Bruton's tyrosine kinase drug-modified peptide–major histocompatibility complex class I complex (BTK-drug-pMHC)

The BTK drug-modified peptide–MHC neoantigen complex is a novel therapeutic target generated through the interaction of covalent small-molecule inhibitors with the intracellular protein Bruton's tyrosine kinase (BTK). When drugs like ibrutinib bind covalently to the Cys481 residue of BTK, the resulting drug-protein adduct is processed by the cell's endogenous antigen presentation machinery. This leads to the display of drug-adducted peptides on the cell surface via Major Histocompatibility Complex (MHC) Class I molecules, effectively creating a "drug-induced neoantigen" (DINA). These complexes are absent in healthy, untreated cells but are highly specific to tumor cells that express BTK and have been exposed to the covalent inhibitor. This target allows for the development of highly selective immunotherapies, such as TCR-like antibodies or bispecific T-cell engagers, which can redirect the immune system to eliminate malignant B-cells, potentially overcoming resistance to traditional kinase inhibition by utilizing the drug itself as a targeting beacon.

Other names

Ibrutinib-modified BTK peptide-MHC complexBTK-Cys481-drug-adduct MHC complexDrug-induced neoantigen (DINA) complexBTK-hapten-peptide MHC complexHapImmune BTK target

Covalent inhibitors (e.g., ibrutinib) bind to the Cys481 residue of BTK, creating a drug-protein adduct. This adduct is subsequently degraded by the proteasome into drug-modified peptides, which are then processed and loaded onto MHC Class I molecules for presentation on the cell surface. These complexes are recognized by specific immunotherapies, such as bispecific T-cell engagers or CAR-T cells, which trigger an immune response against the drug-labeled tumor cells.