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Research Articles: Therapeutics, Targets, and Development

High-resolution single-photon emission computed tomography and X-ray computed tomography imaging of Tc-99m–labeled anti-DR5 antibody in breast tumor xenografts

¹ Comprehensive Cancer Center, Departments of ² Radiology, ³ Medicine, ⁴ Pathology, and ⁵ Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama

Requests for reprints: Kurt R. Zinn, University of Alabama at Birmingham, 802 Boshell Building, 1808 7th Avenue South, Birmingham, AL 35294-0012. Phone: 205-975-6414; Fax: 205-975-6522. E-mail: kurtzinn{at}uab.edu

Abstract

A murine, apoptosis-inducing monoclonal antibody (mTRA-8) targeting human DR5 was radiolabeled with Tc-99m. The binding affinity (K_d) and the number of DR5 receptors were measured in MD MBA-231–derived 2LMP cell lines that were "sensitive" or "resistant" to mTRA-8 killing. Single-photon emission computed tomography and X-ray computed tomography (SPECT/CT) evaluated the Tc-99m-mTRA-8 retention and distribution within xenograft tumors; biodistribution analyses confirmed the levels. Scatchard assays showed specific and high binding affinity of Tc-99m-mTRA-8 to DR5; the killing efficacy of mTRA-8 was unchanged by Tc-99m labeling. There was no significant difference between sensitive and resistant 2LMP cells for K_d values (1.5 ± 0.3 nmol/L = acid labile), or DR5 receptors (mean/cell = 11,000). SPECT/CT imaging analyses at 6 h after injection of Tc-99m-mTRA-8 revealed the second 1.5 mm shell from the surface of the mammary fat pad tumors (n = 5; 5,627 mm³) retained 12.7 ± 1.4%ID/g, higher than the other shells, with no difference between the sensitive and resistant 2LMP tumors. Binding of Tc-99m–labeled mTRA-8 in tumor was specific; excess unlabeled mTRA-8 blocked Tc-99m-mTRA-8 retention in tumor by 45%. Retention of Tc-99m–labeled isotype antibody in tumor was consistent with the blocking study, and 30% lower. These studies show that SPECT/CT imaging provided detailed distribution information of Tc-99m–labeled mTRA-8 within breast tumor xenografts. Imaging could provide a mechanism to assess DR5 modulation when DR5 therapy is combined with chemotherapy and radiation, and thereby aid in optimizing the dosing schedule. [Mol Cancer Ther 2007;6(3):866–75]

Grant support: Financial support and DR5 antibodies were obtained from Sankyo Co., Ltd. Support was also provided by the NIH (P50CA089019 and 5P30CA013148-35) and DAMD (17-02-1-0266 and 17-02-1-0264). Purchase of the SPECT/CT instrument was possible due to support from the University of Alabama at Birmingham Comprehensive Cancer Center, the Arthritis and Musculoskeletal Center, the Health Service Foundation General Endowment Fund, and a gift from Mr. Leon Edwards Advised Fund.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: Conflict of interest: D. Buchsbaum has intellectual property interest related to the mTRA-8 antibody.

⁶ Dr. Alex Szalai, University of Alabama at Birmingham (Birmingham, Alabama), personal communication.

Received 5/ 1/06; revised 12/21/06; accepted 1/31/07.

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				H. Kim, D. E. Morgan, H. Zeng, W. E. Grizzle, J. M. Warram, C. R. Stockard, D. Wang, and K. R. Zinn Breast Tumor Xenografts: Diffusion-weighted MR Imaging to Assess Early Therapy with Novel Apoptosis-Inducing Anti-DR5 Antibody Radiology, September 1, 2008; 248(3): 844 - 851. [Abstract] [Full Text] [PDF]