Specific activation of resting T cells against tumour cells by bispecific antibodies and CD28-mediated costimulation is accompanied by Th1 differentiation and recruitment of MHC-independent cytotoxicity.
Specific activation of resting lymphocytes for tumour targeting can be achieved by bispecific monoclonal antibodies (bi-MoAbs) with specificity for tumour antigens and T cell-activating antigens in combination with a costimulatory anti-CD28 antibody. In this study we focus on the immunomodulatory function of an anti-CD3/CA19-9 bi-MoAb in combination with a costimulatory anti-CD28 antibody which may result not only in antigen-specific, T cell-mediated tumour cell lysis but also in recruitment of other cellular effector functions. In combination with costimulatory anti-CD28 antibodies, resting peripheral lymphocytes could be activated specifically to secrete high amounts of Th1 cytokines (IL-2, interferon-gamma (IFN-gamma)) characterizing a cellular immune response. In contrast, no IL-4 and only low amounts of IL-10 could be detected. Furthermore, bi-MoAb-mediated CA19-9-specific activation of T cells was accompanied by recruitment of MHC- and CA19-9-independent cytotoxicity, as was determined by lysis of different CA19-9-cell lines. This MHC-independent cytotxicity was mediated at least in part by activated natural killer (NK) cells, as depletion of CD16+ NK cells resulted in substantial decrease of cytotoxicity against CA19-9- targets. Our results indicate that specific activation of resting T cells with CD3-associated bi-MoAbs in combination with an anti-CD28 antibody leads to a Th1 differentiation pathway and is accompanied by recruitment of MHC-independent lymphokine-activated killer (LAK) cell cytotoxicity which can possibly be directed against a heterogeneous tumour.
Hombach
A
A
Klinik I für Innere Medizin der Universität zu Köln, Germany.
Tillmann
T
T
Jensen
M
M
Heuser
C
C
Sircar
R
R
Diehl
V
V
Kruis
W
W
Pohl
C
C
D018033:Antibodies, Bispecific / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002051:Burkitt Lymphoma; D018395:CA-19-9 Antigen / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology / Q000502:physiology*; D017252:CD3 Complex / Q000276:immunology; D002277:Carcinoma / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D015179:Colorectal Neoplasms / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007399:Interphase / Q000276:immunology; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology; D008213:Lymphocyte Activation; D008285:Major Histocompatibility Complex / Q000276:immunology*; D010190:Pancreatic Neoplasms / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology*; D014407:Tumor Cells, Cultured
D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D018395:CA-19-9 Antigen; D018106:CD28 Antigens; D017252:CD3 Complex