MON-724 Effect Of CDD866, An Anti-activin Type II Receptor Antibody, On The Melanocortin 3 Receptor (MC3R) Deficiency Obesity Phenotype

Abstract Disclosure: E.A. Jansujwicz: None. T.P. Patel: None. D.M. Elizondo: None. B.T. Cole: None. J.A. Yanovski: Versanis Bio, Inc (CRADA). The melanocortin 3 receptor (MC3R) plays an important role in energy homeostasis. Mice with global MC3R deficiency (MC3RTB/TB) exhibit increased fat mass and reduced lean mass relative to wild-type mice (MC3R+/+). Bimagrumab (BYM338) is a humanized monoclonal antibody that binds to the activin type II receptor (ActRII) and inhibits its signal transduction, thus reducing negative regulation of skeletal muscle growth due to activin and/or myostatin. Bimagrumab has been shown to increase lean mass in adults, and CDD866, an anti-mouse ActRII antibody that blocks murine ActRII signal transduction, increases lean mass in wild-type mice. Therefore, we hypothesized that treatment with CDD866 would be particularly effective at improving body composition and glucose tolerance in MC3RTB/TB mice. Male and female MC3R+/+ and MC3RTB/TB mice were treated with intraperitoneal injections (20 mg/kg b.w.) of an IgG1 isotype control or CDD866 antibody weekly for four weeks starting at 10 weeks of age. Dual-energy X-ray absorptiometry (DEXA) scans were performed before and after treatment, body weight was monitored weekly, and post-treatment glucose and insulin tolerance tests were performed. CDD866 led to increased total body weight in MC3R+/+ females, with trends toward increased body weight in MC3R+/+ males, MC3RTB/TB males, and MC3RTB/TB females. Lean mass increased significantly in all groups relative to isotype control, with comparable changes in both MC3R+/+ and MC3RTB/TB mice. There were no significant group differences in percent fat mass or glucose and insulin tolerance, with trends toward increased fat mass and worsening glucose and insulin tolerance, following CDD866 administration. We conclude that the murine ActRII blocking antibody CDD866 increases lean mass in mice with MC3R deficiency but does not improve overall body composition or glucose homeostasis, suggesting that MC3R deficiency, and the associated dysregulation of fat and lean mass, is unlikely to be related to unduly increased ActRII activation. Presentation: Monday, July 14, 2025