Skip to main content
SpringerLink
Log in

Preclinical investigation of the antitumour effects of anti-CD19-idarubicin immunoconjugates

  • Original Articles
  • Idarubicin, Immunoconjugate, Lymphoma, Anti-DC19, Immunochemotherapy
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Idarubicin (Ida), an analogue of daunomycin, was linked to a mouse monoclonal antibody against the B cell differentiation antigen CD19. Determination of the activity of both the antibody and drug moieties was carried out in vitro using a pre-B cell human acute lymphoblastic leukaemia cell line (NALM-6). A 23% loss in antibody binding and a 20-fold loss in drug activity were observed upon conjugation. Selective cytotoxicity for CD19+ cells, however, was obtained. Measurement of the cytotoxicity, antibody activity and release of the breakdown product, 14-OH-Ida, showed that the conjugates remained stable for more than 100 days after lyophilization and storage at −20° C. In vivo studies were performed in irradiatednu/nu mice bearing NALM-6 tumours. Initial dose response studies with free idarubicin demonstrated that three i.p. doses (every other day) of 10 μg resulted in little antitumour activity, but the death of all the animals by day 23. The same treatment regime using 15 μg Ida-anti-CD19 conjugate caused the disappearance of four out of five tumours with three complete cures and no evidence of toxicity as assessed by weight loss. Administration of a conjugate of idarubicin with an irrelevant antibody at this dose led to no significant antitumour response. The administration of free drug at a dose of 6 μg resulted in a minor antitumour response but high toxicity, whereas injection of Ida-anti-CD19 conjugate at this dose caused no toxicity and a substantial antitumour effect with eradication of two out of five tumours. These results clearly demonstrate that the administration of Ida-anti-CD19 conjugates can result in complete tumour regression in an experimental model. Idarubicin-containing immunoconjugates should be useful for the treatment of patients with non-Hodgkin's lymphoma.

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

Similar content being viewed by others

References

  1. Andrew SM, Teh JG, Johnstone RW, Russell SM, Whitehead RH, McKenzie IFC, Pietersz GA (1990) Tumor localisation by combinations of monoclonal antibodies in a new human colon carcinoma cell line (LIM 1899). Cancer Res 50: 5225

    PubMed  Google Scholar 

  2. Blakey DC, Watson GJ, Knowles PP, Thorpe PE (1987) Effect of chemical deglycosylation of ricin A chain on the in vivo fate and cytotoxic activity of an immunotoxin composed of ricin A chain and anti-Thy 1.1. antibody. Cancer Res 47: 947

    PubMed  Google Scholar 

  3. Bonfante V, Ferrari L, Villani F, Bonadonna G (1983) Phase I study of 4-demethoxy-daunorubicin. Invest New Drugs 1: 161

    PubMed  Google Scholar 

  4. Bradford MM (1976) A rapid and sensitive method of quantitation of microgram quantities of protein utilising the principle of protein dye binding. Anal Biochem 72: 248

    PubMed  Google Scholar 

  5. Braslawsky GR, Edson MA, Pearce W, Kaneko T, Greenfield RS (1990) Antitumor activity of adriamycin (hydrazone-linked) immunoconjugates compared with free adriamycin and specificity of tumor cell killing. Cancer Res 50: 6608

    PubMed  Google Scholar 

  6. Case DC Jr, Hayes DM, Gerber M, Gams R, Ervin TJ, Dorsk BM (1990) Phase II study of oral idarubicin in favorable histology non-Hodgkins lymphoma. Cancer Res 50: 6883

    Google Scholar 

  7. De Rie MA, Zeijlemaker WP, and von dem Borne AE (1988) Inhibition by vinca alkaloids and colchicine of antigenic modulation induced by anti-CD19 monoclonal antibodies. Leukemia Res 12: 135

    Google Scholar 

  8. DeVita VT (1985) Principles of chemotherapy. In: DeVita VT, Hellman S, Rosenberg SA (eds) Cancer; principles and practice of oncology. Lippincott, Philadelphia, pp 257–284

    Google Scholar 

  9. Dillman RO (1990) Human antimouse and antiglobulin responses to monoclonal antibodies. Antibody Immunoconjugates and Radiopharmaceuticals 3: 1

    Google Scholar 

  10. Dillman RO, Shawler DL, Johnson DE, Meyer DL, Koziol JA, Frincke JM (1986) Comparative preclinical trials with combinations and conjugates of T101 and doxorubicin. Cancer Res 46: 4886

    PubMed  Google Scholar 

  11. Ey PL, Prowse SJ, Jenkin CR (1978) Isolation of pure IgG1, IgG2 a and IgG2b immunoglobulins from mouse serum using protein A Sepharose. Immunochemistry 15: 429

    PubMed  Google Scholar 

  12. Foley GE, Lazarus H, Farber S, Uzman BG, Boone BA, McCarthy RE (1965) Continuous culture of human lymphoblasts from peripheral blood of a child with acute leukemia. Cancer 18: 522

    PubMed  Google Scholar 

  13. Ghetie MA, May RD, Till M, Uhr JW, Ghetie V, Knowles PP, Relf M, Brown A, Wallace PM, Janossy G, Amlot P, Vitetta ES, Thorpe PE (1988) Evaluation of ricin A chain-containing immunotoxins directed against CD19 and CD22 antigens on normal and malignant human B-cells as potential reagents for in vivo therapy. Cancer Res 48: 2610

    PubMed  Google Scholar 

  14. Grossbard ML, Freedman AS, Ritz J, Coral F, Goldmacher VS, Eliseo L, Spector N, Dear K, Lambert JM, Blattler WA, Taylor JA, Nadler LM (1992) Serotherapy of B-cell neoplasms with anti-B4-blocked-ricin-a: phase I trial of daily bolus infusion. Blood 79: 576

    PubMed  Google Scholar 

  15. Haruta Y, Seon BK (1986) Distinct human leukemia-associated cell surface glycoprotein GP160 defined by monoclonal antibody SN6. Proc Natl Acad Sci USA 83: 7898

    PubMed  Google Scholar 

  16. Hekman A, Honselaar A, Vuist WMJ, Sein JJ, Rodenhuis S, ten Bokkel-Huinink WW, Somers R, Rumke PH, Melief CJ (1991) Initial experience with treatment of human B cell lymphoma with anti-CD19 monoclonal antibody. Cancer Immunol Immunother 32: 364

    PubMed  Google Scholar 

  17. Herlyn D, Lubeck M, Steplewski Z, Kowprowski H (1985) Destruction of human tumors by IgG2 a monoclonal antibodies and macrophages. In: Reisfeld RA, Sell S (eds) Monoclonal antibodies and cancer therapy. Alan R. Liss, New York, pp 165–172

    Google Scholar 

  18. Hertler AA, Frankel AE (1989) Immunotoxins: a clinical review of their use in the treatment of malignancies. J Clin Oncol 1: 1932

    Google Scholar 

  19. Kaplan S, Sessa C, Willems Y, Pacciarini MA, Tamassia V, Cavalli F (1984) Phase I trial of 4-demethoxydaunorubicin (idarubicin) with single oral doses. Invest New Drugs 2: 281

    PubMed  Google Scholar 

  20. Lambert JM, Goldmacher VS, Collinson AR, Nadler LM, Blattler WA (1991) An immunotoxin prepared with blocked ricin: a natural plant toxin adapted for therapeutic use. Cancer Res 51: 6236

    PubMed  Google Scholar 

  21. Meeker TC, Lowder J, Maloney DG, Miller RA, Thielemans K, Warnke R, Levy R (1985) A clinical trial of anti-idotype therapy for B cell malignancy. Blood 65: 1349

    PubMed  Google Scholar 

  22. McMichael AJ (1987) Leukocyte typing III. Oxford University Press, Oxford, pp 302–363, 432–469

    Google Scholar 

  23. Pietersz GA, Smyth MJ, McKenzie IFC (1988) Immunochemotherapy of a murine thymoma with the use of idarubicin monoclonal antibody conjugates. Cancer Res 48: 926

    PubMed  Google Scholar 

  24. Pietersz GA and McKenzie IFC (1992) Antibody conjugates for the treatment of cancer. Immunological Reviews 129: 57

    PubMed  Google Scholar 

  25. Pimm MV (1988) Drug-monoclonal antibody conjugates for cancer therapy: potentials and limitations. CRC Crit Rev Ther Drug Carrier Syst 5: 189

    Google Scholar 

  26. Press OW, Farr AG, Borroz I, Anderson SK, Martin PJ (1981) Endocytosis and degradation of monoclonal antibodies targeting human B-cell malignancies. Cancer Res 49: 4906

    Google Scholar 

  27. Press OW, Appelbaum F, Ledbetter JA, Martin PJ, Zarling J, Kidd P, Thomas ED (1987) Monoclonal antibody IF5 (Anti-CD20) serotherapy of human B cell lymphomas. Blood 69: 584

    PubMed  Google Scholar 

  28. Press OW, Eary J, Badger C, Martin PJ, Appelbaum F, Levy R, Miller R, Brown S, Nelp WB, Krohn KA, Fisher D, De Santes K, Porter B, Kidd P, Thomas ED, Bernstein ID (1989) Treatment of refractory non-Hodgkin's lymphoma with radiolabelled MB-1 (anti-CD37) antibody. J Clin Oncol 7: 1027

    PubMed  Google Scholar 

  29. Rankin EM, Hekman A, Somers R, ten Bokkel-Huinink W (1985) Treatment of two patients with B cell lymphoma with monoclonal anti-idiotype antibodies. Blood 65: 1373

    PubMed  Google Scholar 

  30. Smyth MJ, Pietersz GA, Classon BJ, McKenzie IFC (1986) Specific targeting of chlorambucil to tumors with the use of monoclonal antibodies. JNCI 76: 503

    PubMed  Google Scholar 

  31. Smyth MJ, Bogdanovski M, McKenzie IFC, Pietersz GA (1991) Antitumor activity of idarubicin-monoclonal antibody conjugates in a disseminated thymic lymphoma model. Cancer Res 51: 310

    PubMed  Google Scholar 

  32. Sole-Rodriguez AM, Uhr JW, Richardson J, Vitetta ES (1992) The toxicity of chemically deglycosylated ricin A-chain in mice. Int J Immunopharmacol 14: 281

    PubMed  Google Scholar 

  33. Sung C, Shockley TR, Morrison PF, Dvorak HF, Yarmush ML, Dedrick RL (1992) Predicted and observed effects of antibody affinity and antigen density on monoclonal antibody uptake in solid tumors. Cancer Res 52: 377

    PubMed  Google Scholar 

  34. Teh J-G, Thompson CH, McKenzie IFC (1987) Production of monoclonal antibodies to serum antigens in colorectal carcinoma. J Immunol Methods 110: 101

    Google Scholar 

  35. Thorpe PE, Detre SI, Foxwell BMJ, Brown ANF, Skilleter DN, Wilson G, Forrester JA, Stirpe F (1985) Modification of the carbohydrate in ricin with metaperiodate-cyanoborohydride mixtures. Effects on toxicity and in vivo distribution. Eur J Biochem 147: 197

    PubMed  Google Scholar 

  36. Uckun FM, Jaszcz W, Ambrus JL, Fauci AS, Gajl-Peczalska K, Song CW, Wick MR, Myers DE, Waddick K, Ledbetter JA (1988) Detailed studies on expression and function of CD19 surface determinant by using B43 monoclonal antibody and the clinical potential of anti-CD19 immunotoxins. Blood 71: 13

    PubMed  Google Scholar 

  37. Vitetta ES, Stone M, Amlot P, Fay J, May R, Till M, Newman J, Clark P, Collins R, Cunningham D, Ghetie B, Uhr JW, Thorpe PE (1991) Phase I immunotoxin trial in patients with B-cell lymphoma. Cancer Res 51: 4052

    PubMed  Google Scholar 

  38. Zola H (1987) The surface antigens of human B lymphocytes. Immunol Today 8: 308

    Google Scholar 

  39. Zola H, MacArdle PJ, Bradford T, Weedon H, Yasui H, Kurosawa Y (1991) Preparation and characterization of a chimeric CD19 monoclonal antibody. Immunol Cell Biol 69: 411

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Austin Research Institute, Austin Hospital, Studley Road, 3084, Heidelberg, VIC, Australia

    A. J. Rowland, G. A. Pietersz & I. F. C. McKenzie

Authors
  1. A. J. Rowland
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G. A. Pietersz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. I. F. C. McKenzie
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rowland, A.J., Pietersz, G.A. & McKenzie, I.F.C. Preclinical investigation of the antitumour effects of anti-CD19-idarubicin immunoconjugates. Cancer Immunol Immunother 37, 195–202 (1993). https://doi.org/10.1007/BF01525435

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01525435

Key words

Search

Navigation