Journal: Immunologic research
Article Title: Preclinical validation of interleukin 6 as a therapeutic target in multiple myeloma
doi: 10.1007/s12026-014-8528-x
Figure Lengend Snippet: Targeting MRD/MMSC with small-drug inhibitors, immune-based interventions and IL-6-targeted therapies may result in a cure for patients with myeloma. a Curative blueprint for myeloma. The currently available myeloma therapies are highly efficient in killing the great majority of myeloma cells (excentric nucleus, rich cytoplasm, paranuclear Golgi zone) but are unable to eradicate a tiny subpopulation of cells that exhibit stem cell-like features and are called MMSCs. These cells underlie MRD and often acquire drug resistance in the course of myeloma treatment, leading to relapse of a therapy-resistant tumor. Treatments that target MMSC/MRD efficiently may result in a cure for myeloma. Owing to the genetic complexity of myeloma and its perpetual clonal diversification [129– 133], targeted eradication of MRD cells may be best accomplished in an adjuvant setting at a relatively early stage of myeloma treatment. b Two principal forms of MRD/MMSC-targeted therapies: small-drug inhibitors and immunological approaches. Inhibitors target stemness genes, such as MYC (JQ1); stemness pathways, such as Wnt (celecoxib), Notch (BMS-906024) and Hedgehog (itraconazole, cyclopamine); drug resistance pathway, such as multidrug resistance (sildenafil); and, last but not least, individual candidate MMSC genes, such as RARA2 (ATRA), NEK2 (CCT250863) and BTK (ibrutinib). Immune-based therapies for targeting MRD include CAR-T cells and dendritic cell vaccines (see main text for details). Also included is a growing panel of therapeutic monoclonal antibodies exhibiting reactivity to CS1 (elotuzumab), CD38 (daratumumab), CD56 (lorvotuzumab), VEGF (bevacizumab), EGR (cetuximab), KIR (IPH2101), FGFR3 (MFGR1877S), BAFF (LY2127399) and other myeloma targets. To be fully effective, immunotherapy must probably be combined with small-drug inhibitors and IL-6-targeted drugs shown in panel C. c Approaches to inhibit IL-6 signaling in myeloma including cancer stem cell-like cells (bottom) and bone marrow stroma cells (top) [70]. Labeled circles indicate active research areas, which can be categorized as follows: a Tocilizumab is a humanized antibody to IL-6R, which competitively inhibits IL-6 signaling by virtue of binding to the receptor's ligand-binding site [134]. The antibody inhibits both canonical/classical IL-6 signaling and IL-6 trans-signaling because it binds to both cell membrane-bound IL-6R and soluble IL-6R [135]. Tocilizumab has been approved for the treatment of arthritis and is currently undergoing clinical testing for other disease. However, there are no clinical trials of myeloma at this juncture. b Antibodies neutralizing IL-6 include mouse BE-8 (elsilimomab) and siltuximab (CNTO 328, Centocor). Siltuximab is a chimeric human-mouse antibody and thus less immunogenic than BE-8. Siltuximab shows promising activity in MM, even under conditions of dexamethasone-refractory disease [136]. Siltuximab is now in clinical trial for patients with high-risk smoldering myeloma (NCT01484275). A fully humanized, high-affinity derivative of B-E8, designated mAb 1339, has been developed recently. It showed promising preclinical activity in studies using mice and the IL-6-dependent HMCL, INA-6 [137], but has not yet been advanced to clinical testing. A different approach for targeting the IL-6R, which relies on a recombinant protein instead of a monoclonal antibody, is afforded by Sant7. “Sant” stands for super antagonist; i.e., a genetically engineered human IL-6 that binds to gp80 with higher affinity than normal IL-6 does. However, because Sant7 does not recruit gp130 to the IL-6R, it blocks IL-6 signaling. Although Sant7 was highly effective in preclinical model systems of myeloma [138–140], it has not been further developed for clinical applications [70]. c An interesting development is a fusion protein that consists of soluble gp130 (sgp130) linked to the Fc-region of human IgG. The recombinant protein, dubbed FE999301, is jointly being developed for clinical use by CONARIS Research Institute (Kiel, Germany) and Ferring Pharmaceuticals (Saint-Prex, Switzerland) [70]. FE999301 builds on knowledge that sgp130 is a natural inhibitor of IL-6/sIL-6R [141]. FE999301 blocks primarily IL-6 trans-signaling, the main driver of IL-6's inflammatory functions. FE999301 was shown to be effective in a mouse model of inflammation-induced cancer [142]. d Inhibitors of gp130, such as gp130-targeting peptides [143]. e Small-molecule inhibitors that may block IL-6 production in BMSCs. One example is a recently developed indolinone inhibitor that abrogates the kinase activity of FGF and VEGF receptor tyrosine kinases, resulting in disruption of the IL-6/VEGF/FGF amplification loop described in the main text. This, in turn, led to enhanced spontaneous and dexamethasone-induced apoptosis of HMCLs and patient myeloma cells without inducing death in normal cells, such as B-lymphocytes [144]. Similarly, a newly developed histone deacetylase inhibitor dramatically reduces IL-6 production in BMSCs (by 80–95 %), and the subsequent induction of apoptosis in HMCLs and freshly isolated myeloma cells [145]
Article Snippet: However, there are no clinical trials of myeloma at this juncture. b Antibodies neutralizing IL-6 include mouse BE-8 (elsilimomab) and siltuximab (CNTO 328, Centocor).
Techniques: Labeling, Binding Assay, Ligand Binding Assay, Activity Assay, Recombinant, Blocking Assay, Amplification, Histone Deacetylase Assay, Isolation
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![Targeting MRD/MMSC with small-drug inhibitors, immune-based interventions and IL-6-targeted therapies may result in a cure for patients with myeloma. a Curative blueprint for myeloma. The currently available myeloma therapies are highly efficient in killing the great majority of myeloma cells (excentric nucleus, rich cytoplasm, paranuclear Golgi zone) but are unable to eradicate a tiny subpopulation of cells that exhibit stem cell-like features and are called MMSCs. These cells underlie MRD and often acquire drug resistance in the course of myeloma treatment, leading to relapse of a therapy-resistant tumor. Treatments that target MMSC/MRD efficiently may result in a cure for myeloma. Owing to the genetic complexity of myeloma and its perpetual clonal diversification [129– 133], targeted eradication of MRD cells may be best accomplished in an adjuvant setting at a relatively early stage of myeloma treatment. b Two principal forms of MRD/MMSC-targeted therapies: small-drug inhibitors and immunological approaches. Inhibitors target stemness genes, such as MYC (JQ1); stemness pathways, such as Wnt (celecoxib), Notch (BMS-906024) and Hedgehog (itraconazole, cyclopamine); drug resistance pathway, such as multidrug resistance (sildenafil); and, last but not least, individual candidate MMSC genes, such as RARA2 (ATRA), NEK2 (CCT250863) and BTK (ibrutinib). Immune-based therapies for targeting MRD include CAR-T cells and dendritic cell vaccines (see main text for details). Also included is a growing panel of therapeutic monoclonal antibodies exhibiting reactivity to CS1 (elotuzumab), CD38 (daratumumab), CD56 (lorvotuzumab), VEGF (bevacizumab), EGR (cetuximab), KIR (IPH2101), FGFR3 (MFGR1877S), BAFF (LY2127399) and other myeloma targets. To be fully effective, immunotherapy must probably be combined with small-drug inhibitors and IL-6-targeted drugs shown in panel C. c Approaches to inhibit IL-6 signaling in myeloma including cancer stem cell-like cells (bottom) and bone marrow stroma cells (top) [70]. Labeled circles indicate active research areas, which can be categorized as follows: a Tocilizumab is a humanized antibody to IL-6R, which competitively inhibits IL-6 signaling by virtue of binding to the receptor's ligand-binding site [134]. The antibody inhibits both canonical/classical IL-6 signaling and IL-6 trans-signaling because it binds to both cell membrane-bound IL-6R and soluble IL-6R [135]. Tocilizumab has been approved for the treatment of arthritis and is currently undergoing clinical testing for other disease. However, there are no clinical trials of myeloma at this juncture. b Antibodies neutralizing IL-6 include mouse <t>BE-8</t> <t>(elsilimomab)</t> and siltuximab (CNTO 328, Centocor). Siltuximab is a chimeric human-mouse antibody and thus less immunogenic than BE-8. Siltuximab shows promising activity in MM, even under conditions of dexamethasone-refractory disease [136]. Siltuximab is now in clinical trial for patients with high-risk smoldering myeloma (NCT01484275). A fully humanized, high-affinity derivative of B-E8, designated mAb 1339, has been developed recently. It showed promising preclinical activity in studies using mice and the IL-6-dependent HMCL, INA-6 [137], but has not yet been advanced to clinical testing. A different approach for targeting the IL-6R, which relies on a recombinant protein instead of a monoclonal antibody, is afforded by Sant7. “Sant” stands for super antagonist; i.e., a genetically engineered human IL-6 that binds to gp80 with higher affinity than normal IL-6 does. However, because Sant7 does not recruit gp130 to the IL-6R, it blocks IL-6 signaling. Although Sant7 was highly effective in preclinical model systems of myeloma [138–140], it has not been further developed for clinical applications [70]. c An interesting development is a fusion protein that consists of soluble gp130 (sgp130) linked to the Fc-region of human IgG. The recombinant protein, dubbed FE999301, is jointly being developed for clinical use by CONARIS Research Institute (Kiel, Germany) and Ferring Pharmaceuticals (Saint-Prex, Switzerland) [70]. FE999301 builds on knowledge that sgp130 is a natural inhibitor of IL-6/sIL-6R [141]. FE999301 blocks primarily IL-6 trans-signaling, the main driver of IL-6's inflammatory functions. FE999301 was shown to be effective in a mouse model of inflammation-induced cancer [142]. d Inhibitors of gp130, such as gp130-targeting peptides [143]. e Small-molecule inhibitors that may block IL-6 production in BMSCs. One example is a recently developed indolinone inhibitor that abrogates the kinase activity of FGF and VEGF receptor tyrosine kinases, resulting in disruption of the IL-6/VEGF/FGF amplification loop described in the main text. This, in turn, led to enhanced spontaneous and dexamethasone-induced apoptosis of HMCLs and patient myeloma cells without inducing death in normal cells, such as B-lymphocytes [144]. Similarly, a newly developed histone deacetylase inhibitor dramatically reduces IL-6 production in BMSCs (by 80–95 %), and the subsequent induction of apoptosis in HMCLs and freshly isolated myeloma cells [145]](https://pub-med-central-images-cdn.bioz.com/pub_med_central_ids_ending_with_9159/pmc04209159/pmc04209159__nihms-634757-f0003.jpg)
