Abstract
We present a novel vascular tumor therapy approach based on lysing endothelial cells by cytotoxic T lymphocytes (CTLs). Retargeting of CTLs is achieved by a recombinant bispecific antibody molecule (bispecific single-chain diabody) directed against human endoglin (CD105, EDG) and the T-cell coreceptor CD3 (scDb EDGCD3). Bacterially expressed scDb EDGCD3 was able to bind to endoglin-expressing endothelial cells as well as CD3-expressing T lymphocytes. The single-chain diabody mediated killing of endothelial cells (HUVEC, HMEC) by activated cytotoxic T lymphocytes at picomolar concentrations, and cells not expressing endoglin were not affected. Because endoglin is up-regulated in the vasculature of many solid tumors, this antibody molecule should be capable of lysing tumor endothelial cells and thus destroying the vascular bed of the tumor.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antibodies, Bispecific / chemistry*
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Antigens / chemistry
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Antigens, CD
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CD3 Complex / biosynthesis
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CD3 Complex / immunology
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Cell Separation
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Cells, Cultured
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Dose-Response Relationship, Immunologic
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Endoglin
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Endothelium, Vascular / cytology
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Endothelium, Vascular / metabolism*
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Flow Cytometry
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Humans
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Immunoglobulin Fragments / chemistry
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Immunotherapy / methods*
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Jurkat Cells
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Neoplasms / immunology
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Neoplasms / therapy*
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Oligonucleotides / chemistry
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Plasmids / metabolism
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Protein Binding
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Receptors, Cell Surface
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Recombinant Proteins / chemistry*
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Recombinant Proteins / metabolism
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T-Lymphocytes, Cytotoxic / metabolism*
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Umbilical Veins / cytology
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Up-Regulation
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Vascular Cell Adhesion Molecule-1 / biosynthesis*
Substances
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Antibodies, Bispecific
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Antigens
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Antigens, CD
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CD3 Complex
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ENG protein, human
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Endoglin
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Immunoglobulin Fragments
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Oligonucleotides
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Receptors, Cell Surface
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Recombinant Proteins
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Vascular Cell Adhesion Molecule-1