Antigen-Specific Immunotherapy with Thyrotropin Receptor Peptides in Graves' Hyperthyroidism: A Phase I Study

Pearce, Simon H. S.; Dayan, Colin; Wraith, David C.; Barrell, Kevin; Olive, Natalie; Jansson, Liselotte; Walker-Smith, Terrie; Carnegie, C.; Martin, Keith F.; Boelaert, Kristien; Gilbert, Jackie; Higham, Claire; Muller, Ilaria; Murray, Robert; Perros, Petros; Razvi, Salman; Vaidya, Bijay; Wernig, Florian; Kahaly, George J.

doi:10.1089/thy.2019.0036

Cited by 74 publications

(77 citation statements)

References 33 publications

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“…These were administered to HLA-DR3 transgenic mice that had been primed for hyperthyroidism by TSHR cDNA immunization, and the TSHR peptide-pretreated mice showed a profound reduction in induced TRAbs and lower thyroid hormone levels ( 88 ). In a phase 1 study, this TSHR peptide mixture, termed ATX-GD-59, was then administered every 2 weeks subcutaneously to patients with treatment-naïve Graves’ hyperthyroidism, leading to normalization of hyperthyroidism in 5 of 10 patients and improvement in 7 of 10 ( 22 ). TRAb levels improved in line with reducing thyroid hormone levels.…”

Section: Novel Therapeutic Strategiesmentioning

confidence: 99%

New Therapeutic Horizons for Graves’ Hyperthyroidism

et al. 2020

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Graves’ hyperthyroidism is characterised by the presence of autoantibodies that stimulate the thyroid stimulating hormone receptor (TSHR), resulting in uncontrolled secretion of excessive thyroid hormone. Conventional treatments including antithyroid medication, radioiodine or surgery have remained largely unchanged for the past 70 years and either lack efficacy for many patients, or result in lifelong thyroid hormone replacement therapy in the case of the latter two options. The demand for new therapeutic options combined with greater insight into basic immunobiology, has led to the emergence of novel approaches to treat Graves’ hyperthyroidism. The current therapies under investigation include biologics, small-molecules and peptide immunomodulation. There is a growing focus on TSHR-specific treatment modalities, which carry the advantage of eliciting a specific, targeted approach, with the aim of avoiding disruption of the functioning immune system. These therapies offer the new opportunity to supersede the inadequate treatments currently available for some Graves’ patients, with the hope of successful restoration of euthyroidism without the need for ongoing therapy. Several of these therapeutic options have the potential to translate into clinical practice in the near future. This review provides a comprehensive summary of the recent advances and various stages of development of the novel therapeutic approaches to treat Graves’ hyperthyroidism.

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Section: Novel Therapeutic Strategiesmentioning

confidence: 99%

New Therapeutic Horizons for Graves’ Hyperthyroidism

et al. 2020

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“…TRAb K1-70 has antagonist activity and can be useful in the inhibition of stimulating TRAb in GD patients [81]. ATX-GD-59 is an apitope that decreases the production of stimulating TRAb and demonstrates potential for the prevention and treatment of GO [82]. Apitopes—antigen processing independent epitopes—mimic naturally processed CD4+ T-cell epitopes.…”

Section: Putative Autoantigens and Potential Treatmentmentioning

confidence: 99%

Immunological Aspects of Graves’ Ophthalmopathy

Łacheta

Miśkiewicz

Głuszko

et al. 2019

BioMed Research International

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The body's autoimmune process is involved in the development of Graves' disease (GD), which is manifested by an overactive thyroid gland. In some patients, autoreactive inflammatory reactions contribute to the development of symptoms such as thyroid ophthalmopathy, and the subsequent signs and symptoms are derived from the expansion of orbital adipose tissue and edema of extraocular muscles within the orbit. The autoimmune process, production of antibodies against self-antigens such as TSH receptor (TSHR) and IGF-1 receptor (IGF-1R), inflammatory infiltration, and accumulation of glycosaminoglycans (GAG) lead to edematous-infiltrative changes in periocular tissues. As a consequence, edema exophthalmos develops. Orbital fibroblasts seem to play a crucial role in orbital inflammation, tissue expansion, remodeling, and fibrosis because of their proliferative activity as well as their capacity to differentiate into adipocytes and myofibroblasts and production of GAG. In this paper, based on the available medical literature, the immunological mechanism of GO pathogenesis has been summarized. Particular attention was paid to the role of orbital fibroblasts and putative autoantigens. A deeper understanding of the pathomechanism of the disease and the involvement of immunological processes may give rise to the introduction of new, effective, and safe methods of treatment or monitoring of the disease activity.

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“…Levels of free thyroid hormones decreased in 70% of subjects receiving the medication and ATX-GD-59 was safe and well tolerated. Further studies are needed for this novel treatment rational for Graves' hyperthyroidism [41].…”

Section: Treatment Studies With In Vivo Models Of Go-translation Intomentioning

confidence: 99%

Lessons from mouse models of Graves’ disease

et al. 2020

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Graves' disease (GD) is an autoimmune condition with the appearance of anti-TSH receptor (TSHR) autoantibodies in the serum. The consequence is the development of hyperthyroidism in most of the patients. In addition, in the most severe cases, patients can develop orbitopathy (GO), achropachy and dermopathy. The central role of the TSHR for the disease pathology has been well accepted. Therefore immunization against the TSHR is pivotal for the creation of in vivo models for the disease. However, TSHR is well preserved among the species and therefore the immune system is highly tolerant. Many differing attempts have been performed to break tolerance and to create a proper animal model in the last decades. The most successful have been achieved by introducing the human TSHR extracellular domain into the body, either by injection of plasmid or adenoviruses. Currently available models develop the whole spectrum of Graves' disease-autoimmune thyroid disease and orbitopathy and are suitable to study disease pathogenesis and to perform treatment studies. In recent publications new immunomodulatory therapies have been assessed and also diseaseprevention by inducing tolerance using small cyclic peptides from the antigenic region of the extracellular subunit of the TSHR.

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Antigen-Specific Immunotherapy with Thyrotropin Receptor Peptides in Graves' Hyperthyroidism: A Phase I Study

Cited by 74 publications

References 33 publications

New Therapeutic Horizons for Graves’ Hyperthyroidism

New Therapeutic Horizons for Graves’ Hyperthyroidism

Immunological Aspects of Graves’ Ophthalmopathy

Lessons from mouse models of Graves’ disease

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