GDF15-GFRAL breaks into the new drug track

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

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). 

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.

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 #	Description
GDF-HE115	Human GDF15, His Tag
GDF-HE415B	Biotinylated Human GDF15, His-Avi Tag
GDF-HM215	Human GDF15, hFc Tag
GDF-HM215B	Biotinylated Human GDF15 Protein
GDF-ME115	Mouse GDF15, His Tag
GDF-MM215	Mouse GDF15, hFc Tag
GDF-MM215B	Biotinylated Mouse GDF15 Protein
GDF-CE115	Cynomolgus GDF15, His Tag
GDF-CM215	Cynomolgus GDF15, hFc Tag
GDF-CM215B	Biotinylated Cynomolgus GDF15 Protein
GFL-HM401	Human GFRAL, His-Avi Tag
GFL-HM401B	Biotinylated Human GFRAL, His-Avi Tag
GFL-HM201	Human GFRAL, hFc Tag
GFL-MM401	Mouse GFRAL, His-Avi Tag
GFL-MM401B	Biotinylated Mouse GFRAL, His-Avi Tag
GFL-CM401	Cynomolgus GFRAL, His-Avi Tag
GFL-CM401B	Biotinylated Cynomolgus GFRAL, His-Avi Tag

References

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[2] Wang D, Day EA, Townsend LK, Djordjevic D, Jørgensen SB, Steinberg GR. GDF15: emerging biology and therapeutic applications for obesity and cardiometabolic disease. Nat Rev Endocrinol. 2021 Oct;17(10):592-607.

[3] Hsu JY, Crawley S, Chen M, Ayupova DA, Lindhout DA, Higbee J, Kutach A, Joo W, Gao Z, Fu D, To C, Mondal K, Li B, Kekatpure A, Wang M, Laird T, Horner G, Chan J, McEntee M, Lopez M, Lakshminarasimhan D, White A, Wang SP, Yao J, Yie J, Matern H, Solloway M, Haldankar R, Parsons T, Tang J, Shen WD, Alice Chen Y, Tian H, Allan BB. Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15. Nature. 2017 Oct 12;550(7675):255-259.

[4] Coll AP, Chen M, Taskar P, Rimmington D, Patel S, Tadross JA, Cimino I, Yang M, Welsh P, Virtue S, Goldspink DA, Miedzybrodzka EL, Konopka AR, Esponda RR, Huang JT, Tung YCL, Rodriguez-Cuenca S, Tomaz RA, Harding HP, Melvin A, Yeo GSH, Preiss D, Vidal-Puig A, Vallier L, Nair KS, Wareham NJ, Ron D, Gribble FM, Reimann F, Sattar N, Savage DB, Allan BB, O'Rahilly S. GDF15 mediates the effects of metformin on body weight and energy balance. Nature. 2020 Feb;578(7795):444-448.

[5] Mullican SE, Lin-Schmidt X, Chin CN, Chavez JA, Furman JL, Armstrong AA, Beck SC, South VJ, Dinh TQ, Cash-Mason TD, Cavanaugh CR, Nelson S, Huang C, Hunter MJ, Rangwala SM. GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates. Nat Med. 2017 Oct;23(10):1150-1157.

[6] Breit SN, Brown DA, Tsai VW. The GDF15-GFRAL Pathway in Health and Metabolic Disease: Friend or Foe? Annu Rev Physiol. 2021 Feb 10;83:127-151.