Adult T cell leukemia: a potential target for ricin A chain immunotoxins.
Adult T cell leukemia (ATL) is an almost uniformly fatal malignancy of mature T cells associated with human T cell leukemia/lymphoma virus type 1 (HTLV-1) infection. Cells from this leukemia are characterized by the expression of large numbers of receptors for interleukin 2 (IL-2). In an attempt to prepare an immunotoxin with selective cytotoxicity for ATL cells, we conjugated anti-Tac, a monoclonal anti-IL-2 receptor antibody, to purified ricin A chains. Although unmodified anti-Tac had no effect on the protein synthesis of these cells, anti-Tac-ricin A chain conjugates produced half-maximal inhibition of protein synthesis in HTLV-1-infected leukemic T cell lines at concentrations of 2 to 6 X 10(-10) mol/L (ID50). An essentially identical ID50 was obtained with leukemic peripheral blood T lymphocytes isolated from two patients with ATL. In contrast, half-maximal inhibition of protein synthesis in HTLV-uninfected, IL-2 receptor-negative T and B cell lines required 200- to 1,000-fold higher concentrations of anti-Tac-ricin A chain conjugates. Both unconjugated anti-Tac and immunoaffinity-purified IL-2 completely inhibited the toxic effects of anti-Tac-ricin A, confirming the specificity of the conjugate-IL-2 receptor interaction. Clonogenic assays demonstrated that anti-Tac-ricin A chain was able to eliminate greater than 99.9% of an HTLV-1-infected T cell population at concentrations only marginally affecting IL-2 receptor-negative cells. The data presented demonstrate that anti-Tac-ricin A is selectively cytotoxic for HTLV-1-infected leukemic T cells in vitro and raises the future possibility of specific therapeutic intervention with immunotoxins in this disease.
Krönke
M
M
Depper
J M
JM
Leonard
W J
WJ
Vitetta
E S
ES
Waldmann
T A
TA
Greene
W C
WC
D000328:Adult; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000954:Antigens, Surface / Q000276:immunology; D001666:Binding Sites, Antibody; D001798:Blood Proteins / Q000096:biosynthesis; D006801:Humans; D007137:Immunoglobulin alpha-Chains; D007938:Leukemia / Q000628:therapy*; D051379:Mice; D011971:Receptors, Immunologic / Q000276:immunology; D015375:Receptors, Interleukin-2; D012276:Ricin / Q000627:therapeutic use*; D013601:T-Lymphocytes; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7
D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D001798:Blood Proteins; D007137:Immunoglobulin alpha-Chains; D011971:Receptors, Immunologic; D015375:Receptors, Interleukin-2; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D012276:Ricin