Logo of brjcancerBJC HomepageBJC Advance online publicationBJC Current IssueSubmitting an article to BJCWeb feeds
Br J Cancer. Dec 1995; 72(6): 1373–1379.
PMCID: PMC2034088

Preclinical studies with the anti-CD19-saporin immunotoxin BU12-SAPORIN for the treatment of human-B-cell tumours.

Abstract

The immunotoxin BU12-SAPORIN was constructed by covalently coupling the single-chain ribosome-inactivating protein saporin to the anti-CD19 monoclonal antibody BU12 via a disulphide linker using the heterobifunctional reagent SPDP. The immunoreactivity and specificity of BU12-SAPORIN was identical to that of unmodified native BU12 antibody. BU12-SAPORIN was selectively cytotoxic in vitro in a dose-dependent manner for the CD19+ human common acute lymphoblastic leukaemia (cALL) cell line NALM-6 but exhibited no toxicity for the CD19- T-cell acute lymphoblastic leukaemia (T-ALL) cell line HSB-2. The survival of severe combined immunodeficient (SCID) mice with disseminated NALM-6 leukaemia was significantly prolonged compared with sham-treated control animals by a course of therapy with BU12-SAPORIN but not with the irrelevant anti-CD7 immunotoxin HB2-SAPORIN. BU12-SAPORIN had no therapeutic effect in SCID mice with disseminated CD19- HSB-2 leukaemia. These preclinical studies have clearly demonstrated the selective cytotoxicity of BU12-SAPORIN for CD19+ target cells both in vitro and in vivo. This, taken together with the lack of expression of the CD19 molecule by any normal life-sustaining tissue and its ubiquitous and homogeneous expression by the majority of cALL and B-NHL cells, provides the rationale for undertaking a phase I trial of systemic therapy with BU12-SAPORIN.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.6M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Adams RA, Pothier L, Flowers A, Lazarus H, Farber S, Foley GE. The question of stemlines in human acute leukemia. Comparison of cells isolated in vitro and in vivo from a patient with acute lymphoblastic leukemia. Exp Cell Res. 1970 Sep;62(1):5–10. [PubMed]
  • de Rie MA, Schumacher TN, van Schijndel GM, van Lier RA, Miedema F. Regulatory role of CD19 molecules in B-cell activation and differentiation. Cell Immunol. 1989 Feb;118(2):368–381. [PubMed]
  • Dorshkind K, Pollack SB, Bosma MJ, Phillips RA. Natural killer (NK) cells are present in mice with severe combined immunodeficiency (scid). J Immunol. 1985 Jun;134(6):3798–3801. [PubMed]
  • Falini B, Bolognesi A, Flenghi L, Tazzari PL, Broe MK, Stein H, Dürkop H, Aversa F, Corneli P, Pizzolo G, et al. Response of refractory Hodgkin's disease to monoclonal anti-CD30 immunotoxin. Lancet. 1992 May 16;339(8803):1195–1196. [PubMed]
  • Fishwild DM, Aberle S, Bernhard SL, Kung AH. Efficacy of an anti-CD7-ricin A chain immunoconjugate in a novel murine model of human T-cell leukemia. Cancer Res. 1992 Jun 1;52(11):3056–3062. [PubMed]
  • Flavell DJ, Boehm DA, Okayama K, Kohler JA, Flavell SU. Therapy of human T-cell acute lymphoblastic leukaemia in severe combined immunodeficient mice with two different anti-CD7-saporin immunotoxins containing hindered or non-hindered disulphide cross-linkers. Int J Cancer. 1994 Aug 1;58(3):407–414. [PubMed]
  • Flavell DJ, Cooper S, Morland B, Flavell SU. Characteristics and performance of a bispecific F (ab'gamma)2 antibody for delivering saporin to a CD7+ human acute T-cell leukaemia cell line. Br J Cancer. 1991 Aug;64(2):274–280. [PMC free article] [PubMed]
  • Ghetie MA, Picker LJ, Richardson JA, Tucker K, Uhr JW, Vitetta ES. Anti-CD19 inhibits the growth of human B-cell tumor lines in vitro and of Daudi cells in SCID mice by inducing cell cycle arrest. Blood. 1994 Mar 1;83(5):1329–1336. [PubMed]
  • Ghetie MA, May RD, Till M, Uhr JW, Ghetie V, Knowles PP, Relf M, Brown A, Wallace PM, Janossy G, et al. 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. 1988 May 1;48(9):2610–2617. [PubMed]
  • Grossbard ML, Gribben JG, Freedman AS, Lambert JM, Kinsella J, Rabinowe SN, Eliseo L, Taylor JA, Blättler WA, Epstein CL, et al. Adjuvant immunotoxin therapy with anti-B4-blocked ricin after autologous bone marrow transplantation for patients with B-cell non-Hodgkin's lymphoma. Blood. 1993 May 1;81(9):2263–2271. [PubMed]
  • Grossbard ML, Lambert JM, Goldmacher VS, Spector NL, Kinsella J, Eliseo L, Coral F, Taylor JA, Blättler WA, Epstein CL, et al. Anti-B4-blocked ricin: a phase I trial of 7-day continuous infusion in patients with B-cell neoplasms. J Clin Oncol. 1993 Apr;11(4):726–737. [PubMed]
  • Hurwitz R, Hozier J, LeBien T, Minowada J, Gajl-Peczalska K, Kubonishi I, Kersey J. Characterization of a leukemic cell line of the pre-B phenotype. Int J Cancer. 1979 Feb;23(2):174–180. [PubMed]
  • Köhler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975 Aug 7;256(5517):495–497. [PubMed]
  • Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. [PubMed]
  • Lambert JM, Senter PD, Yau-Young A, Blättler WA, Goldmacher VS. Purified immunotoxins that are reactive with human lymphoid cells. Monoclonal antibodies conjugated to the ribosome-inactivating proteins gelonin and the pokeweed antiviral proteins. J Biol Chem. 1985 Oct 5;260(22):12035–12041. [PubMed]
  • Ling NR, Richardson PR. A critical appraisal of the direct antibody-rosette test for the detection of cell surface antigens. J Immunol Methods. 1981;47(3):265–274. [PubMed]
  • Morland BJ, Barley J, Boehm D, Flavell SU, Ghaleb N, Kohler JA, Okayama K, Wilkins B, Flavell DJ. Effectiveness of HB2 (anti-CD7)--saporin immunotoxin in an in vivo model of human T-cell leukaemia developed in severe combined immunodeficient mice. Br J Cancer. 1994 Feb;69(2):279–285. [PMC free article] [PubMed]
  • Schuurman HJ, van Baarlen J, Huppes W, Lam BW, Verdonck LF, van Unnik JA. Immunophenotyping of non-Hodgkin's lymphoma. Lack of correlation between immunophenotype and cell morphology. Am J Pathol. 1987 Oct;129(1):140–151. [PMC free article] [PubMed]
  • Shen GL, Li JL, Ghetie MA, Ghetie V, May RD, Till M, Brown AN, Relf M, Knowles P, Uhr JW, et al. Evaluation of four CD22 antibodies as ricin A chain-containing immunotoxins for the in vivo therapy of human B-cell leukemias and lymphomas. Int J Cancer. 1988 Nov 15;42(5):792–797. [PubMed]
  • Stirpe F, Gasperi-Campani A, Barbieri L, Falasca A, Abbondanza A, Stevens WA. Ribosome-inactivating proteins from the seeds of Saponaria officinalis L. (soapwort), of Agrostemma githago L. (corn cockle) and of Asparagus officinalis L. (asparagus), and from the latex of Hura crepitans L. (sandbox tree). Biochem J. 1983 Dec 15;216(3):617–625. [PMC free article] [PubMed]
  • Thorpe PE, Brown AN, Bremner JA, Jr, Foxwell BM, Stirpe F. An immunotoxin composed of monoclonal anti-Thy 1.1 antibody and a ribosome-inactivating protein from Saponaria officinalis: potent antitumor effects in vitro and in vivo. J Natl Cancer Inst. 1985 Jul;75(1):151–159. [PubMed]
  • Uckun FM. Immunotoxins for the treatment of leukaemia. Br J Haematol. 1993 Nov;85(3):435–438. [PubMed]
  • Uckun FM, Jaszcz W, Ambrus JL, Fauci AS, Gajl-Peczalska K, Song CW, Wick MR, Myers DE, Waddick K, Ledbetter JA. Detailed studies on expression and function of CD19 surface determinant by using B43 monoclonal antibody and the clinical potential of anti-CD19 immunotoxins. Blood. 1988 Jan;71(1):13–29. [PubMed]
  • Uckun FM, Manivel C, Arthur D, Chelstrom LM, Finnegan D, Tuel-Ahlgren L, Irvin JD, Myers DE, Gunther R. In vivo efficacy of B43 (anti-CD19)-pokeweed antiviral protein immunotoxin against human pre-B cell acute lymphoblastic leukemia in mice with severe combined immunodeficiency. Blood. 1992 May 1;79(9):2201–2214. [PubMed]
  • Vitetta ES, Thorpe PE, Uhr JW. Immunotoxins: magic bullets or misguided missiles? Immunol Today. 1993 Jun;14(6):252–259. [PubMed]
  • Weiner LM, O'Dwyer J, Kitson J, Comis RL, Frankel AE, Bauer RJ, Konrad MS, Groves ES. Phase I evaluation of an anti-breast carcinoma monoclonal antibody 260F9-recombinant ricin A chain immunoconjugate. Cancer Res. 1989 Jul 15;49(14):4062–4067. [PubMed]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • Compound
    Compound
    PubChem Compound links
  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...