How the Availability of Anti-C5a Agents Could Change the Management of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

BACKGROUND: Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is a cluster of potentially life-threatening disorders, often involving the kidney with a necrotizing crescentic glomerulonephritis with scanty deposition of immunoglobulins and complement. Historically the role of complement has been considered ancillary. Recently, an anti-myeloperoxidase (MPO) AAV model in complement-deficient mice has shown an involvement for the complement cascade in the development of the renal injuries. Further animal studies showing that in contrast to mice deficient for factor B and C5 animals deficient for C4 were susceptible to AAV development by injection of anti-MPO antibodies emphasized the specific involvement of the alternative pathway. Consonantly, the C5a receptor (Cd88) blockade was found to protect mice from MPO-AAV. CCX168, i.e., avacopan, a powerful inhibitor of C5a receptor that can be administered orally, was shown to reduce the proinflammatory effects of C5a and abolish the activation of neutrophils, their migration and adherence to endothelium, and the vascular endothelial cell retraction that increases permeability. SUMMARY: Avacopan was found to be safe in healthy volunteers given a wide range of doses in a phase 1 clinical trial. The phase 2 trial CLEAR assessed the possibility to decrease dose or entirely replace glucocorticosteroids in the standard-of-care therapy of AAV. Avacopan, added to CYC or RTX either in combination with GCs or not, shortened the time to remission in patients with either newly diagnosed or relapsing AAV. The phase 3 ADVOCATE study compared the ability of an avacopan-associated regimen to induce and sustain remission in AAV patients versus a conventional GC-associated scheme. Remission at week 26 was observed in 72.3% of patients given avacopan and in 70.1% of those given prednisone. Sustained remission at week 52 (second primary endpoint) was obtained in 65.7% of patients given avacopan and in 54.9% receiving prednisone. The avacopan-associated regimen was noninferior at week 26 and superior at week 52 in sustaining remission as compared to the GC-based scheme. KEY MESSAGES: The results of the ADVOCATE trial opened new prospects for the treatment of AAV and also other immune-mediated diseases with renal involvement. The possible position of avacopan in a routine clinical setting and its possible indications in specific subsets of patients with AAV are extensively discussed.

Paclitaxel binds and activates C5aR1: A new potential therapeutic target for the prevention of chemotherapy-induced peripheral neuropathy and hypersensitivity reactions.

Chemotherapy-induced peripheral neuropathy (CIPN) and hypersensitivity reactions (HSRs) are among the most frequent and impairing side effects of the antineoplastic agent paclitaxel. Here, we demonstrated that paclitaxel can bind and activate complement component 5a receptor 1 (C5aR1) and that this binding is crucial in the etiology of paclitaxel-induced CIPN and anaphylaxis. Starting from our previous data demonstrating the role of interleukin (IL)-8 in paclitaxel-induced neuronal toxicity, we searched for proteins that activate IL-8 expression and, by using the Exscalate platform for molecular docking simulations, we predicted the high affinity of C5aR1 with paclitaxel. By in vitro studies, we confirmed the specific and competitive nature of the C5aR1-paclitaxel binding and found that it triggers intracellularly the NFkB/P38 pathway and c-Fos. In F11 neuronal cells and rat dorsal root ganglia, C5aR1 inhibition protected from paclitaxel-induced neuropathological effects, while in paclitaxel-treated mice, the absence (knock-out mice) or the inhibition of C5aR1 significantly ameliorated CIPN symptoms-in terms of cold and mechanical allodynia-and reduced the chronic pathological state in the paw. Finally, we found that C5aR1 inhibition can counteract paclitaxel-induced anaphylactic cytokine release in macrophages in vitro, as well as the onset of HSRs in mice. Altogether these data identified C5aR1 as a key mediator and a new potential pharmacological target for the prevention and treatment of CIPN and HSRs induced by paclitaxel.

HIV-1 Trans Infection via TNTs Is Impeded by Targeting C5aR.

Nonadjacent immune cells communicate through a complex network of tunneling nanotubes (TNTs). TNTs can be hijacked by HIV-1, allowing it to spread between connected cells. Dendritic cells (DCs) are among the first cells to encounter HIV-1 at mucosal sites, but they are usually efficiently infected only at low levels. However, HIV-1 was demonstrated to productively infect DCs when the virus was complement-opsonized (HIV-C). Such HIV-C-exposed DCs mediated an improved antiviral and T-cell stimulatory capacity. The role of TNTs in combination with complement in enhancing DC infection with HIV-C remains to be addressed. To this aim, we evaluated TNT formation on the surface of DCs or DC/CD4+ T-cell co-cultures incubated with non- or complement-opsonized HIV-1 (HIV, HIV-C) and the role of TNTs or locally produced complement in the infection process using either two different TNT or anaphylatoxin receptor antagonists. We found that HIV-C significantly increased the formation of TNTs between DCs or DC/CD4+ T-cell co-cultures compared to HIV-exposed DCs or co-cultures. While augmented TNT formation in DCs promoted productive infection, as was previously observed, a significant reduction in productive infection was observed in DC/CD4+ T-cell co-cultures, indicating antiviral activity in this setting. As expected, TNT inhibitors significantly decreased infection of HIV-C-loaded-DCs as well as HIV- and HIV-C-infected-DC/CD4+ T-cell co-cultures. Moreover, antagonizing C5aR significantly inhibited TNT formation in DCs as well as DC/CD4+ T-cell co-cultures and lowered the already decreased productive infection in co-cultures. Thus, local complement mobilization via DC stimulation of complement receptors plays a pivotal role in TNT formation, and our findings herein might offer an exciting opportunity for novel therapeutic approaches to inhibit trans infection via C5aR targeting.

Avacopan, a selective C5a receptor antagonist, for anti-neutrophil cytoplasmic antibody-associated vasculitis.

Avacopan, an orally administered C5a receptor antagonist, has been approved for the treatment of microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) in Japan and the USA. In ADVOCATE Phase III clinical trial, patients with active MPA or GPA received either 30 mg avacopan twice daily or prednisone on a tapering schedule in combination with rituximab or cyclophosphamide (followed by azathioprine). The trial met its two primary endpoints: avacopan showed non-inferiority to prednisone for achieving remission at Week 26 (avacopan, 72.3%; prednisone, 70.1%; p < .001 for non-inferiority and p = .24 for superiority) and superiority for maintaining remission at Week 52 (65.7% for avacopan, 54.9% prednisone, p < .001 for non-inferiority and p = .007 for superiority). Of several key secondary endpoints tested, the glucocorticoid toxicity index (GTI)-cumulative worsening score and GTI-aggregate improvement score were significantly lower in the avacopan group than in the prednisone group at both Weeks 26 and 52. Serious adverse events related and unrelated to the worsening vasculitis were reported at 10.2% and 37.3% in the avacopan group and at 14.0% and 39.0% in the prednisone group, respectively. Avacopan has set the stage for the semi-glucocorticoid-free or glucocorticoid-free treatment of MPA and GPA.

Comparative anti-inflammatory activities of antagonists to C3a and C5a receptors in a rat model of intestinal ischaemia/reperfusion injury.

1. Complement activation is implicated in the pathogenesis of intestinal ischaemia-reperfusion injury (I/R), although the relative importance of individual complement components is unclear. A C3a receptor antagonist N(2)-[(2,2-diphenylethoxy)acetyl]-l-arginine (C3aRA) has been compared with a C5a receptor antagonist (C5aRA), AcF-[OPdChaWR], in a rat model of intestinal I/R. 2. C3aRA (IC(50)=0.15 microm) and C5aRA (IC(50)=0.32 microm) bound selectively to human polymorphonuclear leukocyte (PMN) C3a and C5a receptors, respectively. Effects on circulating neutrophils and blood pressure in the rat were also assessed. 3. Anaesthetised rats, subjected to intestinal ischaemia (30 min) and reperfusion (120 min), were administered intravenously with either (A) the C3aRA (0.1-1.0 mg x kg(-1)); the C5aRA (1.0 mg x kg(-1)); the C3aRA+C5aRA (each 1.0 mg x kg(-1)); or vehicle, 45 min prior, or (B) the C3aRA (1.0 mg x kg(-1)) or vehicle, 120 min prior to reperfusion. 4. The C3aRA and C5aRA, administered 45 min prior to reperfusion, displayed similar efficacies at ameliorating several disease markers (increased oedema, elevated ALT levels and mucosal damage) of rat intestinal I/R. The combination drug treatment did not result in greater injury reduction than either antagonist alone. However, doses of the C3aRA (0.01-10 mg x kg(-1)) caused transient neutropaenia, and the highest dose (10 mg x kg(-1)) also caused a rapid and transient hypertension. 5. The C3aRA (1.0 mg x kg(-1)), delivered 120 min prior to reperfusion to remove the global effect of C3aRA-induced neutrophil sequestration, did not attenuate the markers of intestinal I/R, despite persistent C3aR antagonism at this time. 6. C3aR antagonism does not appear to be responsible for the anti-inflammatory actions of this C3aRA in intestinal I/R in the rat. Instead, C3aRA-mediated global neutrophil tissue sequestration during ischaemia and early reperfusion may account for the protective effects observed.