A Novel Bispecific Antibody against Human CD3 and Ephrin Receptor A10 for Breast Cancer Therapy
Authors: Taki, Shintaro; Kamada, Haruhiko; Inoue, Masaki; Nagano, Kazuya; Mukai, Yohei; Higashisaka, Kazuma; Yoshioka, Yasuo; Tsutsumi, Yasuo; Tsunoda, Shin-ichi
Ephrin receptor A10 (EphA10), a transmembrane receptor that binds to ephrin, is a newly identified breast cancer marker protein that has also been detected in HER2-negative tissue. In this study, we report creation of a novel bispecific antibody (BsAb) binding both EphA10 and CD3, thereby forming a bridge between antigens expressed on both tumor and immune cells and promoting recognition of tumor cells by immune cells and redirection of cytotoxic T cells (CTL). This BsAb (EphA10/CD3) was expressed in supernatants of BsAb gene-transfected cells asmonomeric and dimeric molecules. Redirected T-cell lysis was observed when monomeric and dimeric BsAb were added to EphA10-overexpressing tumor cells in vitro. Furthermore, dimeric BsAb (EphA10/CD3) was more cytotoxic than monomeric BsAb, with efficient tumor cell lysis elicited by lower concentrations (<= 10(-1) mu g/mL) and a lower effector to target (E/T) cell ratio (E/T = 2.5). Dimeric BsAb (EphA10/CD3) also showed significant antitumor effects in human xenograft mouse models. Together, these results revealed opportunities to redirect the activity of CTL towards tumor cells that express EphA10 using the BsAb (EphA10/CD3), which could be tested in future clinical trials as a novel and potent therapeutic for breast cancer tumors.
Ephrin receptor A10 is a promising drug target potentially useful for breast cancers including triple negative breast cancers
JOURNAL OF CONTROLLED RELEASE
Authors: Nagano, Kazuya; Maeda, Yuka; Kanasaki, So-ichiro; Watanabe, Takanobu; Yamashita, Takuya; Inoue, Masaki; Higashisaka, Kazuma; Yoshioka, Yasuo; Abe, Yasuhiro; Mukai, Yohei; Kamada, Haruhiko; Tsutsumi, Yasuo; Tsunoda, Shin-ichi
Ephrin receptor A10 (EphA10) is a relatively uncharacterized protein which is expressed in many breast cancers but not expressed in normal breast tissues. Here, we examined the potential of EphA10 as a drug target in breast cancer. Immunohistochemical staining of clinical tissue sections revealed that EphA10 was expressed in various breast cancer subtypes, including triple negative breast cancers (TNBCs), with no expression observed in normal tissues apart from testis. Ligand-dependent proliferation was observed in EphA10-transfected MDA-MB-435 cells (MDA-MB-435(EphA10)) and native TNBC cells (MDA-MB-436). However, this phenomenon was not observed in parentalMDA-MB-435 cells which express a lowlevel of EphA10. Finally, tumor growth was significantly suppressed by administration of an anti-EphA10 monoclonal antibody in a xenograft mouse model. These results suggest that inhibition of EphA10 signaling may be a novel therapeutic option for management of breast cancer, including TNBCs which are currently not treated with molecularly targeted agents. (C) 2014 Elsevier B.V. All rights reserved.