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

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

doi:10.18632/oncotarget.25414

Gulam M Rather, Siang-Yo Lin + Show 7 more

Open Access

https://doi.org/10.18632/oncotarget.25414

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Journal: Oncotarget	Publication Date: May 25, 2018
Citations: 10	License type: cc-by

Affiliation: Rutgers, The State University of New Jersey

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.

Highlights

The recent development of antibody drug conjugates (ADCs) that are approved by the FDA for treatment of Hodgkin disease [1], breast cancer [2] and acute myelogenous leukemia [3] has stimulated the development of other tumor target directed ADC’s, and many others are being tested in the clinic with anti-tumor activity [2, 4, 5]
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
The conjugation reactions were monitored by MALDI-TOF mass spectrometry showing a 7000 Da increase of the average M.W. that corresponds to an average of 3.5 drug (MMAE) molecules linked to each mAb molecule (Figure 1B)

Summary

INTRODUCTION

The recent development of antibody drug conjugates (ADCs) that are approved by the FDA for treatment of Hodgkin disease [1], breast cancer [2] and acute myelogenous leukemia [3] has stimulated the development of other tumor target directed ADC’s, and many others are being tested in the clinic with anti-tumor activity [2, 4, 5]. Matriptase, called MT-SP1 or epithin, is a member of the family of type II transmembrane serine proteases on the surface of the normal epithelium It is an 80–90 kDa glycoprotein with a complex structure with regulatory mechanisms and functions [11, 12]. The toxin is the potent anti-mitotic agent, monomethyl auristatin-E (MMAE) linked to the activated matriptase-specific monoclonal antibody (M69) via a lysosomal protease (cathepsin B) -cleavable dipeptide linker. This ADC was found to be potent and selective against multiple activated matriptase-positive epithelial carcinoma cell lines in vitro. Treatment of human triple negative breast cancer (TNBC) xenografts and a primary human TNBC (PDX) showed potent anti-tumor effects alone or in combination with cisplatin in mice

RESULTS

DISCUSSION

MATERIALS AND METHODS