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Interleukin-6 (IL-6) is an emerging therapeutic target in myocardial infarction (MI). IL-6 has 2 distinct signaling pathways: trans-signaling, which mediates inflammation, and classic signaling, which also has anti-inflammatory effects. The novel recombinant fusion protein sgp130Fc achieves exclusive trans-signaling blockade, whereas anti–IL-6 anti...
Citations
... The depletion of CCR2+ cells immediately prior to an ischemia/reperfusion injury model resulted in reduced monocyte recruitment and improved cardiac function. The newly recruited macrophages mediate the inflammatory response by producing cytokines such as MCP-1, TNF-ɑ, IL-1, and IL-6 [136][137][138][139][140][141][142][143][144][145][146][147][148][149][150][151] at a much higher rate than the resident CCR2 + macrophages [152]. These cytokines exacerbate tissue inflammation by increasing pro-inflammatory cytokine production in adjacent immune cells and recruiting additional immune cells to the area. ...
As the leading cause of mortality worldwide, cardiovascular disease (CVD) represents a variety of heart diseases and vascular disorders, including atherosclerosis, aneurysm, ischemic injury in the heart and brain, arrythmias, and heart failure. Macrophages, a diverse population of immune cells that can promote or suppress inflammation, have been increasingly recognized as a key regulator in various processes in both healthy and disease states. In healthy conditions, these cells promote the proper clearance of cellular debris, dead and dying cells, and provide a strong innate immune barrier to foreign pathogens. However, macrophages can play a detrimental role in the progression of disease as well, particularly those inflammatory in nature. This review will focus on the current knowledge regarding the role of macrophages in cardiovascular diseases.
... Возможность ингибирования только одного сигнального пути ИЛ-6 представляет собой клинически более безопасную стратегию. На модели реперфузионного инфаркта миокарда у крыс применение антител, нейтрализующих ИЛ-6, не влияло на размер инфаркта, в то время как sgp130Fc, ингибитор транс-сигнального пути ИЛ-6, уменьшил размер инфаркта примерно на 50 %, тем самым сохраняя функцию сердца [20]. Фармакологический селективный ин-гибитор транс-сигнального пути ИЛ-6 оламкицепт, вариант sgp130Fc, показал многообещающие результаты во II фазе клинических исследований при воспалительных заболеваниях кишечника [21]. ...
Aim . Identification of interleukin-6 (IL-6) signaling pathways in patients with chronic heart failure (CHF).
Material and methods . The diversity of IL-6 effects is due to the presence of classical signaling and trans-signaling pathways. The study included 164 patients with CHF hospitalized for acute decompensated heart failure (ADHF), of which 129 had reduced left ventricular ejection fraction (HFrEF), and 35 had preserved ejection fraction (HFpEF). Blood concentrations of IL-6, soluble IL-6 receptor (sIL-6R), soluble transducer protein gp130 (sgp130), and high-sensitivity C-reactive protein (hsCRP) were measured.
Results . Patients with HFpEF had lower concentrations of IL-6 (6.15 [2.78, 10.65] pg/ml) and hsCRP (11.27 [5.84, 24.40] mg/ml) than patients with HFrEF (9.20 [4.70; 15.62] pg/ml and 17.23 [8.70; 34.51 mg/ml], respectively). In contrast, concentrations of rIL-6R were higher in HFpEF (59.06 [40.00; 75.85] ng/ml) than in HFrEF (49.15 [38.20; 64.89] ng/ml). Concentrations of sgp130 were not significantly different. In patients with HFrEF, positive correlations were found between the concentrations of IL-6 and hsCRP, IL-6 and rIL-6R, and IL-6 and sgp130, while in patients with HFpEF, there was a correlation only between IL-6 and hsCRP, which appeared stronger than in patients with HFrEF (r=0.698; p<0.001 and r=0.297; p<0.05, respectively).
Conclusion . Classical IL-6 signaling and trans-signaling are expressed to different degrees in patients with HFrEF and HFpEF in ADHF. The results of the study supplement the existing knowledge about the pathogenesis of inflammation in CHF and may contribute to the development of new methods and approaches to the treatment of the disease.
... sgp130Fc is taught as a specific inhibitor of IL6 trans-signalling that leaves IL6 cis-signalling intact. sgp130 administered to rodents is protective against diseases in multiple mouse and rat models, with superiority over anti-IL6/IL6R monotherapy in some instances [7][8][9]. Following proof-of-concept (POC) therapeutic studies in rodents, sgp130Fc was developed further as an anti-inflammatory drug (olamkicept), which is now in clinical trials [2,6,10,11]. ...
... Here, we tested the hypothesis that sgp130Fc, at concentrations relevant to those used in mouse experiments and in clinical trials [7,10,11,17], is a non-specific inhibitor of IL6 family cytokine signalling, rather than being a selective inhibitor of IL6 trans-signalling. ...
... It is taught that IL6 cis-signalling is homeostatic, whereas IL6 trans-signalling amplifies inflammatory responses in autocrine and paracrine and is disease-causing [2]. As such, sgp130Fc is proposed, and has been shown, to have therapeutic benefits over combined IL6 cisand trans-signalling inhibitors, such as tocilizumab [7]. However, it has also been reported that sgp130 might inhibit some aspects of OSM, CNTF and/or LIF signalling [1,5,6,12] and IL11 trans-signalling [28]. ...
IL6 is a proinflammatory cytokine that binds to membrane-bound IL6 receptor (IL6R) or soluble IL6R to signal via gp130 in cis or trans, respectively. We tested the hypothesis that sgp130Fc, which is believed to be a selective IL6 trans-signalling inhibitor, is in fact a non-specific inhibitor of gp130 signalling. In human cancer and primary cells, sgp130Fc inhibited IL6, IL11, OSM and CT1 cis-signalling. The IC50 values of sgp130Fc for IL6 and OSM cis-signalling were markedly (20- to 200-fold) lower than the concentrations of sgp130Fc used in mouse studies and clinical trials. sgp130 inhibited IL6 and OSM signalling in the presence of an ADAM10/17 inhibitor and the absence of soluble IL6R or OSMR, with effects that were indistinguishable from those of a gp130 neutralising antibody. These data show that sgp130Fc does not exclusively block IL6 trans-signalling and reveal instead that broad inhibition of gp130 signalling likely underlies its therapeutic effects. This proposes global or modular inhibition of gp130 as a therapeutic approach for treating human disease.
... • Because ventricular remodeling is an integral process of heart failure progression, our discovery of a novel neuro/immune/cardio axis mechanism may have clinical relevance with regard to ventricular remodeling and even heart failure. heart for ventricular remodeling, [27][28][29][30][31][32][33] it is critical to determine whether Piezo1 or Piezo2 in the TDRG contributes to ventricular remodeling by regulating IL-6-related neurogenic inflammation. Therefore, understanding the neuronal immune network underlying mechanotransduction is critical to discovering novel targets and devising mechanism-based strategies to lessen the severity of ventricular remodeling. ...
... Piezo1 contributes to enhanced secretion of IL-6 in human atrial fibroblasts, 54 and IL-6, as a local inflammatory cytokine in the heart, is essential to promote ventricular remodeling. [27][28][29][30][31][32][33] However, MI not only triggers a local inflammatory response but also contributes to concurrent neuroinflammation or neurogenic inflammation. Most research on it focuses on the related brain nuclei, 4,5 spinal cord, 7,14 or stellate ganglion, 6 ultimately attributable to outflow of sympathetic excitation to the heart, and these are the main effects of efferent nerves on the heart. ...
BACKGROUND
Heart failure is associated with a high rate of mortality and morbidity, and ventricular remodeling invariably precedes heart failure. Ventricular remodeling is fundamentally driven by mechanotransduction that is regulated by both the nervous system and the immune system. However, it remains unknown which key molecular factors govern the neuro/immune/cardio axis that underlies mechanotransduction during ventricular remodeling. Here, we investigated whether the mechanosensitive Piezo cation channel–mediated neurogenic inflammatory cascade underlies ventricular remodeling–related mechanotransduction.
METHODS
By ligating the left coronary artery of rats to establish an in vivo model of chronic myocardial infarction (MI), lentivirus-mediated thoracic dorsal root ganglion (TDRG)–specific Piezo1 knockdown rats and adeno-associated virus–PHP.S—mediated TDRG neuron–specific Piezo1 knockout mice were used to investigate whether Piezo1 in the TDRG plays a functional role during ventricular remodeling Subsequently, neutralizing antibody–mediated TDRG IL-6 (interleukin-6) inhibition rats and adeno-associated virus–PHP.S—mediated TDRG neuron–specific IL-6 knockdown mice were used to determine the mechanism underlying neurogenic inflammation. Primary TDRG neurons were used to evaluate Piezo1 function in vitro.
RESULTS
Expression of Piezo1 and IL-6 was increased, and these factors were functionally activated in TDRG neurons at 4 weeks after MI. Both knockdown of TDRG-specific Piezo1 and deletion of TDRG neuron–specific Piezo1 lessened the severity of ventricular remodeling at 4 weeks after MI and decreased the level of IL-6 in the TDRG or heart. Furthermore, inhibition of TDRG IL-6 or knockdown of TDRG neuron–specific IL-6 also ameliorated ventricular remodeling and suppressed the IL-6 cascade in the heart, whereas the Piezo1 level in the TDRG was not affected. In addition, enhanced Piezo1 function, as reflected by abundant calcium influx induced by Yoda1 (a selective agonist of Piezo1), led to increased release of IL-6 from TDRG neurons in mice 4 weeks after MI.
CONCLUSIONS
Our findings point to a critical role for Piezo1 in ventricular remodeling at 4 weeks after MI and reveal a neurogenic inflammatory cascade as a previously unknown facet of the neuronal immune signaling axis underlying mechanotransduction.
... Surprisingly, in many disease models, treatment with sgp130Fc was more beneficial than global blockade by IL-6-neutralizing antibodies. Such disease models included sepsis 101 , cerulein-induced acute pancreatitis 102 , bone fracture healing 103,104 and myocardial infarction 105 . In the cerulein-induced acute pancreatitis model, Il6 −/− mice showed more inflammation-associated damage in the pancreas than wild-type mice, but no subsequent lung failure. ...
... In contrast, specific blockade of IL-6 trans-signalling with recombinant sgp130Fc had minor effects on the immune response but did not impede bone fracture healing 103,104 . In a rat model of reperfused myocardial infarction, treatment with an IL-6-neutralizing antibody did not alter the infarct size, whereas treatment with sgp130Fc reduced the infiltration of neutrophils and mononuclear phagocytes into the myocardium and reduced the infarct size by about 50%, thereby preserving cardiac function 28 days after the myocardial infarction 105 . ...
Interleukin-6 (IL-6) is a key immunomodulatory cytokine that affects the pathogenesis of diverse diseases, including autoimmune diseases, chronic inflammatory conditions and cancer. Classical IL-6 signalling involves the binding of IL-6 to the membrane-bound IL-6 receptor α-subunit (hereafter termed 'mIL-6R') and glycoprotein 130 (gp130) signal-transducing subunit. By contrast, in IL-6 trans-signalling, complexes of IL-6 and the soluble form of IL-6 receptor (sIL-6R) signal via membrane-bound gp130. A third mode of IL-6 signalling - known as cluster signalling - involves preformed complexes of membrane-bound IL-6-mIL-6R on one cell activating gp130 subunits on target cells. Antibodies and small molecules have been developed that block all three forms of IL-6 signalling, but in the past decade, IL-6 trans-signalling has emerged as the predominant pathway by which IL-6 promotes disease pathogenesis. The first selective inhibitor of IL-6 trans-signalling, sgp130, has shown therapeutic potential in various preclinical models of disease and olamkicept, a sgp130Fc variant, had promising results in phase II clinical studies for inflammatory bowel disease. Technological developments have already led to next-generation sgp130 variants with increased affinity and selectivity towards IL-6 trans-signalling, along with indirect strategies to block IL-6 trans-signalling. Here, we summarize our current understanding of the biological outcomes of IL-6-mediated signalling and the potential for targeting this pathway in the clinic.
... This suggests that one potential route by which IL6R blockade reduces the odds of severe sepsis is by reducing CRP, although this remains a hypothesis. Given the ongoing development of therapeutics that target trans-specific IL-6 signalling and therapeutics that target CRP itself, this may represent a future avenue in sepsis therapeutics [43,44]; however, this does not alter the interpretation of the primary IL6R blockade-related finding here. Additionally, the concordance of MR effect estimates between cisCRP and cisIL6R genetic variants provides confidence in our primary analysis and strongly supports the role of IL-6 signalling in sepsis. ...
Background:
Sepsis is characterised by dysregulated, life-threatening immune responses, which are thought to be driven by cytokines such as interleukin 6 (IL-6). Genetic variants in IL6R known to down-regulate IL-6 signalling are associated with improved Coronavirus Disease 2019 (COVID-19) outcomes, a finding later confirmed in randomised trials of IL-6 receptor antagonists (IL6RAs). We hypothesised that blockade of IL6R could also improve outcomes in sepsis.
Methods and findings:
We performed a mendelian randomisation (MR) analysis using single nucleotide polymorphisms (SNPs) in and near IL6R to evaluate the likely causal effects of IL6R blockade on sepsis (primary outcome), sepsis severity, other infections, and COVID-19 (secondary outcomes). We weighted SNPs by their effect on CRP and combined results across them in inverse variance weighted meta-analysis, proxying the effect of IL6RA. Our outcomes were measured in UK Biobank, FinnGen, the COVID-19 Host Genetics Initiative (HGI), and the GenOSept and GainS consortium. We performed several sensitivity analyses to test assumptions of our methods, including utilising variants around CRP and gp130 in a similar analysis. In the UK Biobank cohort (N = 486,484, including 11,643 with sepsis), IL6R blockade was associated with a decreased risk of our primary outcome, sepsis (odds ratio (OR) = 0.80; 95% confidence interval (CI) 0.66 to 0.96, per unit of natural log-transformed CRP decrease). The size of this effect increased with severity, with larger effects on 28-day sepsis mortality (OR = 0.74; 95% CI 0.47 to 1.15); critical care admission with sepsis (OR = 0.48, 95% CI 0.30 to 0.78) and critical care death with sepsis (OR = 0.37, 95% CI 0.14 to 0.98). Similar associations were seen with severe respiratory infection: OR for pneumonia in critical care 0.69 (95% CI 0.49 to 0.97) and for sepsis survival in critical care (OR = 0.22; 95% CI 0.04 to 1.31) in the GainS and GenOSept consortium, although this result had a large degree of imprecision. We also confirm the previously reported protective effect of IL6R blockade on severe COVID-19 (OR = 0.69, 95% CI 0.57 to 0.84) in the COVID-19 HGI, which was of similar magnitude to that seen in sepsis. Sensitivity analyses did not alter our primary results. These results are subject to the limitations and assumptions of MR, which in this case reflects interpretation of these SNP effects as causally acting through blockade of IL6R, and reflect lifetime exposure to IL6R blockade, rather than the effect of therapeutic IL6R blockade.
Conclusions:
IL6R blockade is causally associated with reduced incidence of sepsis. Similar but imprecisely estimated results supported a causal effect also on sepsis related mortality and critical care admission with sepsis. These effects are comparable in size to the effect seen in severe COVID-19, where IL-6 receptor antagonists were shown to improve survival. These data suggest that a randomised trial of IL-6 receptor antagonists in sepsis should be considered.
... In a second wave, IL-6 is liberated from invaded leukocytes. Moreover, George and colleagues demonstrated that the blockade of IL-6 trans-signaling reduces local release of CCL2 (but not in the plasma) and the quantity of recruited neutrophils and macrophages in the myocardium [154]. Similarly, the administration of IL-6R antagonist to mice with permanent coronary occlusion decreases neutrophil and macrophage infiltration and attenuates matrix metalloproteinase (MMP) activation leading to higher survival rate, improved left ventricular dilatation and contractile function compared to the control group [155]. ...
Myocardial infarction (MI), a major contributor to worldwide morbidity and mortality, is caused by a lack of blood flow to the heart. Affected heart tissue becomes ischemic due to deficiency of blood perfusion and oxygen delivery. In case sufficient blood flow cannot be timely restored, cardiac injury with necrosis occurs. The ischemic/necrotic area induces a systemic inflammatory response and hundreds of thousands of leukocytes are recruited from the blood to the injured heart. The blood pool of leukocytes is rapidly depleted and urgent re-supply of these cells is needed. Myeloid cells are generated in the bone marrow (BM) and spleen, released into the blood, travel to sites of need, extravasate and accumulate inside tissues to accomplish various functions. In this review we focus on the “leukocyte supply chain” and will separately evaluate different myeloid cell compartments (BM, spleen, blood, heart) in steady state and after MI. Moreover, we highlight the local and systemic kinetics of extracellular factors, chemokines and danger signals involved in the regulation of production/generation, release, transportation, uptake, and activation of myeloid cells during the inflammatory phase of MI.
... Indeed, administration of canakinumab to immunoneutralize interleukin-1b in people with a previous history of MI and elevated levels of C reactive protein, reduced the rates of MACE, including MI, findings correlated with decreased circulating biomarkers of inflammation [64]. Similarly, emerging data using agents to immunoneutralize interleukin-6 (IL-6) or block the IL-6 receptor suggests that reduction of IL-6 receptor activity in the context of acute MI may preserve myocardium and attenuate the severity of experimental and clinical MI [65,66]. Intriguingly, we detected a reduction in IL-6 expression within the left ventricle and left atria within 3 h of acute myocardial infarction in liraglutidetreated mice. ...
Objectives
Glucagon-like peptide-1 receptor (GLP-1R) agonists reduce the rates of major cardiovascular events, including myocardial infarction in people with type 2 diabetes, and decrease infarct size while preserving ventricular function in preclinical studies. Nevertheless, the precise cellular sites of GLP-1R expression that mediate the cardioprotective actions of GLP-1 in the setting of ischemic cardiac injury are uncertain.
Methods
Publicly available single cell RNA sequencing (scRNA-seq) datasets on mouse and human heart cells were analyzed for Glp1r/GLP1R expression. Fluorescent activated cell sorting was used to localize Glp1r expression in cell populations from the mouse heart. The importance of endothelial and hematopoietic cells for the cardioprotective response to liraglutide in the setting of acute myocardial infarction (MI) was determined by inactivating the Glp1r in Tie2+ cell populations. Cardiac gene expression profiles regulated by liraglutide were examined using RNA-Seq to interrogate mouse atria and both infarcted and non-infarcted ventricular tissue after acute coronary artery ligation.
Results
In mice, cardiac Glp1r mRNA transcripts were exclusively detected in endocardial cells by scRNA-seq. In contrast, analysis of human heart by scRNA-seq localized GLP1R mRNA transcripts to populations of atrial and ventricular cardiomyocytes. Moreover, very low levels of GIPR, GCGR and GLP2R mRNA transcripts were detected in the human heart. Cell sorting and RNA analyses detected cardiac Glp1r expression in endothelial cells (ECs) within the atria and ventricle in the ischemic and non-ischemic mouse heart. Transcriptional responses to liraglutide administration were not evident in wild type mouse ventricles following acute MI, however liraglutide differentially regulated genes important for inflammation, cardiac repair, cell proliferation, and angiogenesis in the left atrium, while reducing circulating levels of IL-6 and KC/GRO within hours of acute MI. Inactivation of the Glp1r within the Tie2+ cell expression domain encompassing ECs revealed normal cardiac structure and function, glucose homeostasis and body weight in Glp1rTie2-/- mice. Nevertheless, the cardioprotective actions of liraglutide to reduce infarct size, augment ejection fraction, and improve survival after experimental myocardial infarction (MI), were attenuated in Glp1rTie2-/- mice.
Conclusions
These findings identify the importance of the murine Tie2+ endothelial cell GLP-1R as a target for the cardioprotective actions of GLP-1R agonists and support the importance of the atrial and ventricular endocardial GLP-1R as key sites of GLP-1 action in the ischemic mouse heart. Hitherto unexplored species-specific differences in cardiac GLP-1R expression challenge the exclusive use of mouse models for understanding the mechanisms of GLP-1 action in the normal and ischemic human heart.
... Similarly anti-IL-6 treated rats failed to reduce infarct size and AAR post I/R. Conversely, trans-signaling blockade of IL-6 pathway via fusion protein sgp130Fc attenuated neutrophil infiltration and significantly reduced the infarct size post MI [26]. Due to varying results obtained from all the included studies, the change in the infarct size remains insignificant. ...
... Meta-analysis of the selected studies and these results indicate a minimal to no role of IL-6 inhibition on cardiac remodeling. A recent stated that blocking the trans-signaling of IL-6 has more beneficial and cardio-protective functions, studies exploring the effects of IL-6R inhibition could further generate a potential understanding of cardiac remodeling in these animals [26]. ...
... Whereas, studies targeting IL-6R via antibody or tissue-specific gp130 KO showed better cardiac function by improving the ejection fraction and fraction shortening [23,25]. Inhibition of trans-signaling pathway of IL-6 using sgp130Fc showed improvement of cardiac function [26]. ...
Background
Proinflammatory cytokine cascades play crucial roles in the onset and progression of myocardial ischemia and infarction. Clinically, elevated serum levels of pro-inflammatory cytokine interleukin-6 is a poor prognostic indicator for future cardiac events and cardiac morbidity. Despite several reports, there is no clear evidence of cardiac benefits of inhibiting IL-6 in pre-clinical and clinical settings.
Objective
To analyze the available data systematically and perform a meta-analysis to show the evidence of effects of IL-6 inhibition on cardiac remodeling and mortality in ischemic animal models.
Methods
We used PICO framework and the quality of the studies was assessed using SYRCLE's risk of bias tool. Studies with interventions i.e., genetic deletion or pharmacological inhibition of IL-6/IL-6R were included for the meta-analysis. Systematic review was synthesized by including pre-clinical as well as randomized clinical trials involving myocardial infarction patients treated with IL-6 inhibitors. The effect size of the pooled data was determined using standard mean difference and 95% confidence intervals.
Results
A total of 12 pre-clinical studies were included in the review for analysis. Most of the studies showed an unclear risk of bias as the selection and reporting criteria were poorly described. We observed high heterogeneity in the included studies due to the varying duration of myocardial infarction and the dosage of IL-6 antibodies used in the studies. Overall inhibition of IL-6 significantly increased area at risk [p = 0.001, SMD = 0.49 (95% CI: -0.36, 1.35)] and significantly reduced ejection fraction [p = 0.001, SMD = -0.19 (95% CI: -1.39, 1.01)] and end-diastolic diameter [p = 0.02, SMD = -0.25 (95% CI: -0.87, 0.36)] of left ventricle post-MI, but no effects on infarct size [p < 0.01, SMD = 0.00; 95% CI: -1.34, 0.58). In randomized clinical trials, the overall effect on C-reactive protein remains significantly unchanged on CRP levels (SMD = -0.38; 95% CI: -1.94, 0.55) post-treatment with IL-6R inhibitor tocilizumab. The meta-regression demonstrates a significant positive correlation (p = 0.058) between the increase in ischemic area and duration of ischemia post-surgery in the absence of IL-6. This meta-analysis indicates mixed effect of IL-6 inhibition on cardiac remodeling post-MI, particularly in protecting the myocardium viability from damaging acute inflammation but not significant on cardiac function of ischemic animal models.
Conclusion
Despite the well-established pro-inflammatory nature of IL-6 in myocardial ischemia, our meta-analysis reports a limited contribution of IL-6 in the cardiac remodeling of hearts in animal models of myocardial ischemia. Moreover, genetically deleted IL-6 murine models produced contrasting results. Additional pre-clinical studies exploring the pharmacological inhibition of IL-6R are required to determine the beneficial effects of IL-6 inhibitors in regulating cardiac remodeling. The findings from IL-6R inhibition have better clinical relevance compared to genetically inhibited IL-6.
... Our previous investigations in a standard murine atherosclerosis model (LDL receptor-deficient [Ldlr −/− ] mice on a high-fat, high-cholesterol diet) showed both preventive and therapeutic efficacy of olamkicept, notably with a significant regression of established atherosclerotic lesion size . Importantly, it has recently been shown in a rat myocardial infarction (MI) model that rat sgp130Fc but not an anti-IL-6-antibody attenuated neutrophil and macrophage infiltration into the myocardium, reduced infarct size, and preserved cardiac function 28 days after MI (George et al., 2021). ...
... In murine models, lifetime IL-6 deficiency was atheroprotective (Madan et al., 2008) and inhibition of IL-6R reduced atherosclerotic lesions (Akita et al., 2017). Selective IL-6 trans-signalling inhibition, but not global IL-6 blockade, is efficacious in ameliorating the consequences of MI in a rat model and preserving cardiac function (George et al., 2021). In human atherosclerosis, inhibition of IL-1β by canakinumab led to a significantly lower rate of recurrent cardiovascular events and lowered IL-6 levels. ...
Inflammation is a strong driver of atherosclerotic cardiovascular disease (ASCVD). There is a large unmet need for therapies that prevent or reduce excessive inflammation while avoiding systemic immunosuppression. We showed previously that selective inhibition of pro-inflammatory interleukin-6 (IL-6) trans-signalling by the fusion protein olamkicept (sgp130Fc) prevented and reduced experimental murine atherosclerosis in low-density lipoprotein receptor-deficient (Ldlr −/−) mice on a high-fat, high-cholesterol diet independently of low-density lipoprotein (LDL) cholesterol metabolism. Therefore, we allowed compassionate use of olamkicept (600 mg intravenously biweekly for 10 weeks) in a patient with very-high-risk ASCVD. Despite optimal LDL cholesterol under maximum tolerated lipid-lowering treatment, the patient had a remaining very high risk for future cardiovascular events related to significant arterial wall inflammation with lipoprotein (a) [Lp(a)]-cholesterol as the main contributor. 18Fluorodeoxyglucose positron emission tomography/computed tomography (18FDG PET/CT) measurements were performed before and after the treatment period. Olamkicept reduced arterial wall inflammation in this patient without interfering with lipoprotein metabolism. No clinical or laboratory side effects were observed during or after treatment with olamkicept. Our findings in this patient matched the results from our mechanistic study in Ldlr −/− mice, which were extended by additional analyses on vascular inflammation. Olamkicept may be a promising option for treating ASCVD independently of LDL cholesterol metabolism. A Phase II trial of olamkicept in ASCVD is currently being prepared.
