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

Abstract

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 < 0.005) in a dose-dependent manner and blocked RET phosphorylation up to 87% (P = 0.0593), AKT phosphorylation up to 28% (P = 0.0593) and extracellular signal regulatory kinase phosphorylation up to 75% (P = 0.0636). A11 inhibited the action of cisplatin-induced GDF15 on the brainstem and decreased GFRAL-positive neuron population expressing c-Fos in the area postrema and nucleus of the solitary tract by 62% in vivo (P < 0.05). In a melanoma mouse model treated with cisplatin, A11 recovered anorexia by 21% (P < 0.05) and tumour-free body weight loss by 13% (P < 0.05). A11 significantly improved the cisplatin-induced loss of skeletal muscles (quadriceps: 21%, gastrocnemius: 9%, soleus: 13%, P < 0.05) and adipose tissues (epididymal white adipose tissue: 37%, inguinal white adipose tissue: 51%, P < 0.05). Conclusions Our study suggests that GFRAL antagonist antibody may alleviate chemotherapy-induced cachexia, providing a novel therapeutic approach for patients with cancer experiencing chemotherapy-induced cachexia.

Phase 2 study of the efficacy and safety of ponsegromab in patients with cancer cachexia: PROACC‐1 study design

“…Preliminary phase 1b data suggest that suppression of GDF‐15 with ponsegromab may lead to improvement in cachexia‐related symptom burden, building on promising preclinical observations in animal tumour models where neutralization of GDF‐15 reverses anorexia and weight loss and improves muscle function and survival. 8 , 18 , 19 , 22 Furthermore, given the observations of GDF‐15 elevation with platinum‐based chemotherapy, 8 patients who receive standard‐of‐care antitumor treatment that includes systemic platinum‐based therapy may represent a specific population that could potentially garner greater benefit from GDF‐15 inhibition. Given the lack of established drug therapies for cancer cachexia, the design, implementation and analysis of the PROACC‐1 study will evaluate the potential role of ponsegromab in patients with cancer, cachexia and elevated concentrations of GDF‐15 and will help inform whether larger scale pivotal trials testing ponsegromab are warranted.…”

“…The aim of this study is to support the clinical development of ponsegromab as a novel inhibitor of GDF‐15‐mediated signalling and potential therapy for cancer cachexia. Preliminary phase 1b data suggest that suppression of GDF‐15 with ponsegromab may lead to improvement in cachexia‐related symptom burden, building on promising preclinical observations in animal tumour models where neutralization of GDF‐15 reverses anorexia and weight loss and improves muscle function and survival 8,18,19,22 . Furthermore, given the observations of GDF‐15 elevation with platinum‐based chemotherapy, 8 patients who receive standard‐of‐care antitumor treatment that includes systemic platinum‐based therapy may represent a specific population that could potentially garner greater benefit from GDF‐15 inhibition.…”

“…In a variety of human and mouse GDF‐15 secreting tumour models, tumour implantation caused an increase in circulating GDF‐15 levels, resulting in a decline in body weight (fat and skeletal muscle lean mass), food intake, skeletal muscle strength (force generation), physical activity (home cage locomotion and voluntary wheel running), exercise tolerance (treadmill running) and survival in animals, which were all reversed by GDF‐15/GFRAL neutralizing antibodies, including ponsegromab. 8 , 17 , 18 , 19 When co‐administered with the chemotherapy agent cisplatin, ponsegromab reversed both tumour and cisplatin‐driven body weight loss without interfering with the cisplatin antitumor effect in mice. 8 Ponsegromab also mitigated cisplatin‐induced emesis and anorexia in monkeys.…”