T cell costimulus-independent and very efficacious inhibition of tumor growth in mice bearing subcutaneous or leukemic human B cell lymphoma xenografts by a CD19-/CD3- bispecific single-chain antibody construct.
We have recently demonstrated that a recombinant single-chain bispecific Ab construct, bscCD19xCD3, in vitro induces rapid B lymphoma-directed cytotoxicity at picomolar concentrations with unstimulated peripheral T cells. In this study, we show that treatment of nonobese diabetic SCID mice with submicrogram doses of bscCD19xCD3 could prevent growth of s.c. human B lymphoma xenografts and essentially cured animals when given at an early tumor stage. The effect was dose dependent, dependent on E:T ratio and the time between tumor inoculation and administration of bscCD19xCD3. No therapeutic effect was seen in the presence of human lymphocytes alone, a vehicle control, or with a bispecific single-chain construct of identical T cell-binding activity but different target specificity. In a leukemic nonobese diabetic SCID mouse model, treatment with bscCD19xCD3 prolonged survival of mice in a dose-dependent fashion. The human lymphocytes used as effector cells in both animal models did not express detectable T cell activation markers at the time of coinoculation with tumor cells. The bispecific Ab therefore showed an in vivo activity comparable to that observed in cell culture with respect to high potency and T cell costimulus independence. These properties make bscCD19xCD3 superior to previously investigated CD19 bispecific Ab-based therapies.
Dreier
Torsten
T
Micromet AG, Munich, Germany.
Baeuerle
Patrick A
PA
Fichtner
Iduna
I
Grün
Michael
M
Schlereth
Bernd
B
Lorenczewski
Grit
G
Kufer
Peter
P
Lutterbüse
Ralf
R
Riethmüller
Gert
G
Gjorstrup
Per
P
Bargou
Ralf C
RC
D000818:Animals; D018033:Antibodies, Bispecific / Q000235:genetics / Q000494:pharmacology*; D018941:Antigens, CD19 / Q000276:immunology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D017252:CD3 Complex / Q000276:immunology*; D002478:Cells, Cultured; D006085:Graft Survival / Q000235:genetics / Q000276:immunology; D006131:Growth Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D015448:Leukemia, B-Cell / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D008213:Lymphocyte Activation / Q000235:genetics; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D012878:Skin Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013997:Time Factors; D014183:Transplantation, Heterologous / Q000379:methods; D014407:Tumor Cells, Cultured
D018033:Antibodies, Bispecific; D018941:Antigens, CD19; D000970:Antineoplastic Agents; D017252:CD3 Complex; D006131:Growth Inhibitors