{"entity":{"id":"idea-bio1-pmhc-bispecifics-public-drivers","kind":"idea","name":"Antibodies that see mutant KRAS and p53 fragments displayed on the cell surface","aka":[],"tldr":"Cells chop up their internal proteins and display the pieces on their surface. That means even undruggable proteins inside the cell can be attacked from outside by the immune system.","summary":"TCR-mimic antibodies and bispecific T-cell engagers can recognise mutant peptide-MHC complexes, including KRAS G12V and TP53 R175H presented on HLA-A*02:01, with published proof of concept. Tebentafusp validated the ImmTAC format clinically in uveal melanoma. The proposal is a coordinated programme covering the commonest driver mutations across the commonest HLA alleles, treating public neoantigens as an off-the-shelf target class.","asOf":"2026-09-08","links":[{"label":"Bottleneck evidence (The undruggable drivers): Dang et al., Drugging the 'undruggable' cancer targets (Nature Reviews Cancer 2017)","url":"https://doi.org/10.1038/nrc.2017.36"}],"tags":[],"related":[],"cancers":[],"sections":[],"technologies":["t-cell-engager","bispecific-antibody","tcr-t"],"targets":["kras","tp53"],"drugs":["tebentafusp"],"companies":["immunocore","immatics","tscan"],"institutions":[],"pathways":[],"terms":["neoantigen"],"trials":[],"people":[],"bottlenecks":["b-undruggable-targets","b-immunotherapy-response"],"keyPapers":["paper-vogelstein-surfing-p53-network-nature-2000","paper-dang-nat-rev-cancer"],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"A pMHC-directed bispecific against a public driver neoantigen produces objective responses in HLA-matched, mutation-positive patients, demonstrating that intracellular undruggable drivers are immunologically targetable.","rationale":"The approach makes druggability a question of antigen presentation rather than protein pockets, and the driver mutations are truncal, so escape by antigen loss requires losing the driver itself.","test":"First-in-human study in HLA-A*02:01-positive, KRAS G12V-positive pancreatic or colorectal cancer, with mandatory HLA and mutation screening and on-treatment biopsies for T-cell infiltration.","maturity":"preclinical-evidence","actor":"industry","cost":"large","horizonYears":6},"route":"/ideas/idea-bio1-pmhc-bispecifics-public-drivers/","neighbours":{"technology":[{"id":"bispecific-antibody","kind":"technology","name":"Bispecific antibodies","route":"/technologies/bispecific-antibody/"},{"id":"t-cell-engager","kind":"technology","name":"T-cell engagers (bispecific)","route":"/technologies/t-cell-engager/"},{"id":"tcr-t","kind":"technology","name":"TCR-T cell therapy","route":"/technologies/tcr-t/"}],"target":[{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"drug":[{"id":"tebentafusp","kind":"drug","name":"Tebentafusp","route":"/drugs/tebentafusp/"}],"company":[{"id":"immatics","kind":"company","name":"Immatics","route":"/companies/immatics/"},{"id":"immunocore","kind":"company","name":"Immunocore","route":"/companies/immunocore/"},{"id":"tscan","kind":"company","name":"TScan Therapeutics","route":"/companies/tscan/"}],"term":[{"id":"neoantigen","kind":"term","name":"Neoantigen","route":"/terms/neoantigen/"}],"bottleneck":[{"id":"b-immunotherapy-response","kind":"bottleneck","name":"No one can predict who responds to immunotherapy","route":"/bottlenecks/b-immunotherapy-response/"},{"id":"b-undruggable-targets","kind":"bottleneck","name":"The undruggable drivers","route":"/bottlenecks/b-undruggable-targets/"}],"paper":[{"id":"paper-dang-nat-rev-cancer","kind":"paper","name":"Drugging the 'undruggable' cancer targets","route":"/key-papers/paper-dang-nat-rev-cancer/"},{"id":"paper-vogelstein-surfing-p53-network-nature-2000","kind":"paper","name":"Vogelstein, Lane and Levine 2000: surfing the p53 network","route":"/key-papers/paper-vogelstein-surfing-p53-network-nature-2000/"}],"cancer":[{"id":"kras-g12c-nsclc","kind":"cancer","name":"KRAS G12C-mutant non-small-cell lung cancer","route":"/cancers/kras-g12c-nsclc/"}]}}