Abstract
To target NK cells against non-Hodgkin's lymphoma, we constructed a bispecific diabody (BsDb) with reactivity against both human CD19 and FcgammaRIII (CD16). Bacterially produced CD19 x CD16 BsDb specifically interacted with both CD19(+) and CD16(+) cells and exhibited significantly higher apparent affinity and slower dissociation from the tumor cells than from effector cells. It was able to induce specific lysis of tumor cells in the presence of isolated human NK cells or nonfractionated PBLs. The combination of the CD19 x CD16 BsDb with a previously described CD19 x CD3 BsDb and CD28 costimulation significantly increased the lytic potential of human PBLs. Treatment of SCID mice bearing an established Burkitt's lymphoma (5 mm in diameter) with human PBLs, CD19 x CD16 BsDb, CD19 x CD3 BsDb, and anti-CD28 mAb resulted in the complete elimination of tumors in 80% of animals. In contrast, mice receiving human PBLs in combination with either diabody alone showed only partial tumor regression. These data clearly demonstrate the synergistic effect of small recombinant bispecific molecules recruiting different populations of human effector cells to the same tumor target.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Bispecific / administration & dosage
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Antibodies, Bispecific / biosynthesis
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Antibodies, Bispecific / genetics
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Antibodies, Bispecific / pharmacology*
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Antibody Specificity / genetics
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Antigens, CD19 / genetics
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Antigens, CD19 / immunology*
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Antigens, CD19 / metabolism
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / pharmacology*
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Binding Sites, Antibody / genetics
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Biosensing Techniques
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Burkitt Lymphoma / immunology
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Burkitt Lymphoma / therapy
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CD3 Complex / genetics
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CD3 Complex / immunology*
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Cell Line
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Cytotoxicity, Immunologic / genetics
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Drug Screening Assays, Antitumor / methods*
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Drug Synergism
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Humans
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Injections, Intravenous
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Jurkat Cells
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Killer Cells, Natural / immunology
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Lymphoma, Non-Hodgkin / immunology*
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Lymphoma, Non-Hodgkin / pathology
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Lymphoma, Non-Hodgkin / therapy*
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Mice
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Mice, SCID
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Receptors, IgG / genetics
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Receptors, IgG / immunology*
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Receptors, IgG / metabolism
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Recombinant Proteins / administration & dosage
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Recombinant Proteins / chemical synthesis
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Recombinant Proteins / genetics
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Recombinant Proteins / pharmacology
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Tumor Cells, Cultured
Substances
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Antibodies, Bispecific
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Antigens, CD19
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Antineoplastic Agents
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CD3 Complex
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Receptors, IgG
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Recombinant Proteins