Antitenascin antibody 81C6 armed with 177Lu: in vivo comparison of macrocyclic and acyclic ligands.
BACKGROUND
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 gamma-ray properties, lutetium-177 might be a better low-energy beta-emitter for this type of therapy.


METHODS
Chimeric 81C6 (ch81C6) was labeled with (177)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 the (177)Lu-labeled immunoconjugates plus (125)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 and (125)I-labeled ch81C6, and ch81C6-MeO-DOTA-(177)Lu and (125)I-labeled ch81C6. Similar comparisons were done using murine (mu) instead of ch81C6. The primary parameter utilized for evaluation was the (177)Lu/(125)I uptake ratio in each tissue.


RESULTS
In the studies performed in normal mice, the NHS-DOTA ligand yielded the highest (177)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. The (177)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 the (177)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.


CONCLUSIONS
With these antitenascin constructs, the nature of the mAb had a profound influence on the relative degree of loss of (177)Lu from these immunoconjugates. MeO-DOTA shows promise as a bifunctional chelate for labeling 81C6 mAbs with (177)Lu.
Yordanov
Alexander T
AT
Department of Radiology, Duke University Medical Center Durham, NC 27710, USA.
Hens
Marc
M
Pegram
Charles
C
Bigner
Darell D
DD
Zalutsky
Michael R
MR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D001932:Brain Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism*; D045744:Cell Line, Tumor; D005910:Glioma / Q000000981:diagnostic imaging / Q000378:metabolism*; D006839:Hydrocarbons, Acyclic / Q000493:pharmacokinetics; D008187:Lutetium / Q000493:pharmacokinetics*; D047028:Macrocyclic Compounds / Q000493:pharmacokinetics; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D009928:Organ Specificity; D011868:Radioisotopes / Q000493:pharmacokinetics*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D019063:Tenascin / Q000276:immunology*; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D006839:Hydrocarbons, Acyclic; D047028:Macrocyclic Compounds; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D019063:Tenascin; D008187:Lutetium