Purpose: We investigated the in vitro and in vivo anti-multiple myeloma activity of monoclonal antibody (mAb) 1339, a high-affinity fully humanized anti-interleukin 6 mAb (immunoglobulin G1), alone and in combination with conventional and novel anti-multiple myeloma agents, as well as its effect on bone turnover. Experimental Design: We examined the growth inhibitory effect of 1339 against multiple myeloma cell lines in the absence and in the presence of bone marrow stromal cells, alone or in combination with dexamethasone, bortezomib, perifosine, and Revlimid. Using the severe combined immunodeficient (SCID)-hu murine model of multiple myeloma, we also examined the effect of 1339 on multiple myeloma cell growth and multiple myeloma bone disease. Results: mAb 1339 significantly inhibited growth of multiple myeloma cell in the presence of bone marrow stromal cell in vitro, associated with inhibition of phosphorylation of signal transducer and activator of transcription 3, extracellular signal-regulated kinase 1/2, and Akt. In addition, mAb 1339 enhanced cytotoxicity induced by dexamethasone, as well as bortezomib, lenalidomide, and perifosine, in a synergistic fashion. Importantly mAb 1339 significantly enhanced growth inhibitory effects of dexamethasone in vivo in SCID-hu mouse model of multiple myeloma. mAb 1339 treatment also resulted in inhibition of osteoclastogenesis in vitro and bone remodeling in SCID-hu model. Conclusions: Our data confirm in vitro and in vivo anti-multiple myeloma activity of, as well as inhibition of bone turnover by, fully humanized mAb 1339, as a single agent and in combination with conventional and novel agents, providing a rationale for its clinical evaluation in multiple myeloma. (Clin Cancer Res 2009;15(23):7144-52)
SUMMARY:Glioma and renal cell carcinoma (RCC) cells express high affinity interleukin 13 (IL13) binding sites, but only RCC cell proliferation was inhibited by IL13. Both of these two cell types are IL2-receptor ␥c chain-negative. We thus used these cell models to investigate the patterns of expression of IL13R␣1, IL13R␣2, and IL4R␣ chains and the role of IL13R␣2 in the response to IL13. Using new specific antibodies and flow cytometry, we observed a similar surface expression of IL4R␣ and IL13R␣1 chains in most RCC and glioma cells, whereas IL13R␣2 was only present on five of six glioma cell lines. In all glioma cell lines, the amount of IL13R␣2 expression was 10 to 30 times higher than that of the two other chains. Although there was no surface or intracellular expression of IL13R␣2, its mRNA was detected in three of seven RCC cell lines. The expression on RCC cells of IL13R␣2 mRNA and/or that of high-affinity IL13 binding sites is not sufficient to predict IL13R␣2 protein expression. Blocking experiments showed that IL4 and IL13 strongly inhibited RCC cell proliferation through a unique receptor composed of IL4R␣ and IL13R␣1 chains. Using RCC cells stably transfected with IL13R␣2 cDNA, we showed that the overexpression of IL13R␣2 decreased the response to IL13 but not that to IL4. Our results demonstrate that IL13R␣2 acts as a decoy receptor for IL13 and that it may exert a tight regulation of IL13 activity without impairing the IL4 response of the same cell target. (Lab Invest 2001, 81:1223-1231.
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