Normal-tissue peptide–HLA complexes corresponding to shared tumor-associated antigens (Normal pMHC-TAA)

Normal-tissue peptide–HLA complexes corresponding to shared tumor-associated antigens (TAAs) are molecular assemblies consisting of a self-peptide derived from a TAA and a Human Leukocyte Antigen (HLA) molecule, presented on the surface of healthy cells [Source: Nature Reviews Cancer, 2021]. While TAAs are highly expressed in tumors, their basal expression in healthy tissues means these complexes are present throughout the body, albeit often at lower densities than in cancerous tissues [Source: Frontiers in Immunology, 2020]. These complexes are critical in the context of immunotherapy, particularly for T-cell receptor (TCR) engineered T-cells and TCR-bispecifics, where they act as off-targets that can trigger on-target, off-tumor toxicity [Source: Journal for ImmunoTherapy of Cancer, 2019]. Interaction between a therapeutic T-cell and these normal-tissue complexes can lead to the destruction of healthy organs, as seen in clinical trials where TCRs targeting MAGE-A3 caused fatal damage to the brain or heart due to cross-reactivity with similar peptides in those tissues [Source: Journal of Clinical Oncology, 2013]. Consequently, these complexes represent a major safety hurdle and a primary focus of preclinical specificity testing and ligandomics to ensure therapeutic safety [Source: Molecular & Cellular Proteomics, 2018]. Understanding the distribution and density of these complexes is essential for defining the therapeutic window of any drug targeting shared antigens.

Other names

Normal tissue pMHCOff-target TAA-HLA complexesSelf-antigen HLA complexesOn-target off-tumor antigensNormal tissue peptide-MHC complexes

Unintended binding of TCR-based or TCR-mimetic therapies to normal tissue pMHCs, leading to off-tumor T-cell activation and cytotoxic tissue destruction [Source: Nature Reviews Drug Discovery, 2018].