Bruton's tyrosine kinase peptide–major histocompatibility complex (BTK-pMHC) neoantigen (BTK-pMHC neoantigen)

The Bruton's tyrosine kinase (BTK) peptide–major histocompatibility complex (pMHC) neoantigen is a specialized therapeutic target found on the surface of malignant B cells, particularly in patients with chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). BTK is a vital enzyme in the B-cell receptor signaling pathway, and mutations such as C481S frequently arise as a mechanism of resistance to covalent BTK inhibitors like ibrutinib. These mutations create novel peptide sequences, or neoantigens, that are processed by the cell and presented by MHC class I molecules (most commonly HLA-A*02:01) to the immune system. Because these neoantigen-pMHC complexes are unique to tumor cells and absent in healthy tissues, they serve as highly specific targets for advanced immunotherapies, including T-cell receptor (TCR)-engineered T cells and bispecific T-cell engagers. By targeting the pMHC complex, these therapies can effectively recognize and eliminate resistant cancer clones that are no longer sensitive to traditional small-molecule inhibitors. This approach leverages the high specificity of the immune system to provide a potential solution for relapsed or refractory B-cell malignancies.

Other names

BTK C481S neoantigenBTK-pMHC complexBTK-derived neoantigen-HLA complexBruton's tyrosine kinase-derived peptide-MHCBTK-HLA-A*02:01 neoantigen

T-cell mediated cytotoxicity through the specific recognition of the mutated BTK peptide-MHC complex by engineered T-cell receptors or bispecific molecules, leading to targeted lysis of tumor cells.