An anti‑TROP2 monoclonal antibody TrMab‑6 exerts antitumor activity in breast cancer mouse xenograft models.

Tomohiro Tanaka,Masato Sano,Junko Takei,Hiroyuki Harada,Tomokazu Ohishi,Teizo Asano,Manabu Kawada,Yukinari Kato,Ren Nanamiya,Mika Kaneko,Hideki Hosono

doi:10.3892/or.2021.8083

Abstract

Trophoblast cell surface antigen 2 (TROP2), reported to be overexpressed in several types of cancer, is involved in cell proliferation, invasion, metastasis, and poor prognosis of many types of cancer. Previously, a highly sensitive anti-TROP2 monoclonal antibody (clone TrMab-6; mouse IgG2b, κ) was developed using a Cell-Based Immunization and Screening (CBIS) method. TrMab-6 was useful for investigations using flow cytometry, western blot, and immunohistochemistry. The aim of the present study was to investigate whether TrMab-6 possesses in vitro antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC) activities or in vivo antitumor activities using mouse xenograft models of TROP2-overexpressed CHO-K1 (CHO/TROP2) and breast cancer cell lines, including MCF7, MDA-MB-231, and MDA-MB-468. In vitro experiments revealed that TrMab-6 strongly induced ADCC and CDC activities against CHO/TROP2 and the three breast cancer cell lines, whereas it did not show those activities against parental CHO-K1 and MCF7/TROP2-knockout cells. Furthermore, in vivo experiments on CHO/TROP2 and MCF7 ×enografts revealed that TrMab-6 significantly reduced tumor growth, whereas it did not show antitumor activities against parental CHO-K1 and MCF7/TROP2-knockout xenografts. The findings suggest that TrMab-6 is a promising treatment option for TROP2-expressing breast cancers.

Highlights

The loss of epithelial features in tumors, known as epithe‐ lial‐mesenchymal transition (EMT), is significantly involved in the malignant transformation of cancers, such as tumor initia‐ tion, migration, and metastasis [1,2]
TrMab‐6 detected Trophoblast cell surface antigen 2 (TROP2) with a 40‐kDa band in CHO/TROP2 [16], MCF7, MDA‐MB‐231, and MDA‐MB‐468 cells; it did not detect any proteins in CHO‐K1 and BINDS‐29 cells (Fig. 1A), indicating that TrMab‐6 is specific for TROP2
We investigated whether TrMab‐6 can react with CHO‐K1, CHO/TROP2 [16], MCF7, BINDS‐29 (MCF7/ TROP2‐KO), MDA‐MB‐231, and MDA‐MB‐468 by flow cytometry

Summary

Introduction

The loss of epithelial features in tumors, known as epithe‐ lial‐mesenchymal transition (EMT), is significantly involved in the malignant transformation of cancers, such as tumor initia‐ tion, migration, and metastasis [1,2]. Previous findings have identified several molecules associated with the maintenance of the epithelial features of cells [3]. Epithelial cell adhesion molecule (EpCAM) is a cell adhesion transmembrane molecule, which is overexpressed in tumors. EpCAM is known as trophoblast cell surface antigen 1 (TROP1) and it is encoded by the tumor‐associated calcium signal transducer 1 (TACSTD1) gene [3]. Trophoblast cell surface antigen 2 (TROP2), another molecule of the TACSTD gene family, was identified as a cell surface marker for invasive trophoblast cells [4]. TROP2 is a promising therapeutic target [5], and its expression is associ‐ ated with cancer malignancy in various solid tumors including breast cancers [6]

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