A novel soluble complement receptor 1 fragment with enhanced therapeutic potential.
C3b
CSL040
complement
glomerulonephritis
glycosylation
pharmacokinetics
receptor
recombinant protein expression
Journal
The Journal of biological chemistry
ISSN: 1083-351X
Titre abrégé: J Biol Chem
Pays: United States
ID NLM: 2985121R
Informations de publication
Date de publication:
Historique:
received:
22
09
2020
revised:
14
12
2020
accepted:
16
12
2020
pubmed:
19
12
2020
medline:
31
8
2021
entrez:
18
12
2020
Statut:
ppublish
Résumé
Human complement receptor 1 (HuCR1) is a pivotal regulator of complement activity, acting on all three complement pathways as a membrane-bound receptor of C3b/C4b, C3/C5 convertase decay accelerator, and cofactor for factor I-mediated cleavage of C3b and C4b. In this study, we sought to identify a minimal soluble fragment of HuCR1, which retains the complement regulatory activity of the wildtype protein. To this end, we generated recombinant, soluble, and truncated versions of HuCR1 and compared their ability to inhibit complement activation in vitro using multiple assays. A soluble form of HuCR1, truncated at amino acid 1392 and designated CSL040, was found to be a more potent inhibitor than all other truncation variants tested. CSL040 retained its affinity to both C3b and C4b as well as its cleavage and decay acceleration activity and was found to be stable under a range of buffer conditions. Pharmacokinetic studies in mice demonstrated that the level of sialylation is a major determinant of CSL040 clearance in vivo. CSL040 also showed an improved pharmacokinetic profile compared with the full extracellular domain of HuCR1. The in vivo effects of CSL040 on acute complement-mediated kidney damage were tested in an attenuated passive antiglomerular basement membrane antibody-induced glomerulonephritis model. In this model, CSL040 at 20 and 60 mg/kg significantly attenuated kidney damage at 24 h, with significant reductions in cellular infiltrates and urine albumin, consistent with protection from kidney damage. CSL040 thus represents a potential therapeutic candidate for the treatment of complement-mediated disorders.
Identifiants
pubmed: 33334893
pii: S0021-9258(20)00196-9
doi: 10.1074/jbc.RA120.016127
pmc: PMC7948397
pii:
doi:
Substances chimiques
CR1 protein, human
0
Receptors, Complement 3b
0
Recombinant Proteins
0
Complement C3b
80295-43-8
Complement C4b
80295-50-7
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
100200Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Conflict of interest S. W., H. C., A. B. M., T. R., and M. P. H. are listed as inventors on International Patent Publication number WO2019/218009. All authors with the exception of A. G. N., G. A. P., G. M.- R., M. M., and M. S. are CSL shareholders.
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