Switch to
| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
6
|
| pubmed:dateCreated |
1997-4-2
|
| pubmed:abstractText |
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.
|
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
AIM
|
| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antibodies, Monoclonal,
http://linkedlifedata.com/resource/pubmed/chemical/Antigens, CD19,
http://linkedlifedata.com/resource/pubmed/chemical/Antigens, CD34,
http://linkedlifedata.com/resource/pubmed/chemical/Enterotoxins,
http://linkedlifedata.com/resource/pubmed/chemical/Histocompatibility Antigens Class II,
http://linkedlifedata.com/resource/pubmed/chemical/Immunoglobulin Fab Fragments,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Fusion Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Superantigens,
http://linkedlifedata.com/resource/pubmed/chemical/enterotoxin A, Staphylococcal
|
| pubmed:status |
MEDLINE
|
| pubmed:month |
Mar
|
| pubmed:issn |
0006-4971
|
| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:day |
15
|
| pubmed:volume |
89
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
2089-97
|
| pubmed:dateRevised |
2006-11-15
|
| pubmed:meshHeading |
pubmed-meshheading:9058731-Animals,
pubmed-meshheading:9058731-Antibodies, Monoclonal,
pubmed-meshheading:9058731-Antigens, CD19,
pubmed-meshheading:9058731-Antigens, CD34,
pubmed-meshheading:9058731-B-Lymphocytes,
pubmed-meshheading:9058731-Burkitt Lymphoma,
pubmed-meshheading:9058731-Cell Line,
pubmed-meshheading:9058731-Cytotoxicity, Immunologic,
pubmed-meshheading:9058731-Enterotoxins,
pubmed-meshheading:9058731-Female,
pubmed-meshheading:9058731-Genetic Vectors,
pubmed-meshheading:9058731-Histocompatibility Antigens Class II,
pubmed-meshheading:9058731-Humans,
pubmed-meshheading:9058731-Immunoglobulin Fab Fragments,
pubmed-meshheading:9058731-Immunotherapy, Adoptive,
pubmed-meshheading:9058731-Interphase,
pubmed-meshheading:9058731-Lymphocyte Activation,
pubmed-meshheading:9058731-Lymphoma, B-Cell,
pubmed-meshheading:9058731-Macrophages,
pubmed-meshheading:9058731-Mice,
pubmed-meshheading:9058731-Mice, SCID,
pubmed-meshheading:9058731-Monocytes,
pubmed-meshheading:9058731-Mutagenesis, Site-Directed,
pubmed-meshheading:9058731-Recombinant Fusion Proteins,
pubmed-meshheading:9058731-Sensitivity and Specificity,
pubmed-meshheading:9058731-Staphylococcus aureus,
pubmed-meshheading:9058731-Superantigens,
pubmed-meshheading:9058731-T-Lymphocytes,
pubmed-meshheading:9058731-T-Lymphocytes, Cytotoxic,
pubmed-meshheading:9058731-Tumor Cells, Cultured
|
| pubmed:year |
1997
|
| pubmed:articleTitle |
A superantigen-antibody fusion protein for T-cell immunotherapy of human B-lineage malignancies.
|
| pubmed:affiliation |
Department of Clinical Immunology, University Hospital, Uppsala, Sweden.
|
| pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
|