AGT‑110 is an investigational inhibitor of tumor necrosis factor (TNF), a substance that causes inflammation and tissue destruction. ArmaGen engineered AGT-110 to cross the BBB for the treatment of neurodegenerative conditions such as Parkinson’s disease, amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease), Alzheimer’s disease and stroke. These chronic inflammatory conditions of the brain are mediated in part by TNF-alpha.1 Currently available biologic TNF inhibitors (TNFIs) block the action of TNF-alpha in peripheral tissues, but cannot be used to treat these diseases because large-molecule drugs do not cross the BBB.1

ArmaGen validated AGT-m110, a fusion protein that targets the transferrin receptor, in a mouse model of stroke, reducing stroke volume by 62% and neural deficit after stroke by 54%. By contrast, etanercept had no therapeutic effect in the mouse model because it does not cross the BBB.2 Similarly, AGT-m110 demonstrated a neuroprotective effect in a mouse model of PD, generating a 130% increase in activity of an enzyme, tyrosine hydrozylase, which shows reduced activity in PD. AGT-m110 also showed marked reduction in amphetamine-induced rotation behavior (i.e., running around in circles), compared to etanercept, which did not exert a therapeutic effect.3 The efficacy of AGT-m110 was also investigated in a mouse model of Alzheimer’s disease.4 AGT-m110 demonstrated therapeutic benefits improving recognition memory.4


References:

1 Boado RJ, Hui EK, Lu JZ, Zhou QH, Pardridge WM (2010) Selective targeting of a TNFR decoy receptor pharmaceutical to the primate brain as a receptor-specific IgG fusion protein. J Biotechnol. 146:84-91

2 Sumbria RK, et al. Brain protection from stroke with intravenous TNFα decoy receptor-Trojan horse fusion protein. J Cerebral Blood Flow Metab. 2012;32:1933-1938

3 Zhou-Q-H, et al. Neuroprotection with a brain-penetrating biologic tumor necrosis factor inhibitor. J Pharmacol Exp Ther. 2011;339:618-623

4 Chang R, Knox J, Chang J, Derbedrossian A, Vasilevko V, Cribbs D, Boado RJ, Pardridge WM, Sumbria R. (2017) Blood-brain barrier penetrating biologic TNF-α inhibitor for Alzheimer’s disease. Mol Pharm. 14:2340-2349