Injury site‐specific targeting of complement inhibitors for treating stroke

Abstract

Summary Cumulative evidence indicates a role for the complement system in both pathology and recovery after ischemic stroke. Here, we review the current understanding of the dual role of complement in post-stroke injury and recovery, and discuss the challenges of anti-complement therapies. Most complement directed therapeutics currently under investigation or development systemically inhibit the complement system, but since complement is important for immune surveillance and is involved in various homeostatic activities, there are potential risks associated with systemic inhibition. Depending on the target within the complement pathway, other concerns are high concentrations of inhibitor required, low efficacy and poor bioavailability. To overcome these limitations, approaches to target complement inhibitors to specific sites have been investigated. Here we discuss targeting strategies, with a focus on strategies developed in our lab, to specifically localize complement inhibition to sites of tissue injury and complement activation, and in particular to the post-ischemic brain. We discuss various injury site-specific targeted complement inhibitors as potential therapeutic agents for the treatment of ischemic stroke treatment, as well as their use as investigate tools for probing complement-dependent pathophysiological processes.

The complex functioning of the complement system in xenotransplantation

“…191 (b) Many efforts have been made to directly target complement at sites of activation. 192 For example, CR2-complement inhibitor fusion proteins (CR2-FH, CR2-Crry, and CR2-CD59) 193,194 make local targeting feasible. Ergidina, a neutralizing recombinant anti-C5 antibody, protected rat kidneys from IRI by binding to injured endothelium.…”

Complement C3-targeted gene therapy restricts onset and progression of neurodegeneration in chronic mouse glaucoma

“…Inhibitors affecting the central step of formation of C3 convertase formation and cleavage/activation have become a focus for development of therapeutics that effectively modulate complement activation, regardless of the initiation pathway 32 . Furthermore, the deposition of C3 activation fragments, iC3b, C3dg and C3d, covalently bound to cell surfaces, serves as a long-lived indicator of local complement activation amenable to imaging in the living animal or ex vivo, and as ligand for CR2-fused inhibitors to achieve localized regulation of complement activation 8,33,34 . In rodents, the main regulator of C3 convertase formation is Crry, a structural and functional ortholog of human complement receptor 1 (CR1) 35,36 .…”

“…Systemically administered CR2-Crry crosses defective blood-brain barriers in these models of acute CNS injury 34,43 , but would have limited capacity to cross an intact barrier.…”

Preformed mediators of defense—Gatekeepers enter the spotlight

“…explores this sometimes helpful, sometimes devastating liaison between preformed mediators that is essential for maintaining barriers and defense but can also lead to thromboinflammatory complications if excessively or erroneously triggered; examples with clinical relevance range from transplantation and biomaterial‐induced complications to thrombotic events during myocardial infarction or stroke. In their review, Alawieh and Tomlinson take ischemic stroke as an example to illustrate the impact of this unholy alliance between the complement, coagulation, and contact systems in a pathological context and highlight the therapeutic promise of using injury site‐targeted complement inhibitors . New insight has also been gained concerning the crosstalk between complement and the contact (kallikrein‐kinin) system, as discussed in the review by Ghebrehiwet et al …”

“…3 The current picture of the inner workings of complement has been largely shaped by elegant structural studies, and high-resolution structures are now available for numerous com- as an example to illustrate the impact of this unholy alliance between the complement, coagulation, and contact systems in a pathological context and highlight the therapeutic promise of using injury sitetargeted complement inhibitors. 17 New insight has also been gained concerning the crosstalk between complement and the contact (kallikrein-kinin) system, as discussed in the review by Ghebrehiwet et al 18 ; mediated by the receptor gC1qR and involving other players, this cooperation may assist host defense but has also been shown to have clinical implications, not only for hereditary angioedema but also for tumor progression and metastasis. The latter example underscores the dual role of defense pathways in cancer biology, which is the focus of the review by Berraondo et al 19 While complement and other mediators may help to control tumor growth, most cancer cells possess mechanisms to escape attack by the host defense systems.…”