CC49 is a """"""""second generation"""""""" MAb to B72.3, which reacts with the pancarcinoma antigen TAG-72. CC49 has been shown to efficiently target human colon carcinoma xenografts and is currently being evaluated in both diagnostic and therapeutic clinical trials. We have described the construction and characterization of a recombinant single-chain Fv (sFv) of CC49. The sFv was shown to be a Mr 27,000 homogeneous entity which could be efficiently radiolabeled with 125-1 or 131-1. Metabolism studies in mice, using radiolabeled CC49 IgG, F(ab')2, Fab', and sFv, demonstrated an extremely rapid plasma and whole body clearance for the sFv. CC49 sFv plasma pharmacokinetic studies in rhesus monkeys also showed a very rapid plasma clearance. Tumor targeting studies with all four radiolabeled Ig CC49 forms, using the LS-174T human colon carcinoma xenograft model, revealed a much lower percentage injected dose/g tumor binding for the CC49 monomeric sFv and Fab' as compared to the dimeric F(ab')2 and intact IgG. However, tumor:normal tissue ratios (radiolocalization indices) for the sFv were comparable to or greater than those of the other Ig forms. The CC49 sFv may thus have utility in diagnostic and therapeutic applications for a range of human carcinomas. 177-Lutetium (177-Lu) is a member of the family of elements known as lanthanides or rare earths. We have demonstrated the first use of a 177-Lu-labeled immunoconjugate, 177-Lu-CC49, in an experimental therapy model for human carcinoma. 177-Lu-CC49 was shown to delay the growth of established LS-1 74T human colon carcinomas in athymic mice at a single dose of 50 mu-Ci. A single administration of 200 or 350 mu-Ci of 177-Lu-CC49 was shown to eliminate established tumors through the 77-day observation period after MAb administration. Dose fractionation experiments revealed that at least 750 mu-Ci of 177-Lu-CC49 (250 mu-Ci/week for 3 consecutive weeks) was well tolerated and this dose schedule was able to eliminate the growth of relatively large human colon tumor xenografts in 90% of the animals treated. The merits of the use of 177-Lu-labeled immunoconjugated (in particular, 177-Lu-CC49) should now be considered in terms of potential novel therapeutics for human carcinoma.
