Clinical THYROIDOLOGY

ISSN: 2329-9711 | OCTOBER 2021 | VOLUME 33 | ISSUE 10

Clin Thyroidol 2021;33:433–436.

THYROID AUTOIMMUNITY

K1-70 — A Thyrotropin Receptor Antagonist with

Therapeutic Potential in Graves’ Disease, Thyroid Eye
Disease, and Differentiated Thyroid Cancer
Matthew I. Balcerek1 and Donald S. A. McLeod1,2
1 Department of Endocrinology and Diabetes, Royal Brisbane and Women’s Hospital, Herston, Queensland,
Australia
2 Population Health Department, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
Downloaded by 182.56.69.226 from www.liebertpub.com at 10/21/21. For personal use only.

Review of: Ryder M, Wentworth M, Algeciras-Schimnich A, Morris JC, Garrity J, Sanders J, Young S,
Sanders P, Furmaniak J, Rees Smith B 2021 Blocking the thyrotropin receptor with K1-70 in a patient with
follicular thyroid cancer, Graves' disease, and Graves' ophthalmopathy. Thyroid. Epub 2021 Jul 8. PMID:
34114495.

SUMMARY

Background
The thyrotropin (TSH) receptor (TSHR) is a major
thyroid autoantigen and plays a key role in the
regulation of thyroid function (1). Graves’ disease
typically manifests with hyperthyroidism caused by
TSHR autoantibodies (TRAbs) with agonist (stimu-
lating) activity. Rarely, patients may develop hypo-
thyroidism due to a predominance of antagonist
(blocking) TRAbs (1).
The human monoclonal TSH receptor antibody
K1-70 is a highly selective TSHR antagonist that was
isolated from peripheral lymphocytes of a patient
with autoimmune hypothyroidism over 10 years
ago (1,2). It binds to the TSHR with high affinity
and blocks TSHR cAMP stimulation by TSH- and
TSHR-stimulating autoantibodies (3).
Although phase 1 trials of K1-70 in human subjects
with Graves’ disease are ongoing, the clinical use of
K1-70 may extend to other populations who would
benefit from TSHR antagonism (3). The therapeutic
potential of K1-70 is illustrated in the following case
of a patient with Graves’ disease, thyroid eye disease
(TED), and follicular thyroid cancer (FTC).
Methods
A 51-year-old woman presented in October
2014 with thyrotoxicosis, severe active TED, high
TSH-stimulating antibody (TSAb) levels, and a large
left thyroid mass with left lateral neck adenopa-
thy. She was currently a smoker. An 8.7-cm widely
invasive FTC with extrathyroidal extension and
metastatic cervical lymph nodes was confirmed
on postoperative histology. A recombinant thy-
rotropin-stimulated 123I whole-body scan demon-
strated widespread iodine-avid metastatic disease,
and she received 250 mCi 131I therapy followed
by suppressive doses of thyroxine. Progressive
disease resulted in two further neck dissections,
debulking thoracotomies, and a second treatment
with 131I (4).
The TED worsened (persistent smoking, high TRAb
activity, and 131I therapy), with a clinical activity
score (CAS) of 6 of 7 and diplopia. Both her severe
TED and progressive FTC were thought to be influ-
enced by her high serum TSAb titer, which was
unresponsive to intravenous immunoglobulin and
high-dose steroids. Lenvatanib was commenced 2
years after the initial FTC diagnosis, with a partial

433   l  © 2021 American Thyroid Association

 Clinical THYROIDOLOGY
ISSN: 2329-9711 | OCTOBER 2021 | VOLUME 33 | ISSUE 10
THYROID AUTOIMMUNITY K1-70 — A Thyrotropin Receptor Matthew I. Balcerek and
Antagonist with Therapeutic Potential in Graves’ Disease, Donald S. A. McLeod
Thyroid Eye Disease, and Differentiated Thyroid Cancer
response; however, its use was limited by drug-re-
lated toxicity (4). Her case was reviewed by a mul-
tispecialty tumor board, who recommended a trial
of K1-70 in combination with systemic antineo-
plastic therapies. A single-patient expanded-access
application was granted by the U.S. Food and Drug
Administration (4).
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Results
The first intramuscular dose of K1-70 was admin-
istered in April 2017 (17.6 mg), followed by
3-weekly intervals with dose escalation up to
120 mg by July 2017, after which doses were
titrated based on serum TSAb levels. K1-70 was
well tolerated with no observed adverse effects
other than mild discomfort at the intramuscular
injection site.
Despite ongoing smoking, there was rapid resolu-
tion of TED, with subjective improvement noted by
22 days and objective benefit demonstrated at 4
months with reduction in CAS to 1, and a 2-mm
reduction in exophthalmos (21 to 19 mm bilaterally).
She was able to undergo corrective eye surgery,
with resolution of diplopia. However, symptoms
worsened when K1-70 was withheld prior to her
third 123I whole-body scan, correlating with an
increased serum TSAb titer. Symptoms persisted
despite oral prednisone; however, these symptoms
promptly resolved 3 weeks after treatment with
131I, when K1-70 was recommenced. By October
2018, TED had quiesced, with a CAS of 0, and there
was a further mild reduction in exophthalmos (18
mm bilaterally), which persisted for the duration of
K1-70 therapy.
434   l  © 2021 American Thyroid Association
®
Regarding the FTC, serum thyroglobulin levels were
190 ng/ml at the start of K1-70 therapy while she
was taking lenvatanib 20 mg daily. Three months
after commencing K1-70 (July 2017), lenvatanib
therapy was paused for 4 months (treatment
toxicity) and K1-70 continued, with improved quali-
ty-of-life scores. During this time, serum thyroglob-
ulin remained relatively stable and there was a mixed
tumor response on imaging, including slight tumor
regression and progression attenuation. A rise in
serum thyroglobulin to 492 ng/ml with some tumor
foci showing progression prompted lenvatanib
recommencement in October 2017. Because of
dose-limiting toxicity and overall disease progres-
sion, lenvatanib was changed to pazopanib in January
2019 (during which time K1-70 was continued), with
stable structural disease and reduction in serum thy-
roglobulin from 5737 ng/ml to 694 ng/ml by June
2019. The patient died in July 2019 from acute car-
diopulmonary collapse, deemed to be unrelated to
K1-70 therapy (4).
Conclusions
Targeting the TSHR with K1-70 reflects a potential
new therapeutic strategy for the management of
Graves’ disease, TED, and differentiated thyroid
cancer (DTC). The human monoclonal autoantibody
K1-70 appears to effectively block TSHR stimulation,
as evidenced by a reduction in the serum TSAb titer
on therapy. In this single case report, the reduction in
TSAb translated to a clinically meaningful benefit in
TED, despite continued smoking and high-dose 131I
therapy. Further studies could investigate whether
K1-70 may also have synergistic activity with
systemic antineoplastic therapies for DTC.
 Clinical THYROIDOLOGY
ISSN: 2329-9711 | OCTOBER 2021 | VOLUME 33 | ISSUE 10
THYROID AUTOIMMUNITY K1-70 — A Thyrotropin Receptor Matthew I. Balcerek and
Antagonist with Therapeutic Potential in Graves’ Disease, Donald S. A. McLeod
Thyroid Eye Disease, and Differentiated Thyroid Cancer
COMMENTARY
This case report highlights the potential therapeu-
tic uses of K1-70. Current options for the manage-
ment of Graves’ hyperthyroidism (antithyroid drugs,
radioiodine ablation, and surgery) are effective for
most patients; however, all of these treatments have
adverse effects. K1-70 is very effective in reducing
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TSAb activity and inducing hypothyroidism (3).
Obvious therapeutic uses could be for rapid resto-
ration of euthyroidism (i.e., thyroid storm or before
emergent surgery) (5) and as a “block-and-replace”
strategy while awaiting immunologic remission or
definitive treatment. However, with flexible dosing
formulations, one could also conceive the possibil-
ity of dose titration strategies akin to current anti-
thyroid drug use. Other synthetic TSHR antagonists
are in varying stages of development, including
NCGC00242364 (ANTAG3), Org274179-0, and
5C9 (6). These agents have been shown to inhibit
TSH- and TRAb-mediated TSHR activation, although
K1-70 is the first TSHR antagonist to progress to
human clinical trials (4).
Perhaps the most easily translatable therapeutic use
of K1-70 could be in TED, where limited therapeu-
tic options are currently available. Novel targeted
therapies have been developed, most notably tepro-
tumumab. Teprotumumab’s efficacy appears to
exceed that of other first- and second-line therapeu-
tic options for TED (7); however, its worldwide use
is limited by availability and cost. K1-70 represents
another promising monoclonal antibody for TED,
with early improvements in subjective eye symptoms
(occurring in this patient by 22 days) and impressive
reductions in CAS (from 6 to 1) occurring over 4
months in this single case report. The improvement
in TED was temporally associated with K1-70, with
symptoms deteriorating when K1-70 was withheld
and resolving quickly after its resumption, with
responses persisting beyond 2 years of therapy.
435   l  © 2021 American Thyroid Association
®
K1-70 was also used in this patient as a bridge to
corrective orbital surgery, enabling complete resolu-
tion of diplopia. Although not applicable to this case
report, pretibial myxedema is another closely related
TRAb-mediated complication of Graves’ disease in
which TSHR antagonism may also prove valuable (8).
It may have been coincidental, but during adminis-
tration of K1-70, the growth of some FTC foci was
reported to stall during a period of lenvatanib with-
drawal. Potentially, an effect could be analogous
to using suppressive doses of thyroxine to reduce
TSH levels and attenuate tumor growth in DTC (4,5).
Another interesting possibility could be assessing
K1-70 in combination with established antineoplas-
tic therapies for patients with progressive DTC (par-
ticularly in those with a history of Graves’ disease
with high TSAb titers).
In terms of safety, in vivo studies of K1-70 in rats
and primates have demonstrated the expected
pharmacodynamic effect of hypothyroidism (3).
There were no adverse effects attributed to K1-70
in animal studies except for decreases in weight
gain, body weight, and food consumption in rats (3).
K1-70 was well tolerated by this patient, and studies
are ongoing to evaluate its safety and tolerability
when administered as an intramuscular injection or
intravenous infusion in patients with Graves’ disease
(https://clinicaltrials.gov/ct2/show/NCT02904330).
Overall, this single case report raises enticing possi-
bilities that blocking the TSHR with K1-70, a novel
TSHR antagonist, could be an effective treatment for
TED and may have additional therapeutic potential
in Graves’ disease and DTC, as well as for other
patients who would benefit from blocking TSHR
activity. Phase 1 trial results of this monoclonal
antibody are eagerly awaited.
 Clinical THYROIDOLOGY
®

ISSN: 2329-9711 | OCTOBER 2021 | VOLUME 33 | ISSUE 10

THYROID AUTOIMMUNITY K1-70 — A Thyrotropin Receptor Matthew I. Balcerek and

Antagonist with Therapeutic Potential in Graves’ Disease, Donald S. A. McLeod
Thyroid Eye Disease, and Differentiated Thyroid Cancer

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436   l  © 2021 American Thyroid Association