Complement factor I: Regulatory nexus, driver of immunopathology, and therapeutic

Hallam, Thomas M.; Sharp, Stephen J.; Andreadi, Aikaterini; Kavanagh, David

doi:10.1016/j.imbio.2023.152410

Cited by 11 publications

(4 citation statements)

References 261 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As summarized in a recent review, recombinant FI-variants with mutations in the SP domain have been mainly associated with reduced iC3b generation and C3b co-factor activity, while mutations in the FIMAC domain tend to lead to decreased iC3b in serum. However, a great number of recombinantly expressed FI-variants has not been evaluated (31). In our experiments, the majority of the mutations occurring in the catalytic SP domain resulted in complete loss of activity of FI, with both FH and sCR1 as co-factors.…”

Section: Discussionmentioning

confidence: 86%

Functional evaluation of complement factor I variants by immunoassays and SDS-PAGE

Gerogianni,

Baas,

Sjöström

et al. 2023

Front. Immunol.

View full text Add to dashboard Cite

Factor I (FI) is an essential regulator of the complement system. Together with co-factors, FI degrades C3b, which inhibits further complement activation. Genetic mutations in FI are associated with pathological conditions like age-related macular degeneration and atypical hemolytic uremic syndome. Here, we evaluated eight recombinant FI genetic variants found in patients. We assessed FI’s co-factor activity in the presence of two co-factors; Factor H and soluble CR1. Different analytical assays were employed; SDS-PAGE to evaluate the degradation of C3b, ELISA to measure the generation of fluid phase iC3b and the degradation of surface-bound C3b using a novel Luminex bead-based assay. We demonstrate that mutations in the FIMAC and SP domains of FI led to significantly reduced protease activity, whereas the two analyzed mutations in the LDLRA2 domain did not result in any profound changes in FI’s function. The different assays employed displayed a strong positive correlation, but differences in the activity of the genetic variants Ile55Phe and Gly261Asp could only be observed by combining different methods and co-factors for evaluating FI activity. In conclusion, our results provide a new perspective regarding available diagnostic tools for assessing the impact of mutations in FI.

show abstract

Section: Discussionmentioning

confidence: 86%

Functional evaluation of complement factor I variants by immunoassays and SDS-PAGE

Gerogianni,

Baas,

Sjöström

et al. 2023

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…Genotyping results were not required at screening if already available through participation in a previous Gyroscope sponsored study. The term ‘rare’ was defined as variants that changed the CFI coding sequence, had ≤1% minor allele frequency in GnomAD non-Finnish Europeans (V2.1.1, accessed http://gnomad.broadinstitute.org), and were previously associated with FI haploinsufficiency 11 . A detailed description of study design, route of administration, dose, number of subjects, biomarker matrices, sampling timing and methodology are provided in Supplementary Methods and Supplementary Table 1.…”

Section: Methodsmentioning

confidence: 99%

“…The AP is a part of the complement system that constantly surveys for foreign cells and debris and requires tight regulation to prevent inflammation and self-cell damage 10 . Regulatory proteins like factor H (FH), decay-accelerating factor (DAF; CD55), membrane cofactor protein (MCP; CD46), complement receptor 1 (CR1; CD35), and FI help control the AP, with FI being the only regulatory enzyme 11 . FI, expressed from the CFI gene, cleaves C3b by forming a trimolecular complex with cofactors FH for C3b, and MCP and CR1 for C3b and C4b 12–18 .…”

Section: Introductionmentioning

confidence: 99%

Ocular biomarker profiling after complement factor I gene therapy in geographic atrophy secondary to age-related macular degeneration

Hallam,

Gardenal,

McBlane

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

ObjectiveComplement biomarker analysis in ocular fluid samples from subjects with geographic atrophy (GA) in a Phase I/II clinical trial of subretinal AAV2 complement factor I (CFI; FI) gene therapy, PPY988 (formerly GT005), to understand target pharmacokinetics/pharmacodynamics. Clinical findings were subsequently utilized to investigate the therapeutic dose in anin vitrocomplement activation assay.Design, setting and participantsBiomarker data were evaluated from 28 subjects in FOCUS, a Phase I/II clinical trial evaluating the safety and efficacy of three ascending doses of PPY988.Main outcomes and measuresVitreous humor (VH), and aqueous humor (AH) from subjects before surgery and at serial timepoints (week 5 or 12, 36, 96) were evaluated for changes in levels of intact complement factors I, B and H (FI, FB, FH) components C3, C4, and C1q and breakdown products (Ba, C3a, C3b/iC3b, C4b) using validated assays and OLINK®proteomics.A modifiedin vitroassay of complement activation modelling VH complement concentrations was used to compare PPY988 potency to the approved intravitreal C3 inhibitor pegcetacoplan (Apellis) and complement Factor H (FH).ResultsAn average 2-fold increase in VH FI was observed post-treatment at week 36 and week 96. This correlated with a marked post-treatment reduction in VH concentration of the FB breakdown product Ba and Ba:FB ratio, but minimal changes in C3a and C3b/iC3b levels. Variable concordance in complement biomarker levels in VH versus AH suggest AH is not a reliable proxy for VH for complement activation. During the experimental comparison of doses, a 2-fold increase of FI achieved in the vitreous had only a minor effect on the complement amplification loopin vitro, indicating limited impact [IC50: 1229nM]. Pegcetacoplan completely blocks C3a generation at concentrations much lower than the estimated trough level for monthly intravitreal injections [IC50: 2nM]. Supplementation with FH in the assay revealed similar potency to pegcetacoplan [IC50: 6nM].Conclusions and relevancePPY988 subretinal gene therapy may not have provided sufficient FI protein to meaningfully modulate complement activation to slow GA growth. Reviewing VH biomarkers is important for understanding target expression, pathway engagement, and determining optimal dose, thereby informing future clinical development.

show abstract

“…Factor I (FI) is a serine protease which degrades C3b and C4b in the presence of cofactors. Consequently, it is a common inhibitor of all three complement pathways at the level of C3 convertases [91,92]. FI circulates as a cleaved, pre-activated protease (like MASP-3 and FD) in human blood.…”

Section: Factor I the Common Regulator Of The Three Pathwaysmentioning

confidence: 99%

The Lectin Pathway of the Complement System—Activation, Regulation, Disease Connections and Interplay with Other (Proteolytic) Systems

Dobó,

Kocsis,

Farkas

et al. 2024

IJMS

View full text Add to dashboard Cite

The complement system is the other major proteolytic cascade in the blood of vertebrates besides the coagulation–fibrinolytic system. Among the three main activation routes of complement, the lectin pathway (LP) has been discovered the latest, and it is still the subject of intense research. Mannose-binding lectin (MBL), other collectins, and ficolins are collectively termed as the pattern recognition molecules (PRMs) of the LP, and they are responsible for targeting LP activation to molecular patterns, e.g., on bacteria. MBL-associated serine proteases (MASPs) are the effectors, while MBL-associated proteins (MAps) have regulatory functions. Two serine protease components, MASP-1 and MASP-2, trigger the LP activation, while the third component, MASP-3, is involved in the function of the alternative pathway (AP) of complement. Besides their functions within the complement system, certain LP components have secondary (“moonlighting”) functions, e.g., in embryonic development. They also contribute to blood coagulation, and some might have tumor suppressing roles. Uncontrolled complement activation can contribute to the progression of many diseases (e.g., stroke, kidney diseases, thrombotic complications, and COVID-19). In most cases, the lectin pathway has also been implicated. In this review, we summarize the history of the lectin pathway, introduce their components, describe its activation and regulation, its roles within the complement cascade, its connections to blood coagulation, and its direct cellular effects. Special emphasis is placed on disease connections and the non-canonical functions of LP components.

show abstract

Complement factor I: Regulatory nexus, driver of immunopathology, and therapeutic

Cited by 11 publications

References 261 publications

Functional evaluation of complement factor I variants by immunoassays and SDS-PAGE

Functional evaluation of complement factor I variants by immunoassays and SDS-PAGE

Ocular biomarker profiling after complement factor I gene therapy in geographic atrophy secondary to age-related macular degeneration

The Lectin Pathway of the Complement System—Activation, Regulation, Disease Connections and Interplay with Other (Proteolytic) Systems

Contact Info

Product

Resources

About