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, in this model of ATL (Zhang et al., 2004). Thus, in terms of 1997 the FDA provided marketing clearance for the use its modeof action, daclizumab acts by a numberof of daclizumab in the prevention of acute kidney mechanisms that includeblockadeof theinteraction of transplant rejection. In subsequent studies, in clinical IL-2 with its receptor as well as by an FcR receptor trials involving a large group of recipients, daclizumab requiring mechanism. Recently, yet another mechanism provided a reduction in the rejection episodes in patients of action has been reported. In particular, in humans the receiving renal, liver, cardiac and pancreatic islet interaction of daclizumab with the IL-2 receptor was transplants (Beniaminovitz et al., 2000; Eckhoff et al., associated with a 4- to 20-fold increase in the number of 2000; Shapiro et al., 2000). circulating CD56 bright, CD25 expressing, IL-10 secret- ing natural killer cells that mediate negative immunomo- dulatory actions (Li et al., 2005; Bielekova et al., 2006). Daclizumab therapyof IL-2R alpha (CD25) expressing leukemia/lymphoma Clinical trials of daclizumab in IL-2R alpha (CD25) IL-2R alpha, the target of daclizumab, is expressed by the directed monoclonal antibody-mediated therapy of human malignant cells from select patients with ATL/lymphoma, leukemia/lymphoma cutaneous T-cell lymphomas, anaplastic large-cell lymphoma, hairy cell leukemia, granulocytic neoplasms and Thefirst clinical trials involving murineanti-Tac were the Reed–Sternberg cells and associated polyclonal T directed toward the treatment of patients with the

Oncogene Daclizumab treatment of leukemia TA Waldmann 3701 retrovirus HTLV-I-associated ATL (Waldmann et al., Waldmann, 2000). An escalation analysis was used to 1988). The retrovirus HTLV-I encodes a transactivating define the dose required to maintain saturation of the protein, tax, that stimulates the transcription of IL-2 receptor. In patients with high numbers of numerous host genes, including those of IL-2 and IL- leukemic/lymphoma cells, a dose of 8 mg/kg of daclizu- 2R alpha (Uchiyama et al., 1977; Jeang, 2001). The mab every 3 weeks was required to maintain saturation malignant ATL cells constitutively expressed approxi- of the IL-2R alpha expressed on the lymph node cells of mately 10 000–28 000 IL-2R alpha receptor subunits the patients. Daclizumab therapy was associated with identified by the anti-Tac monoclonal antibody. These partial responses that were predominantly observed in observations stimulated us to perform a therapeutic trial patients with smoldering or chronic ATL who appear to with the unmodified murine version of the anti-Tac bein theIL-2/IL-2R alpha autocrinephaseof their monoclonal antibody. Seven of the 19 patients devel- disease. oped mixed (one case), partial (four cases) or complete (two cases) responses (Waldmann et al., 1993). In one case, the remission has persisted for more than 17 years Daclizumab cytotoxic conjugates: immunotoxin-linked after initiation of a short course of antibody therapy. monoclonal antibodies None of the patients treated suffered any untoward reactions. However, six of 10 patients treated with the A limitation in theuseof daclizumab for thetreatment murine antibody that developed clinical remissions of T-cell leukemia/lymphoma is the fact that like other produced antibodies to this therapeutic agent. Addi- unmodified monoclonal antibodies it is relatively tional limitations in themurineanti-Tac antibody were ineffective as a cytocidal agent. This limited efficacy that it had a short in vivo survival of only 50 h in the of unmodified daclizumab in leukemia/lymphoma circulation of humans, precluding its long-term use as an therapy led to the alternative approach of using agent to provide the antibody-mediated saturation of this antibody as a carrier of cytotoxic agents such as receptors that is required to prevent the interaction of toxins or radionuclides. In one series of studies in the growth factor IL-2 with its receptor. An additional conjunction with Krietman and Pastan, we evaluated problem was that the antibody did not function in theclinical efficacyof a fusion immunotoxin that antibody-dependent cellular cytotoxicity (ADCC) with involved a truncated version of Pseudomonas exotoxin human mononuclear cells and was relatively ineffective A (PE38) linked genetically to the Fv region of anti- as a cytocidal agent. Tac (Kreitman et al., 2000). Theanti-Tac Fv PE38 We joined with Cary Queen to generate a humanized (LMB-2) was evaluated in a Phase I/II clinical trial version of the anti-Tac monoclonal antibody (daclizu- that involved 35 patients who had leukemia/lymphoma mab) that is reactive with the human IL-2R alpha that expressed CD25 (IL-2R alpha). In this trial, there subunit (Queen et al., 1989; Junghans et al., 1990). In were eight responders including four with hairy cell this effort, the human IgG1 framework sequence from leukemia and one each with chronic lymphocytic the Eu-myeloma antibody was chosen to be as homo- leukemia, Hodgkin’s disease, cutaneous T-cell lympho- logous as possibleto theoriginal mouseantibody to ma and ATL. reduce any deformation of the mouse complementarity determining regions (CDRs). Second, computer model- ing was used to identify several framework amino acids Daclizumab armed with radionuclide from themouseantibody that interactwith theCDRs or directly with antigen. These amino acids were retained In an alternative approach, anti-Tac and its humanized as were the murine or more typical human amino acids form, daclizumab, were armed with radionuclides for and were transferred to the human framework along use in systemic radioimmunotherapy of leukemia/ with the murine CDRs. This latter action proved to be lymphoma. Our systemic radioimmunotherapy clinical critical in generating a high-affinity humanized anti-Tac trials havefocusedon theuseof 90Y linked to anti-Tac. (daclizumab). The parent murine anti-Tac molecule had Eighteen patients with ATL were treated with a total of an affinity of 9 Â 10À9 M to its target IL-2R alpha, 55 doses of 90Y-labeled anti-Tac involving 5–15 Ci of whereas the hyperchimeric humanized version had an 90Y-labeled anti-Tac per patient dose (Waldmann et al., affinity of 3 Â 10À9 M – still very high (Queen et al., 1995). Ten of the evaluable patients responded to 90Y- 1989). Theoriginal humanizedanti-Tac monoclonal anti-Tac with partial (eight) or complete (two) remis- antibody, daclizumab, and the parent murine version sions. Theonly meaningful (>grade3) toxicity was manifested comparable inhibition of the T-cell prolif- limited to the hematopoietic system. Recently, we have eration in response to the tetanus-toxoid antigen also had encouraging results with the humanized form indicating that humanization was not associated with of 90Y daclizumab in the treatment of patients with the loss of functional activity. Furthermore, in contrast Hodgkin’s disease where there were seven complete to the murine version, daclizumab manifested ADCC responses (CRs) and five partial responses (PRs) with human mononuclear cells (Junghans et al., 1990). observed in the 17 patients with Hodgkin’s disease Finally, the humanized version daclizumab had a treated with repeated doses of 15 Ci of 90Y (O’Mahony prolonged terminal t1/2 of 20 7 0.6 days in humans. et al., 2006). Thus, it appears that daclizumab armed Daclizumab is being evaluated in clinical trials of with theradionuclide 90Y provides meaningful therapy patients with CD25-expressing ATL (Morris and for select patients with ATL and Hodgkin’s disease.

Oncogene Daclizumab treatment of leukemia TA Waldmann 3702 Future directions select alpha-emitting radionuclides such as astatine-211 in lieu of the beta-emitting radionuclide yttium-90 A number of approaches could be exploited to whose cross-ﬁre effect is relatively ineffective when optimizetheaction of daclizumab in thetherapyof directed toward isolated malignant cells (Zhang et al., IL-2R alpha (CD25) expressing lymphoid leukemias 2006). and lymphomas. A paradigm is being established that In summary, basic insights concerning the IL-2/IL-2R monoclonal antibodies will not be used in monother- system, developed using the daclizumab monoclonal apy of human malignancy, but rather will be used in antibodies, when coupled with the experience with this association with an array of agents including che- humanized antibody in clinical trials are providing an motherapeutic agents that utilize a different mode of effective monoclonal antibody-mediated approach for action. In the murine MET-I model, there was the treatment of select patients with IL-2R alpha considerable synergy when the daclizumab antibody (CD25) expressing leukemia and lymphoma. was used in conjunction with Velcade (bortezoumib) or with ﬂavopiridol (Tan and Waldmann, 2002; Zhang Acknowledgements et al., 2005). Furthermore, another insight derived from the studies involving systemic radioimmunother- This work was supported by the Intramural Research Program apy in preclinical models of adult human T-cell of the National Cancer Institute, NIH. All animal studies were leukemia should be translated into clinical trials. In approved by the Animal Care and Use Committee of the particular, patients who have T-cell leukemia with its National Cancer Institute (NCI) and all clinical investigations isolated cells could be treated with antibodies linked to received prior approach by the IRB, NCI.

References

Beniaminovitz A, Itescu S, Lietz K, Donovan M, Burke EM, Lehky TJ, Levin MC, Kubota R, Bamford RN, Flerlage AN, Groff BD et al. (2000). Prevention of rejection in cardiac Soldan SS et al. (1998). Reduction in HTLV-I proviral load transplantation by blockade of the interleukin-2 receptor and spontaneous lymphoproliferation in HTLV-I-associated with a monoclonal antibody. N Engl J Med 342: 613–619. myelopathy/tropical spastic paraparesis patients treated Bielekova B, Catalfamo M, Reichert-Scrivner S, Packer A, with humanized anti-Tac. Ann Neurol 44: 942–947. Cerna M, Waldmann TA et al. (2006). Regulatory Leonard WJ, Depper JM, Crabtree GR, Rudikoff S, CD56(bright) natural killer cells mediate immunomodula- Pumphrey J, Robb RJ et al. (1984). Molecular cloning and tory effects of IL-2Ralpha-targeted therapy (daclizumab) in expression of cDNAs for the human interleukin-2 receptor. multiplesclerosis. Proc Natl Acad Sci USA 103: 5941–5946. Nature 311: 626–631. Bielekova B, Richert N, Howard T, Blevins G, Markovic- Leonard WJ, Depper JM, Kronke M, Robb RJ, Waldmann Plese S, McCartin J et al. (2004). Humanized anti-CD25 TA, Greene WC. (1985). The human receptor for T-cell (daclizumab) inhibits disease activity in multiple sclerosis growth factor. Evidence for variable post-translational patients failing to respond to interferon beta. Proc Natl processing phosphorylation sulfation and the ability of Acad Sci USA 101: 8705–8708. precursor forms of the receptor to bind T-cell growth factor. Depper JM, Leonard WJ, Kronke M, Noguchi PD, J Biol Chem 260: 1872–1880. Cunningham RE, Waldmann TA et al. (1984). Regulation Leonard WJ, Depper JM, Uchiyama T, Smith KA, Waldmann of interleukin 2 receptor expression: effects of phorbol TA, Greene WC. (1982). A monoclonal antibody that appears diester, phospholipase C, and reexposure to lectin or to recognize the receptor for human T-cell growth factor: antigen. J Immunol 133: 3054–3061. partial characterization of the receptor. Nature 300: 267–269. Eckhoff DE, McGuire B, Sellers M, Contreras J, Frenette L, Li Z, Lim WK, Mahesh SP, Liu B, Nussenblatt RB. (2005). Young C et al. (2000). The safety and efficacy of a two-dose Cutting edge: in vivo blockade of human IL-2 receptor daclizumab (Zenapax) induction therapy in liver transplant induces expansion of CD56(bright) regulatory NK cells in recipients. Transplantation 69: 1867–1872. patients with active uveitis. J Immunol 174: 5187–5191. Jeang KT. (2001). Functional activities of the human T-cell Maciejewski JP, Sloand EM, Nunez O, Boss C, Young NS. leukemia virus type I Tax oncoprotein: cellular signaling (2003). Recombinant humanized anti-IL-2 receptor anti- through NF-kappa B. Cytokine Growth Factor Rev 12: 207–217. body (daclizumab) produces responses in patients with Junghans RP, Waldmann TA, Landolfi NF, Avdalovic NM, moderate aplastic anemia. Blood 102: 3584–3586. Schneider WP, Queen C. (1990). Anti-Tac-H a humanized Morris JC, Waldmann TA. (2000). Advances in interleukin 2 antibody to the interleukin 2 receptor with new features for receptor targeted treatment. Ann Rheum Dis 59(Suppl 1): immunotherapy in malignant and immune disorders. Cancer i109–i114. Res 50: 1495–1502. Nashan B, Light S, HardieIR, Lin A, Johnson JR. (1999). Kreitman RJ, Wilson WH, White JD, Stetler-Stevenson M, Reduction of acute renal allograft rejection by daclizumab. JaffeES, Giardina S et al. (2000). PhaseI trial of Daclizumab DoubleTherapyStudy Group. Transplantation recombinant immunotoxin anti-Tac(Fv)-PE38 (LMB-2) in 67: 110–115. patients with hematologic malignancies. J Clin Oncol 18: Nussenblatt RB, Fortin E, Schiffman R, Rizzo L, Smith J, 1622–1636. Van VP et al. (1999). Treatment of noninfectious inter- Krueger JG, Walters IB, Miyazawa M, Gilleaudeau P, Hakimi mediate and posterior uveitis with the humanized anti-Tac J, Light S et al. (2000). Successful in vivo blockadeof CD25 mAb: a phaseI/II clinical trial. Proc Natl Acad Sci USA 96: (high-affinity interleukin-2 receptor) on T cells by adminis- 7462–7466. tration of humanized anti-Tac antibody to patients with O’Mahony D, Morris JC, Carrasquillo JA, LeN, Paik CH, psoriasis. J Am Acad Dermatol 43: 448–458. Whatley M et al. (2006). PhaseI/II study of Yttrium-90

Oncogene Daclizumab treatment of leukemia TA Waldmann 3703 labeled humanized anti-Tac (HAT) monoclonal antibody Expression of Tac antigen on activated cytotoxic killer T and calcium DTPA in CD25-expressing malignancies. cells suppressor cells and on one of two types of helper T J Nucl Med 47: 98P. cells. J Immunol 126: 1398–1403. Phillips KE, Herring B, Wilson LA, Rickford MS, Zhang M, Uchiyama T, Yodoi J, Sagawa K, Takatuski K, Uchino H. Goldman CK et al. (2000). IL-2R alpha directed mono- (1977). Adult T-cell leukemia: clinical and hematologic clonal antibodies provide effective therapy in a murine features of 16 cases. Blood 50: 481–492. model of adult T-cell leukemia by a mechanism other than Vincenti F, Kirkman R, Light S, Bumgardner G, Pescovitz M, blockadeof IL-2/IL-2R alpha interaction. Cancer Res 60: Halloran P et al. (1998). Interleukin-2-receptor blockade 6977–6984. with daclizumab to prevent acute rejection in renal Queen C, Schneider WP, Selick HE, Payne PW, Landolfi NF, transplantation: daclizumab tripletherapystudy group. N Duncan JF et al. (1989). A humanized antibody that binds Eng J Med 338: 161–165. to the interleukin 2 receptor. Proc Natl Acad Sci USA 86: Waldmann TA. (1986). The structure, function, and expres- 10029–10033. sion of interleukin-2 receptors on normal and malignant Rubin LA, Nelson DL. (1990). The soluble interleukin-2 lymphocytes. Science 232: 727–732. receptor: biology function and clinical application. Ann Waldmann TA. (1989). The multi-subunit interleukin-2 Intern Med 113: 619–627. receptor. Annu Rev Biochem 58: 875–911. Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Waldmann TA. (2003). The meandering 45-year odyssey of a Warnock GL et al. (2000). Islet transplantation in seven clinical immunologist. Annu Rev Immunol 21: 1–27. patients with type 1 diabetes mellitus using a glucocorticoid- Waldmann TA, Goldman CK, Bongiovanni KF, Sharrow SO, free immunosuppressive regimen. N Engl J Med 343: Davey MP, Cease KB et al. (1988). Therapy of patients with 230–238. human T-cell lymphotrophic virus I-induced adult T-cell Sharon M, Klausner RD, Cullen BR, Chizzonite R, Leonard leukemia with anti-Tac a monoclonal antibody to the WJ. (1986). Novel interleukin-2 receptor subunit detected by receptor for interleukin-2. Blood 72: 1805–1816. cross-linking under high-affinity conditions. Science 234: Waldmann TA, WhiteJD, Carrasquillo JA, ReynoldsJC, Paik 859–863. CH, Gansow OA et al. (1995). Radioimmunotherapy of Sloand EM, Scheinberg P, Maciejewski J, Young NS. (2006). interleukin-2R alpha-expressing adult T-cell leukemia with Brief communication: successful treatment of pure red-cell Yttrium-90-labeled anti-Tac. Blood 86: 4063–4075. aplasia with an anti-interleukin-2 receptor antibody Waldmann TA, WhiteJD, Goldman CK, Top L, Grant A, (daclizumab). Ann Intern Med 144: 181–185. Bamford R et al. (1993). The interleukin-2 receptor: a target Sugamura K, Asao H, Kondo M, Tanaka N, Ishii N, Ohbo K for monoclonal antibody treatment of human T-cell et al. (1996). The interleukin-2 receptor gamma chain: its lymphotropic virus I-induced adult T-cell leukemia. Blood role in the multiple cytokine receptor complexes and T cell 82: 1701–1712. development in XSCID. Annu Rev Immunol 14: 179–205. Wiseman LR, Faulds D. (1999). Daclizumab: a review of its Tan C, Waldmann TA. (2002). Proteasome inhibitor PS-341 a use in the prevention of acute rejection in renal transplant potential therapeutic agent for adult T-cell leukemia. Cancer recipients. Drugs 58: 1029–1042. Res 62: 1083–1086. Zhang M, Yao Z, Zhang Z, Garmestani K, Talanov VS, Tsudo M, Kozak RW, Goldman CK, Waldmann TA. (1986). Plascjak PS et al. (2006). Theanti-CD25 monoclonal Demonstration of a non-Tac peptide that binds inter- antibody 7G7/B6, armed with the {alpha}-emitter 211At, leukin 2: a potential participant in a multichain inter- provides effective radioimmunotherapy for a murine model leukin 2 receptor complex. Proc Natl Acad Sci USA 83: of leukemia. Cancer Res 66: 8227–8232. 9694–9698. Zhang M, Zhang Z, Garmestani K, Goldman CK, Ravetch Uchiyama T, Broder S, Waldmann TA. (1981a). A mono- JV, Brechbiel MW et al. (2004). Activating Fc receptors are clonal antibody (anti-Tac) reactive with activated and required for antitumor efficacy of the antibodies directed functionally maturehuman T cells.I. Production of anti- toward CD25 in a murine model of adult T-cell leukemia. Tac monoclonal antibody and distribution of Tac (+) cells. Cancer Res 64: 5825–5829. J Immunol 126: 1393–1397. Zhang M, Zhang Z, Goldman CK, Janik J, Waldmann TA. Uchiyama T, Nelson DL, Fleisher TA, Waldmann TA. (2005). Combination of therapy for adult T-cell leukemia- (1981b). A monoclonal antibody (anti-Tac) reactive with xenografted mice: flavopiridol and anti-CD25 monoclonal activated and functionally mature human T cells II. antibody. Blood 105: 1231–1236.

Oncogene