Novel Anti-FOLR1 Antibody-Drug Conjugate MORAb-202 in Breast Cancer and Non-Small Cell Lung Cancer Cells.

Yuki Matsunaga,Masafumi Takimoto,Toshimitsu Yamaoka,Motoi Ohba,Takafumi Sangai,Seigo Nakamura,Hiroko Masuda,Sakiko Miura,Junji Tsurutani

doi:10.3390/antib10010006

Abstract

Antibody–drug conjugates (ADCs), which are currently being developed, may become promising cancer therapeutics. Folate receptor α (FOLR1), a glycosylphosphatidylinositol-anchored membrane protein, is an attractive target of ADCs, as it is largely absent from normal tissues but is overexpressed in malignant tumors of epithelial origin, including ovarian, lung, and breast cancer. In this study, we tested the effects of novel anti-FOLR1 antibody–eribulin conjugate MORAb-202 in breast cancer and non-small cell lung cancer (NSCLC) cell lines. FOLR1 expression, cell proliferation, bystander killing effects, and apoptosis were evaluated in seven breast cancer and nine NSCLC cell lines treated with MORAb-202. Tumor growth and FOLR1 expression were assessed in T47D and MCF7 orthotopic xenograft mouse models after a single intravenous administration of MORAb-202 (5 mg/kg). MORAb-202 was associated with inhibited cell proliferation, with specific selectivity toward FOLR1-expressing breast cancer cell lines. Eribulin, the payload of MORAb-202, was unleashed in HCC1954 cells, diffused into intercellular spaces, and then killed the non-FOLR1-expressing MCF7 cells in co-culture systems. In orthotopic xenograft mouse models, FOLR1-expressing T47D tumors and non-FOLR1-expressing MCF7 tumors were suppressed upon MORAb-202 administration. The novel anti-FOLR1 antibody–eribulin conjugate MORAb-202 has potential antitumor effects in breast cancer.

Highlights

Antibody–drug conjugates (ADCs) represent a developing class of drugs with the potential to become key anticancer therapeutics [1,2,3]
The mRNA expression of FOLR1 was examined by real-time RTPCR in normal human mammary epithelial cells (HMECs) and in bronchial epithelial cells (BEAS-2B), which were used as controls for breast cancer and non-small cell lung cancer (NSCLC) cells, respectively
The alteration of the cell cycle distribution with MORAb-202 treatment was similar to that with eribulin treatment (Figure 4a,b). These findings indicate that the linker in MORAb-202 is enzymatically cleaved in the lysosome, and eribulin is released from farletuzumab in T47D cells; the free eribulin induces G2-M phase arrest and the accumulation of cells in the sub-G1 phase of the cell cycle

Summary

Introduction

Antibody–drug conjugates (ADCs) represent a developing class of drugs with the potential to become key anticancer therapeutics [1,2,3]. These drugs are composed of a monoclonal antibody (mAb) conjugated to a cytotoxic payload via a chemical linker and are tailored to highly specific target antigens expressed on cancer cell surfaces. ADCs are capable of delivering highly potent drugs to tumor cells while sparing normal cells, attenuating the clinical obstacles of traditional chemotherapy [4]. MORAb-202 is an ADC comprising the antibody farletuzumab, which targets folate receptor α (FRα, known as FOLR1), and a cathepsin-cleavable linker with eribulin as a payload.

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Conclusion