Self peptide–Human Leukocyte Antigen complexes (self-pHLA)

Self peptide–Human Leukocyte Antigen (self-pHLA) complexes are molecular assemblies on the surface of normal, non-malignant cells that present fragments of endogenous proteins to the immune system. These complexes are essential for maintaining immunological self-tolerance and are the primary mechanism through which the immune system identifies healthy tissue (Rock et al., 2016). In modern drug development, particularly for T-cell receptor (TCR) engineered therapies and bispecific T-cell engagers, these complexes represent the most significant safety liability. If a drug's binding domain cross-reacts with a self-peptide that mimics the target tumor antigen, it can lead to severe "on-target, off-tumor" toxicity. Clinical trials have demonstrated that such cross-reactivity can lead to lethal cardiac or neurological damage when the therapeutic TCR recognizes a self-peptide on vital organs (Linette et al., 2013; Morgan et al., 2013). Consequently, the characterization of the "normal immunopeptidome" via high-resolution mass spectrometry is a critical step in validating the specificity of any HLA-restricted therapeutic (Abelin et al., 2017). Beyond oncology, these complexes are also the primary targets in autoimmune diseases, where the breakdown of tolerance leads to the destruction of healthy tissue by self-reactive T cells. Understanding the diversity and distribution of self-pHLA complexes across different tissues is therefore paramount for both safety assessment and the development of tolerogenic therapies.

Other names

Self-antigen–MHC complexesEndogenous peptide–HLA complexesNormal tissue immunopeptidomeAutoantigen–HLA complexesSelf-pHLA

Recognition by T-cell receptors (TCRs) or TCR-mimetic antibodies leading to immune-mediated cytotoxicity or suppression (Rock et al., 2016).