Efficiency of T cell triggering by anti-CD3 monoclonal antibodies (mAB) with potential usefulness in bispecific mAB generation

Nathalie Jacobs, Alessandra Mazzoni, Delia Mezzanzanica, Donatella R M Negri, Olga Valota, Maria I. Colnaghi, Michel P. Moutschen, Jacques Boniver, Silvana Canevari

Research output: Contribution to journalArticle

Abstract

T cell triggering can be achieved by monoclonal antibodies (mAbs) specific for the CD3/TcR complex. In the presence of appropriate costimulation and/or progression factors, such triggering permits the generation of effector cells for immunotherapy protocols involving the redirection of T cell lysis against tumor cells by mAbs bispecific for anti- CD3/anti-tumor cells (bs-mAbs). Focusing our analysis on the clinically relevant bs-mAb OC/TR, we found that bs-mAbs generated with the same anti tumor specificity, but two other anti-CD3 mAbs, TR66 and OKT3, have the same and a significantly lower lytic potential, respectively, compared with that of OC/TR. To evaluate the relevance of the anti-CD3 component, we examined several anti-CD3 mAbs with respect to binding parameters and the ability to trigger T lymphocytes. Competitive binding assays suggested that all anti- CD3 mAbs recognized the same or overlapping epitopes, although mAbs BMA030 and OC/TR bound with lower avidity than did αCD3 (the bivalent anti-CD3 mAb produced by the hybrid hybridoma OC/TR), TR66 and OKT3, as determined by measurement of the affinity constants. In all lymphocyte populations examined, which included resting peripheral blood mononuclear cells (PBMC), activated PBMC and T cell clones, OKT3, BMA033 and OC/TR failed to mobilize Ca2+ without cross-linking, whereas αCD3, in both murine and murine-human chimeric versions, TR66 and BMA030, did not require cross-linking. The ability to induce CD3 modulation was associated in part with the induction of Ca2+ fluxes. Despite the differences in the behavior of these mAbs in triggering the events that precede proliferation, all of them ultimately led to expression of the IL-2 receptor and to proliferation in T cells in the presence of accessory cells. Our data suggest that anti-CD3 mAbs that bind more rapidly (strong Ca2+ mobilizers) and more tightly under physiological conditions are good candidates for retargeting T cells in the bs-mAb clinical application.

Original languageEnglish
Pages (from-to)257-264
Number of pages8
JournalCancer Immunology, Immunotherapy
Volume44
Issue number5
DOIs
Publication statusPublished - 1997

Keywords

  • Anti- tumor bs-mAb Retargeting
  • Ca flux
  • CD3 modulation
  • T cell activation
  • T cell proliferation

ASJC Scopus subject areas

  • Cancer Research
  • Immunology
  • Oncology

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    Jacobs, N., Mazzoni, A., Mezzanzanica, D., Negri, D. R. M., Valota, O., Colnaghi, M. I., Moutschen, M. P., Boniver, J., & Canevari, S. (1997). Efficiency of T cell triggering by anti-CD3 monoclonal antibodies (mAB) with potential usefulness in bispecific mAB generation. Cancer Immunology, Immunotherapy, 44(5), 257-264. https://doi.org/10.1007/s002620050381