Cross-reactive self peptide–HLA complex (pHLA)

Cross-reactive self peptide–HLA (pHLA) complexes on normal tissues are molecular assemblies consisting of a host-derived peptide fragment bound to a Major Histocompatibility Complex (MHC) molecule, which are inadvertently recognized by engineered immune cells or antibodies. In the context of cancer immunotherapy, specifically T-cell receptor (TCR) therapies, these complexes serve as "off-targets" where the therapeutic agent mistakes a normal tissue peptide for a tumor-specific antigen due to structural similarity or molecular mimicry (Cameron et al., 2013). This recognition triggers an unintended immune response against healthy organs, potentially leading to severe or fatal immunotoxicity (Linette et al., 2013). For example, TCRs designed to target MAGE-A3 were found to cross-react with a peptide from the muscle protein Titin presented on HLA-A*01, causing lethal cardiotoxicity. Consequently, these complexes are a primary focus of safety assessments during the development of TCR-T cells and bispecific T-cell engagers to ensure high specificity and avoid "off-target" effects (Sanderson et al., 2020). Rigorous preclinical screening, including X-scan assays and primary human cell panels, is essential to identify and mitigate the risks associated with these complexes. These structures are not therapeutic targets but represent critical safety barriers in precision medicine.

Other names

Off-target peptide-HLA complexMolecular mimicry epitopeCross-reactive epitopeSelf-peptide MHC complexOff-target pHLA

T-cell receptor (TCR) or TCR-mimetic binding to the pHLA complex on healthy cells leads to unintended T-cell activation, cytokine release, and cytotoxic destruction of normal tissue (Stone et al., 2015).