Abstract
Human C1-esterase inhibitor (C1-INH) is a unique anti-inflammatory multifunctional plasma protein best known for its key role in regulation of the classical complement pathway, contact activation system and intrinsic pathway of coagulation. By sequence homology and mechanism of protease inhibition it belongs to the serine proteinase inhibitor (serpin) superfamily. However, in addition to its inhibitory capacities for several proteases, it also exhibits a broad spectrum of non-inhibitory biological activities. C1-INH plays a key role in the regulation of vascular permeability, best demonstrated in Hereditary Angioedema (HAE) which is triggered by the deficiency of functional C1-INH in plasma? Since 1963, when the link between HAE and C1-INH was first identified, considerable progress has been made in the investigation of C1-INH structure and biological activities, understanding its therapeutic potential, and in the research and development of C1-INH-based therapies for the treatment of HAE and several other clinical conditions. However, augmentation therapy with C1-INH concentrates for patients with HAE is currently the only approved therapeutic application of C1-INH. This manuscript provides an overview of the structure and functions of human C1-INH, its role in HAE, summarizes published data available for recently approved C1-INH therapeutic products, and considers possible use of C1-INH for other applications.
Highlights
Half-life in the circulation c Recombinant C1-INH (Human) C1-esterase inhibitor (C1-INH) is an important anti-inflammatory plasma protein with a wide range of inhibitory and non-inhibitory biological activities
During the last five years, several C1INH products have been licensed in the US and EU for the treatment C1-INH-deficient patients with hereditary angioedema (HAE) that dramatically improved the therapeutic options in the battle with this rare disease
Considering HAE as a BK-mediated swelling disorder caused by C1-INH deficiency, current therapeutic strategies target three key steps in the contact pathway leading from reduced levels of functional C1-INH to BK-induced edematous conditions, i.e.: (a) C1-INH replacement to restore plasma levels of functional C1-INH; (b) Inhibition of plasma kallikrein to prevent BK formation; and (c) Blockade of BK B2-receptor (Β2R) to prevent BK binding (Figure 3) [69,94,95]
Summary
Human C1-INH is an important anti-inflammatory plasma protein with a wide range of inhibitory and non-inhibitory biological activities. Over the past fifty years, our knowledge about C1-INH structure and its biological functions, the cause(s) of its deficiency, and its role in HAE and other conditions has been significantly advanced. During the last five years, several C1INH products have been licensed in the US and EU for the treatment C1-INH-deficient patients with HAE that dramatically improved the therapeutic options in the battle with this rare disease. Human C1-INH is a positive acute-phase plasma glycoprotein with normal concentration in healthy subjects ~ 240 μg/mL (~3 μM), but its level may increase by 2-2.5 times during inflammation [8,9]. Decrease in C1-INH plasma content to levels lower than 55 μg/mL (~25% of normal) was shown to induce spontaneous activation of C1 [13]
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