Oncotarget

Research Papers:

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 M. Hirshfield, Chen-Yong Lin, Michael D. Johnson, Zoltan Szekely, Joseph R. Bertino _

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Oncotarget. 2018; 9:25983-25992. https://doi.org/10.18632/oncotarget.25414

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Abstract

Gulam M. Rather1,*, Siang-Yo Lin1,*, Hongxia Lin1, Whitney Banach-Petrosky1, Kim M. Hirshfield1,2, Chen-Yong Lin3, Michael D. Johnson3, Zoltan Szekely4 and Joseph R. Bertino1,2,5

1Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA

2Department of Medicine, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA

3Department of Oncology, Georgetown Medical School, Washington, DC, USA

4Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ USA

5Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA

*These authors have contributed equally to this work

Correspondence to:

Joseph R. Bertino, email: bertinoj@cinj.rutgers.edu

Zoltan Szekely, email: zoltan@pharmacy.rutgers.edu

Keywords: matriptase; monomethyl auristatin E; antibody-drug conjugate; copper-free click chemistry; xenograft

Received: January 24, 2018    Accepted: March 21, 2018    Published: May 25, 2018

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.


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