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International Immunology,

Immunology Vol. 27, No. 1, pp. 2129 The Japanese Society for Immunology. 2014. All rights reserved.
doi:10.1093/intimm/dxu081 For permissions, please e-mail: journals.permissions@oup.com
Advance Access publication 20 August 2014

Therapeutic uses of anti-interleukin-6 receptor antibody


SujinKang1,2, ToshioTanaka1,2 andTadamitsuKishimoto3
1
Department of Clinical Application of Biologics, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita City,
Osaka 565-0871, Japan
2
Department of Immunopathology, World Premier International Immunology Frontier Research Center, Osaka University, 3-1
Yamada-oka, Suita City, Osaka 565-0871, Japan
3
Laboratory of Immune Regulation, World Premier International Immunology Frontier Research Center, Osaka University, 3-1
Yamada-oka, Suita City, Osaka 565-0871, Japan

Review
Downloaded from http://intimm.oxfordjournals.org/ at Pontificia Universidad Catolica de Chile on January 14, 2015
Correspondence to: T.Kishimoto; E-mail: kishimoto@ifrec.osaka-u.ac.jp
Received 13 July 2014, accepted 8 August 2014

Abstract
Cytokine-targeted therapy has generated a paradigm shift in the treatment of several immune-
mediated diseases. Interleukin-6 (IL-6), which was initially identified as B-cell stimulatory factor 2, is
a prototypical cytokine with wide-ranging biological effects on immune cells such as B and T cells,
on hepatocytes, hematopoietic cells, vascular endothelial cells and on many others. IL-6 is thus
crucially involved in the regulation of immune responses, hematopoiesis and inflammation. When
infections and tissue injuries occur, IL-6 is promptly synthesized and performs a protective role
in host defense against such stresses and traumas. However, excessive production of IL-6 during
this emergent process induces potentially fatal complications, including systemic inflammatory
response syndrome (SIRS), and dysregulated, persistently high expression of IL-6 causes the onset
or development of various chronic immune-mediated disorders. For these reasons, IL-6 blockade
was expected to become a novel therapeutic strategy for various diseases characterized by IL-6
overproduction. Indeed, worldwide clinical trials of tocilizumab, a humanized anti-IL-6 receptor
monoclonal antibody, have successfully proved its outstanding efficacy against rheumatoid arthritis,
juvenile idiopathic arthritis and Castleman disease, leading to the approval of tocilizumab for
the treatment of these diseases. Moreover, various reports regarding off-label use of tocilizumab
strongly suggest that it will be widely applicable for acute, severe complications such as SIRS and
cytokine-release syndrome and other refractory chronic immune-mediated diseases.

Keywords: autoimmune diseases, chronic inflammatory diseases, IL-6, tocilizumab

Introduction
Cytokines are soluble regulators that facilitate intercellular com- of these effects have been shown to be made redundant by
munication in immune responses and hematopoiesis. Different those of other members of the IL-6 family of cytokines (46).
from hormones, the characteristic features of cytokines are IL-6 is not expressed in healthy individuals, but when
functional pleiotropy and redundancy (1). Although cytokines infections or tissue injuries occur, IL-6 is rapidly synthesized
perform critical roles in host defense and maintenance of tis- and contributes to host defense (7). However, excessive
sue homeostasis, abnormal production of cytokines causes production of IL-6 during this process has been implicated
the onset or development of acute and chronic diseases, so in the development of acute, severe complications, includ-
that novel therapeutic strategies using cytokines themselves ing systemic inflammatory response syndrome (SIRS) and
or cytokine-targeted biologics have been developed and suc- cytokine-release syndrome (CRS), and chronic dysregu-
cessfully used for the treatment of various diseases. lated production of IL-6 plays a pathological role in the onset
Interleukin-6 (IL-6), composed of 184 amino acids, was and development of chronic immune-mediated diseases (5,
originally identified as B-cell stimulatory factor 2 (BSF-2) 8). For these reasons, it was anticipated that IL-6 blockade
that promotes immunoglobulin synthesis by activated B would constitute a novel therapeutic strategy for such dis-
cells (2); its complementary DNA was successfully cloned in eases, resulting in the development of tocilizumab, a human-
1986 (3). Later, IL-6 was found to be a prototypical cytokine ized anti-IL-6 receptor antibody (810). This review article
with pleiotropic biological effects on immune responses, focuses on recent findings of IL-6-related research and pro-
acute-phase responses and hematopoiesis, although some gress in IL-6-targeting therapy.
22 Therapeutic uses of anti-IL-6R, tocilizumab
IL-6, a pleiotropic cytokine Other actions of IL-6 are the promotion of T-follicular helper
cell differentiation and IL-21 production (16), as well as induc-
IL-6 exerts various biological effects on different target
tion of cytotoxic CD8+ T-cell differentiation by augmenting
cells and organs (Fig.1). When acting on hepatocytes, IL-6
expression of IL-2 and its receptor. During inflammation, IL-6
induces the synthesis of a wide range of acute-phase proteins,
increases the level of adhesion molecules and molecules that
including C-reactive protein (CRP), serum amyloid A (SAA),
regulate migration, such as monocyte chemoattractant pro-
fibrinogen, hepcidin and 1-antichymotrypsin, but inhibits
tein-1 in endothelial cells (17). Finally, during hematopoiesis,
expression of fibronectin, albumin and transferrin (11, 12). At
IL-6, together with IL-3, synergistically affects the formation of
the site of infection or injury, IL-6 is rapidly generated from
pleiotropic blast cell precursors, which support the formation
innate immune cells, including monocytes, macrophages and
of macrophage and megakaryocyte differentiation.
dendritic cells, via molecules that recognize pathogen-asso-
Besides its crucial involvement in the immune system, IL-6
ciated molecular patterns or damage-associated molecular
is also involved in bone homeostasis. When released from
patterns, thus triggering innate immune responses.
bone marrow stromal cells, it is required for the expression
IL-6 is also important for adaptive immune responses by pro-
of the receptor activator of the NF-B ligand (RANKL), and
moting B- and T-cell differentiation. As originally reported, IL-6

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subsequently promotes osteoclast differentiation, through
helps activated B cells to differentiate into antibody-producing
which systemic as well as peri-articular osteoporosis and
cells, and it also promotes the growth of myelomas/plasmacyto-
joint destruction is induced, as seen, for example, in patients
mas and enhances the survival of plasmablasts (13, 14). As one
with rheumatoid arthritis (RA) (18). In fact, it has been found
of its most important functions, IL-6 regulates the differentiation
that an increase in serum IL-6 levels strongly correlates with
of naive CD4+ helper T cells into effector subsets. IL-6, together
severity of radiographically detectable joint destruction (19).
with TGF-, preferentially induces differentiation of the naive
Robust angiogenesis and vascular permeability are char-
CD4+ helper T cells into Th17 cells, which produce the inflamma-
acteristic features of RA synovial tissues and these charac-
tory cytokine IL-17, but IL-6 inhibits TGF--induced differentia-
teristics are mediated by excessive production of vascular
tion of those cells into Treg cells. This results in an immunological
endothelial growth factor (VEGF), whose synthesis is also
imbalance between Treg/Th17 subsets, which is believed to be
up-regulated by IL-6 (20). In dermal tissue, IL-6 appears to
an important pathological mechanism for the development of
promote keratinocyte proliferation and collagen production
autoimmune and chronic inflammatory diseases (15).
in dermal fibroblasts. Finally, IL-6 has been demonstrated to

Fig.1. Pleiotropic activity of IL-6 and the pathological implications in disease. IL-6 exerts a variety of biological effects by acting on various
cells, and overexpression of IL-6 is pathologically involved in the status of various diseases, including immunological disorders, bone and car-
tilage destruction, persistent acute-phase responses and angiogenesis.
Therapeutic uses of anti-IL-6R, tocilizumab 23
interact with many other cells and organ systems, including pathway is widely used, and the pleiotropic activity of IL-6 can
vascular endothelial cells, the neuropsychological system be explained by the broad range expression of gp130 (6, 25).
and the hypothalamicpituitaryadrenal endocrinal system. gp130 is also used as a common signal-transducing molecule
for the IL-6 family cytokines, including leukemia inhibitory
factor, oncostatin M, ciliary neurotrophic factor, IL-11, cardio-
The IL-6 signaling system: IL-6 receptor andgp130
trophin 1, cardiotrophin-like cytokine, IL-27 and IL-35. These
IL-6 is structurally classified as a member of the four-helix- mechanisms account for the redundancy of characteristic fea-
bundle family of cytokines (21) and interacts with two differ- tures of cytokines at the molecular level (26, 27).
ent types of molecules, namely, IL-6 receptor (IL-6R, CD126) As schematically shown in Fig.2, IL-6 stimulation causes
(22) and the signal-transducing receptor subunit gp130 tyrosine phosphorylation of a cytoplasmic protein, the
(23). IL-6R exists in two forms, an 80-kDa transmembrane kinase JAK that is constitutively bound with gp130, and
form and a 5055-kDa soluble form. Transmembrane IL-6R, then activates two main signal transduction pathways, the
with a short cytoplasmic domain, interacts with gp130 and STAT3 pathway and the MAPK pathway, through phospho-
transduces the signal upon binding of IL-6, which is known rylation of the SH2-domain containing protein tyrosine phos-

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as the classic IL-6 signaling pathway (Fig. 2). Due to the phatase-2 (SHP-2). STAT3 activated by JAK forms a dimer,
limited expression of transmembrane IL-6R on hepatocytes, translocates into the nucleus, and then acts as a transcrip-
monocytes, macrophages and lymphocytes, cell activation tion factor to induce expression of IL-6 responsive genes.
through the classic pathway is limited (24). Furthermore, STAT3 activated by IL-6IL-6R interaction also
Soluble IL-6R, which lacks a cytoplasmic region, can also induces SOCS1 and SOCS3 expression (28, 29). SOCS1
form a complex with IL-6, leading to homodimerization of gp130 binds directly to JAK, which attenuates its catalytic activ-
and subsequent triggering of the downstream signaling cas- ity. SOCS3, on the other hand, inhibits the signaling through
cade, which is known as the trans-signaling pathway. Soluble directly binding to gp130. Putting these findings together,
IL-6R is found in serum and tissue fluids, and gp130 is ubiq- IL-6 signaling is controlled by SOCSs as negative feedback
uitously expressed in various cells, so that this trans-signaling regulators.

Fig.2. The classic IL-6 signaling system. IL-6 is capable of activating two major pathways: the STAT3 and MAPK pathways. These pathways
activate downstream signaling of IL-6R, leading to induction of a variety of gene expression. This signaling also induces SOCS1 and SOCS3
expression, which in turn suppress the IL-6 signaling pathway.
24 Therapeutic uses of anti-IL-6R, tocilizumab
Regulation of IL-6 production two counteractive molecules that regulate IL-6 mRNA stabil-
ity (Fig. 3): regulatory RNase-1 (Regnase-1, also known as
When infections or tissue damage occur, IL-6 synthesis is
Zc3h12a) (36) and AT-rich interactive domain-containing pro-
promptly induced to contribute to host defense. After removal
tein 5a (Arid5a) (37).
of such stresses from the host, the IL-6 production ends as the
Regnase-1 is a nuclease and binds to the 3-UTR of IL-6
result of strict control of IL-6 synthesis at the transcriptional
mRNA, resulting in the destabilization of this mRNA. This
and post-transcriptional stages. Anumber of cis-transcription
resulted in the development of spontaneous autoimmune dis-
factors have been identified to be involved in IL-6 gene acti-
eases, accompanied by splenomegaly and lymphadenopathy,
vation, including NF-B, specificity protein 1 (SP1), nuclear
in Regnase-1-deficient mice (36). Stimulation with an IL-1R/
factor IL-6 (NF-IL6), activator protein 1 (AP-1) and interferon
TLR agonist induces phosphorylation of Regnase-1, while the
regulatory factor 1 (IRF-1) (Table1). Stimulation with TNF-,
inhibitor of the NF-B (IB) kinase (IKK) complex destabilizes
IL-1, and even IL-6 activates the functional cis-regulatory fac-
IL-6 mRNA. Phosphorylated Regnase-1 is subject to both
tors to bind to their specific elements at the 5-flanking region
ubiquitination and degradation. Regnase-1 also binds to the
in the IL-6 gene. IL-6 in liver in particular can strongly induce
stemloop site of the 3-UTR of Regnase-1 mRNA and func-
NF-IL6 activation, suggesting that NF-IL6 might be a main

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tions itself as a negative regulator. These findings demonstrate
transcriptional factor for acute-phase protein expression. In
that IKK induces not only phosphorylation of IB but also that
addition to inflammatory cytokines, some virus products such
of Regnase-1 to prevent IL-6 mRNA expression (38).
as the human T-lymphotropic virus 1-derived transactivator
We recently identified a novel RNA-binding protein, Arid5a
protein (Tax) have been shown to modulate the DNA-binding
(37) and found that its expression is rapidly induced and
activity of NF-B and NF-IL6 to the IL-6 promoter region.
degraded within 6h in macrophages upon LPS, IL-1 or
On the other hand, inflammatory stimuli also modulate the
IL-6 stimulation. Arid5a binds to the 3-UTR of IL-6 mRNA
expression of factors involved in IL-6 transcription suppres-
and selectively stabilizes IL-6 but not TNF- or IL-12 mRNA.
sion, including the aryl hydrocarbon receptor (Ahr) (Table1).
Arid5a-deficient mice show a striking reduction in serum IL-6
Ahr is a ligand-activated transcription factor, which acts as
levels, induced by LPS injection, and in Th17 cell develop-
a receptor for several exogenous toxins. It forms a complex
ment in a mouse modelexperimental autoimmune enceph-
with NF-B and STAT1, leading to inhibition of the promoter
alomyelitis (EAE). Interestingly, Arid5a can interfere with the
activity of IL-6 in macrophages, so that Ahr-deficient mac-
destabilizing effect of Regnase-1 on IL-6 mRNA, thus demon-
rophages feature enhanced production of IL-6 (30). In addi-
strating that the balance between Arid5a and Regnase-1 is
tion, a number of studies have recently demonstrated that Ahr
canonical for the stability of IL-6 mRNA, and also suggesting
activation may also act on various immune cells such as T
that predominance of Arid5a over Regnase-1 may give rise
cells, B cells and dendritic cells, and thus affect their func-
to the development of autoimmune inflammatory diseases
tion in immune responses (3134). For example, the specific
(Fig. 3) (39). A deeper understanding of the role of these
depletion of Ahr in T cells inhibits Th17 cell differentiation and
RNA-binding proteins may thus result in novel therapeutic
the development of collagen-induced arthritis (33), and Ahr-
approaches to target IL-6 mRNA stability in various diseases.
deficient dendritic cells produce less of the anti-inflammatory
cytokine, IL-10 (34). In addition, some micro-RNAs (miRs)
Pathological involvement of IL-6 in diseases
reportedly modulate, either directly or indirectly, the bind-
ing activities of several transcription factors to the IL-6 gene. The immediate and transient expression of IL-6 contributes to
Most post-transcriptional control mechanisms of cytokines host defense against environmental stress factors. When the
target the 5-untranslated region (UTR) or 3-UTR of mRNAs source of stress is removed from the host, the production of
to modify initiation of translation or stability, respectively IL-6 is terminated and results in normalization of serum lev-
(35). Modification of post-transcription of IL-6 mRNA primar- els of acute-phase proteins such as CRP and SAA. However,
ily occurs at AU-rich elements located in the 3-UTR region, IL-6 is also involved in disease development (4, 5). First,
and a number of RNA-binding proteins or miRs are involved during immune response against infectious agents, exces-
in the regulation of IL-6 mRNA stabilization/degradation sive production of IL-6 induces potentially fatal complica-
(Table 1). Interestingly, some recent studies have identified tions, such as SIRS and CRS. Second, chronic, dysregulated

Table1. Transcriptional and post-transcriptional regulation of IL-6 gene expression

Function Protein microRNA

Transcription Promotion NF-B, SP1, NF-IL6, AP-1, IRF-1, Tax, TAT, HBVX,
mutant p53
Repression GR, ER, p53, PPAR, Ahr miR-155 (targeting NF-IL6), miR-146a/b
(targeting IRAK1), miR-223 (targeting STAT3)
Post-transcription Stabilization P38, ORF57, Arid5a
Degradation TTP, BRF-1, BRF-2, Regnase-1 miR-365, miR-608

Transcription of IL-6 is regulated by transcription factors or by miRs, and several RNA-binding proteins or miRs are post-transcriptional regula-
tors for IL-6 mRNA. BRF, butyrate response factor; ER, estrogen receptor; GR, glucocorticoid receptor; HBVX, hepatitis B virus X protein; IRAK1,
IL-1 receptor-associated kinase 1; ORF, open reading frame; PPAR, peroxisome proliferator-activated receptor ; Rb, retinoblastoma; TAT,
human immunodeficiency virus 1-derived transactivator of the transcription protein; TTP, tristetraprolin.
Therapeutic uses of anti-IL-6R, tocilizumab 25

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Fig.3. Regulatory mechanisms of IL-6 production. Regnase-1 promotes degradation of IL-6 mRNA, whereas Arid5a counteracts this by desta-
bilizing the effect of Regnase-1. The functional balance between Arid5a and Regnase-1 determines IL-6 mRNA stability. IRAK1, IL-1 receptor-
associated kinase 1; NEMO, NF-B essential modulator; TRAF6, TNF receptor-associated factor 6; Ub, ubiquitination.

IL-6 production by particular cell populations leads to the prevent the onset or ameliorate the severity of diseases in ani-
development of various chronic immune-mediated diseases. mal models. For instance, IL-6 blockade resulted in a striking
However, at present the reason(s) for excessive or chronic reduction in susceptibility to Castleman disease-like symptoms
IL-6 production remains unknown; it may be partly due to an in IL-6 transgenic mice, and also suppressed disease devel-
imbalance between Arid5a and Regnase-1. opment in models of RA, systemic lupus erythematosus, sys-
The first evidence that IL-6 was pathologically involved temic sclerosis, polymyositis, EAE, experimental autoimmune
in disease development was observed in a case of cardiac uveoretinitis and other autoimmune inflammatory diseases.
myxoma (40). The culture fluid obtained from the myxoma tis- On the basis of these findings, IL-6 targeting was expected to
sue of a patient with unclassified connective tissue disease, constitute a novel therapeutic strategy against immune-mediated
who had presented with fever, polyarthritis, increased serum diseases (810). This led to the development of tocilizumab, a
CRP level, anemia and hypergammaglobulinemia with posi- humanized monoclonal antibody, with the CDR of a mouse anti-
tivity for anti-nuclear factor, contained a large quantity of IL-6 IL-6R grafted on to human IgG1 molecule (41). Tocilizumab can
and the myxoma tissues could be positively stained with anti- block both classic and trans-signaling pathways by inhibiting IL-6
IL-6 antibody. Subsequent studies have demonstrated that binding to transmembrane IL-6R and soluble IL-6R. The produc-
excessive expression of IL-6 is found in synovial cells of RA, tion of CRP in hepatocytes is mediated by the classic signaling
germinal center B cells in swollen lymph nodes of Castleman pathway, and if the free concentration of tocilizumab is maintained
disease, myeloma cells and peripheral blood cells or infiltrat- in serum at more than 1g ml1, CRP remains negative (42).
ing cells in tissues involved in various other diseases, as well
as in many tumor cells (4, 5, 8, 13).
Moreover, the concept of the pathological role of IL-6 in dis- Therapeutic uses of the anti-IL-6R antibody,
ease development has been supported by numerous experi- tocilizumab
mental findings that IL-6 blockade by means of gene knockout The first clinical trial of tocilizumab was performed with seven
or injection of neutralizing anti-IL-6 or anti-IL-6R antibody could patients with Castleman disease, a chronic lymphoproliferative
26 Therapeutic uses of anti-IL-6R, tocilizumab
disorder characterized by multiple lymph node swellings with superior to adalimumab, as evaluated by several indices of
massive infiltration of mature plasma cells and persistent pro- disease activity in RA patients (50). For instance, at week 24,
duction of IL-6 in germinal center B cells. These patients had the proportion of patients attaining remission assessed by
presented with severe inflammatory symptoms and labora- DAS28 (disease activity score in 28 joints) was 39.9% with
tory findings such as high fever, anemia, increased levels of tocilizumab and 10.5% with adalimumab. ACR20%, ACR50%
acute-phase proteins, hypoalbuminemia and hypergamma- and ACR70% response rates were achieved in 65% and
globulinemia, but the administration of tocilizumab promptly 49.4%, 47.2% and 27.8% and 32.5% and 17.9% of patients
ameliorated clinical symptoms together with normalization of treated with tocilizumab and adalimumab, respectively. Thus,
serum CRP levels and improvement of anemia, serum albu- tocilizumab appears to be the most powerful antirheumatic
min concentration and hypergammaglobulinemia (43). The biologic.
outstanding efficacy of tocilizumab was subsequently con- In addition to the outstanding clinical efficacy, tocilizumab
firmed in another clinical trial with an enrollment of 28 patients has unique properties in comparison with other biologics.
with Castleman disease (44), and this resulted in the approval First, as described elsewhere, IL-6 promotes the synthesis of
of tocilizumab as an orphan drug in 2005 inJapan. acute-phase proteins such as SAA and hepcidin, which are

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The first randomized controlled trial of tocilizumab for RA proteins responsible for the development of amyloid Aamy-
was performed in 45 patients, who were sequentially allo- loidosis and anemia of chronic disorder, respectively. Indeed,
cated to receive a single intravenous dose of either 0.1, 1, 5 tocilizumab appears to be the most powerful suppressant to
or 10mg kg1 of tocilizumab or placebo (45). At week 2, a sig- reduce the expression of these acute-phase proteins and the
nificant difference was observed between the group treated treatment reportedly produces prominent ameliorative effects
with 5mg kg1 of tocilizumab and the placebo group, with on these complications (51, 52). Second, the predominance
five patients (56%) in the tocilizumab cohort and none in the of Th17 cells over Treg cells in the effector CD4+ T-cell subsets,
placebo cohort achieving a 20% improvement in the defined which is thought to be a fundamental immunological abnor-
range of symptoms formulated by the American College of mality in RA, is possibly induced by continual expression of
Rheumatology (ACR20%). IL-6 (15); tocilizumab may correct this Th17/Treg imbalance.
A 12-week, multicenter, double-blind, placebo-controlled The results of recent studies have demonstrated that inhibi-
late phase II trial was performed in Japan (46). In this trial, tion of IL-6 function by tocilizumab could rectify the imbal-
164 patients with refractory RA were randomized to receive ance between Th17 and Treg cells in the peripheral CD4+ T-cell
either 8 or 4mg kg1 of tocilizumab every 4 weeks or placebo. population (5355).
At week 12, an ACR20% response was observed in 78, 57 The third disease for which tocilizumab is currently on
and 11% of RA patients treated with 8mg kg1 of tocilizumab, label is systemic juvenile idiopathic arthritis (sJIA), which is
4mg kg1 of tocilizumab and placebo, respectively, while a subtype of chronic childhood arthritis that leads to joint
40% of patients in the 8mg kg1 group and 1.9% in the pla- destruction, functional disability and growth impairment,
cebo group achieved an ACR50% response. Subsequently, and is accompanied by systemic inflammation. A clinical
seven phase III clinical trials verified the outstanding efficacy trial, composed of a 6-week open-label lead-in phase and a
of tocilizumab in the suppression of disease activity and pro- 12-week double-blind phase, was performed for 56 children
gression of joint destruction associated with RA, and this with sJIA in Japan (56). At the end of the open-label phase,
drug is currently approved for the treatment of RA in more tocilizumab treatment (8mg kg1, every 2 weeks) resulted
than 130 countries (47). in ACR Pediatric 30, 50 and 70% responses for 91, 86 and
The European League Against Rheumatism now recom- 68% of the patients, respectively. Forty-three patients contin-
mends tocilizumab as one of eight first-line biologics to be ued to the double-blind phase and 16 (80%) of 20 patients in
used for RA patients with an inadequate response to the the tocilizumab group could maintain an ACR Pediatric 30%
standard disease-modifying antirheumatic drug (DMARD), response, compared with only 4 (17%) of 23 patients in the
methotrexate (MTX). First-line biologics include five TNF placebogroup.
inhibitors (infliximab, adalimumab, golimumab, certolizumab A global phase III trial, in which 112 children with active
and etanercept), a T-cell activation blocker (abatacept) and a sJIA were enrolled, has also proved that tocilizumab is highly
B-cell depletory (rituximab) as well as tocilizumab. However, efficacious for the suppression of disease activity of sJIA (57),
tocilizumab is the only biologic that has proved to be more leading to the acknowledgement that a new era has started
efficacious as monotherapy than MTX or other DMARDs. TNF in the treatment of this disease, which had long been consid-
inhibitors require the concomitant use of MTX to achieve their ered to be one of the most intractable juvenile diseases.
maximal effects, but tocilizumab monotherapy is not inferior Moreover, various case studies, series and pilot stud-
to the combination therapy of tocilizumab plus MTX in the ies of off-label use with tocilizumab have produced favora-
suppression of disease activity (48). ble results, indicating that tocilizumab may be used for the
Since it is observed that MTX treatment reduces the plasma treatment of various chronic, intractable immune-mediated
level of IL-6 but not that of TNF- in patients with early RA diseases (9, 10, 39). These include systemic and organ-spe-
(49), it is likely that the effect of MTX in RA is partly medi- cific autoimmune diseases, chronic inflammatory diseases,
ated via inhibition of IL-6 production and this may be one including autoinflammatory syndromes, and other diseases
reason why tocilizumab does not require concomitant use of such as atherosclerosis, type 2 diabetes mellitus, atopic der-
MTX for the maximal effect. Moreover, a direct comparison of matitis, sciatica and amyotrophic lateral sclerosis (Fig.4). In
tocilizumab and adalimumab, a fully human anti-TNF- anti- particular, accumulated evidence provides strong indications
body, demonstrated that as monotherapy tocilizumab was that tocilizumab looks highly promising for the treatment of
Therapeutic uses of anti-IL-6R, tocilizumab 27

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Fig.4. The widespread application of the IL-6 targeting strategy for various diseases. Tocilizumab is currently used for the treatment of RA,
systemic and polyarticular JIA and Castleman disease. Numerous favorable results from off-label use with tocilizumab suggest that it will be
widely applicable for the treatment of other intractable diseases. RS3PE, remitting seronegative symmetrical synovitis with pitting edema.

systemic sclerosis, large-vessel vasculitis, adult-onset Stills diseases, an IL-6-blockade strategy could serve as rescue
disease, amyloid Aamyloidosis and polymyalgia rheumatica, therapy for acute life-threatening conditions. CRS entails
for all of which clinical trials are in progress. potentially fatal immediate complications and is sometimes
Neuromyelitis optica (NMO) is a chronic inflammatory induced by non-physiologic T-cell activation after therapies
demyelinating disease of the central nervous system that pri- that engage T cells by using a chimeric, modified antigen-
marily affects the spinal cord and optic nerves. Autoantibodies receptor or by using a CD19CD3-bi-specific antibody
against the astrocyte water channel protein, aquaporin-4 (blinatumomab) (63). IL-6 and IL-10 as well as the effector
(AQP-4), play a pathological role in the disease development. cytokine, IFN-, have been shown to be markedly elevated
Anti-AQP-4 antibodies are produced by the plasmablast in patients with CRS. Surprisingly, one administration of toci-
population showing a CD19intermediateCD29highCD38highCD180 lizumab for three patients with CRS receiving T-cell-engaging
phenotype that is increased in the peripheral blood of NMO therapies dramatically resolved their serious conditions (64,
patients (58). IL-6 enhances the survival of the plasmablast 65). These findings suggest that this IL-6R antibody may
population, whereas the addition of tocilizumab into the cul- constitute a novel therapeutic drug for emergent fatal com-
ture diminishes the survival (58). These findings suggest that plications mediated by a cytokine storm, such as CRS, SIRS,
an IL-6-blockage strategy is promising for the treatment of macrophage activation syndrome, hemophagocytic syn-
NMO by inhibiting anti-AQP-4 antibody production. Indeed, drome or septic shock.
the prominent beneficial effects of tocilizumab have been
recently reported in patients with NMO that is refractory to
Conclusions
conventional treatment regimens (5961), and a clinical trial
of a new fully human antibody against IL-6R (SA237) (62) Following the successful cloning of the IL-6 gene, IL-6-related
generated from tocilizumab by techniques for structural anti- research has progressed rapidly (8). Clarification of the whole
body optimizationfor NMO is in progress. picture of the IL-6-mediated signaling system solved the long-
In addition to these indications of the potential of tocili- standing mystery of the functional pleiotropy and redundancy
zumab for the successful treatment of a variety of chronic of cytokines. In line with this progress, the pathological role
28 Therapeutic uses of anti-IL-6R, tocilizumab
of IL-6 in various diseases has been thoroughly documented, 10 Tanaka, T., Narazaki, M., Ogata, A. and Kishimoto, T. 2014. A new
and this resulted in the development of the humanized anti- era for the treatment of inflammatory autoimmune diseases by
interleukin-6 blockade strategy. Semin. Immunol. 26:88.
IL-6R monoclonal antibody, tocilizumab. 11 Gauldie, J., Richards, C., Harnish, D., Lansdorp, P. and Baumann,
Clinical trials of tocilizumab started in the late 1990s, H. 1987. Interferon beta 2/B-cell stimulatory factor type 2 shares
and this biologic was first approved for the treatment of identity with monocyte-derived hepatocyte-stimulating factor and
Castleman disease in Japan in 2005. During the following regulates the major acute phase protein response in liver cells.
years, tocilizumab has been adopted as a first-line biologic Proc. Natl Acad. Sci. USA 84:7251.
12 Andus, T., Geiger, T., Hirano, T. etal. 1987. Recombinant human B
for the treatment of RA and is currently being used in more cell stimulatory factor 2 (BSF-2/IFN-beta 2)regulates beta-fibrino-
than 130 countries. The outstanding efficacy of tocilizumab gen and albumin mRNA levels in Fao-9 cells. FEBS Lett. 221:18.
for sJIA heralded a new era for the treatment of this disease. 13 Kawano, M., Hirano, T., Matsuda, T. etal. 1988. Autocrine genera-
Moreover, the success of tocilizumab has accelerated the tion and requirement of BSF-2/IL-6 for human multiple myelomas.
Nature 332:83.
development of other IL-6 inhibitors (24). It is expected that 14 Suematsu, S., Matsusaka, T., Matsuda, T. etal. 1992. Generation
during the next decade IL-6 inhibitors will be widely used for of plasmacytomas with the chromosomal translocation t(12;15) in
the treatment of various as-yet-intractable diseases, and that interleukin 6 transgenic mice. Proc. Natl Acad. Sci. USA 89:232.

Downloaded from http://intimm.oxfordjournals.org/ at Pontificia Universidad Catolica de Chile on January 14, 2015
their application is certain to overcome the refractory nature 15 Kimura, A. and Kishimoto, T. 2010. IL-6: regulator of Treg/Th17 bal-
of such diseases. ance. Eur. J.Immunol. 40:1830.
16 Ma, C. S., Deenick, E. K., Batten, M. and Tangye, S. G. 2012. The
However, a mystery remains as to why excessive or chronic origins, function, and regulation of T follicular helper cells. J. Exp.
production of IL-6 is associated with various diseases. The Med. 209:1241.
findings of further analyses of RNA-binding proteins such as 17 Romano, M., Sironi, M., Toniatti, C. etal. 1997. Role of IL-6 and
Arid5a and Regnase-1, transcription factors and miRs that its soluble receptor in induction of chemokines and leukocyte
recruitment. Immunity 6:315.
regulate IL-6 synthesis may solve this mystery, while clarifica- 18 Kotake, S., Sato, K., Kim, K. J. etal. 1996. Interleukin-6 and solu-
tion of the mechanism(s) involved is likely to result in the iden- ble interleukin-6 receptors in the synovial fluids from rheumatoid
tification of more-specific target molecules and lead to further arthritis patients are responsible for osteoclast-like cell formation.
investigations into the pathogenesis of specific diseases. J. Bone Miner. Res. 11:88.
19 Dasgupta, B., Corkill, M., Kirkham, B., Gibson, T. and Panayi, G.
1992. Serial estimation of interleukin 6 as a measure of systemic
Funding disease in rheumatoid arthritis. J. Rheumatol. 19:22.
Ministry of Education, Culture, Sports, Science, and 20 Nakahara, H., Song, J., Sugimoto, M. etal. 2003. Anti-interleukin-6
receptor antibody therapy reduces vascular endothelial growth
Technology of Japan (S.K.); Uehara Memorial Foundation factor production in rheumatoid arthritis. Arthritis Rheum. 48:1521.
(S.K.). 21 Bazan, J. F. 1990. Haemopoietic receptors and helical cytokines.
Immunol. Today 11:350.
Acknowledgements 22 Yamasaki, K., Taga, T., Hirata, Y. etal. 1988. Cloning and expres-
sion of the human interleukin-6 (BSF-2/IFN beta 2) receptor.
T.K. holds a patent for tocilizumab and has received royalties for Science 241:825.
Actemra. T.T.has received a grant and payment for lectures includ- 23 Hibi, M., Murakami, M., Saito, M., Hirano, T., Taga, T. and

ing services for speakers bureaus from Chugai Pharmaceutical Kishimoto, T. 1990. Molecular cloning and expression of an IL-6
Co., Ltd. The Department of Clinical Application of Biologics of signal transducer, gp130. Cell 63:1149.
Osaka University Graduate School of Medicine is an endowment 24 Jones, S. A., Scheller, J. and Rose-John, S. 2011. Therapeutic
department, supported with an unrestricted grant from Chugai strategies for the clinical blockade of IL-6/gp130 signaling. J.
Pharmaceutical Co., Ltd. S.K.declares no conflict of interest. Clin. Invest. 121:3375.
25 Kishimoto, T., Taga, T. and Akira, S. 1994. Cytokine signal trans-
Conflict of interest statement: The authors declared no conflicts of duction. Cell 76:253.
interest. 26 Kishimoto, T., Akira, S., Narazaki, M. and Taga, T. 1995.

Interleukin-6 family of cytokines and gp130. Blood 86:1243.
27 Taga, T. and Kishimoto, T. 1997. Gp130 and the interleukin-6 fam-
ily of cytokines. Annu. Rev. Immunol. 15:797.
References 28 Naka, T., Narazaki, M., Hirata, M. etal. 1997. Structure and func-
1 Paul, W. E. 1989. Pleiotropy and redundancy: T cell-derived lym- tion of a new STAT-induced STAT inhibitor. Nature 387:924.
phokines in the immune response. Cell 57:521. 29 Chung, C. D., Liao, J., Liu, B. et al. 1997. Specific inhibition of
2 Kishimoto, T. and Hirano, T. 1988. Molecular regulation of B lym- Stat3 signal transduction by PIAS3. Science 278:1803.
phocyte response. Annu. Rev. Immunol. 6:485. 30 Kimura, A., Naka, T., Nakahama, T. etal. 2009. Aryl hydrocarbon
3 Hirano, T., Yasukawa, K., Harada, H. etal. 1986. Complementary receptor in combination with Stat1 regulates LPS-induced inflam-
DNA for a novel human interleukin (BSF-2) that induces B lympho- matory responses. J. Exp. Med. 206:2027.
cytes to produce immunoglobulin. Nature 324:73. 31 Nguyen, N. T., Hanieh, H., Nakahama, T. and Kishimoto, T. 2013.
4 Kishimoto, T. 1989. The biology of interleukin-6. Blood 74:1. The roles of aryl hydrocarbon receptor in immune responses. Int.
5 Akira, S., Taga, T. and Kishimoto, T. 1993. Interleukin-6 in biology Immunol. 25:335.
and medicine. Adv. Immunol. 54:1. 32 Veldhoen, M., Hirota, K., Westendorf, A. M. etal. 2008. The aryl
6 Kishimoto, T., Akira, S. and Taga, T. 1992. Interleukin-6 and its hydrocarbon receptor links TH17-cell-mediated autoimmunity to
receptor: a paradigm for cytokines. Science 258:593. environmental toxins. Nature 453:106.
7 Kopf, M., Baumann, H., Freer, G. et al. 1994. Impaired immune 33 Nakahama, T., Kimura, A., Nguyen, N. T. etal. 2011. Aryl hydro-
and acute-phase responses in interleukin-6-deficient mice. carbon receptor deficiency in T cells suppresses the develop-
Nature 368:339. ment of collagen-induced arthritis. Proc. Natl Acad. Sci. USA
8 Kishimoto, T. 2005. Interleukin-6: from basic science to medi- 108:14222.
cine40years in immunology. Annu. Rev. Immunol. 23:1. 34 Nguyen, N. T., Kimura, A., Nakahama, T. etal. 2010. Aryl hydro-
9 Tanaka, T., Narazaki, M. and Kishimoto, T. 2012. Therapeutic carbon receptor negatively regulates dendritic cell immunogenic-
targeting of the interleukin-6 receptor. Annu. Rev. Pharmacol. ity via a kynurenine-dependent mechanism. Proc. Natl Acad. Sci.
Toxicol. 52:199. USA 107:19961.
Therapeutic uses of anti-IL-6R, tocilizumab 29
35 Anderson, P. 2008. Post-transcriptional control of cytokine pro- (ADACTA): a randomised, double-blind, controlled phase 4 trial.
duction. Nat. Immunol. 9:353. Lancet 381:1541.
36 Matsushita, K., Takeuchi, O., Standley, D. M. etal. 2009. Zc3h12a 51 Tanaka, T., Hagihara, K., Hishitani, Y. and Ogata, A. 2011.

is an RNase essential for controlling immune responses by regu- Tocilizumab for the treatment of AA amyloidosis. In Guvenc,
lating mRNA decay. Nature 458:1185. I. A., ed., AmyloidosisAn Insight to Disease of Systems
37 Masuda, K., Ripley, B., Nishimura, R. etal. 2013. Arid5a controls and Novel Therapies, p. 155. InTech Open Access Publisher,
IL-6 mRNA stability, which contributes to elevation of IL-6 level in Croatia.
vivo. Proc. Natl Acad. Sci. USA 110:9409. 52 Song, S. N., Iwahashi, M., Tomosugi, N. etal. 2013. Comparative
38 Iwasaki, H., Takeuchi, O., Teraguchi, S. etal. 2011. The IB kinase evaluation of the effects of treatment with tocilizumab and TNF-
complex regulates the stability of cytokine-encoding mRNA inhibitors on serum hepcidin, anemia response and disease
induced by TLR-IL-1R by controlling degradation of regnase-1. activity in rheumatoid arthritis patients. Arthritis Res. Ther.
Nat. Immunol. 12:1167. 15:R141.
39 Tanaka, T. and Kishimoto, T. 2014. The biology and medical impli- 53 Samson, M., Audia, S., Janikashvili, N. et al. 2012. Brief report:
cations of interleukin-6. Cancer Immunol. Res. 2:288. inhibition of interleukin-6 function corrects Th17/Treg cell imbal-
40 Hirano, T., Taga, T., Yasukawa, K. etal. 1987. Human B-cell differ- ance in patients with rheumatoid arthritis. Arthritis Rheum.
entiation factor defined by an anti-peptide antibody and its pos- 64:2499.
sible role in autoantibody production. Proc. Natl Acad. Sci. USA 54 Pesce, B., Soto, L., Sabugo, F. etal. 2013. Effect of interleukin-6

Downloaded from http://intimm.oxfordjournals.org/ at Pontificia Universidad Catolica de Chile on January 14, 2015
84:228. receptor blockade on the balance between regulatory T cells and
41 Sato, K., Tsuchiya, M., Saldanha, J. et al. 1993. Reshaping a T helper type 17 cells in rheumatoid arthritis patients. Clin. Exp.
human antibody to inhibit the interleukin 6-dependent tumor cell Immunol. 171:237.
growth. Cancer Res. 53:851. 55 Thiolat, A., Semerano, L., Pers, Y. M. et al. 2014. Interleukin-6
42 Nishimoto, N., Terao, K., Mima, T., Nakahara, H., Takagi, N. and receptor blockade enhances CD39+ regulatory T cell develop-
Kakehi, T. 2008. Mechanisms and pathologic significances in ment in rheumatoid arthritis and in experimental arthritis. Arthritis
increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor Rheumatol. 66:273.
after administration of an anti-IL-6 receptor antibody, tocilizumab, 56 Yokota, S., Imagawa, T., Mori, M. etal. 2008. Efficacy and safety
in patients with rheumatoid arthritis and Castleman disease. of tocilizumab in patients with systemic-onset juvenile idiopathic
Blood 112:3959. arthritis: a randomised, double-blind, placebo-controlled, with-
43 Nishimoto, N., Sasai, M., Shima, Y. et al. 2000. Improvement in drawal phase III trial. Lancet 371:998.
Castlemans disease by humanized anti-interleukin-6 receptor 57 De Benedetti, F., Brunner, H. I., Ruperto, N. et al.; PRINTO;

antibody therapy. Blood 95:56. PRCSG. 2012. Randomized trial of tocilizumab in systemic juve-
44 Nishimoto, N., Kanakura, Y., Aozasa, K. etal. 2005. Humanized nile idiopathic arthritis. N. Engl. J.Med. 367:2385.
anti-interleukin-6 receptor antibody treatment of multicentric 58 Chihara, N., Aranami, T., Sato, W. etal. 2011. Interleukin 6 sign-
Castleman disease. Blood 106:2627. aling promotes anti-aquaporin 4 autoantibody production from
45 Choy, E. H., Isenberg, D. A., Garrood, T. etal. 2002. Therapeutic plasmablasts in neuromyelitis optica. Proc. Natl Acad. Sci. USA
benefit of blocking interleukin-6 activity with an anti-interleukin-6 108:3701.
receptor monoclonal antibody in rheumatoid arthritis: a rand- 59 Araki, M., Aranami, T., Matsuoka, T., Nakamura, M., Miyake, S.
omized, double-blind, placebo-controlled, dose-escalation trial. and Yamamura, T. 2013. Clinical improvement in a patient with
Arthritis Rheum. 46:3143. neuromyelitis optica following therapy with the anti-IL-6 receptor
46 Nishimoto, N., Yoshizaki, K., Miyasaka, N. etal. 2004. Treatment monoclonal antibody tocilizumab. Mod. Rheumatol. 23:827.
of rheumatoid arthritis with humanized anti-interleukin-6 receptor 60 Ayzenberg, I., Kleiter, I., Schrder, A. et al. 2013. Interleukin 6
antibody: a multicenter, double-blind, placebo-controlled trial. receptor blockade in patients with neuromyelitis optica nonre-
Arthritis Rheum. 50:1761. sponsive to anti-CD20 therapy. JAMA Neurol. 70:394.
47 Tanaka, T., Hishitani, Y. and Ogata, A. 2014. Monoclonal anti- 61 Araki, M., Matsuoka, T., Miyamoto, K. etal. 2014. Efficacy of the
bodies in rheumatoid arthritis: comparative effectiveness of anti-IL-6 receptor antibody tocilizumab in neuromyelitis optica: a
tocilizumab with tumor necrosis factor inhibitors. Biologics pilot study. Neurology 82:1302.
8:141. 62 Igawa, T., Ishii, S., Tachibana, T. etal. 2010. Antibody recycling by
48 Dougados, M., Kissel, K., Sheeran, T. et al. 2013. Adding toci- engineered pH-dependent antigen binding improves the duration
lizumab or switching to tocilizumab monotherapy in methotrex- of antigen neutralization. Nat. Biotechnol. 28:1203.
ate inadequate responders: 24-week symptomatic and structural 63 Maude, S. L., Barrett, D., Teachey, D. T. and Grupp, S. A. 2014.
results of a 2-year randomised controlled strategy trial in rheuma- Managing cytokine release syndrome associated with novel T
toid arthritis (ACT-RAY). Ann. Rheum. Dis. 72:43. cell-engaging therapies. Cancer J. 20:119.
49 Nishina, N., Kaneko, Y., Kameda, H., Kuwana, M. and Takeuchi, T. 64 Grupp, S. A., Kalos, M., Barrett, D. etal. 2013. Chimeric antigen
2013. Reduction of plasma IL-6 but not TNF- by methotrexate in receptor-modified T cells for acute lymphoid leukemia. N. Engl.
patients with early rheumatoid arthritis: a potential biomarker for J.Med. 368:1509.
radiographic progression. Clin. Rheumatol. 32:1661. 65 Teachey, D. T., Rheingold, S. R., Maude, S. L. etal. 2013. Cytokine
50 Gabay, C., Emery, P., van Vollenhoven, R. et al.; ADACTA
release syndrome after blinatumomab treatment related to abnor-
Study Investigators. 2013. Tocilizumab monotherapy versus mal macrophage activation and ameliorated with cytokine-
adalimumab monotherapy for treatment of rheumatoid arthritis directed therapy. Blood 121:5154.