Taxanes synergize with the bispecific antibody MDXH447 to enhance antibody-dependent cell-mediated cytotoxicity.
The interaction between antibody based therapy and cytotoxic chemotherapy is complex. To explore these interactions we investigated, in vitro, the effects of IC20 growth inhibitory concentrations of taxanes on bispecific antibody-mediated tumor cell cytotoxicity. MDXH447 is a bispecific antibody with specificity for the high affinity IgG receptor (CD64) and the type I epidermal growth factor receptor type (EGF-R). A431 cells, an epidermoid carcinoma cell line that over expresses EGF-R, were exposed to a range of IC20 growth inhibitory concentrations of paclitaxel or docetaxel. Interferon gamma activated monocytes were armed with MDXH447 and a standard chromium release antibody-dependent cell-mediated cytotoxicity (ADCC) assay was performed. Using the Chou and Talalay median effect analysis, we found that MDXH447-mediated ADCC was enhanced when A431 target cells were pretreated with paclitaxel or docetaxel. Median effect analysis of these interactions supported a synergistic interaction (CI < 1). Pretreatment of A431 cells with taxanes did not increase EGF-R expression compared to untreated controls. A431 epidermoid carcinoma cells pretreated with IC20 growth inhibitory concentrations of taxanes enhanced interferon gamma activated monocyte mediated ADCC killing through MDXH447.
Norris Cotton Cancer Center's Immunology and Immunotherapy Program, Section of Hematology/Oncology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire 03756, USA.
C P G
CP
Tretter
L D
LD
Lewis
J
J
Fisher
M G
MG
Waugh
M S
MS
Ernstoff
D018033:Antibodies, Bispecific / Q000276:immunology / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002277:Carcinoma / Q000473:pathology; D004347:Drug Interactions; D066246:ErbB Receptors / Q000096:biosynthesis / Q000187:drug effects / Q000502:physiology; D017239:Paclitaxel / Q000494:pharmacology; D017452:Receptors, IgG / Q000276:immunology; D012878:Skin Neoplasms / Q000473:pathology; D043823:Taxoids / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D018033:Antibodies, Bispecific; D000972:Antineoplastic Agents, Phytogenic; D017452:Receptors, IgG; D043823:Taxoids; C480118:antibody MDXH447; D066246:ErbB Receptors; D017239:Paclitaxel