Transport study of interleukin-1 inhibitors using a human in vitro model of the blood-brain barrier

Abstract

The proinflammatory cytokine Interleukin-1 (IL-1), with its two isoforms α and β, has important roles in multiple pathogenic processes in the central nervous system. The present study aimed to evaluate and compare the blood-to-brain distribution of anakinra (IL-1 receptor antagonist), bermekimab (IL-1α antagonist) and canakinumab (IL-1β antagonist). A human in vitro model of the blood-brain barrier derived from human umbilical cord blood stem cells was used, where isolated CD34 + cells co-cultured with bovine pericytes were matured into polarized brain-like endothelial cells. Transport rates of the three test items were evaluated after 180 ​min incubation at concentrations 50, 250 and 1250 ​nM in a transwell system. We report herein that anakinra passes the human brain-like endothelial monolayer at a 4-7-fold higher rate than the monoclonal antibodies tested. Both antibodies had similar transport rates at all concentrations. No dose-dependent effects in transport rates were observed, nor any saturation effects at supraphysiological concentrations. The larger propensity of anakinra to pass this model of the human blood-brain barrier supports existing data and confirms that anakinra can reach the brain compartment at clinically relevant concentrations. As anakinra inhibits the actions of both IL-1α and IL-1β, it blocks all effects of IL-1 downstream signaling. The results herein further add to the growing body of evidence of the potential utility of anakinra to treat neuroinflammatory disorders.

The Inflammation in the Cytopathology of Patients With Mucopolysaccharidoses- Immunomodulatory Drugs as an Approach to Therapy

“…Large proteins, like monoclonal antibodies are estimated to enter the brain compartment in a range of 0.1%-1% only. Sjöström et al (2021) recently reported, that Anakinra passes the human brain-like endothelial monolayer at 4.7-fold higher rate than the monoclonal antibodies tested. Therefore, Anakinra may reach the brain compartment at clinically relevant levels, encouraging the utility of Anakinra for treatment of neuroinflammatory diseases.…”

Anti-cytokine strategies targeting CAR-T cell therapy-induced cytokine release syndrome

“…In other diseases, for example, in RA, anakinra is approved to be a relatively safe and modestly efficacious therapy. To be mentioned that existing data suggests that anakinra can cross the blood-brain barrier and reach the brain compartment at clinically relevant concentrations [28].…”

Immune Mechanisms in Epileptogenesis: Update on Diagnosis and Treatment of Autoimmune Epilepsy Syndromes

“…Canakinumab is a human monoclonal antibody directed against IL-1ß and is amongst others used to treat juvenile idiopathic arthritis [ 195 ] and refractory gout [ 196 ]. The use of canakinumab in AIE may be hampered by its failure to cross the intact BBB [ 197 ]; however, the BBB is likely to become more permissible in AIE and, thus, canakinumab may penetrate the brain parenchyma, as data showing that both canakinumab and anakinra can reach the brain compartment in significant concentration in an in vitro model [ 198 ]. A case report on a patient with generalised epilepsy and poor response to multiple ASMs-reported clinical response after therapeutic IL-1 blockade, first by treatment with anakinra followed by canakinumab with near resolution of seizures [ 199 ].…”