In vivo retargeting of T cell effector function by recombinant bispecific single chain Fv (anti-CD3 x anti-idiotype) induces long-term survival in the murine BCL1 lymphoma model.
As demonstrated in several preclinical models, bispecific Abs are attractive immunotherapeutic agents for tumor treatment. We have previously reported that a bacterially produced anti-CD3 x antitumor bispecific single chain variable fragment of Ab fragment (BsscFv), which is capable of retargeting CTLs toward BCL1 tumor cells, exhibits antitumor activity in vitro. To further facilitate BsscFv production, the coding sequence was subcloned in a eukaryotic expression vector and introduced into Chinese hamster ovary cells for large-scale production. In this report, we have determined the serum stability and the clearance rate from the circulation of BsscFv. Most important, we prove here the therapeutic value of BsscFv in the treatment of BCL1 lymphoma, a murine model for human non-Hodgkin's lymphoma. Tumor-bearing mice that were treated with rscFv in combination with staphylococcal enterotoxin B superantigen, human rIL-2, or murine rIL-12 showed long-term survival, whereas untreated mice all died. This is the first report of the successful in vivo use of BsscFv as an immunotherapeutic agent. Furthermore, long-term survival was the result of complete tumor removal and was not due to the induction of dormancy.
Vrije Universiteit Brussel, Medical School, Laboratory of Physiology-Immunology, Belgium.
J
J
De Jonge
C
C
Heirman
M
M
de Veerman
S
S
Van Meirvenne
M
M
Moser
O
O
Leo
K
K
Thielemans
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use*; D018033:Antibodies, Bispecific / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use*; D017252:CD3 Complex / Q000276:immunology*; D004195:Disease Models, Animal; D018572:Disease-Free Survival; D004768:Enterotoxins / Q000008:administration & dosage; D005260:Female; D005822:Genetic Vectors / Q000008:administration & dosage / Q000276:immunology; D007128:Immunoglobulin Fragments / Q000096:biosynthesis / Q000235:genetics* / Q000627:therapeutic use; D007135:Immunoglobulin Variable Region / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use; D007275:Injections, Intravenous; D008213:Lymphocyte Activation; D016393:Lymphoma, B-Cell / Q000276:immunology* / Q000401:mortality / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000276:immunology* / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000276:immunology; D014407:Tumor Cells, Cultured
D000888:Antibodies, Anti-Idiotypic; D018033:Antibodies, Bispecific; D017252:CD3 Complex; D004768:Enterotoxins; D007128:Immunoglobulin Fragments; D007135:Immunoglobulin Variable Region; D011994:Recombinant Proteins; C055966:immunoglobulin Fv; C031818:enterotoxin B, staphylococcal