Recombinant
immunotoxins have been shown to cure human
tumor xenografts in mice, but their biodistribution to both
tumors and normal organs has not been reported.
Anti-Tac(Fv)-PE38 is a single-chain recombinant
immunotoxin composed of the variable heavy and light domains of the anti-Tac
monoclonal antibody that reacts with the primate
interleukin 2 (
IL2) receptor alpha subunit (IL2R alpha or CD25) fused to a truncated form of Pseudomonas
exotoxin (PE). 125I-labeled
anti-Tac(Fv)-PE38 was given i.v. to immunodeficient mice each bearing two A431
tumors, one that expresses IL2R alpha (ATAC-4) and one that does not (A431, parental). A single i.v. dose of 4 microg/mouse caused complete regression of the IL2R alpha +
tumor. At 6 h, over 6% of the injected dose/g was found in the ATAC-4
tumor, and 2% was in the A431
tumor. Uptake in the ATAC-4
tumor was higher than in any other tissue. Sections of
tumor examined by autoradiography indicated that
anti-Tac(Fv)-PE38 was distributed throughout the entire
tumor, with some portions having higher uptake than others. By subtracting uptake in
tumors without receptor (A431) from uptake in receptor-containing
tumors (ATAC-4), we calculated that at least 400 molecules/cell specifically bound to IL2R alpha-positive
tumor cells at 90 min and 750 molecules/cell bound at 360 min. This is similar to the 400-870 molecules/cell required for >99.9% killing of ATAC-4 cells growing as a monolayer. The results show that solid
tumors in mice can be eradicated like cells in tissue culture, and that delivery of less than 1000 molecules/cell is sufficient to cause complete
tumor regressions.