2000 32876/id} In general, {IL-6 activity was strongly inhibited,|IL-6 activity was inhibited,} as indicated by reduced CRP levels. from six structured clinical trials of monoclonal antibodies to antiCinterleukin-6 including BE8 and CNTO 328 in the treatment of cancer including multiple myeloma, renal cell carcinoma, and B-lymphoproliferative disorders have produced a number Agrimol B of interesting observations: in all cases, antiCinterleukin-6 mAb treatment had a substantial impact on CRP levels, and in most instances levels were reduced to below detectable limits. Patients exhibited good tolerance and no toxic side effects were observed in the vast majority of studies. The therapeutic impact of antiCinterleukin-6 Agrimol B mAb on cancer-related anorexia and cachexia may also be of clinical significance in a vast number of cancer patients. was proposed.{Poupart, Vandenabeele, et al. 1987 36238/id} The physiologic activity of IL-6 is complex, producing both pro-inflammatory and anti-inflammatory effects in the immune system (Figure 1). {Interleukin-6 promotes inflammation by contributing to the activation and proliferation of T cells,|Interleukin-6 promotes inflammation by contributing to the proliferation and activation of T cells,} stimulating the differentiation of B cells, and inducing the acute-phase reactants of the hepatocyte population.{Jones, Horiuchi, et al. 2001 36225/id} In contrast, {IL-6 also inhibits aspects of the inflammatory cascade.|IL-6 inhibits aspects of the inflammatory cascade also.} Both of the two primary inflammatory cytokines, tumor necrosis factor alpha (TNF-) and IL-1, stimulate the production of prostaglandins, nitric oxide, and matrix metalloproteinases. Interleukin-6, on the other hand, does not promote the production of these inflammatory mediators, and it is hypothesized that IL-6 may play a role in regulating or turning off the in vivo synthesis of TNF- and IL-1.{Barton 1997 32109/id} Despite these functions, IL-6 modulates the transcription of several liver-specific genes during acute inflammatory states, particularly C-reactive protein (CRP), and controls the proliferation of normal plasmablastic cells, as demonstrated in reactive plasmacytosis by using monoclonal antibody (mAb) directed against IL-6 {Gavarotti, Boccadoro, et al. 1985 38022/id}In addition, IL-6 has been shown to be an activator or an inhibitor of T-cell responses, {depending on the target and the system used in vitro.|depending on the target and the operational system used in vitro.} This intricate interaction of pro-inflammatory and anti-inflammatory activities hints at the critical role IL-6 potentially plays in regulating the physiologic response to disease. Open in a separate window Figure 1 Physiologic activity of interleukin-6 (NGF, nerve growth factor). Increased production of IL-6 has been implicated in a variety of disease processes, including neoplasia, Alzheimers disease, autoimmunity (e.g., rheumatoid arthritis), inflammation, myocardial infarction, aging, Pagets disease, osteoporosis, neoplasia (renal cell carcinoma [RCC], prostatic and bladder cancers, certain neurologic cancers), B-cell malignancies (e.g., Castlemans disease), some lymphoma subtypes, and, particularly, multiple myeloma (MM) {Keller, Wanagat, et al. 1996 36226/id}{Simpson, Hammacher, et al. 1997 35743/id}{Tupitsyn, Kadagidze, et al. 1998 36232/id}. In addition, IL-6 is implicated in proliferation pathways as a central proliferation factor or acting in cooperation with other factors, such as heparin-binding epithelial growth factor and hepatocyte growth factor (Oncogene 2002, 21:460; Cancer Res 2001, 61: 383; {Wang, De Vos, et al. {2002 38024/id}This reinforces the hypothesis that blocking IL-6 may have significant benefit in a large variety of pathologic situations.|2002 38024/id}This reinforces the hypothesis that blocking IL-6 might have significant benefit in a large variety of pathologic situations.} {In the following discussion we review the role of IL-6 in the etiology and pathogenesis of cancer,|In the following discussion we review the role of IL-6 in the pathogenesis and etiology of cancer,} as well as a comprehensive review of clinical trials of targeted cancer therapy using mAb to IL-6. Interleukin-6/Interleukin-6 Receptor Interaction Interleukin-6 is a multifunctional cytokine that binds to a specific IL-6 receptor ( chain, IL-6R, or CD126) on target cells. This IL-6/IL6R complex associates with two molecules of the ubiquitously expressed gp130 ( chain, CD130), the second chain of the receptor, resulting in the formation of high-avidity IL-6 binding receptors {Kishimoto, Akira, et al. 1992 38003/id}; {Ward, Howlett, et al. 1994 38023/id}The gp130 functions as an affinity converter, since the resulting affinity of IL-6 for the ternary complex is around 10?11 M, {instead of 10?|of 10 instead?}9 M for IL-6R. {Whereas gp80 binds specifically to IL-6,|Whereas gp80 binds to IL-6 specifically,} gp130 is a common signal-transducing receptor for a subfamily of cytokines, including IL-6, IL-11, leukemia-inhibiting factor (LIF), ciliary neurotrophic factor (CNTF), oncostatin M (OM), and cardiotropin 1 (CT-1), named the gp130 cytokine family. After binding to their specific receptors, all these cytokines induce homodimerization of gp130 or its heterodimerization with the LIF receptor (LIFR), which initiates cell signaling {Kishimoto, Akira, et al. 1992 38003/id}. In contrast with the wide distribution of gp130, gp80 is limited to hepatocytes and specialized subsets of leukocytes, including monocytes, neutrophils, T cells, and B cells (Jones et al 2001). Stimulation of gp130 is essential for hematopoiesis in vivo. {The system is complicated by the presence of soluble forms of both gp80 and gp130.|The operational system is complicated by the presence of soluble forms of both gp80 and gp130.} These circulating compounds are cleaved from the cell membrane molecule or translated from an alternative spliced mRNA, yielding a protein that differs at its COOH-terminus by 14 amino-acid residues {Mullberg, Schooltink, et al. 1993 38008/id}{Horiuchi, Koyanagi, et al. 1994 38030/id}. Cleavage of transmembrane proteins can be done by a transmembrane metalloproteinase, distinct from matrix-type metalloproteases, that belongs to the family domains containing metalloproteinases (ADAM).1994 32969/id} For the patients with disease stabilization, follow-up assessments indicated that stabilization was sustained for 8 to 28 weeks. no toxic side effects were observed in the vast majority of studies. The therapeutic impact of antiCinterleukin-6 mAb on cancer-related anorexia and cachexia may also be of clinical significance in a vast number of cancer patients. was proposed.{Poupart, Agrimol B Vandenabeele, et al. 1987 36238/id} The physiologic activity of IL-6 is complex, producing both pro-inflammatory and anti-inflammatory effects in the immune system (Figure 1). Interleukin-6 promotes inflammation by contributing to the activation and proliferation of T cells, stimulating the differentiation of B cells, and inducing the acute-phase reactants of the hepatocyte population.{Jones, Horiuchi, et al. 2001 36225/id} In contrast, IL-6 also inhibits aspects of the inflammatory cascade. Both of the two primary inflammatory cytokines, tumor necrosis factor alpha (TNF-) and IL-1, stimulate the production of prostaglandins, nitric oxide, and matrix metalloproteinases. Interleukin-6, on the other hand, does not promote the production of these inflammatory mediators, and it is hypothesized that IL-6 may play a role in regulating or turning off the in vivo synthesis of TNF- and IL-1.{Barton 1997 32109/id} Despite these functions, IL-6 modulates the transcription of several liver-specific genes during acute inflammatory states, particularly C-reactive protein (CRP), and controls the proliferation of normal plasmablastic cells, as demonstrated in reactive plasmacytosis by using monoclonal antibody (mAb) directed against IL-6 {Gavarotti, Boccadoro, et al. 1985 38022/id}In addition, IL-6 has been shown to be an Rabbit Polyclonal to WAVE1 (phospho-Tyr125) activator or an inhibitor of T-cell responses, depending on the target and the system used in vitro. This intricate interaction of pro-inflammatory and anti-inflammatory activities hints at the critical role IL-6 potentially plays in regulating the physiologic response to disease. Open in a separate window Figure 1 Physiologic activity of interleukin-6 (NGF, nerve growth factor). Increased production of IL-6 has been implicated in a variety of disease processes, including neoplasia, Alzheimers disease, autoimmunity (e.g., rheumatoid arthritis), inflammation, myocardial infarction, aging, Agrimol B Pagets disease, osteoporosis, neoplasia (renal cell carcinoma [RCC], prostatic and bladder cancers, certain neurologic cancers), B-cell Agrimol B malignancies (e.g., Castlemans disease), some lymphoma subtypes, and, particularly, multiple myeloma (MM) {Keller, Wanagat, et al. 1996 36226/id}{Simpson, Hammacher, et al. 1997 35743/id}{Tupitsyn, Kadagidze, et al. 1998 36232/id}. In addition, IL-6 is implicated in proliferation pathways as a central proliferation factor or acting in cooperation with other factors, such as heparin-binding epithelial growth factor and hepatocyte growth factor (Oncogene 2002, 21:460; Cancer Res 2001, 61: 383; {Wang, De Vos, et al. 2002 38024/id}This reinforces the hypothesis that blocking IL-6 may have significant benefit in a large variety of pathologic situations. In the following discussion we review the role of IL-6 in the etiology and pathogenesis of cancer, as well as a comprehensive review of clinical trials of targeted cancer therapy using mAb to IL-6. Interleukin-6/Interleukin-6 Receptor Interaction Interleukin-6 is a multifunctional cytokine that binds to a specific IL-6 receptor ( chain, IL-6R, or CD126) on target cells. This IL-6/IL6R complex associates with two molecules of the ubiquitously expressed gp130 ( chain, CD130), the second chain of the receptor, resulting in the formation of high-avidity IL-6 binding receptors {Kishimoto, Akira, et al. 1992 38003/id}; {Ward, Howlett, et al. 1994 38023/id}The gp130 functions as an affinity converter, since the resulting affinity of IL-6 for the ternary complex is around 10?11 M, instead of 10?9 M for IL-6R. Whereas gp80 binds specifically to IL-6, gp130 is a common signal-transducing receptor for a subfamily of cytokines, including IL-6, IL-11, leukemia-inhibiting factor (LIF), ciliary neurotrophic factor (CNTF), oncostatin M (OM), and cardiotropin 1 (CT-1), named the gp130 cytokine family. After binding to their specific receptors, all these cytokines induce homodimerization of gp130 or its heterodimerization with the LIF receptor (LIFR), which initiates cell signaling {Kishimoto, Akira, et al. 1992 38003/id}. In contrast with the wide distribution of gp130, gp80 is limited to hepatocytes and specialized subsets of leukocytes, including monocytes, neutrophils, T cells, and B cells (Jones.