GDF15-GFRAL breaks into the new drug track

By Mallory Griffin

A variety of metabolic diseases that plague today's society, such as obesity, diabetes, cancer, etc., have yet to be solved. Several major studies have confirmed that the GDF15-GFRAL pathway is involved in regulating the body's metabolism, inflammation, and immune response. This suggests that GDF15-GFRAL can be a target for the treatment of related diseases.


GDF15 (Growth Differentiation Factor 15) belongs to the TGFβ (Transforming growth factor β) superfamily. The two proteins of GDF15 first form a dimer structure through a disulfide bond, which is then hydrolyzed at the RXXR site to form the mature form of GDF15. This form is then secreted outside the cell. In some cells, the precursor dimer can also be secreted separately and attach to the extracellular matrix until cleaved (Figure 1). 

GDF15 is an endocrine hormone mainly involved in cell growth, differentiation, and tissue repair. Under normal physiological conditions, GDF15 is highly expressed in the prostate and placenta, and is weakly expressed in most tissues such as the heart. However, it can be up-regulated when subjected to external stress (such as hypoxia, mitochondrial damage, metformin, and endurance exercise) (Figure 1). This feature gives GDF15 important auxiliary diagnosis or treatment value in myocardial infarction, stroke, and acute coronary syndrome.

GDF15, first discovered in 1997 [1], acts as an autoregulatory factor in macrophages that inhibits lipopolysaccharide-induced tumor necrosis factor-alpha (TNFα) release. Due to its discovery by different researchers, GDF15 has been given different names: TGF-PL, MIC-1 (Macrophage Inhibitory cytokine-1), PDF (Prostate-derived factor), PLAB (Placental bone morphogenetic protein), NAG-1 ( Non-steroidal anti-inflammatory drug-inducible gene), PTGFB (Placental transforming growth factor-beta). 

Figure 1. Synthesis mechanism of GDF15 (dotted line means unknown mechanism) [2].

Features of GDF15

GDF15 acts by binding to its receptor GFRAL (glial cell line-derived neurotrophic factor-family receptor α-like). GFRAL was found in 2017 to bind to GDF15 and activate the "emergency pathway" involved in the regulation of body weight under unsteady conditions [3]. GFRAL, a transmembrane protein expressed only in the hindbrain, requires the help of the accessory protein RET for signaling. When GDF15 binds to GFRAL, RET will autophosphorylate and lead to the activation of downstream signaling pathways such as PI3K-AKT and PLC-PKC, thereby regulating many physiological processes, including affecting food intake and leading to weight loss (this is more pronounced in the presence of metformin) (Figure 2). GDF15 is also called the "anorexia hormone" [4]. As an immune checkpoint, GDF15 can inhibit the maturation of dendritic cells, hinder the activation of cytotoxic T lymphocytes, and promote the immune escape of tumor cells. In addition, GDF15-GFRAL also plays an important role in non-alcoholic fatty liver, cardiovascular and other diseases.

Figure 2. GDF15 mediates the transmission of the signaling pathway by binding GFRAL-RET [5].

GDF15 Related Drugs

The GDF15-GFRAL-mediated signaling pathway is a natural stress response mechanism in the human body and is involved in the progression of many common diseases. The diverse functions of GDF15 give it various potential therapeutic scenarios. It can affect food intake to control obesity and as an immune checkpoint, it can be used for the treatment of solid tumors. There are no GDF15-related drugs on the market, but many have entered clinical trials, focusing on GDF15 analogs and GFRAL agonists as well as their monoclonal antibodies. The main idea is to either activate the GDF15-GFRAL signaling pathway to control food intake and thereby inhibit the development of metabolic diseases, or to inhibit this pathway to enhance the immune system's attack on solid tumors while reducing the cancer cachexia syndrome caused by GDF15-GFRAL.

Notably, injection of exogenous GDF15 may induce anorexia and spontaneous motility, which may counteract the positive effects of targeting GDF15 in the treatment of metabolic diseases. Some studies have found that elevated GDF15 exerts a tumor suppressor effect in the early stage of the tumor, but becomes a tumor-promoting agent in the later stage [6]. Therefore, the relevant mechanism needs to be clarified in order to balance safety and efficacy. In addition, existing research shows that the development of monoclonal antibodies for GFRAL may be superior to GDF15, because GDF15 is more sensitive to cellular stress response, and may require higher concentrations of monoclonal antibodies to be neutralized. ​​GFRAL, on the other hand, is tissue-restricted, so the corresponding low-level monoclonal antibody can still achieve a therapeutic effect. The following are GDF15 and GFRAL drugs entering clinical trials:

Drug Name


Drug Type



Clinical Stage

Visugromab (CTL-002)


Monoclonal Antibody

Solid tumor


Phase II

Ponsegromab (PF-06946860)


Monoclonal Antibody

Cachexia, Heart failure


Phase I



Monoclonal Antibody



Phase I



Monoclonal Antibody

Solid tumor


Phase I





Eli Lilly

Phase I





Novo Nordisk

Phase I



Monoclonal Antibody



Phase I

CIN 109 (JNJ-9090)




Johnson & Johnson

Phase I

Among them, NGM-120 has entered clinical phase II for solid tumors and pancreatic cancer, another indication for the drug. This is one of the four clinical phase II drugs of NGM Bio. At present, domestic companies entering the GDF15-GFRAL target have shown an upward trend, and it is believed that promising drugs will come out in the future to benefit patients. 

KACTUS has a self-developed prokaryotic expression system and recombinant GDF15 protein expressed by a eukaryotic expression system, which overcomes the problem of low solubility of GDF15 protein expressed in a prokaryotic expression system. It also provides various types of GFRAL proteins. Multiple species and tags are available for both proteins and have all been verified by activity testing. They have high biological activity and stability and can be used in the development of GDF15-GFRAL-related drugs.

Product Data

Immobilized Human GDF15, His Tag at 0.5μg/ml (100μl/well) on the plate. Dose-response curve for Human GFRAL, hFc Tag with an EC50 of 22.8ng/ml determined by ELISA.

Immobilized Human GDF15, mouse IgG2a Fc Tag at 0.5μg/ml (100μl/well) on the plate. Dose-response curve for Anti-GDF15 Antibody, hFc Tag with an EC50 of 6.0ng/ml determined by ELISA.

Serial dilutions of Anti-GDF15 Antibody were added into Human GDF15, His Tag: Biotinylated Human GFRAL, His Tag binding reactions. The IC50 is 40.8ng/ml.

KACTUS Product List

Catalog #



Human GDF15, His Tag


Biotinylated Human GDF15, His-Avi Tag


Human GDF15, hFc Tag


Biotinylated Human GDF15 Protein


Mouse GDF15, His Tag


Mouse GDF15, hFc Tag


Biotinylated Mouse GDF15 Protein


Cynomolgus GDF15, His Tag


Cynomolgus GDF15, hFc Tag


Biotinylated Cynomolgus GDF15 Protein


Human GFRAL, His-Avi Tag


Biotinylated Human GFRAL, His-Avi Tag


Human GFRAL, hFc Tag


Mouse GFRAL, His-Avi Tag


Biotinylated Mouse GFRAL, His-Avi Tag


Cynomolgus GFRAL, His-Avi Tag


Biotinylated Cynomolgus GFRAL, His-Avi Tag


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