An <scp>EGFR</scp>‐targeting antibody–drug conjugate <scp>LR</scp>004‐<scp>VC</scp>‐<scp>MMAE</scp>: potential in esophageal squamous cell carcinoma and other malignancies

Abstract

Epidermal growth factor receptor ( EGFR ) is a rational target for cancer therapy, because its overexpression plays an important oncogenic role in a variety of solid tumors; however, EGFR ‐targeted antibody–drug conjugate ( ADC ) therapy for esophageal squamous cell carcinoma ( ESCC ) is exceedingly rare. LR 004 is a novel anti‐ EGFR antibody with the advantages of improved safety and fewer hypersensitivity reactions. It may be of great value as a carrier in ADC s with high binding affinity and internalization ability. Here, we prepared an EGFR ‐targeting ADC , LR 004‐ VC ‐ MMAE , and evaluated its antitumor activities against ESCC and EGFR ‐positive cells. LR 004 was covalently conjugated with monomethyl auristatin E ( MMAE ) via a VC linker by antibody interchain disulfide bond reduction. VC ‐ MMAE was conjugated with LR 004 with approximately 4.0 MMAE molecules per ADC . LR 004‐ VC ‐ MMAE showed a potent antitumor effect against ESCC and other EGFR ‐positive cells with IC 50 values of nM concentrations in vitro . The in vivo antitumor effects of LR 004‐ VC ‐ MMAE were investigated in ESCC KYSE 520 and A431 xenograft nude mice models. Significant activity was seen at 5 mg·kg −1 , and complete tumor regression was observed at 15 mg·kg −1 in the KYSE 520 xenograft nude mice after four injections, while the naked antibody LR 004 had little effect on inhibiting tumor growth. Similar promising results were obtained in the A431 models. In addition, the tumors also remained responsive to LR 004‐ VC ‐ MMAE for large tumor experiments (tumor volume 400–500 mm 3 ). The study results demonstrated that LR 004‐ VC ‐ MMAE could be a potential therapeutic agent for ESCC and other EGFR ‐expressing malignancies. We also evaluated PK profile of LR 004‐ VC ‐ MMAE ADC in the mice model, which would provide qualitative guiding significance for the further research.