Researchers at the Korea Advanced Institute of Science and Technology (KAIST) in Daejeon, South Korea, led by Professor Byung-Ha Oh and collaborating with KAIST-founded biotech Therazyne, have engineered a novel TCR-like antibody capable of targeting intracellular KRAS G12D mutations, a historically undruggable driver in pancreatic, colorectal, and lung cancers. Published recently in Molecular Therapy, the breakthrough overcomes the fundamental limitation of conventional antibody therapeutics, which cannot penetrate cell membranes to access internal proteins. The development addresses a critical blind spot in oncology. While standard antibodies effectively target surface antigens, intracellular cancer mutations have remained inaccessible to direct treatment. The KAIST team circumvented this by exploiting the body’s natural protein degradation pathway. Inside malignant cells, mutated KRAS proteins are cleaved into small peptide fragments known as neoantigens. These fragments are transported to the cell surface and displayed for immune surveillance. By integrating AI-driven computational protein design with high-throughput cell-based screening, the researchers engineered an antibody that mimics T-cell receptor function. This TCR-like antibody effectively grants traditional antibodies the ability to detect these intracellular mutation signatures presented on the exterior of cancer cells. Preclinical validation in animal disease models confirmed that the engineered antibody selectively binds to and eliminates KRAS G12D-positive cells while showing negligible reactivity with healthy tissue or unrelated proteins. The construct also demonstrated potent immunotherapeutic activity in vivo. Professor Oh noted that the platform technology establishes a new paradigm for precision antibody engineering, proving that computational design can successfully convert previously inaccessible intracellular targets into clinically actionable therapies. The success of this approach positions both the antibody candidate and its underlying design methodology as a scalable platform for next-generation cancer treatments. Beyond KRAS G12D, the framework is expected to accelerate the development of targeted immunotherapies for a broad spectrum of intracellular oncogenic mutations, potentially transforming the clinical landscape for aggressive and therapy-resistant malignancies.