GEORG H. FEY:  FRIDAY 31 MARCH 2006, 11:15

Targeting CD19 and CD33 by Antibody-derived Molecules for the Treatment of Leukemias and Lymphomas

Georg Fey, Michael Schwemmlein, Jörg Brünke, Karin Barbin, Julia Stieglmaier, Matthias Peipp
Faculty of Natural Sciences II (Naturwissenschaftliche Fakultät II), Chair of Genetics, Institute of Biology, University of Erlangen-Nuremberg, 91058 Erlangen, Germany

Several immunotoxins (ITs) were developed in our group, consisting of single chain Fv fragments (scFvs) specific for leukemia antigens, which were genetically fused to a truncated version of Pseudomonas Exotoxin A (ETA). A recombinant CD7-scFv toxin (CD7scFv-ETA') effectively killed acute T-cell leukemia (T-ALL)-derived cell lines, and a similar IT derived from a newly generated CD33-scFv (CD33scFv-ETA') induced apoptosis of the human myeloid leukemic cell lines U937, HL-60 and THP-1. Killing was antigen-specific and occured by apoptosis. In a direct comparison, CD33scFv-ETA' showed no cytotoxic activity for antigen-negative T-ALL-derived CEM cells, whereas Gemtuzumab Ozogamicin (Mylotarg™), a monoclonal CD33 antibody coupled to the cytotoxic compound calicheamicin, also lysed antigen-negative CEM cells. CD33scFv-ETA' also mediated apoptosis of fresh patient-derived acute myeloid leukemia (AML) cells from bone marrow and peripheral blood, and efficiently eliminated colony forming units from peripheral blood of an AML patient. The pronounced antigen-restricted cytotoxicity of this new immunotoxin, its action in low nanomolar concentrations, and its ability to eliminate clonogenic progenitors make it a promising candidate for further evaluation of its therapeutic potential.

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