K1-70 — A Thyrotropin Receptor Antagonist with Therapeutic Potential

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K1-70 — A Thyrotropin Receptor Antagonist with Therapeutic Potential

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K1-70 — A Thyrotropin Receptor Antagonist with Therapeutic Potential in Graves' Disease, Thyroid Eye Disease, and Differentiated Thyroid Cancer

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 (stimulating) activity. Rarely, patients may develop hypothyroidism 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 adenopathy. 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 thyrotropin-stimulated 123I whole-body scan demonstrated 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 influenced 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 response; however, its use was limited by drug-related toxicity (4). Her case was reviewed by a multispecialty tumor board, who recommended a trial of K1-70 in combination with systemic antineoplastic therapies. A single-patient expanded-access application was granted by the U.S. Food and Drug Administration (4).

Results
The first intramuscular dose of K1-70 was administered 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 resolution 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.

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 quality-of-life scores. During this time, serum thyroglobulin 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 progression, lenvatanib was changed to pazopanib in January 2019 (during which time K1-70 was continued), with stable structural disease and reduction in serum thyroglobulin from 5737 ng/ml to 694 ng/ml by June 2019. The patient died in July 2019 from acute cardiopulmonary 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.

COMMENTARY
This case report highlights the potential therapeutic uses of K1-70. Current options for the management 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 TSAb activity and inducing hypothyroidism (3). Obvious therapeutic uses could be for rapid restoration 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 possibility of dose titration strategies akin to current antithyroid 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 therapeutic options are currently available. Novel targeted therapies have been developed, most notably teprotumumab. Teprotumumab's efficacy appears to exceed that of other first- and second-line therapeutic 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. K1-70 was also used in this patient as a bridge to corrective orbital surgery, enabling complete resolution 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 administration of K1-70, the growth of some FTC foci was reported to stall during a period of lenvatanib withdrawal. 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 antineoplastic therapies for patients with progressive DTC (particularly 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 possibilities 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.

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Copyright 2021 American Thyroid Association, Inc.

To cite this article:
Matthew I. Balcerek and Donald S. A. McLeod.Clinical Thyroidology.Oct 2021.433-436.http://doi.org/10.1089/ct.2021;33.433-436
Published in Volume: 33 Issue 10: October 7, 2021
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