TY - JOUR
T1 - Adult T cell leukemia
T2 - A potential target for ricin A chain immunotoxins
AU - Kronke, M.
AU - Depper, J. M.
AU - Leonard, W. J.
AU - Vitetta, E. S.
AU - Waldmann, T. A.
AU - Greene, W. C.
PY - 1985
Y1 - 1985
N2 - 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 inhibiton 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 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.
AB - 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 inhibiton 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 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.
UR - http://www.scopus.com/inward/record.url?scp=0021819830&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0021819830&partnerID=8YFLogxK
U2 - 10.1182/blood.v65.6.1416.bloodjournal6561416
DO - 10.1182/blood.v65.6.1416.bloodjournal6561416
M3 - Article
C2 - 2986744
AN - SCOPUS:0021819830
SN - 0006-4971
VL - 65
SP - 1416
EP - 1421
JO - Blood
JF - Blood
IS - 6
ER -