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

• Published in: Molecular cancer therapeutics 2007-03, Vol.6 (3), p.866-875
• Main Authors: Kim, Hyunki, Chaudhuri, Tandra R, Buchsbaum, Donald J, Wang, Deli, Zinn, Kurt R
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal; Antineoplastic Agents - therapeutic use; apoptosis; Apoptosis - immunology; breast cancer; Breast Neoplasms - diagnostic imaging; Breast Neoplasms - immunology; DR5; Humans; imaging; Immunoconjugates; Mice; Mice, Nude; mTRA-8 antibody; Neoplasm Staging; Radioimmunodetection; Radiopharmaceuticals; Receptors, TNF-Related Apoptosis-Inducing Ligand - immunology; Sodium Pertechnetate Tc 99m; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-06-0230

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 mm 3 ) 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]