Chimeric Anti-CD14 IGG2/4 Hybrid Antibodies for Therapeutic Intervention in Pig and Human Models of Inflammation

Lau, Corinna; Gunnarsen, Kristin Støen; Høydahl, Lene Støkken; Andersen, Jan Terje; Berntzen, Gøril; Pharo, Anne; Lindstad, Julie Katrine; Ludviksen, Judith Krey; Brekke, Ole-Lars; Barratt‐Due, Andreas; Stokes, Christopher; Espevik, Terje; Sandlie, Inger; Mollnes, Tom Eirik

doi:10.4049/jimmunol.1301653

Cited by 38 publications

(47 citation statements)

References 60 publications

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“…Eculizumab is a humanized IgG2/4ĸ hybrid antibody aimed at minimizing the effector functions mediated by complement activation and Fcγ receptor engagement, as previously demonstrated (47). While the binding activity towards the classical Fcγ receptors are lacking or low, eculizumab binds the non-classical Fc receptor FcRn in a strictly pH dependent manner, similar to that of two commercially available human IgG1ĸ antibodies, infliximab and rituximab.…”

Section: Discussionmentioning

confidence: 89%

Eculizumab treatment during pregnancy does not affect the complement system activity of the newborn

et al. 2015

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Eculizumab is a humanized IgG2/4 chimeric anti-complement C5 antibody used to treat patients with paroxysmal nocturnal hemoglobinuria (PNH) or atypical hemolytic uremic syndrome. The aim of this study was to evaluate whether or not the complement activity in newborns from pregnant women who receive eculizumab is impaired. A novel eculizumab-C5 complex (E-C5) specific assay was developed and revealed that two newborns carried only 6-7% of the E-C5 detected in their eculizumab-treated PNH mothers. Serum from the pregnant women completely lacked terminal complement pathway activity, whereas the complement activity in the serum of the newborns was completely normal. Data from the pregnant women and their newborns were compared with that of healthy age-matched female controls and healthy newborns, as well as a non-treated pregnant woman with PNH and her newborn. These all showed normal complement activity without detectable E-C5 complexes. Furthermore, absence of eculizumab or E-C5 in the newborn could not be explained by lack of eculizumab binding to the neonatal Fc receptor (FcRn), as eculizumab bound strongly to the receptor in vitro. In conclusion, despite binding to FcRn neither eculizumab nor E-C5 accumulates in fetal plasma, and eculizumab treatment during pregnancy does not impair the complement function in the newborn.

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Section: Discussionmentioning

confidence: 89%

Eculizumab treatment during pregnancy does not affect the complement system activity of the newborn

et al. 2015

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“…In contrast, the anti-CD14 Abs are frequently species specific. Thus, we recently produced a recombinant human-specific anti-CD14 IgG2/4 chimeric Ab that showed no Fc-mediated effector function, but efficiently neutralized CD14 (65).…”

Section: Discussionmentioning

confidence: 99%

Double Blockade of CD14 and Complement C5 Abolishes the Cytokine Storm and Improves Morbidity and Survival in Polymicrobial Sepsis in Mice

Huber‐Lang

Barratt‐Due

Pischke

et al. 2014

The Journal of Immunology

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Sepsis and septic shock, caused by an excessive systemic host-inflammatory response, are associated with high morbidity and mortality. The complement system and TLRs provide important pattern recognition receptors initiating the cytokine storm by extensive cross-talk. We hypothesized that double blockade of complement C5 and the TLR coreceptor CD14 could improve survival of experimental polymicrobial sepsis. Mice undergoing cecal ligation and puncture (CLP)–induced sepsis were treated with neutralizing anti-CD14 Ab biG 53, complement C5 inhibitor coversin (Ornithodoros moubata C inhibitor), or a combination thereof. The inflammatory study (24-h observation) revealed statistically significant increases in 22 of 24 measured plasma biomarkers in the untreated CLP group, comprising 14 pro- and anti-inflammatory cytokines and 8 chemokines, growth factors, and granulocyte activation markers. Single CD14 or C5 blockade significantly inhibited 20 and 19 of the 22 biomarkers, respectively. Combined CD14 and C5 inhibition significantly reduced all 22 biomarkers (mean reduction 85%; range 54–95%) compared with the untreated CLP group. Double blockade was more potent than single treatment and was required to significantly inhibit IL-6 and CXCL1. Combined inhibition significantly reduced morbidity (motility and eyelid movement) and mortality measured over 10 d. In the positive control CLP group, median survival was 36 h (range 24–48 h). Combined treatment increased median survival to 96 h (range 24–240 h) (p = 0.001), whereas survival in the single-treatment groups was not significantly increased (median and range for anti-CD14 and anti-C5 treatment were 36 h [24–48 h] and 48 h [24–96 h]). Combined with standard intervention therapy, specific blockade of CD14 and C5 might represent a promising new therapeutic strategy for treatment of polymicrobial sepsis.

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“…SOBI002 (molecular weight 12 kDa) consists of 2 protein domains, an Affibody ligand, targeting and preventing the cleavage of C5, which is fused to an albumin-binding domain that extends its half-life by binding plasma albumin [13]. Inhibition of CD14 was obtained by using a recombinant anti-porcine CD14 IgG2/4 monoclonal antibody (clone rMIL2), and a recombinant anti-human CD14 IgG2/4 (clone r18D11), previously described in detail [14]. …”

Section: Methodsmentioning

confidence: 99%

Combined Inhibition of C5 and CD14 Attenuates Systemic Inflammation in a Piglet Model of Meconium Aspiration Syndrome

et al. 2018

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Background: Meconium aspiration syndrome (MAS) is a severe lung condition affecting newborns and it can lead to a systemic inflammatory response. We previously documented complement activation and cytokine release in a piglet MAS model. Additionally, we showed ex vivo that meconium-induced inflammation was dependent on complement and Toll-like receptors. Objectives: To assess the efficacy of the combined inhibition of complement (C5) and CD14 on systemic inflammation induced in a forceful piglet MAS model. Methods: Thirty piglets were randomly allocated to a treatment group receiving the C5-inhibitor SOBI002 and anti-CD14 (n = 15) and a nontreated control group (n = 15). MAS was induced by intratracheal meconium instillation, and the piglets were observed for 5 h. Complement, cytokines, and myeloperoxidase (MPO) were measured by ELISA. Results: SOBI002 ablated C5 activity and the formation of the terminal complement complex in vivo. The combined inhibition attenuated the inflammasome cytokines IL-1β and IL-6 by 60 (p = 0.029) and 44% (p = 0.01), respectively, and also MPO activity in the bronchoalveolar fluid by 42% (p = 0.017). Ex vivo experiments in human blood revealed that the combined regimen attenuated meconium-induced MPO release by 64% (p = 0.008), but there was only a negligible effect with single inhibition, indicating a synergic cross-talk between the key molecules C5 and CD14. Conclusion: Combined inhibition of C5 and CD14 attenuates meconium-induced inflammation in vivo and this could become a future therapeutic regimen for MAS.

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Chimeric Anti-CD14 IGG2/4 Hybrid Antibodies for Therapeutic Intervention in Pig and Human Models of Inflammation

Cited by 38 publications

References 60 publications

Eculizumab treatment during pregnancy does not affect the complement system activity of the newborn

Eculizumab treatment during pregnancy does not affect the complement system activity of the newborn

Double Blockade of CD14 and Complement C5 Abolishes the Cytokine Storm and Improves Morbidity and Survival in Polymicrobial Sepsis in Mice

Combined Inhibition of C5 and CD14 Attenuates Systemic Inflammation in a Piglet Model of Meconium Aspiration Syndrome

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