A Library of Potent TCRs Derived from Healthy Donors Targeting Kras G12d and G12v Neoantigens

Abstract Kirsten rat sarcoma (KRAS), the most frequently altered oncogene, is a key target for T cell-based therapies. Mutant KRAS (mKRAS)-specific T cell receptors (TCRs) enable targeted treatment for patients with matching mKRAS/HLA allele pairs. We generated a TCR warehouse library covering approximately one-quarter of pancreatic ductal adenocarcinoma patients and 10% of colorectal cancer patients. Warehouse TCRs exhibit strong avidities and cytotoxicity, comparable to existing benchmark TCRs. Detailed characterization of each TCR revealed unique biology for specific KRAS neoantigens. TCRs with high sensitivity for KRAS G12V/HLA-C*01:02 also recognize the wild-type epitope. However, the wild-type epitope abundance appears to be significantly lower, potentially creating a therapeutic window, albeit necessitating deeper evaluation. Additionally, we show that TCRs recognize KRAS G12V on HLA-C*03:03 and HLA-C*03:04 interchangeably, thereby resulting in a single neoantigen with one of the highest frequencies. In summary, this mKRAS-targeted TCR library comprises candidates for further preclinical and clinical development.