C1-Inhibitor

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Greg L. Plosker - One of the best experts on this subject based on the ideXlab platform.

  • Recombinant Human C1 Inhibitor (Conestat Alfa)
    BioDrugs, 2012
    Co-Authors: Greg L. Plosker
    Abstract:

    Conestat alfa is a recombinant human C1 inhibitor used in the treatment of angioedema attacks in patients with hereditary angioedema (HAE). Patients with type I or II HAE have a deficiency in functional C1 inhibitor, which is an important regulator of complement and contact system activation.

  • Recombinant Human C1 Inhibitor (Conestat Alfa)
    BioDrugs, 2012
    Co-Authors: Greg L. Plosker
    Abstract:

    Conestat alfa is a recombinant human C1 inhibitor used in the treatment of angioedema attacks in patients with hereditary angioedema (HAE). Patients with type I or II HAE have a deficiency in functional C1 inhibitor, which is an important regulator of complement and contact system activation. The therapeutic efficacy of conestat alfa in the treatment of angioedema attacks in patients with HAE was evaluated in two similar randomized, double-blind, placebo-controlled trials conducted in North America and Europe. The randomized controlled phases of both studies were closed after interim analyses provided compelling evidence of statistically significant positive efficacy findings and showed no apparent adverse safety findings. Results of the pooled analysis of the two trials showed that conestat alfa provided significantly faster initial relief of symptoms than placebo. The median time to the beginning of relief of symptoms (primary endpoint) was 66 minutes with conestat alfa 100 units/kg, 122 minutes with conestat alfa 50 units/kg, and 495 minutes with placebo. Conestat alfa was also statistically superior to placebo for the secondary endpoint of median time to minimal symptoms, with values of 266, 247, and 1210 minutes for the respective treatment groups. On the basis of data from open-label extension studies and integrated analyses of clinical trial data, conestat alfa has demonstrated efficacy in the treatment of repeated HAE attacks and in patients with potentially life-threatening HAE attacks with involvement of the upper airways. Conestat alfa was generally well tolerated in clinical trials, with the most frequently reported adverse event being headache. In the two randomized controlled trials, headache and vertigo were the only adverse events deemed to be related to study treatment.

Marco Cicardi - One of the best experts on this subject based on the ideXlab platform.

  • C1 Inhibitor Autoantibodies
    Autoantibodies, 2020
    Co-Authors: Andrea Zanichelli, Marco Cicardi, Chiara Suffritti, Roberto Perricone
    Abstract:

    Abstract Autoantibodies to C1 inhibitor (C1-INH) bind to epitopes on the reactive center of the C1-INH molecule. As a consequence of this binding, C1-INH is converted into an inactive substrate that can be cleaved by proteases. C1-INH is a serine protease inhibitor that plays a role in the complement, contact, fibrinolytic, and coagulation cascades. Autoantibodies to C1-INH cause acquired C1-INH deficiency, activation of the classical complement pathway, and defective control of the contact-kinin system. This eventually leads to recurrent bradykinin release with increased vascular permeability and symptoms of angioedema involving subcutaneous tissue, gastrointestinal mucosa, and the upper respiratory tract. Autoantibodies inactivate C1-INH protein and may dramatically reduce efficacy of replacement therapy with plasma derived C1 inhibitor. Autoantibodies to C1-INH have also been described in absence of angioedema symptoms. They have been found in patients with systemic lupus erythematosus (SLE), with lupus-like syndrome and anticardiolipin antibodies and in a patient with primary antiphospholipid syndrome: their effect on C1-INH function in these conditions is only partially defined.

  • C1 inhibitor: molecular and clinical aspects
    Springer Seminars in Immunopathology, 2005
    Co-Authors: Marco Cicardi, Andrea Zanichelli, Lorenza Zingale, Emanuela Pappalardo, Benedetta Cicardi
    Abstract:

    C1 inhibitor (C1-INH) is a serine protease inhibitor (serpins) that inactivates several different proteases in the complement, contact, coagulation, and fibrinolytic systems. By its C-terminal part (serpin domain), characterized by three β-sheets and an exposed mobile reactive loop, C1-INH binds, and blocks the activity of its target proteases. The N-terminal end (nonserpin domain) confers to C1-INH the capacity to bind lipopolysaccharides and E-selectin. Owing to this moiety, C1-INH intervenes in regulation of the inflammatory reaction. The heterozygous deficiency of C1-INH results in hereditary angioedema (HAE). The clinical picture of HAE is characterized by bouts of local increase in vascular permeability. Depending on the affected site, patients suffer from disfiguring subcutaneous edema, abdominal pain, vomiting and/or diarrhoea for edema of the gastrointestinal mucosa, dysphagia, and dysphonia up to asphyxia for edema of the pharynx and larynx. Apart from its genetic deficiency, there are several pathological conditions such as ischemia–reperfusion, septic shock, capillary leak syndrome, and pancreatitis, in which C1-INH has been reported to either play a pathogenic role or be a potential therapeutic tool. These potential applications were identified long ago, but controlled studies have not been performed to confirm pilot experiences. Recombinant C1-INH, produced in transgenic animals, has recently been produced for treatment of HAE, and clinical trials are in progress. We can expect that the introduction of this new product, along with the existing plasma derivative, will renew interest in exploiting C1-INH as a therapeutic agent.

  • Molecular defects in hereditary angioneurotic edema.
    Proceedings of the Association of American Physicians, 1997
    Co-Authors: John J Bissler, Virginia H Donaldson, Kulwant S. Aulak, Marco Cicardi, Harrison Ra, Fred S. Rosen, Davis Ae
    Abstract:

    Thirty-eight previously unreported, unrelated patients with hereditary angioneurotic edema were studied, and each was found to have a single mutation in the C1 inhibitor gene. On the basis of serine protease inhibitor crystal structure, these and published mutations affect critical domains in the reactive center loop, alpha-helices A, B, C, E, and F, and beta-sheets A and C. Almost all mutations, other than in the reactive center loop, occur at residues that are highly conserved among serine protease inhibitors, and the others are likely to interfere with molecular movement. These mutations begin to identify residues critical for molecular function of the C1 inhibitor molecule.

  • Antiproteasic activity of C1 inhibitor. Therapeutic perspectives.
    Annali italiani di medicina interna : organo ufficiale della Società italiana di medicina interna, 1994
    Co-Authors: Marco Cicardi, Luigi Bergamaschini, Massimo Cugno, Pier Alberto Testoni, Guzzoni S, M. Buizza, F. Bagnolo
    Abstract:

    : Kallikrein is a protease involved in the inflammatory process causing acute pancreatitis. Attempts to prevent this process with antiprotease agents have been successful in experimental animal models but disappointing in humans. We studied 40 consecutive patients undergoing endoscopic papillosphincterotomy. This procedure can induce a transient, moderate pancreatic inflammatory reaction, characterized by hyperamylasemia, which in 1-6% of the patients may evolve to acute pancreatitis. To assess the capacity of C1 inhibitor, the main physiological inhibitor of kallikrein, to prevent such complications, we pretreated 20 patients with 3000 U of C1 inhibitor plasma concentrate i.v.; 20 patients served as controls. Serum levels of amylase and functional C1 inhibitor were determined before the procedure and after 2, 4, 8 and 24 hours. Serum levels of amylase in the control group (146 +/- 21 IU) and in the group treated with C1 inhibitor (158 +/- 25 IU) were similar before treatment. Four and 8 hours after the end of the procedure, amylase levels were significantly lower (p < 0.001) in the treated group (231 +/- 46 and 355 +/- 104 IU) than in the control subjects (969 +/- 229 and 923 +/- 207 IU). After 24 hours both groups had normal amylase levels. In treated patients, functional levels of C1 inhibitor increased from 104 +/- 30 to 175 +/- 30% and remained elevated throughout the observation period. These data indicate that C1 inhibitor plasma concentrate can prevent hyperamylasemia following pancreas injury, probably, by inhibiting the kallikrein-mediated inflammatory process. C1 inhibitor might benefit patients at high risk of pancreatitis who undergo endoscopic papillosphincterotomy.

  • A hinge region mutation in C1-Inhibitor (Ala436-->Thr) results in nonsubstrate-like behavior and in polymerization of the molecule.
    Journal of Biological Chemistry, 1993
    Co-Authors: Kulwant S. Aulak, Marco Cicardi, C. E. Hack, Eric Eldering, Y. P. T. Lubbers, R.a. Harrison, A. Mast, Alvin E. Davis
    Abstract:

    Abstract C1-Inhibitor(Mo), a dysfunctional C1-Inhibitor molecule produced in two kindred with type II hereditary angioedema, has a mutation at the P10 position (Ala436 to Thr). Like most serpins with hinge region mutations (P14, P12, P10), C1-Inhibitor(Mo) loses its inhibitory activity. However, unlike the other hinge region mutations, this mutant is not converted to a substrate. As shown by nondenaturing gel electrophoresis, gel filtration, sucrose density gradient ultracentrifugation, and electron microscopy, C1-Inhibitor(Mo) exists in both monomeric and multimeric forms. Polymerization probably results from reactive center loop insertion into the A sheet of an adjacent molecule. Native C1-Inhibitor(Mo) was shown to have a thermal stability profile intermediate to those of intact and of cleaved normal C1-Inhibitor. Native C1-Inhibitor(Mo) did not bind to monoclonal antibody KII, which binds only to reactive center-cleaved normal C1-Inhibitor. It did, however, react with monoclonal antibody KOK12, which recognizes complexed or cleaved C1-Inhibitor but not intact normal C1-Inhibitor. Native C1-Inhibitor(Mo), therefore, exists in a conformation similar to the complexed form of normal C1-Inhibitor.

Alvin E. Davis - One of the best experts on this subject based on the ideXlab platform.

  • BIOLOGICAL ACTIVITIES OF C1 INHIBITOR
    Molecular Immunology, 2008
    Co-Authors: Alvin E. Davis, Pedro Mejia, Fengxin Lu
    Abstract:

    Broadly speaking, C1 inhibitor plays important roles in the regulation of vascular permeability and in the suppression of inflammation. Vascular permeability control is exerted largely through inhibition of two of the proteases involved in the generation of bradykinin, factor XIIa and plasma kallikrein (the plasma kallikrein-kinin system). Anti-inflammatory functions, however, are exerted via several activities including inhibition of complement system proteases (C1r, C1s, MASP2) and the plasma kallikrein-kinin system proteases, in addition to interactions with a number of different proteins, cells and infectious agents. These more recently described, as yet incompletely characterized, activities serve several potential functions, including concentration of C1 inhibitor at sites of inflammation, inhibition of alternative complement pathway activation, inhibition of the biologic activities of gram negative endotoxin, enhancement of bacterial phagocytosis and killing, and suppression of the influx of leukocytes into a site of inflammation. C1 inhibitor has been shown to be therapeutically useful in a variety of animal models of inflammatory diseases, including gram negative bacterial sepsis and endotoxin shock, suppression of hyperacute transplant rejection, and treatment of a variety of ischemia-reperfusion injuries (heart, intestine, skeletal muscle, liver, brain). In humans, early data appear particularly promising in myocardial reperfusion injury. The mechanism (or mechanisms) of the effect of C1 inhibitor in these conditions is (are) not completely clear, but involve inhibition of complement and contact system activation, in addition to variable contributions from other C1 inhibitor activities that do not involve protease inhibition.

  • New treatments addressing the pathophysiology of hereditary angioedema
    Clinical and Molecular Allergy, 2008
    Co-Authors: Alvin E. Davis
    Abstract:

    Hereditary angioedema is a serious medical condition caused by a deficiency of C1-Inhibitor. The condition is the result of a defect in the gene controlling the synthesis of C1-Inhibitor, which regulates the activity of a number of plasma cascade systems. Although the prevalence of hereditary angioedema is low – between 1:10,000 to 1:50,000 – the condition can result in considerable pain, debilitation, reduced quality of life, and even death in those afflicted. Hereditary angioedema presents clinically as cutaneous swelling of the extremities, face, genitals, and trunk, or painful swelling of the gastrointestinal mucosa. Angioedema of the upper airways is extremely serious and has resulted in death by asphyxiation. Subnormal levels of C1-Inhibitor are associated with the inappropriate activation of a number of pathways – including, in particular, the complement and contact systems, and to some extent, the fibrinolysis and coagulation systems. Current findings indicate bradykinin, a product of contact system activation, as the primary mediator of angioedema in patients with C1-Inhibitor deficiency. However, other systems may play a role in bradykinin's rapid and excessive generation by depleting available levels of C1-Inhibitor. There are currently no effective therapies in the United States to treat acute attacks of hereditary angioedema, and currently available agents used to treat hereditary angioedema prophylactically are suboptimal. Five new agents are, however, in Phase III development. Three of these agents replace C1-Inhibitor, directly addressing the underlying cause of hereditary angioedema and re-establishing regulatory control of all pathways and proteases involved in its pathogenesis. These agents include a nano-filtered C1-Inhibitor replacement therapy, a pasteurized C1-Inhibitor, and a recombinant C1-Inhibitor isolated from the milk of transgenic rabbits. All C1-Inhibitors are being investigated for acute angioedema attacks; the nano-filtered C1-Inhibitor is also being investigated for prophylaxis of attacks. The other two agents, a kallikrein inhibitor and a bradykinin receptor-2 antagonist, target contact system components that are mediators of vascular permeability. These mediators are formed by contact system activation as a result of C1-Inhibitor consumption.

  • C1 Inhibitor-Mediated Protection from Sepsis
    Journal of Immunology, 2007
    Co-Authors: Fengxin Lu, Stacey M. Fernandes, Jinan Li, Alvin E. Davis
    Abstract:

    C1 inhibitor (C1INH) protects mice from lethal Gram-negative bacterial LPS-induced endotoxin shock and blocks the binding of LPS to the murine macrophage cell line, RAW 264.7, via an interaction wi ...

  • Deficiencies of C1 inhibitor.
    Best Practice & Research in Clinical Gastroenterology, 2005
    Co-Authors: Fred S. Rosen, Alvin E. Davis
    Abstract:

    Hereditary and acquired deficiencies of the C1 inhibitor result in a single prominent symptom, namely angioedema. Angioedema may involve the skin, the gastrointestinal tract or the upper airway. Genetically determined defects in C1INH cause hereditary angioedema. The defect may be acquired as the result of an auto-antibody to C1INH or be due to the generation of anti-idiotypic antibody to monoclonal immunoglobulins as occurs in various B cell lymphoproliferative diseases. Androgens provide prophylaxis against attacks of angioedema. There is no widely approved treatment for acute attacks of angioedema although several promising drugs are now in the final stages of clinical trials.

  • Biological effects of C1 inhibitor.
    Drug News & Perspectives, 2004
    Co-Authors: Alvin E. Davis
    Abstract:

    Abstract C1 inhibitor is a serine proteinase inhibitor (serpin) that regulates activation of both the complement and contact systems. Regulation of complement system activation takes place through inactivation of the classical pathway proteases, C1r and C1s, the lectin pathway protease, MASP2, and perhaps via inhibition of alternative pathway activation by reversible binding to C3b. Regulation of contact system activation takes place through inactivation of plasma kallikrein and coagulation factor XIIa. Deficiency of C1 inhibitor results in hereditary angioedema, which is characterized by recurrent episodes of localized angioedema of the skin, gastrointestinal mucosa or upper respiratory mucosa. A variety of clinical, in vitro and animal experiments indicate that the mediator of increased vascular permeability in hereditary angioedema is bradykinin. Animal models suggest that in addition to its utility in therapy of hereditary angioedema, C1 inhibitor may prove useful in a variety of other diseases including septic shock, reperfusion injury, hyperacute transplant rejection, traumatic and hemorrhagic shock, and the increased vascular permeability associated with thermal injury, interleukin-2 therapy and cardiopulmonary bypass. The therapeutic effect in these disease models very likely results from a combination of complement system activation, contact system activation and perhaps from other activities of C1 inhibitor. These other activities include a direct interaction with endotoxin, which may help to prevent endotoxic shock and an interaction with selectin molecules on endothelial cells, which may serve both to concentrate C1 inhibitor at sites of inflammation and to inhibit the transmigration of leukocytes across the endothelium.

Dominique Michaud - One of the best experts on this subject based on the ideXlab platform.

  • a protease activity depleted environment for heterologous proteins migrating towards the leaf cell apoplast
    Plant Biotechnology Journal, 2012
    Co-Authors: Charles Goulet, Moustafa Khalf, Marcandre Daoust, Frank Sainsbury, Dominique Michaud
    Abstract:

    Recombinant proteins face major constraints along the plant cell secretory pathway, including proteolytic processing compromising their structural integrity. Here, we demonstrate the potential of protease inhibitors as in situ stabilizing agents for recombinant proteins migrating towards the leaf apoplast. Genomic data for Arabidopsis, rice and Nicotiana spp. were assessed to determine the relative incidence of protease families in the cell secretory pathway. Transient expression assays with the model platform Nicotiana benthamiana were then performed to test the efficiency of protease inhibitors in stabilizing proteins targeted to the apoplast. Current genomic data suggest the occurrence of proteases from several families along the secretory pathway, including A1 and A22 Asp proteases; C1A and C13 Cys proteases; and S1, S8 and S10 Ser proteases. In vitro protease assays confirmed the presence of various proteases in N. benthamiana leaves, notably pointing to the deposition of A1- and S1-type activities preferentially in the apoplast. Accordingly, transient expression and secretion of the A1/S1 protease inhibitor, tomato cathepsin D inhibitor (SlCDI), negatively altered A1 and S1 protease activities in this cell compartment, while increasing the leaf apoplast protein content by ~45% and improving the accumulation of a murine diagnostic antibody, C5-1, co-secreted in the apoplast. SlCYS9, an inhibitor of C1A and C13 Cys proteases, had no impact on the apoplast proteases and protein content, but stabilized C5-1 in planta, presumably upstream in the secretory pathway. These data confirm, overall, the potential of protease inhibitors for the in situ protection of recombinant proteins along the plant cell secretory pathway. © 2011 The Authors. Plant Biotechnology Journal

  • A protease activity–depleted environment for heterologous proteins migrating towards the leaf cell apoplast
    Plant Biotechnology Journal, 2011
    Co-Authors: Charles Goulet, Moustafa Khalf, Frank Sainsbury, Marc-andre D'aoust, Dominique Michaud
    Abstract:

    Recombinant proteins face major constraints along the plant cell secretory pathway, including proteolytic processing compromising their structural integrity. Here, we demonstrate the potential of protease inhibitors as in situ stabilizing agents for recombinant proteins migrating towards the leaf apoplast. Genomic data for Arabidopsis, rice and Nicotiana spp. were assessed to determine the relative incidence of protease families in the cell secretory pathway. Transient expression assays with the model platform Nicotiana benthamiana were then performed to test the efficiency of protease inhibitors in stabilizing proteins targeted to the apoplast. Current genomic data suggest the occurrence of proteases from several families along the secretory pathway, including A1 and A22 Asp proteases; C1A and C13 Cys proteases; and S1, S8 and S10 Ser proteases. In vitro protease assays confirmed the presence of various proteases in N. benthamiana leaves, notably pointing to the deposition of A1- and S1-type activities preferentially in the apoplast. Accordingly, transient expression and secretion of the A1/S1 protease inhibitor, tomato cathepsin D inhibitor (SlCDI), negatively altered A1 and S1 protease activities in this cell compartment, while increasing the leaf apoplast protein content by ~45% and improving the accumulation of a murine diagnostic antibody, C5-1, co-secreted in the apoplast. SlCYS9, an inhibitor of C1A and C13 Cys proteases, had no impact on the apoplast proteases and protein content, but stabilized C5-1 in planta, presumably upstream in the secretory pathway. These data confirm, overall, the potential of protease inhibitors for the in situ protection of recombinant proteins along the plant cell secretory pathway. © 2011 The Authors. Plant Biotechnology Journal

Luqing Shang - One of the best experts on this subject based on the ideXlab platform.

  • 4 iminooxazolidin 2 one as a bioisostere of the cyanohydrin moiety inhibitors of enterovirus 71 3c protease
    Journal of Medicinal Chemistry, 2018
    Co-Authors: Chengyou Shang, Yangyang Zhai, Linfeng Li, Peng Yang, Binghe Wang, Luqing Shang
    Abstract:

    A recently reported potent inhibitor of enterovirus 71 3C protease, (R)-1, was found to have stability and potential toxicity issues due to the presence of a cyanohydrin moiety. Modifying the labile cyanohydrin moiety, by serendipity, led to the discovery of 4-iminooxazolidin-2-one-based inhibitors 4e and 4g with potent inhibitory activity and significantly improved stability. In vivo pharmacokinetic studies of 4e also demonstrated high plasma exposure and moderate half-life. These compounds have shown potential of becoming anti-EV71 drug candidates.