Endogenous interleukin 6 production in multiple myeloma patients treated with chimeric monoclonal anti-IL6 antibodies indicates the existence of a positive feed-back loop.

Zaanen, H.C.T. van; Koopmans, Richard P.; Aarden, Lucien A.; Rensink, H. J. A. M.; Stouthard, J.M.L.; Warnaar, S. O.; Lokhorst, H. M.; Oers, Marinus H. J. van

doi:10.1172/jci118932

Cited by 52 publications

(36 citation statements)

References 28 publications

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“…9,[32][33][34] Malignant PC expansions, ie, multiple myeloma, plasma cell leukemia, and Castleman disease, were also IL-6 dependent, and these PC expansions were reduced with anti-IL-6 treatment. [35][36][37][38][39] Furthermore, the overall level of IgG was significantly reduced in IL-6 KO mice, again indicating a central role for IL-6 in PC generation in vivo. 2 Thus, our current data in vitro are in good agreement with the central role played by IL-6 in supporting nonmalignant or malignant PC expansions in vivo.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-6 is a growth factor for nonmalignant human plasmablasts

Jégo

Bataille

Pellat‐Deceunynck

2001

Blood

164

169

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Interleukin-6 (IL-6), although often regarded as a B-cell differentiation factor, was recently described as the essential survival factor for human plasmablasts in vivo in reactive plasmacytosis. The present study reinvestigated the roles of IL-6 and IL-2 in the generation of plasma cells from human memory B cells in vitro. The cells involved in this differentiation process were identified as preplasmablasts (CD20 ؎ CD38 ؎ CD138 ؊ ), plasmablasts (CD20 ؊ CD38 ؉؉ CD138 ؊ ), and early plasma cells (CD20 ؊ CD38 ؉؉؉ CD138 ؉؉؉ ).IL-2 or IL-10 induced a strong generation of plasmablasts and early plasma cells (PCs). Compared to IL-2 or IL-10, IL-6 alone was inefficient at PC generation. However, when combined with IL-2 or IL-10, IL-6 enhanced generation of early PCs. Moreover, anti-IL-6 monoclonal antibody markedly reduced IL-2-induced generation of early plasma cells, but not of plasmablasts. These roles of IL-2 and IL-6 were consistent with the difference in the expression of their respective receptors (R). CD25 (IL-2R␣) was increased 72 ؎ 10-fold on activated B cells, but decreased and then disappeared on plasmablasts. Conversely, CD126 (IL-6R␣) was barely expressed on activated B cells, but increased 18 ؎ 2-fold on preplasmablasts. Finally, IL-6 enhanced the proliferation (2-fold increase) of IL-2-generated plasmablasts. In conclusion, the data indicate that IL-6 is a growth factor for nonmalignant human plasmablasts. IntroductionThe study of plasma cell (PC) generation remains difficult in humans because these cells are located within bone marrow and represent less than 0.5% of mononuclear cells. PC generation has been investigated in mice using transgenic or knockout models, 1,2 whereas studies in humans have essentially involved in vitro models of B-cell activation and differentiation. [3][4][5][6][7][8] Most of these models have supported an essential role for interleukin-2 (IL-2) and IL-10 in the differentiation of B cells previously activated through T-cell contact or upon CD40 or Staphylococcus aureus Cowan stimulation. A recent study by our group showed that reactive plasmacytosis is a very suitable model for in vivo investigation of PC generation from plasmablasts, their progenitors, in humans. 9 This model allowed us to isolate and characterize plasmablasts and study their transition into early PCs. The reactive plasmacytoses studied were all associated with high serum levels of C-reactive protein, indicating the presence of systemic IL-6 in excess, and the plasmablasts and early PCs expressed IL-6R (receptor) (CD126) strongly. Finally, IL-6 was found to be the essential survival factor for plasmablasts in this model.In the transgenic mouse, overexpression or disruption of IL-6 in vivo has profound effects on the synthesis of immunoglobulin (Ig) and PC generation, suggesting a fundamental role of IL-6 in the B-cell immune response. 1,2 These observations in mice and humans are in contrast to the apparent lack of IL-6 involvement in the differentiation of B cells in vitro. In fact, IL-6, although unable ...

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Section: Discussionmentioning

confidence: 99%

Interleukin-6 is a growth factor for nonmalignant human plasmablasts

Jégo

Bataille

Pellat‐Deceunynck

2001

Blood

164

169

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“…To overcome resistance, the challenge remains as to how to selectively reduce ferritin levels of malignant plasma cells, to induce apoptosis upon bortezomib, and how to further supplement iron to accelerate the death of early apoptotic cells. We speculate that the high IL-6 levels in the MM microenvironment 27 sequesters iron in macrophages through an autocrine mechanism induced by local hepcidin overproduction. 28 In the bone marrow this would amplify the hepcidin systemic effect that leads to iron sequestration, iron restricted erythropoiesis, and anemia of chronic diseases in patients.…”

Section: Iron Toxicity In Primary MM Cellsmentioning

confidence: 94%

Iron increases the susceptibility of multiple myeloma cells to bortezomib

et al. 2012

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ABSTRACTbeen reported following proteasome inhibition in cells treated with H 2 O 2 and nitric oxide generators. 13,14 Ferritin might undergo proteasomal degradation to recycle stored iron in cells pre-loaded with ferric ammonium citrate (FAC) 15 in conditions of decreased cell iron content 16,17 or in the presence of oxidative stress stimuli. 18 Here we report the analysis of iron metabolism and the effects of iron manipulation in MM cell lines and primary cells of patients treated with bortezomib. We observed that the basal iron storage capacity of MM cell lines directly correlates with bortezomib resistance and that bortezomib sensitizes MM cells to iron toxicity. Manipulation of iron homeostasis might be a tool to increase the susceptibility of MM cells to the effect of bortezomib and to overcome bortezomib resistance. Design and Methods Cell culture and cellular extractsCell culture media and reagents were from Invitrogen (Karlsruhe, Germany) and from Sigma-Aldrich (St. Louis, MO, USA). Bortezomib was purchased from LC Laboratories (Wobun, MA, USA). Patient-derived plasma cells were purified from bone marrow aspirates by density gradient centrifugation and then by CD138 immunomagnetic positive selection (Miltenyi Biotec, Bergisch Gladbach, Germany). Samples from Patient 2 were collected both at diagnosis (sample a) and relapse (sample b). Informed consent was obtained in accordance with the Declaration of Helsinki and the approval for use of primary samples was obtained from the Institutional Review Board of the San Raffaele Scientific Institute. MM cell lines and primary cells were cultured in RPMI medium supplemented with 10% fetal bovine serum (FBS), 100 units/mL penicillin, 100 mg/mL streptomycin and 2 mM L-glutamine.Cellular extracts were prepared as described in the Online Supplementary Appendix. Iron manipulationsIron removal was obtained by addition of deferoxamine (DFO; Biofutura Pharma, Milan, Italy). Ferric ammonium citrate (FAC), holo-transferrin (FeTf) (Sigma-Aldrich) and N-acetyl Cysteine (NAC) (Sigma-Aldrich) were used for iron loading experiments. FAC and 55 FeAC were prepared by mixing FeCl 3 -HCl (Merk Millipore, Billerica, MA, USA) or 55 FeCl 3 -HCl (PerkinElmer, Monza, Italy) with citric acid at 1:2 ratios and then by adjusting pH to 7.4 with NH 4 OH.To estimate ferritin content in patients' cells, cellular extracts were incubated in vitro with a molar excess of 55 FeAC plus ascorbic acid. Then extracts were loaded without heating on sodium dodecylsulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and exposed to autoradiography. Cell viabilityCell viability was determined by measuring the reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) (Sigma-Aldrich). Briefly, cells were seeded in 96-well plates and assay performed on at least three wells for every condition. MTT was then added for 3 h at a final concentration of 0.25 mg/mL. Plates were centrifuged at 3200g for 5 min and the soluble fraction decanted. Crystal pellets were suspended in DMSO a...

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“…The starting dosage regimen for part 1 of this phase I/II study was selected in an attempt to sufficiently neutralize the circulating level and endogenous production of IL-6. During the previous study of siltuximab in patients with multiple myeloma, IL-6 levels reached 50 pg/mL, with median IL-6 production rates of 60 μg/day (16). In a clinical study of the murine anti-IL-6 mAb BE-8 in patients with metastatic RCC, total inhibition of CRP production was only achieved in patients producing <18 μg/day of IL-6 (13), which equates to a mean concentration of ∼6 ng/mL per day, assuming a blood volume of ∼3,000 mL.…”

mentioning

confidence: 99%

“…Siltuximab binds with high affinity and specificity to IL-6 (16). The first clinical study of siltuximab administered 2-hour i.v.…”

mentioning

confidence: 99%

Pharmacokinetic and Pharmacodynamic Modeling of an Anti–Interleukin-6 Chimeric Monoclonal Antibody (Siltuximab) in Patients with Metastatic Renal Cell Carcinoma

Puchalski¹,

Prabhakar²,

Jiao³

et al. 2010

Clinical Cancer Research

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Purpose: Interleukin-6 (IL-6) induces tumor growth, invasion, metastasis, and angiogenesis. Siltuximab (CNTO 328) is a chimeric, murine-human monoclonal antibody that specifically binds human IL-6 with high affinity. C-reactive protein (CRP) can be a pharmacodynamic (PD) marker of IL-6 bioactivity. Reductions in CRP may correlate with clinical activity and IL-6 bioactivity.Experimental Design: Starting-dose selection for this study was based on a previous siltuximab study in multiple myeloma patients. Pharmacokinetic (PK)/PD modeling explored the relationship between siltuximab PK and CRP suppression following i.v. siltuximab infusion in a three-part phase I/II study in 68 metastatic renal cell carcinoma patients. Modeling results were then used to simulate and determine which siltuximab dosage regimens would maintain CRP suppression below the lower limit of quantification (4 mg/L). Siltuximab was given at 1, 3, 6, or 12 mg/kg at weeks 1 and 4 and then every 2 weeks for 2 cycles in part 1; at 3 or 6 mg/kg every 3 weeks for 4 cycles in part 2; and at 6 mg/kg every 2 weeks for 6 cycles in part 3.Results: A two-compartment PK model adequately described the serum siltuximab concentration-time data. An inhibitory indirect response PD model examined the relationship between siltuximab concentrations and CRP suppression. PD parameter estimates seemed reliable and physiologically relevant. Simulations showed that 6 mg/kg siltuximab every 2 weeks or 9 mg/kg every 3 weeks would reduce serum CRP to below 4 mg/L.Conclusions: Using a stepwise design, PK/PD modeling was used to select the dose levels in this study. Furthermore, PK/PD modeling results were used to help select doses to be used in future siltuximab clinical development. Clin Cancer Res; 16(5); 1652-61. ©2010 AACR.

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Endogenous interleukin 6 production in multiple myeloma patients treated with chimeric monoclonal anti-IL6 antibodies indicates the existence of a positive feed-back loop.

Cited by 52 publications

References 28 publications

Interleukin-6 is a growth factor for nonmalignant human plasmablasts

Interleukin-6 is a growth factor for nonmalignant human plasmablasts

Iron increases the susceptibility of multiple myeloma cells to bortezomib

Pharmacokinetic and Pharmacodynamic Modeling of an Anti–Interleukin-6 Chimeric Monoclonal Antibody (Siltuximab) in Patients with Metastatic Renal Cell Carcinoma

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