Site-specific expression of transferrin receptor by human colon cancer cells directly correlates with eradication by antitransferrin recombinant immunotoxin

We determined the efficacy of HB21(Fv)PE40, a single-chain immunotoxin made by fusing the variable regions of a monoclonal antibody directed at the hu man transferrin receptor (TW) with a truncated mutant of Pseudomonas exotox in (PE), against metastatic human colon carcinoma KM12L4 cells growing in t he liver or subcutis of nude mice. Organ-specific modulation of TfR express ion was examined by immunohistochemistry and flow cytometry using anti-huma n CD71 antibody. KM12L4 cells expressed human TW and were lysed in vitro by HB21(Fv)PE40 but not LMB-7 (a control immunotoxin specific for a Lewis Y-r elated carbohydrate antigen). KM12L4 cells growing in the liver expressed h igher levels of TfR than cells growing s.c. Systemic administration of HB21 (Fv)PE40 eliminated KM12L4 liver metastasis, whereas administration of LMB- 7 did not. Treatment of mice with HB21(Fv)PE40 only delayed the growth of s .c. tumors. KM12L4 cells recovered from liver metastases, expressed higher levels of TfR, and were more sensitive to lysis by HB21(Fv)PE40 than KM12L4 cells recovered from s.c. tumors. Indeed, collectively, the data show that the expression level of the TfR by human colon cancer cells is modulated b y the organ microenvironment which can be advantageous for the use of thera peutic immunotoxins.