GDNF family receptor alpha‐like antagonist antibody alleviates chemotherapy‐induced cachexia in melanoma‐bearing mice

Background Patients with cancer undergoing chemotherapy experience cachexia with anorexia, body weight loss, and the depletion of skeletal muscles and adipose tissues. Effective treatment strategies for chemotherapy‐induced cachexia are scarce. The growth differentiation factor 15 (GDF15)/GDNF family receptor alpha‐like (GFRAL)/rearranged during transfection (RET) axis is a critical signalling pathway in chemotherapy‐induced cachexia. In this study, we developed a fully human GFRAL antagonist antibody and investigated whether it inhibits the GDF15/GFRAL/RET axis, thereby alleviating chemotherapy‐induced cachexia in tumour‐bearing mice. Methods Anti‐GFRAL antibodies were selected via biopanning, using a human combinatorial antibody phage library. The potent GFRAL antagonist antibody A11 was selected via a reporter cell assay and its inhibitory activity of GDF15‐induced signalling was evaluated using western blotting. To investigate the in vivo function of A11, a tumour‐bearing mouse model was established by inoculating 8‐week‐old male C57BL/6 mice with B16F10 cells (n = 10–16 mice per group). A11 was administered subcutaneously (10 mg/kg) 1 day before intraperitoneal treatment with cisplatin (10 mg/kg). Animals were assessed for changes in food intake, body weight, and tumour volume. Plasma and key metabolic tissues such as skeletal muscles and adipose tissues were collected for protein and mRNA expression analysis. Results A11 reduced serum response element‐luciferase reporter activity up to 74% (P