Therapeutic Modulation of the Complement System: Clinical Indications and Emerging Drug Leads

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Background

The complement system is a multi-tasking gatekeeper of innate immunity that intricately interacts with other key defense systems, such as the endothelial barrier, contact activation and coagulation systems, in maintaining tissue immunosurveillance and homeostasis. Its rapid and forceful activation in the bloodstream not only ensures the effective containment of microbial infections through potent cytolytic mechanisms, but also alerts the adaptive immune compartment to ensure the mounting of a proper humoral immune response against foreign antigens. However, there is a lurking ‘dark side’ that can lead complement astray, fueling a self-perpetuating vicious cycle of inflammation, exuberant immune activation and irreversible tissue injury that collectively exacerbate both acute and chronic pathologies. Indeed, complement dysregulation or excessive activation have been widely recognized as key pathogenic drivers in a wide spectrum of inflammatory or immune-mediated diseases. Targeted modulation of the complement system at various points of the cascade has revealed promising therapeutic targets for ameliorating disease scores in a number of conditions ranging from ocular, neurodegenerative and thromboinflammatory disorders, to cancer, periodontal diseases, chronic hemolytic anemias, ischemia-reperfusion organ injury, antibody-mediated transplant rejection and hemodialysis-triggered inflammation.

Elegant pre-clinical studies employing a diversified toolbox of highly specific complement inhibitors in rodent models of disease have opened new avenues of therapeutic exploration by providing proof of concept for the therapeutic efficacy of complement modulation. At the same time, the clinical experience gained during this last decade with the sole complement-specific drug currently in the clinic, eculizumab, has rekindled the interest of biopharmaceutical companies in developing new and potent complement therapeutics for complement-driven diseases.

In this respect, the complement field is witnessing a new surge of clinical trials that are evaluating the safety, PK/PD profile and clinical efficacy of promising drug candidates in a number of clinical conditions driven by complement imbalance or over-activation.

The aim of this Research Topic is to assemble Reviews, Mini-Reviews, and Perspective articles providing an up-to-date and authoritative survey of the most recent developments in the clinical translation of complement-based therapeutics, with an emphasis on ongoing clinical trials of complement inhibitors for priority indications within major disease areas. Selected topics will also discuss exciting new opportunities and emerging indications that could benefit from targeted modulation of the complement system in the near future. The primary disease areas covered in this Research Topic have been selected on the basis of the prominent and well-documented involvement of complement activation/or dysregulation in disease pathogenesis and will include acute or transiently treatable indications as well as chronic indications that could benefit from systemic or local administration of complement inhibitors.

The sub-topics to be covered in this Research Topic include:

1. Ocular inflammatory diseases: challenges, mechanistic insights and opportunities in view of the ongoing clinical trials with first-in-class complement inhibitors.
2. Ischemia/ Reperfusion Organ injury (e.g. including but not limited to ischemic stroke, myocardial infarction and other target organs).
3. Thrombotic microangiopathies (TMAs) such as aHUS, transplant-associated TMAs, HELPP etc. Emphasis should be placed on the clinical feasibility of new and emerging therapeutic options exploiting complement modulation in the post-eculizumab era.
4. Thrombogenic/thromboinflammatory disorders.
5. Rheumatic and autoimmune diseases.
6. Novel anti-cancer agents and multi-modal cancer immunotherapies exploiting targeted complement modulation (e.g. combination therapies with clinically approved immune checkpoint inhibitors).
7. Complement-based therapies for renal diseases (e.g. complement-mediated glomerular pathogies). A critical update will be provided on emerging therapeutic targets, candidate drugs and ongoing clinical trials evaluating complement inhibitors for the treatment of renal disorders.
8. Targeting complement pathways/effectors in polytrauma and sepsis-induced multi-organ dysfunction.
9. Hemodialysis-evoked inflammatory complications.
10. Transplant rejection.
11. Neurological conditions (potential acute indications: traumatic brain or spine injury; chronic indications: chronic inflammatory and neurodegenerative diseases such as Alzheimer’s disease, glaucoma, Parkinson’s, Huntington’s disease etc).
12. Hematological disorders.
13. Periodontal Disease.
14. Novel and less explored clinical indications for which complement involvement in disease pathogenesis has been shown but robust translational or clinical findings are still lacking.
15. Complement assaying platforms: Streamlining complement diagnostics for monitoring patient responses to anti-complement agents.

This Research Topic will highlight cutting-edge research authored by the investigators participating in the 11th International Aegean Conference on Complement Therapeutics in Crete, Greece (23rd - 28th June 2018) with the aim of further increasing the visibility of the event and of the organization.

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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