Activation of T cell cytotoxicity against autologous common acute lymphoblastic leukemia (cALL) blasts by CD3xCD19 bispecific antibody.
To develop an effective immunotherapy for B-lineage acute lymphoblastic leukemia (ALL), bispecific monoclonal antibodies (bsAb) were raised by cell fusion of two hybridoma cell lines secreting CD3 and CD19 antibodies. The resulting bispecific antibody contains two different specificities within a single antibody molecule. One binding site (CD3) activates the T cells via the T cell receptor complex, whereas the second binding site (CD19) targets the cytolytic T cells to malignant B cells. Leukemic blasts from children with B-lineage ALL showed stable and strong CD19 expression. CD3xCD19 bsAb were used to activate peripheral blood mononuclear cells (PBMC) from healthy donors or from patients with ALL during remission. Cytotoxic activity against autologous ALL cells by PBMC was induced upon addition of 100 ng/ml CD3xCD19 bsAb after 3 days of preincubation. Costimulation through CD28 increased T cell proliferation to some extent, but did not increase cytotoxic activity of PBMC against leukemic blasts. We present evidence for an effective and specific activation of resting human T lymphocytes by CD3xCD19 bsAb in vitro. Activation of cytotoxic effector T cells is feasible by preincubation with bsAb CD3xCD19 alone and does not rely on additional external costimulation. Thus, targeting of T cell cytotoxicity towards leukemic blasts via CD3xCD19 bsAb may represent a promising strategy for immunotherapy of B-lineage ALL.
Division of Molecular Immunology, Tumorimmunology Programme, German Cancer Research Center, Heidelberg.
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M
Csóka
G
G
Strauss
K M
KM
Debatin
G
G
Moldenhauer
D018033:Antibodies, Bispecific / Q000276:immunology / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D018941:Antigens, CD19 / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D005434:Flow Cytometry; D006801:Humans; D007167:Immunotherapy; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured
D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D018941:Antigens, CD19; D017252:CD3 Complex