Monoclonal Antibody-based Therapy of a Human Tumor Xenograft with a 177Lutetium-labeled Immunoconjugate

Abstract 177 Lutetium ( 177 Lu) is a member of the family of elements known as lanthanides or rare earths. Monoclonal antibody (MAb) CC49, a murine IgG1, which is reactive with the tumor-associated antigen, TAG-72, has been shown previously to react with a wide range of human carcinomas; CC49 reacts to a different epitope on the TAG-72 molecule than MAb B72.3 and has a higher binding affinity. We report here 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-174T human colon carcinomas in athymic mice at a single dose of 50 µCi. Overt toxicity was observed with the administration of approximately 500 µCi of 177 Lu-CC49 in which 5 of 9 mice died of apparent marrow toxicity. A single administration of 200 or 350 µCi of 177 Lu-CC49, however, was shown to eliminate established tumors through the 77-day observation period after MAb administration. Dose fractionation experiments revealed that at least 750 µCi of 177 Lu-CC49 (250 µCi/week for 3 consecutive weaks) was well tolerated in that 9 of 10 mice survived. Moreover, this dose schedule was able to eliminate the growth of relatively large (300 mm 3 ) human colon tumor xenografts in 90% of the animals treated. Single-dose and dose fractionation studies were also carried out with an isotype-matched control MAb, 177 Lu-MOPC-21. In all dose schedules, a large differential was seen between the therapeutic effects of the 177 Lu-CC49 versus that of the 177 Lu-control MAb. The merits and limitations of the use of 177 Lu-labeled immunoconjugates (in particular, 177 Lu-CC49) are discussed in terms of potential novel therapeutics for human carcinoma.