Targeting intracellular KRAS G12D /HLA-A11 pMHC with a novel TCR-mimic antibody-drug conjugate (TCRm-ADC) demonstrates potent antitumor activity in preclinical models

Antibody-drug conjugates (ADCs) targeting tumor-associated antigens (TAAs) frequently cause on-target, off-tumor side effects. TCR-mimic antibodies (TCRms) imitate the capacity of T cell receptors (TCRs) to interact with peptide-MHC complexes (pMHCs), offering a solution to target previously undruggable intracellular cancer antigens, such as KRAS mutations. Here, we screened and identified a TCRm with high specificity and affinity for the KRAS G12D /HLA-A*11 pMHC complex using phage display, ELISA, and cell-based assays. We further confirmed the specificity and safety of the TCRm antibody in vitro and in vivo . Furthermore, the TCRm-ADC, NDV-ADC01-exatecan, which targets the KRAS G12D /HLA-A*11 pMHC complex, mediated specific antitumor activity in vitro and in vivo without obvious toxicity in xenograft models of lung, pancreatic, and colorectal cancer. Additionally, NDV-ADC01-exatecan significantly elicited antitumor immunity and reshaped the tumor microenvironment when combined with low-dose radiotherapy in a humanized HLA-A*11/hB2M transgenic model. Together, these screening and engineering processes provide a novel therapeutic strategy to target undruggable KRAS G12D -mutated cancers.