Skip to main content

Advertisement

SpringerLink
Log in

Cytokine-induced killer cells targeted by the novel bispecific antibody CD19xCD5 (HD37xT5.16) efficiently lyse B-lymphoma cells

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

Abstract

Due to their dual binding capacity, bispecific antibodies (bsAb) can be used to cross-link cytotoxic effector cells with malignant targets and may thereby improve adoptive immunotherapy. In this study, the development and preclinical testing of the quadroma-derived bsAb HD37xT5.16 of the specificity CD19xCD5 is reported. Effector cells used were a population of ex vivo expanded and activated T cells called cytokine-induced killer (CIK) cells expressing CD5. When combined with CIK cells, the cytolytic potency of HD37xT5.16 against CD19 positive B cell lymphoma lines was comparable to that observed with a previously described CD19xCD3 bsAb. Further on, we could demonstrate that bsAb CD19xCD5, in contrast to its CD3-binding counterpart, does not induce proliferation of resting T cells and causes only little activation-induced cell death. Therefore, this novel bsAb binding effector T cells via CD5 may be particularly useful in combination with adoptive transfer of ex vivo activated T cells, e.g., in the setting of adoptive immunotherapy after allogeneic stem cell transplantation. The in vitro studies outlined here support the experimental use of bsAb HD37xT5.16 in preclinical in vivo models for evaluation of its safety and efficacy profile.

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

References

  1. Alderson MR, Tough TW, Davis-Smith T, Braddy S, Falk B, Schooley KA, Goodwin RG, Smith CA, Ramsdell F, Lynch DH (1995) Fas ligand mediates activation-induced cell death in human T lymphocytes. J Exp Med 181:71–77

    Article  PubMed  CAS  Google Scholar 

  2. Baeuerle PA, Kufer P, Lutterbuse R (2003) Bispecific antibodies for polyclonal T-cell engagement. Curr Opin Mol Ther 5:413–419

    PubMed  CAS  Google Scholar 

  3. Bohlen H, Hopff T, Manzke O, Engert A, Kube D, Wickramanayake PD, Diehl V, Tesch H (1993) Lysis of malignant B cells from patients with B-chronic lymphocytic leukemia by autologous T cells activated with CD3 x CD19 bispecific antibodies in combination with bivalent CD28 antibodies. Blood 82:1803–1812

    PubMed  CAS  Google Scholar 

  4. Bohlen H, Manzke O, Patel B, Moldenhauer G, Dorken B, von Fliedner V, Diehl V, Tesch H (1993) Cytolysis of leukemic B-cells by T-cells activated via two bispecific antibodies. Cancer Res 53:4310–4314

    PubMed  CAS  Google Scholar 

  5. Brunner T, Mogil RJ, LaFace D, Yoo NJ, Mahboubi A, Echeverri F, Martin SJ, Force WR, Lynch DH, Ware CF et al (1995) Cell–autonomous Fas (CD95)/Fas–ligand interaction mediates activation-induced apoptosis in T-cell hybridomas. Nature 373:441–444

    Article  PubMed  CAS  Google Scholar 

  6. Canevari S, Stoter G, Arienti F, Bolis G, Colnaghi MI, Di Re EM, Eggermont AM, Goey SH, Gratama JW, Lamers CH et al (1995) Regression of advanced ovarian carcinoma by intraperitoneal treatment with autologous T lymphocytes retargeted by a bispecific monoclonal antibody. J Natl Cancer Inst 87:1463–1469

    Article  PubMed  CAS  Google Scholar 

  7. Cochlovius B, Kipriyanov SM, Stassar MJ, Christ O, Schuhmacher J, Strauss G, Moldenhauer G, Little M (2000) Treatment of human B cell lymphoma xenografts with a CD3 x CD19 diabody and T cells. J Immunol 165:888–895

    PubMed  CAS  Google Scholar 

  8. Csoka M, Strauss G, Debatin KM, Moldenhauer G (1996) Activation of T cell cytotoxicity against autologous common acute lymphoblastic leukemia (cALL) blasts by CD3xCD19 bispecific antibody. Leukemia 10:1765–1772

    PubMed  CAS  Google Scholar 

  9. Daniel PT, Kroidl A, Cayeux S, Bargou R, Blankenstein T, Dorken B (1997) Costimulatory signals through B7.1/CD28 prevent T cell apoptosis during target cell lysis. J Immunol 159:3808–3815

    PubMed  CAS  Google Scholar 

  10. de Gast GC, Haagen IA, van Houten AA, Klein SC, Duits AJ, de Weger RA, Vroom TM, Clark MR, Phillips J, van Dijk AJ et al. (1995) CD8 T cell activation after intravenous administration of CD3 x CD19 bispecific antibody in patients with non-Hodgkin lymphoma. Cancer Immunol Immunother 40:390–396

    Article  PubMed  Google Scholar 

  11. Dhein J, Walczak H, Baumler C, Debatin KM, Krammer PH (1995) Autocrine T-cell suicide mediated by APO-1/(Fas/CD95). Nature 373:438–441

    Article  PubMed  CAS  Google Scholar 

  12. Haagen IA, de Lau WB, Bast BJ, Geerars AJ, Clark MR, de Gast BC (1994) Unprimed CD4+ and CD8+ T cells can be rapidly activated by a CD3 x CD19 bispecific antibody to proliferate and become cytotoxic. Cancer Immunol Immunother 39:391–396

    Article  PubMed  CAS  Google Scholar 

  13. Hoyle C, Bangs CD, Chang P, Kamel O, Mehta B, Negrin RS (1998) Expansion of Philadelphia chromosome-negative CD3(+)CD56(+) cytotoxic cells from chronic myeloid leukemia patients: in vitro and in vivo efficacy in severe combined immunodeficiency disease mice. Blood 92:3318–3327

    PubMed  CAS  Google Scholar 

  14. Kipriyanov SM, Moldenhauer G, Strauss G, Little M (1998) Bispecific CD3 x CD19 diabody for T cell-mediated lysis of malignant human B cells. Int J Cancer 77:763–772

    Article  PubMed  CAS  Google Scholar 

  15. Kornacker M, Moldenhauer G, Herbst M, Weilguni E, Tita-Nwa F, Harter C, Hensel M, Ho AD (2006) Cytokine-induced killer cells against autologous CLL: direct cytotoxic effects and induction of immune accessory molecules by interferon-gamma. Int J Cancer 119:1377–1382

    Article  PubMed  CAS  Google Scholar 

  16. Kroesen BJ, Bakker A, van Lier RA, The HT, de Leij L (1995) Bispecific antibody-mediated target cell-specific costimulation of resting T cells via CD5 and CD28. Cancer Res 55:4409–4415

    PubMed  CAS  Google Scholar 

  17. Leemhuis T, Wells S, Scheffold C, Edinger M, Negrin RS (2005) A phase I trial of autologous cytokine-induced killer cells for the treatment of relapsed Hodgkin disease and non-Hodgkin lymphoma. Biol Blood Marrow Transplant 11:181–187

    Article  PubMed  Google Scholar 

  18. Lu PH, Negrin RS (1994) A novel population of expanded human CD3+CD56+ cells derived from T cells with potent in vivo antitumor activity in mice with severe combined immunodeficiency. J Immunol 153:1687–1696

    PubMed  CAS  Google Scholar 

  19. Manzke O, Titzer S, Tesch H, Diehl V, Bohlen H (1997) CD3 x CD19 bispecific antibodies and CD28 costimulation for locoregional treatment of low-malignancy non-Hodgkin’s lymphoma. Cancer Immunol Immunother 45:198–202

    Article  PubMed  CAS  Google Scholar 

  20. Marme A, Strauss G, Bastert G, Grischke EM, Moldenhauer G (2002) Intraperitoneal bispecific antibody (HEA125xOKT3) therapy inhibits malignant ascites production in advanced ovarian carcinoma. Int J Cancer 101:183–189

    Article  PubMed  CAS  Google Scholar 

  21. Mehta BA, Schmidt-Wolf IG, Weissman IL, Negrin RS (1995) Two pathways of exocytosis of cytoplasmic granule contents and target cell killing by cytokine-induced CD3+ CD56+ killer cells. Blood 86:3493–3499

    PubMed  CAS  Google Scholar 

  22. Pezzutto A, Dorken B, Rabinovitch PS, Ledbetter JA, Moldenhauer G, Clark EA (1987) CD19 monoclonal antibody HD37 inhibits anti-immunoglobulin-induced B cell activation and proliferation. J Immunol 138:2793–2799

    PubMed  CAS  Google Scholar 

  23. Ruf P, Lindhofer H (2001) Induction of a long-lasting antitumor immunity by a trifunctional bispecific antibody. Blood 98:2526–2534

    Article  PubMed  CAS  Google Scholar 

  24. Scheffold C, Kornacker M, Scheffold YC, Contag CH, Negrin RS (2002) Visualization of effective tumor targeting by CD8+ natural killer T cells redirected with bispecific antibody F(ab’)(2)HER2xCD3. Cancer Res 62:5785–5791

    PubMed  CAS  Google Scholar 

  25. Schlereth B, Quadt C, Dreier T, Kufer P, Lorenczewski G, Prang N, Brandl C, Lippold S, Cobb K, Brasky K, Leo E, Bargou R, Murthy K, Baeuerle PA (2006) T-cell activation and B-cell depletion in chimpanzees treated with a bispecific anti-CD19/anti-CD3 single-chain antibody construct. Cancer Immunol Immunother 55:503–514

    Article  PubMed  CAS  Google Scholar 

  26. Schmidt-Wolf GD, Negrin RS, Schmidt-Wolf IG (1997) Activated T cells and cytokine-induced CD3+CD56+ killer cells. Ann Hematol 74:51–56

    Article  PubMed  CAS  Google Scholar 

  27. Schmidt-Wolf IG, Lefterova P, Johnston V, Huhn D, Blume KG, Negrin RS (1994) Propagation of large numbers of T cells with natural killer cell markers. Bri J Haematol 87:453–458

    CAS  Google Scholar 

  28. Schmidt-Wolf IG, Lefterova P, Mehta BA, Fernandez LP, Huhn D, Blume KG, Weissman IL, Negrin RS (1993) Phenotypic characterization and identification of effector cells involved in tumor cell recognition of cytokine-induced killer cells. Exp Hematol 21:1673–1679

    PubMed  CAS  Google Scholar 

  29. Schmidt-Wolf IG, Negrin RS, Kiem HP, Blume KG, Weissman IL (1991) Use of a SCID mouse/human lymphoma model to evaluate cytokine-induced killer cells with potent antitumor cell activity. J Exp Med 174:139–149

    Article  PubMed  CAS  Google Scholar 

  30. Segal DM, Weiner GJ, Weiner LM (1999) Bispecific antibodies in cancer therapy. Curr Opin Immunol 11:558–562

    Article  PubMed  CAS  Google Scholar 

  31. Strasser A (1995) Apoptosis: death of a T cell. Nature 373:385–386

    Article  PubMed  CAS  Google Scholar 

  32. van Spriel AB, van Ojik HH, van De Winkel JG (2000) Immunotherapeutic perspective for bispecific antibodies. Immunol Today 21:391–397

    Article  PubMed  Google Scholar 

  33. Verneris MR, Ito M, Baker J, Arshi A, Negrin RS, Shizuru JA (2001) Engineering hematopoietic grafts: purified allogeneic hematopoietic stem cells plus expanded CD8+ NK-T cells in the treatment of lymphoma. Biol Blood Marrow Transplant 7:532–542

    Article  PubMed  CAS  Google Scholar 

  34. Verneris MR, Karami M, Baker J, Jayaswal A, Negrin RS (2004) Role of NKG2D signaling in the cytotoxicity of activated and expanded CD8+ T cells. Blood 103:3065–3072

    Article  PubMed  CAS  Google Scholar 

  35. Verneris MR, Kornacker M, Mailander V, Negrin RS (2000) Resistance of ex vivo expanded CD3+CD56+ T cells to Fas-mediated apoptosis. Cancer Immunol Immunother 49:335–345

    Article  PubMed  CAS  Google Scholar 

  36. Zeidler R, Mysliwietz J, Csanady M, Walz A, Ziegler I, Schmitt B, Wollenberg B, Lindhofer H (2000) The Fc-region of a new class of intact bispecific antibody mediates activation of accessory cells and NK cells and induces direct phagocytosis of tumour cells. Br J Cancer 83:261–266

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Dr. Fabrice Le Gall (Affimed Therapeutics, Heidelberg) for the advice and help with the FPLC separation and Elvira Hallauer for expert technical assistance. This work was supported by the Deutsche Krebshilfe and the Tumorzentrum Heidelberg/Mannheim.

Author information

Authors and Affiliations

  1. Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany

    Freddy Tita-Nwa, Markus Herbst, Anthony D. Ho & Martin Kornacker

  2. Department of Molecular Immunology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

    Gerhard Moldenhauer

  3. Institute for Immunology, University of Heidelberg, Heidelberg, Germany

    Christian Kleist

Authors
  1. Freddy Tita-Nwa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gerhard Moldenhauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Markus Herbst
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christian Kleist
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anthony D. Ho
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Martin Kornacker
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gerhard Moldenhauer.

Additional information

Freddy Tita-Nwa and Gerhard Moldenhauer contributed equally to the study and share first authorship.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tita-Nwa, F., Moldenhauer, G., Herbst, M. et al. Cytokine-induced killer cells targeted by the novel bispecific antibody CD19xCD5 (HD37xT5.16) efficiently lyse B-lymphoma cells. Cancer Immunol Immunother 56, 1911–1920 (2007). https://doi.org/10.1007/s00262-007-0333-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-007-0333-0

Keywords

Search

Navigation