Activated matriptase as a target to treat breast cancer with a drug conjugate

Gulam M. Rather, Siang Yo Lin, Hongxia Lin, Whitney Banach-Petrosky, Kim Hirshfield, Chen Yong Lin, Michael D. Johnson, Zoltan Szekely, Joseph Bertino

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

The antitumor effects of a novel antibody drug conjugate (ADC) was tested against human solid tumor cell lines and against human triple negative breast cancer (TNBC) xenografts in immunosuppressed mice. The ADC targeting activated matriptase of tumor cells was synthesized by using the potent anti-tubulin toxin, monomethyl auristatin-E linked to the activated matriptase-specific monoclonal antibody (M69) via a lysosomal protease-cleavable dipeptide linker. This ADC was found to be cytotoxic against multiple activated matriptase-positive epithelial carcinoma cell lines in vitro and markedly inhibited growth of triple negative breast cancer xenografts and a primary human TNBC (PDX) in vivo. Overexpression of activated matriptase may be a biomarker for response to this ADC. The ADC had potent anti-tumor activity, while the unconjugated M69 antibody was ineffective in a mouse model study using MDA-MB-231 xenografts in mice. Treatment of a human TNBC (MDA-MB-231) showed potent anti-tumor effects in combination with cisplatin in mice. This ADC alone or in combination with cisplatin has the potential to improve the treatment outcomes of patients with TNBC as well as other tumors overexpressing activated matriptase.

Original languageEnglish (US)
Pages (from-to)25983-25992
Number of pages10
JournalOncotarget
Volume9
Issue number40
DOIs
StatePublished - 2018

All Science Journal Classification (ASJC) codes

  • Oncology

Keywords

  • Antibody-drug conjugate
  • Copper-free click chemistry
  • Matriptase
  • Monomethyl auristatin E
  • Xenograft

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  • Cite this

    Rather, G. M., Lin, S. Y., Lin, H., Banach-Petrosky, W., Hirshfield, K., Lin, C. Y., Johnson, M. D., Szekely, Z., & Bertino, J. (2018). Activated matriptase as a target to treat breast cancer with a drug conjugate. Oncotarget, 9(40), 25983-25992. https://doi.org/10.18632/oncotarget.25414