LAUSR

Acetaminophen (N-acetyl-p-aminophenol; APAP) overdose is a common cause of drug-induced acute liver injury, thereby making APAP administration a frequently used experimental model due to its highly reproducible and dose-dependent hepatoxicity. APAP-induced liver injury (AILI) mouse models exhibited upregulated IL11 expression, indicating that targeting IL11 or its cognate receptor, IL11RA, could have therapeutic potential. To evaluate the in vivo efficacy of anti-human IL11RA antibodies in AILI mouse models, we first generated a human IL11RA knock-in mouse model (B-hIL11RA), in which human IL11RA replaced murine Il11ra, in situ. Human IL11RA mRNA and protein levels were detected in B-hIL11RA mice. We next examined whether therapeutic inhibition of IL11 signaling was effective in reducing AILI following administration of an anti-human IL11RA antibody. In vivo efficacy data showed that anti-human IL11RA antibody inhibited all aspects of AILI, including hepatocyte death (ALT, AST and TUNEL) and centrilobular necrosis. These data suggest that B-hIL11RA mice are an effective tool for preclinical in vivo efficacy evaluation of therapeutic anti-human IL11RA antibodies. Citation Format: Fang He, Rufeng Zhang, Mari Kuraguchi, Lei Zhao, Zhaoxue Yu. In vivo efficacy of an anti-human IL11RA antibody in B-hIL11RA mice with APAP-induced liver damage. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3993.