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Selective targeted delivery of doxorubicin via conjugating to anti-CD24 antibody results in enhanced antitumor potency for hepatocellular carcinoma both in vitro and in vivo

Abstract

Purpose

Antibody–drug conjugates (ADCs) represent a promising therapeutic approach for clinical application. Cluster of differentiation 24 (CD24) is over-expressed in several human malignancies, especially in hepatocellular carcinoma (HCC). We aimed to develop a new class of CD24-targeted ADCs for HCC.

Methods

DOX was conjugated with G7mAb by a heterobifunctional cross-linker GMBS (N-[gamma-maleimido butyryloxy] succinimide ester) and further analyzed using HPLC. The targeting specificity and endocytosis of the newly generated ADC, G7mAb–DOX, were characterized using flow cytometry assay, near-infrared fluorescence imaging and laser scanning confocal microscope. The antitumor effects were evaluated in nude mice bearing HCC xenografts.

Results

G7mAb–DOX with average two drug molecules per antibody was selectively captured and endocytosed by CD24 (+) tumor cells in vitro. In vivo, the ADC was proved to target tumor tissues, suppress tumor growth and prolong the survival of HCC-bearing nude mice with improved efficacy and less systemic toxicity compared with either G7mAb or DOX single-agent treatment.

Conclusion

These studies provide proof of concept for development of DOX-based ADCs which provide a novel approach for HCC-targeted immune therapy in clinical application.

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Acknowledgements

We thank Prof. Yueqing Gu and her lab for technical assistance of near infrared imaging.

Author information

Correspondence to Min Wang or Juan Zhang.

Ethics declarations

Funding

This study was supported by the National Natural Science Foundation of China (NSFC81273425 and NSFC81473125); Natural Science Foundation of Jiangsu Province (BK20161459); Jiangsu Province Qinglan Project (2014), a project funded by the Priority Academic Program Development Innovation Program of Jiangsu Higher Education Institutions; Graduate Student Innovation Project Funded by Zhejiang Huahai Pharmaceutical Co (1010040003); The Graduate Innovation Program of Jiangsu Province (KYLX15_0670); Under-graduate Training Program of Jiangsu Province for Innovation and Entrepreneurship (SY15090).

Conflict of interest

The authors declare no competing financial interests.

Ethical approval

All experimental procedures were conducted in conformity with institutional guidelines for the care and use of laboratory animals in Yangzhou University, Yangzhou, China, and conformed to the National Institutes of Regulations for the Administration of Affairs Concerning Experimental Animals.

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Ma, Z., He, H., Sun, F. et al. Selective targeted delivery of doxorubicin via conjugating to anti-CD24 antibody results in enhanced antitumor potency for hepatocellular carcinoma both in vitro and in vivo. J Cancer Res Clin Oncol 143, 1929–1940 (2017). https://doi.org/10.1007/s00432-017-2436-0

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Keywords

  • CD24
  • Antibody–drug conjugates (ADCs)
  • Doxorubicin (DOX)
  • G7mAb
  • Hepatocellular carcinoma