Overview of the Complement System

Complement is the backbone of our innate immune system and is a key component of our adaptive immune system. It is a sophisticated and phylogenetically ancient defense mechanism that has been traced back over 450 million years. Its purpose is to recognize and attack invaders and to get rid of damaged tissue.


The complement system works in every tissue of our body, providing an immediate response to trauma and foreign invaders. It is a powerful system that needs to be tightly regulated at every stage to avoid mistakes in distinguishing friend from foe. If the severity of the response exceeds regulatory levels damage to healthy tissue can occur.  The system is designed to carry out four major functions:

  • Marking invading pathogens and damaged tissues as targets for disposal (opsonization)
  • Stimulating their elimination (phagocytosis),
  • Generation of inflammatory signaling agents (anaphylatoxins), and
  • Direct killing of cells by insertion of the membrane attack complex (MAC) into cell surfaces.

The complement system operates in two distinct phases:

  • The initiation phase marks cellular debris and pathogens with proteins to facilitate their elimination by the process known as opsonization followed by uptake and digestion by phagocytic cells in the process known as phagocytosis.
  • The second phase involves assembly of the terminal complement components to form the MAC, which attaches to viable cells and has the purpose of directly killing them by punching holes in their protective cell membrane.

When there is a failure to distinguish friend from foe, and host cells are mistakenly killed, the process is known as bystander lysis. Three complement initiation pathways are recognized:

  • Classical pathway
  • Lectin pathway, and
  • Alternative pathway.

Since all initiation pathways trigger the terminal cascade that results in the formation of the MAC, it must be tightly regulated to prevent bystander lysis.

The alternative pathway differs from the other two in several important ways.  It is largely serum based rather than being tissue based and is continuously activated at a low level.  This ‘tick-over’ process is a result of spontaneous hydrolysis of C3, which is naturally present in high levels in the serum.  The continuously cleaved C3b fragments attach to cells in circulating blood, to blood vessels and to other cells that serum can reach. This bound C3b must be quickly destroyed by protective proteins or there is escalation of the process leading to formation of the MAC. Under normal circumstances, complement regulatory proteins prevent the accumulation of C3b on host cells, while foreign cells, pathogens and abnormal surfaces may be heavily ‘decorated’ with C3b.

The complement system consists of over 30 proteins that must work together like clockwork.  The following simplified diagram shows how the classical and the alternative pathways converge at complement protein C5 to trigger the membrane attack pathway, which culminates with the insertion of multiple copies of C9 to form the MAC. Since the complement system functions in all tissues within the body, the effects of its aberrant activation are implicated in a wide spectrum of conditions. This is illustrated in the diagram, which shows how Alzheimer disease is associated with the classical pathway and age-related macular degeneration is associated with the alternative pathway.

Schematic illustration of the classical and alternative pathways of complement.

Schematic illustration of the classical pathway and alternative pathway of complement and their role in the pathologies of Alzheimer Disease (AD) and Age-related Macular Degeneration (AMD). Red lines indicate where our lead drug candidate, AUR1107, inhibits the complement cascade by binding to Factor D in the initiation stage of the alternative pathway and to C9 in the terminal pathway that forms the MAC.

Although complement is an essential defense system of living organisms, it is widely regarded as a double-edged sword. The initiation phase with its opsonizing components is essential; however, the MAC is potentially self-damaging.

Membrane Attack Complex (MAC)

While the membrane attack complex (MAC) is intended to destroy invaders, it can turn on the host by literally punching holes in one's own cells, causing what is known as bystander lysis.  This self-attack is known to occur in a spectrum of diseases.


Formation of the MAC exacerbates the pathology in all diseases where there is persistent over activity of the complement system. The following figures show the MAC and how it attacks cell membranes.

Photomicrograph of membrane lesions in cells under attack by the MAC.
Source: Immunobiology, 6/e. Garland Science 2005.

Photomicrograph showing a MAC generated lesion.
Source: Immunobiology, 6/e. Garland Science 2005.

Electron micrograph showing the poly C9 complex as formed in the MAC.
Source: Aleshin et al. JBC 287 p10210.


Illustration of the membrane attack complex (MAC) showing sequential assembly of C5b, C6, C7, C8 and multiple copies of C9. Source: Aleshin et al. JBC 287 p10210.

Illustration of the membrane attack complex (MAC) showing sequential assembly of C5b, C6, C7, C8 and multiple copies of C9.
Source: Aleshin et al. JBC 287 p10210.

 

Aurin Biotech’s drug candidates bind to C9 thus blocking its ability to bind to C5b678 and form the membrane attack complex (MAC). This mechanism of action creates the temporary biochemical equivalent of being born with what could be viewed as a fortunate genetic adaptation.