Eculizumab treatment efficiently prevents C5 cleavage without C5a generation in vivo

Volokhina, Elena; Bergseth, Grethe; Kar, Nicole C. A. J. van de; Heuvel, Lambertus P. van den; Mollnes, Tom Eirik

doi:10.1182/blood-2015-03-637645

Cited by 17 publications

(14 citation statements)

References 8 publications

(13 reference statements)

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“…Interestingly, C5a levels have been described recently to be increased in contrast to reduced sC5b-9 levels after initiation of eculizumab treatment in a case of the haemolysis, elevated liver enzymes and low platelets (HELLP) syndrome [35]. However, in a response to this report, results were claimed to be falsepositive, due to either cross-reactivity to other epitopes or to C5-eculizumab complexes recognized particularly in the applied ELISA [36,37]. Whereas a significant decrease of C5a in our aHUS cohort could be demonstrated, this was not the case for C3G patients despite the high pretreatment levels of sC5b-9.…”

Section: Complement and Eculizumab Monitoringmentioning

confidence: 78%

“…Whereas a significant decrease of C5a in our aHUS cohort could be demonstrated, this was not the case for C3G patients despite the high pretreatment levels of sC5b-9. The discrepancy between sC5b-9 and C5a levels can be explained partially by the short half-life of approximately 1 min of the anaphylatoxin C5a due to binding to leucocyte receptors and decay by carboxypeptidases compared to the 60 times longer half-life of sC5b-9 [37]. However, at all measured time-points in both patient groups, C5a levels were in the normal or above-normal range of the measurements for healthy human volunteers within the ELISA, and did not correlate with inhibition of complement function (CH50, APH50) upon eculizumab treatment.…”

Section: Complement and Eculizumab Monitoringmentioning

confidence: 99%

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Monitoring of complement activation biomarkers and eculizumab in complement-mediated renal disorders

Wehling

Amon

Bommer

et al. 2016

Clinical and Experimental Immunology

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SummaryVarious complement-mediated renal disorders are treated currently with the complement inhibitor eculizumab. By blocking the cleavage of C5, this monoclonal antibody prevents cell damage caused by complement-mediated inflammation. We included 23 patients with atypical haemolytic uraemic syndrome (aHUS, n 5 12), C3 glomerulopathies (C3G, n 5 9) and acute antibody-mediated renal graft rejection (AMR, n 5 2), treated with eculizumab in 12 hospitals in Germany. We explored the course of complement activation biomarkers and the benefit of therapeutic drug monitoring of eculizumab. Complement activation was assessed by analysing the haemolytic complement function of the classical (CH50) and the alternative pathway (APH50), C3 and the activation products C3d, C5a and sC5b-9 prior to, 3 and 6 months after eculizumab treatment. Eculizumab concentrations were determined by a newly established specific enzyme-linked immunosorbent assay (ELISA). Serum eculizumab concentrations up to 1082 lg/ml point to drug accumulation, especially in paediatric patients. Loss of the therapeutic antibody via urine with concentrations up to 56 lg/ml correlated with proteinuria. In aHUS patients, effective complement inhibition was demonstrated by significant reductions of CH50, APH50, C3d and sC5b-9 levels, whereas C5a levels were only reduced significantly after 6 months' treatment. C3G patients presented increased C3d and consistently low C3 levels, reflecting ongoing complement activation and consumption at the C3 level, despite eculizumab treatment. A comprehensive complement analysis together with drug monitoring is required to distinguish mode of complement activation and efficacy of eculizumab treatment in distinct renal disorders. Accumulation of the anti-C5 antibody points to the need for a patient-orientated tailored therapy.

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Section: Complement and Eculizumab Monitoringmentioning

confidence: 78%

Section: Complement and Eculizumab Monitoringmentioning

confidence: 99%

Monitoring of complement activation biomarkers and eculizumab in complement-mediated renal disorders

Wehling

Amon

Bommer

et al. 2016

Clinical and Experimental Immunology

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“…The commercially available assays were used to measure plasma C4d (SVAR Life Science), C5a, and MBL (Hycult Biotech). The reference values for C4d were given by the supplier, testing EDTA plasma from healthy donors, and, for C5a and MBL, the reference range was based on previously published data from us and others (32,37).…”

Section: Methodsmentioning

confidence: 99%

Systemic complement activation is associated with respiratory failure in COVID-19 hospitalized patients

Holter

Pischke

Boer

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

317

316

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Respiratory failure in the acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is hypothesized to be driven by an overreacting innate immune response, where the complement system is a key player. In this prospective cohort study of 39 hospitalized coronavirus disease COVID-19 patients, we describe systemic complement activation and its association with development of respiratory failure. Clinical data and biological samples were obtained at admission, days 3 to 5, and days 7 to 10. Respiratory failure was defined as PO2/FiO2 ratio of ≤40 kPa. Complement activation products covering the classical/lectin (C4d), alternative (C3bBbP) and common pathway (C3bc, C5a, and sC5b-9), the lectin pathway recognition molecule MBL, and antibody serology were analyzed by enzyme-immunoassays; viral load by PCR. Controls comprised healthy blood donors. Consistently increased systemic complement activation was observed in the majority of COVID-19 patients during hospital stay. At admission, sC5b-9 and C4d were significantly higher in patients with than without respiratory failure (P = 0.008 and P = 0.034). Logistic regression showed increasing odds of respiratory failure with sC5b-9 (odds ratio 31.9, 95% CI 1.4 to 746, P = 0.03) and need for oxygen therapy with C4d (11.7, 1.1 to 130, P = 0.045). Admission sC5b-9 and C4d correlated significantly to ferritin (r = 0.64, P < 0.001; r = 0.69, P < 0.001). C4d, sC5b-9, and C5a correlated with antiviral antibodies, but not with viral load. Systemic complement activation is associated with respiratory failure in COVID-19 patients and provides a rationale for investigating complement inhibitors in future clinical trials.

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“…This leads to endothelial cell activation, including tissue factor expression, with subsequent serious fatal thrombus formation observed in CAPS [ 5 ]. Both C5a- and C5b-9 formation is efficiently inhibited by eculizumab [ 6 ]. In conclusion, complement inhibition should be regarded as an important and possibly life-saving medical intervention for patients with CAPS.…”

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confidence: 99%

Complement activation is a crucial pathogenic factor in catastrophic antiphospholipid syndrome

et al. 2016

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Eculizumab treatment efficiently prevents C5 cleavage without C5a generation in vivo

Cited by 17 publications

References 8 publications

Monitoring of complement activation biomarkers and eculizumab in complement-mediated renal disorders

Monitoring of complement activation biomarkers and eculizumab in complement-mediated renal disorders

Systemic complement activation is associated with respiratory failure in COVID-19 hospitalized patients

Complement activation is a crucial pathogenic factor in catastrophic antiphospholipid syndrome

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