|
|
 Previous Article | Table of Contents | Next Article 
Blood, Vol. 95 No. 6 (March 15), 2000:
pp. 2098-2103
A recombinant bispecific single-chain antibody,
CD19 × CD3, induces rapid and high lymphoma-directed
cytotoxicity by unstimulated T lymphocytes
Anja Löffler,
Peter Kufer,
Ralf Lutterbüse,
Florian Zettl,
Peter T. Daniel,
Jan M. Schwenkenbecher,
Gert Riethmüller,
Bernd Dörken, and
Ralf
C. Bargou
From the Max Delbrück Center for Molecular Medicine,
Berlin-Buch, Germany; Department of Internal Medicine,
Robert-Rössle-Klinik, University Medical Center Charité,
Humboldt University of Berlin, Berlin, Germany; and Institute of
Immunology, University of Munich, Munich, Germany.
Although bispecific antibodies directed against malignant lymphoma
have been shown to be effective in vitro and in vivo, extended clinical
trials so far have been hampered by the fact that conventional approaches to produce these antibodies suffer from low yields, ill-defined byproducts, or laborious purification procedures. To
overcome this problem, we have generated a small, recombinant, lymphoma-directed, bispecific single-chain (bsc) antibody according to
a novel technique recently described. The antibody
consists of 2 different single-chain Fv fragments joined by a
glycine-serine linker. One specificity is directed against the CD3
antigen of human T cells, and the other antigen-binding site engages
the pan-B-cell marker CD19, uniformly expressed on the vast majority of B-cell malignancies. The construct was expressed in Chinese hamster
ovary cells and purified by its C-terminal histioline tag. Specific
binding to CD19 and CD3 was demonstrated by fluorescence-activated cell
sorter analysis. By redirecting unstimulated primary human T cells
derived from the peripheral blood against CD19-positive lymphoma cells,
the bscCD19 × CD3 antibody showed significant cytotoxic activity at
very low concentrations of 10 to 100 pg/mL and at effector to target
cell ratios as low as 2:1. Moreover, strong
lymphoma-directed cytotoxicity at low antibody concentrations was
rapidly induced during 4 hours even in experiments without any T-cell
prestimulation. Thus, this particular antibody proves to be much more
efficacious than the bispecific antibodies described until now.
Therefore, the described bscCD19 × CD3 molecule should be a
suitable candidate to prove the therapeutic benefit of bispecific antibodies in the treatment of non-Hodgkin lymphoma.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
C. Germain, E. Campigna, I. Salhi, S. Morisseau, I. Navarro-Teulon, J.-P. Mach, A. Pelegrin, and B. Robert
Redirecting NK cells mediated tumor cell lysis by a new recombinant bifunctional protein
Protein Eng. Des. Sel.,
November 1, 2008;
21(11):
665 - 672.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Bargou, E. Leo, G. Zugmaier, M. Klinger, M. Goebeler, S. Knop, R. Noppeney, A. Viardot, G. Hess, M. Schuler, et al.
Tumor Regression in Cancer Patients by Very Low Doses of a T Cell-Engaging Antibody
Science,
August 15, 2008;
321(5891):
974 - 977.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Amann, K. Brischwein, P. Lutterbuese, L. Parr, L. Petersen, G. Lorenczewski, E. Krinner, S. Bruckmeier, S. Lippold, R. Kischel, et al.
Therapeutic Window of MuS110, a Single-Chain Antibody Construct Bispecific for Murine EpCAM and Murine CD3
Cancer Res.,
January 1, 2008;
68(1):
143 - 151.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. A. Hammond, R. Lutterbuese, S. Roff, P. Lutterbuese, B. Schlereth, E. Bruckheimer, M. S. Kinch, S. Coats, P. A. Baeuerle, P. Kufer, et al.
Selective Targeting and Potent Control of Tumor Growth Using an EphA2/CD3-Bispecific Single-Chain Antibody Construct
Cancer Res.,
April 15, 2007;
67(8):
3927 - 3935.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Natsume, M. Wakitani, N. Yamane-Ohnuki, E. Shoji-Hosaka, R. Niwa, K. Uchida, M. Satoh, and K. Shitara
Fucose Removal from Complex-Type Oligosaccharide Enhances the Antibody-Dependent Cellular Cytotoxicity of Single-Gene-Encoded Bispecific Antibody Comprising of Two Single-Chain Antibodies Linked to the Antibody Constant Region
J. Biochem.,
September 1, 2006;
140(3):
359 - 368.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Schlereth, I. Fichtner, G. Lorenczewski, P. Kleindienst, K. Brischwein, A. da Silva, P. Kufer, R. Lutterbuese, I. Junghahn, S. Kasimir-Bauer, et al.
Eradication of Tumors from a Human Colon Cancer Cell Line and from Ovarian Cancer Metastases in Immunodeficient Mice by a Single-Chain Ep-CAM-/CD3-Bispecific Antibody Construct
Cancer Res.,
April 1, 2005;
65(7):
2882 - 2889.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Grosse-Hovest, S. Muller, R. Minoia, E. Wolf, V. Zakhartchenko, H. Wenigerkind, C. Lassnig, U. Besenfelder, M. Muller, S. D. Lytton, et al.
Cloned transgenic farm animals produce a bispecific antibody for T cell-mediated tumor cell killing
PNAS,
May 4, 2004;
101(18):
6858 - 6863.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X.-B. Wang, B.-F. Zhao, Q. Zhao, J.-H. Piao, J. Liu, Q. Lin, and H.-L. Huang
A New Recombinant Single Chain Trispecific Antibody Recruits T Lymphocytes to Kill CEA (Carcinoma Embryonic Antigen) Positive Tumor Cells In Vitro Efficiently
J. Biochem.,
April 1, 2004;
135(4):
555 - 565.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Y. Mapara and M. Sykes
Tolerance and Cancer: Mechanisms of Tumor Evasion and Strategies for Breaking Tolerance
J. Clin. Oncol.,
March 15, 2004;
22(6):
1136 - 1151.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Dreier, P. A. Baeuerle, I. Fichtner, M. Grun, B. Schlereth, G. Lorenczewski, P. Kufer, R. Lutterbuse, G. Riethmuller, P. Gjorstrup, et al.
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
J. Immunol.,
April 15, 2003;
170(8):
4397 - 4402.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Yoshida, T. Kobayashi, H. Matsuoka, C. Seki, W. L. Gosnell, S. P. Chang, and A. Ishii
T-cell activation and cytokine production via a bispecific single-chain antibody fragment targeted to blood-stage malaria parasites
Blood,
March 15, 2003;
101(6):
2300 - 2306.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. M. Kipriyanov, B. Cochlovius, H. J. Schafer, G. Moldenhauer, A. Bahre, F. Le Gall, S. Knackmuss, and M. Little
Synergistic Antitumor Effect of Bispecific CD19 x CD3 and CD19 x CD16 Diabodies in a Preclinical Model of Non-Hodgkin's Lymphoma
J. Immunol.,
July 1, 2002;
169(1):
137 - 144.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
