51. Development of a Novel EGFR-Targeting Antibody-Drug Conjugate for Pancreatic Cancer Therapy
- Author
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Changjiang Huang, Xue Li, Mingxue Wang, Deling Yu, Zhuanglin Li, Yaocheng Qu, Yao Xuejing, Jianmin Fang, and Luo Wenting
- Subjects
0301 basic medicine ,Cancer Research ,Antibody-drug conjugate ,Immunoconjugates ,medicine.drug_class ,Mice, Nude ,Apoptosis ,Monoclonal antibody ,Antibodies, Monoclonal, Humanized ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Nude mouse ,In vivo ,Pancreatic cancer ,medicine ,Tumor Cells, Cultured ,Animals ,Humans ,Pharmacology (medical) ,Epidermal growth factor receptor ,Cell Proliferation ,Mice, Inbred BALB C ,biology ,business.industry ,biology.organism_classification ,medicine.disease ,Xenograft Model Antitumor Assays ,body regions ,ErbB Receptors ,Pancreatic Neoplasms ,030104 developmental biology ,Oncology ,Monomethyl auristatin E ,chemistry ,030220 oncology & carcinogenesis ,Monoclonal ,Cancer research ,biology.protein ,Female ,business - 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 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. 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.
- Published
- 2019