Inside the body, C1INH works by inhibiting the formation of the most important complex at the top of the complement system.
The complement system, sometimes known as the complement cascade, is a major part of the immune system, responsible for certain immune-mediated inflammation reactions, including most reactions that cause vascular edema (swelling). The complement cascade enhances (i.e. complements) the ability of antibodies and phagocytic cells (a type of white blood cells) to clear microbes and damaged cells from our bodies, promotes inflammation, and attacks the pathogen’s cell membrane.
The complement system consists of a number of complex proteins found in the blood, in general synthesized by the liver, and normally circulating as inactive precursors (pro-proteins). When stimulated by one of several triggers, enzymes called proteases produced for the purpose in the system cleave specific proteins to release active fragments called cytokines and initiate an amplifying cascade of further cleavages. The end result of this complement activation or complement fixation cascade is stimulation of the phagocytes to clear foreign and damaged material, inflammation to attract additional phagocytes, and activation of the cell-killing membrane attack complex. Over 30 proteins and protein fragments make up the complement system, including serum proteins and specific cell membrane receptors.
Once the complement cascade has been triggered, the body also produces C1INH to start to slow the reaction down, and the rate at which the reaction can be slowed down is constant as the body can only produce a low maximum level of C1INH. This means that serious trigger events take longer to resolve than minor ones, because the level of C1INH production catches up to the level of minor releases of cytokines more quickly than it can to major releases of cytokines, sometimes known as ‘cytokine storms’. This system is the villain in many disease conditions and injury situations, where inflammation or vascular leakage running out of control are responsible for the symptoms of those conditions. In others, hypoxic conditions can result, where blood has not been able to circulate properly to bring oxygen to various tissues.
The detrimental effects of such hypoxia can be exacerbated upon reperfusion with blood by local activation of the complement cascade. In some of those conditions, there may be a role to play for externally administered C1 esterase inhibitor which could act as a handbrake more quickly on that situation, allowing the body to have a more measured response or to prevent the symptoms entirely.
hile C1INH is unlikely to ‘cure’ the underlying problem, this extra supply might allow for the damage caused or even the risk of death to be reduced and/or delayed long enough for the problem to be resolved either naturally or through the intervention of the patient’s physician team.
The following diagram shows the most important indications in this area. Many of these conditions are entirely unmet medical needs, often with no approved therapy. Sometimes this is because they cause death very quickly, or because they lead to other more serious morbidities. A few do have approved treatments, largely because other mechanisms are also involved or are more important, such as for asthma.