ArticleJournal of immunology (Baltimore, Md. : 1950)2016
Comparative Analysis of Novel Complement-Targeted Inhibitors, MiniFH, and the Natural Regulators Factor H and Factor H-like Protein 1 Reveal Functional Determinants of Complement Regulation.
Article in Journal of immunology (Baltimore, Md. : 1950), 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 37 citations in OpenAlex.
- CG001, a C3b-targeted complement inhibitor, blocks 3 complement pathways: development and preclinical evaluation.Blood advances · 2024Article
- The Production of Complement Inhibitor Proteins in Mammalian Cell Lines-Light at the End of the Tunnel?Biomedicines · 2024Review
- The human factor H protein family - an update.Frontiers in immunology · 2024Review
- Praziquantel and factor H recruitment differentially affect the susceptibility ofFrontiers in immunology · 2024Article
- The Complement-Targeted Inhibitor Mini-FH Protects against Experimental Periodontitis via Both C3-Dependent and C3-Independent Mechanisms.Journal of immunology (Baltimore, Md. : 1950) · 2023Article
- AAV Gene Augmentation of Truncated Complement Factor H Differentially Rescues Ocular Complement Dysregulation in a Mouse Model.Investigative ophthalmology & visual science · 2023Article
- Structural modelling of human complement FHR1 and two of its synthetic derivatives provides insight into their in-vivo functions.Computational and structural biotechnology journal · 2023Article
- Protein therapeutics and their lessons: Expect the unexpected when inhibiting the multi-protein cascade of the complement system.Immunological reviews · 2023Review
- Halting targeted and collateral damage to red blood cells by the complement system.Seminars in immunopathology · 2021Review
- Deregulation of Factor H by Factor H-Related Protein 1 Depends on Sialylation of Host Surfaces.Frontiers in immunology · 2021Article
- Ex vivo assays to detect complement activation in complementopathies.Clinical immunology (Orlando, Fla.) · 2020Article
- Evaluation of Anti-Tumor Effects of Whole-Body Low-Dose Irradiation in Metastatic Mouse Models.Cancers · 2020Article
- Mathematical Modelling of Alternative Pathway of Complement System.Bulletin of mathematical biology · 2020Article
- Tuning the Functionality by Splicing: Factor H and Its Alternative Splice Variant FHL-1 Share a Gene but Not All Functions.Frontiers in immunology · 2020Review
- Therapeutic Lessons to be Learned From the Role of Complement Regulators as Double-Edged Sword in Health and Disease.Frontiers in immunology · 2020Review
- Combining SPR with atomic-force microscopy enables single-molecule insights into activation and suppression of the complement cascade.The Journal of biological chemistry · 2019Article
- Factor H interferes with the adhesion of sickle red cells to vascular endothelium: a novel disease-modulating molecule.Haematologica · 2019Article
- Potentiation of complement regulator factor H protects human endothelial cells from complement attack in aHUS sera.Blood advances · 2019Article
- Different Levels of Incomplete Terminal Pathway Inhibition by Eculizumab and the Clinical Response of PNH Patients.Frontiers in immunology · 2019Article
- [How I diagnose and treat paroxysmal nocturnal hemoglobinuria].Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi · 2018Article
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 3 countries.
Funding
Abstract
The serum proteins factor H (FH), consisting of 20 complement control protein modules (CCPs), and its splice product FH-like protein 1 (FHL-1; consisting of CCPs 1-7) are major regulators of the alternative pathway (AP) of complement activation. The engineered version of FH, miniFH, contains only the N- and C-terminal portions of FH linked by an optimized peptide and shows ∼ 10-fold higher ex vivo potency. We explored the hypothesis that regulatory potency is enhanced by unmasking of a ligand-binding site in the C-terminal CCPs 19-20 that is cryptic in full-length native FH. Therefore, we produced an FH variant lacking the central domains 10-15 (FHΔ10-15). To explore how avidity affects regulatory strength, we generated a duplicated version of miniFH, termed midiFH. We compared activities of FHΔ10-15 and midiFH to miniFH, FH, and FHL-1. Relative to FH, FHΔ10-15 exhibited an altered binding profile toward C3 activation products and a 5-fold-enhanced complement regulation on a paroxysmal nocturnal hemoglobinuria patient's erythrocytes. Contrary to dogma, FHL-1 and FH exhibited equal regulatory activity, suggesting that the role of FHL-1 in AP regulation has been underestimated. Unexpectedly, a substantially increased avidity for complement opsonins, as seen in midiFH, did not potentiate the inhibitory potential on host cells. In conclusion, comparisons of engineered and native FH-based regulators have identified features that determine high AP regulatory activity on host cells. Unrestricted availability of FH CCPs 19-20 and an optimal spatial orientation between the N- and C-terminal FH regions are key.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.