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.
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The authors thank both Hongwen Li and Xiaoyu Xu at RemeGen Ltd. for their input regarding the preparation of the RC68 antibody.
This work was supported by a grant from the National Science and Technology Major Project of China (Grant number: 2014ZX09508004–003).
Conflicts of Interest
Zhuanglin Li, Xuejing Yao, Jianmin Fang, and Changjiang Huang are stock holders of RemeGen, Ltd. All other authors declare no conflicts of interest.
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Li, Z., Wang, M., Yao, X. et al. Development of a Novel EGFR-Targeting Antibody-Drug Conjugate for Pancreatic Cancer Therapy. Targ Oncol 14, 93–105 (2019). https://doi.org/10.1007/s11523-018-0616-8