Furmaniak Jadwiga, Sanders Jane, Clark Jill, Wilmot Jane, Sanders Paul, Li Yang, Rees Smith Bernard
AV7 Limited, FIRS Laboratories, Parc Ty Glas, Llanishen, Cardiff, CF14 5DU UK.
Auto Immun Highlights. 2019 Nov 7;10(1):11. doi: 10.1186/s13317-019-0121-9. eCollection 2019 Dec.
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.
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.
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.
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.
人源单克隆自身抗体K1-70™以高亲和力结合促甲状腺激素受体（TSHR），并阻断TSH和甲状腺刺激性自身抗体对TSHR环磷酸腺苷的刺激作用。
在大鼠和食蟹猴中进行了为期29天的每周一次静脉注射（IV）或肌肉注射（IM）K1-70™的临床前毒理学评估。在另外4周的无治疗期内评估毒性的延迟发作和/或可逆性。在大鼠和灵长类动物静脉注射和肌肉注射后，测定了K1-70™的药代动力学参数以及不同剂量的K1-70™对研究动物血清甲状腺激素水平的影响。
在静脉注射和肌肉注射K1-70™后，研究动物中观察到血清T3和T4水平较低，同时TSH水平显著升高。毒理学结果归因于K1-70™的药理作用，与甲状腺功能减退状态一致。在大鼠研究中无法确定无观察到不良作用水平（NOAEL），而在灵长类动物研究中，雄性和雌性的NOAEL均为100mg/kg/剂量。
这项临床前研究中的毒理学、药效学和药代动力学数据有助于设计针对Graves病患者的K1-70™首次人体研究。
