Work

Pre-clinical characterization of CSL040, a soluble complement receptor 1 (CR1) fragment

Year: 2025

Type: article

Abstract: Human Complement Receptor 1 (CR1) is a potent regulator of complement both in vitro and in vivo . It functions by binding to its ligands C3b and C4b and inhibiting the classical, lectin and alternative pathways of the complement cascade via the mechanisms of decay acceleration activity and co-factor activity. We have generated and characterized CSL040, a soluble version of CR1 containing the long homologous repeat (LHR) -A, -B and -C domains. CSL040 exhibits significantly greater in vitro and in vivo inhibition of all three complement pathways compared to sCR1/TP10, the full extracellular domain of sCR1. Extensive pharmacokinetic (PK) and pharmacodynamic (PD) assessments of CSL040 in rats and cynomolgus monkeys have been performed, with a demonstrated relationship between the PK properties and asialo content of recombinant protein preparations. The contribution of each LHR domain to C3b and C4b binding and complement pathway activity was comprehensively assessed. Dose-dependent attenuation of tissue damage by CSL040 was shown in two renal mouse models of disease: warm renal ischemia-reperfusion injury, and glomerulonephritis. In addition, the systemic toxicity, toxicokinetics and PD effects of CSL040 were assessed in two-week intravenous (IV) bolus studies in Han Wistar rats and cynomolgus monkeys at daily doses of 50, 150 and 500 mg/kg. CSL040 was demonstrated to be safe and well tolerated; the NOAEL for rats and cynomolgus monkeys is 500 mg/kg. The pre-clinical program demonstrated that CSL040 has a favorable safety profile and supported the clinical development of CSL040 into First-in-Human studies (NCT0593758).

Source: Immunobiology

DOI: 10.1016/j.imbio.2025.152992