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Previously we reported on the therapeutic monoclonal anti-human C2 antibody empasiprubart that inhibits activation of the classical and lectin pathways of complement. Preclinical studies with this antibody are hampered by its low affinity for C2 of animal species other than primates. We developed a high affinity, Ca -dependent anti-rat C2 antibody using the sequences and structural data of empasiprubart. Pharmacokinetics and pharmacodynamics of the resulting antibody in Sprague Dawley rats were assessed and used for an intervention study in a rat model of delayed graft function following kidney transplantation. The anti-rat C2 antibody improved kidney function and health in the rats within the first 2 weeks post-transplantation. Our study shows the successful development of an analogue of empasiprubart that can be used in preclinical disease models and highlights the potential of C2-blocking as a therapeutic strategy for preventing delayed graft function following kidney transplantation.

Activation of the complement system propagates neuroinflammation and brain damage early and chronically after traumatic brain injury (TBI). The complement system is complex and comprises more than 50 components, many of which remain to be characterized in the normal and injured brain. Moreover, complement therapeutic studies have focused on a limited number of histopathological outcomes, which while informative, do not assess the effect of complement inhibition on neuroprotection and inflammation in a comprehensive manner. Using high throughput gene expression technology (NanoString), we simultaneously analyzed complement gene expression profiles with other neuroinflammatory pathway genes at different time points after TBI. We additionally assessed the effects of complement inhibition on neuropathological processes. Analyses of neuroinflammatory genes were performed at days 3, 7, and 28 post injury in male C57BL/6 mice following a controlled cortical impact injury. We also characterized the expression of 59 complement genes at similar time points, and also at 1- and 2-years post injury. Overall, TBI upregulated the expression of markers of astrogliosis, immune cell activation, and cellular stress, and downregulated the expression of neuronal and synaptic markers from day 3 through 28 post injury. Moreover, TBI upregulated gene expression across most complement activation and effector pathways, with an early emphasis on classical pathway genes and with continued upregulation of C2 , C3 and C4 expression 2 years post injury. Treatment using the targeted complement inhibitor, CR2-Crry, significantly ameliorated TBI-induced transcriptomic changes at all time points. Nevertheless, some immune and synaptic genes remained dysregulated with CR2-Crry treatment, suggesting adjuvant anti-inflammatory and neurotropic therapy may confer additional neuroprotection. In addition to characterizing complement gene expression in the normal and aging brain, our results demonstrate broad and chronic dysregulation of the complement system after TBI, and strengthen the view that the complement system is an attractive target for TBI therapy.

Complement component C5 is crucial for experimental animal inflammatory tissue damage; however, its involvement in human inflammation is incompletely understood. The responses to Gram-negative bacteria were here studied taking advantage of human genetic complement-deficiencies--nature's own knockouts--including a previously undescribed C5 defect. Such deficiencies provide a unique tool for investigating the biological role of proteins. The experimental conditions allowed cross-talk between the different inflammatory pathways using a whole blood model based on the anticoagulant lepirudin, which does not interfere with the complement system. Expression of tissue factor, cell adhesion molecules, and oxidative burst depended highly on C5, mediated through the activation product C5a, whereas granulocyte enzyme release relied mainly on C3 and was C5a-independent. Release of cytokines and chemokines was mediated to varying degrees by complement and CD14; for example, interleukin (IL)-1β and IL-8 were more dependent on complement than IFN-γ and IL-6, which were highly dependent on CD14. IL-1 receptor antagonist (IL-1ra) and IFN-γ inducible protein 10 (IP-10) were fully dependent on CD14 and inversely regulated by complement, that is, complement deficiency and complement inhibition enhanced their release. Granulocyte responses were mainly complement-dependent, whereas monocyte responses were more dependent on CD14. Notably, all responses were abolished by combined neutralization of complement and CD14. The present study provides important insight into the comprehensive role of complement in human inflammatory responses to Gram-negative bacteria.

Objective: To evaluate the frequency of primary immunodeficiencies (PID) in juvenile systemic lupus erythematosus (JSLE) patients. Methods: Some 72 JSLE patients were analyzed for levels of immunoglobulin classes and IgG subclasses and early components of the classical complement pathway. Determination of C4 gene copy number (GCN) and detection of type I C2 deficiency (D) were also performed. Results: PID was identified in 16 patients (22%): C2D in three, C4D in three, C1qD in two, IgG2D (<20 mg/dl) in four, IgAD (<7 mg/dl) in three, and IgMD (<35 mg/dl) in three; one of these patients presented IgA, C2 and C4D. Two patients had low C4 GCN and two had type I C2D. Demographic data, family history of autoimmune disease and PID, JSLE clinical findings, occurrence of infections, disease activity and therapies were similar in patients with and without PID (p > 0.05). Remarkably, the median of Systemic Lupus International Collaborating Clinics/ACR-damage index (SLICC/ACR-DI) was significantly higher in JSLE patients with PID compared with patients without these abnormalities (p = 0.0033), likewise the high frequency of SLICC/ACR-DI > 1 (p = 0.023). Conclusions: A high frequency of PID was observed in JSLE patients, suggesting that these defects may contribute to lupus development. Our findings indicate that these two groups of PID should be investigated in severe pediatric lupus.

PurposeTo determine whether gene polymorphisms which are associated with age-related macular degeneration (AMD) influence treatments’ response and specifically the antioxidant supplementation in dry AMD patients, as well as the anti-vascular endothelial growth factor (anti-VEGF) therapy in neovascular AMD patients.MethodsA total of 170 patients with dry AMD and 52 neovascular AMD patients were genotyped for the following single nucleotide polymorphisms (SNPs): rs1061170/Y402H in CFH gene, rs10490924/A69S in ARMS2 gene, rs9332739/E318D and rs547154/IVS10 in C2 gene, and rs4151667/L9H and rs2072633/IVS17 in CFB gene. Treatment response was evaluated by comparing visual acuity and optical coherence tomography between baseline and at the end of the treatment.ResultsΤhe CFH/Y402H variant was associated with the response to antioxidants in dry AMD patients. Carriers of one or two CFH risk alleles displayed a lower chance of responding compared to those with no risk allele. No association of antioxidants’ response and ARMS2/A69S genotype was identified. The analysis of the C2 and CFB genetic variants (protective SNPs) revealed that antioxidant supplementation was much more effective in protective SNP carriers. In neovascular AMD patients, the analysis indicated that Y402H homozygous patients were less likely to respond to anti-VEGF therapy compared to heterozygous. Regarding the ARMS2/A69S genotype, carriers of the risk variant experienced significantly worse treatment outcome compared to wild-type patients.ConclusionIn AMD patients, the efficacy of the antioxidant supplementation and the anti-VEGF therapy appears to differ by genotype. The detection of genetic variants, associated with treatment responsiveness, could lead to improved visual outcomes through genotype-directed therapy.