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

Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892 [J. S., K. S., D. E. M., D. E., D. C.]; Battelle Memorial Institute, Columbus, Ohio 43201 [L. S. M., D. H.]; and The Dow Chemical Company, Midland, Michigan 48674 [R. C., D. K., W. G.]

¹⁷⁷Lutetium (¹⁷⁷Lu) 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 ¹⁷⁷Lu-labeled immunoconjugate, ¹⁷⁷Lu-CC49, in an experimental therapy model for human carcinoma. ¹⁷⁷Lu-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 ¹⁷⁷Lu-CC49 in which 5 of 9 mice died of apparent marrow toxicity. A single administration of 200 or 350 µCi of ¹⁷⁷Lu-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 ¹⁷⁷Lu-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 mm³) 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, ¹⁷⁷Lu-MOPC-21. In all dose schedules, a large differential was seen between the therapeutic effects of the ¹⁷⁷Lu-CC49 versus that of the ¹⁷⁷Lu-control MAb. The merits and limitations of the use of ¹⁷⁷Lu-labeled immunoconjugates (in particular, ¹⁷⁷Lu-CC49) are discussed in terms of potential novel therapeutics for human carcinoma.

¹ To whom requests for reprints should be addressed, at the Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health, Building 10, Room 8B07, Bethesda, MD 20892.

² Current address: University of Nebraska Medical Center, Department of Pathology and Microbiology, Omaha, NE 68198.

³ Current address: Neoprobe Corporation, Columbus, OH 43212.

Received 1/ 8/91. Accepted 3/20/91.

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