Antibody – VX30 Inflammatory DiseaseInterleukin-6 (IL-6) is a key cytokine produced by monocytes, fibroblasts and endothelial cells. IL-6 is a stimulator of both B and T cell functions. In particular, IL-6 promotes the proliferation of plasmablasts during their final stages of maturation into immunoglobulin producing plasma cells (REF 1). In addition to regulating immune responses, IL-6 also regulates acute phase reactions and hematopoiesis (REF 2). It exerts its biological effects through binding to its immediate receptor CD126 (gp80) and thereupon binding of the complex to two signal transducing receptor subunits CD130 (gp130), common to other four-helix bundle cytokines (REF 2). Dimerization of gp130 and the subsequent phosphorylation of its intracellular domain lead to activation through phosphorylation of the Jak kinase family and STAT1/ STAT3 (REF 3). IL-6 is a major myeloma survival factor in vitro, and it has been shown that anti-IL-6 monoclonal antibodies (MAb) can block the in vitro proliferation of primary myeloma cells. (REF 4) It has also been shown that in vivo, IL-6 is overproduced by the tumor environment in multiple myeloma (MM) patients and that increase in serum levels of IL-6 is associated with a poor prognosis (REF 5). Moreover, there is evidence that treatment with anti-IL6 in a mouse model of multiple myeloma can reduce tumor cell growth (REF 6). IL-6 is believed to play an important role in the development and progression of rheumatoid arthritis (RA). IL-6, in conjunction with the soluble IL-6 receptor (sIL-6Rα), has been shown to activate endothelial cells to produce inflammatory chemokines and also to up-regulate expression of adhesion molecules, contributing directly to recruitment of leukocytes at inflammatory sites. In addition, IL-6 can stimulate synoviocyte proliferation and osteoclast maturation and activation, suggesting a role in synovial pannus formation and in bone resorption in inflamed joints (6). Neutralization of IL-6 using a monoclonal antibody specific for the IL-6 receptor (tocilizumab, Actemra) has shown promise in clinical trials of patients with RA. The IL-6R is, however, also expressed on hepatocytes. Data generated from the clinical studies with Actema have indicated that treatment can trigger changes in lipid levels as well as liver abnormalities. This is a significant concern for treatment of any chronic disease, a concern further elevated by the increased risk of cardiovascular complications for RA patients. It is possible that neutralizing the activity of IL-6 using a monoclonal antibody directed to the cytokine itself rather than to the receptor will result in similar clinical benefit without detrimental effects on lipid metabolism. Early clinical trials with anti-IL-6 have shown that treatment of late stage cancer patients with the murine anti-IL-6 MAb BE8 can block the in vivo proliferation of tumor cells and reduce IL-6-related toxicities (ie fever, cachexia) (9-13). Clinical use of a murine antibody is not desirable because the murine antibodies have short half-lives in humans, require frequent dosing, and murine antibodies are usually immunogenic, preventing long term treatment. These observations suggest a rationale for developing a fully human anti-IL-6 antibody for the treatment of inflammatory disease with possible application to cancer. We have selected a high affinity human IgG1 antibody with the same specificity for human IL-6 as the murine BE8 antibody and demonstrated inhibition of IL-6 function in cell proliferation assays in vitro. VX30 is currently in IND-directed pre-clinical development
Figure 1. VX30 inhibits multiple myeloma cell proliferation in a time- and dose-dependent manner.
TOP: IL-6–dependent INA-6 cells were cultured in the presence of murine, human or chimeric antibodies to IL-6, to gp130, or to gp80, as well as with isotype control antibodies, at various concentrations. Cell proliferation was assessed by [3H]thymidine uptake at 72 h.
BOTTOM: IL-6–dependent INA-6 and XG1 cells were cultured in the presence of VX30, as well as with isotype antibody control, at various concentrations for variable time (24-72 h) at 37°C. Data are means ± SD of four independent experiments done in triplicate. VX30 inhibits IL-6–dependent multiple myeloma cell growth in a dose-dependent manner. This figure can be found in REF 6. 
Figure 2. Additive in vivo effect of VX30 in combination with dexamethasone in a murine model of human multiple myeloma (SCID-hu). INA-6 multiple myeloma cells were injected directly into human bone implant in SCID-hu mice. Sera were monitored for the production of soluble human IL-6 receptor as a marker of multiple myeloma cell growth. After the first detection of soluble human IL-6 receptor, mice were injected with isotype control (100 µg per mouse once a week; n = 6), VX30 (100 µg per mouse once a week; n = 4), dexamethasone (1 mg/kg 3X/week; n = 4), or VX30 plus dexamethasone (n = 4). Baseline values before treatment were not significantly different among groups. This figure can be found in REF 6.
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