Growth differentiation factor 1 5 (GDF15), also known as macrophage inhibitory cytokine 1 (MIC1), is a diverse member of the transforming growth factor (TGF-β) superfamily. It is a multifunctional cytokine and a promising target for the treatment of obesity. GDF15 is a stress-responsive cytokine whose expression levels surge in response to various cellular stress signals, such as inflammation, hypoxia, tissue damage, myocardial ischemia, and various malignancies. Elevated levels of circulating GDF15 have been reported in several cancers, including prostate, pancreatic, endometrial, and colorectal cancers.
Expression distribution of GDF15
GDF15 is mainly expressed in trophoblast cells, and is also expressed in glandular epithelial cells, squamous epithelial cells, specialized epithelial cells, and endocrine cells.
(Data source: uniprot)
GDF15 is tissue-specifically expressed, with high expression in the placenta, low expression in the prostate and colon, and certain expression in the kidney.
(Data source: uniprot)
Structure and maturation of GDF15
The gene encoding GDF15 is located on chromosome 19P-13.11. GDF15 is a secreted protein. It is synthesized as a precursor protein, termed pre-pro-GDF15 (308 amino acids), a less active form consisting of an N-terminal signal peptide, a leader peptide, and GDF15. Removal of the signal peptide and further proteolytic cleavage by subtilisin/kexin-type (PCSK) proteases yield mature GDF15 (114 amino acids) with a size of approximately 13 kDa. Secreted mature GDF15 exists as a disulfide-linked homodimer, the predominant form of GDF15 found in serum. GFRAL serves as the receptor for GDF15 with high affinity, and dimeric GDF15 interacts with GFRAL to carry out its biological functions, such as weight regulation and metabolism.
(Data source: Siddiqui JA, et al. Cytokine Growth Factor Rev. 2022)
signaling pathways and regulation in cancer and obesity:
In cancer, GDF15, secreted by cancer cells , binds to TGF-β and promotes metastasis through the SMAD2/3 signaling pathway. Furthermore, GDF15 forms a complex with ErbB2 and activates the PI3K/AKT and MAPK pathways to promote cancer cell proliferation and migration. This latter effect involves phosphorylation of the CREB1 transcription factor, which binds to the GDF15 promoter and activates an autocrine loop for GDF15 secretion.
In obesity and cachexia, GFRAL binds to GDF15, recruiting and phosphorylating the co-receptor RET, which subsequently mediates the activation of downstream AKT, ERK, and PLC molecules. Activation of these targets leads to regulation of body weight and energy intake and reduces the incidence of diabetes. In cancer cachexia, GDF15 signaling also induces muscle proteolysis.
(Data source: Siddiqui JA, et al. Cytokine Growth Factor Rev. 2022)
GDF15 targeted therapy:
Currently, targeted drugs targeting GDF15 primarily focus on monoclonal antibodies, fusion proteins, and small molecule drugs. Seven monoclonal antibodies are in preclinical and clinical research stages, and three have entered clinical trials.
Ponsegromab is a monoclonal antibody targeting GDF15, developed by Pfizer for the treatment of anorexia, cachexia,colorectal cancer. Currently in Phase 2 clinical studies. It inhibits circulating unbound GDF15 levels. Ponsegromab resulted in superior changes from baseline in body weight compared to placebo at all doses tested, with the highest dose resulting in a mean increase of 5.6% at 12 weeks. Ponsegromab was generally considered safe and well-tolerated across all dose levels. At the highest dose evaluated, improvements in appetite and cachexia symptoms, physical activity, and muscle mass were observed compared to baseline.
Visugromab is a monoclonal antibody developed by CatalYm GmbH that neutralizes tumor-derived GDF15, a locally acting immunosuppressant that promotes resistance to immunotherapy. GDF15 inhibits the activation and relocalization of important players in the anti-tumor immune response. Neutralization of GDF15 with visugromab reverses key cancer resistance mechanisms, restoring an effective anti-tumor response by re-enabling immune cell activation and tumor infiltration. Additionally, visugromab offers the potential to mitigate treatment-related side effects such as nausea, vomiting, decreased appetite, and exacerbated weight and muscle mass loss (cachexia), thereby improving patients' quality of life and tolerability of cancer treatment.
Rilogrotug (AV-380) is a humanized inhibitory IgG1 antibody against GDF15 being developed by AVEO for the potential treatment and prevention of cancer cachexia and is currently in Phase 1 clinical development.
(Data source: New Drug Intelligence Database)
