C3-targeted host-modulation approaches to oral inflammatory conditions.

Periodontitis is an inflammatory disease caused by biofilm accumulation and dysbiosis in subgingival areas surrounding the teeth. If not properly treated, this oral disease may result in tooth loss and consequently poor esthetics, deteriorated masticatory function and compromised quality of life. Epidemiological and clinical intervention studies indicate that periodontitis can potentially aggravate systemic diseases, such as, cardiovascular disease, type 2 diabetes mellitus, rheumatoid arthritis, and Alzheimer disease. Therefore, improvements in the treatment of periodontal disease may benefit not only oral health but also systemic health. The complement system is an ancient host defense system that plays pivotal roles in immunosurveillance and tissue homeostasis. However, complement has unwanted consequences if not controlled appropriately or excessively activated. Complement overactivation has been observed in patients with periodontitis and in animal models of periodontitis and drives periodontal inflammation and tissue destruction. This review places emphasis on a promising periodontal host-modulation therapy targeting the complement system, namely the complement C3-targeting drug, AMY-101. AMY-101 has shown safety and efficacy in reducing gingival inflammation in a recent Phase 2a clinical study. We also discuss the potential of AMY-101 to treat peri-implant inflammatory conditions, where complement also seems to be involved and there is an urgent unmet need for effective treatment.

Complement C3 vs C5 inhibition in severe COVID-19: Early clinical findings reveal differential biological efficacy.

Growing clinical evidence has implicated complement as a pivotal driver of COVID-19 immunopathology. Deregulated complement activation may fuel cytokine-driven hyper-inflammation, thrombotic microangiopathy and NET-driven immunothrombosis, thereby leading to multi-organ failure. Complement therapeutics have gained traction as candidate drugs for countering the detrimental consequences of SARS-CoV-2 infection. Whether blockade of terminal complement effectors (C5, C5a, or C5aR1) may elicit similar outcomes to upstream intervention at the level of C3 remains debated. Here we compare the efficacy of the C5-targeting monoclonal antibody eculizumab with that of the compstatin-based C3-targeted drug candidate AMY-101 in small independent cohorts of severe COVID-19 patients. Our exploratory study indicates that therapeutic complement inhibition abrogates COVID-19 hyper-inflammation. Both C3 and C5 inhibitors elicit a robust anti-inflammatory response, reflected by a steep decline in C-reactive protein and IL-6 levels, marked lung function improvement, and resolution of SARS-CoV-2-associated acute respiratory distress syndrome (ARDS). C3 inhibition afforded broader therapeutic control in COVID-19 patients by attenuating both C3a and sC5b-9 generation and preventing FB consumption. This broader inhibitory profile was associated with a more robust decline of neutrophil counts, attenuated neutrophil extracellular trap (NET) release, faster serum LDH decline, and more prominent lymphocyte recovery. These early clinical results offer important insights into the differential mechanistic basis and underlying biology of C3 and C5 inhibition in COVID-19 and point to a broader pathogenic involvement of C3-mediated pathways in thromboinflammation. They also support the evaluation of these complement-targeting agents as COVID-19 therapeutics in large prospective trials.

Complement C3-Targeted Therapy: Replacing Long-Held Assertions with Evidence-Based Discovery.

Complement dysregulation underlies several inflammatory disorders, and terminal complement inhibition has thus far afforded significant clinical gains. Nonetheless, emerging pathologies, fueled by complement imbalance and therapy-skewing genetic variance, underscore the need for more comprehensive, disease-tailored interventions. Modulation at the level of C3, a multifaceted orchestrator of the complement cascade, opens up prospects for broader therapeutic efficacy by targeting multiple pathogenic pathways modulated by C3-triggered proinflammatory crosstalk. Notably, C3 intervention is emerging as a viable therapeutic strategy for renal disorders with predominantly complement-driven etiology, such as C3 glomerulopathy (C3G). Using C3G as a paradigm, we argue that concerns about the feasibility of long-term C3 intervention need to be placed into perspective and weighed against actual therapeutic outcomes in prospective clinical trials.

Taming hemodialysis-induced inflammation: Are complement C3 inhibitors a viable option?

Owing to an increasing shortage of donor organs, the majority of patients with end-stage kidney disease remains reliant on extracorporeal hemodialysis (HD) in order to counter the lifelong complications of a failing kidney. While HD remains a life-saving option for these patients, mounting evidence suggests that it also fuels a vicious cycle of thromboinflammation that can increase the risk of cardiovascular disease. During HD, blood-borne innate immune systems become inappropriately activated on the biomaterial surface, instigating proinflammatory reactions that can alter endothelial and vascular homeostasis. Complement activation, early during the HD process, has been shown to fuel a multitude of detrimental thromboinflammatory reactions that collectively contribute to patient morbidity. Here we discuss emerging aspects of complement's involvement in HD-induced inflammation and put forth the concept that targeted intervention at the level of C3 might constitute a promising therapeutic approach in HD patients.

Safety profile after prolonged C3 inhibition.

The central component of the complement cascade, C3, is involved in various biological functions, including opsonization of foreign bodies, clearance of waste material, activation of immune cells, and triggering of pathways controlling development. Given its broad role in immune responses, particularly in phagocytosis and the clearance of microbes, a deficiency in complement C3 in humans is often associated with multiple bacterial infections. Interestingly, an increased susceptibility to infections appears to occur mainly in the first two years of life and then wanes throughout adulthood. In view of the well-established connection between C3 deficiency and infections, therapeutic inhibition of complement at the level of C3 is often considered with caution or disregarded. We therefore set out to investigate the immune and biochemical profile of non-human primates under prolonged treatment with the C3 inhibitor compstatin (Cp40 analog). Cynomolgus monkeys were dosed subcutaneously with Cp40, resulting in systemic inhibition of C3, for 1 week, 2 weeks, or 3 months. Plasma concentrations of both C3 and Cp40 were measured periodically and complete saturation of plasma C3 was confirmed. No differences in hematological, biochemical, or immunological parameters were identified in the blood or tissues of animals treated with Cp40 when compared to those injected with vehicle alone. Further, skin wounds showed no signs of infection in those treated with Cp40. In fact, Cp40 treatment was associated with a trend toward accelerated wound healing when compared with the control group. In addition, a biodistribution study in a rhesus monkey indicated that the distribution of Cp40 in the body is associated with the presence of C3, concentrating in organs that accumulate blood and produce C3. Overall, our data suggest that systemic C3 inhibition in healthy adult non-human primates is not associated with a weakened immune system or susceptibility to infections.

C3 Targeted Complement Therapy for Chronic Periodontitis - A Scoping Review.

Aim: Chronic Periodontitis (CP) is a complex disease initiated by inflammation caused by dysbiotic bacterial communities in the subgingival environment. The Porphyromonas gingivalis, a keystone pathogen at low colonization, causes immune subversion of complement component C5aR, leading to complement C3-dependent destructive inflammation responsible for the inflammatory bone loss in CP. Animal studies have shown that targeting complement C3 with its inhibitor like AMY-101 may help reduce inflammatory bone loss in CP. This scoping review elaborates on the role of complement C3 targeted therapy for CP. Materials and Methods: About 66 original studies were obtained during an initial electronic search in Medline (Pubmed), Scopus, Web of Science, and Embase. About four articles were included in the review after screening the duplicates and reading the full text. Their aims and objectives, drug dosage, route of administration, results, and conclusions were recorded. Results: Of the four-original research, 3 were animal studies and one randomized Phase IIa clinical trial. They showed that C3 targeted complement therapy reduced the inflammatory and clinical periodontal parameters in CP. Conclusion: C3 targeted complement therapy may be regarded as a valuable adjunct to non-surgical periodontal treatment for CP. However, the results are still under investigation and require further verification through clinical trials.

Complement-Dependent Mechanisms and Interventions in Periodontal Disease.

Periodontitis is a prevalent inflammatory disease that leads to the destruction of the tooth-supporting tissues. Current therapies are not effective for all patients and this oral disease continues to be a significant public health and economic burden. Central to periodontal disease pathogenesis is a reciprocally reinforced interplay between microbial dysbiosis and destructive inflammation, suggesting the potential relevance of host-modulation therapies. This review summarizes and discusses clinical observations and pre-clinical intervention studies that collectively suggest that complement is hyperactivated in periodontitis and that its inhibition provides a therapeutic benefit. Specifically, interception of the complement cascade at its central component, C3, using a locally administered small peptidic compound (Cp40/AMY-101) protected non-human primates from induced or naturally occurring periodontitis. These studies indicate that C3-targeted intervention merits investigation as an adjunctive treatment of periodontal disease in humans.

Safety and Efficacy of the Complement Inhibitor AMY-101 in a Natural Model of Periodontitis in Non-human Primates.

Periodontitis is a chronic inflammatory disease associated with overactivation of the complement system. Recent preclinical studies suggest that host-modulation therapies may contribute to effective treatment of human periodontitis, which may lead to loss of teeth and function if untreated. We previously showed that locally administered AMY-101 (Cp40), a peptidic inhibitor of the central complement component C3, can inhibit naturally occurring periodontitis in non-human primates (NHPs) when given once a week. This study was undertaken to determine the local safety of increasing doses of the drug as well as its efficacy when given at a reduced frequency or after systemic administration. Our findings have determined a local dose of AMY-101 (0.1 mg/site) that is free of local irritation and effective when given once every 3 weeks. Moreover, a daily subcutaneous dose of AMY-101 (4 mg/kg bodyweight) was protective against NHP periodontitis, suggesting that patients treated for systemic disorders (e.g., paroxysmal nocturnal hemoglobinuria) can additionally benefit in terms of improved periodontal condition. In summary, AMY-101 appears to be a promising candidate drug for the adjunctive treatment of human periodontitis, a notion that merits investigation in human clinical trials.

From orphan drugs to adopted therapies: Advancing C3-targeted intervention to the clinical stage.

Complement dysregulation is increasingly recognized as an important pathogenic driver in a number of clinical disorders. Complement-triggered pathways intertwine with key inflammatory and tissue destructive processes that can either increase the risk of disease or exacerbate pathology in acute or chronic conditions. The launch of the first complement-targeted drugs in the clinic has undeniably stirred the field of complement therapeutic design, providing new insights into complement's contribution to disease pathogenesis and also helping to leverage a more personalized, comprehensive approach to patient management. In this regard, a rapidly expanding toolbox of complement therapeutics is being developed to address unmet clinical needs in several immune-mediated and inflammatory diseases. Elegant approaches employing both surface-directed and fluid-phase inhibitors have exploited diverse components of the complement cascade as putative points of therapeutic intervention. Targeting C3, the central hub of the system, has proven to be a promising strategy for developing biologics as well as small-molecule inhibitors with clinical potential. Complement modulation at the level of C3 has recently shown promise in preclinical primate models, opening up new avenues for therapeutic intervention in both acute and chronic indications fueled by uncontrolled C3 turnover. This review highlights recent developments in the field of complement therapeutics, focusing on C3-directed inhibitors and alternative pathway (AP) regulator-based approaches. Translational perspectives and considerations are discussed, particularly with regard to the structure-guided drug optimization and clinical advancement of a new generation of C3-targeted peptidic inhibitors.

Complement in paroxysmal nocturnal hemoglobinuria: exploiting our current knowledge to improve the treatment landscape.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematological disorder associated with an acquired deficiency in glycophosphatidylinositol-anchor biosynthesis that renders erythrocytes susceptible to complement attack. Intravascular hemolysis via the membrane attack complex is a clinical hallmark of the disease, and C5 blockade is currently the only approved treatment for PNH. However, residual anemia is an emerging observation for many PNH patients receiving anti-C5 treatment. A range of complement-targeted therapeutic approaches, encompassing surface-directed inhibition of C3 convertases, blockade of membrane attack complex assembly or C3 interception using peptidic inhibitors, has yielded promising results and offers leverage for even more effective treatment of PNH. This article discusses recent advances in this rapidly evolving field, integrating critical perspectives from preclinical PNH models and diverse complement modulation strategies with genetic insights and therapy response profiles. It also evaluates the relative efficacy, limitations and benefits afforded by C3 or C5 inhibition in the context of PNH therapeutics.