Interleukin-4 priming enhances a target for human complement-mediated cytotoxicity of CLL.
JD118 is a murine immunoglobulin M monoclonal antibody (mAb) under study as a therapeutic agent that is capable of potent human complement-mediated cytotoxicity (CMC) against B-cell lymphoma and leukemia targets. The JD118 antigen target was upregulated on fresh human B cells and B-cell neoplasms after brief in vitro incubation in media containing calf serum. To determine if cytokines could also lead to upregulation of JD118 antigen, alpha-interferon (alpha-IFN), gamma-interferon (gamma-IFN), interleukin 2 (IL-2), or IL-4 were added to fresh neoplastic B cells in serum-free media and changes in JD118 antigen expression were evaluated by flow cytometry (FCM). IL-4 was found to be the predominant cytokine responsible for inducing upregulation of the JD118 antigen. Marked JD118 upregulation by IL-4 was seen in 14 out of 14 chronic lymphocytic leukemia (CLL) samples tested, with 50 to 750-fold increases in four samples, 11 to 49-fold increases in four samples, and up to 10-fold increase in six samples. One B-cell lymphoma specimen was upregulated 18-fold, but no up-regulation was demonstrated in one hairy cell leukemia and two acute myelogenous leukemia specimens tested. The specificity of the IL-4 up-regulation was demonstrated by the elimination of its activity by blocking with a neutralizing anti-IL-4 mAb. IL-4 upregulation allows JD118 mAb CMC against otherwise antigen-negative targets and argues for phase I trials using a combination of IL-4 cytokine and mAb for B-cell neoplasms.
Czuczman
M S
MS
Laboratory of Hematopoietic Cancer Immunochemistry, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
Class
K
K
Scheinberg
D A
DA
D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000920:Antibody-Dependent Cell Cytotoxicity; D015703:Antigens, CD / Q000378:metabolism; D018941:Antigens, CD19; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism; D000954:Antigens, Surface / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007167:Immunotherapy; D015847:Interleukin-4 / Q000008:administration & dosage*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D008562:Membrane Glycoproteins / Q000378:metabolism*; D015854:Up-Regulation
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018941:Antigens, CD19; D000944:Antigens, Differentiation, B-Lymphocyte; D000954:Antigens, Surface; D008562:Membrane Glycoproteins; D015847:Interleukin-4