Abstract：
The toxicity of ATR-107, a human anti-interleukin-21 receptor (IL-21R) monoclonal antibody (mAb), was evaluated in CD-1 mice and cynomolgus monkeys after single-dose intravenous (IV) administration, and in Sprague-Dawley (SD) rats and cynomolgus monkeys after weekly IV and subcutaneous (SC) administration in 13-week toxicity studies that included recovery. Adverse liver necrosis, diffuse bridging fibrosis, and higher liver enzymes occurred in rats in the low-dose IV group (10 mg/kg), but not at 50 or 250 mg/kg IV, and not following SC administration despite overlapping systemic ATR-107 exposures. Similar findings were not seen in mice or cynomolgus monkeys. A series of investigative rat toxicity studies showed liver findings only occurred after administration of at least 3 weekly doses, only occurred in rats that developed anti-drug antibodies (ADAs), and the incidence was associated with higher ADAs titers. However, the presence of ADAs did not always result in liver injury. Liver findings did not occur in nude rats, which had high ATR-107 exposures and no ADAs. These findings suggest an adaptive immune response with formation of ADAs was necessary for development of ATR-107-related liver findings, and that liver injury can occur in rats secondary to development of ADAs following repeated administration of a human therapeutic mAb.
摘要：
人抗白细胞介素21受体（IL-21R）单克隆抗体（mAb）ATR-107的毒性，在单剂量静脉内（IV）给药后，在CD-1小鼠和食蟹猴中进行了评估，在为期13周的毒性研究中，每周IV和皮下（SC）给药后，以及Sprague-Dawley（SD）大鼠和食蟹猴。不良肝坏死，弥漫性桥接纤维化，低剂量IV组（10mg/kg）大鼠肝酶升高，但不是在50或250毫克/千克的静脉注射，尽管全身性ATR-107暴露重叠，但SC给药后未出现。在小鼠或食蟹猴中没有看到类似的发现。一系列调查性大鼠毒性研究表明，肝脏发现仅发生在至少3周剂量给药后，仅发生在产生抗药物抗体（ADAs）的大鼠中，发病率与较高的ADAs滴度相关。然而,ADAs的存在并不总是导致肝损伤。在裸大鼠中没有发现肝脏，ATR-107暴露率高，没有ADAs。这些发现表明，随着ADAs的形成，适应性免疫反应对于ATR-107相关肝脏的发展是必要的。并且在反复施用人治疗性mAb后，在ADAs发育的大鼠中可能发生肝损伤。
