Abstract
BackgroundThe 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.MethodsThe 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.ResultsLow 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.ConclusionsThe 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.
Highlights
K1-70TM is a high affinity human monoclonal autoantibody to the thyroid stimulating hormone (TSH) receptor (TSHR) with the ability to block TSH receptor (TSHR) stimulation by TSH or TSHR stimulating autoantibodies [1,2,3].K1-70TM was isolated from the peripheral lymphocytes of a patient with a history of autoimmune thyroid disease and as such represents a “natural” inhibitor of TSHR stimulation [1,2,3]
Targeting of the TSHR with K1-70TM may provide new therapeutic strategies for the management of patients with Graves’ disease, patients with Graves’ ophthalmopathy, patients with thyroid cancer and other patients who would benefit from controlling TSHR activity [10,11,12,13,14,15]
Rat toxicology There were no unscheduled deaths; no clinical, post dose, or injection site observations; and no ophthalmic findings considered to be related to infusion or injection of K1-70TM
Summary
K1-70TM is a high affinity human monoclonal autoantibody to the TSH receptor (TSHR) with the ability to block TSHR stimulation by TSH or TSHR stimulating autoantibodies [1,2,3].K1-70TM was isolated from the peripheral lymphocytes of a patient with a history of autoimmune thyroid disease and as such represents a “natural” inhibitor of TSHR stimulation [1,2,3]. K1-70TM is a high affinity human monoclonal autoantibody to the TSH receptor (TSHR) with the ability to block TSHR stimulation by TSH or TSHR stimulating autoantibodies [1,2,3]. The currently available options for the management of thyroid over activity in Graves’ disease include anti-thyroid drugs, surgery or radioiodine ablation that are effective in the majority but not all of the patients [4,5,6]. There are limited specific therapies currently available for the management of Graves’ ophthalmopathy [7,8,9]. The human monoclonal autoantibody K1-70TM binds to the TSH receptor (TSHR) with high affinity and blocks TSHR cyclic AMP stimulation by TSH and thyroid stimulating autoantibodies
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
