ACT‐1004‐1239, a first‐in‐class CXCR7 antagonist with both immunomodulatory and promyelinating effects for the treatment of inflammatory demyelinating diseases

Abstract

Current strategies for the treatment of demyelinating diseases such as multiple sclerosis (MS) are based on anti‐inflammatory or immunomodulatory drugs. Those drugs have the potential to reduce the frequency of new lesions but do not directly promote remyelination in the damaged central nervous system (CNS). Targeting CXCR7 (ACKR3) has been postulated as a potential therapeutic approach in demyelinating diseases, leading to both immunomodulation by reducing leukocyte infiltrates and promyelination by enhancing myelin repair. ACT‐1004‐1239 is a potent, selective, insurmountable, and orally available first‐in‐class CXCR7 receptor antagonist. The effect of ACT‐1004‐1239 was evaluated in the myelin oligodendrocyte glycoprotein (MOG)‐induced experimental autoimmune encephalomyelitis (EAE) and the cuprizone‐induced demyelination mouse models. In addition, ACT‐1004‐1239 was assessed in a rat oligodendrocyte precursor cell (OPC) differentiation assay in vitro. In the MOG‐induced EAE model, ACT‐1004‐1239 treatment (10‐100 mg/kg, twice daily, orally) showed a significant dose‐dependent reduction in disease clinical scores, resulting in increased survival. At the highest dose tested (100 mg/kg, twice daily), ACT‐1004‐1239 delayed disease onset and significantly reduced immune cell infiltrates into the CNS and plasma neurofilament light chain concentration. Treatment with ACT‐1004‐1239 dose‐dependently increased plasma CXCL12 concentration, which correlated with a reduction of the cumulative disease score. Furthermore, in the cuprizone model, ACT‐1004‐1239 treatment significantly increased the number of mature myelinating oligodendrocytes and enhanced myelination in vivo. In vitro, ACT‐1004‐1239 promoted the maturation of OPCs into myelinating oligodendrocytes. These results provide evidence that ACT‐1004‐1239 both reduces neuroinflammation and enhances myelin repair substantiating the rationale to explore its therapeutic potential in a clinical setting.

CXCR7 Antagonism Reduces Acute Lung Injury Pathogenesis

“…To date, the role of the CXCR3/CXCR7/CXCL11 axis in preclinical ALI models has not been investigated as previous studies were conducted in C57BL/6 mice, a mouse strain lacking CXCL11 (Sierro et al, 2007). We show here that antagonizing CXCR7 with ACT-1004-1239 not only led to the elevation of CXCL12 in the plasma, confirming previous data (Richard-Bildstein et al, 2020;Pouzol et al, 2021) but also of the inducible chemokine CXCL11, in a dose-dependent manner, confirming the inhibition of the scavenging activity of CXCR7 in vivo. In contrast, CXCR7 antagonism did not further increase the LPS-induced elevation of CXCL11 and CXCL12 concentrations in the inflamed lung tissue, but rather tended to normalize them, likely leading to a disruption in the chemokine concentration gradient from the blood to the injured lung tissue.…”

“…Blockade of CXCR7 is expected to increase the systemic CXCL11 and CXCL12 levels and, therefore, modulate CXCR3 and CXCR4 signaling activities such as leukocyte chemotaxis and tissue retention (Berahovich et al, 2014;Pouzol et al, 2021). In line with this hypothesis, treatment with CCX771, a CXCR7 functional antagonist, which is known to increase plasma CXCL12 levels (Berahovich et al, 2014), led to reduced alveolar inflammation and lung microvascular permeability in a murine model of ALI (Konrad et al, 2017;Ngamsri et al, 2017).…”

“…The scavenging activity of CXCR7 expressed on endothelial cells has been proposed to generate CXCL11 and CXCL12 chemokine gradients, thus, enabling a directional migration of CXCR3 + and CXCR4 + cells, respectively, from the circulation toward sites of inflammation (Berahovich et al, 2014;Tobia et al, 2019;Pouzol et al, 2021). To evaluate this hypothesis, the impact of CXCR7 antagonism on plasma and lung tissue CXCL11 and CXCL12 levels and BAL immune cell infiltrates was investigated in the ALI/ARDS DBA/1 mouse model following treatment with ACT-1004-1239.…”

“…CXCR7 functions predominantly as a scavenger receptor for its chemokine ligands CXCL11 and CXCL12 (Naumann et al, 2010), which bind to, and activate, the signaling chemokine receptors CXCR3 and CXCR4, respectively. While CXCR7 is not expressed on leukocytes (Berahovich et al, 2010), its scavenging activity in endothelial cells contributes to the establishment and maintenance of CXCL11 and CXCL12 concentration gradients along which CXCR3 + and CXCR4 + cells can migrate from the blood toward the inflamed tissue (Lewellis and Knaut, 2012;Quinn et al, 2018;Pouzol et al, 2021).…”

Plasma neurofilament light, glial fibrillary acidic protein and lysosphingolipid biomarkers for pharmacodynamics and disease monitoring of GM2 and GM1 gangliosidoses patients

“…Full details of the mouse study will be published elsewhere. Concentrations of NF-L were measured in mouse plasma samples using a customized Meso Scale Discovery assay as previously described [43] . The left lateral liver lobe (~110 mg each) was homogenized in 1 mL methanol using a Tissue-Lyzer II (300 Hz, 3 min) and centrifuged.…”