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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 construct1

Item Type:Article
Title: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 construct1
Creators Name:Dreier, T. and Baeuerle, P.A. and Fichtner, I. and Gruen, M. and Schlereth, B. and Lorenczewski, G. and Kufer, P. and Lutterbuese, R. and Riethmueller, G. and Gjorstrup, P. and Bargou, R.C.
Abstract: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.
Keywords:Antineoplastic Agents, B-Cell Leukemia, B-Cell Lymphoma, Bispecific Antibodies, CD19 Antigens, CD3 Antigens, Cultured Cells, Cultured Tumor Cells, Graft Survival, Growth Inhibitors, Heterologous Transplantation, Inbred NOD Mice, Intravenous Injections, Lymphocyte Activation, Neoplasm Transplantation, SCID Mice, Skin Neoplasms, Subcutaneous Injections, T-Lymphocyte Subsets, Time Factors, Animals, Mice
Source:Journal of Immunology
ISSN:0022-1767
Publisher:American Association of Immunologists (U.S.A.)
Volume:170
Number:8
Page Range:4397-4402
Date:15 April 2003
Official Publication:http://www.jimmunol.org/cgi/content/abstract/170/8/4397
PubMed:View item in PubMed

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