A potent truncated form of human soluble CR1 is protective in a mouse model of renal ischemia–reperfusion injury

• Published in: Scientific reports Vol. 11; no. 1; p. 21873
• Main Authors: Bongoni, Anjan K., Vikstrom, Ingela B., McRae, Jennifer L., Salvaris, Evelyn J., Fisicaro, Nella, Pearse, Martin J., Wymann, Sandra, Rowe, Tony, Morelli, Adriana Baz, Hardy, Matthew P., Cowan, Peter J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08-11-2021; Nature Publishing Group; Nature Portfolio
• Subjects: 631/250; 631/443; 692/4022; 692/420; 692/699; Animals; Cell activation; Complement activation; Complement Activation - drug effects; Complement component C3; Complement receptors; Complement system; Disease Models, Animal; Humanities and Social Sciences; Humans; Ischemia; Kidney - drug effects; Kidney - immunology; Kidney - injuries; Kidney transplantation; Kidney Transplantation - adverse effects; Male; Membrane proteins; Mice; Mice, Inbred C57BL; multidisciplinary; Peptide Fragments - chemistry; Peptide Fragments - pharmacology; Pharmacokinetics; Receptors, Complement 3b - administration & dosage; Receptors, Complement 3b - chemistry; Renal function; Reperfusion; Reperfusion Injury - etiology; Reperfusion Injury - immunology; Reperfusion Injury - prevention & control; Science; Science (multidisciplinary); Solubility
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-01423-y

The complement system is a potent mediator of ischemia–reperfusion injury (IRI), which detrimentally affects the function and survival of transplanted kidneys. Human complement receptor 1 (HuCR1) is an integral membrane protein that inhibits complement activation by blocking the convertases that activate C3 and C5. We have previously reported that CSL040, a truncated form of recombinant soluble HuCR1 (sHuCR1), has enhanced complement inhibitory activity and improved pharmacokinetic properties compared to the parent molecule. Here, we compared the capacity of CSL040 and full-length sHuCR1 to suppress complement-mediated organ damage in a mouse model of warm renal IRI. Mice were treated with two doses of CSL040 or sHuCR1, given 1 h prior to 22 min unilateral renal ischemia and again 3 h later. 24 h after reperfusion, mice treated with CSL040 were protected against warm renal IRI in a dose-dependent manner, with the highest dose of 60 mg/kg significantly reducing renal dysfunction, tubular injury, complement activation, endothelial damage, and leukocyte infiltration. In contrast, treatment with sHuCR1 at a molar equivalent dose to 60 mg/kg CSL040 did not confer significant protection. Our results identify CSL040 as a promising therapeutic candidate to attenuate renal IRI and demonstrate its superior efficacy over full-length sHuCR1 in vivo.