Antitenascin antibody 81C6 armed with177 Lu: in vivo comparison of macrocyclic and acyclic ligands

• Published in: Nuclear medicine and biology Vol. 34; no. 2; pp. 173 - 183
• Main Authors: Yordanov, Alexander T, Hens, Marc, Pegram, Charles, Bigner, Darell D, Zalutsky, Michael R
• Format: Journal Article
• Language: English
• Published: 2007
• Subjects: Radiology; NHS-DOTA; MeO-DOTA; Radioimmunotherapy; Lu-177; 1B4M
• ISSN: 0969-8051
• DOI: 10.1016/j.nucmedbio.2006.11.003

Abstract Introduction When labeled with iodine-131, the antitenascin monoclonal antibody (mAb) 81C6 has shown promise as a targeted radiotherapeutic in patients with brain tumors. Because of its more favorable γ-ray properties, lutetium-177 might be a better low-energy β-emitter for this type of therapy. Materials and Methods Chimeric 81C6 (ch81C6) was labeled with177 Lu using the acyclic 1B4M ligand and the macrocyclic ligands NHS-DOTA and MeO-DOTA and evaluated for binding to tenascin. Three paired-label tissue distribution experiments were performed in normal mice receiving one of the177 Lu-labeled immunoconjugates plus125 I-labeled ch81C6 labeled using Iodogen. Paired-label experiments in athymic mice bearing subcutaneous D54 MG human glioma xenografts were done to directly compare the biodistribution of ch81C6–1B4M–177 Lu and125 I-labeled ch81C6, and ch81C6–MeO-DOTA–177 Lu and125 I-labeled ch81C6. Similar comparisons were done using murine (mu) instead of ch81C6. The primary parameter utilized for evaluation was the177 Lu/125 I uptake ratio in each tissue. Results In the studies performed in normal mice, the NHS-DOTA ligand yielded the highest177 Lu/125 I uptake ratios in tissues indicative of loss of label from the chelate; for this reason, only 1B4M and MeO-DOTA were evaluated further. The177 Lu/125 I ratio in bone increased gradually with time for the chimeric conjugates; however, there were no significant differences between ch81C6–1B4M–DTPA–177 Lu and ch81C6–MeO-DOTA–177 Lu. In contrast, mu81C6–1B4M-DTPA–177 Lu and mu81C6–MeO-DOTA–177 Lu showed a more dramatic increase in the177 Lu/125 I ratio in bone — from 2.4±0.3 and 1.7±0.2 at Day 1 to 8.5±1.1 and 4.2±0.5 at Day 7, respectively. Conclusion With these antitenascin constructs, the nature of the mAb had a profound influence on the relative degree of loss of177 Lu from these immunoconjugates. MeO-DOTA shows promise as a bifunctional chelate for labeling 81C6 mAbs with177 Lu.