Abstract
Targeted therapy of acute myeloid leukemia (AML) with monoclonal antibodies (MoAbs) has thus far been mostly directed at CD33, CD45, and CD66. The notion that some AMLs may predominantly or entirely involve committed CD33+ myeloid precursors provided the rationale for eradicating underlying stem cells with anti-CD33 antibodies. Emerging data demonstrating efficacy of the anti-CD33 immunoconjugate, gemtuzumab ozogamicin, in acute promyelocytic leukemia and other favorable- and intermediate-risk AMLs validate CD33 as drug target. Unlike CD33, CD45 and CD66 are noninternalizing antigens and have primarily been targeted to deliver radionuclides to sites of hematopoietic tissue, particularly to augment pre-transplant conditioning regimens. Early studies document the feasibility of this approach in selected patients, although future controlled studies will need to assess whether this strategy indeed leads to improved outcomes. Given this encouraging clinical experience, the use of MoAbs is likely expanding significantly in the future with identification of additional AML (stem) cell-associated antigens.
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References
Abutalib SA, Tallman MS (2006) Monoclonal antibodies for the treatment of acute myeloid leukemia. Curr Pharm Biotechnol 7:343–369
Andres TL, Kadin ME (1983) Immunologic markers in the differential diagnosis of small round cell tumors from lymphocytic lymphoma and leukemia. Am J Clin Pathol 79:546–552
Andrews RG, Torok-Storb B, Bernstein ID (1983) Myeloid-associated differentiation antigens on stem cells and their progeny identified by monoclonal antibodies. Blood 62:124–132
Andrews RG, Takahashi M, Segal GM et al (1986) The L4F3 antigen is expressed by unipotent and multipotent colony-forming cells but not by their precursors. Blood 68:1030–1035
Appelbaum FR (1999) Antibody-targeted therapy for myeloid leukemia. Semin Hematol 36:2–8
Appelbaum FR, Matthews DC, Eary JF et al (1992) The use of radiolabeled anti-CD33 antibody to augment marrow irradiation prior to marrow transplantation for acute myelogenous leukemia. Transplantation 54:829–833
Becker W, Goldenberg DM, Wolf F (1994) The use of monoclonal antibodies and antibody fragments in the imaging of infectious lesions. Semin Nucl Med 24:142–153
Bernstein ID, Singer JW, Andrews RG et al (1987) Treatment of acute myeloid leukemia cells in vitro with a monoclonal antibody recognizing a myeloid differentiation antigen allows normal progenitor cells to be expressed. J Clin Invest 79:1153–1159
Bernstein ID, Singer JW, Smith FO et al (1992) Differences in the frequency of normal and clonal precursors of colony-forming cells in chronic myelogenous leukemia and acute myelogenous leukemia. Blood 79:1811–1816
Breccia M, Lo-Coco F (2011) Gemtuzumab ozogamicin for the treatment of acute promyelocytic leukemia: mechanisms of action and resistance, safety and efficacy. Expert Opin Biol Ther 11:225–234
Breccia M, Cimino G, Diverio D et al (2007) Sustained molecular remission after low dose gemtuzumab-ozogamicin in elderly patients with advanced acute promyelocytic leukemia. Haematologica 92:1273–1274
Bross PF, Beitz J, Chen G et al (2001) Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin Cancer Res 7:1490–1496
Bunjes D (2002) 188Re-labeled anti-CD66 monoclonal antibody in stem cell transplantation for patients with high-risk acute myeloid leukemia. Leuk Lymphoma 43:2125–2131
Bunjes D, Buchmann I, Duncker C et al (2001) Rhenium 188-labeled anti-CD66 (a, b, c, e) monoclonal antibody to intensify the conditioning regimen prior to stem cell transplantation for patients with high-risk acute myeloid leukemia or myelodysplastic syndrome: results of a phase I–II study. Blood 98:565–572
Burnett AK, Hills RK, Milligan D et al (2011) Identification of patients with acute myeloblastic leukaemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial J Clin Oncol 29:369–377
Burnett AK, Russell N, Hill RK et al (2012) The addition of gemtuzumab ozogamicin to induction chemotherapy improves survival in older patients with acute myeloid leukemia. J Clin Oncol 30(32):3924–3931
Caron PC, Co MS, Bull MK et al (1992) Biological and immunological features of humanized M195 (anti-CD33) monoclonal antibodies. Cancer Res 52:6761–6767
Caron PC, Jurcic JG, Scott AM et al (1994) A phase 1B trial of humanized monoclonal antibody M195 (anti-CD33) in myeloid leukemia: specific targeting without immunogenicity. Blood 83:1760–1768
Caron PC, Dumont L, Scheinberg DA (1998) Supersaturating infusional humanized anti-CD33 monoclonal antibody HuM195 in myelogenous leukemia. Clin Cancer Res 4:1421–1428
Castaigne S, Pautas C, Terré C et al (2012) Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet 379:1508–1516
Clift RA, Buckner CD, Appelbaum FR et al (1990) Allogeneic marrow transplantation in patients with acute myeloid leukemia in first remission: a randomized trial of two irradiation regimens. Blood 76:1867–1871
Clift RA, Buckner CD, Appelbaum FR et al (1998) Long-term follow-up of a randomized trial of two irradiation regimens for patients receiving allogeneic marrow transplants during first remission of acute myeloid leukemia. Blood 92:1455–1456
Dahlke MH, Larsen SR, Rasko JE et al (2004) The biology of CD45 and its use as a therapeutic target. Leuk Lymphoma 45:229–236
Delaunay J, Recher C, Pigneux A et al (2011) Addition of gemtuzumab ozogamycin to chemotherapy improves event-free survival but not overall survival of AML patients with intermediate cytogenetics not eligible for allogeneic transplantation. Results of the GOELAMS AML 2006 IR study [abstract #79]. Blood 118:37–38
Dick JE (2008) Stem cell concepts renew cancer research. Blood 112:4793–4807
Dinndorf PA, Andrews RG, Benjamin D et al (1986) Expression of normal myeloid-associated antigens by acute leukemia cells. Blood 67:1048–1053
Estey EH, Giles FJ, Beran M et al (2002) Experience with gemtuzumab ozogamycin (“mylotarg”) and all-trans retinoic acid in untreated acute promyelocytic leukemia. Blood 99:4222–4224
Farhat H, Reman O, Raffoux E et al (2012) Fractionated doses of gemtuzumab ozogamicin with escalated doses of daunorubicin and cytarabine as first acute myeloid leukemia salvage in patients aged 50-70-year old: a phase 1/2 study of the acute leukemia French association. Am J Hematol 87:62–65
Feldman E, Kalaycio M, Weiner G et al (2003) Treatment of relapsed or refractory acute myeloid leukemia with humanized anti-CD33 monoclonal antibody HuM195. Leukemia 17:314–318
Feldman EJ, Brandwein J, Stone R et al (2005) Phase III randomized multicenter study of a humanized anti-CD33 monoclonal antibody, lintuzumab, in combination with chemotherapy, versus chemotherapy alone in patients with refractory or first-relapsed acute myeloid leukemia. J Clin Oncol 23:4110–4116
Fenton C, Perry CM (2005) Gemtuzumab ozogamicin: a review of its use in acute myeloid leukaemia. Drugs 65:2405–2427
Fialkow PJ, Singer JW, Adamson JW et al (1981) Acute nonlymphocytic leukemia: heterogeneity of stem cell origin. Blood 57:1068–1073
Fialkow PJ, Singer JW, Raskind WH et al (1987) Clonal development, stem-cell differentiation, and clinical remissions in acute nonlymphocytic leukemia. N Engl J Med 317:468–473
Giles F, Estey E, O’brien S (2003) Gemtuzumab ozogamicin in the treatment of acute myeloid leukemia. Cancer 98:2095–2104
Goemans BF, Zwaan CM, Vijverberg SJ et al (2008) Large interindividual differences in cellular sensitivity to calicheamicin may influence gemtuzumab ozogamicin response in acute myeloid leukemia. Leukemia 22:2284–2285
Gray-Owen SD, Blumberg RS (2006) CEACAM1: contact-dependent control of immunity. Nature Rev 6:433–446
Green DJ, Pagel JM, Nemecek ER et al (2009) Pretargeting CD45 enhances the selective delivery of radiation to hematolymphoid tissues in nonhuman primates. Blood 114:1226–1235
Griffin JD, Linch D, Sabbath K et al (1984) A monoclonal antibody reactive with normal and leukemic human myeloid progenitor cells. Leuk Res 8:521–534
Grimwade D, Enver T (2004) Acute promyelocytic leukemia: where does it stem from? Leukemia 18:375–384
Jager E, Van Der Velden VHJ, Te Marvelde JG et al (2011) Targeted drug delivery by gemtuzumab ozogamicin: mechanism-based mathematical model for treatment strategy improvement and therapy individualization. PLoS One 6:e24265
Jordan CT, Guzman ML (2004) Mechanisms controlling pathogenesis and survival of leukemic stem cells. Oncogene 23:7178–7187
Jurcic JG (2001) Antibody therapy for residual disease in acute myelogenous leukemia. Crit Rev Oncol Hematol 38:37–45
Jurcic JG, Deblasio T, Dumont L et al (2000) Molecular remission induction with retinoic acid and anti-CD33 monoclonal antibody HuM195 in acute promyelocytic leukemia. Clin Cancer Res 6:372–380
Jurcic JG, Larson SM, Sgouros G et al (2002) Targeted alpha particle immunotherapy for myeloid leukemia. Blood 100:1233–1239
Kelly LM, Gilliland DG (2002) Genetics of myeloid leukemias. Annu Rev Genomics Hum Genet 3:179–198
Klein SA, Hermann S, Dietrich JW et al (2002) Transplantation-related toxicity and acute intestinal graft-versus-host disease after conditioning regimens intensified with Rhenium 188-labeled anti-CD66 monoclonal antibodies. Blood 99:2270–2271
Koenecke C, Hofmann M, Bolte O et al (2008) Radioimmunotherapy with [(188)Re]-labelled anti-CD66 antibody in the conditioning for allogeneic stem cell transplantation for high-risk acute myeloid leukemia. Int J Hematol 87:414–421
Lane SW, Gilliland DG (2010) Leukemia stem cells. Semin Cancer Biol 20:71–76
Lapusan S, Vidriales MB, Thomas X et al (2012) Phase I studies of AVE9633, an anti-CD33 antibody-maytansinoid conjugate, in adult patients with relapsed/refractory acute myeloid leukemia. Invest New Drugs 30:1121–1131
Larson RA, Sievers EL, Stadtmauer EA et al (2005) Final report of the efficacy and safety of gemtuzumab ozogamicin (Mylotarg) in patients with CD33-positive acute myeloid leukemia in first recurrence. Cancer 104:1442–1452
Linenberger ML (2005) CD33-directed therapy with gemtuzumab ozogamicin in acute myeloid leukemia: progress in understanding cytotoxicity and potential mechanisms of drug resistance. Leukemia 19:176–182
Lo-Coco F, Cimino G, Breccia M et al (2004) Gemtuzumab ozogamicin (Mylotarg) as a single agent for molecularly relapsed acute promyelocytic leukemia. Blood 104:1995–1999
Majeti R (2011) Monoclonal antibody therapy directed against human acute myeloid leukemia stem cells. Oncogene 30:1009–1019
Matthews DC, Appelbaum FR (2004) Radioimmunotherapy and hematopoietic cell transplantation. In: Blume KG, Forman SJ, Appelbaum FR (eds) Thomas’ hematopoietic cell transplantion, 3rd edn. Blackwell Publishing Ltd, Massachusetts, pp 198–208
Matthews DC, Appelbaum FR, Eary JF et al (1991) Radiolabeled anti-CD45 monoclonal antibodies target lymphohematopoietic tissue in the macaque. Blood 78:1864–1874
Matthews DC, Badger CC, Fisher DR et al (1992) Selective radiation of hematolymphoid tissue delivered by anti-CD45 antibody. Cancer Res 52:1228–1234
Matthews DC, Appelbaum FR, Eary JF et al (1999) Phase I study of (131)I-anti-CD45 antibody plus cyclophosphamide and total body irradiation for advanced acute leukemia and myelodysplastic syndrome. Blood 94:1237–1247
Mcdevitt MR, Finn RD, Ma D et al (1999) Preparation of alpha-emitting 213Bi-labeled antibody constructs for clinical use. J Nucl Med 40:1722–1727
Mcdevitt MR, Ma D, Lai LT et al (2001) Tumor therapy with targeted atomic nanogenerators. Science 294:1537–1540 (New York)
Miederer M, Mcdevitt MR, Sgouros G et al (2004) Pharmacokinetics, dosimetry, and toxicity of the targetable atomic generator, 225Ac-HuM195, in nonhuman primates. J Nucl Med 45:129–137
Nakano A, Harada T, Morikawa S et al (1990) Expression of leukocyte common antigen (CD45) on various human leukemia/lymphoma cell lines. Acta Pathol Jpn 40:107–115
Nikula TK, Mcdevitt MR, Finn RD et al (1999) Alpha-emitting bismuth cyclohexylbenzyl DTPA constructs of recombinant humanized anti-CD33 antibodies: pharmacokinetics, bioactivity, toxicity and chemistry. J Nucl Med 40:166–176
Pagano L, Fianchi L, Caira M et al (2007) The role of gemtuzumab ozogamicin in the treatment of acute myeloid leukemia patients. Oncogene 26:3679–3690
Pagel JM, Appelbaum FR, Eary JF et al (2006a) 131I-anti-CD45 antibody plus busulfan and cyclophosphamide before allogeneic hematopoietic cell transplantation for treatment of acute myeloid leukemia in first remission. Blood 107:2184–2191
Pagel JM, Gooley T, Rajendran JG et al (2006b) Targeted radiotherapy using 131I-anti-CD45 antibody followed by allogeneic hematopoietic cell transplantation (HCT): the relationships among dosimetry, bone marrow uptake, and relapse [abstract]. Eur J Nucl Med Mol Imaging 33:S193
Pagel JM, Hedin N, Drouet L et al (2008) Eradication of disseminated leukemia in a syngeneic murine leukemia model using pretargeted anti-CD45 radioimmunotherapy. Blood 111:2261–2268
Pagel JM, Gooley TA, Rajendran J et al (2009a) Allogeneic hematopoietic cell transplantation after conditioning with 131I-anti-CD45 antibody plus fludarabine and low-dose total body irradiation for elderly patients with advanced acute myeloid leukemia or high-risk myelodysplastic syndrome. Blood 114:5444–5453
Pagel JM, Matthews DC, Kenoyer A et al (2009b) Pretargeted radioimmunotherapy using anti-CD45 monoclonal antibodies to deliver radiation to murine hematolymphoid tissues and human myeloid leukemia. Cancer Res 69:185–192
Passegué E, Jamieson CH, Ailles LE et al (2003) Normal and leukemic hematopoiesis: are leukemias a stem cell disorder or a reacquisition of stem cell characteristics? Proc Natl Acad Sci U S A 100(Suppl 1):11842–11849
Petersdorf S, Kopecky K, Stuart RK et al (2009) Preliminary results of Southwest Oncology Group Study S0106: an international intergroup phase 3 randomized trial comparing the addition of gemtuzumab ozogamicin to standard induction therapy versus standard induction therapy followed by a second randomization to post-consolidation gemtuzumab ozogamicin versus no additional therapy for previously untreated acute myeloid leukemia [abstract #790]. Blood 114:326–327
Petti MC, Pinazzi MB, Diverio D et al (2001) Prolonged molecular remission in advanced acute promyelocytic leukaemia after treatment with gemtuzumab ozogamicin (Mylotarg CMA-676). Br J Haematol 115:63–65
Pfizer Inc (2010) http://media.pfizer.com/files/products/mylotarg_hcp_letter.pdf. Accessed 23 Jan 2012
Pollard JA, Alonzo TA, Loken M et al (2012) Correlation of CD33 expression level with disease characteristics and response to gemtuzumab ozogamicin containing chemotherapy in childhood AML. Blood 119:3705–3711
Press OW, Howell-Clark J, Anderson S et al (1994) Retention of B-cell-specific monoclonal antibodies by human lymphoma cells. Blood 83:1390–1397
Press OW, Shan D, Howell-Clark J et al (1996) Comparative metabolism and retention of iodine-125, yttrium-90, and indium-111 radioimmunoconjugates by cancer cells. Cancer Res 56:2123–2129
Ravandi F, Estey E, Jones D et al (2009) Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol 27:504–510
Raza A, Jurcic JG, Roboz GJ et al (2009) Complete remissions observed in acute myeloid leukemia following prolonged exposure to lintuzumab: a phase 1 trial. Leuk Lymphoma 50:1336–1344
Ricart AD (2011) Antibody-drug conjugates of calicheamicin derivative: gemtuzumab ozogamicin and inotuzumab ozogamicin. Clin Cancer Res 17:6417–6427
Ringhoffer M, Blumstein N, Neumaier B et al (2005) 188Re or 90Y-labelled anti-CD66 antibody as part of a dose-reduced conditioning regimen for patients with acute leukaemia or myelodysplastic syndrome over the age of 55: results of a phase I-II study. Br J Haematol 130:604–613
Rosenblat TL, Mcdevitt MR, Pandit-Taskar N et al (2007) Phase I trial of the targeted alpha-particle nano-generator actinium-225 (225Ac)-HuM195 (anti-CD33) in acute myeloid leukemia (AML) [abstract #910]. Blood 110:277a
Rottinger EM, Bartkowiak D, Bunjes D et al (2003) Enhanced renal toxicity of total body irradiation combined with radioimmunotherapy. Strahlenther Onkol 179:702–707
Scheinberg DA, Lovett D, Divgi CR et al (1991) A phase I trial of monoclonal antibody M195 in acute myelogenous leukemia: specific bone marrow targeting and internalization of radionuclide. J Clin Oncol 9:478–490
Sekeres MA, Lancet JE, Wood BL et al (2013) Randomized phase IIb study of low-dose cytarabine and lintuzumab versus low-dose cytarabine and placebo in older adults with untreated acute myeloid leukemia. Haematologica 98:119–129
Sievers EL, Appelbaum FR, Spielberger RT et al (1999) Selective ablation of acute myeloid leukemia using antibody-targeted chemotherapy: a phase I study of an anti-CD33 calicheamicin immunoconjugate. Blood 93:3678–3684
Sievers EL, Larson RA, Stadtmauer EA et al (2001) Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J Clin Oncol 19:3244–3254
Stasi R, Evangelista ML, Buccisano F et al (2008) Gemtuzumab ozogamicin in the treatment of acute myeloid leukemia. Cancer Treat Rev 34:49–60
Stubbs MC, Armstrong SA (2007) Therapeutic implications of leukemia stem cell development. Clin Cancer Res 13:3439–3442
SWOG (2010) http://www.swogstat.org/ROS/ROSBooks/Spring2010/Leukemia.pdf. Accessed 23 Jan 2012
Taksin AL, Legrand O, Raffoux E et al (2007) High efficacy and safety profile of fractionated doses of Mylotarg as induction therapy in patients with relapsed acute myeloblastic leukemia: a prospective study of the alfa group. Leukemia 21:66–71
Thomas ED, Storb R, Clift RA et al (1975) Bone-marrow transplantation. N Engl J Med 292:832–843
Tsimberidou AM, Giles FJ, Estey E et al (2006) The role of gemtuzumab ozogamicin in acute leukaemia therapy. Br J Haematol 132:398–409
Van Der Jagt RH, Badger CC, Appelbaum FR et al (1992) Localization of radiolabeled antimyeloid antibodies in a human acute leukemia xenograft tumor model. Cancer Res 52:89–94
Van Der Velden VH, Te Marvelde JG, Hoogeveen PG et al (2001) Targeting of the CD33-calicheamicin immunoconjugate Mylotarg (CMA-676) in acute myeloid leukemia: in vivo and in vitro saturation and internalization by leukemic and normal myeloid cells. Blood 97:3197–3204
Walter RB, Pagel JM (2011) Targeted radionuclide therapy for leukemia. In: Speer TW (ed) Targeted radionuclide therapy. Walters Kluwer/Lippincott Williams & Wilkins, Philadelphia, pp 441–457
Walter RB, Raden BW, Kamikura DM et al (2005) Influence of CD33 expression levels and ITIM-dependent internalization on gemtuzumab ozogamicin-induced cytotoxicity. Blood 105:1295–1302
Walter RB, Press OW, Pagel JM (2010) Pretargeted radioimmunotherapy for hematologic and other malignancies. Cancer Biother Radiopharm 25:125–142
Walter RB, Appelbaum FR, Estey EH et al (2012) Acute myeloid leukemia stem cells and CD33-targeted immunotherapy. Blood 119:6198–6208
Zenz T, Schlenk RF, Glatting G et al (2006) Bone marrow transplantation nephropathy after an intensified conditioning regimen with radioimmunotherapy and allogeneic stem cell transplantation. J Nucl Med 47:278–286
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Conclusion
The clinical studies conducted so far with unconjugated, toxin-loaded, and radiolabeled MoAbs have demonstrated that CD33 and perhaps CD45 and CD66 are valid targets for the treatment of AML. Given this encouraging experience, the use of antibodies is likely expanding significantly in the future with identification of additional AML (stem) cell-associated antigens. However, AML comprises a heterogeneous group of diseases, and antibody-based therapeutics likely only benefit defined patient subsets, as exemplified by the clinical experience with GO. This will pose formidable challenges to the identification of adequate numbers of suitable patients in whom specific therapies can be tested in a controlled fashion.
Acknowledgements
This work was supported by grants P30-CA015704-35S6, P01-CA044991, R01-CA109663, and R01-CA136639 from the National Cancer Institute/National Institutes of Health (NCI/NIH) and a Specialized Center of Research grant (#7008-08) from the Leukemia & Lymphoma Society. R.B.W. is a Leukemia & Lymphoma Scholar in Clinical Research.
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Walter, R., Press, O., Bernstein, I. (2015). Antibody-Based Therapeutics Targeting CD33, CD45, and CD66. In: Andreeff, M. (eds) Targeted Therapy of Acute Myeloid Leukemia. Current Cancer Research. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1393-0_27
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