Killing of autologous B-lineage malignancy using CD3 x CD19 bispecific monoclonal antibody in end stage leukemia and lymphoma.
To develop an effective tumor immunotherapy for B-lineage non-Hodgkin's lymphoma (NHL) and acute lymphoblastic leukemia (ALL), a bispecific monoclonal antibody (BsAb) has been generated with the first specificity for the CD3 epsilon-chain and the second for the CD19 antigen. Peripheral blood mononuclear cells (PBMCs) isolated from patients with NHL or ALL during remission or relapse rapidly proliferated (up to 179-fold increase) on in vitro activation combining phytohemagglutinin or CD3 monoclonal antibody with interleukin-2. After 3 weeks of stimulation, more than 90% of the PBMCs was CD3+ and CD8+, even when cultures were started with only 5% CD3+ cells. Cytotoxic activity against autologous malignant B cells was markedly enhanced (from 5% baseline to 70% lysis) by the addition of the CD3 x CD19 BsAb in all samples tested. Immunophenotypic examination of a series of tumor target cells showed that all samples examined showed CD54 (intercellular adhesion molecule-1) and HLA class I, but showed no B7 expression. CD11a (lymphocyte function-associated antigen-1) expression was heterogeneous. Various types of experiments showed that efficient CD3 x CD19 BsAb-mediated cytolytic capacity was not dependent on expression of either of these surface proteins. This contrasts with normal major histocompatibility complex-restricted antigen-specific cytotoxicity and may be essential for effective in vivo application of this BsAb.
Haagen
I A
IA
Department of Immunology, University Hospital Utrecht, The Netherlands.
Geerars
A J
AJ
de Lau
W B
WB
Clark
M R
MR
van de Griend
R J
RJ
Bast
B J
BJ
de Gast
B C
BC
D018033:Antibodies, Bispecific / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000276:immunology*; D015703:Antigens, CD / Q000032:analysis / Q000276:immunology*; D018941:Antigens, CD19; D000944:Antigens, Differentiation, B-Lymphocyte / Q000032:analysis / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D018122:B7-1 Antigen / Q000502:physiology; D017252:CD3 Complex / Q000032:analysis / Q000276:immunology*; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D006801:Humans; D015448:Leukemia, B-Cell / Q000276:immunology / Q000628:therapy*; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000628:therapy*
D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018941:Antigens, CD19; D000944:Antigens, Differentiation, B-Lymphocyte; D018122:B7-1 Antigen; D017252:CD3 Complex