CNTO 328, a monoclonal antibody to IL‐6, inhibits human tumor‐induced cachexia in nude mice

Abstract

IL-6 is a multifunctional cytokine implicated in several cancers. IL-6 is a growth factor for certain tumors and contributes to drug resistance, cachexia and bone resorption. Cachexia is characterized by progressive weight loss and depletion of host reserves of adipose tissue and skeletal muscle. We have developed CNTO 328 (cCLB8), a humanmouse chimeric MAb to IL-6 (K d approx. 10 ؊12 M) that inhibits IL-6 function. A phase I study with CNTO 328 in multiple myeloma patients demonstrated that the antibody was safe and had a circulating half-life of approximately 17 days. Since IL-6 is implicated in cachexia, we hypothesized that CNTO 328 could inhibit tumor-induced cachexia. We used 2 human tumor-induced cachexia models in nude mice. In the first model, human melanoma cells were inoculated in female nude mice. Control treated animals lost 19% (؎7.7%) body weight from day 0 to day 31, whereas CNTO 328 (10 mg/kg)-treated animals lost only 1.5% (؎1.3%) body weight from day 0 to day 31 (p ‫؍‬ 0.023). Cachexia (wasting syndrome) is a debilitating state of involuntary weight loss that is characterized by hypercatabolism of the body's carbon sources, proteins and lipids, for conversion into energy. 1 Cachexia is induced by a variety of pathologic conditions, including cancer, where an estimated 30% of cancer deaths are attributed to cachexia. Tumor necrosis factor (TNF)-␣, IL-1, IFN-␥ and IL-6 contribute to many of the host changes seen in cancer cachexia, including loss of appetite, loss of body weight and induction of acute-phase proteins. 2 These cytokines induce cachexia by altering the metabolism of lipids and proteins. IL-6 is a 26 kDa protein with a broad range of activities, involving not only immunomodulation but also hemostatic, neuroendocrine and cancer-associated disorders. 3 IL-6 is an acute phase-inducing cytokine that is secreted to a large extent by human adipose tissue under noninflammatory conditions. 4 It also influences atrophy and increases catabolism of muscle protein. IL-6 is expressed together with its receptor in neurons of hypothalamic nuclei that regulate body composition. IL-6 levels in serum correlate with body mass index (BMI), and IL-6-deficient mice developed mature-onset obesity. 4 Although several studies have suggested that host-derived IL-6 contributes to cachexia, the role for tumor cell-secreted IL-6 in cachexia is less clear.IL-6 is also implicated in regulating the growth and differentiation of several malignant diseases. The ability of IL-6 to mediate tumor cell survival and disease progression has been demonstrated by the inhibitory effects of an anti-IL-6 MAb on tumor growth both in vitro and in vivo. Blockade of IL-6 can inhibit growth of human glioblastoma cells in vitro. 5 Using the same approach, it was shown that injection of an antihuman IL-6 MAb prolonged the survival of human lymphoma-bearing mice. 6 Several clinical trials using monoclonal antibodies (MAbs) against IL-6 have been conducted on various diseases, including plasma cell leukemia, multiple myeloma, B-lymphop...

Molecular and neuroendocrine mechanisms of cancer cachexia

“…Accordingly, treatment with an IL6 receptor antagonist, or MABs to murine IL6, was able to suppress key cachexia parameters (Strassmann et al 1992, Enomoto et al 2004, Zaki et al 2004). …”

Role of physical activity in tumor patients and possible underlying mechanisms

“…Animal studies could show that an injection of TNF-α leads to a loss of muscle and fat mass by activating the proteasomal degradation of proteins via the NFκ pathway [67]. Further cachexia-reducing effects have been described for the injection of IFN-γ and IL-6 antibodies [48,90]. Interestingly, physical activity has the potential to reduce the proinflammatory environment.…”

IL-6 involvement in epithelial cancers

“…IL-6 or IL-6 receptor antagonists (i.e., CNTO 328, a human-mouse chimeric antibody to human IL-6, and Tocilizumab, humanized anti-IL-6 receptor antibody) are currently in either phase I or phase II clinical trials in a small subset of cancers and other diseases (21,22). It is difficult to predict the outcome of IL-6 antagonism in human tumors, because the studies in these reports did not address whether inhibition of IL-6 would lead to tumor regression or merely prevent expansion of existing tumors that are IL-6 dependent.…”