Peptide-major histocompatibility complex class I presenting RAS and TP53 neoantigens (pMHC-I (RAS/TP53))

Peptide-major histocompatibility complex class I (pMHC-I) complexes presenting RAS and TP53 neoantigens are specialized molecular targets that allow the immune system to recognize intracellular oncogenic mutations [1, 3]. These complexes are generated when mutant proteins, such as KRAS (e.g., G12D, G12V) or TP53 (e.g., R175H), are degraded by the proteasome into short peptides and loaded onto HLA class I molecules for presentation on the tumor cell surface [13, 14]. Because these mutations are driver mutations essential for tumor survival and are shared across many patients, they are referred to as public neoantigens [3, 17]. Targeting these complexes bypasses the challenge of RAS and TP53 being intracellular and largely undruggable by conventional antibodies [2, 8]. Current therapeutic approaches include T-cell receptor (TCR)-engineered T cells (TCR-T) and TCR-mimic (TCRm) bispecific antibodies, which redirect the cytotoxic activity of T cells specifically toward cells displaying the mutant peptide-HLA complex [4, 5, 16]. However, clinical development faces hurdles such as the extremely low copy number of these complexes on the cell surface and the potential for off-target reactivity if the therapy cross-reacts with wild-type peptides [1, 14, 20].

Other names

Neoantigen-HLA complexpHLA complexpMHC complexMutant peptide-MHC complexPublic neoantigen-MHC complexRAS-HLA complexTP53-HLA complex

T-cell redirection and activation via high-affinity recognition of specific peptide-MHC complexes by engineered T-cell receptors (TCRs) or TCR-mimic antibodies.