Immune-Mediated Liver Effects Associated With Administration of a Human Anti-IL-21 Receptor Antibody (ATR-107) in Rats.

Autor:	Hu W; Pfizer Inc., San Diego, California, USA.; Vividion Therapeutics, San Diego, California, USA., Buetow BS; Pfizer Inc., San Diego, California, USA., Sachdeva K; Wyeth, Chazy, New York, USA., Leach MW; Pfizer Inc., Cambridge, Massachusetts, USA.; Trident Toxicology, Inc., Shrewsbury, Massachusetts, USA.
Jazyk:	angličtina
Zdroj:	Toxicologic pathology [Toxicol Pathol] 2024 Jul; Vol. 52 (5), pp. 232-250. Date of Electronic Publication: 2024 Jul 25.
DOI:	10.1177/01926233241259011
Abstrakt:	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. Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: All authors have been employed by Wyeth and/or Pfizer. Wenyue Hu is currently an employee of Vividion Therapeutics, Karuna Sachdeva is currently an employee of Jazz Pharmaceuticals, and Michael Leach is currently an employee of Trident Toxicology, Inc. Bernard Buetow is currently employed by Pfizer. The authors declare no other potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Databáze:	MEDLINE
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