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

摘要

The radiolanthanides ~(149)Pm,~(166)Ho,and ~(177)Lu 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 ~(149)Pm,~(166)Ho,and ~(177)Lu.While both DOTA conjugates could be labeled to high specific activity with ~(177)Lu,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 ~(177)Lu than DOTA-OSSu.The in vitro stability of ~(149)Pm-,~(166)Ho-,and ~(177)Lu-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 ~(177)Lu showing the highest stability after 96 to 168 h at 37 deg C.In contrast,MeO-DOTA-CC49 labeled with all three radiolanthanides was >92% stable to hydroxyapatite challenge for 168 h at 37 deg C.Comprehensive biodistributions of ~(149)Pm-,~(166)Ho-,and ~(177)Lu-MeO-DOTA-CC49 were obtained in LS174T-bearing nude mice.Maximum tumor uptakes were 100.0% ID/g for ~(149)Pm at 96 h,69.5% ID/g for ~(166)Ho at 96 h,and 132.4% ID/g for ~(177)Lu 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 ~(149)Pm,~(166)Ho,and ~(177)Lu,MeO-DOTA-CC49 has potential for RIT of colorectal cancer and other carcinomas.