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The AAPS Journal

, Volume 17, Issue 3, pp 525–534 | Cite as

Antibody Drug Conjugates: Preclinical Considerations

Review Article Theme: Critical Considerations for Design and Development of Antibody Drug Conjugates
Part of the following topical collections:
  1. Theme: Critical Considerations for Design and Development of Antibody Drug Conjugates

ABSTRACT

The development path for antibody drug conjugates (ADCs) is more complex and challenging than for unmodified antibodies. While many of the preclinical considerations for both unmodified and antibody drug conjugates are shared, special considerations must be taken into account when developing an ADC. Unlike unmodified antibodies, an ADC must preferentially bind to tumor cells, internalize, and traffic to the appropriate intracellular compartment to release the payload. Parameters that can impact the pharmacological properties of this class of therapeutics include the selection of the payload, the type of linker, and the methodology for payload drug conjugation. Despite a plethora of in vitro assays and in vivo models to screen and evaluate ADCs, the challenge remains to develop improved preclinical tools that will be more predictive of clinical outcome. This review will focus on preclinical considerations for clinically validated small molecule ADCs. In addition, the lessons learned from Mylotarg®, the first in class FDA-approved ADC, are highlighted.

KEY WORDS

antibody drug conjugate preclinical tumor 

References

  1. 1.
    Decarvalho S, Rand HJ, Lewis A. Coupling of cyclic chemotherapeutic compounds to immune gamma-globulins. Nature. 1964;202:255–8.PubMedGoogle Scholar
  2. 2.
    Mullard A. Maturing antibody-drug conjugate pipeline hits 30. Nat Rev Drug Discov. 2013;12(5):329–32.PubMedGoogle Scholar
  3. 3.
    Zheng B, Fuji RN, Elkins K, et al. In vivo effects of targeting CD79b with antibodies and antibody-drug conjugates. Mol Cancer Ther. 2009;8(10):2937–46.PubMedGoogle Scholar
  4. 4.
    Graversen JH, Svendsen P, Dagnaes-Hansen F, et al. Targeting the hemoglobin scavenger receptor CD163 in macrophages highly increases the anti-inflammatory potency of dexamethasone. Mol Ther. 2012;20(8):1550–8.PubMedCentralPubMedGoogle Scholar
  5. 5.
    Gerber HP, Senter PD, Grewal IS. Antibody drug-conjugates targeting the tumor vasculature: current and future developments. MAbs. 2009;1(3):247–53.PubMedCentralPubMedGoogle Scholar
  6. 6.
    Sassoon I, Blanc V. Antibody-drug conjugate (ADC) clinical pipeline: a review. Methods Mol Biol. 2013;1045:1–27.PubMedGoogle Scholar
  7. 7.
    Bander NH. Antibody-drug conjugate target selection: critical factors. Methods Mol Biol. 2013;1045:29–40.PubMedGoogle Scholar
  8. 8.
    Baselga J, Verma S, Ro J, et al. Relationship between tumor biomarkers and efficacy in EMILIA, a phase III study of trastuzumab emtansine (T-DM1) in HER2-positive metastatic breast cancer. Cancer Res. 2013;73(8):LB–63.Google Scholar
  9. 9.
    Perez HL, Cardarelli PM, Deshpande S, et al. Antibody-drug conjugates: current status and future directions. Drug Discov Today. 2014;19(7):869–81.PubMedGoogle Scholar
  10. 10.
    Press MF et al. Expression of the HER-2/neu proto-oncogene in normal human adult and fetal tissues. Oncogene. 1990;5:953–62.PubMedGoogle Scholar
  11. 11.
    Solal-Celligny P. Safety of rituximab maintenance therapy in follicular lymphomas. Leuk Res. 2006;30 Suppl 1:S16–21.Google Scholar
  12. 12.
    Wahl AF, Klussman K, Thompson JD, et al. The anti-CD30 monoclonal antibody SGN-30 promotes growth arrest and DNA fragmentation in vitro and affects antitumor activity in models of Hodgkin’s disease. Cancer Res. 2002;62:3736–42.PubMedGoogle Scholar
  13. 13.
    Stein H, Foss HD, Durkop H, et al. CD30(+) anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features. Blood. 2000;96:3681–95.PubMedGoogle Scholar
  14. 14.
    Falini B, Pileri S, Pizzolo G, et al. CD30 (Ki-1) molecule: a new cytokine receptor of the tumor necrosis factor receptor superfamily as a tool for diagnosis and immunotherapy. Blood. 1995;85:1–14.PubMedGoogle Scholar
  15. 15.
    Chari RVJ. Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc Chem Res. 2008;41:98–107.PubMedGoogle Scholar
  16. 16.
    Doronina SO, Toki BE, Torgov MY, et al. Development of potent monoclonal antibody auristatin conjugates for cancer therapy. Nat Biotechnol. 2003;21(7):778–84.PubMedGoogle Scholar
  17. 17.
    Teicher BA. Antibody-drug conjugate targets. Curr Cancer Drug Targets. 2009;9(8):982–1004.PubMedGoogle Scholar
  18. 18.
    Carter P, Smith L, Ryan M. Identification and validation of cell surface antigens for antibody targeting in oncology. Endocrinol Relat Cancer. 2004;11(4):659–87.Google Scholar
  19. 19.
    Firer MA. Antibody-drug conjugates in cancer therapy—filling in the potholes that lie ahead. OA Cancer. 2013;1(1):8.Google Scholar
  20. 20.
    Alley SC, Zhang X, Okeley NM, et al. The pharmacologic basis for antibody-auristatin conjugate activity. J Pharmacol Exp Ther. 2009;330(3):932–8.PubMedGoogle Scholar
  21. 21.
    Thurber GM, Schmidt MM, Wittrup KD, et al. Antibody tumor penetration: transport opposed by systemic and antigen-mediated clearance. Adv Drug Deliv Rev. 2008;60:1421–34.PubMedCentralPubMedGoogle Scholar
  22. 22.
    Sievers EL, Senter PD. Antibody-drug conjugates in cancer therapy. Annu Rev Med. 2013;64:15–29.PubMedGoogle Scholar
  23. 23.
    Law CL, Cerveny CG, Gordon KA, et al. Efficient elimination of B-lineage lymphomas by anti-CD20-auristatin conjugates. Clin Cancer Res. 2004;10:7842–51.PubMedGoogle Scholar
  24. 24.
    Smith LM, Nesterova A, Alley SC, Torgov MY, Carter PJ. Potent cytotoxicity of an auristatin-containing antibody-drug conjugate targeting melanoma cells expressing melanotransferrin/p97. Mol Cancer Ther. 2006;5:1474–82.PubMedGoogle Scholar
  25. 25.
    Yoshikawa M, Mukai Y, Okada Y, et al. Robo4 is an effective tumor endothelial marker for antibody-drug conjugates based on the rapid isolation of the anti-Robo4 cell-internalizing antibody. Blood. 2013;121:2804–13.PubMedGoogle Scholar
  26. 26.
    Ackerman ME, Pawlowski D, Wittrup KD, et al. Effect of antigen turnover rate and expression level on antibody penetration into tumor spheroids. Mol Cancer Ther. 2008;7(7):2233–40.PubMedCentralPubMedGoogle Scholar
  27. 27.
    Carter PJ. Potent antibody therapeutics by design. Nat Rev Immunol. 2006;6:343–57.PubMedGoogle Scholar
  28. 28.
    Owen SC, Patel N, Logie J, et al. Targeting HER2+ breast cancer cells: lysosomal accumulation of anti-HER2 antibodies is influenced by antibody binding site and conjugation to polymeric nanoparticles. J Control Release. 2013;172(2):395–404.PubMedGoogle Scholar
  29. 29.
    Rudnick SI, Lou J, Shaller CC, et al. Influence of affinity and antigen internalization on the uptake and penetration of anti-HER2 antibodies in solid tumors. Cancer Res. 2011;71(6):2250–9.PubMedCentralPubMedGoogle Scholar
  30. 30.
    Flygare JA, Pillow TH, Aristoff P. Antibody-drug conjugates for the treatment of cancer. Chem Biol Des. 2013;81:113–21.Google Scholar
  31. 31.
    Henry MD, Wen S, Silva MD, et al. A prostate-specific membrane antigen-targeted monoclonal antibody-chemotherapeutic conjugate designed for the treatment of prostate cancer. Cancer Res. 2004;64(21):7995–8001.PubMedGoogle Scholar
  32. 32.
    Legrand O. An open label dose escalation study of AVE9633 administered as a single agent by intravenous (IV) infusion weekly for 2 weeks in 4-week cycle to patients with relapsed or refractory CD33-positive acute myeloid leukemia (AML). Blood. 2007;110:1850.Google Scholar
  33. 33.
    Polson AG, Calemine-Fenaux J, Chan P, et al. Antibody-drug conjugates for the treatment of non-Hodgkin’s lymphoma: target and linker-drug selection. Cancer Res. 2009;69(6):2358–64.PubMedGoogle Scholar
  34. 34.
    Tassone P, Goldmacher VS, Neri P, et al. Cytotoxic activity of the maytansinoid immunoconjugate B-B4-DM1 against CD138+ multiple myeloma cells. Blood. 2004;104(12):3688–96.PubMedGoogle Scholar
  35. 35.
    Tassone P, Gozzini A, Goldmacher VS, et al. In vitro and in vivo activity of the maytansinoid immunoconjugate huN901-N2’-deacetyl-N2’-(3-mercapto-1-oxopropyl)-maytansine against CD56+ multiple myeloma cells. Cancer Res. 2004;64(13):4629–36.PubMedGoogle Scholar
  36. 36.
    Lewis Phillips GD, Li G, Dugger DL, et al. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res. 2008;68(22):9280–90.PubMedGoogle Scholar
  37. 37.
    Katz J, Janik JE, Younes A. Brentuximab vedotin (SGN-35). Clin Cancer Res. 2011;17:6428–36.PubMedGoogle Scholar
  38. 38.
    Kovtun YV, Goldmacher VS. Cell killing by antibody-drug conjugates. Cancer Lett. 2007;255(2):232–40.PubMedGoogle Scholar
  39. 39.
    Hamann PR, Hinman LM, Hollander I, et al. Gemtuzumab ozogamicin, a potent and selective anti-CD33 antibody-calicheamicin conjugate for treatment of acute myeloid leukemia. Bioconjug Chem. 2002;13(1):47–58.PubMedGoogle Scholar
  40. 40.
    Hamann PR, Hinman LM, Beyer CF, et al. An anti-CD33 antibody-calicheamicin conjugate for treatment of acute myeloid leukemia. Choice of linker. Bioconjug Chem. 2002;13(1):40–6.PubMedGoogle Scholar
  41. 41.
    Zhou BB, Zhang H, Damelin M, Geles KG, Grindley JC, Dirks PB. Tumour-initiating cells: challenges and opportunities for anticancer drug discovery. Nat Rev Drug Discov. 2009;8:806–23.PubMedGoogle Scholar
  42. 42.
    Gottesman MM. Mechanisms of cancer drug resistance. Annu Rev Med. 2002;53:615–27.PubMedGoogle Scholar
  43. 43.
    Frankfurt OS, Greco WR, Slocum HK, et al. Proliferative characteristics of primary and metastatic human solid tumors by DNA flow cytometry. Cytometry. 1984;5(6):629–35.PubMedGoogle Scholar
  44. 44.
    Friberg S, Mattson SJ. On the growth rates of human malignant tumors: implications for medical decision making. Surg Oncol. 1997;65(4):284–97.Google Scholar
  45. 45.
    Hlatky L, Olesiak M, Hahnfeldt P. Measurement of potential doubling time for human tumor xenografts using the cytokinesis-block method. Cancer Res. 1996;56:1660–3.PubMedGoogle Scholar
  46. 46.
    DiJoseph JF, Armellino DC, Boghaert ER, et al. Antibody-targeted chemotherapy with CMC-544: a CD22-targeted immunoconjugate of calicheamicin for the treatment of B-lymphoid malignancies. Blood. 2004;103(5):1807–14.PubMedGoogle Scholar
  47. 47.
    Boghaert ER, Sridharan L, Khandke KM, et al. The oncofetal protein, 5T4, is a suitable target for antibody-guided anti-cancer chemotherapy with calicheamicin. Int J Oncol. 2008;32(1):221–34.PubMedGoogle Scholar
  48. 48.
    Bross PF, Beitz J, Chen G, et al. Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin Cancer Res. 2001;7(6):1490–6.PubMedGoogle Scholar
  49. 49.
    Kantarjian H, Thomas D, Jorgensen J, et al. Inotuzumab ozogamicin, an anti-CD22-calecheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia: a phase 2 study. Lancet Oncol. 2012;13(4):403–11.PubMedGoogle Scholar
  50. 50.
    Senter PD. Potent antibody drug conjugates for cancer therapy. Curr Opin Chem Biol. 2009;13(3):235–44.PubMedGoogle Scholar
  51. 51.
    Kaneko T, Willner D, Monkovic I, et al. New hydrazone derivatives of adriamycin and their immunoconjugates—a correlation between acid stability and cytotoxicity. Bioconjug Chem. 1991;2(3):133–41.PubMedGoogle Scholar
  52. 52.
    Ducry L, Stump B. Antibody-drug conjugates: linking cytotoxic payloads to monoclonal antibodies. Bioconjug Chem. 2010;21(1):5–13.PubMedGoogle Scholar
  53. 53.
    Toki BE, Cerveny CG, Wahl AF, Senter PD. Protease-mediated fragmentation of p-amidobenzyl ethers: a new strategy for the activation of anticancer prodrugs. J Org Chem. 2002;67(6):1866–72.PubMedGoogle Scholar
  54. 54.
    Dubowchik GM, Radia S, Mastalerz H, et al. Doxorubicin immunoconjugates containing bivalent, lysosomally-cleavable dipeptide linkages. Bioorg Med Chem Lett. 2002;12(11):1529–32.PubMedGoogle Scholar
  55. 55.
    Polakis P. Arming antibodies for cancer therapy. Curr Opin Pharmacol. 2005;5(4):382–7.PubMedGoogle Scholar
  56. 56.
    Wu AM, Senter PD. Arming antibodies: prospects and challenges for immunoconjugates. Nat Biotechnol. 2005;23(9):1137–46.PubMedGoogle Scholar
  57. 57.
    KovtunYV, Audette CA, Ye Y, et al. Antibody-drug conjugates designed to eradicate tumors with homogeneous and heterogeneous expression of the target antigen. Cancer Res. 66(6):3214–21.Google Scholar
  58. 58.
    Erickson HK, Widdison WC, Mayo MF, et al. Tumor delivery and in vivo processing of disulfide-linked and thioether-linked antibody-maytansinoid conjugates. Bioconjug Chem. 2010;21:84–92.PubMedGoogle Scholar
  59. 59.
    Okeley NM, Miyamaoto JB, Zhang X, et al. Intracellular activation of SGN-35, a potent anti-CD30 antibody-drug conjugate. Clin Cancer Res. 2010;16:888–97.PubMedGoogle Scholar
  60. 60.
    Flygare JA, Pillow TH, Aristoff P. Antibody-drug conjugates for the treatment of cancer. Chem Biol Drug Des. 2013;81:113–21.PubMedGoogle Scholar
  61. 61.
    Sanderson RJ, Hering MA, James SF, et al. In vivo drug-linker stability of an anti-CD30 dipeptide-linked auristatin immunoconjugate. Clin Cancer Res. 2005;11:843–52.PubMedGoogle Scholar
  62. 62.
    McDonagh CF, Turcott E, Westendorf L, et al. Engineered antibody-drug conjugates with defined sites and stoichiometries of drug attachment. Protein Eng Des Sel. 2006;19(7):299–307.PubMedGoogle Scholar
  63. 63.
    Hamblett KJ, Senter PD, Chace DF, et al. Effects of drug loading on the antitumor activity of a monoclonal antibody drug conjugate. Clin Cancer Res. 2004;10(20):7063–70.PubMedGoogle Scholar
  64. 64.
    Strop P, Liu SH, Dorywalska M, et al. Location matters: site of conjugation modulates stability and pharmacokinetics of antibody drug conjugates. Chem Biol. 2013;20(2):161–7.PubMedGoogle Scholar
  65. 65.
    Adams GP, Weiner LM. Monoclonal antibody therapy of cancer. Nat Biotechnol. 2005;23:1147–57.PubMedGoogle Scholar
  66. 66.
    Lewis GD, Figari I, Fendly B, et al. Differential responses of human tumor cell lines to anti-p185HER2 monoclonal antibodies. Cancer Immunol Immunother. 1993;37(4):255–63.PubMedGoogle Scholar
  67. 67.
    Junttila TT, Li G, Parsons K, et al. Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer. Breast Cancer Res Treat. 2011;128(2):347–56.PubMedGoogle Scholar
  68. 68.
    Linenberger ML, Hong T, Flowers D, et al. Multidrug-resistance phenotype and clinical responses to gemtuzumab ozogamicin. Blood. 2001;98(4):988–94.PubMedGoogle Scholar
  69. 69.
    Linenberger ML. CD33-directed therapy with gemtuzumab ozogamicin in acute myeloid leukemia: progress in understanding cytotoxicity and potential mechanisms of drug resistance. Leukemia. 2005;19(2):176–82.PubMedGoogle Scholar
  70. 70.
    Walter RB, Gooley TA, van der Velden VH, et al. CD33 expression and P-glycoprotein-mediated drug efflux inversely correlate and predict clinical outcome in patients with acute myeloid leukemia treated with gemtuzumab ozogamicin monotherapy. Blood. 2007;109(10):4168–70.PubMedCentralPubMedGoogle Scholar
  71. 71.
    Tang R, Cohen S, Perrot JY, et al. P-gp activity is a critical resistance factor against AVE9633 and DM4 cytotoxicity in leukaemia cell lines, but not a major mechanism of chemoresistance in cells from acute myeloid leukaemia patients. BMC Cancer. 2009;9:199.PubMedCentralPubMedGoogle Scholar
  72. 72.
    Kovtun YV, Audette CA, Mayo MF, et al. Antibody-maytansinoid conjugates designed to bypass multidrug resistance. Cancer Res. 2010;70(6):2528–37.PubMedGoogle Scholar
  73. 73.
    Espenetos AA, Snook D, Durbin H, et al. Limitations of radiolabeled monoclonal antibodies for localization of human neoplasms. Cancer Res. 1986;46(6):3183–91.Google Scholar
  74. 74.
    Jain RK. Barriers to drug delivery in solid tumors. Sci Am. 1994;271(1):58–65.PubMedGoogle Scholar
  75. 75.
    The JRK, Eugene M. Landis Award Lecture 1996. Delivery of molecular and cellular medicine to solid tumors. Microcirculation. 1997;4(1):1–23.Google Scholar
  76. 76.
    Jain RK, Munn LL, Fukumura D. Dissecting tumour pathophysiology using intravital microscopy. Nat Rev Cancer. 2002;2(4):266–76.PubMedGoogle Scholar
  77. 77.
    Leu AJ, Berk DA, Lymboussaki A, Alitalo K, Jain RK. Absence of functional lymphatics within a murine sarcoma: a molecular and functional evaluation. Cancer Res. 2000;60(16):4324–7.PubMedGoogle Scholar
  78. 78.
    Heldin CH, Rubin K, Pietras K, Ostman A. High interstitial fluid pressure—an obstacle in cancer therapy. Nat Rev Cancer. 2004;4(10):806–13.PubMedGoogle Scholar
  79. 79.
    Milosevic MF, Fyles AW, Wong R, Pintilie M, Kavanagh MC, Levin W, et al. Interstitial fluid pressure in cervical carcinoma: within tumor heterogeneity, and relation to oxygen tension. Cancer. 1998;82(12):2418–26.PubMedGoogle Scholar
  80. 80.
    Jain RK. Transport of molecules in the tumor interstitium: a review. Cancer Res. 1987;47(12):3039–51.PubMedGoogle Scholar
  81. 81.
    Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis? Nat Rev Cancer. 2004;4(11):891–9.PubMedGoogle Scholar
  82. 82.
    Tannock IF, Rotin D. Acid pH in tumors and its potential for therapeutic exploitation. Cancer Res. 1989;49(16):4373–84.PubMedGoogle Scholar
  83. 83.
    Kim KM, McDonagh CF, Westendorf L, et al. Anti-CD30 diabody—drug conjugates with potent antitumor activity. Mol Cancer Ther. 2008;7:2486–97.PubMedGoogle Scholar
  84. 84.
    Newell DR. Flasks, fibres and flanks—pre-clinical tumour models for predicting clinical antitumor activity. Br J Cancer. 2001;84(10):1289–90.PubMedCentralPubMedGoogle Scholar
  85. 85.
    Johnson JI, Decker S, Zaharevitz D, et al. Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials. Br J Cancer. 2001;84(10):1424–31.PubMedCentralPubMedGoogle Scholar
  86. 86.
    Plowman J, Dykes DJ, Hollingshead M, et al. Anticancer drug development guide. Cancer Drug Discov Dev. 1997:101-125.Google Scholar
  87. 87.
    Hoffman RM. Orthotopic metastatic mouse models for anticancer drug discovery and evaluation: a bridge to the clinic. Investig New Drugs. 1999;17:343–59.Google Scholar
  88. 88.
    Steel GG et al. The response to chemotherapy of a variety of human tumour xenografts. Br J Cancer. 1983;47:1–13.PubMedCentralPubMedGoogle Scholar
  89. 89.
    Hood JD, Cheresh DA. Building a better trap. Proc Natl Acad Sci U S A. 2003;100:8624–5.PubMedCentralPubMedGoogle Scholar
  90. 90.
    Fichtner I, Rolff J, Soong R, et al. Establishment of patient-derived non-small cell lung cancer xenografts as models for the identification of predictive biomarkers. Clin Cancer Res. 2008;14:6456–68.PubMedGoogle Scholar
  91. 91.
    Lute KD, May Jr KF, Lu P, et al. Human CTLA4 knock-in mice unravel the quantitative link between tumor immunity and autoimmunity induced by anti-CTLA-4 antibodies. Blood. 2005;106:3127–33.PubMedCentralPubMedGoogle Scholar
  92. 92.
    Tabrizi MA, Bornstein GG, Klakamp SL, et al. Translational strategies for development of monoclonal antibodies from discovery to the clinic. Drug Discov Today. 2009;14(5–6):298–305.PubMedGoogle Scholar
  93. 93.
    Griffin JD, Linch D, Sabbath K, et al. A monoclonal antibody reactive with normal and leukemic human myeloid progenitor cells. Leuk Res. 1984;8:521–34.PubMedGoogle Scholar
  94. 94.
    Hamann PR, Hinman LM, Hollander I, et al. Gemtuzumab ozogamicin, a potent and selective anti-CD33 antibody-calicheamicin conjugate for treatment of acute myeloid leukemia. Bioconjug Chem. 2002;13:47–58.PubMedGoogle Scholar
  95. 95.
    Bross PF, Beitz J, Chen G, et al. Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin Cancer Res. 2001;7:1490–6.PubMedGoogle Scholar
  96. 96.
    Matusmoto T, Jimi S, Hara S, et al. Importance of inducible multidrug resistance1 expression in HL-60 cells resistant to gemtuzumab ozogamicin. Leuk Lymphoma. 2012;53:1399–405.Google Scholar
  97. 97.
    van Der Velden VH, te Marvelde JG, Hoogeveen PG, et al. 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. 2001;97:3197–204.Google Scholar
  98. 98.
    Polakis P. Arming antibodies for cancer therapy. Curr Opin Pharmacol. 2005;5:382–7.PubMedGoogle Scholar
  99. 99.
    McKoy JM, Angelotta C, Bennett CL, et al. Gemtuzumab ozogamicin-associated sinusoidal obstructive syndrome (SOS): an overview from the research on adverse drug events and reports (RADAR) project. Leuk Res. 2007;31:599–604.PubMedGoogle Scholar
  100. 100.
    Larson RA, Sievers EL, Stadtmaeur EA, et al. Final report of the efficacy and safety of gemtuzumab ozogamicin (Mylotarg) in patients with CD33-positive acute myeloid leukemia in first recurrence. Cancer. 2005;104:1442–52.PubMedGoogle Scholar
  101. 101.
    Maniecki MB, Hasle H, Fris-Hansen L, et al. Impaired CD163-mediated hemoglobin-scavenging and severe toxic symptoms in patients treated with gemtuzumab ozogamicin. Blood. 2008;112:1510–4.PubMedGoogle Scholar
  102. 102.
    Maniecki MB, Hasle H, Bendix K, et al. Is hepatotoxicity in patients treated with gentuzumab ozogamicin due to specific targeting of hepatocytes? Leuk Res. 2011;35:e84–6.PubMedGoogle Scholar
  103. 103.
    Lo Coco F, Ammatuna E, Noguera N. Treatment of acute promyelocytic leukemia with gemtuzumab ozogamicin. Clin Adv Hematol Oncol. 2006;4:57–62.PubMedGoogle Scholar
  104. 104.
    Candoni A, Damiani D, Michelutti A, et al. Clinical characteristics, prognostic factors and multidrug resistance related protein expression in 36 adult patients with acute promyelocytic leukemia. Eur J Haematol. 2003;71:1–8.PubMedGoogle Scholar
  105. 105.
    Burnett AK, Hills RK, Milligan D, et al. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011;29:369–77.PubMedGoogle Scholar
  106. 106.
    Prebet T, Etienne A, Devillier R, et al. Improved outcome of patients with low- and intermediate-risk cytogenetics acute myeloid leukemia (AML) in first relapse with gemtuzumab and cytarabine versus cytarabrine: results of a retrospective comparative study. Cancer. 2011;117:974–81.PubMedGoogle Scholar
  107. 107.
    Manoukian G, Hagemeister F. Denileukin diftitox: a novel immunotoxin. Expert Opin Biol Ther. 2009;9:1445–51.PubMedGoogle Scholar
  108. 108.
    Martin A, Gutierrez E, Muglia J, et al. A multicenter dose-escalation trial with denileukin diftitox (ONTAK, DAB389IL-2) in patients with severe psoriasis. J Am Acad Dermatol. 2001;45:871–8.PubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2015

Authors and Affiliations

  1. 1.Centers for Therapeutic Innovation (CTI)Pfizer Inc.New YorkUSA

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