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

  • Zhuanglin Li
  • Mingxue Wang
  • Xuejing Yao
  • Wenting Luo
  • Yaocheng Qu
  • Deling Yu
  • Xue Li
  • Jianmin Fang
  • Changjiang Huang
Original Research Article

Abstract

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.

Notes

Acknowledgments

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

Funding

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.

Supplementary material

11523_2018_616_MOESM1_ESM.pdf (55 kb)
ESM 1 (PDF 55 kb)

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.RemeGen, Ltd.YantaiChina
  2. 2.Mabplex International Ltd.YantaiChina
  3. 3.School of Life Science and TechnologyTongji UniversityShanghaiChina

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