Review 789
Future Prospects for the Treatment of Graves’
Hyperthyroidism and Eye Disease
Authors S. Neumann1, R. F. Place2, C. C. Krieger1, M. C. Gershengorn1
Affiliations  Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases,
Key words
●
▶ Graves’ hyperthyroidism
●
▶ Graves’ orbitopathy
●
▶ TSH receptor (TSHR)
●
▶ IGF-1 receptor (IGF-1R)
received 19.03.2015
accepted 26.06.2015
Bibliography
DOI http://dx.doi.org/
10.1055/s-0035-1555901
Published online:
July 21, 2015
Horm Metab Res 2015;
47: 789–796
© Georg Thieme Verlag KG
Stuttgart · New York
ISSN 0018-5043
Correspondence
S. Neumann
National Institute of Diabetes
and Digestive and Kidney
Diseases
National Institutes of Health
Laboratory of Endocrinology
and Receptor Biology
50 South Drive
Bethesda
MD 20892-8029
USA
Tel.:  + 1/301/451 6307
Fax:  + 1/301/480 4214
susannen@intra.niddk.nih.gov
1
National Institutes of Health, Bethesda, USA
2
 Nova Therapeutics LLC, E Foothill Blvd, Pasadena, USA
Abstract
▼ known about the pathogenesis of these 2 major
Although there are adequate therapies for Graves’
hyperthyroidism, mild to moderate Graves’ orbit-
opathy (GO) is usually treated symptomatically
whereas definitive therapy is reserved for severe,
vision-threatening GO. Importantly, none of the
treatment regimens for Graves’ disease used
today are directed at the pathogenesis of the dis-
TSHR and IGF-1R Appear to be Disease
Targets in Graves’ Disease
▼ nective tissues including enlargement of extra-
The thyrotropin [thyroid-stimulating hormone
(TSH)] receptor (TSHR) is a major regulator of
thyroid function by controlling the size and num-
ber of thyrocytes, and the synthesis and secretion
of thyroid hormones [1]. In recent years, it has
become evident that TSHR is also expressed in a
variety of extrathyroidal tissues including, for
example, orbital preadipocytes/fibroblasts, bone,
white and brown adipose tissue, peripheral
blood cells, anterior pituitary, and hypothalamus
[2]. Although of high interest and being studied
intensively, the functional role and physiological
importance of the TSHR in these extrathyroidal
tissues are not yet well understood.
TSHR plays a major role in several thyroid pathol-
ogies including hyperthyroidism, hypothyroid-
ism, and thyroid tumors [3]. TSHR is the main
target of thyroid-stimulating auto-antibodies
(TSAbs) in patients with Graves’ disease (GD). GD
is an autoimmune disease with a prevalence of
about 1 % of the U.S. population that is caused by
persistent, unregulated TSAb stimulation of
TSHRs on thyroid cells causing overproduction of
thyroid hormones leading to hyperthyroidism [3].
GD is the most common form of hyperthyroidism
in iodine-replete areas [4]. Graves’ orbitopathy
(GO), also known as Graves’ ophthalmopathy or
thyroid eye disease, is an extrathyroidal manifes-
tation of GD with a prevalence of 25 % in patients
Neumann S et al. Future Treatment of Graves’ Disease  …  Horm Metab Res 2015; 47: 789–796
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ease. Herein, we review some aspects of what is
components of Graves’ disease, specifically the
apparent important roles of the TSH and IGF-1
receptors, and thereafter describe future thera-
peutic approaches directed at these receptors.
We propose that targeting these receptors will
yield effective and better tolerated treatments for
Graves’ disease, especially for GO.
with GD [5]. GO involves inflammation of orbital
tissue and extensive remodeling of orbital con-
ocular muscles, increased numbers of adipose
cells, and excessive deposition of hyaluronan
[hyaluronic acid (HA)] [6]. The underlying mech-
anisms of the pathogenesis of GO remain unclear.
TSHR expression in orbital fat tissue and extra-
ocular muscles [7] suggests that TSHR is one of
the primary targets in orbital tissues in patients
with GO. A low TSHR abundance has been
observed in cultured orbital fibroblasts and in
normal adipose tissue; however, TSHR expres-
sion is elevated in differentiated human orbital
fibroblasts in vitro [8, 9]. Lastly, there is a direct
correlation between the levels of TSAbs and the
severity of GO, as well as a prognostic value for
TSAbs in GO outcome [10].
The insulin-like growth factor 1 (IGF-1) receptor
(IGF-1R) has been suggested to be another impor-
tant target in GO and IGF-1/IGF-1R signaling
appears to participate in the pathogenesis of auto-
immune diseases in general. Although the role(s)
of IGF-1R signaling is not completely understood,
it is known that IGF-1 influences several aspects
of immunity by, for example, affecting thymic B
and T cells development [11]. IGF-1R has been
found to be overexpressed on orbital fibroblasts
of patients with GO compared with those from
non-Graves’ controls [12]. A functional relation-
ship between TSH- and IGF-1 mediated pathways
was first described by Tramontano et al. in rat
790 Review
thyroid cells [13], and co-localization of TSHR and IGF-1R has
been demonstrated [14]. IGF-1R and TSHR can be co-immuno-
precipitated from human thyrocytes and orbital fibroblasts.
Selective activation of both receptors by their cognate ligands
TSH and IGF-1 has been shown to stimulate HA secretion by
Graves’ orbital fibroblasts (GOFs), which are fibroblast-like cells
derived from tissue excised in decompression surgery for GO
[15, 16]. Recently, our group provided evidence for bi-directional
crosstalk between TSHR and IGF-1R that leads to increased
TSAb-induced HA production in GOFs [17]. Our current knowl-
edge of the pathogenesis of GO supports the idea that TSHR and
IGF-1R on orbital fibroblasts are primarily involved [10, 17, 18].
Current Treatments for Graves’ Hyperthyroidism and GO
▼ et al. [30] did not show a benefit of RTX over placebo. More stud-
Untreated Graves’ hyperthyroidism results in increased morbid-
ity and mortality mainly due to cardiovascular and skeletal
(osteoporosis) complications [19]. Moreover, GD has a negative
long-term influence on the quality of life, due to either the dis-
ease process itself or its treatment [20]. Treatment options for
GD are thyroidectomy and radioactive iodine (RAI) therapy that
aim at preventing recurrence of hyperthyroidism but often induce
permanent hypothyroidism requiring thyroid hormone replace-
ment, or anti-thyroid medication (methimazole, carbimazole,
­propylthiouracil) to restore the euthyroid state while awaiting
resolution of the autoimmune process and disease remission.
None of these therapies is optimal. Thyroid surgery and RAI ther-
apy may have acute morbidity and usually require lifelong thyroid
hormone replacement. The antithyroid drugs methimazole and
propylthiouracil have potential side effects including agranulocy-
tosis and hepatotoxicity. Side effects of methimazole are dose-
related, whereas those of propylthiouracil are less clearly related to
dose [21]. Long-term low-dose treatment with methimazole has
been proven safe and successful in sustained control of hyperthy-
roidism and is in particular a recommended treatment option for
patients with Graves’ orbitopathy [22–24]. However, the relapse
rate upon discontinuation of antithyroid drugs is high [25].
Table 1  Potential novel therapies for Graves’ hyperthyroidism and Graves’ orbitopathy (GO) that directly target TSHR or IGF-1R.
Potential Treatment Drug Type Mechanism of Action
Antibody 5C9 Monoclonal TSHR blocking activity
Antibody K1–70 antibody
NCGC00229600 (ANTAG2) Small molecule TSHR blocking activity
NCGC00242364 (ANTAG3)
Teprotumumab (RV001, Monoclonal IGF-1R blocking
R1507) antibody activity
Linsitinib (OSI-906) Small molecule IGF-1R blocking
activity
Neumann S et al. Future Treatment of Graves’ Disease  …  Horm Metab Res 2015; 47: 789–796
Management of GO is still a major challenge, and the existing
therapies are not uniformly effective and have substantial side
effects as well. Treatment strategies for patients with severe eye
disease include oral or intravenous corticosteroids, orbital radi-
otherapy or orbital decompression surgery [5, 26]. Rituximab
(RTX), a humanized chimeric anti-CD20 monoclonal antibody
that depletes both B lymphocytes in the intermediate stages of
maturation and short-lived plasma cells, has been reported to be
effective for the treatment of active moderate to severe GO
[27, 28]. However, very recent randomized controlled studies
have led to inconsistent results. Salvi et al. [29] report a better
therapeutic outcome of RTX in active moderate to severe GO
when compared with intravenous administration of methyl-
prednisolone and suggest a disease-modifying effect of the drug.
In contrast, the randomized controlled trial by the group of Stan
ies will be necessary to draw a definitive conclusion.
Advantages and disadvantages of current treatment strategies as
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well as causes for the incomplete effectiveness of available thera-
pies are reviewed by Bartalena [5]. Variable success of treatment of
GO is caused in part due to incomplete understanding of the
pathogenesis of GO and persisting difficulties in diagnosis and
early assessment of GO activity and severity in clinical practice [5].
Current treatment options for GD and GO are also less than opti-
mal because they target the signs and symptoms of these dis-
eases rather than the pathogenic mechanisms. None of the
currently approved therapies target TSHR or IGF-1R directly. In
an ideal case the same drug would treat GD hyperthyroidism and
GO due to the close link between these diseases [31]. Future treat-
ment strategies might include TSHR-blocking antibodies or small
molecule antagonists, which directly act at the TSHR. The involve-
ment of the IGF-1R in GO suggests targeting the IGF-1R as a com-
plementary therapy for GO [18, 32]. In summary, the development
of treatment strategies that target the TSHR or IGF-1R alone or in
combination is desirable. Such potential new therapies are sum-
marized in ●  ▶  Table 1 and will be described in more detail below.
Pros Cons
Potential for treatment of hyperthyroidism Parenteral administration
and GO Difficult to produce in large
Inverse agonist activity quantities
High affinity Intensive quality controls
Long half-life (weeks) are required
Potential for treatment of hyperthyroidism Short half-life
and GO
Inverse agonist activity
Oral administration
Relative ease of production in large quantities
Phase 2 clinical trial in patients with GO Parenteral administration
Long half-life (weeks) Difficult to produce in large
quantities
Intensive quality controls
are required
Nonspecific for GO
Phase 3 clinical trial for adrenocortical Short half-life
carcinoma Nonspecific for GO
Phase 2 clinical trial for lung, ovarian, and Unknown impact on GO
prostate cancer
Oral administration
Relative ease of production in large quantities

TSHR Antagonists
▼ ▼
TSHR is a member of a small subfamily of related glycoprotein hor-
mone receptors (GPHRs) that includes receptors for LH/chorionic
gonadotropin (CG) and FSH, within class A of the large family of G
protein-coupled (7 transmembrane-spanning) receptors (GPCRs).
GPHRs are different than other members of class A GPCRs by
­having a very large amino-terminal extracellular domains. TSH
and TSAbs bind primarily to TSHR via interactions with regions
within the extracellular domain [33]. The receptor signaling is
induced by ligand binding and transduced by the intracellular
­surface of the transmembrane helices and the carboxyl-terminal
tail of TSHR interacting with G-proteins and arrestins [33, 34].
Antagonists that inhibit TSHR signaling directly by binding to
the TSHR are promising new drug treatments. With regard to
clinical usefulness, neutral antagonists (ligands that inhibit
receptor activation by agonists) could be used as leads to develop
drugs to antagonize TSAb activation of TSHR in patients with
Graves’ hyperthyroidism and GO. Inverse agonists (ligands that
inhibit receptor activation by agonists and additionally inhibit
agonist-independent, also termed basal or constitutive receptor
signaling) could be used as leads to develop drugs to inhibit con-
stitutive TSHR signaling in patients with residual thyroid cancer
and thereby treat them more effectively than by TSH suppres-
sion alone. Furthermore, patients with non-autoimmune hyper-
thyroidism caused by constitutively activating germline
mutations [35] could benefit from an inverse agonist. Two types
of molecules that are TSHR antagonists have been developed in
parallel, TSHR-blocking antibodies [36, 37] and small molecule
“drug-like” compounds [38] ( ● ▶  Table 1).
Blocking Monoclonal TSHR Autoantibodies
▼ TSHRs in a model cell system. Treatment with NCGC00161856
The first human monoclonal blocking antibody was produced
from B cells of a patient with Graves’ hyperthyroidism. This anti-
body, 5C9, has high affinity for the TSHR and blocks TSAb- and
TSH-induced activation by inhibition of binding of TSAbs or TSH
to the extracellular domain and inhibits basal activity of TSHR as
well [39]. Another blocking TSHR antibody, K1–70, was obtained
from a patient with autoimmune thyroid eye disease who was
clinically hypothyroid [40]. The patient’s serum showed both
stimulating and blocking activity at the TSHR and this observa-
tion provided the first evidence that stimulating and blocking
TSHR autoantibodies can be produced in a patient at the same
time. The functional characterization of the blocking antibodies
5C9 and K1–70, their similarities and differences as well as the
potential binding sites at the ectodomain of the TSHR have been
reviewed recently [36]. From a therapeutic point of view, the
advantage of these “natural” inhibitors is the high affinity to the
TSHR and their long half-life of several weeks. However, the
need for parenteral administration and the difficulty of genera-
tion, purification and quality control of these antibodies are lim-
iting factors to their potential use in the clinic. Although TSHR
activation by the majority of tested TSAbs could be blocked by
5C9 and K1–70, it has been demonstrated that there are differ-
ences in the way 5C9 and K1–70 bind to the TSHR [37], which
might have an impact on the general applicability of blocking
TSHR antibodies. These antibodies have not yet been studied for
pharmacodynamics and potential side effects commonly associ-
ated with monoclonal antibody-based therapies including the risk
of mild immune reactions (i. e., allergic-like responses) in humans.
Neumann S et al. Future Treatment of Graves’ Disease  …  Horm Metab Res 2015; 47: 789–796
Review 791
Small Molecule Antagonists for TSHR
Recently developed small molecule “drug-like” antagonists
(SMANTAGs) for TSHR are also promising drug candidates for
the treatment of Graves’ hyperthyroidism and GO [9, 41–43]. All
SMANTAGs that have been reported to date bind to an allosteric
site within the transmembrane domain of TSHR rather than the
orthosteric site in the extracellular domain where TSH and
TSAbs bind (see below). We reported the first well-characterized
neutral SMANTAG (NIDDK-CEB-52) that selectively antagonizes
TSHR in 2008 [44]. NIDDK-CEB-52 was shown to inhibit activa-
tion of TSHR by TSH and TSAbs in a model cell system and inhib-
ited upregulation of thyroperoxidase (TPO) expression by these
agonists in primary cultures of human thyrocytes. These find-
ings represented proof of principle that SMANTAGs could serve
as drugs to treat patients with Graves’ hyperthyroidism. Subse-
quently, we developed a series of TSHR antagonists by chemical
modification of the scaffold of the TSHR agonist NCGC00161870
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[45]. Interestingly, all antagonists based on the NCGC00161870
scaffold except one were inverse agonists. Only NCGC00242595
was a neutral antagonist at TSHR [46]. A neutral antagonist is a
good tool to be able to distinguish between effects of TSH- or
TSAb-stimulated and basal TSHR activation, and therefore it is
useful as a probe of TSHR function in addition to its clinical
potential.
Therapeutic Potential of SMANTAGs in the Treatment
of Hyperthyroidism
▼
NCGC00161856 was the first inverse agonist of TSHR to be
described [47]. It inhibited basal and TSH-stimulated signaling
of TSHR and basal signaling by constitutively active mutant
also lowered basal expression levels of 4 thyroid-specific genes
– thyroglobulin, TPO, sodium iodide symporter (NIS), and TSHR
in primary cultures of normal human thyrocytes. These data
demonstrated that a SMANTAG could act as an inverse agonist in
human thyroid cells.
Further chemical modification led to the promising new ligand
ANTAG2 (NCGC00229600, ●  ▶  Fig. 1), which is also an allosteric
inverse agonist that inhibited basal and TSH-stimulated signal-
ing [41]. Our group demonstrated first that small molecule TSHR
agonists and antagonists bind in a pocket within the 7 trans-
membrane helical bundle of TSHR [45, 48]. To have potential as
therapy for Graves’ hyperthyroidism and GO, it would be impor-
tant that an antagonist inhibits TSHR activation by the majority
N
O
O O
N
NHAc
N
N O N O
H H
OMe OMe
ANTAG2 (NCGC00229600) ANTAG3 (NCGC00242364)
Fig. 1  Structures of TSHR small molecule antagonists. ANTAG2:
NCGC00229600, 2-[3-[(2,6-dimethylphenoxy)methyl]-4-methoxyphenyl]-
3-(pyridin-3-ylmethyl)-1,2-dihydroquinazolin-4-one. ANTAG3:
NCGC00242364, N-[4-[[5-[3-(furan-2-ylmethyl)-4-oxo-1,2-dihydroquina-
zolin-2-yl]-2-methoxyphenyl]methoxy]-3,5-dimethylphenyl]acetamide.
792 Review
of TSAbs. Because TSAbs bind to the extracellular domain of
TSHR, whereas SMANTAGs bind within the transmembrane
domain, the likelihood is high that signal transduction initiated
by the majority of TSAbs can be blocked by SMANTAGs. In pri-
mary cultures of human thyrocytes, the inverse agonist ANTAG2
inhibited TSAb-induced increase in TPO gene expression by
average 65 % by all 30 GD sera tested [41]. These data suggested
that an antagonist like ANTAG2 would likely be an effective
inhibitor of TSAbs from most, if not all, patients with GD and
could be used to treat the hyperthyroidism of GD.
Independently, a TSHR antagonist developed at Merck Sharp &
Dohme Corporation (Org 274179–0) was characterized [9, 43].
In the first report [43], the authors showed that Org 274179–0
was a TSHR inverse agonist that inhibited the basal, TSH- and
TSAb-stimulated signaling in a model system expressing TSHRs,
basal signaling by constitutively active mutant TSHRs in a model
system, and TSH- and TSAb-stimulated signaling in a rat thyroid
cell line (FRTL-5). Org 274179–0 has the advantage of higher
nanomolar potency than the reported TSHR antagonists from
our group [43]. This ligand changes neither 125I-TSH binding nor
the dissociation of 125I -TSH from the TSHR, which suggests that
Org274179–0, like ANTAG2, is an allosteric antagonist and most
likely interacts with the transmembrane domain of the TSHR.
However, Org274179–0 has a significant disadvantage in that it
is a partial agonist at the LH receptor and also exhibits equipo-
tent antagonistic activity at the FSHR [43]. This is not completely
unexpected since the receptors for LH and FSH have their high-
est homology to TSHR within the 7 transmembrane domain [49]
in which SMANTAGs bind. The TSHR antagonist ANTAG2 is also
a nonselective antagonist for TSHR. ANTAG2 inhibits LH- and
FSH receptor activation as well, although with lower efficacy and
potency (unpublished data). Chemical modification of ANTAG2
has led to the development of ANTAG3 (NCGC00242364,
 ▶  Fig. 1) which exhibits 2 properties that are important for drug
● derived from resident orbital fibroblasts and fibroblasts derived
treatment in humans. First, ANTAG3 is selective for TSHR and
does not affect signaling by LH or FSH receptors. Secondly,
ANTAG3 inhibits TSHR activation in mice in vivo [50]. This selec-
Neumann S et al. Future Treatment of Graves’ Disease  …  Horm Metab Res 2015; 47: 789–796
tive antagonist is so far the only small molecule candidate drug
to have been shown to effectively inhibit TSHR-mediated
responses in vivo [50]. In a mouse model of thyroid gland stimu-
lation by endogenous TSH, ANTAG3 inhibited the elevation in
serum free T4. Furthermore, ANTAG3 inhibited the increases in
TPO and NIS mRNA expression caused by continuous adminis-
tration of TRH. In a second mouse model, which is more relevant
to GD, endogenous TSH effects were inhibited by administering
T3 [51] and thyroid glands were stimulated by administering the
human monoclonal TSAb M22 [52] ( ● ▶  Fig. 2a, reproduced from
[50]). ANTAG3 inhibited the increase in free T4 and the eleva-
tions of TPO and NIS mRNAs caused by M22 ( ● ▶  Fig. 2b, c, repro-
duced from [50]). Although acute administration of M22
antibody is not a model for the chronic presence of TSAbs found
in GD, these data indicate that ANTAG3 can inhibit thyroid acti-
vation by a stimulating antibody in vivo. These data suggest that
a TSHR antagonist like ANTAG3 could be used to treat Graves’
hyperthyroidism. These findings also suggest that SMANTAGs
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would be able to inhibit TSHR signaling in vivo in extrathyroidal
tissues.
Potential Role for SMANTAGs in the Treatment of GO
▼
Orbital fibroblasts appear to be a primary target of the autoim-
mune attack in GO and functional TSHR has been found on GOFs
(see above). Recently, it has been shown that fibrocytes in the
circulation expressing antigen CD34, which is found on hemat-
opoietic precursor cells, also express TSHR. TSHR-expressing
fibrocytes have been reported to be found at high levels in GO
patients and have been proposed to infiltrate orbital connective
tissue and play an important role in the pathophysiology of GO
[18]. The population of GOFs that are studied in vitro may be
from fibrocytes. To our knowledge, however, the data published
on fibrocytes has not yet been confirmed by other investigators.
Fig. 2  ANTAG3 inhibits the increases in the levels
of serum free T4 and TPO and NIS mRNAs in the
thyroid in mice stimulated by a single injection
of TSAb M22. a T3 (5 μg/day for 4 days) was
administered by daily intraperitoneal (IP) injection
and ANTAG3 was given for 3 days (2 mg/day) via
osmotic pump. On day 4, the animals were given
an IP injection of vehicle or ANTAG3 (2 mg) and
4 h later an IP injection of M22 (0.5 μg) or vehicle.
The animals were euthanized 24 h after the M22
injection on day 5. b Serum free T4 (FT4) levels.
c mRNA levels of TPO and NIS in thyroid gland
lysates (reproduced from [50]).

Models of GO have been reported in animal studies [53, 54], but
none have been proven to be adequate models that reproducibly
or consistently recapitulate the disease. Therefore, the majority
of the studies of GO have been performed in tissue culture using
GOFs obtained from patients with GO at orbital decompression
surgery. Experimental evidence supports the idea that activa-
tion of TSHR by TSAbs leads to proliferation of preadipocyte
fibroblasts or adipocytes, increase in HA production and differ-
entiation of a subset of preadipocytes into mature adipocytes.
Therefore, showing that TSHR antagonists inhibit activation of
TSHRs on GOFs would be an important step in the development
of a medical therapy for GO.
Two studies demonstrated in parallel that SMANTAGs can inhibit
TSHR activation in GOFs. Van Zeijl et al. showed that Org
274179–0 inhibited TSH-, TSAb- and M22-stimulated cAMP pro-
duction by GOFs that had been made to differentiate into adipo-
cytes in vitro [9]. Our group determined the effects of ANTAG2
on undifferentiated GOFs and GOFs differentiated into adipo-
cytes. GOFs exhibited higher absolute levels of basal and forsko-
lin-stimulated cAMP production than differentiated adipocytes.
Consistent with previous findings, TSH stimulated cAMP pro-
duction in the majority of differentiated adipocyte strains and
less consistently in GOFs. ANTAG2 reduced both TSH- and
M22-stimulated signaling in both cell types. Moreover, ANTAG2
was a selective TSHR antagonist in these GOFs because it did not
inhibit signaling by activation of prostaglandin D2 receptors,
which use the same cAMP signaling pathway as TSHRs [42].
A follow-up study demonstrated that ANTAG2 inhibited TSAb-
induced HA production in undifferentiated GOFs [55]. The find-
ings reported with ANTAG2 and Org274179–0 support a
potential role of SMANTAGs in the treatment of GO.
In summary, TSHR SMANTAGs have potential as treatment for
Graves’ hyperthyroidism and GO. In comparison to antithyroid
drugs, SMANTAGs have the advantage of targeting the TSHR
directly and therefore, the same drug could be used to treat both
major components of GD, hyperthyroidism and orbitopathy.
These advantages are also valid for the use of monoclonal block-
ing TSHR antibodies (as described above). While SMANTAGs
have a short half-life compared to antibodies, these small organic
molecules have the advantages of oral administration and rela-
tive ease of production and quality control ( ● ▶  Table 1). Since
chronic treatment with TSHR antagonists might be necessary to
control hyperthyroidism and associated orbitopathy, an adjusted
lower dose of a SMANTAG could be administered to control
hyperthyroidism and to avoid hypothyroidism.
IGF-1R Antagonists
▼ = OSI-906).
The IGF-1R is a transmembrane receptor that belongs to the
class of tyrosine kinase receptors and is activated and auto-
phosphorylated following IGF-1 binding [56]. The IGF-1R is
expressed in orbital fibroblasts and circulating fibrocytes, its
expression is increased in GO fibroblasts compared to orbital
fibroblasts from non-Graves’ patients, and may be acting in con-
cert with the TSHR in the pathophysiology of GO [18, 32]. The
potential role of IGF-1R-mediated signaling in GO was first sug-
gested when antibodies from GO patients were found to com-
pete with binding of radiolabeled IGF-1 to the surface of GOFs
[57]. It has been postulated that stimulating antibodies against
the IGF-1R [11] or a subset of TSAbs that stimulate the IGF-1R
are contributing to GO pathogenesis [58] but data remain con-
Neumann S et al. Future Treatment of Graves’ Disease  …  Horm Metab Res 2015; 47: 789–796
Review 793
troversial. Varewijck et al. [59] concluded that in a subset of
patients with GO, circulating antibodies may stimulate the IGF-
1R and therefore may be involved in GO pathogenesis. In con-
trast, Minich et al. [60] detected antibodies to the IGF-1 receptor
in 11 % of healthy controls and 10 % of patients with GO. IGF-1R
antibodies failed to stimulate IGF-1R signaling but inhibited IGF-
1-induced activation of the receptor. The authors concluded that
IGF-1R antibodies do not contribute to the pathogenesis of GO.
Serum IGF-1, IGF-II and IGF-binding proteins are present at nor-
mal levels in GO patients [61]. Therefore, one hypothesis is that
local production of IGF-1, acting in autocrine or paracrine fash-
ion, might be involved in the autoimmune reaction [10]. In sum-
mary, the major contributing IGF-1R activating ligand in the
pathogenesis of GO, that is, IGF-1R-stimulating antibodies or
endogenous IGF-1, has yet to be determined ( ● ▶  Fig. 3, see below).
Strategies for interrupting IGF-1R signaling directly at the recep-
tor are being developed ( ● ▶  Table 1). Teprotumumab (RV001,
R1507) is a human monoclonal anti-IGF-1R antibody that antag-
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onizes receptor activation by binding to the extracellular
α-subunit domain [62]. In fibrocytes, Teprotumumab reduced
cell surface expression of IGF-1R and TSHR, inhibited IGF-1 and
TSH-induced Akt phosphorylation, and reduced TSHR-mediated
IL-6 and IL-8 expression [63]. These findings are another impor-
tant indication for crosstalk between TSHR and IGF-1R and sup-
port the therapeutic potential of this blocking IGF-1R antibody.
A multi-center placebo-controlled therapeutic trial specifically
directed at examining the impact of teprotumumab on the activ-
ity and progression of moderate to severe GO is being conducted.
The currently performed phase 2 clinical trial will evaluate the
safety, tolerability and effectiveness of teprotumumab in the
treatment of GO (https://clinicaltrials.gov/show/NCT01868997).
Teprotumumab is administered every 3 weeks by intravenous
infusion. Considering parenteral administration and high pro-
duction costs for a therapeutically used antibody, a small mole-
cule antagonist for IFG-1R may exhibit important advantages
due to oral administration and ease of production ( ● ▶  Table 1).
Linsitinib (OSI-906) is an orally bioavailable small-molecule IGF-
1R kinase inhibitor [64]. Linsitinib potently inhibits ligand-
dependent auto-phosphorylation of IGF-1R in cells, while
displaying a high degree of selectivity vs. a wide panel of protein
kinases. Linsitinib prevents ligand-induced activation of down-
stream pathways including pAKT and pERK1/2 and, therefore,
inhibits proliferation in a variety of tumor cell lines and has
demonstrated in vivo efficacy in tumor models [64]. Phase 2
clinical trials with linsitinib for the treatment of small cell lung
cancer, ovarian cancer and prostate cancer, and a phase 3 clinical
trial for the treatment of patients with adrenocortical carcinoma
have been completed (https://clinicaltrials.gov/ct2/results?term 
A major challenge in the development of IGF-1R inhibitors is to
avoid blocking the closely related insulin receptor (IR) that regu-
lates glucose levels in the blood. Linsitinib is a dual inhibitor of
IGF-1R and IR [64]. Activation of the insulin receptor induces
glucose uptake, and a decrease in IR signaling leads to hypergly-
cemia. Two phase 1 trials have tested continuous or intermittent
dosing of Linsitinib in patients with advanced solid tumors and
hyperglycemia has been reported as an adverse side effect
[65, 66]. Therefore, selective targeting of the IGF-1R with small
molecule ligands is the major challenge due to the close rela-
tionship with the IR. An additional challenge for the use of IGF-1
inhibitors in the treatment of GO is the fact that the IGF-1R sign-
aling axis plays many essential roles in the growth, differentia-
794 Review

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Fig. 3  Combination therapy that antagonizes TSHR and IGF-1R may be the most effective treatment of Graves’ orbitopathy (GO). Left panel. TSHR is
activated by thyroid stimulating antibodies (TSAbs). IGF-1R may be activated via cross-talk by TSHR, IGF-1R-activating antibodies or endogenous IGF-1.
Middle panels: TSAb-stimulated hyaluronan secretion by Graves’ orbital fibroblasts is inhibited by antagonizing either TSHR with a SMANTAG or IGF-1R with
linsitinib. TSHR and IGF-1R could also be inhibited by monoclonal TSHR blocking antibodies and monoclonal blocking IGF-1R antibodies, respectively (not
shown). Right panel: Combined treatment with submaximal doses of a TSHR antagonist and an IGF-1R antagonist may provide the most effective medical
therapy for GO with the fewest side effects.

tion and development of mammalian tissues [67]. Therefore,

inhibition of IGF-1R-mediated signaling by antibodies or small 1000
Control
molecule antagonists might lead to undesirable side effects in
normal tissue. 800 Linsitinib
ANTAG2
HA (µg/ml)

600
Future Therapy for GO – Hypothesis
▼ 400
Recent findings support the idea that targeting both TSHR and
IGF-1R may be advantageous in treating patients with GO. We
200
have shown that simultaneous stimulation of GOFs by TSH and
IGF-1 synergistically increased HA secretion [17] ( ● ▶  Fig. 3, left

panel); that is, these receptors are functionally interdependent. 0

Bidirectional crosstalk between TSHR and IGF-1R in GOFs
induced by the TSAb M22 appears to both directly activate TSHR
and indirectly trigger IGF-1R signaling supporting a strategy for
targeting TSHR as the primary approach for GO therapy. How-
ever, a combination therapy that antagonizes the activation of
both receptors might be even more effective.
By using primary GOF cells in culture as an in vitro model for GO,
we have shown that antagonizing either IGF-1R or TSHR leads to
inhibition of HA secretion stimulated by monoclonal TSAb M22
▶  Fig. 4; adapted from [17]). Our data show that a maximally
( ●
effective dose of linsitinib causes partial inhibition of HA secre-
tion whereas ANTAG2, a TSHR antagonist, completely inhibited
HA secretion. These findings suggest that antagonism of TSHR is
more effective in inhibiting HA secretion by TSAbs than antago-
nism of IGF-1R. However, since we have shown that there is
cross-talk between TSHR and IGF-1R on HA secretion when
GOFs are stimulated by TSAbs ( ● ▶  Fig. 3), it is possible that co-
Basal IGF-1 M22
Fig. 4  Inhibition of IGF-1- and M22-stimulated HA secretion from GOFs
by TSHR antagonist ANTAG2 and IGF-1R antagonist linsitinib. GOFs were
incubated in medium containing M22 (2 nM) or IGF-1 (13 nM) with or
without ANTAG2 (10 μM) or linsitinib (10 μM). After 5 days, the mediums
were collected and HA was assayed. The maximally effective dose of
linsitinib causes partial inhibition, whereas ANTAG2 completely inhibited
M22-stimulated HA secretion.
lower doses and fewer potential side effects as compared to
maximally effective doses of either drug alone. We, therefore,
suggest that combined treatment with a TSHR antagonist and an
IGF-1R antagonist may provide the most effective medical ther-
apy for GO.

treatment with IGF-1R inhibitors may further augment the ther- Acknowledgements
apeutic potential of targeted TSHR therapies. In preliminary ▼
experiments, we have found that co-treatment with SMANTAGs This work was supported by the Intramural Research Program of
and linsitinib have cooperative drug effects allowing improved the National Institute of Diabetes and Digestive and Kidney
efficacy at reduced doses when used in combination ( ● ▶  Fig. 3) ­Diseases, National Institutes of Health (Z01 DK011006, Z01
(unpublished data). This strategy would allow disease control at DK047044).

Neumann S et al. Future Treatment of Graves’ Disease  …  Horm Metab Res 2015; 47: 789–796

Conflict of Interest
▼ hyperthyroidism. Arch Iran Med 2012; 15: 477–484
Nova Therapeutics LLC holds licenses for intellectual property
related to TSH receptor small molecule ligand technologies. Rob-
ert F. Place is employed at Nova Therapeutics LLC. Susanne Neu-
mann, Christine C. Krieger, and Marvin C. Gershengorn have no
conflict of interest.
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