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

Authors
  • Furmaniak, Jadwiga1
  • Sanders, Jane1
  • Clark, Jill1
  • Wilmot, Jane1
  • Sanders, Paul1
  • Li, Yang1
  • Rees Smith, Bernard1
  • 1 AV7 Limited, FIRS Laboratories, Parc Ty Glas, Llanishen, Cardiff, CF14 5DU, UK , Cardiff (United Kingdom)
Type
Published Article
Journal
Autoimmunity Highlights
Publisher
BioMed Central
Publication Date
Nov 07, 2019
Volume
10
Issue
1
Identifiers
DOI: 10.1186/s13317-019-0121-9
Source
Springer Nature
Keywords
License
Green

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.

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