Non-viral self or allo peptide–Human Leukocyte Antigen complexes (Non-viral self/allo pHLA)

Non-viral self or allo peptide–Human Leukocyte Antigen (HLA) complexes are molecular assemblies consisting of an intracellularly derived peptide bound to an HLA molecule and presented on the cell surface. These complexes are the fundamental units recognized by T-cell receptors (TCRs), allowing the immune system to monitor the internal health of a cell by distinguishing between normal self-proteins, mutated neoantigens, or foreign allo-antigens (Nathan et al., 2021, NEJM). In oncology, these complexes are critical therapeutic targets because they allow drugs to address intracellular proteins—such as MAGE-A4 or NY-ESO-1—that are otherwise inaccessible to traditional antibody therapies (D'Angelo et al., 2023, Lancet Oncology). In the context of transplantation, allo-peptide-HLA complexes (minor histocompatibility antigens) are the primary drivers of graft-versus-host disease and organ rejection when donor and recipient proteomes differ (Griffioen et al., 2016, Blood). Therapeutic interventions targeting these complexes include TCR-engineered T-cells (TCR-T) and bispecific molecules like ImmTACs, which redirect the immune system to kill cells presenting specific disease-associated peptides. However, the high structural similarity between different self-peptides poses a significant risk of off-target toxicity, as seen in historical clinical trials where TCRs cross-reacted with essential proteins in healthy organs (Linette et al., 2013, Blood).

Other names

Self-peptide-HLA complexesAllo-peptide-HLA complexesMinor histocompatibility antigensmHagsTumor-associated antigen peptide-MHC complexesNeoantigen-HLA complexesEndogenous peptide-HLA complexes

T-cell receptor (TCR) mediated recognition of specific peptide-HLA complexes, leading to targeted cytotoxicity via engineered T-cells (TCR-T) or bispecific T-cell engagers (ImmTACs).