Mutant KRAS G12V neoantigen peptide-HLA-A*11:01 complex (mKRAS^G12V-HLA-A*11:01 complex)

The mutant KRAS G12V neoantigen peptide-HLA-A*11:01 complex forms when a 9-mer peptide (KRAS^G12V) derived from the G12V mutation in the KRAS oncogene binds to the HLA-A*11:01 allele, creating a tumor-specific antigen (neoantigen) on cancer cell surfaces. This complex exhibits strong HLA binding stability (dissociation half-life 3-5 hours), superior to other mutant KRAS-HLA pairings, enabling effective immune recognition by T cells. KRAS G12V mutations drive constitutive activation of RAF-MEK-ERK and PI3K pathways, promoting proliferation in cancers like lung, pancreatic, and colorectal adenocarcinomas. TCRs targeting this complex, such as KT18, demonstrate high functional avidity, selectively killing KRAS^G12V tumor cells in xenograft models without cross-reactivity to wild-type KRAS or most self-peptides. However, many KRAS^G12V-HLA-A*11:01-specific TCRs cross-recognize the self-antigen RAB7B^13-21, posing an off-target risk mitigated in optimized clones like KT18. Therapeutics like TCR-T cells, TCR-mimic CARs (e.g., with Strep-tagII hinge), and BiTEs exploit this complex for immunotherapy, though challenges include low natural presentation density on tumors. The target is not a traditional receptor or enzyme but a peptide-major histocompatibility complex (pMHC) neoantigen, prioritized for immunotherapy due to its tumor specificity. HLA-A*11:01 restriction shows preferential binding for KRAS^G12V over other alleles like HLA-A*03:01 or HLA-C alleles. KT18 TCR-T cells eradicated tumors in solid tumor xenografts, highlighting clinical promise. For HLA-A*02:01 contexts, related KRAS^G12V^5-14 peptides face stability issues (half-life <1 hour endogenously). Peptide specifics: KRAS^G12V (9-mer) binds HLA-A*11:01 with high stability; RAB7B^13-21 has weaker affinity but cross-reactivity risk. Therapeutic validation: KT18 TCR shows no off-target killing of RAB7B; CAR/BiTE formats potent on peptide-pulsed cells but limited on endogenous tumor expression. Broader context: Mutant KRAS neoantigens like G12V are ideal for adaptive immunity due to public prevalence (~25% of KRAS mutations).

Other names

KRAS^G12V-HLA-A*11:01 complexHLA-A*11:01-presented KRAS^G12V neoantigenKRAS G12V peptide-HLA-A*11:01

TCR-mediated recognition and cytotoxicity of mutant KRAS-presenting tumor cells, CAR-redirected T/NK cell activation and IFN-γ release, Bispecific T cell engager redirection of T cells to pHLA complex