861-P: Targeting Activin Type II Receptors—Develop Monoclonal Antibodies LAE102, LAE103, and LAE123 as Candidate Therapeutics for Muscle Growth and Fat Reduction

Introduction and Objective: Ligands of the TGF-β superfamily including myostatin, activins, and GDFs, are known to negatively regulate skeletal muscle mass and lipolysis via Activin Type II receptors (ActRII) signaling. This study aims to investigate the effects of ActRII receptor antagonist antibodies on promoting muscle growth and fat reduction. Methods: We have developed three monoclonal antibodies: LAE102, specific to ActRIIA; LAE103, specific to ActRIIB; and LAE123, bi-specific to both ActRIIA and ActRIIB. The roles of ActRIIA and ActRIIB signaling in skeletal muscle and adipose tissue are being investigated using cell-based functional assays, lean mouse, and diet-induced obesity mouse models. Results: LAE102, LAE103, and LAE123 are high-affinity functional antagonists. They can completely inhibit the signaling transduced by ligands such as activin A, B, AB, and myostatin, all of which are known to contribute to muscle atrophy. In addition, they also inhibit activin E and GDF3, which promote lipid accumulation. In mouse models, LAE102 alone significantly induced muscle growth and reduced fat mass, while LAE103 had much less effect. Notably, a synergistic effect on muscle increase and fat loss was observed when combining LAE102 with LAE103, achieving the maximal effect comparable to the bi-specific antibody LAE123. Conclusion: The findings indicate that ActRIIA is a major regulator of muscle growth and fat loss. LAE102 shows great potential as muscle preserving weight loss management with a favorable safety profile. On the other hand, LAE123 could be utilized to treat diseases requiring completely inhibition of both ActRIIA and ActRIIB, such as spinal muscle atrophy. Disclosure R. Zhang: None. M. Yang: None. J. Gu: None. M. Hu: None. J. Chen: None. W.A. Li: None. L. Xiaofen: None. X. Zhang: None. C. Lu: None.