Development of a Novel EGFR-Targeting Antibody-Drug Conjugate for Pancreatic Cancer Therapy
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.
The authors thank both Hongwen Li and Xiaoyu Xu at RemeGen Ltd. for their input regarding the preparation of the RC68 antibody.
Compliance with Ethical Standards
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.
- 16.Lu X, Yu L, Zhang Z, Ren X, Smaill JB, Ding K. Targeting EGFRL858R/T790M and EGFRL858R/T790M/C797S resistance mutations in NSCLC: current developments in medicinal chemistry. Med Res Rev. 2018;38:1550–1581.Google Scholar
- 20.Thatcher N, Hirsch FR, Luft AV, Szczesna A, Ciuleanu TE, Dediu M, et al. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2015;16(7):763–74.CrossRefGoogle Scholar
- 24.van den Bent M, Gan HK, Lassman AB, Kumthekar P, Merrell R, Butowski N, et al. Efficacy of depatuxizumab mafodotin (ABT-414) monotherapy in patients with EGFR-amplified, recurrent glioblastoma: results from a multi-center, international study. Cancer Chemother Pharmacol. 2017;80(6):1209–17.CrossRefGoogle Scholar
- 29.Huang C, Fang J, Ye H, Zhang L. Covalent linkers in antibody-drug conjugates and methods of making and using the same [P]. WO 2017/031034 A2.Google Scholar
- 36.Kamisawa T, Wood LD, Itoi T, Takaori K. Pancreatic cancer. Lancet. 2016;388:73–85.Google Scholar
- 38.Zeitouni D, Pylayeva-Gupta Y, Der CJ, Bryant KL. KRAS mutant pancreatic cancer: no lone path to an effective treatment. Cancer. 2016;6:166–175.Google Scholar
- 47.Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada clinical trials group. J Clin Oncol. 2007;25(15):1960–6.CrossRefGoogle Scholar