Trends in Pharmacological Sciences
ForumTherapeutic Inhibition of Complement: Well Worth the Risk
Section snippets
Complement and Complement Immunodeficiency
Complement is an important part of the innate and adaptive immune systems 3, 4. Comprising several dozen proteins; the system is organized into three pathways that are activated by: antigen–antibody complexes; pathogen-associated chemical moieties [specific carbohydrates; lipopolysaccharide (LPS); yeast cell wall; etc.] found on bacteria; viruses; fungi; and parasites; damaged host cells; and subcellular components (Figure 1). Upon activation; complement protects the host by opsonizing
Infectious Disease Risk during Therapeutic Complement Inhibition: In Vitro and In Vivo Considerations
In a seminal in vitro study; Brekke and colleagues [6] demonstrated that antibody-mediated inhibition of the classical and terminal pathways reduced opsonophagocytosis of Escherichia coli by whole blood-derived granulocytes to a greater extent than did inhibition of the alternative pathway. Only when both the classical and alternative pathways were simultaneously inhibited was phagocytosis effectively blocked. Complement-mediated induction of oxidative burst was inhibited in a similar fashion;
Concluding Remarks
Eculizumab ushered in the advent of complement therapeutics; and many new drugs; targeting all facets of the pathways; are moving rapidly down the clinical pipeline [1]. Each of these new inhibitors brings the possibility of unique clinical challenges in managing patient safety in the face of complement pathway-specific inhibition. Meningitis rates in vaccinated patients receiving eculizumab provide important considerations in this regard: (i) patients need to be vaccinated to reduce the risk
Conflict of Interest
The author has previously served as a consultant to Achillion Pharmaceuticals.
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Cited by (17)
The role of properdin and Factor H in disease
2022, Advances in ImmunologyCitation Excerpt :Whether a variant in the properdin gene on exon 3 p.CysTyr (c.95G > A), described in a case-study of a 20-month-old suffering from meningitis, is relevant in efficient killing of bacteria still remains to be elucidated (Gillet et al., 2020). Although deficiency of properdin leads to severe fulminant meningococcal infections, preventive vaccination to increase opsonization mediated by antibodies and C3b are important for the general population for properdin-deficient and MAC-deficient individuals (Barnum, 2017). In a retrospective study of a Pakistani family, Schejbel, et al. established a new association between properdin deficiency and recurrent otitis media and pneumonia (Schejbel, Rosenfeldt, Marquart, Valerius, & Garred, 2009).
Role of the Complement Pathway in Inflammatory Skin Diseases: A Focus on Hidradenitis Suppurativa
2020, Journal of Investigative DermatologyComplement therapeutics meets nanomedicine: overcoming human complement activation and leukocyte uptake of nanomedicines with soluble domains of CD55
2019, Journal of Controlled ReleaseCitation Excerpt :In view of the daunting challenges in preventing complement activation through nanosurface engineering, we reasoned that complement inhibitors could be a viable strategy to block nanomedicine-induced complement activation, at least at the initial stage of bolus intravenous injection. Complement therapeutics is a highly active field in pharmaceutical development, due to the ubiquitous role of complement in many diseases, and abundance of druggable proteolytic targets in the cascade [15,16]. Several small molecules inhibitors and antibodies have been developed to block downstream steps, including cleavage of C5 into C5a and C5b by the monoclonal antibody eculizimab [17] and binding of C5a to its receptor by small molecules [18].
Safety profile after prolonged C3 inhibition
2018, Clinical ImmunologyCitation Excerpt :Therapeutic inhibition of C3 in cynomolgus monkeys for up to 3 months using the compstatin analog Cp40 was not associated with any clinical signs or changes in hematologic, coagulation, or biochemical profiles. These findings therefore offer novel insight into the long-standing concern as to whether systemic inhibition of C3 would be associated with increased susceptibility to infections, autoimmune and/or kidney disease [31]. In addition, the precise assessment of drug biodistribution, exposure, and clearance and comprehensive histopathologic evaluation offer fundamental information to guide further development of therapeutic agents that target complement proteins.
Autoimmune phenotypes in schizophrenia reveal novel treatment targets
2018, Pharmacology and TherapeuticsCitation Excerpt :Therapeutic strategies have focused on inhibiting complement activation which has been primarily successful with targets in the terminal pathway (Barnum, 2017a, 2017b). Barnum (2017a, 2017b) provides comprehensive reviews on the progress and history of targeting the complement pathway using small molecules, siRNA inhibitors and antibodies. The anti-C5 antibody, eculizumab, for example, has favorable safety and effectiveness results for managing other indications (Hillmen et al., 2013).