Bruton tyrosine kinase peptide-Major Histocompatibility Complex (BTK-pMHC) (BTK-pMHC)

The Bruton tyrosine kinase (BTK) peptide-Major Histocompatibility Complex (pMHC) is a molecular target consisting of a short peptide fragment derived from the BTK protein presented on the cell surface by MHC molecules (UniProt: P35991). While BTK is primarily known as a cytoplasmic kinase essential for B-cell receptor signaling, its degradation products serve as epitopes for T-cell recognition (PubMed: 31533831). This pMHC complex is a significant target in the development of immunotherapies for B-cell malignancies, such as chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). Specifically, research has focused on targeting pMHC complexes containing the BTK C481S mutation, which confers resistance to covalent BTK inhibitors (PubMed: 33057635). Therapeutic interventions, including TCR-engineered T cells and TCR-like antibodies, are designed to bind this specific complex, thereby redirecting the immune system to selectively eliminate malignant cells. This approach is particularly valuable for patients who have relapsed on standard BTK inhibitor therapy. The specificity of the pMHC target helps minimize off-target effects compared to systemic kinase inhibition, although potential toxicity to healthy B cells remains a consideration.

Other names

BTK-HLA complexBTK peptide-HLA-A*02:01BTK-derived peptide-MHCBruton tyrosine kinase pMHCBTK-derived neoantigen-MHC complex

T-cell receptor (TCR) recognition of the BTK peptide-MHC complex leads to the formation of an immunological synapse and subsequent granzyme/perforin-mediated lysis of the target cell.