Bispecific single-chain diabody-mediated killing of endoglin-positive endothelial cells by cytotoxic T lymphocytes.
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.
Korn
Tina
T
Institut für Molekularbiologie und Tumorforschung, Philipps-Universität Marburg, Emil-Mannkopff-Str. 2, 35033 Marburg, Germany.
Müller
Rolf
R
Kontermann
Roland E
RE
D018033:Antibodies, Bispecific / Q000737:chemistry*; D000941:Antigens / Q000737:chemistry; D015703:Antigens, CD; D017252:CD3 Complex / Q000096:biosynthesis / Q000276:immunology; D002469:Cell Separation; D002478:Cells, Cultured; D004306:Dose-Response Relationship, Immunologic; D000071063:Endoglin; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D007128:Immunoglobulin Fragments / Q000737:chemistry; D007167:Immunotherapy / Q000379:methods*; D019169:Jurkat Cells; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D009841:Oligonucleotides / Q000737:chemistry; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins / Q000737:chemistry* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism*; D014471:Umbilical Veins / Q000166:cytology; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis*
D018033:Antibodies, Bispecific; D000941:Antigens; D015703:Antigens, CD; D017252:CD3 Complex; C064206:ENG protein, human; D000071063:Endoglin; D007128:Immunoglobulin Fragments; D009841:Oligonucleotides; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D019010:Vascular Cell Adhesion Molecule-1