# Antibodies that see mutant KRAS and p53 fragments displayed on the cell surface

Source: https://onco.cc/ideas/idea-bio1-pmhc-bispecifics-public-drivers/  
OnCo record `idea-bio1-pmhc-bispecifics-public-drivers` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Fields

- Kind: Idea
- Last checked: 2026-09-08
- 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.
- Proposed 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

## Sources

- Bottleneck evidence (The undruggable drivers): Dang et al., Drugging the 'undruggable' cancer targets (Nature Reviews Cancer 2017): https://doi.org/10.1038/nrc.2017.36

## Connected records

- technologies: [Bispecific antibodies](https://onco.cc/technologies/bispecific-antibody/), [T-cell engagers (bispecific)](https://onco.cc/technologies/t-cell-engager/), [TCR-T cell therapy](https://onco.cc/technologies/tcr-t/)
- targets: [KRAS](https://onco.cc/targets/kras/), [TP53](https://onco.cc/targets/tp53/)
- drugs: [Tebentafusp](https://onco.cc/drugs/tebentafusp/)
- companies: [Immatics](https://onco.cc/companies/immatics/), [Immunocore](https://onco.cc/companies/immunocore/), [TScan Therapeutics](https://onco.cc/companies/tscan/)
- terms: [Neoantigen](https://onco.cc/terms/neoantigen/)
- bottlenecks: [No one can predict who responds to immunotherapy](https://onco.cc/bottlenecks/b-immunotherapy-response/), [The undruggable drivers](https://onco.cc/bottlenecks/b-undruggable-targets/)
- key papers: [Drugging the 'undruggable' cancer targets](https://onco.cc/key-papers/paper-dang-nat-rev-cancer/), [Vogelstein, Lane and Levine 2000: surfing the p53 network](https://onco.cc/key-papers/paper-vogelstein-surfing-p53-network-nature-2000/)
- cancers: [KRAS G12C-mutant non-small-cell lung cancer](https://onco.cc/cancers/kras-g12c-nsclc/)

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