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Title: Cytokine enhancement of in vitro antibody-dependent cellular cytotoxicity mediated by chimeric anti-GD3 monoclonal antibody KM871.
Austin Authors: Liu, Zhanqi;Lee, Fook-Thean;Hanai, Nobuo;Smyth, Fiona E;Burgess, Antony W;Old, Lloyd J;Scott, Andrew M 
Affiliation: Ludwig Institute for Cancer Research, Melbourne Tumour Biology Branch, Austin and Repatriation Medical Centre, Heidelberg, Victoria, 3084, Australia
Issue Date: 7-Oct-2002
Publication information: Cancer Immunity 2002; 2(): 13
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 micro g/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.
Gov't Doc #: 12747758
Journal: Cancer immunity
Type: Journal Article
Subjects: Antibodies, Monoclonal.pharmacology
Antibody-Dependent Cell Cytotoxicity.drug effects
Antigens, CD3.analysis
Antigens, CD56.analysis
Antigens, CD8.analysis
Flow Cytometry
Granulocyte-Macrophage Colony-Stimulating Factor.pharmacology
Killer Cells, Natural.cytology.drug effects.immunology
Leukocytes, Mononuclear.cytology.drug effects.immunology
Receptors, IgG.analysis
Recombinant Fusion Proteins.immunology.pharmacology
T-Lymphocytes.cytology.drug effects.immunology
Time Factors
Tumor Cells, Cultured
Appears in Collections:Journal articles

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