Development and evaluation of a novel antibody-photon absorber conjugate reveals the possibility of photoimmunotherapy-induced vascular occlusion during treatment <i>in vivo</i>

Abstract

// Yuya Isoda 1 , Wen Piao 1 , Eri Taguchi 1 , Junko Iwano 1 , Shigeki Takaoka 1 , Aiko Uchida 1 , Kiyomi Yoshikawa 1 , Junichi Enokizono 2 , Emi Arakawa 3 , Kazuma Tomizuka 1 , Yasuhisa Shiraishi 1 and Kazuhiro Masuda 1 1 Research Functions Unit, R&amp;D Division, Kyowa Hakko Kirin Co., Ltd, Machida-shi, Tokyo, Japan 2 Translational Research Unit, R&amp;D Division, Kyowa Hakko Kirin Co., Ltd, Suntou-gun, Shizuoka, Japan 3 Fuji Research Park, R&amp;D Division, Kyowa Hakko Kirin Co., Ltd, Suntou-gun, Shizuoka, Japan Correspondence to: Kazuhiro Masuda, email: kazuhiro.masuda@kyowa-kirin.co.jp Keywords: antibody-photon absorber conjugate; EpCAM; photoimmunotherapy; vascular occlusion; targeted cancer therapy Received: May 17, 2018&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Accepted: July 13, 2018&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Published: July 31, 2018 ABSTRACT Photodynamic therapy (PDT) utilize a photosensitizing agent and light for cancer therapy. It exerts anti-cancer effect mainly by inducing vascular occlusion at the irradiated site. By controlling the irradiation area, PDT can be used in a tumor-specific manner. However, the non-specific cellular damage in the surrounding normal tissue is still a serious concern. Photoimmunotherapy (PIT) is a new type of targeted cancer therapy that uses an antibody-photon absorber conjugate (APC). The superiority of PIT to PDT is the improved target specificity, thereby reducing the damage to normal tissues. Here, we developed a novel APC targeting epithelial cell adhesion molecule (EpCAM) as well as a negative control APC that does not bind to the EpCAM antigen. Our in vitro analysis of APC cytotoxicity demonstrated that the EpCAM APC, but not the negative control, was cytotoxic to EpCAM expressing COLO 205 cells after photoirradiation, suggesting that the cytotoxicity is antigen-dependent. However, in our in vivo analysis using a mouse xenograft tumor model, decreased volume of the tumors was observed in all the mice treated with irradiation, regardless of whether they were treated with the EpCAM APC or the negative control. Detailed investigation of the mechanism of these in vivo reveal that both APCs induce vascular occlusion at the irradiation site. Furthermore, the level of vascular occlusion was correlated with the blood concentration of APC, not the tumor concentration. These results imply that, similar to PDT, PIT can also induce non-targeted vascular occlusion and further optimization is required before widespread clinical use.