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Inhibitors of the complement system currently in development for cardiovascular disease
M K Pugsley1, M Abramova, T Cole
1Department of Pharmacology, XOMA (US) LLC, Berkeley, CA 94710, USA. pugsley@xoma.com
Insights
The complement system, crucial for immunity, can cause organ damage if improperly activated. This review explores complement pathways, regulation, cardiovascular roles, and therapeutic inhibitors for immune system control.
Area of Science:
- Immunology
- Biochemistry
- Cardiovascular Medicine
Background:
- The complement system is vital for host defense against pathogens.
- Dysregulated complement activation can lead to severe organ damage.
- Understanding complement control is key to managing inflammatory responses.
Purpose of the Study:
- To review complement system activation pathways and regulatory mechanisms.
- To examine the role of complement in cardiovascular diseases, including ischemia-reperfusion injury and cardiopulmonary bypass.
- To provide an overview of current and developing complement inhibitors as therapeutic agents.
Main Methods:
- Literature review of complement system pathways and regulation.
- Analysis of complement's involvement in cardiovascular pathologies.
- Survey of existing and emerging complement-targeting therapies.
Main Results:
- Detailed explanation of complement activation cascades (classical, lectin, alternative).
- Elucidation of intrinsic and extrinsic control mechanisms for complement.
- Evidence linking complement activation to myocardial ischemia-reperfusion injury and cardiopulmonary bypass complications.
Conclusions:
- Controlled complement activation is essential for immunity, but dysregulation causes disease.
- Targeting complement pathways offers promising therapeutic strategies for cardiovascular and inflammatory conditions.
- A range of complement inhibitors are progressing through discovery and clinical development.
Abstract:
Controlled activation of the complement system is critical to the host-defense response of the immune system. Activated complement is responsible for the stimulation of a localized protective inflammatory response to either invading microorganisms or foreign molecules (toxins). However, the autologous activation of the complement system can have devastating consequences on many organ systems. This review discusses the various pathways involved in the activation of the complement system and the multiple levels of control established within the body to regulate activation. It also focuses on the role of complement activation in cardiovascular disease, especially myocardial ischemia and reperfusion injury as well as in cardiopulmonary bypass procedures. Lastly, this review also provides a comprehensive overview of both biologically derived proteins and chemically developed inhibitors of the complement system that range from those that are currently in the discovery stage to those that are in clinical development as novel therapeutic agents.