Targeting the Complement System in Bacterial Meningitis

Diederik L.H. Koelman; Matthijs C. Brouwer; Diederik van de Beek

Disclosures

Brain. 2019;142(11):3325-3337. 

In This Article

Therapeutic Options

Targeting the complement system in bacterial meningitis has the goal to decrease complications deriving from the uncontrolled, massive inflammatory response in the CNS, mainly driven by anaphylatoxin C5a production. To date, only two complement-targeted drugs, eculizumab (Alexion) and C1-INH [Cinryze (Shire), Berinert (CSL Behring), Cetor (Sanquin), Ruconest/conestat alfa (Pharming)], have received approval for its use in clinical practice, but dozens are currently investigated in one or multiple clinical trials covering almost the whole complement cascade, each with its own benefits and caveats (Ricklin et al., 2017; Harris, 2018).

The main detrimental effects of complement activation are considered to be caused by the spurring inflammatory effects of the complement system further upstream. The caveat of targeting the initiating pathway is the resulting opsonization deficit that may result in decreased bacterial killing (Brown et al., 2002), neither is complement activation in bacterial meningitis restricted to a single pathway. A potential advantage of intervening early in the complement system is the inhibition of the anaphylatoxin C3a produced early in the complement cascade, but no data to date support the importance of this less potent anaphylatoxin in the pathophysiology of bacterial meningitis (Woehrl et al., 2011; Mook-Kanamori et al., 2014). C4a does not share the inflammatory activities of C3a and C5a, and therefore should not be considered as an anaphylatoxin (Barnum, 2015). Targeting the amplification loop or C3 has the benefit of reducing complement amplification and concurrent massive anaphylatoxin production irrespective of the initiation pathway, but was not found to be beneficial in experimental meningitis models (Table 3). None of these models included antibiotic treatment, which may have over-emphasized the impaired opsonophagocytosis. Nevertheless, a C3-bypass mechanism has been shown with thrombin to be able to act as a potent C5 convertase in the absence of C3, in a dose-dependent manner (Huber-Lang et al., 2006). This suggests conversion to C5a can still occur in patients despite total blockage of C3, further limiting it as a good treatment option in bacterial meningitis.

Experimental evidence makes targeting C5a, the anaphylatoxin most broadly associated with disease severity and clinical outcome, the most promising therapeutic intervention to add to the current treatment regimen for bacterial meningitis patients. Three strategies are available to target C5a production. This includes targeting C5 to prevent conversion to C5a and C5b, specifically targeting C5a, or targeting the C5a receptor (C5aR). A multitude of therapeutic options has been developed to accomplish this (Supplementary Table 1). Eculizumab is a monoclonal C5 antibody registered for PNH, aHUS and generalized myasthenia gravis (Hillmen et al., 2006; Legendre et al., 2013; Howard et al., 2017). Functional C5a generation ex vivo despite eculizumab treatment in extreme complement activation situations has, however, been reported (Harder et al., 2017). Also in patients with aHUS, C5a was only partly suppressed to normal range or above (Wehling et al., 2017).

The major problem with targeting C5 conversion is the inhibition of MAC formation. The MAC complex is not considered as a modulator of the inflammatory response, although blockage is considered harmful as it may limit bacterial killing, especially in patients with meningococcal meningitis. In these patients, low concentration of the MAC complex in CSF was significantly associated with unfavourable clinical outcome despite subsequent administration of antibiotics, warranting caution (Mook-Kanamori et al., 2014). Exemplary, eculizumab, abrogates meningococcal killing in whole blood (Konar and Granoff, 2017), and patients treated with eculizumab are at high risk of developing invasive meningococcal disease even when vaccinated (McNamara et al., 2017).

An alternative approach might be to use anti-C5a or C5a receptor antagonists, which are more selective than eculizumab, and have been shown to inhibit the potentially harmful effects of N. meningitidis-induced C5a formation, at least in vitro, while preserving complement-mediated meningococcal killing via MAC (Sprong et al., 2003; Herrmann et al., 2018). It is therefore assumed that specific C5a targeting will be safe, even for patients with meningococcal meningitis. Of note, the effect of anti-C5 antibodies in bacterial meningitis other than pneumococcal meningitis is unclear and needs to be carefully evaluated. Two monoclonal antibodies against C5a exist to date, IFX-1 (InflaRx) and ALXN1007 (Alexion) (Supplementary Table 1). Targeting the C5a receptor with Avacopan/CCX168 (Chemocentryx) or IPH5401 (Innate Pharma) is another option (Supplementary Table 1).

The blood–CNS barrier (either the blood–brain barrier or the blood–CSF barrier) protects and regulates the homeostasis of the brain. However, this barrier also limits the access of drugs to the brain, posing—in spite of increased permeability due to inflammation—several challenges for C5-targeted therapies to cross the blood–CNS barrier, which to date have only partially been unravelled (Nau et al., 2010; Mook-Kanamori et al., 2011; Carpanini et al., 2019; Tattevin et al., 2019): monoclonal antibodies such as eculizumab and IFX-1 do not cross the blood–brain barrier, though ~0.1% of circulating antibodies penetrate in the CNS with a hypothetically increasing proportion due to inflammation (Freskgård and Urich, 2017). Eculizumab reduced the attack frequency in AQP4-positive neuromyelitis optica spectrum disorders, a disease where the blood–CNS barrier is disrupted (Pittock et al., 2013; Carpanini et al., 2019).

Small-molecules (<400 Da) can passively diffuse into the CNS if they are lipophilic (Freskgård and Urich, 2017). Small peptides (Zilucoplan) have the advantage of increased blood–CNS barrier penetration, stressing the importance of these treatments in neurological disease without blood–CNS barrier breaching, such as Alzheimer's disease (Craik et al., 2013; Baig et al., 2018). In addition, several new techniques are in development to accomplish brain delivery, such as receptor-mediated transport and transcytosis to shuttle therapeutics into the brain, or manipulating the blood–CNS barrier through signalling cascades, and barrier gene expression (Oller-Salvia et al., 2016; Greenwood et al., 2017).

It is also important to acknowledge that effectivity of complement inhibition may differ between patients. Patients with more pronounced complement activation due to genetic variations will likely benefit more from complement intervention (Harris et al., 2012; Kavanagh et al., 2015). Moreover, some patients may not respond to certain treatments because of mutations, as is seen with eculizumab (Nishimura et al., 2014). Some patients are therefore likely to require a tailored approach. The acute disease course of bacterial meningitis limits the options for extensive workup before enrolling patients in a clinical trial to reduce the risk of false-negative trial designs. Timely bedside genetic biomarkers are currently not available. Another important factor for trial design in bacterial meningitis is the variety in causative pathogens. Patients with pneumococcal meningitis have significantly more pronounced complement activation in the CSF and are therefore more likely to benefit from complement inhibition. Previously, the benefit of dexamethasone was shown to be most pronounced in patients with pneumococcal meningitis (de Gans et al., 2002; Bijlsma et al., 2016). CSF Gram staining or bedside PCR may identify the causative pathogen relatively quick compared to CSF culture, but will inevitably lead to treatment delays. As complement inhibition is considered most beneficial when started early, it makes sense to treat all patients with bacterial meningitis till the causative pathogen is identified.

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