Alpha-fetoprotein peptide–Major Histocompatibility Complex (AFP-MHC complex)

Alpha-fetoprotein (AFP) is a 69 kDa oncofetal glycoprotein primarily produced by the fetal liver and yolk sac, with expression typically ceasing shortly after birth. In adults, AFP is frequently re-expressed in hepatocellular carcinoma (HCC) and other germ cell tumors, where it serves as a diagnostic biomarker and contributes to an immunosuppressive tumor microenvironment. Because AFP is an intracellular and secreted protein, it is not accessible to standard antibody-based therapies. However, it is processed into peptides, such as the immunodominant AFP158-166 epitope, which are presented on the cell surface by Major Histocompatibility Complex (MHC) class I molecules, most commonly HLA-A*02:01. The AFP peptide–MHC complex represents a critical target for next-generation immunotherapies, including T-cell receptor-engineered T-cell (TCR-T) and TCR-mimic chimeric antigen receptor (CAR) T-cell therapies. Drugs like Adaptimmune's ADP-A2AFP and Eureka Therapeutics' ET1402L1 are engineered to specifically recognize this complex, allowing T cells to identify and eliminate tumor cells that express intracellular AFP. While this approach expands the range of targetable antigens to include intracellular proteins, it requires patient selection based on both AFP expression and specific HLA genotypes. Potential safety concerns include off-target cross-reactivity with similar peptides and on-target/off-tumor effects if AFP is expressed in non-malignant tissues, such as during liver regeneration.

Other names

AFP-MHC complexAFP-HLA complexAFP-HLA-A*02:01 complexAFP158-166/HLA-A*02:01 complexAFP peptide-MHC class I complexAlpha-fetoprotein peptide–human leukocyte antigen A2 complex

Presentation of intracellularly derived AFP peptides (e.g., AFP158-166) on the cell surface via MHC Class I (specifically HLA-A*02:01) for recognition by engineered T-cell receptors (TCRs) or TCR-mimic antibodies (CARs), leading to T-cell activation, cytokine release, and targeted cytotoxic lysis of tumor cells.