Abstract 1867: LBL-049: A novel neutralizing antibody against GDF15 for the treatment of cachexia

Abstract Background: Cachexia is a disorder characterized by loss of body weight with specific losses of skeletal muscle and adipose tissue and occurs in the progression of many diseases, especially in cancer. Growth differentiation factor 15 (GDF15) belongs to the transforming growth factor β (TGFβ) superfamily. GDF15 can bind to the glial cell-derived neurotrophic factor (GDNF) family receptor α-like (GFRAL) protein, which is primarily expressed in the hindbrain. This interaction activates the GFRAL-RET signaling pathway, which transmits anorectic neural signals, leading to weight loss, affecting fat and muscle degradation, and inducing cachexia. Anti-GDF-15/GFRAL antibodies have the potential to reverse this response, making them vital therapeutic targets for cachexia. Herein, a novel humanized GDF-15 neutralizing antibody (LBL-049) was developed with higher efficacy and better specificity than ponsegromab, the same target antibody from Pfizer, in pre-clinical studies. Methods: LBL-049 was generated from mouse hybridoma, humanized by CDR grafting, the Fc region was further engineered to silence Fc effector. The binding affinity and specificity were detected by Fortebio and ELISA respectively. The function of blocking GDF15/GFRAL/RET signaling was examined in the reporter-gene cell assays. The in vivo efficacy of restoring cachexia was demonstrated in both tumor-induced and cisplatin-induced mouse cachexia models, in which preliminary pharmacokinetics (PK) and pharmacodynamics (PD) studies were also conducted. And a single-dose PK study was conducted in rats. Results: LBL-049 had high binding affinities to both human and cynomolgus GDF-15 proteins with high specificity, did not bind with other TGF family members as compared with ponsegromab. In reporter-gene cell assays, LBL-049 blocked GDF15/GFRAL signaling more potently than ponsegromab. In HT1080 tumor-induced or cisplatin-induced mouse cachexia model, LBL-049 prevented weight loss by neutralizing circulating GDF-15 in a dose dependent manner, at low dose of 1 mpk in HT1080 cachexia model, LBL-049 was more efficacious than ponsegromab to restore the body weight loss. The PK profile was excellent after single dosing of LBL-049 in rats. LBL-049 also showed good developability, i.e., low viscosity and good stability. Conclusion: LBL-049, a novel GDF15 neutralizing antibody with high affinity and specificity, showed great potency to inhibit GDF15/GFRAL/RET signaling in vitro and prevent weight loss in various mouse cachexia models, which are encouraging for future development for the treatment of cachexia. Citation Format: Baohui Wang, Xiao Huang, Mi Ding, Jing Huang, Yurong Qin, Fengxia Li, Jing Guan, Jianming Sun, Guojin Wu, Xiaoxiao Liu, Jordan Zhu, Shoupeng Lai, Xiaoqiang Kang, Hong Ling. LBL-049: A novel neutralizing antibody against GDF15 for the treatment of cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1867.