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

• Published in: Targeted oncology Vol. 14; no. 1; pp. 93 - 105
• Main Authors: Li, Zhuanglin, Wang, Mingxue, Yao, Xuejing, Luo, Wenting, Qu, Yaocheng, Yu, Deling, Li, Xue, Fang, Jianmin, Huang, Changjiang
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.02.2019; Springer Nature B.V
• Subjects: Animals; Antibodies, Monoclonal, Humanized - administration & dosage; Apoptosis; Biomedicine; Cell Proliferation; Epidermal growth factor; ErbB Receptors - immunology; Female; Humans; Immunoconjugates - administration & dosage; Medical prognosis; Medicine; Medicine & Public Health; Mice; Mice, Inbred BALB C; Mice, Nude; Oncology; Original Research Article; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - immunology; Pancreatic Neoplasms - pathology; Targeted cancer therapy; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 1776-2596; 1776-260X
• DOI: 10.1007/s11523-018-0616-8

Background Overexpression of epidermal growth factor receptor (EGFR) is common in pancreatic cancer and associated with the poor prognosis of this malignancy. Objective To develop anti-EGFR antibody–drug conjugates (ADCs) for use in a novel EGFR-targeting approach to treat pancreatic cancer. Methods 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. Results 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 10 mg/kg) were more potent than gemcitabine hydrochloride (60 mg/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. Conclusion 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.