Current Oncology Reports

, 13:386

Ongoing Development of Monoclonal Antibodies and Antibody Drug-Conjugates in Lymphoma



Rituximab, a monoclonal antibody (mAb) directed against CD20, has changed practices in the treatment of patients with B-cell lymphoma. The large success of rituximab has contributed to validate immunotherapy with monoclonal antibodies as a valuable strategy in lymphoma. Recently, better-engineered anti-CD20-mAbs have been designed to improve efficacy and safety. Also, new antibodies targeting other lymphoma subtypes including T-cell lymphoma and Hodgkin’s disease have been developed. Ongoing pharmacology development is concentrating on immuno-drug-conjugates combining the toxicity of chemotherapy, isotopes, or toxins with the specificity of mAbs. This article offers an overview on the development of new antibodies and immuno conjugates in lymphoma.


Lymphoma Monoclonal antibodies Drug-conjugates Radioimmunotherapy 


Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    • Alduaij W, Illidge TM. The future of anti-CD20 monoclonal antibodies: are we making progress? Blood. 2011;117:(11)2993–3001. Epub 2011 Jan 5. This is a nice update on anti-CD20 therapeutic antibodies PubMedCrossRefGoogle Scholar
  2. 2.
    Teeling JL, French RR, Cragg MS, et al. Characterization of new human CD20 monoclonal antibodies with potent cytolytic activity against non-Hodgkin lymphomas. Blood. 2004;104(6):1793–800.PubMedCrossRefGoogle Scholar
  3. 3.
    van Meerten T, Rozemuller H, Holet S, et al. HuMab-7D8, a monoclonal antibody directed against the membrane-proximal small loop epitope of CD20 can effectively eliminate CD20 low expressing tumor cells that resist rituximab-mediated lysis. Haematologica. 2010;95(12):2063–71.PubMedCrossRefGoogle Scholar
  4. 4.
    Hagenbeek A, Gadeberg O, Johnson P, et al. First clinical use of ofatumumab, a novel fully human anti-CD20 monoclonal antibody in relapsed or refractory follicular lymphoma: results of a phase 1/2 trial. Blood. 2008;111(12):5486–95.PubMedCrossRefGoogle Scholar
  5. 5.
    • Hagenbeek A. Fayad L., Delwail V, et al. Evaluation of Ofatumumab, a novel human CD20 monoclonal antibody, as single agent therapy in Rituximab-Refractory Follicular Lymphoma. ASH2009. Important reference showing how difficult it is to improve efficacy of new antibodies in rituximab-refractory patients. Google Scholar
  6. 6.
    Clinical trials:
  7. 7.
    Morschhauser F, Leonard JP, Fayad L, et al. Humanized anti-CD20 antibody, veltuzumab, in refractory/recurrent non-Hodgkin’s lymphoma: phase I/II results. J Clin Oncol. 2009;27(20):3346–53.PubMedCrossRefGoogle Scholar
  8. 8.
    • Negrea OG, Elstrom R, Allen SL, et al. Subcutaneous injections of low-dose veltuzumab (humanized anti-CD20 antibody) are safe and active in patients with indolent non-Hodgkin lymphoma. Haematologica. 2010; First report that an anti-CD20 SC, veltuzumab, has activity in indolent lymphoma. Google Scholar
  9. 9.
    Morschhauser F, Marlton P, Vitolo U, et al. Results of a phase I/II study of ocrelizumab, a fully humanized anti-CD20 mAb, in patients with relapsed/refractory follicular lymphoma. Ann Oncol. 2010;21(9):1870–6. Epub 2010 Feb 15.PubMedCrossRefGoogle Scholar
  10. 10.
    Friedberg JW, Vose JM, et al. A phase I study of PRO131921, a novel anti-CD20 monoclonal antibody in patients with relapsed/refractory CD20+ Indolent NHL: correlation between clinical responses and AUC Pharmacokinetics ASH 2010.Google Scholar
  11. 11.
    Tobinai K, Ogura K, Kobayashi Y, et al. Phase I study of LY2469298, an Fc-engineered humanized anti-CD20 antibody, in patients with relapsed or refractory follicular lymphoma. Cancer Sci. 2011;102(2):432–8.PubMedCrossRefGoogle Scholar
  12. 12.
    Cartron G, Cazin B, Coiffier B, et al. A phase I study of LFB-R603, a novel anti-CD20 antibody, in patients with relapsed Chronic Lymphocytic Leukemia (CLL) ASH 2010.Google Scholar
  13. 13.
    Sehn LH, et al. A phase I study of GA101 (RO5072759) monotherapy followed by maintenance in patients with multiply relapsed/refractory CD20+ Malignant Disease ASH 2009.Google Scholar
  14. 14.
    Salles GA, Morschhauser F, Thieblemont C, et al. Promising efficacy with the new anti-CD20 antibody GA101 in heavily pre-treated patients- first results from a phase II study in patients with relapsed/refractory indolent NHL. Haematologica. 2010;95(Suppl2):229. abs. 0558.Google Scholar
  15. 15.
    • Salles A, Morschhauser F, Thieblemont C, et al. Promising efficacy with the new anti-CD20 antibody GA101 in heavily pre-treated NHL patients – updated results with encouraging Progression Free Survival (PFS) data from a phase II study in patients with relapsed/refractory Indolent NHL (iNHL) ASH 2010; Obitumomab, a type II antibody, has promising efficacy with data suggesting a dose-efficacy relationship in indolent NHL. Google Scholar
  16. 16.
    • Press OW, Unger JM, Braziel RM, et al. Phase II trial of CHOP chemotherapy followed by tositumomab/iodine I-131 tositumomab for previously untreated follicular non-Hodgkin’s lymphoma: five-year follow-up of Southwest Oncology Group Protocol S9911. J Clin Oncol. 1;24:(25)4143–9. Epub 2006 Aug 8. Best PFS results so far in a phase 2 study of RIT consolidation in indolent NHL. PubMedCrossRefGoogle Scholar
  17. 17.
    Link BK, Martin P, Kaminski MS, et al. Cyclophosphamide, vincristine, and prednisone followed by tositumomab and iodine-131-tositumomab in patients with untreated low-grade follicular lymphoma: eight-year follow-up of a multicenter phase II study. J Clin Oncol. 2010;28(18):3035–41. Epub 2010 May 10.PubMedCrossRefGoogle Scholar
  18. 18.
    • Morschhauser F, Radford J, Van Hoof A, et al. Phase III trial of consolidation therapy with yttrium-90-ibritumomab tiuxetan compared with no additional therapy after first remission in advanced follicular lymphoma. J Clin Oncol. 2008;26:(32)5156–64. Epub 2008 Oct 14. First phase 3 trial in first-line FL showing a 3-year PFS benefit for RIT consolidation with an acceptable safety profile. PubMedCrossRefGoogle Scholar
  19. 19.
    Scholz CW, Pinto A, Linkesch W, et al. 90Yttrium Ibritumomab Tiuxetan as first line treatment for follicular lymphoma. First results from an International Phase II Clinical Trial ASH 2010.Google Scholar
  20. 20.
    Zinzani PL, Tani M, Fanti S, et al. A phase II trial of Rituximab-CHOP chemotherapy followed by Yttrium 90 (90Y) Ibritumomab Tiuxetan (90Y-IT) for previously untreated elderly diffuse large B-cell lymphoma (DLBCL). Ann Oncol. 2008;19(4):769–73. Epub 2008 Feb 25.PubMedCrossRefGoogle Scholar
  21. 21.
    Hamlin PA, et al. Sequential R-CHOP and Ibritumomab Tiuxetan (Zevalin(R) regimen produces impressive survival rates in high risk elderly patients with untreated aggressive diffuse large B-cell lymphoma Lugano. 2008.Google Scholar
  22. 22.
    Lohri A, Forrer F, Campana1 B. et al. Radioimmunotherapy (RIT) with 177 Lutetium-DOTA-Rituximab (177LU-D-R): a phase I/II-study in 30 patients with relapsing follicular, mantle cell and other indolent B-Cell lymphomas ASH 2008.Google Scholar
  23. 23.
    Xuan C, Steward KK, Timmerman JM, et al. Targeted delivery of interferon-alpha via fusion to anti-CD20 results in potent antitumor activity against B-cell lymphoma. Blood. 2010;115(14):2864–71.PubMedCrossRefGoogle Scholar
  24. 24.
    O’Mahony D, Morris JC, Stetler-Stevenson M, et al. EBV-related lymphoproliferative disease complicating therapy with the anti-CD2 monoclonal antibody, siplizumab, in patients with T-cell malignancies. Clin Cancer Res. 2009;15(7):2514–22.PubMedCrossRefGoogle Scholar
  25. 25.
    Kim YH, Duvic M, Obitz E, et al. Clinical efficacy of zanolimumab (HuMax-CD4): two phase 2 studies in refractory cutaneous T-cell lymphoma. Blood. 2007;109(11):4655–62. Epub 2007 Feb 20.PubMedCrossRefGoogle Scholar
  26. 26.
    D’amore F, Radford J, Relander T, et al. Phase II trial of zanolimumab (HuMax-CD4) in relapsed or refractory non-cutaneous peripheral T cell lymphoma. Br J Haematol. 2010;150(5):565–73. Epub 2010 Jul 14.PubMedCrossRefGoogle Scholar
  27. 27.
    Yoshie O, Fujisawa R, Nakayama T, et al. Frequent expression of CCR4 in adult T-cell leukemia and human T-cell leukemia virus type 1-transformed T cells. Blood 99:1505–1511.Google Scholar
  28. 28.
    Yamamoto K, Ueda R, et al. Phase I study of KW-0761, a Defucosylated humanized anti-CCR4 antibody, in relapsed patients with adult T-Cell leukemia-lymphoma and peripheral T-Cell lymphoma. J Clin Oncol. 2010;28:1591–8.PubMedCrossRefGoogle Scholar
  29. 29.
    Ishida T, Tatsuro Joh, Naokuni Uike et al. Multicenter phase II study of KW-0761, a Defucosylated anti-CCR4 antibody, in relapsed patients with adult T-Cell leukemia-lymphoma (ATL) ASH 2010.Google Scholar
  30. 30.
    Younes A. Phase I multi-dose escalation study of the anti-CD19 Maytansinoid Immunoconjugate SAR3419 phase I multi-dose escalation study of the anti-CD19 Maytansinoid Immunoconjugate SAR3419 administered by intravenous (IV) infusion every 3 weeks to patients with relapsed/refractory B-Cell Non-Hodgkin’s Lymphoma (NHL)” (abstract #585).Google Scholar
  31. 31.
    Goebeler M, et al. Abstract 559 EHA 2010.Google Scholar
  32. 32.
    Leonard JP, Coleman M, Ketas JC, et al. Epratuzumab, a humanized anti-CD22 antibody, in aggressive non-Hodgkin’s lymphoma: phase I/II clinical trial results. Clin Cancer Res. 2004;10(16):5327–34.PubMedCrossRefGoogle Scholar
  33. 33.
    Grant B, Leonard JP, Johnson JL, et al. Combination biologic therapy as initial treatment for follicular lymphoma: initial results from CALGB 50701-a phase II trial of extended induction Epratuzumab (anti-CD22) and Rituximab (anti-CD20) ASH 2010.Google Scholar
  34. 34.
    Micallef IN, Kahl BS, Maurer MJ, et al. A pilot study of epratuzumab and rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy in patients with previously untreated, diffuse large B-cell lymphoma. Cancer. 2006;107(12):2826–32.PubMedCrossRefGoogle Scholar
  35. 35.
    Zhengxing Qu, Goldenberg DM, Thomas M, Cardillo TM, et al. Bispecific anti-CD20/22 antibodies inhibit B-cell lymphoma proliferation by a unique mechanism of action. 2007; doi: 10.1182/blood-2007-08-110072.
  36. 36.
    Takeshita A. - aff1#aff1 Yamakage N, Shinjo K, et al. CMC-544 (inotuzumab ozogamicin), an anti-CD22 immuno-conjugate of calicheamicin, alters the levels of target molecules of malignant B-cells leukemia (2009) 23, 1329–1336; doi:10.1038/leu.2009.77; published online 16 April 2009.
  37. 37.
    Goy A, Leach J, Ehmann WC, et al. Inotuzumab Ozogamicin (CMC-544) in patients with indolent B-Cell NHL that is refractory to Rituximab alone, Rituximab and chemotherapy, or Radioimmunotherapy: preliminary safety and efficacy from a phase 2 trial ASH2010.Google Scholar
  38. 38.
    Wagner-Johnston N, Goy A, Feldman T, et al. Anti-CD22 Immunoconjugate Inotuzumab Ozogamicin (CMC-544) + Rituximab in relapsed DLBCL patients followed by stem cell transplantation: preliminary safety and efficacy ASH 2010.Google Scholar
  39. 39.
    Polson AG, Williams M, Gray AM, et al. Anti-CD22-MCC-DM1: an antibody-drug conjugate with a stable linker for the treatment of non-Hodgkin’s lymphoma. Leukemia. 2010;24(9):1566–73. Epub 2010 Jul 1.PubMedCrossRefGoogle Scholar
  40. 40.
    Lindén O, Hindorf C, Cavallin-Ståhl E, et al. Dose-fractionated radioimmunotherapy in non-Hodgkin’s lymphoma using DOTA-conjugated, 90Y-radiolabeled, humanized anti-CD22 monoclonal antibody, epratuzumab. Clin Cancer Res. 2005;11(14):5215–22.PubMedCrossRefGoogle Scholar
  41. 41.
    Morschhauser F, Kraeber-Bodéré F, Wegener WA. High rates of durable responses with anti-CD22 fractionated radioimmunotherapy: results of a multicenter, phase I/II study in Non-Hodgkin’s lymphoma JCO. 2008.Google Scholar
  42. 42.
    Prince HM, Duvic M, Martin A, et al. Phase III placebo-controlled trial of denileukin diftitox for patients with cutaneous T-cell lymphoma. J Clin Oncol. 2010;28(11):1870–7. Epub 2010 Mar 8.PubMedCrossRefGoogle Scholar
  43. 43.
    Foss FM, Sjak-Shie NN, Goy A, et al. Phase II study of denileukin diftitox with CHOP chemotherapy in newly-diagnosed PTCL: CONCEPT trial. J Clin Oncol. 2010;28:15s, (suppl; abstr 8045).Google Scholar
  44. 44.
    Dancey G, Violet J, Malaroda A, et al. A phase I clinical trial of CHT-25 a 131I-labeled Chimeric anti-CD25 antibody showing efficacy in patients with refractory lymphoma. Clin Cancer Res. 2009;15(24):7701–10.PubMedCrossRefGoogle Scholar
  45. 45.
    Linden O. Remission of a refractory, anaplastic large-cell lymphoma after treatment with daclizumab. N Engl J Med. 2004;351(14):1466–67.Google Scholar
  46. 46.
    O’Mahony D, Janik JE, Carrasquillo JA, et al. Yttrium-90 Radiolabeled humanized monoclonal antibody to CD25 in refractory and relapsed Hodgkin’s lymphoma. ASH 2010.Google Scholar
  47. 47.
    Ansell SM, Horwitz SM, Engert A, et al. Phase I/II study of an anti-CD30 monoclonal antibody (MDX-060) in Hodgkin's lymphoma and anaplastic large-cell lymphoma. J Clin Oncol. 2007;25(19):2764–9. Epub 2007 May 21.PubMedCrossRefGoogle Scholar
  48. 48.
    Hartmann F. Anti-CD16/CD30 bispecific antibody treatment for Hodgkin’s disease: role of infusion schedule and costimulation with cytokines. Clin Cancer Res. 2001;7(7):1873–81.PubMedGoogle Scholar
  49. 49.
    • Younes A, et al. Brentuximab Vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med. 2010; 363:1812–1821 Immunoconjugates such as brentuximab have promising efficacy with interesting OR and CR rates in HD; best single-agent treatment observed in a long time in HL; proof of concept that CD30 is a valid target. PubMedCrossRefGoogle Scholar
  50. 50.
    Schnell R, Dietlein M, Staak JO, et al. Treatment of refractory Hodgkin’s lymphoma patients with an iodine-131-labeled murine anti-CD30 monoclonal antibody. J Clin Oncol. 2005;23(21):4669–78.PubMedCrossRefGoogle Scholar
  51. 51.
    Advani R. Phase I study of the humanized anti-CD40 monoclonal antibody dacetuzumab in refractory or recurrent non-Hodgkin’s lymphoma. J Clin Oncol. 2009;27(26):4371–7. Epub 2009 Jul 27.PubMedCrossRefGoogle Scholar
  52. 52.
    Freedman AS, Kuruvilla J, MD Assouline SE, et al. Clinical activity of lucatumumab (HCD122) in patients (pts) with relapsed/refractory Hodgkin or non-Hodgkin lymphoma treated in a phase Ia/II Clinical Trial (NCT00670592) ASH 2010.Google Scholar
  53. 53.
    Chao MP, Alizadeh AA, Tang C, et al. Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma. Cell. 2010;142(5):699–713.PubMedCrossRefGoogle Scholar
  54. 54.
    Enblad G, Hagberg H, Erlanson M, et al. A pilot study of alemptuzumab in patients with relapsed or refractory PTCL. Blood. 2004;103:2920–4.PubMedCrossRefGoogle Scholar
  55. 55.
    Lundin J, Hagberg H, Reep R, et al. Phase II study of alemtuzumab in patients with MM/SS. Blood. 2003;101:4267–72.PubMedCrossRefGoogle Scholar
  56. 56.
    Gallamini A, Zaja F, Patti C, et al. Alemtuzumab (Campath-1H) and CHOP chemotherapy as first-line treatment of peripheral T-cell lymphoma: results of a GITIL (Gruppo Italiano Terapie Innovative nei Linfomi) prospective multicenter trial. Blood. 2007;110(7):2316–23. Epub 2007 Jun 20.PubMedCrossRefGoogle Scholar
  57. 57.
    Kluin-Nelemans C, Marinus Van Marwijk Kooij M, Lugtenburg PJ. Alemtuzumab-CHOP for aggressive T cell lymphoma. A phase II HOVON 69 Trial ASH 2008.Google Scholar
  58. 58.
    Czuczman MS, Witzig TE, Younes A. Phase I/II study of galiximab, an anti-CD80 antibody, for relapsed or refractory follicular lymphoma. J Clin Oncol. 2005;23(19):4390–8.PubMedCrossRefGoogle Scholar
  59. 59.
    Leonard JP, Friedberg JW, Younes, et al. A phase I/II study of galiximab (an anti-CD80 monoclonal antibody) in combination with rituximab for relapsed or refractory, follicular lymphoma. Ann Oncol. 2007;18(7):1216–23.Google Scholar
  60. 60.
    Smith M, Bartlett N, Johnson JL, et al. Galiximab, an anti-CD80 primatized monoclonal antibody, in relapsed Hodgkin lymphoma: final results of CALGB 50602. ASCO Annual Meeting. 2010.Google Scholar
  61. 61.
    Zhang L, Wang Q, Wang X, et al. Anti-CD137 monoclonal antibody promotes the direct anti-tumor effect mediated by peripheral blood-derived human dendritic cells in vitro. Cell Mol Immunol. 2004;1(1):71–6.PubMedGoogle Scholar
  62. 62.
    Stopeck AT, Bellamy WW, Unger JJ. Phase II trial of single agent bevacizumab (Avastin) in patients with relapsed, aggressive non-Hodgkin’s lymphoma (NHL): southwest oncology group study S0108. Journal of Clinical Oncology, 2005 ASCO Annual Meeting Proceedings. Vol 23, No. 16S, Part I of II (June 1 Supplement), 2005: 6592.Google Scholar
  63. 63.
    Ganjoo KN, An CS, Robertson MJ, et al. Rituximab, bevacizumab and CHOP (RA-CHOP) in untreated diffuse large B-cell lymphoma: safety, biomarker and pharmacokinetic analysis Avastin (Bevacizumab) plus Adriamycin, Bleomycin, Vinblastine and Dacarbazine (ABVD) for advanced stage Hodgkin lymphoma NCT00722865.Google Scholar
  64. 64.
  65. 65.
    Younes A et al. A Phase 1b/2 trial of mapatumumab in patients with relapsed/refractory non-Hodgkin's lymphoma. Br J Cancer. 2010;103(12):1783–7. Lymphomas (Paul A. Hamlin, Section Editor).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of HematologyHôpital Claude Huriez, CHRULilleFrance
  2. 2.EA 4481 GRIIOT, Université de Lille 2Lille, CedexFrance

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