TCR-mimic antibody-drug conjugates targeting intracellular tumor-specific mutant antigen KRAS G12V mutation

Limited clinical application of antibody-drug conjugates(ADCs) targeting tumor associated antigens(TAAs) is usually caused by on-target off-tumor side effect. Tumor-specific mutant antigens(TSMAs) only expressed in tumor cells which are ideal targets for ADCs. In addition, intracellular somatic mutant proteins can be presented on the cell surface by human leukocyte antigen class I(HLA I)molecules forming tumor-specific peptide/HLA I complexes. KRAS G12 V mutation frequently occurred in varied cancer and was verified as a promising target for cancer therapy. In this study, we generated two TCR-mimic antibodydrug conjugates(TCRm-ADCs), 2E8-MMAE and 2 A5-MMAE, targeting KRAS G12 V/HLAA*0201 complex, which mediated specific antitumor activity in vitro and in vivo without obvious toxicity. Our findings are the first time validate the strategy of TCRm-ADCs targeting intracellular TSMAs, which improves the safety of antibody-based drugs and provides novel strategy for precision medicine in cancer therapy.