Selective Interleukin-6 Trans-Signaling Blockade Is More Effective Than Panantagonism in Reperfused Myocardial Infarction

George, Marc J.; Jasmin, Nur Hayati; Cummings, Valerie Taylor; Richard-Loendt, Angela; Launchbury, Francesca; Woollard, Kevin J.; Turner‐Stokes, Tabitha; Díaz, Ana García; Lythgoe, Mark F.; Stuckey, Daniel J; Hingorani, Aroon D.; Gilroy, Derek W.

doi:10.1016/j.jacbts.2021.01.013

Cited by 34 publications

(29 citation statements)

References 31 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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 ( Schuett et al, 2012 ). 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 ).…”

Section: Introductionmentioning

confidence: 99%

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Case Report: Arterial Wall Inflammation in Atherosclerotic Cardiovascular Disease is Reduced by Olamkicept (sgp130Fc)

et al. 2022

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Case Report: Arterial Wall Inflammation in Atherosclerotic Cardiovascular Disease is Reduced by Olamkicept (sgp130Fc)

et al. 2022

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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 ].…”

Section: Discussionmentioning

confidence: 99%

Meta-analysis reveals inhibition of the inflammatory cytokine IL-6 affords limited protection post-myocardial ischemia/infarction

Duddu

Agrawal²,

Chakrabarti³

et al. 2022

Heliyon

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“…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 39,40 , 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.…”

Section: Sensitivity Analysesmentioning

confidence: 94%

Therapeutic potential of IL6R blockade for the treatment of sepsis and sepsis-related death: Findings from a Mendelian randomisation study

Hamilton

Thomas

Arnold

et al. 2022

Preprint

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Introduction 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 downregulate IL-6 signalling are associated with improved COVID-19 outcomes, a finding later confirmed in randomised trials of IL-6 receptor antagonists (IL6RA). We hypothesised that blockade of IL6R could also improve outcomes in sepsis. Methods We performed a Mendelian randomisation analysis using single nucleotide polymorphisms (SNPs) in and near IL6R to evaluate the likely causal effects of IL6R blockade on sepsis, sepsis severity, other infections, and COVID-19. 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 in a similar analysis. Results In the UK Biobank cohort (N=485,825, including 11,643 with sepsis), IL6R blockade was associated with a decreased risk of sepsis (OR=0.80; 95% CI 0.66-0.96, 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 0.38-0.70); critical care admission with sepsis (OR=0.48, 95% CI 0.30-0.78) and critical care death with sepsis (OR=0.37, 95% CI 0.14 - 0.98) Similar associations were seen with severe respiratory infection: OR for pneumonia in critical care 0.69 (95% CI 0.49 - 0.97) and for sepsis survival in critical care (OR=0.22; 95% CI 0.04- 1.31) in the GainS and GenOSept consortium. We also confirm the previously reported protective effect of IL6R blockade on severe COVID-19 (OR=0.69, 95% 0.57 - 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. Conclusions IL6R blockade is causally associated with reduced incidence of sepsis, sepsis related critical care admission, and sepsis related mortality. These effects are comparable in size to the effect seen in severe COVID-19, where IL-6 receptor antagonists were shown to improve survival. This data suggests a randomised trial of IL-6 receptor antagonists in sepsis should be considered.

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Selective Interleukin-6 Trans-Signaling Blockade Is More Effective Than Panantagonism in Reperfused Myocardial Infarction

Cited by 34 publications

References 31 publications

Case Report: Arterial Wall Inflammation in Atherosclerotic Cardiovascular Disease is Reduced by Olamkicept (sgp130Fc)

Case Report: Arterial Wall Inflammation in Atherosclerotic Cardiovascular Disease is Reduced by Olamkicept (sgp130Fc)

Meta-analysis reveals inhibition of the inflammatory cytokine IL-6 affords limited protection post-myocardial ischemia/infarction

Therapeutic potential of IL6R blockade for the treatment of sepsis and sepsis-related death: Findings from a Mendelian randomisation study

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