Development of a Novel EGFR-Targeting Antibody-Drug Conjugate for Pancreatic Cancer Therapy.

Abstract

Overexpression of epidermal growth factor receptor (EGFR) is common in pancreatic cancer and associated with the poor prognosis of this malignancy. To develop anti-EGFR antibody-drug conjugates (ADCs) for use in a novel EGFR-targeting approach to treat pancreatic cancer. A humanized anti-EGFR monoclonal antibody (RC68) was generated by mouse immunization and complementary-determining region grafting technology. Two RC68-based ADCs, RC68-MC-VC-PAB-MMAE and RC68-PY-VC-PAB-MMAE, were synthesized by conjugating monomethyl auristatin E (MMAE), a small-molecule cytotoxin, to RC68 through two distinct linkers (MC and PY). Internalization of the RC68-based ADCs was examined by flow cytometry. The in vitro and in vivo antitumor activities of RC68-based ADCs were evaluated in human pancreatic cancer cells and in a BXPC-3 xenograft nude mouse model, respectively. The RC68-based ADCs bound to EGFR on the surface of tumor cells and were effectively internalized, resulting in the death of EGFR-positive cancer cell lines. The RC68-based ADCs (at 5 or 10mg/kg) were more potent than gemcitabine hydrochloride (60mg/kg) at inhibiting the growth of BXPC-3 xenografts. Moreover, RC68-PY-VC-PAB-MMAE was found to have superior stability in human plasma compared with RC68-MC-VC-PAB-MMAE. A novel EGFR-targeting ADC, RC68-PY-VC-PAB-MMAE, shows promise as an effective, selective, and safe therapeutic agent for EGFR-positive pancreatic cancer.