Adult T Cell Leukemia: A Potential Target for Ricin A Chain Immunotoxins

• Published in: Blood 1985-06, Vol.65 (6), p.1416-1421
• Main Authors: Kronke, Martin, Depper, Joel M., Leonard, Warren J., Vitetta, Ellen S., Waldmann, Thomas A., Greene, Warner C.
• Format: Article
• Language: English
• Subjects: Adult; Animals; Antibodies, Monoclonal - therapeutic use; Antigens, Surface - immunology; Binding Sites, Antibody; Biological and medical sciences; Blood Proteins - biosynthesis; Hematologic and hematopoietic diseases; Humans; Immunoglobulin alpha-Chains; Leukemia - therapy; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Mice; Receptors, Immunologic - immunology; Receptors, Interleukin-2; Ricin - therapeutic use; T-Lymphocytes; Tumor Necrosis Factor Receptor Superfamily, Member 7
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V65.6.1416.bloodjournal6561416

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 mono-clonal 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 >99.9% of an HTLV-1-infected T cell population at concentrations only marginally affecting IL-2 recep-tor-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 immu-notoxins in this disease. © 1985 by Grune & Stratton, Inc.