-tumour cytotoxic T lymphocytes.

The Oxford Invention

The Oxford invention comprises a series of mutations in the conserved parts of the MHC class I molecule. This unique technology allows the detection of all T cells that respond to a particular antigen and can be used at greatly reduced concentrations yet still give better results in many applications. Numerous requests have been received for these reagents even though their properties have not yet been described in the scientific literature.

 

The use of CD8-null, wildtype and CD8-enhanced pMHC multimers enables the grading of T cells based on the strength of their interaction with the soluble pMHC ligand.

Commercial Opportunity

This technology is subject to a patent application. The mutated antigens,either as soluble molecules or when expressed on the cell surface of an antigen presenting cell, have been shown to enhance T cell signalling and T cell effector function without altering specificity of the T cell response. There are numerous potential uses of the invention in addition to its application to pMHC multimer technology.

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