ideasIdea
Antibodies that see mutant KRAS and p53 fragments displayed on the cell surface
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.
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.
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.
What would test it
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
Who has to act
industry
Cost to try
Large (over $50M)
Years to first evidence
6
Bottlenecks it attacks
- The undruggable drivers · The proteins that drive most cancers, such as MYC, mutant p53 and most RAS variants, still have no good drug.
- No one can predict who responds to immunotherapy · Checkpoint drugs cure some patients and do nothing for most. We still cannot tell the two apart before treating.