The consecutive cleavage and activation of several proteases constitutes the driving force behind complement function. Eight serine proteases are integral elements of the complement cascade itself (C1r, C1s, C2a, MASP-1, MASP-2, factor D, factor B, factor I), whereas others are involved through the extrinsic protease pathway. Because proteases are among the most druggable targets in the complement system, it is not surprising that early drug development efforts focused on protease inhibitors.
The only complement-associated protease inhibitor currently on the market is C1-inhibitor (C1-INH), a heavily glycosylated plasma protein that is used in the treatment of hereditary angioedema / HAE. This disease is characterized by recurrent episodes of severe skin and mucous membrane edema and is caused by either an insufficient production of C1-INH (type 1) or a mutation around its binding site that leads to inactivity (type 2). In both types, therapeutic supplementation of this protein has proven to be an effective and safe treatment for HAE and helps prevent severe disease relapses and life-threatening complications. A third HAE type of unknown etiology and low prevalence does not benefit from supplementation, because it is not dependent on C1-INH activity. Although C1-INH gained its name from its ability to block the serine esterase activities of C1r and C1s, its specificity includes other proteases, such as MASP, kallikrein and coagulation factors XI and XII. Although plasma levels of C2 and C4 are clearly affected by HAE, the primary mechanism of C1-INH seems to be more closely associated with bradykinin-kallikrein than with the complement system. However, there is increasing evidence that therapeutic administration of C1-INH may also be beneficial in other disorders with a direct connection to complement, such as ischemia/reperfusion (I/R) injury.
1. Ricklin D, et al. (2007). Complement-targeted therapeutics. Nature biotechnology, 25(11), 1265-1275.
2. Hajishengallis G, et al. (2013). Complement-targeted therapeutics in periodontitis. In Complement Therapeutics (pp. 197-206). Springer US.
3. Ricklin D, et al. (2013). Progress and trends in complement therapeutics. In Complement Therapeutics (pp. 1-22). Springer US.