Phase I trial of an interleukin-2 (IL-2) fusion toxin (DAB486IL-2) in hematologic malignancies expressing the IL-2 receptor.

DAB486IL-2 is a recombinant fusion toxin in which the native receptor binding domain of diphtheria toxin has been replaced with human interleukin-2 (IL-2). It selectively binds and intoxicates only cells that bear the high-affinity receptor for IL-2. In the first clinical trial of a genetically engineered ligand fusion-toxin, we have treated 18 patients with chemotherapy-resistant IL-2 receptor expressing hematologic malignancies with escalating doses of DAB486IL-2. The maximal tolerated dose of a daily intravenous bolus of DAB486IL-2 was 0.1 mg/kg per day for 10 doses, established by asymptomatic, reversible elevations of hepatic transaminases without changes in other tests of liver function. Other mild reversible side effects noted were rash, nausea, elevated creatinine, chest tightness, and fever. Pharmacokinetic analysis showed a monophasic clearance of 5.8 +/- 0.7 minutes with peak levels of 3,549 +/- 1,041 mg/mL at the 0.1 mg/kg dose. Approximately 50% of patients developed an antibody response to diphtheria toxin or DAB486IL-2. The presence of such antibodies did not preclude patients from experiencing an antitumor response as four of the six patients with antitumor effect had detectable antibody titers. Although this was a phase I trial designed to define the safety of DAB486IL-2, remissions were observed in three patients lasting from 5 to over 18 months. The ability to achieve significant tumor reductions in this group of heavily treated patients is encouraging and suggests additional trials are warranted in hematologic malignancies.

[1]  S. Rosen,et al.  Phase I trial of H65-RTA immunoconjugate in patients with cutaneous T-cell lymphoma. , 1991, Blood.

[2]  Kendall A. Smith,et al.  Interleukin 2 receptor‐targeted cytotoxicity. Receptor binding requirements for entry of a diphtheria toxin‐related interleukin 2 fusion protein into cells , 1990, European journal of immunology.

[3]  T. Chisesi,et al.  Evaluation of serum levels of soluble interleukin‐2 receptor in patients with chronic lymphoproliferative disorders of T‐lymphocytes , 1989, Cancer.

[4]  K. Yamaguchi,et al.  Elevated serum levels of soluble interleukin-2 receptors in HTLV-I--associated myelopathy. , 1989, The Journal of laboratory and clinical medicine.

[5]  F. Menestrina,et al.  Serum levels of soluble interleukin‐2 receptor in hairy cell leukaemia: a reliable marker of neoplastic bulk , 1989, British journal of haematology.

[6]  T. Uchiyama,et al.  Elevated serum-soluble interleukin-2 receptor (Tac antigen) levels in chronic myelogenous leukemia patients with blastic crisis. , 1989, Blood.

[7]  G. Marti,et al.  Expression of interleukin-2 receptor beta subunit in hematopoietic malignancies. , 1989, Blood.

[8]  D. Longo,et al.  Elevated serum levels of soluble Tac peptide in adult T-cell leukemia: correlation with clinical status during chemotherapy. , 1988, Annals of internal medicine.

[9]  N. Kay,et al.  The malignant B cells from B-chronic lymphocytic leukemia patients release TAC-soluble interleukin-2 receptors. , 1988, Blood.

[10]  T. Strom,et al.  Interleukin2 Receptor-mediated Action of a DiphtheriaToxin-related Interleukin2 Fusion Protein , 1988 .

[11]  D. Longo,et al.  Serum soluble IL-2 receptor as a tumor marker in patients with hairy cell leukemia. , 1988, Blood.

[12]  R. Foà,et al.  High serum levels of soluble interleukin 2 receptor in patients with B chronic lymphocytic leukemia. , 1987, Blood.

[13]  B. Cullen,et al.  A second human interleukin-2 binding protein that may be a component of high-affinity interleukin-2 receptors , 1987, Nature.

[14]  Y. Yamamoto,et al.  Heterogeneity in response to interleukin 2 and interleukin 2-producing ability of adult T cell leukemic cells. , 1987, Journal of immunology.

[15]  T. Waldmann,et al.  Expression of functional IL 2 receptors by lipopolysaccharide and interferon-gamma stimulated human monocytes. , 1987, Journal of immunology.

[16]  W. Greene,et al.  Interleukin 2 binding molecule distinct from the Tac protein: analysis of its role in formation of high-affinity receptors. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[17]  D. Blayney,et al.  Distribution of lymphocytes with interleukin-2 receptors (TAC antigens) in reactive lymphoproliferative processes, Hodgkin's disease, and non-Hodgkin's lymphomas. An immunohistologic study of 300 cases. , 1987, The American journal of pathology.

[18]  J. Strauchen,et al.  IL-2 receptor expression in human lymphoid lesions. Immunohistochemical study of 166 cases. , 1987, The American journal of pathology.

[19]  K. Kato,et al.  Interleukin 2 high-affinity receptor expression requires two distinct binding proteins , 1987, The Journal of experimental medicine.

[20]  W. Bishai,et al.  Diphtheria toxin receptor binding domain substitution with interleukin-2: genetic construction and properties of a diphtheria toxin-related interleukin-2 fusion protein. , 1987, Protein engineering.

[21]  T. Waldmann,et al.  Demonstration of a non-Tac peptide that binds interleukin 2: a potential participant in a multichain interleukin 2 receptor complex. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[22]  B. Cullen,et al.  Novel interleukin-2 receptor subunit detected by cross-linking under high-affinity conditions. , 1986, Science.

[23]  B. Löwenberg,et al.  Acute lymphoblastic leukemia and non-Hodgkin's lymphoma of T lineage: colony-forming cells retain growth factor (interleukin 2) dependence. , 1986, Blood.

[24]  T. Waldmann.  The structure, function, and expression of interleukin-2 receptors on normal and malignant lymphocytes. , 1986, Science.

[25]  A. Okayama,et al.  Clinical analysis of 33 patients with adult T‐cell leukemia (ATL)‐diagnostic criteria and significance of high‐ and low‐risk ATL , 1986, International journal of cancer.

[26]  T. Waldmann,et al.  Only high-affinity receptors for interleukin 2 mediate internalization of ligand. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[27]  Relationship of exposure to human T lymphotropic virus and T helper cells in homosexual men. , 1986, AIDS research.

[28]  J. Lowenthal,et al.  Intracellular pathway of interleukin 2 following receptor‐mediated endocytosis , 1986, European journal of immunology.

[29]  J. Platt,et al.  Lymphocyte populations and TAC-antigen in diffuse B-cell lymphomas. , 1986, Leukemia research.

[30]  D. Nelson,et al.  Soluble interleukin 2 receptors are released from activated human lymphoid cells in vitro. , 1985, Journal of immunology.

[31]  T. Waldmann,et al.  Interleukin 2 receptor (Tac antigen) expression in HTLV-I-associated adult T-cell leukemia. , 1985, Cancer research.

[32]  J. Yodoi,et al.  Interleukin-2 receptor (Tac antigen) expressed on adult T cell leukemia cells. , 1985, The Journal of clinical investigation.

[33]  J. Lowenthal,et al.  Similarities between interleukin-2 receptor number and affinity on activated B and T lymphocytes , 1985, Nature.

[34]  W. Greene,et al.  Low and high affinity cellular receptors for interleukin 2. Implications for the level of Tac antigen , 1984, The Journal of experimental medicine.

[35]  J. Murphy,et al.  Monoclonal antibody analysis of diphtheria toxin--I. Localization of epitopes and neutralization of cytotoxicity. , 1984, Molecular immunology.

[36]  D. Mann,et al.  Transformation of human umbilical cord blood T cells by human T-cell leukemia/lymphoma virus. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[37]  T. Waldmann,et al.  Rearrangement and expression of immunoglobulin genes and expression of Tac antigen in hairy cell leukemia. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[38]  R. Rossen,et al.  Immunological characterization of homosexual males. , 1983, Cancer research.

[39]  Kendall A. Smith,et al.  Quantitation, Specificity, and Biological Relevance* , 1981 .

[40]  J. Murphy,et al.  Determination of Corynebacterium diphtheriae toxigenicity by a colorimetric tissue culture assay , 1978, Journal of clinical microbiology.