Effective Elimination of Acute Myeloid Leukemic Cells by Recombinant Bispecific Antibody Derivatives Directed Against CD33 and CD16
| Autor: | Georg H. Fey, Kristin Mentz, Christian Kellner, Michael Schwemmlein, Christoph Stein, Andreas Mackensen, Bernhard Stockmeyer, Harald Lanig, Heiko Singer, Michael Aigner, Fuat Oduncu |
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| Rok vydání: | 2010 |
| Předmět: |
Cancer Research
Recombinant Fusion Proteins Sialic Acid Binding Ig-like Lectin 3 Immunology CD33 Antibody Affinity Antigens Differentiation Myelomonocytic CHO Cells Biology Protein Engineering Natural killer cell Cricetulus Antigen Antigens CD Cricetinae Antibodies Bispecific medicine Animals Humans Immunology and Allergy Computer Simulation Avidity Pharmacology Antibody-dependent cell-mediated cytotoxicity Protein Stability Receptors IgG Antibody-Dependent Cell Cytotoxicity Myeloid leukemia medicine.disease Virology Molecular biology Leukemia Myeloid Acute Leukemia medicine.anatomical_structure Leukocytes Mononuclear biology.protein Immunotherapy Antibody |
| Zdroj: | Journal of Immunotherapy. 33:599-608 |
| ISSN: | 1524-9557 |
| DOI: | 10.1097/cji.0b013e3181dda225 |
| Popis: | Single-chain Fv triplebodies (sctb), consisting of a single polypeptide chain with 3 single-chain antibody variable fragments connected in tandem, were generated as antileukemic agents. A CD19-specific sctb of this format has previously been shown to be superior to a bispecific single-chain Fv antibody fragment (bsscFv) for the elimination of leukemic B-lineage cells, but corresponding targeted agents for the treatment of acute myeloid leukemia are still lacking. For this purpose, both a bsscFv and a sctb specific for CD33 and the trigger molecule CD16 (FcgammaRIII) were produced. The sctb displayed 3.5-fold greater avidity for CD33 than the bsscFv 33xds16, whereas both had close to equal affinity for CD16. In antibody-dependent cellular cytotoxicity (ADCC) reactions with human mononuclear cells as effectors, both the bsscFv 33xds16 and the sctb induced lysis of tumor cells with half maximum effective concentrations (EC50) in the low picomolar range. It is interesting to note that the sctb promoted equal lysis of human leukemia-derived cell lines at 10 to 200-fold lower concentrations than the bsscFv. Both molecules mediated ADCC of primary patient cells. In conclusion, both the bsscFv 33xds16 and the sctb 33xds16x33 eliminated acute myeloid leukemia cells in ADCC reactions, but the novel sctb format showed significantly greater specific activity. |
| Databáze: | OpenAIRE |
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