THE SCIENCE BEHIND
ANG-3070 is a highly selective, orally-bioavailable small molecule tyrosine kinase receptor inhibitor developed internally as a potential treatment for fibrotic diseases, particularly in the kidney and lung.*
ANG-3070 was designed to target platelet-derived growth factor receptor alpha and beta (PDGFRα and PDGFRβ, respectively) and Discoidin Domain Receptors 1 and 2 (DDR1 and DDR2).
*ANG-3070 is an investigational product and is not approved by any regulatory authority.
THE ROLE OF DDR1 and DDR2 in FIBROSIS
DDR1 is a tyrosine kinase transmembrane receptor of collagens, expressed in several cell types and organs, including the gastrointestinal tract, brain, lung, mammary gland and kidney. Despite collagen being the most abundant protein in the body, DDR1 is not induced or activated under normal conditions. Several studies show DDR1 is overexpressed in pathological conditions and participates in tissue adaptation to acute and chronic inflammatory lesions, including renal inflammation and fibrosis. In a mouse model of Alport’s Syndrome (AS), for example, deletion of DDR1 delays renal fibrosis. Other animal studies suggest DDR1 could play an important role in idiopathic pulmonary fibrosis mediating the creation of permanent pulmonary epithelial lesions.
In contrast to DDR1’s primary expression in epithelial cells and activation by multiple types of collagens, DDR2 is abundantly expressed in fibroblasts or cells of mesenchymal origin and activated by fibrillar collagens and type X collagen. In the early phase of fibrosis formation in IPF, TGF-β induces expression of DDR2 in lung fibroblasts and synergizes with the resulting downstream signals to accelerate cell phenotypic transition toward myofibroblasts. In later stages of fibrosis with the fibrotic process is already established, the abundant fibrillar collagens within fibrotic tissues may gradually augment the activation of myofibroblasts via DDR2/ERK axis in a positive feedback manner, promotes the oversynthesis of extracellular matrix components as well as the secretion of VEGF, resulting in massive fibrosis and angiogenesis.
THE ROLE OF PDGFRα and PDGFRβ in FIBROSIS
PDGFRα and PDGFRβ are expressed in renal mesenchymal cells, i.e. glomerular mesangial cells, in vascular smooth-muscle cells and in interstitial cortical fibroblasts and medullary pericytes. Renal fibrosis is the underlying pathological process of almost all CKD, a disease affecting more than 10% of the world population, and CKD is currently also the best predictor of disease progression. Further, no specific anti-fibrotic treatments currently exist to combat renal fibrosis. In human renal disease, PDGFRα is upregulated in glomerulus as well as arterial smooth muscle cells and endothelial cells. Activation of PDGFRβ specifically in renal mesenchymal cells is sufficient to induce and drive progressive glomerulosclerosis and interstitial renal fibrosis.
In patients with early, but not late stage, IPF, mononuclear phagocytes, alveolar type 2 cells, vascular endothelial cells, VSMC and fibroblasts express increased PDGFRα. Alveolar type 2 cells, vascular endothelial cells, VSMC and fibroblasts express increased PDGFRβ. During lung fibrosis, both PDGFRα and PDGFRβ are involved in pro-fibrotic activation of interstitial myofibroblasts and smooth muscle cells, suggesting a specific anti-PDGF therapy might exert beneficial anti-fibrotic effects.
Both PDGFRα and PDGFRβ play a role in several other indications related to organ fibrosis including hepatic and gastrointestinal fibrosis, systemic sclerosis, and cardiac fibrosis.
- Dorison, et al. The Role of Discoidin Domain Receptor 1 in Inflammation, Fibrosis, and Renal Disease. Experimental Nephrology and Genetics (2017).
- Floege, et al. A New Look at Platele-Derived Growth Factor in Renal Disease. JASN (2008).
- Kavvadas, et al. Searching Novel Diagnostic Markers and Targets for Therapy of CKD. Kidney International (2014).
- Klinkhammer, et al. PDGF in Organ Fibrosis. Molecular Aspects of Medicine (2017).
- Zhao H., et al. Targeting Discoiding Domain Receptor 2 (DDR2) Prevents Myofibroblast Activation and Neovessel Formation during Pulmonary Fibrosis. Molecular Therapy (2016).