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Anti-human CD73 monoclonal antibody inhibits metastasis formation in human breast cancer by inducing clustering and internalization of CD73 expressed on the surface of cancer cells

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Authors:
  • Terp, Mikkel G ;
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    Ditzel group, Department of Molecular Medicine, Faculty of Health Sciences, SDU
  • Olesen, Kristina A ;
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    Ditzel group, Department of Molecular Medicine, Faculty of Health Sciences, SDU
  • Christensen, Eva Arnspang ;
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    Orcid logo0000-0002-3095-4070
    Department of Physics, Chemistry and Pharmacy, Faculty of Science, SDU
  • Lund, Rikke R ;
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    Ditzel group, Department of Molecular Medicine, Faculty of Health Sciences, SDU
  • Lagerholm, B Christoffer ;
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    Department of Physics, Chemistry and Pharmacy, Faculty of Science, SDU
  • Ditzel, Henrik J ;
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    Ditzel group, Department of Molecular Medicine, Faculty of Health Sciences, SDU
  • Leth-Larsen, Rikke
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    Ditzel group, Department of Molecular Medicine, Faculty of Health Sciences, SDU
DOI:
10.4049/jimmunol.1301274
Abstract:
Recent studies have shown that Abs that target the cell-surface enzyme CD73 (ecto-5'-nucleotidase) reduce growth of primary tumors and metastasis in syngenic mice by inhibiting the catalytic activity of CD73, and thus increasing the activity of cytotoxic T lymphocytes. In this article, we report another anticancer mechanism of anti-CD73 Abs and show that an anti-CD73 mAb (AD2) inhibits metastasis formation by a mechanism independent of CD73 catalytic activity and inhibition of primary tumor growth. This mechanism involves clustering and internalization of CD73, but does not require cross-linking of CD73, because both whole IgG anti-CD73 AD2 mAb and Fab' fragments thereof exhibited this effect. Ex vivo treatment of different breast cancer cell lines with anti-CD73 AD2 mAb before i.v. injection into mice inhibited extravasation/colonization of circulating tumor cells and significantly reduced metastasis development. This effect was also observed when the cancer cell-surface expression of CD73 was significantly reduced by small interfering RNA knockdown. The antimetastatic activity is epitope specific, as another Ab that efficiently binds CD73-expressing live cancer cells did not lead to CD73 internalization and metastasis inhibition. Furthermore, anti-CD73 AD2 mAb inhibited development of metastasis in a spontaneous animal model of human metastatic breast cancer. Our study shows that some anti-CD73 mAbs cause cell-surface clustering of CD73 followed by internalization, thus inhibiting the ability of circulating tumor cells to extravasate and colonize, leading to inhibition of metastasis. Ab-based CD73 cancer therapy should include a combination of Abs that target the catalytic activity of CD73, as well as those with the characteristics described in this article.
Type:
Journal article
Language:
English
Published in:
Journal of Immunology, 2013, Vol 191, Issue 8, p. 4165-4173
Keywords:
5'-Nucleotidase; Animals; Antibodies, Monoclonal; Biological Transport; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Female; Humans; Immunoglobulin Fab Fragments; Mice; Neoplasm Metastasis; Neoplasm Transplantation; Neoplastic Cells, Circulating; RNA Interference; RNA, Small Interfering; Xenograft Model Antitumor Assays
Main Research Area:
Medical science
Publication Status:
Published
Review type:
Peer Review
Submission year:
2013
Scientific Level:
Scientific
ID:
248807812

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