C1 Esterase Inhibitor
The most important natural inhibitor of the lectin pathway of complement is C1INH. C1INH, a member of the serpin superfamily of serine protease inhibitors, is an acute-phase protein that has manifold targets and biological functions. Although the primary function of serpins involves the inhibition of proteases, they are also implicated in additional biological interactions, such as the inhibition of leukocyte rolling and interactions with endothelial cells and microorganisms (20). For example, treatment with C1INH was shown to limit the activation of endothelial cells and their subsequent transition into a procoagulatory and antifibrinolytic state after I/R injury (21). Proteases that are inactivated by C1INH include C1r, C1s (classical pathway of complement), MASP-1 and MASP-2 (lectin pathway), factor XII and plasma kallikrein (contact system), factor XI and thrombin (coagulation system), and plasmin and tissue plasminogen activator (fibrinolytic system) (22, 23) (Figure 1). Binding of C1INH to any of its target proteases leads to tight complexes which are subsequently cleared from the circulation and can be summarized as suicide inhibition (9). Decreased plasmatic antigenic levels of C1INH result in uncontrolled production of vasoactive peptides, which leads to the characteristic episodes of local soft tissue swelling observed in hereditary angioedema (HAE) (24).
Regarding the complement system, MASP-1 and -2 seem to be the major target of C1INH with less effective inhibition of the classical pathway (25). Interestingly, the lectin pathway and in particular MASP-1 have been recently implicated in the pathophysiology of HAE, which underscores the central role of C1INH in controlling the activation of the lectin pathway. C1INH deficiency seems to cause uncontrolled activation of MASP-1, which may aggravate HAE (26).
Currently, three C1INH preparations are approved for the treatment and/or prevention of HAE, two plasma-derived, pasteurized, and nanofiltered (pdC1-INH, Berinert® and Cinryze®), and one recombinant product [rhC1-INH, Conestat alfa (Ruconest®), derived from the breast milk of transgenic rabbits]. Conestat alfa shares an identical protein structure with plasma-derived C1INH, but has a different glycosylation pattern of the amino-terminal domain of the protein (containing abundant oligomannose residues), which is responsible for a markedly shorter half-life compared with plasma-derived C1INH (3 vs. 30 h) (27). In fact, the unique glycosylation pattern introduced by the production of Conestat alfa in the mammary gland of transgenic rabbits may have additional, yet undiscovered consequences. For example, artificial variation of the glycosylation pattern of pdC1INH was previously shown to selectively impact on its target proteases with little impact on C1s inhibition in contrast to its interaction with kallikrein (28). Moreover, an important regulatory function of the amino-terminal domain of C1INH has been identified preventing inhibition of MASP-1-mediated alternative pathway activation (29), which may be influenced by the glycosylation pattern of C1INH. Although comparable inhibition for most target proteases was demonstrated (including C1s, factor XIa, XIIa, and Kallikrein) (30), Conestat alfa seems to target MBL and activation of the lectin pathway more effectively compared with plasma-derived preparations (31). This may be related to the fact that oligomannose-type glycans on average account for 15% of the total amount of glycans of Conestat alfa (compared with less than 1% in pdC1INH) (32), which may expedite the targeting and subsequent inhibition of MBL-MASP-1/MASP-2 complex by Conestat alfa.
Despite the rather broad interference with several cascades and targets, major adverse events or unique toxicities have not been demonstrated in previous studies, with the exception of a potential risk of allergic reactions in patients with rabbit dander allergy receiving Conestat alfa. Previous concerns of an increased thrombotic risk of pdC1INH (33) have not been confirmed in recent trials and registry data of both, pdC1INH and rhC1INH (34, 35). Common side effects described in trials include headache, nausea, and diarrhea. Currently, C1INH is evaluated in interventional clinical trials in the context of transplantation, acute antibody-mediated rejection after transplantation, and contrast-induced nephropathy.