Introduction of Brolucizumab

Brolucizumab (RTH258) is the first and only single-chain variable fragment (scFv) targeting vascular endothelial growth factor (VEGF)-A. It has a smaller molecular weight (26 kDa). The mAb is undergoing evaluation as a treatment for neovascular age-related macular degeneration (nAMD).

Mechanism of Action of Brolucizumab

Angiogenesis is the process by which new vessels are created from pre-existing vasculature. Increased rates of angiogenesis are associated with several disease states, including cancer, age-related macular degeneration (AMD), psoriasis, rheumatoid arthritis, and diabetic retinopathy. AMD is a multifaceted disease characterized by early subclinical changes at the choroidea-retinal pigment epithelium interface. Vascular endothelial growth factor (VEGF) is an important modulator of angiogenesis, and has been implicated in the pathology of a number of conditions, including AMD, diabetic retinopathy, and cancer. VEGF belongs to a family of dimeric glycoproteins within the superfamily of PDGFs. While VEGF, also known as VEGF-A, is the most comprehensively studied, other members of this family include VEGF-B, VEGF-C, VEGF-D, and PLGF. VEGF-A has several isoforms that arise from alternative splicing. All VEGF ligands bind to tyrosine kinase receptors, causing the receptors to dimerize and autophosphorylate. Upon binding to its receptor, VEGF initiates a cascade of signaling events that begins with auto-phosphorylation of both receptor kinases, followed by activation of numerous downstream proteins, including phosphoinositide-3-kinase (PI3K), the Ras GTPase activating protein, Ras, mitogen-activated protein kinase (MAPK), and others. VEGF-A binds to VEGF receptor (VEGFR)-1 and VEGFR-2. VEGF promotes the growth, migration, and proliferation of endothelial cells. In addition, VEGF induces vasodilatation and enhances endothelial cell survival. These biologic activities occur in few physiologic processes outside wound healing and ovulation, making VEGF an attractive target for therapy. Brolucizumab binds to VEGF-A, and thereby inhibits the binding of VEGF-A to its receptors, neutralizing the biological activity of VEGF-A and regressing the vascularization, thereby inhibiting the AMD process.

Fig.1 Mechanism of action of brolucizumab

For research use only. Not intended for any clinical use.