KAIST develops antibody that targets only cancer-causing mutations, opening path to precision treatment

South Korean researchers have developed a new antibody capable of precisely targeting mutations in hard-to-treat cancers — including pancreatic, colon and lung cancer — that have long been out of reach for conventional antibody therapies.

KAIST announced Friday that a research team led by Oh Byung-ha, a professor in the Department of Biological Sciences, working jointly with researchers at Theradesign — a protein design company Oh founded — has developed an antibody that selectively recognizes cancer cells carrying the KRAS(G12D) mutation, one of the most common cancer-driving mutations. The team combined computational antibody design technology with experimental validation and is currently verifying the antibody's efficacy in animal disease models.

KRAS(G12D) is a mutated form of the KRAS protein, which regulates cell growth and proliferation. It is commonly found in pancreatic, colon and lung cancers. Because the KRAS protein resides inside cells rather than on their surface, it has long been considered an "undruggable target" beyond the reach of conventional antibody therapies.

The research team focused on the natural process by which cells break down aged or damaged proteins into small fragments. KRAS(G12D) proteins inside cells are similarly degraded into small peptide fragments known as neoantigens, some of which migrate to the cell surface and are presented to immune cells. By combining computational protein design with experimental screening, the team developed a TCR-like antibody that precisely recognizes only these cancer mutation fragments.

T-cell receptors, or TCRs, act as "sensors" on immune cells, reading protein fragments displayed on cell surfaces to detect cancer cells or virus-infected cells. The newly developed TCR-like antibody works on the same principle as equipping a conventional antibody with the "eyes" of a T cell, allowing it to selectively recognize traces of intracellular cancer mutations that were previously inaccessible to standard antibody therapies.

In experiments, the antibody showed little reaction to normal cells or other proteins, selectively recognizing only cancer cells carrying the KRAS(G12D) mutation. When applied in immunotherapy, it also proved capable of effectively eliminating those cancer cells. The results expand the range of treatable targets to include cancer-driving proteins inside cells that conventional antibody therapies could not reach, and the technology is expected to serve as a foundation for developing next-generation precision antibody treatments targeting not only KRAS but a broad range of cancer mutations.

"This could be administered as a tailored precision immunotherapy for patients with mutant pancreatic cancer, colon cancer and non-small cell lung cancer who currently have no adequate treatment options," Oh said. He added that the team plans to advance preclinical data to secure global exclusive rights and pursue co-development and technology transfer with major domestic and international pharmaceutical companies to accelerate entry into clinical trials.

The findings were published in Molecular Therapy, an international journal covering gene and cell therapy.