High-resolution single-photon emission computed tomography and X-ray computed tomography imaging of Tc-99m-labeled anti-DR5 antibody in breast tumor xenografts.
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.
Kim
Hyunki
H
Department of Radiology, Comprehensive Cancer Center, University of Alabama at Birmingham, 1808 7th Avenue South, Birmingham, AL 35294-0012, USA.
Chaudhuri
Tandra R
TR
Buchsbaum
Donald J
DJ
Wang
Deli
D
Zinn
Kurt R
KR
D000818:Animals; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000276:immunology; D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000276:immunology; D006801:Humans; D018796:Immunoconjugates; D051379:Mice; D008819:Mice, Nude; D009367:Neoplasm Staging; D016719:Radioimmunodetection; D019275:Radiopharmaceuticals; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology*; D013670:Sodium Pertechnetate Tc 99m; D015899:Tomography, Emission-Computed, Single-Photon; D014057:Tomography, X-Ray Computed
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D019275:Radiopharmaceuticals; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D013670:Sodium Pertechnetate Tc 99m