In vivo effects of a human thyroid-stimulating monoclonal autoantibody (M22) and a human thyroid-blocking autoantibody (K1-70)

Furmaniak, Jadwiga; Sanders, Jane; Young, Stuart; Kabelis, Katarzyna; Sanders, Paul G.; Evans, Michele K.; Clark, J. C. D.; Wilmot, Jane; Smith, Bernard Rees

doi:10.1007/s13317-011-0025-9

Cited by 38 publications

(43 citation statements)

References 24 publications

(41 reference statements)

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“…The monoclonal TSAbs derived from experimental models of Graves' disease have been shown to be pathogenic in vivo, confirming their role in disease pathogenesis (8)(9)(10). Importantly, human monoclonal TSAbs from patients with Graves' disease have also been derived, providing detail into their molecular and biochemical properties, and pathogenicity in vivo (11)(12)(13). A major advance has been the delineation of the atomic structures of immune complex of human monoclonal TSAb, M22 and human monoclonal TSBAb, and K1-70 with human TSHR A-subunit (14)(15)(16).…”

mentioning

confidence: 72%

Yersinia enterocolitica Provides the Link between Thyroid-Stimulating Antibodies and Their Germline Counterparts in Graves’ Disease

Hargreaves

Grasso

Hampe

et al. 2013

The Journal of Immunology

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Graves’ disease results from thyroid-stimulating Abs (TSAbs) activating the thyrotropin receptor (TSHR). How TSAbs arise from early precursor B cells has not been established. Genetic and environmental factors may contribute to pathogenesis, including the bacterium Yersinia enterocolitica. We developed two pathogenic monoclonal TSAbs from a single experimental mouse undergoing Graves’ disease, which shared the same H and L chain germline gene rearrangements and then diversified by numerous somatic hypermutations. To address the Ag specificity of the shared germline precursor of the monoclonal TSAbs, we prepared rFab germline, which showed negligible binding to TSHR, indicating importance of somatic hypermutation in acquiring TSAb activity. Using rFab chimeras, we demonstrate the dominant role of the H chain V region in TSHR recognition. The role of microbial Ags was tested with Y. enterocolitica proteins. The monoclonal TSAbs recognize 37-kDa envelope proteins, also recognized by rFab germline. MALDI-TOF identified the proteins as outer membrane porin (Omp) A and OmpC. Using recombinant OmpA, OmpC, and related OmpF, we demonstrate cross-reactivity of monoclonal TSAbs with the heterogeneous porins. Importantly, rFab germline binds recombinant OmpA, OmpC, and OmpF confirming reactivity with Y. enterocolitica. A human monoclonal TSAb, M22 with similar properties to murine TSAbs, also binds recombinant porins, showing cross-reactivity of a spontaneously arising pathogenic Ab with Y. enterocolitica. The data provide a mechanistic framework for molecular mimicry in Graves’ disease, where early precursor B cells are expanded by Y. enterocolitica porins to undergo somatic hypermutation to acquire a cross-reactive pathogenic response to TSHR.

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mentioning

confidence: 72%

Yersinia enterocolitica Provides the Link between Thyroid-Stimulating Antibodies and Their Germline Counterparts in Graves’ Disease

Hargreaves

Grasso

Hampe

et al. 2013

The Journal of Immunology

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“…From the maximum 145 mg HED from the rat toxicology study data the maximum systemic exposure to K1-70 ™ for the first in human study was determined at C max of 0.031 mg/mL. Furthermore, a starting dose of K1-70 ™ for human studies was calculated based upon Food and Drug Administration (FDA) guidance [37] using in vivo effects of IM injections of K1-70 ™ on thyroid hormone production in rats made hyperthyroid with M22 ™ [17]. Dose dependent suppression of thyroid activity was observed following IM doses of 50 to 200 µg K1-70 ™ , with no significant effects observed at doses of 4 and 10 µg K1-70 ™ .…”

Section: Discussionmentioning

confidence: 99%

“…Preliminary in vivo studies have demonstrated that administration of K1-70 ™ causes biochemical hypothyroidism in untreated rats and in rats made hyperthyroid with the thyroid stimulating human monoclonal autoantibody M22 [16][17][18]. The decreases in thyroid hormone levels post K1-70 ™ were associated with thyroid follicular Open Access Furmaniak et al Autoimmun Highlights (2019) 10:11 cell atrophy and enlarged thyroid follicles filled with colloid, consistent with hypothyroidism [17,18].…”

Section: Introductionmentioning

confidence: 99%

Preclinical studies on the toxicology, pharmacokinetics and safety of K1-70TM a human monoclonal autoantibody to the TSH receptor with TSH antagonist activity

Furmaniak¹,

Sanders²,

Clark³

et al. 2019

Autoimmun Highlights

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Background: The human monoclonal autoantibody K1-70 ™ binds to the TSH receptor (TSHR) with high affinity and blocks TSHR cyclic AMP stimulation by TSH and thyroid stimulating autoantibodies. Methods:The preclinical toxicology assessment following weekly intravenous (IV) or intramuscular (IM) administration of K1-70 ™ in rats and cynomolgus monkeys for 29 days was carried out. An assessment of delayed onset toxicity and/or reversibility of toxicity was made during a further 4 week treatment free period. The pharmacokinetic parameters of K1-70 ™ and the effects of different doses of K1-70 ™ on serum thyroid hormone levels in the study animals were determined in rats and primates after IV and IM administration.Results: Low serum levels of T3 and T4 associated with markedly elevated levels of TSH were observed in the study animals following IV and IM administration of K1-70 ™ . The toxicological findings were attributed to the pharmacology of K1-70 ™ and were consistent with the hypothyroid state. The no observable adverse effect level (NOAEL) could not be established in the rat study while in the primate study it was 100 mg/kg/dose for both males and females. Conclusions:The toxicology, pharmacodynamic and pharmacokinetic data in this preclinical study were helpful in designing the first in human study with K1-70 ™ administered to subjects with Graves' disease. which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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“…Among other small molecules are those that can block thyroid-stimulating immunoglobulin actions in vitro and can also exert inhibition in vivo in small animal models (84,85). Besides small molecules, several anti-TSHR antibodies have shown receptor-blocking activities (44,86,87). Included among these are inverse agonists, which inhibit constitutive TSHR activities (88).…”

Section: Tshr As a Therapeutic Target In Gdmentioning

confidence: 99%

“…These include IL-1β, IL-6 and TNF-α (40,41,42). They can undergo differentiation into adipocytes, myofibroblasts, chondrocytes and osteoblasts, depending on molecular environment surrounding them within tissues (43,44). Several factors have been shown to influence fibrocyte differentiation; Th1 cytokines and lumican enhance while Th2 cytokines (45,46), Slit2 (47) and serum amyloid P (48) inhibit this process.…”

Section: Introductionmentioning

confidence: 99%

Will biological agents supplant systemic glucocorticoids as the first-line treatment for thyroid-associated ophthalmopathy?

Smith

Bartalena

2019

European Journal of Endocrinology

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In this article, the two authors present their opposing points of view concerning the likelihood that glucocorticoids will be replaced by newly developed biological agents in the treatment of active, moderate-to-severe thyroid-associated ophthalmopathy (TAO). TAO is a vexing, disfiguring and potentially blinding autoimmune manifestation of thyroid autoimmunity. One author expresses the opinion that steroids are nonspecific, frequently fail to improve the disease and can cause sometimes serious side effects. He suggests that glucocorticoids should be replaced as soon as possible by more specific and safer drugs, once they become available. The most promising of these are biological agents. The other author argues that glucocorticoids are proven effective and are unlikely to be replaced by biologicals. He reasons that while they may not uniformly result in optimal benefit, they have been proven effective in many reports. He remains open minded about alternative therapies such as biologicals but remains skeptical that they will replace steroids as the first-line therapy for active, moderate-to-severe TAO without head-to-head comparative clinical trials demonstrating superiority. Despite these very different points of view, both authors are optimistic about the availability of improved medical therapies for TAO, either as single agents or in combination. Further, both agree that better treatment options are needed to improve the care of our patients with active moderate-to-severe TAO.

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In vivo effects of a human thyroid-stimulating monoclonal autoantibody (M22) and a human thyroid-blocking autoantibody (K1-70)

Cited by 38 publications

References 24 publications

Yersinia enterocolitica Provides the Link between Thyroid-Stimulating Antibodies and Their Germline Counterparts in Graves’ Disease

Yersinia enterocolitica Provides the Link between Thyroid-Stimulating Antibodies and Their Germline Counterparts in Graves’ Disease

Preclinical studies on the toxicology, pharmacokinetics and safety of K1-70TM a human monoclonal autoantibody to the TSH receptor with TSH antagonist activity

Will biological agents supplant systemic glucocorticoids as the first-line treatment for thyroid-associated ophthalmopathy?

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