GM-CSF Enhances 3F8 Monoclonal Antibody-Dependent Cellular Cytotoxicity Against Human Melanoma and Neuroblastoma

• Published in: Blood Vol. 73; no. 7; pp. 1936 - 1941
• Main Authors: Kushner, Brian H., Cheung, Nai-Kong V.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15.05.1989; The Americain Society of Hematology
• Subjects: Adjuvants, Immunologic - pharmacology; Antibodies, Monoclonal - physiology; Antibody-Dependent Cell Cytotoxicity - drug effects; Biological and medical sciences; Cell Line; Colony-Stimulating Factors - pharmacology; Cytotoxic reactions (adcc reaction, cell-mediated lympholysis, complement-dependent cytotoxicity and others); Fundamental and applied biological sciences. Psychology; Fundamental immunology; Granulocyte-Macrophage Colony-Stimulating Factor; Granulocytes - immunology; Granulomatous Disease, Chronic - immunology; Growth Substances - pharmacology; Humans; Immunobiology; Immunological reactions in vitro; Melanoma - immunology; Neuroblastoma - immunology; Receptors, Fc - physiology; Recombinant Proteins - pharmacology; Cell culture; Fc-Fragment; Antibody-dependent cell cytotoxicity; Cytokine; Melanoma; IgG3; Cytotoxicity; Receiver; Monoclonal antibody; Neuroblastoma; Granulocyte macrophage colony stimulating factor
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V73.7.1936.1936

3F8 is a murine monoclonal lgG3 antibody specific for the tumor-associated antigen ganglioside GD2. Previous in vitro studies suggest that tumor regressions observed in a phase I clinical trial of 3F8 may be attributable to complement activation by 3F8 and to 3F8-dependent cellular cytotoxicity (ADCC) with lymphocytes. We now describe 3F8-mediated ADCC of GD2-positive tumor targets (mela-noma and neuroblastoma) with human granulocytes and report that recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) enhanced this phenomenon. Cytotoxicity required binding of 3F8 to the low-affinity Fc receptor type III (CD16) on the granulocytes and was poor with tumor-binding monoclonal antibodies of other immunoglobulin (ie, non-lgG3) subclasses. GM-CSF (2 to 20 ng/mL) increased ADCC by 93% to 267% at limiting dilutions of 3F8 (1 μg/mL). With most GD2-positive cell lines tested, this effect translated into a tenfold or greater augmentation in 3F8 efficiency at mediating ADCC. Comparable enhancement occurred whether GM-CSF was present in the ADCC assay or granulocytes were incubated with GM-CSF and washed before the assay. Nonoxidetive mechanisms may be important for ADCC since 3F8 mediated ADCC with granulocytes from two children with chronic granulomatous disease; this cytotoxicity was also enhanced by GM-CSF. Since GM-CSF induces a neutrophilia in patients, our data suggest that this cytokine may have the potential of amplifying 3F8 antitumor activity in patients by increasing effector cell numbers and by priming granulocytes for greater cytotoxicity.© 1989 by Grune & Stratton, Inc. 0006-4971/89/7307-0005$ 3.00/0