Vegf inhibitors

VEGF inhibitors are a group of structurally different, targeted therapeutics that bind to the growth factor VEGF and thereby inhibit its function. These are monoclonal antibodies, their fragments or so-called false receptors (VEFG traps - e.g. Aflibercept).

VEGF inhibitors have the same mode of action as VEGFR inhibitors (VEGF receptor inhibitors). They inhibit the downstram signalling cascade conducted via the VEGF receptor. Sometimes the terms are also used synonymously in clinical language. However, VEGF inhibitors bind to ligands of the receptor, not to the receptor protein itself. VEGFR inhibitors, on the other hand, enter into a direct connection with the extracellular domain of the receptor, so that the ligand (VEGF) cannot dock or the receptor function is blocked.

How it works: The different VEGF ligands bind to the extracellular domain of transmembrane VEGF receptors, which are expressed by endothelial cells, among others.

Currently, 3 subtypes of the VEGF receptor are known:

• VEGFR-1 (Flt-1): The function of VEGFR-1 is currently not clearly understood: A modulation of VEGFR-2 action and important functions in embryonic angiogenesis are under discussion. A non membrane-bound, soluble form (sFlt1) still exists.
• VEGFR-2: This receptor is responsible for almost all cellular responses to VEGF and plays an important role in the control of angiogenesis and vasculogenesis in the human body. It binds VEGF-A and also acts as fetal liver kinase (Flk1).
• VEGFR-3 (Flt-4): This receptor regulates lymphangiogenesis in response to VEGF-C and VEGF-D. Unlike VEGFR-1 and VEGFR-2, VEGF-A is not an active ligand of VEGFR-3.

The binding of VEGF ligands to VEGF receptors leads to dimerization of these receptors. This releases an ATP binding site, allowing ATP to bind to the intracellular domain of the receptor. This binding triggers a transphosphorylation of the intracellular tyrosine residues of the dimerized receptors. The activation of transcription factors influences proliferation, migration of endothelial cells and thus vasculogenesis.

VEGF inhibitors block VEGF so that it can no longer bind to VEGF receptors. The intracellular signalling cascade that depends on them is interrupted. This results in an inhibition of angiogenesis. The latter is essential for tumour growth (tumour angiogenesis), but also for proliferative physiological or pathological vascular processes (e.g. wound healing, e.g. wet macular degeneration; e.g. retinopathy of prematurity). The antineoplastic effect therefore does not affect the tumor cells themselves, but the vascular supply of the tumor parenchyma. If the blood supply to the tumour is no longer sufficient, a regression of the tumour parenchyma occurs (Itatani Y et al. 2018).

The currently available VEGF inhibitors are therapeutic proteins of different composition; they are:

• antibodies
• Antibody fragments
• Fusion proteins.

They differ in molecular size. The Fv fragment brolucizumab has the smallest mass. Ranibizumab is derived from the same antibody used for the production of bevacizumab. Aflibercept is a so-called "false VEGF receptor" a receptor trap (VEGF trap) that traps VEGF (hence the suffix -cept). The VEGF receptor trap is a recombinant fusion protein: by combining the Fc fragment of immunoglobulin G with the binding domain of the soluble VEGF receptor, this fusion protein is obtained (Stewart MW 2011). This fusion protein can bind different VEGF isoforms. VEGF traps are used in oncology and ophthalmology (Papadopoulos N et al. 2012).

• Bevacizumab (antibody)
• Brolucizumab (Fv fragment)
• Ranibizumab (Fab fragment)
• Aflibercept (wrong receptor, VEFG trap)

1. Itatani Y et al (2018) Resistance to Anti-Angiogenic Therapy in Cancer-Alterations to Anti-VEGF Pathway. Int J Mol Sci 19:1232.
2. Modi YS et al. (2015) Comparative safety and tolerability of anti-VEGF therapy in age-related macular degeneration. Drug Saf 38: 279-93
3. Papadopoulos N et al (2012) Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab. Angiogenesis 15:171-185.
4. Stewart MW (2011) Aflibercept (VEGF-TRAP): the next anti-VEGF drug. Inflammation Allergy Drug Targets. 10:497-508.
5. of Wijngaarden P et al (2008) Inhibitors of vascular endothelial growth factor (VEGF) in the management of neovascular age-related macular degeneration: a review of current practice. Clin Exp Optom 91: 427-437