Drug–peptide–MHC class I complex (p*MHC)

The drug–peptide–MHC class I complex is a synthetic neoantigen presented on the surface of cancer cells, formed when covalent small-molecule inhibitors react with their intracellular target proteins. Following the administration of a covalent drug (such as sotorasib or osimertinib), the drug-protein conjugate is processed by the proteasome into peptide fragments, some of which retain the covalently attached drug (haptens). These haptenated peptides are then loaded onto MHC class I molecules and displayed on the cell surface, effectively flagging the cancer cell for immune recognition. This complex serves as a highly specific therapeutic target for engineered antibodies, bispecific T-cell engagers (BiTEs), and CAR-T cells, such as those developed through the HapImmune platform. By targeting these drug-induced neoantigens, researchers aim to overcome resistance to targeted therapies by recruiting the patient's immune system to eliminate cells that still express the mutant driver protein but no longer respond to the drug's inhibitory effects. This approach represents a novel convergence of targeted therapy and immunotherapy, potentially offering more durable clinical outcomes in oncogene-driven cancers.

Other names

Drug-modified peptide/MHC class I complexHapten-peptide-MHC complexChemically induced neoantigen (CiNA)Drug-induced neoantigen (DINA)HapImmune targetp*MHCDrug-modified peptide/HLA complex

Targeting of drug-induced neoantigens by bispecific T-cell engagers or CAR-T cells to induce cytotoxic T-cell responses against cancer cells.