CD3xCD19 bispecific antibodies and CD28 bivalent antibodies enhance T-cell reactivity against autologous leukemic cells in pediatric B-ALL bone marrow.
Bispecific CD3xCD19 antibodies and CD28 co-stimulating antibodies were used to activate T cells in bone marrow aspirates (n = 8) of children with B cell-derived acute lymphoblastic leukemia. Bone marrow specimens were incubated for 10 days with CD3xCD19 bispecific and CD28 antibodies. Changes in the numbers of T lymphocytes and tumoral B cells as well as surface expression of T cell-activation markers were determined by flow cytometry, and cytokines (human IFN-gamma, IL-2, IL-4 and IL-12) were measured in the cell culture supernatant. In 7 of 8 bone marrow samples, an increase in the number of CD4- and CD8-positive T lymphocytes was found, which correlated with an up-regulation of T cell-activation markers. Additionally, we demonstrated a decrease of tumoral B cells in 3 samples and enhanced cytotoxic T-cell activity against autologous malignant B cells. ELISpot analyses in an autologous Epstein-Barr virus model showed that bispecific antibodies (CD3xCD19+CD28) were more potent at generating T-cell responses against autologous and allogeneic tumoral targets than a combination of monospecific antibodies (CD3+CD28). Thus, T-cell targeting by CD3xCD19 bispecific and CD28 antibodies may be used to eliminate leukemic B cells ex vivo and reconstitute immunological control of residual malignant disease by the induction of anti-tumoral T-cell responses.
Manzke
O
O
Clinic I for Internal Medicine, University of Cologne, Germany.
Berthold
F
F
Huebel
K
K
Tesch
H
H
Diehl
V
V
Bohlen
H
H
D018033:Antibodies, Bispecific / Q000276:immunology*; D015703:Antigens, CD / Q000276:immunology; D018941:Antigens, CD19 / Q000276:immunology*; D001752:Blast Crisis / Q000276:immunology; D001853:Bone Marrow / Q000276:immunology* / Q000473:pathology; D001854:Bone Marrow Cells / Q000276:immunology / Q000473:pathology; D002051:Burkitt Lymphoma / Q000276:immunology* / Q000473:pathology; D018106:CD28 Antigens / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology*; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000032:analysis; D003602:Cytotoxicity, Immunologic; D005260:Female; D005434:Flow Cytometry; D006684:HLA-DR Antigens / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D008213:Lymphocyte Activation; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology* / Q000473:pathology; D011289:Preleukemia / Q000276:immunology / Q000473:pathology; D012008:Recurrence
D018033:Antibodies, Bispecific; D015703:Antigens, CD; D018941:Antigens, CD19; D018106:CD28 Antigens; D017252:CD3 Complex; D016207:Cytokines; D006684:HLA-DR Antigens