Daclizumab (Anti-Tac, Zenapax) in the Treatment of Leukemia/Lymphoma
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Oncogene (2007) 26, 3699–3703 & 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00 www.nature.com/onc REVIEW Daclizumab (anti-Tac, Zenapax) in the treatment of leukemia/lymphoma TA Waldmann Metabolism Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA Daclizumab (Zenapax) identifies the alpha subunit of the an IL-2R alpha subunit. Furthermore, there was the interleukin-2 (IL-2) receptor and blocks the interaction of issueof thestructural explanation for thegreat this cytokine with its growth factor receptor. The scientific difference in affinity between high- (10À11 M) and low- basis for the choice of the IL-2 receptor alpha subunit as a 10À8 M) affinity receptors. We resolved these issues in target for monoclonal antibody-mediated therapy of parallel with investigators in the laboratory of Warren leukemia/lymphoma is that very few normal cells express Leonard by co-discovering a novel non-Tac 70 kDa IL-2 IL-2R alpha, whereas the abnormal T cells in patients with binding protein, IL-2R beta, that is shared with IL-15 an arrayof lymphoid malignancies express this receptor. In (Sharon et al., 1986; Tsudo et al., 1986). Subsequently, 1997, daclizumab was approved bythe FDA for use in the the high-affinity IL-2 receptor was shown to also include prevention of renal allograft rejection. In addition, anti-Tac the64 kDa IL-2R g chain (or gc) shared by IL-4, IL-7, provided effective therapyfor select patients with T-cell IL-9, IL-15 and IL-21 (Sugamura et al., 1996)). The malignancies and an arrayof inflammatoryautoimmune cellular distribution of the55 kDa subunit of theIL-2 disorders. Finally, therapy with this antibody armed with receptor defined using the anti-Tac monoclonal anti- 90Y has led to clinical responses in the majorityof patients body revealed that o5% of unstimulated human with adult T-cell leukemia. These insights concerning the peripheral blood T cells react with the anti-Tac IL-2/IL-2 receptor system facilitated the development of monoclonal antibody (Waldmann, 1989). However, effective daclizumab antibodytherapyfor select patients high IL-2R alpha expression was demonstrated on an with leukemia/lymphoma. array of abnormal cells including the malignant cells in Oncogene (2007) 26, 3699–3703. doi:10.1038/sj.onc.1210368 patients with adult T-cell leukemia (ATL), cutaneous T-cell lymphoma, anaplastic large-cell lymphoma, hairy Keywords: IL-2 receptor; adult T-cell leukemia; anti-Tac; cell B-cell leukemia, and the Reed Sternberg and monoclonal antibody associated polyclonal T cells in Hodgkin’s disease as well as acute and chronic granulocytic leukemia cells (Waldmann 1986, 1989). Furthermore, such abnormal- ities of IL-2R alpha expression have been demonstrated in the autoimmune diseases such as rheumatoid Introduction arthritis, systemic lupus erythematosus, aplastic anemia, insulin-dependent diabetes mellitus, Crohn’s disease, In 1981, in our laboratory, Uchiyama reported the sarcoidosis, scleroderma, noninfectious uveitis, chronic development of the anti-Tac monoclonal antibody activehepatitis,multiplesclerosis and tropical spastic directed toward the interleukin-2 (IL-2) receptor alpha paraparesis (TSP) (Waldmann, 1989, 2003). Further- subunit (Uchiyama et al., 1981a, b). The IL-2 receptor more, such elevations of IL-2 R alpha expression have subunit identified by the murine monoclonal antibody, been detected in the serum of patients during organ anti-Tac, was shown to be a densely glyclosylated, allograft rejection and from those with graft-versus-host sulfated integral membrane protein with an apparent Mr disease (Rubin and Nelson, 1990). This discordance in of 55 000 (Leonard et al., 1982, 1984, 1985). TheIL-2 IL-2R alpha expression between normal cells, which we receptor is composed of 272 amino acids including a 21 wish to retain that do not express the receptor, and amino-acid signal peptide, a single hydrophobic mem- abnormal cells in disease that express the receptor brane region of 19 amino acids and a very short 13 provided the scientific basis for the use of anti-Tac and amino-acid cytoplasmic domain (Leonard et al., 1984). its humanized form, daclizumab, for an array of clinical The cytoplasmic domain of the IL-2 receptor alpha conditions including CD25-expressing leukemias and subunit appeared to be too small for enzymatic lymphomas, autoimmune diseases and to prevent function. Furthermore, it did not contain a cytoplasmic allograft rejection. In 1997 daclizumab, the humanized tyrosine. Thus, the issue was how the IL-2 receptor form of this antibody was approved by the FDA for use signals were transduced to the nucleus if there was only in the prevention of renal allograft rejection (Vincenti et al., 1998; Wiseman and Faulds, 1999). In addition, we and our collaborators demonstrated that daclizumab is Correspondence: Dr TA Waldmann, Metabolism Branch, Center for of value in the treatment of patients with non-infectious Cancer Research, National Cancer Institute, NIH, Building 10, Room 4N115, 10 Center Drive 1374, Bethesda, MD 20892-1374, USA. uveitis, multiple sclerosis and the neurological disease, E-mail: [email protected] human T-cell lymphotropic virus I (HTLV-I)-associated Daclizumab treatment of leukemia TA Waldmann 3700 myelopathy (HAM)/TSP (Lehky et al., 1998; Nussenblatt cells in Hodgkin’s disease. We developed a murine model et al., 1999; Bielekova et al., 2004). Others demonstrated of human ATL (MET-I) to evaluate the different therapeutic efficacy with daclizumab in patients with therapeutic approaches involving daclizumab (Phillips pure red cell aplasia, aplastic anemia and psoriasis et al., 2000). To establish this murine model of human (Krueger et al., 2000; Maciejewski et al., 2003; Sloand ATL, we injected human ATL cells into non-obese, et al., 2006). In addition, unmodified daclizumab as well diabetic (NOD), severe combined immunodeficient as daclizumab armed with toxins and radionuclides has (SCID) mice(Phillips et al., 2000). Thetransferred proven effective in the treatment of select patients with disease progressed to death of the mice after 4–6 weeks. T-cell leukemias and lymphomas and Hodgkin’s disease Various forms of antibody directed to the IL-2 receptor (Waldmann et al., 1988, 1993, 1995; Kreitman et al., alpha subunit including daclizumab, thehumanizedform 2000). These latter studies will be the primary focus of of anti-Tac, murineanti-Tac and the7G7/B6 monoclonal this review. antibody that targets this IL-2 receptor subunit at an epitope other than the IL-2 and anti-Tac binding sites, significantly delayed the progression of the leukemia and Daclizumab therapyfor patients receiving organ prolonged the survival of tumor-bearing mice (Phillips allografts et al., 2000). Thus, it appeared that in this MET-I model, daclizumab and the other IL-2R alpha receptor-directed Organ allograft rejection is associated with an elevated antibodies acted by a mechanism that had not been serum-soluble IL-2R alpha level that is linked to the anticipated. The prevailing view was that the antibodies activation of T cells mediated by major histocompat- to theIL-2R alpha receptor havean effectiveaction that ibility complex mismatch recognition. Two major phase is limitedto theblockadeof theinteraction of IL-2 with III studies were used to evaluate the clinical efficacy of its growth factor receptor, thereby inducing cytokine daclizumab linked to immunosuppression compared deprivation-mediated apoptotic cell death (Depper et al., with a placebo with the same immunosuppressive 1984). However, the 7G7/B6 monoclonal antibody regimen (Vincenti et al., 1998; Nashan et al., 1999). In defines an epitope on the IL-2 receptor subunit that is the two phase III multicenter studies, which were not involved in IL-2 binding. Furthermore, in the MET-I double-blind and randomized, the end points were the model, the human ATL cells obtained from the spleen of incidence of biopsy-proven rejection that occurred in the the leukemia-bearing mice did not produce human IL-2 first 6 months after transplantation. A total of 535 nor did they respond to murine IL-2. We considered an patients was studied. In both studies, the patients alternativemechanism of action of theanti-CD25 receiving daclizumab and immunosuppression had a antibodies, by requiring FcR receptor expression on host significantly reduced biopsy confirmed number of cells such as monocytes or polymorphonuclear leuko- episodes of rejection when compared with the patient cytes. To test this hypothesis, we evaluated daclizumab in groups receiving standard immunosuppression plus thetherapy of theMET-I modelin both wild-typeSCID/ placebo. In one of the studies, the patients on NOD miceas well as in SCID/NOD FcR gÀ/À micethat daclizumab therapy had better graft function, reduced lacked effective FcRgI, FcRgIII and FcRgIV receptors requirement for antithrombocyte or antilymphocyte (Zhang et al., 2004). TheIL-2R alpha directedmono- globulin, lower administered corticosteroid doses, a clonal antibody, daclizumab, that was effective in wild- lower incidence of cytomegalovirus infection, a lower typemicewas not activein theseFcR gamma À/À mice, incidence of infectious deaths and a greater 1-year supporting the view that an action requiring Fc-receptor survival than did the patients on placebo (Nashan et al., expression on monocytes or polymorphonuclear leuko- 1999). On the basis of the efficacy in these multicenter cytes was probably involved in the therapeutic efficacy in trials and the lack of associated increase in toxicity,