Evaluating the potential of 188Re-SOCTA–trastuzumab as a new radioimmunoagent for breast cancer treatment

Luo, Tsai-Yueh; Tang, I-Chang; Wu, Yu-Long; Hsu, Kwel-Luen; Liu, Show-Wen; Kung, Hong-Chang; Lai, Ping-Shan; Lin, Wuu-Jyh

doi:10.1016/j.nucmedbio.2008.10.014

« Previous Next »Nuclear Medicine and Biology
Volume 36, Issue 1 , Pages 81-88, January 2009

Evaluating the potential of ¹⁸⁸Re-SOCTA–trastuzumab as a new radioimmunoagent for breast cancer treatment

Tsai-Yueh Luo
- Isotope Application Division, Institute of Nuclear Energy Research, P.O. Box 3-27, Longtan, Taoyuan 325, Taiwan
- Corresponding author. Tel.: +886 3 4711400x7004; fax: +886 3 4711416.
I-Chang Tang
- Isotope Application Division, Institute of Nuclear Energy Research, P.O. Box 3-27, Longtan, Taoyuan 325, Taiwan
Yu-Long Wu
- Isotope Application Division, Institute of Nuclear Energy Research, P.O. Box 3-27, Longtan, Taoyuan 325, Taiwan
Kwel-Luen Hsu
- Isotope Application Division, Institute of Nuclear Energy Research, P.O. Box 3-27, Longtan, Taoyuan 325, Taiwan
Show-Wen Liu
- Chemistry Division, Institute of Nuclear Energy Research, Taoyuan 325, Taiwan
Hong-Chang Kung
- Department of Electrical Engineering, Tung Nan University, Taipei 222, Taiwan
Ping-Shan Lai
- Department of Chemistry, National Chung Hsing University, Taichung 402, Taiwan
Wuu-Jyh Lin
- Isotope Application Division, Institute of Nuclear Energy Research, P.O. Box 3-27, Longtan, Taoyuan 325, Taiwan

Received 18 July 2008; received in revised form 16 October 2008; accepted 21 October 2008.

Abstract

Introduction

Radioimmunotherapy, which utilizes monoclonal antibodies and therapeutic radioisotopes against antigen-expressing tumor tissues, is an attractive therapeutic approach for cancer therapy. Trastuzumab (Herceptin) is a humanized anti-HER-2/neu monoclonal antibody for breast cancer treatment. In this paper, we introduce a new radioimmunoagent, ¹⁸⁸Re-trastuzumab, via a bifunctional ligand, succinimidyl 3,6-diaza-5-oxo-3-[2-((triphenylmethyl)thio)ethyl]-8-[(triphenylmethyl)thio]octanoate (SOCTA), and evaluate its potential to be a therapeutic radiopharmaceutical for breast cancer treatment.

Methods

Equimolar amounts of SOCTA and trastuzumab were selected to react, and the conjugation ratio of SOCTA–trastuzumab was evaluated by the MALDI-TOF method. The immunoreactivity of SOCTA–trastuzumab was compared with nonconjugated trastuzumab in HER-2/neu overexpressing human breast cancer cell BT-474. Biodistribution experiment and microSPECT/CT images of ¹⁸⁸Re-SOCTA–trastuzumab being administered intravenously to SCID mice bearing xenografted BT-474 breast cancer were investigated to evaluate the tumor-targeting capability.

Results

The covalent attachment of SOCTA to trastuzumab (at 1:1 molar ratio) resulted in the averaged conjugation ratio of 0.27±0.06 (n=3). The complex could easily be labeled with ¹⁸⁸Re and achieve 95% radiochemical purity (RCP) after 1 h of reaction at room temperature. The in vitro stability study also revealed that the RCP of ¹⁸⁸Re-SOCTA–trastuzumab was at a value of more than 85% after 48 h of incubation with human serum. The immunoreactivity evaluation showed that SOCTA–trastuzumab and nonconjugated trastuzumab had similar binding capacity (B_max) to HER-2/neu receptor in BT-474 cells. The animal experiments showed that ¹⁸⁸Re-SOCTA–trastuzumab accumulated more intensively in the tumor site as compared to normal tissue.