Selective killing of human T-lymphotropic virus-I infected leukemic T-cells by monoclonal anti-interleukin 2 receptor antibody-ricin A chain conjugates: potentiation by ammonium chloride and monensin.
Adult T-cell leukemia is a progressive disease produced by infection of mature T-cells with the human T-lymphotropic virus-I (HTLV-I). These retrovirus infected T-cells express large numbers of receptors for interleukin 2 (or T-cell growth factor). Due to the presence of these receptors, these leukemic T-cells can be selectively killed in vitro by monoclonal anti-interleukin 2 receptor antibody covalently linked to the A chain of the plant toxin, ricin (anti-TAC-A), suggesting that such immunotoxins may be useful in the therapy of this disease. In this report we demonstrate that the lysosomotropic agent ammonium chloride and the carboxylic ionophore monensin substantially potentiate the cytotoxicity of anti-TAC-A on HUT 102 cells, a long-term cultured HTLV-I infected T-cell line. Anti-TAC-A alone produces half-maximal inhibition of protein synthesis in HUT 102 cells at a concentration of 2.2 X 10(-10) M (the 50% inhibitor, concentration). Addition of ammonium chloride or monensin augments the potency of anti-TAC-A killing 100-fold (50% inhibitory concentration = 2.5 X 10(-12) M) and 400-fold (50% inhibitory concentration = 8 X 10(-13) M), respectively; furthermore, these agents accelerate rate of anti-TAC-A intoxication and increase the specific killing of interleukin 2 receptor-bearing leukemic cells. At concentrations which cause only minor harm to colony forming hematopoietic progenitor cells (granulocyte-erythroid, monocytic, megakaryocytic colony forming unit, granulocyte-macrophage colony forming unit, macrophage colony forming unit, and granulocyte colony forming unit), anti-TAC-A alone is able to eliminate greater than 99.99% of an HTLV-I infected T-cell population. In the presence of ammonium chloride or monensin, respectively, a 3.5- and 20-fold greater cytoreduction of HTLV-I infected T-cells is achieved. Combined treatment with anti-TAC-A and monensin may offer an efficient and highly selective means of purging bone marrow of patients with adult T-cell leukemia, which may then be used for autologous marrow transplantation.
D000643:Ammonium Chloride / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001853:Bone Marrow / Q000187:drug effects; D001854:Bone Marrow Cells; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D017977:Deltaretrovirus / Q000254:growth & development*; D004357:Drug Synergism; D006801:Humans; D008247:Lysosomes / Q000187:drug effects; D008985:Monensin / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000276:immunology*; D015375:Receptors, Interleukin-2; D012192:Retroviridae Infections / Q000276:immunology*; D012276:Ricin / Q000008:administration & dosage*; D013601:T-Lymphocytes / Q000276:immunology / Q000382:microbiology*
D000911:Antibodies, Monoclonal; D011971:Receptors, Immunologic; D015375:Receptors, Interleukin-2; D000643:Ammonium Chloride; D012276:Ricin; D008985:Monensin