IgM‐enriched solution <scp>BT</scp>086 improves host defense capacity and energy store preservation in a rabbit model of endotoxemia

Shmygalev, S.; Damm, Martin; Knels, Lilla; Strassburg, A.; Wünsche, K; Dumke, Roger; Stehr, Sebastian; Koch, Thea; Heller, Axel R.

doi:10.1111/aas.12652

Cited by 11 publications

(7 citation statements)

References 36 publications

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“…Trimodulin is a novel human plasma-derived native polyclonal antibody preparation for intravenous administration [ 16 , 17 ]. Trimodulin contains IgM (~ 23%), IgA (~ 21%), and IgG (~ 56%).…”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of trimodulin, a novel polyclonal antibody preparation, in patients with severe community-acquired pneumonia: a randomized, placebo-controlled, double-blind, multicenter, phase II trial (CIGMA study)

et al. 2018

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PurposeThe CIGMA study investigated a novel human polyclonal antibody preparation (trimodulin) containing ~ 23% immunoglobulin (Ig) M, ~ 21% IgA, and ~ 56% IgG as add-on therapy for patients with severe community-acquired pneumonia (sCAP).MethodsIn this double-blind, phase II study (NCT01420744), 160 patients with sCAP requiring invasive mechanical ventilation were randomized (1:1) to trimodulin (42 mg IgM/kg/day) or placebo for five consecutive days. Primary endpoint was ventilator-free days (VFDs). Secondary endpoints included 28-day all-cause and pneumonia-related mortality. Safety and tolerability were monitored. Exploratory post hoc analyses were performed in subsets stratified by baseline C-reactive protein (CRP; ≥ 70 mg/L) and/or IgM (≤ 0.8 g/L).ResultsOverall, there was no statistically significant difference in VFDs between trimodulin (mean 11.0, median 11 [n = 81]) and placebo (mean 9.6; median 8 [n = 79]; p = 0.173). Twenty-eight-day all-cause mortality was 22.2% vs. 27.8%, respectively (p = 0.465). Time to discharge from intensive care unit and mean duration of hospitalization were comparable between groups. Adverse-event incidences were comparable. Post hoc subset analyses, which included the majority of patients (58–78%), showed significant reductions in all-cause mortality (trimodulin vs. placebo) in patients with high CRP, low IgM, and high CRP/low IgM at baseline.ConclusionsNo significant differences were found in VFDs and mortality between trimodulin and placebo groups. Post hoc analyses supported improved outcome regarding mortality with trimodulin in subsets of patients with elevated CRP, reduced IgM, or both. These findings warrant further investigation.Trial registration: NCT01420744.Electronic supplementary materialThe online version of this article (10.1007/s00134-018-5143-7) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Efficacy and safety of trimodulin, a novel polyclonal antibody preparation, in patients with severe community-acquired pneumonia: a randomized, placebo-controlled, double-blind, multicenter, phase II trial (CIGMA study)

et al. 2018

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“…Immunoglobulin preparations combine several modes of action and could therefore perform immune modulatory functions while simultaneously fighting co-infections ( 9 , 119 ). Anti-microbial effects of trimodulin, as well as reduction of secondary bacterial infections in severe patients, are hints that trimodulin could improve clinical outcome of co-infected COVID-19 patients ( 87 , 120 ).…”

Section: Discussionmentioning

confidence: 99%

Immunomodulation: Immunoglobulin Preparations Suppress Hyperinflammation in a COVID-19 Model via FcγRIIA and FcαRI

et al. 2021

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The rapid spread of SARS-CoV-2 has induced a global pandemic. Severe forms of COVID-19 are characterized by dysregulated immune response and “cytokine storm”. The role of IgG and IgM antibodies in COVID-19 pathology is reasonably well studied, whereas IgA is neglected. To improve clinical outcome of patients, immune modulatory drugs appear to be beneficial. Such drugs include intravenous immunoglobulin preparations, which were successfully tested in severe COVID-19 patients. Here we established a versatile in vitro model to study inflammatory as well as anti-inflammatory processes by therapeutic human immunoglobulins. We dissect the inflammatory activation on neutrophil-like HL60 cells, using an immune complex consisting of latex beads coated with spike protein of SARS-CoV-2 and opsonized with specific immunoglobulins from convalescent plasma. Our data clarifies the role of Fc-receptor-dependent phagocytosis via IgA-FcαRI and IgG-FcγR for COVID-19 disease followed by cytokine release. We show that COVID-19 associated inflammation could be reduced by addition of human immunoglobulin preparations (IVIG and trimodulin), while trimodulin elicits stronger immune modulation by more powerful ITAMi signaling. Besides IgG, the IgA component of trimodulin in particular, is of functional relevance for immune modulation in this assay setup, highlighting the need to study IgA mediated immune response.

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“…This finding is in agreement with an in vivo study showing no change in oxidative-burst activity of polymorphonuclear leukocytes after trimodulin treatment. 38 Trimodulin appears to reduce the disproportionate expression of the CD64 receptor, which might prevent excessive release of pro-inflammatory cytokines induced by this receptor (Figures 2 and 5). 39 Thus, our ex vivo experiments demonstrated that early intervention with trimodulin impedes various important pro-inflammatory functions of monocytes and lymphocytes induced by endotoxins.…”

Section: Discussionmentioning

confidence: 99%

The novel polyclonal Ab preparation trimodulin attenuates ex vivo endotoxin-induced immune reactions in early hyperinflammation

et al. 2019

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Sepsis is a syndrome associated with excessive inflammation. Since mortality from sepsis remains high, more laboratory research is needed to provide insight into more effective ways to use novel, potentially more beneficial agents in sepsis. We investigated the ex vivo immunomodulatory effect of a novel polyclonal Ab preparation, trimodulin, containing IgM (∼23%), IgA (∼21%) and IgG (∼56%). Using whole blood and purified PBMCs from healthy volunteers and patients with sepsis, various ex vivo investigations upon endotoxin challenge and pre- and post-trimodulin treatment were performed. Endotoxin-induced TNF-α secretion was noticeably lower with than without trimodulin, implying attenuation of the hyper-responsive state. Trimodulin also lowered TLR2, TLR4, CD11b and CD64 detection on LPS/lipoteichoic acid-stimulated monocytes. These responses were observed in cells from healthy volunteers only shortly after ex vivo endotoxin stimulation and in whole blood from patients with early-stage sepsis. Furthermore, trimodulin markedly reduced lymphocyte proliferation and release of pro- and anti-inflammatory cytokines, but did not affect phagocytosis or oxidative-burst activities of endoxin-stimulated cells. Thus, trimodulin mitigated monocyte and lymphocyte hyperinflammatory responses early after endotoxin exposure. Determining whether early in vivo administration of trimodulin will elicit similar positive immunomodulatory effects and offer a clinical benefit warrants investigation.

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IgM‐enriched solution BT086 improves host defense capacity and energy store preservation in a rabbit model of endotoxemia

Cited by 11 publications

References 36 publications

Efficacy and safety of trimodulin, a novel polyclonal antibody preparation, in patients with severe community-acquired pneumonia: a randomized, placebo-controlled, double-blind, multicenter, phase II trial (CIGMA study)

Efficacy and safety of trimodulin, a novel polyclonal antibody preparation, in patients with severe community-acquired pneumonia: a randomized, placebo-controlled, double-blind, multicenter, phase II trial (CIGMA study)

Immunomodulation: Immunoglobulin Preparations Suppress Hyperinflammation in a COVID-19 Model via FcγRIIA and FcαRI

The novel polyclonal Ab preparation trimodulin attenuates ex vivo endotoxin-induced immune reactions in early hyperinflammation

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