A novel soluble complement receptor 1 fragment with enhanced therapeutic potential Article Swipe
Sandra Wymann
,
Yun Dai
,
Anup G. Nair
,
Helen Cao
,
Glenn A. Powers
,
Anna Schnell
,
Genevieve Martin-Roussety
,
David Tai Leong
,
Jason Simmonds
,
Kim G. Lieu
,
Mitchell J. de Souza
,
Marcel Mischnik
,
Shirley M. Taylor
,
Saw Yen Ow
,
M. Spycher
,
R.E. Butcher
,
Martin J. Pearse
,
Adrian W. Zuercher
,
Adriana Baz Morelli
,
Con Panousis
,
Michael J. Wilson
,
Tony Rowe
,
Matthew P. Hardy
·
YOU?
·
· 2021
· Open Access
·
· DOI: https://doi.org/10.1074/jbc.ra120.016127
YOU?
·
· 2021
· Open Access
·
· DOI: https://doi.org/10.1074/jbc.ra120.016127
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.
Related Topics
Concepts
Fragment (logic)
Complement (music)
Computational biology
Chemistry
Biology
Computer science
Biochemistry
Algorithm
Complementation
Gene
Phenotype
Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1074/jbc.ra120.016127
- http://www.jbc.org/article/S0021925820001969/pdf
- OA Status
- gold
- Cited By
- 19
- References
- 94
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W3117512045
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
-
https://openalex.org/W3117512045Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.1074/jbc.ra120.016127Digital Object Identifier
- Title
-
A novel soluble complement receptor 1 fragment with enhanced therapeutic potentialWork title
- Type
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articleOpenAlex work type
- Language
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enPrimary language
- Publication year
-
2021Year of publication
- Publication date
-
2021-01-01Full publication date if available
- Authors
-
Sandra Wymann, Yun Dai, Anup G. Nair, Helen Cao, Glenn A. Powers, Anna Schnell, Genevieve Martin-Roussety, David Tai Leong, Jason Simmonds, Kim G. Lieu, Mitchell J. de Souza, Marcel Mischnik, Shirley M. Taylor, Saw Yen Ow, M. Spycher, R.E. Butcher, Martin J. Pearse, Adrian W. Zuercher, Adriana Baz Morelli, Con Panousis, Michael J. Wilson, Tony Rowe, Matthew P. HardyList of authors in order
- Landing page
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https://doi.org/10.1074/jbc.ra120.016127Publisher landing page
- PDF URL
-
https://www.jbc.org/article/S0021925820001969/pdfDirect link to full text PDF
- Open access
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YesWhether a free full text is available
- OA status
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goldOpen access status per OpenAlex
- OA URL
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https://www.jbc.org/article/S0021925820001969/pdfDirect OA link when available
- Concepts
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Fragment (logic), Complement (music), Computational biology, Chemistry, Biology, Computer science, Biochemistry, Algorithm, Complementation, Gene, PhenotypeTop concepts (fields/topics) attached by OpenAlex
- Cited by
-
19Total citation count in OpenAlex
- Citations by year (recent)
-
2025: 2, 2024: 7, 2023: 3, 2022: 6, 2021: 1Per-year citation counts (last 5 years)
- References (count)
-
94Number of works referenced by this work
- Related works (count)
-
10Other works algorithmically related by OpenAlex
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