Drug–peptide–MHC neoantigen complex

A **drug–peptide–MHC neoantigen complex** is a molecular entity formed when a **covalent drug or inhibitor** modifies an endogenous peptide (often a tumor antigen), which is subsequently processed and presented on the cell surface by a **major histocompatibility complex (MHC)** molecule[5][4][6]. These complexes function as “neoantigens”—non-self or altered self-peptides that can be specifically recognized by immune effector molecules such as **T cell receptors (TCRs)** or antibodies. The drug moiety, which may result from mutation-targeted covalent inhibition (e.g., of KRAS-G12C or EGFR), alters the peptide’s structure and chemistry, generating a unique surface on the peptide–MHC complex[5][4]. This allows for selective immune targeting, enabling precision immunotherapies such as bispecific T-cell engaging antibodies or engineered TCR therapies that specifically recognize and kill cells presenting the drug–peptide–MHC complex[5][4][6]. This target class is being actively explored in cancer immunotherapy, especially for **personalized tumor vaccines** and adoptive cell therapy strategies[3][6][2]. The selectivity and sensitivity of immune targeting depend critically on the precise structural features of the drug-conjugated peptide–MHC, the HLA genotype, and the unique biology of tumor-specific neoantigens[4][1][2][6]. Potential therapeutic challenges include safety concerns around antigen specificity (to avoid targeting normal tissues), efficient detection and quantification of the rare drug-modified peptide–MHC complexes, and variability in patient MHC genetics and antigen processing pathways[5][6].

Other names

drug–peptide–MHC complexdrug-modified peptide–MHC complexinhibitor–peptide–MHC complexhapten–peptide–MHC complexneoantigen–MHC complexdrug–peptide conjugate–MHC complex

Immune recognition by T cell receptor (TCR) | Recognition by engineered TCRs or bispecific antibodies | Immune-mediated killing of target cells | Immune checkpoint modulation through altered antigenicity | Other mechanisms involving immune effector engagement