Cytokine enhancement of in vitro antibody-dependent cellular cytotoxicitymediated by chimeric anti-GD3 monoclonal antibody KM871 Journal Article


Authors: Liu, Z.; Lee, F. T.; Hanai, N.; Smyth, F. E.; Burgess, A. W.; Old, L. J.; Scott, A. M.
Article Title: Cytokine enhancement of in vitro antibody-dependent cellular cytotoxicitymediated by chimeric anti-GD3 monoclonal antibody KM871
Abstract: The chimeric KM871 monoclonal antibody targets the GD3 disialoganglioside antigen and is under investigation for its immunotherapeutic potential in melanoma. Preclinical and phase I studies have demonstrated the biodistribution and specific tumour targeting of KM871 to metastatic melanoma in vivo, with a long half-life and lack of immunogenicity making it an attractive candidate for further clinical trials. In vitro studies have demonstrated KM871 induces high levels of cytotoxicity in both antibody-dependent cellular-cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) assays. In order to investigate the potential for cytokine upregulation of KM871-mediated ADCC, freshly isolated healthy donor PBMC effector cells were cultured in the presence or absence of the cytokines interleukin-2, interleukin-12 and granulocyte/macrophage-colony stimulating factor and the ADCC determined over a 10-day period. In the absence of these cytokines, ADCC activity of 1 μg/ml KM871 on (51)Cr-labeled SK-MEL-28 target cells could not be detected after 72 hrs of culture of PBMC effector cells in media. In contrast, ADCC mediated by KM871 was significantly enhanced and maintained for the 10-day study period upon culturing PBMCs with media containing IL-2 and/or IL-12, but not with GM-CSF. FACS analysis of the effector cell population indicated CD3-/CD16+56+ NK cells were primarily responsible for the KM871-mediated ADCC activity and a direct correlation was observed between the percentage of NK cells and the level of cytotoxicity mediated by the PBMCs. Furthermore, ADCC was significantly reduced using NK-depleted PBMCs. These results suggest combining IL-2 or IL-12 with KM871 may enhance KM871 immune-mediated cell killing in patients with metastatic melanoma.
Keywords: controlled study; unclassified drug; human cell; cd3 antigen; interleukin 2; melanoma; granulocyte macrophage colony stimulating factor; cytotoxicity; in vitro study; monoclonal antibodies; monoclonal antibody; cd16 antigen; cytokine; cytokines; cell culture; natural killer cell; effector cell; upregulation; fluorescence activated cell sorting; interleukin 12; ganglioside gd3; peripheral blood mononuclear cell; antibody dependent cellular cytotoxicity; gangliosides; chimeric antibody; cd56 antigen; chimeric; antibody-dependent cell cytotoxicity; human; article; cultured tumor cells; monoclonal antibody km 871
Journal Title: Cancer Immunity
Volume: 2
ISSN: 1424-9634
Publisher: Academy of Cancer Immunology  
Date Published: 2002-10-07
Start Page: 13
Language: English
PROVIDER: scopus
PUBMED: 12747758
DOI/URL:
Notes: Export Date: 14 November 2014 -- Source: Scopus
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MSK Authors
  1. Lloyd J Old
    593 Old