Complement comprises a cluster of activation pathways that are triggered in various ways and progress through several amplifying enzymes to converge on a final common cell-killing pathway 1, 2. Bacteria or other foreign surfaces lacking regulator proteins provoke massive activation and amplification of complement, generating activation products that label the invader, attract and activate phagocytic cells and directly cause lytic pathogen killing. In health, these regulator proteins maintain a fragile truce in which complement is continuously activated in what is known as tickover. The powerful cell-targeting and cell-killing properties of complement can be turned against self, a scenario that is prevented by the abundant expression of regulator proteins. Complement is a key part of innate immunity and a modulator of the adaptive immune response inherited deficiencies in complement proteins predispose individuals to bacterial infection and/or immune complex disease.
The complement system includes more than 30 component proteins, regulators and receptors, present in plasma and on cells, which collaborate to provide defence against infection and to clear toxic materials. In this Review, we describe the history, current landscape and future directions for anti-complement therapies. Only two anti-complement drugs are currently on the market, but many more are being developed for diseases that include infectious, inflammatory, degenerative, traumatic and neoplastic disorders. Drug design is facilitated by the increasingly detailed structural understanding of the molecules involved in the complement system. Complement provides numerous options for drug development as it is a proteolytic cascade that involves nine specific proteases, unique multimolecular activation and lytic complexes, an arsenal of natural inhibitors, and numerous receptors that bind to activation fragments. Inappropriate or uncontrolled activation of complement can cause local and/or systemic inflammation, tissue damage and disease.
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The complement system is a key innate immune defence against infection and an important driver of inflammation however, these very properties can also cause harm. There is an urgent need to develop biomarkers and imaging methods that enable monitoring of the effects and efficacy of anti-complement agents. Other agents, both biologic and small molecule, are in Phase II or III trials for both rare and common diseases - administration routes include localized (for example, intravitreal) and systemic routes. Numerous novel agents targeting different parts of the complement system in different ways are now emerging from pre-clinical studies and are entering Phase I/II trials these agents bring the potential for more-effective and more-specific anti-complement therapies in disease.
Numerous challenges, such as target concentration or high turnover, limit the efficacy of these agents in humans. Complement is a key component of immunity with crucial inflammatory and opsonic properties inappropriate activation of complement triggers or exacerbates inflammatory disease.Ĭomplement dysregulation is a core feature of some diseases and contributes to pathology in many others.Īpproved agents have been developed for and are highly effective in some orphan applications, but their progress to use in more common diseases has been slow.
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