Radiolanthanide-Labeled Monoclonal Antibody CC49 for Radioimmunotherapy of Cancer:  Biological Comparison of DOTA Conjugates and ¹⁴⁹Pm, ¹⁶⁶Ho, and ¹⁷⁷Lu

Abstract

The radiolanthanides 149Pm, 166Ho, and 177Lu have decay characteristics suitable for radioimmunotherapy (RIT) of cancer. N-Hydroxysulfosuccinimidyl DOTA (DOTA-OSSu) and methoxy-DOTA (MeO-DOTA) were conjugated to the anti-TAG-72 monoclonal antibody CC49 for radiolabeling with 149Pm, 166Ho, and 177Lu. While both DOTA conjugates could be labeled to high specific activity with 177Lu, MeO-DOTA afforded superior conjugate stability, radiolabeling, and radiochemical purity. Pilot biodistributions in nude mice bearing LS174T human colon carcinoma xenografts demonstrated that MeO-DOTA afforded higher tumor uptake and lower kidney retention of 177Lu than DOTA-OSSu. The in vitro stability of 149Pm-, 166Ho-, and 177Lu-MeO-DOTA-CC49 was evaluated using serum and hydroxyapatite assays. Serum stability of radiolanthanide-labeled MeO-DOTA-CC49 followed a trend based on the coordination energies of the radiometals, with 177Lu showing the highest stability after 96 to 168 h at 37 C. In contrast, MeO-DOTA-CC49 labeled with all three radiolanthanides was >92% stable to hydroxyapatite challenge for 168 h at 37 C. Comprehensive biodistributions of 149Pm-, 166Ho-, and 177Lu-MeO-DOTA-CC49 were obtained in LS174T-bearing nude mice. Maximum tumor uptakes were 100.0% ID/g for 149Pm at 96 h, 69.5% ID/g for 166Ho at 96 h, and 132.4% ID/g for 177Lu at 168 h. Normal organ uptakes were generally low, except in the liver, spleen, and kidney at early time points. By 96 to 168 h postinjection, nontarget organ uptake decreased to approximately 7% ID/g (kidney), 12% ID/g (spleen), and 20% ID/g (liver) for each radiolanthanide. When labeled with 149Pm, 166Ho, and 177Lu, MeO-DOTA-CC49 has potential for RIT of colorectal cancer and other carcinomas.

Diels–Alder Reaction for Tumor Pretargeting: In Vivo Chemistry Can Boost Tumor Radiation Dose Compared with Directly Labeled Antibody

“…The typical mAb biodistribution data obtained for 177 Lu-DOTA-CC49, with a sustained circulation, high tumor uptake, and substantial radioactivity retention in blood-rich organs and in excretory organs, were in good agreement with those previously published for other 177 Lu-CC49 constructs (24). In contrast, in mice pretreated with CC49-TCO, 177 Lu-2 cleared rapidly from blood and all nonreacted probe was eliminated via the urine within a few hours.…”

Chelating agents for radiolanthanides: Applications to imaging and therapy

“…While the coordination chemistry of these early lanthanides is slightly varied from the later lanthanides, 7 134 Ce/ 134 La could find similar utility as other more familiar lanthanide isotopes. 134 Ce was produced from a natural abundance lanthanum metal disc bombarded with 70-72 MeV protons. The product was dissolved using NaBrO 3 and HNO 3 and extracted into methylisobutylketone.…”

“…Despite reports of the Auger electron and positron emitting 134 Ce/ 134 La isotopes 6 (halflives: 3.16 d, 6.45 min) there are no reports of the development of the use of this PET isotope in preclinical experiments. While the coordination chemistry of these early lanthanides is slightly varied from the later lanthanides, 7 134 Ce/ 134 La could find similar utility as other more familiar lanthanide isotopes.…”

“…Lewis and co-workers have prepared complex conjugates of various radiolanthanides, including 149 Pm, 166 Ho and 177 Lu (from the University of Missouri Research Reactor), with the CC49 monocolonal antibody as potential agents in radioimmunotherapy. 134 The CC49 antibody reacts with the tumour-associated glycoprotein-72 expressed in 85% of human adenocarcinomas (e.g. colon, breast, pancreatic, ovarian, prostrate, non-small cell lung and gastric).…”

In Vitro and In Vivo Evaluation of Melanin-Binding Decapeptide 4B4 Radiolabeled with 177Lu, 166Ho, and 153Sm Radiolanthanides for the Purpose of Targeted Radionuclide Therapy of Melanoma

“…The 177 Lu DO3A-4B4 peptide was evaluated over a period of 72 hours using a modification to the procedure previously reported. 16 Briefly, 100 lL of the lyophilized radiolabeled peptide was added to 400 lL of human serum and incubated at 37°C. A 100 lL aliquot was removed for each time point, diluted with 200 lL of PBS (pH 7.4), and filtered using a 0.45-lm filter, after which, 100 lL injections of the samples were analyzed using an SE-HPLC equipped with a TosoHaas size exclusion column (TSKGel Ò G4000 SW 30 cm · 7.5 mm).…”