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

Autor: Bongoni AK; Immunology Research Centre, St. Vincent's Hospital, Melbourne, PO Box 2900, Fitzroy, VIC, 3065, Australia. anjan.bongoni@svha.org.au., Vikstrom IB; CSL Limited, Melbourne, VIC, 3052, Australia., McRae JL; Immunology Research Centre, St. Vincent's Hospital, Melbourne, PO Box 2900, Fitzroy, VIC, 3065, Australia., Salvaris EJ; Immunology Research Centre, St. Vincent's Hospital, Melbourne, PO Box 2900, Fitzroy, VIC, 3065, Australia., Fisicaro N; Immunology Research Centre, St. Vincent's Hospital, Melbourne, PO Box 2900, Fitzroy, VIC, 3065, Australia., Pearse MJ; CSL Limited, Melbourne, VIC, 3052, Australia., Wymann S; CSL Behring AG, 3014, Bern, Switzerland., Rowe T; CSL Limited, Melbourne, VIC, 3052, Australia., Morelli AB; CSL Limited, Melbourne, VIC, 3052, Australia., Hardy MP; CSL Limited, Melbourne, VIC, 3052, Australia., Cowan PJ; Immunology Research Centre, St. Vincent's Hospital, Melbourne, PO Box 2900, Fitzroy, VIC, 3065, Australia.; Department of Medicine, University of Melbourne, Melbourne, VIC, 3052, Australia.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2021 Nov 08; Vol. 11 (1), pp. 21873. Date of Electronic Publication: 2021 Nov 08.
DOI: 10.1038/s41598-021-01423-y
Abstrakt: 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.
(© 2021. The Author(s).)
Databáze: MEDLINE
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