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Radioimmunotherapy of Human Colon Cancer Xenografts Using a Dimeric Single-Chain Fv Antibody Construct¹

Departments of Pathology and Microbiology [G. P., B. J. M. B.] and Biochemistry and Molecular Biology [S. K. B.], University of Nebraska Medical Center, Omaha, Nebraska 68198-3135; and Coulter Pharmaceuticals Inc., San Francisco, California 94080 [D. C.]

Progress in the use of monoclonal antibodies (MAbs) for the treatment of solid tumors is limited by a number of factors, including poor penetration of the labeled IgG molecule into the tumors, their inability to reach the tumor in sufficient quantities without significant normal tissue toxicity, and the development of a human antimouse antibody response to the injected MAb. One possible way to alter the pharmacology of antibodies is via the use of smaller molecular weight antibody fragments called single-chain Fvs (scFvs). A divalent construct of MAb CC49, CC49 (scFv)₂, composed of two noncovalently associated scFvs, was generated and shown to bind a tumor-associated antigen (TAG-72) epitope with a similar binding affinity to that of the murine IgG. The therapeutic potential of this construct after labeling with ¹³¹I was examined in athymic mice bearing established s.c. human colon carcinoma (LS-174T) xenografts. Treatment groups (n = 10) received a single dose of ¹³¹I-labeled CC49 (scFv)₂ (500–2000 µCi) or ¹³¹I-labeled CC49 IgG (250 and 500 µCi). The group of mice treated with the lowest dose of ¹³¹I-(scFv)₂ (500 µCi) showed statistically significant prolonged survival, compared with controls (P = 0.036). Complete tumor regression was observed in 20% of mice given 1500 µCi of labeled (scFv)₂ and 30 and 60% of mice treated with 250 and 500 µCi of labeled IgG, respectively. In conclusion, the CC49 (scFv)₂ construct provides a promising delivery vehicle for therapeutic applications.

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