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

Abstract

Bispecific antibodies (bsAb) are considered as promising tools for the elimination of disseminated tumour cells in a minimal residual disease situation. The bsAb-mediated recruitment of an immune effector cell in close vicinity of a tumour cell is thought to induce an antitumoural immune response. However, classical bispecific molecules activate only a single class of immune effector cell that may not yield optimal immune responses. We therefore constructed an intact bispecific antibody, BiUII (anti-CD3 x anti-EpCAM), that not only recognizes tumour cells and T lymphocytes with its two binding arms, but also binds and activates Fcgamma-receptor positive accessory cells through its Fc-region. We have demonstrated recently that activated accessory cells contribute to the bsAb-induced antitumoural activity. We now analyse this stimulation in more detail and demonstrate here the BiUII-induced upregulation of activation markers like CD83 and CD95 on accessory cells and the induction of neopterin and biopterin synthesis. Experiments with pure cell subpopulations revealed binding of BiUII to CD64+ accessory cells and CD16+ NK cells, but not to CD32+ B lymphocytes. We provide further evidence for the importance of the Fc-region in that this bispecific molecule stimulates Fcgamma-R-positive accessory cells to eliminate tumour cells in vitro by direct phagocytosis.

References 29

1. 1.

   Cella M., Scheidegger D., Palmer-Lehmann K., Lane P., Lanzavecchia A., Alber G. Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T-T help via APC activation. J Exp Med. 1996;184(2):747-752.

   Not in our library10.1084/jem.184.2.747

2. 2.

   Clynes R., Takechi Y., Moroi Y., Houghton A., Ravetch J. V. Fc receptors are required in passive and active immunity to melanoma. Proc Natl Acad Sci U S A. 1998;95(2):652-656.

   Not in our library10.1073/pnas.95.2.652

3. 3.

   Czerniecki B. J., Carter C., Rivoltini L., Koski G. K., Kim H. I., Weng D. E., Roros J. G., Hijazi Y. M., Xu S., Rosenberg S. A. Calcium ionophore-treated peripheral blood monocytes and dendritic cells rapidly display characteristics of activated dendritic cells. J Immunol. 1997;159(8):3823-3837.

   Not in our library

4. 4.

   Daniel P. T., Kroidl A., Kopp J., Sturm I., Moldenhauer G., Dörken B., Pezzutto A. Immunotherapy of B-cell lymphoma with CD3x19 bispecific antibodies: costimulation via CD28 prevents "veto" apoptosis of antibody-targeted cytotoxic T cells. Blood. 1998;92(12):4750-4757.

   Not in our library

5. 5.

   Fanger M. W., Segal D. M., Wunderlich J. R. Going both ways: bispecific antibodies and targeted cellular cytotoxicity. FASEB J. 1990;4(11):2846-2849.

   Not in our library10.1096/fasebj.4.11.2199282

6. 6.

   Haagen I. A., Geerars A. J., Clark M. R., van de Winkel J. G. Interaction of human monocyte Fc gamma receptors with rat IgG2b. A new indicator for the Fc gamma RIIa (R-H131) polymorphism. J Immunol. 1995;154(4):1852-1860.

   Not in our library

7. 7.

   Heo D. S., Park J. G., Hata K., Day R., Herberman R. B., Whiteside T. L. Evaluation of tetrazolium-based semiautomatic colorimetric assay for measurement of human antitumor cytotoxicity. Cancer Res. 1990;50(12):3681-3690.

   Not in our library

8. 8.

   Inaba K., Steinman R. M. Resting and sensitized T lymphocytes exhibit distinct stimulatory (antigen-presenting cell) requirements for growth and lymphokine release. J Exp Med. 1984;160(6):1717-1735.

   Not in our library10.1084/jem.160.6.1717

9. 9.

   Kerler F., Hültner L., Ziegler I., Katzenmaier G., Bacher A. Analysis of the tetrahydrobiopterin synthesizing system during maturation of murine reticulocytes. J Cell Physiol. 1990;142(2):268-271.

   Not in our library10.1002/jcp.1041420208

10. 10.

    Klein S. C., Boer L. H., de Weger R. A., de Gast G. C., Bast E. J. Release of cytokines and soluble cell surface molecules by PBMC after activation with the bispecific antibody CD3 x CD19. Scand J Immunol. 1997;46(5):452-458.

    Not in our library10.1046/j.1365-3083.1997.d01-151.x

11. 11.

    Lindhofer H., Menzel H., Günther W., Hültner L., Thierfelder S. Bispecific antibodies target operationally tumor-specific antigens in two leukemia relapse models. Blood. 1996;88(12):4651-4658.

    Not in our library

12. 12.

    Lindhofer H., Mocikat R., Steipe B., Thierfelder S. Preferential species-restricted heavy/light chain pairing in rat/mouse quadromas. Implications for a single-step purification of bispecific antibodies. J Immunol. 1995;155(1):219-225.

    Not in our library

13. 13.

    Mayer B., Hemmens B. Biosynthesis and action of nitric oxide in mammalian cells. Trends Biochem Sci. 1997;22(12):477-481.

    Not in our library10.1016/s0968-0004(97)01147-x

14. 14.

    McLellan A. D., Sorg R. V., Williams L. A., Hart D. N. Human dendritic cells activate T lymphocytes via a CD40: CD40 ligand-dependent pathway. Eur J Immunol. 1996;26(6):1204-1210.

    Not in our library10.1002/eji.1830260603

15. 15.

    Medvedev A. E., Johnsen A. C., Haux J., Steinkjer B., Egeberg K., Lynch D. H., Sundan A., Espevik T. Regulation of Fas and Fas-ligand expression in NK cells by cytokines and the involvement of Fas-ligand in NK/LAK cell-mediated cytotoxicity. Cytokine. 1997;9(6):394-404.

    Not in our library10.1006/cyto.1996.0181

16. 16.

    Quak J. J., Van Dongen G., Brakkee J. G., Hayashida D. J., Balm A. J., Snow G. B., Meijer C. J. Production of a monoclonal antibody (K 931) to a squamous cell carcinoma associated antigen identified as the 17-1A antigen. Hybridoma. 1990;9(4):377-387.

    Not in our library10.1089/hyb.1990.9.377

17. 17.

    Ridge J. P., Di Rosa F., Matzinger P. A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell. Nature. 1998;393(6684):474-478.

    Not in our library10.1038/30989

18. 18.

    Robertson M. J., Manley T. J., Pichert G., Cameron C., Cochran K. J., Levine H., Ritz J. Functional consequences of APO-1/Fas (CD95) antigen expression by normal and neoplastic hematopoietic cells. Leuk Lymphoma. 1995;17(1-2):51-61.

    Not in our library10.3109/10428199509051703

19. 19.

    Schott K., Gütlich M., Ziegler I. Induction of GTP-cyclohydrolase I mRNA expression by lectin activation and interferon-gamma treatment in human cells associated with the immune response. J Cell Physiol. 1993;156(1):12-16.

    Not in our library10.1002/jcp.1041560103

20. 20.

    Steinman R. M. The dendritic cell system and its role in immunogenicity. Annu Rev Immunol. 1991;9:271-296.

    Not in our library10.1146/annurev.iy.09.040191.001415

21. 21.

    Stuber E., Strober W., Neurath M. Blocking the CD40L-CD40 interaction in vivo specifically prevents the priming of T helper 1 cells through the inhibition of interleukin 12 secretion. J Exp Med. 1996;183(2):693-698.

    Not in our library10.1084/jem.183.2.693

22. 22.

    Valerius T., Stockmeyer B., van Spriel A. B., Graziano R. F., van den Herik-Oudijk I. E., Repp R., Deo Y. M., Lund J., Kalden J. R., Gramatzki M. FcalphaRI (CD89) as a novel trigger molecule for bispecific antibody therapy. Blood. 1997;90(11):4485-4492.

    Not in our library

23. 23.

    Van Gool S. W., Vandenberghe P., de Boer M., Ceuppens J. L. CD80, CD86 and CD40 provide accessory signals in a multiple-step T-cell activation model. Immunol Rev. 1996;153:47-83.

    Not in our library10.1111/j.1600-065x.1996.tb00920.x

24. 24.

    Weiner L. M., Clark J. I., Ring D. B., Alpaugh R. K. Clinical development of 2B1, a bispecific murine monoclonal antibody targeting c-erbB-2 and Fc gamma RIII. J Hematother. 1995;4(5):453-456.

    Not in our library10.1089/scd.1.1995.4.453

25. 25.

    Weiner L. M., Holmes M., Adams G. P., LaCreta F., Watts P., Garcia de Palazzo I. A human tumor xenograft model of therapy with a bispecific monoclonal antibody targeting c-erbB-2 and CD16. Cancer Res. 1993;53(1):94-100.

    Not in our library

26. 26.

    Zeidler R., Reisbach G., Wollenberg B., Lang S., Chaubal S., Schmitt B., Lindhofer H. Simultaneous activation of T cells and accessory cells by a new class of intact bispecific antibody results in efficient tumor cell killing. J Immunol. 1999;163(3):1246-1252.

    Not in our library

27. 27.

    Zhou L. J., Tedder T. F. CD14+ blood monocytes can differentiate into functionally mature CD83+ dendritic cells. Proc Natl Acad Sci U S A. 1996;93(6):2588-2592.

    Not in our library10.1073/pnas.93.6.2588

28. 28.

    Ziegler I. Production of pteridines during hematopoiesis and T-lymphocyte proliferation: potential participation in the control of cytokine signal transmission. Med Res Rev. 1990;10(1):95-114.

    Not in our library10.1002/med.2610100104

29. 29.

    de Gast G. C., Haagen I. A., van Houten A. A., Klein S. C., Duits A. J., de Weger R. A., Vroom T. M., Clark M. R., Phillips J., van Dijk A. J. CD8 T cell activation after intravenous administration of CD3 x CD19 bispecific antibody in patients with non-Hodgkin lymphoma. Cancer Immunol Immunother. 1995;40(6):390-396.

    Not in our library10.1007/bf01525390

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