| Abstract: |
A leukemia-selective immunotoxin was constructed by linking recombinant gelonin (rGel), a single chain ribosome inhibitory protein, to recombinant humanized M195 antibody (HuM195), which recognizes the cell-surface protein designated CD33. CD33 is an antigen found on myeloid leukemia blasts as well as myeloid progenitor cells but it is not expressed in detectable amounts on the ultimate hematopoietic progenitor stem cell. Our previous studies indicated that a non-recombinant humanized immunotoxin displayed specific, potent toxicity towards CD33-positive cells but not to CD33-negative cells in vitro. In the current study, a recombinant humanized immunotoxin, HuM195-rGel, was evaluated in vivo in a nude mouse model of human myeloid leukemias. HuM195-rGel was found to target leukemia cells rapidly in vivo and was subsequently internalized into the cells. For trials in vivo, nude mice were injected tip) with 107 log-phase HL60 human leukemia cells 10 days prior to the start of i.p. HuM195-rGel treatments. HuM195-rGel demonstrated significant tumor suppressive activity in this model. While all mice treated with either saline, rGel alone, or HuM195 plus unconjugated rGel (at 10 or 14 days after transplantation) had rapid tumor growth or early deaths, 50% of mice treated with HuM195-rGel failed to develop leukemic tumors for 5 months and the other 50% had significantly retarded tumor growth after treatment with HuM195-rGel. Mice treated at later times (28 days after transplantation of leukemia cells) also showed delayed leukemia cell growth, but no cures. These data show that HuM195-rGel can target leukemia cells in vivo and can result in pronounced anti-leukemic effects. |
| Keywords: |
controlled study; human cell; drug activity; nonhuman; drug targeting; mouse; animals; mice; animal experiment; animal model; tumor cells, cultured; cancer inhibition; antibodies, monoclonal; death; mice, nude; leukemia, myeloid; recombinant proteins; hematopoietic stem cell; drug cytotoxicity; antigens, cd; neoplasm transplantation; tumor growth; cd33 antigen; antigens, differentiation, myelomonocytic; hum195; myeloid leukemia; immunotoxin; immunotoxins; antileukemic agent; intraperitoneal drug administration; protein synthesis inhibitors; hl-60 cells; plant proteins; gelonin; cd33; humans; human; female; priority journal; article
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