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This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Gidlöf, C. Articles by Tötterman, T. H. Search for Related Content PubMed PubMed Citation Articles by Gidlöf, C. Articles by Tötterman, T. H. Related Collections Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  A superantigen-antibody fusion protein for T-cell immunotherapy of human B-lineage malignancies C Gidlof, M Dohlsten, P Lando, T Kalland, C Sundstrom and TH Totterman Department of Clinical Immunology, University Hospital, Uppsala, Sweden. The bacterial superantigen staphylococcal enterotoxin A (SEA) is an efficient activator of cytotoxic T cells when presented on major histocompatibility complex (MHC) class II molecules of target cells. Our previous studies showed that such SEA-directed T cells efficiently lysed chronic B-lymphocytic leukemia (B-CLL) cells. Next, we made a mutated SEA-protein A (SEAm-PA) fusion protein with more than 1,000- fold reduced binding affinity for MHC class II compared with native SEA. The fusion protein was successfully used to direct T cells to B- CLL cells coated with different B lineage-directed monoclonal antibodies (MoAbs). In this communication, we constructed a recombinant anti-CD19-Fab-SEAm fusion protein. The MHC class II binding capacity of the SEA part was drastically reduced by a D227A point mutation, whereas the T-cell activation properties were retained. The Fab part of the fusion protein displayed a binding affinity for CD19+ cells in the nanomolar range. The anti-CD19-Fab-SEAm molecule mediated effective, specific, rapid, and perforin-like T-cell lysis of B-CLL cells at low effector to target cell ratios. Normal CD19+ B cells were sensitive to lysis, whereas CD34+ progenitor cells and monocytes/macrophages were resistant. A panel of CD19+ B-cell lines representing different B-cell developmental stages were efficiently lysed, and the sensitivity correlated with surface ICAM-1 expression. The anti-CD19-Fab-SEAm fusion protein mediated highly effective killing of tumor biopsy cells representing several types of B-cell non-Hodgkin's lymphoma (B-NHL). Humanized severe combined immune deficiency (SCID) mice carrying Daudi lymphoma cells were used as an in vivo therapy model for evaluation of the anti-CD19-Fab-SEAm fusion protein. Greater than 90% reduction in tumor weight was recorded in anti-CD19-Fab-SEAm-treated animals compared with control animals receiving an irrelevant Fab-SEAm fusion protein. The present results indicate that MoAb-targeted superantigens (SAgs) may represent a promising approach for T-cell-based therapy of CD19+ B-cell malignancies. Volume 89, Issue 6, pp. 2089-2097, 03/15/1997 Copyright © 1997 by The American Society of Hematology CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: 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]

	Copyright © 1997 by American Society of Hematology         Online ISSN: 1528-0020