An immunotoxin with therapeutic potential in T cell leukemia: WT1-ricin A.
A conjugate of the monoclonal antibody WT1 and ricin A-chain was studied for its suitability for purging marrow of leukemic T cells for autologous transplantation in T cell acute lymphocytic leukemia (T-ALL). The conjugate was powerfully cytotoxic to the human T-ALL cell line, GH1, which expresses the WT1 antigen at a high density. Treatment of the cells with the conjugate at 10(-11) M reduced their rate of protein synthesis by 50%, and the inclusion of 6 mM ammonium chloride in the cultures enhanced the potency of cytotoxic effect by 10-100-fold. Clonogenic assays indicated that less than 0.1% of GH1 cells survived 3-hr exposure to the conjugate in ammonium chloride. WT1 alone did not react with multipotent (CFU-GEMM) hematopoietic progenitors in normal human bone marrow, as measured by fluorescence-activated cell sorting. Under conditions giving maximal killing of GH1 cells, there was no toxicity to multipotential progenitors in normal human marrow.
D000911:Antibodies, Monoclonal / Q000276:immunology / Q000502:physiology*; D000951:Antigens, Neoplasm / Q000276:immunology; D000992:Antitoxins / Q000494:pharmacology* / Q000627:therapeutic use; D001666:Binding Sites, Antibody; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D016026:Bone Marrow Transplantation; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000473:pathology; D003602:Cytotoxicity, Immunologic; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy; D007945:Leukemia, Lymphoid / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D008562:Membrane Glycoproteins; D012276:Ricin / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000276:immunology*
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D000992:Antitoxins; D008562:Membrane Glycoproteins; C028388:thymus-leukemia antigens; D012276:Ricin