Skip to main content

Advertisement

SpringerLink
Log in

CD20-specific antibody-targeted chemotherapy of non-Hodgkin’s B-cell lymphoma using calicheamicin-conjugated rituximab

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Tumor-targeted delivery of a potent cytotoxic agent, calicheamicin, using its immunoconjugates is a clinically validated therapeutic strategy. Rituximab is a human CD20-specific chimeric antibody extensively used in B-NHL therapy. We investigated whether conjugation to calicheamicin can improve the anti-tumor activity of rituximab against human B-cell lymphoma (BCL) xenografts in preclinical models. BCL cells were cultured with rituximab or its calicheamicin conjugates and their in vitro growth was monitored. BCL cells were injected s.c. to establish localized xenografts in nude mice or i.v. to establish disseminated BCL in severe combined immunodeficient (scid) mice. I.p. treatment with rituximab or its calicheamicin conjugates was initiated and its effect on s.c. BCL growth or survival of mice with disseminated BCL was monitored. Conjugation of calicheamicin to rituximab vastly enhanced its growth inhibitory activity against BCL in vitro. Conjugation to calicheamicin had no deleterious effect on the effector functional activity of rituximab. Calicheamicin conjugated to rituximab with an acid-labile linker exhibited greater anti-tumor activity against s.c. BCL xenografts and improved survival of mice with disseminated BCL over that of unconjugated rituximab. Anti-tumor activities of rituximab conjugated to calicheamicin via an acid-stable linker were similar to that of unconjugated rituximab. Superior anti-tumor efficacy exhibited by a calicheamicin immunoconjugate of rituximab with an acid-labile linker over that of rituximab demonstrates the therapeutic potential of CD20-specific antibody-targeted chemotherapy strategy in the treatment of B-NHL.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

BCL:

B-cell lymphoma

CalichDM:

N-Acetyl gamma calicheamicin dimethyl derivative(s)

CalichDMH:

CalichDM hydrazide

References

  1. Damle NK (2004) Tumor-targeted chemotherapy with immunoconjugates of calicheamicin. Expert Opin Biol Ther 4:1445–1452

    Article  PubMed  CAS  Google Scholar 

  2. Bross PF, Beitz J, Chen G et al (2001) Gemtuzumab ozogamicin: approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin Cancer Res 7:1490–1496

    PubMed  CAS  Google Scholar 

  3. 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

    PubMed  CAS  Google Scholar 

  4. Sievers E, Larson R, Stadmauer E 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

    PubMed  CAS  Google Scholar 

  5. Hamann PR, Hinman LM, Hollander I et al (2002) A potent and selective anti-CD33 antibody-calicheamicin conjugate for treatment of acute myeloid leukemia. Bioconj Chem 13:47–58

    Article  CAS  Google Scholar 

  6. Lee M, Dunne T, Chang C et al. (1992) Calicheamicins, a novel family of antibiotics. 4. Structural elucidations of calicheamicins. J Am Chem Soc 114:985–987

    Article  CAS  Google Scholar 

  7. Zein N, Sinha A, McGahren W, Ellestad G (1988) Calicheamicin γI: an antitumor antibiotic that cleaves double-stranded DNA site specifically. Science 240:1198–1201

    Article  PubMed  CAS  Google Scholar 

  8. Grillo-Lopez A (2003) Rituximab (Rituxan/MabThera): the first decade (1993–2003). Expert Rev Anticancer Ther 3:767–779

    Article  PubMed  CAS  Google Scholar 

  9. Ghobrial I, Witzig T (2004) Radioimmunotherapy: a new treatment modality for B-cell non-Hodgkin’s lymphoma. Oncology 18:623–630

    PubMed  Google Scholar 

  10. Uchida J, Hamaguchi Y, Oliver JA et al (2004) The innate mononuclear phagocyte network depletes B lymphocytes through Fc receptor-dependent mechanisms during anti-CD20 antibody immunotherapy. J Exp Med 199:1659–1669

    Article  PubMed  CAS  Google Scholar 

  11. Gaetano ND, Cittera E, Nota R et al (2003) Complement activation determines the therapeutic activity of rituximab in vivo. J Immunol 171:1581–1587

    PubMed  Google Scholar 

  12. Manches O, Lui G, Chaperot L et al (2003) In vitro mechanisms of action of rituximab on primary non-Hodgkin lymphomas. Blood 101:949–954

    Article  PubMed  CAS  Google Scholar 

  13. Hainsworth JD, Litchy S, Burris HA et al (2002) Rituximab as first-line and maintenance therapy for patients with indolent non-Hodgkin’s lymphoma. J Clin Oncology 20:4261–4267

    Article  CAS  Google Scholar 

  14. Edwards JC, Szczepanski L, Szechinski J et al (2004) Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 350:2572–2581

    Article  PubMed  CAS  Google Scholar 

  15. DiJoseph JF, Armellino DC, Boghaert E et al (2004) Antibody-targeted chemotherapy with CMC-544: a CD22-targeted immunoconjugate of calicheamicin for the treatment of B lymphoid malignancies. Blood 103:1807–1814

    Article  PubMed  CAS  Google Scholar 

  16. Advani A, Giné E, Gisselbrecht C et al (2005) Preliminary report of a phase 1 study of cmc-544, an antibody-targeted chemotherapy agent, in patients with b-cell non-Hodgkin’s lymphoma (NHL). Blood 106(11): abstract No. 230

  17. DiJoseph JF, Dougher MM, Kalyandrug LB et al (2006) Antitumor efficacy of a combination of CMC-544 (inotuzumab ozogamicin), a CD22-targeted cytotoxic immunoconjugate of calicheamicin, and rituximab against non-Hodgkin’s B-cell lymphoma. Clin Cancer Res 12:242–249

    Article  PubMed  CAS  Google Scholar 

  18. DiJoseph JF, Goad ME, Dougher MM et al (2004) Potent and specific anti-tumor efficacy of CMC-544, a CD22-targeted immunoconjugate of calicheamicin, against systemically disseminated B-cell lymphoma. Clin Cancer Res 10:8620–8629

    Article  PubMed  CAS  Google Scholar 

  19. Flavell DJ, Noss A, Pulford KAF, Ling N, Flavell SU (1997) Systemic therapy with 3BIT, a triple combination cocktail of anti-CD19, -CD22, and -CD38-saporin immunotoxins, is curative of human B-cell lymphoma in severe combined immunodeficient mice. Cancer Res 57:4824–4829

    PubMed  CAS  Google Scholar 

  20. Flavell DJ, Boehm DA, Emery L, Noss A, Ramsay A, Flavell SU (1995) Therapy of human B-cell lymphoma bearing SCID mice is more effective with anti-CD19- and anti-CD38-saporin immunotoxins used alone in combination than with either immunotoxin alone. Int J Cancer 62:337–344

    Article  PubMed  CAS  Google Scholar 

  21. Hinman LM, Hamann PR, Wallace R, Menendez AT, Dur FE, Upeslacis J (2003) Preparation and characterization of monoclonal antibody conjugates of the calicheamicins: a novel and potent family of antitumor antibiotics. Cancer Res 53:3336–3342

    Google Scholar 

  22. Hamann P, Hinman L, Beyer C et al (2002) An anti-CD33 antibody–calicheamicin conjugate for treatment of acute myeloid leukemia. Choice of linker. Bioconj. Chem 13:40–46

    Article  CAS  Google Scholar 

  23. DiJoseph JF, Popplewell A, Tickle S et al (2005) Antibody-targeted chemotherapy of B-cell lymphoma using calicheamicin conjugated to murine or humanized antibody against CD22. Cancer Immunol Immunother 54:11–24

    Article  PubMed  CAS  Google Scholar 

  24. Press OW, Farr AG, Borroz KI, Anderson SK, Martin PJ (1989) Endocytosis and degradation of monoclonal antibodies targeting human B-cell malignancies. Cancer Res 49:4906–4912

    PubMed  CAS  Google Scholar 

  25. Vangeepuram N, Ong GL, Mattes MJ (1997) Processing of antibodies bound to B-cell lymphomas and lymphoblastoid cell lines. Cancer 80(Suppl):2425–2430

    Article  PubMed  CAS  Google Scholar 

  26. Law CL, Cerveny CG, Gordon KA et al (2004) Efficient elimination of B-lineage lymphomas by anti-CD20–Auristatin conjugates. Clin Cancer Res 10:7842–7851

    Article  PubMed  CAS  Google Scholar 

  27. Vervoordeldonk SF, Merle PA, van Leeuwen EF, van der Schoot CE, von dem Borne AE, Slaper-Cortenbach IC (1994) Fc gamma receptor II (CD32) on malignant B cells influences modulation induced by anti-CD19 monoclonal antibody. Blood 83:1632–1639

    PubMed  CAS  Google Scholar 

  28. Van Den Herik-Oudijk IE, Westerdaal NA, Henriquez NV, Capel PJ, Van De Winkel JG (1994) Functional analysis of human Fc gamma RII (CD32) isoforms expressed in B lymphocytes. J Immunol 152:574–585

    Google Scholar 

  29. Flieger D, Renoth S, Beier I, Sauerbruch T, Schmidt-Wolf I (2000) Mechanism of cytotoxicity induced by chimeric mouse human monoclonal antibody IDEC-C2B8 in CD20-expressing lymphoma cell lines. Cell Immunol 205:55–63

    Article  Google Scholar 

  30. Miettinen HM, Matter K, Hunzinker W et al (1992) Fc receptor endocytosis is controlled by a cytoplasmic domain determinant that actively prevents coated pit localization. J Cell Biol 116:875–888

    Article  PubMed  CAS  Google Scholar 

  31. Costello LC, Franklin RB (2005) ‘Why do tumour cells glycolyse?’: from glycolysis through citrate to lipogenesis. Mol Cell Biochem 280:1–8

    Article  PubMed  CAS  Google Scholar 

  32. Boghaert ER, Khanke K, Sridharan L et al (2006) Tumoricidal effect of calicheamicin immuno-conjugates using a passive targeting strategy. Int J Oncol 28:675–684

    PubMed  CAS  Google Scholar 

  33. Harder T, Engelhardt (2004) Membrane domains in lymphocytes-from lipid rafts to protein scaffolds. Traffic 5:265–275

  34. Polyak MJ, Tailor SH, Deans JP (1998) Identification of a cytoplasmic region of CD20 required for its redistribution to a detergent-insoluble membrane compartment. J Immunol 161:3242–3248

    PubMed  CAS  Google Scholar 

  35. Fujimoto M, Kuwano Y, Wananabe R et al (2006) B cell antigen receptor and CD40 differentially regulate CD22 tyrosine phosphorylation. J Immunol 176:873–879

    PubMed  CAS  Google Scholar 

  36. Gaetano ND, Cittera E, Nota R et al (2003) Complement activation determines the therapeutic activity of rituximab in vivo. J Immunol 171:1581–1587

    PubMed  Google Scholar 

  37. Cragg MS, Glennie MJ (2004) Antibody specificity controls effector mechanisms of anti-CD20 reagents. Blood 103:2738–2743

    Article  PubMed  CAS  Google Scholar 

  38. Cragg MS, Morgan SM, Claude Chan HT et al (2003) Complement-mediated lysis by anti-CD20 mAb correlated with segregation into lipid rafts. Blood 101:1045–1052

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Fred Immermann of Wyeth Biometrics Research for statistical analysis of the data.

Author information

Authors and Affiliations

  1. Oncology Discovery, Wyeth Research, 200/4604, 401 North Middletown Road, Pearl River, NY, 10965, USA

    John F. DiJoseph, Maureen M. Dougher, Douglas C. Armellino, Lyka Kalyandrug, Erwin R. Boghaert & Nitin K. Damle

  2. Chemical and Screening Sciences, Wyeth Research, Pearl River, NY, USA

    Arthur Kunz & Philip R. Hamann

Authors
  1. John F. DiJoseph
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maureen M. Dougher
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Douglas C. Armellino
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lyka Kalyandrug
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Arthur Kunz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Erwin R. Boghaert
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Philip R. Hamann
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Nitin K. Damle
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nitin K. Damle.

Additional information

All authors are employed by Wyeth Research.

Rights and permissions

Reprints and permissions

About this article

Cite this article

DiJoseph, J.F., Dougher, M.M., Armellino, D.C. et al. CD20-specific antibody-targeted chemotherapy of non-Hodgkin’s B-cell lymphoma using calicheamicin-conjugated rituximab. Cancer Immunol Immunother 56, 1107–1117 (2007). https://doi.org/10.1007/s00262-006-0260-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-006-0260-5

Keywords

Search

Navigation