Human Plasma-derived C1 Esterase Inhibitor Research Articles

Biochemical and Functional Characterization of Plasma Derived Human Celestrase 1

Background C1-esterase inhibitor (C1-INH) is a protein derived from fresh frozen human plasma and is widely used in the treatment of Hereditary Angioedema. C1-INH product must have high purity with preserved functionality. Objective The aim of the study was to perform extensive characterization of human C1-esterase inhibitor (Celestrase 1) with special emphasis on functionality of the protein by different mechanisms along with its purity and structural elucidation. Design Comparative study. Methods This study describes the purification and characterization of an economically viable, highly pure and efficient human plasma-derived C1-INH prepared from cryopoor plasma by combination of chromatography steps, capable of removing protein contaminants. The purification process includes two orthogonal virus clearance steps -solvent detergent and virus retentive filtration and further, characterized by various biochemical and functional assays along with other commercially available entities. Results The developed process yields 0.75 ± 0.1 vials of C1-INH /L of cryopoor plasma with 44.4 ± 3.6% overall process recovery. Celestrase 1 shows comparability with an existing market comparator, with respect to its purity by different methods. Celestrase 1 proved its functionality in binding irreversibly to the complement protein by classical pathway of the complement system and in the Kallikrein system. Additionally, the antigen-to-biologic activity ratio an indicative of the functionality for Celestrase 1 (0.94) was found comparable to market comparator (0.79). Identity of the product was confirmed by Western blot analysis. The structural analysis of Celestrase 1 was found to be similar to market comparator and exists predominantly in α-helix secondary structure by Far UV Circular Dichroism (CD). Conclusion For the treatment of Hereditary Angioedema (HAE), the current study presents a pure, safe, and functionally efficient product that can meet the therapeutic needs of patients deficient in C1-INH.

Hereditary angioedema (HAE) in Belgium: results from a national survey.

Hereditary angioedema (HAE) is a rare heritable disorder that is characterized by recurrent, circumscribed, nonpitting, nonpruritic, often painful subepithelial swellings of sudden unpredictable onset that generally fade during 48-72 h. Epidemiological data of hereditary angioedema patients in Belgium is lacking. We set up a nation-wide, multicentric study involving the 8 Belgian hospitals known to follow-up patients with Type I and II HAE. All Belgium HAE patients were asked to fill out questionnaires that mainly covered demographic data, family history, and detailed information about diagnosis, treatment and burden of their Type I and II HAE. 112 patients with type I or type II HAE could be included. Median delay between first symptoms and diagnosis was 7 years. 51% of patients had experienced pharyngeal or tongue swelling and 78% had experienced abdominal symptoms, both known to cause an important reduction in quality of life. 60% of symptomatic patients reported to receive long term prophylactic treatment. Human plasma-derived C1-esterase inhibitor concentrate was used by 56.3% of patients. 16.7% and 27.1% of patients used a 17-α-alkylated androgen and tranexamic acid as long term prophylactic therapy. We present the first nation-wide epidemiological study regarding HAE in Belgium. Our data show that the morbidity of HAE is not to be underestimated. Knowledge and dissemination of this data is critical in raising awareness, encouraging development of therapies and optimising nationwide management.

No prominent role for complement C1-esterase inhibitor in Marfan syndrome mice.

Marfan syndrome (MFS) is a connective tissue disorder causing aortic aneurysm formation. Currently, only prophylactic aortic surgery and blood pressure lowering drugs are available to reduce the risk for aortic rupture. Upon whole genome sequencing (WGS) of a Marfan family, we identified a complement gene C1R variant (p.Ser152Leu), which associated with the severe aortic patients. Therefore, we assessed the role of complement activation in MFS aortic tissue. Expression of various complement genes and proteins was detected in human and murine MFS aneurysm tissue, which prompted us to study complement inhibition in MFS mice. Treatment of the Fbn1C1041G/+ MFS mice with human plasma-derived C1-esterase inhibitor Cetor® resulted in reduced complement deposition, decreased macrophage influx in the aorta and lower circulating TNFα levels. However, in line with previous anti-inflammatory treatments, complement inhibition did not change aortic dilatation rate in this MFS mouse model. Thus, while complement factors/C3 activation were detected in human/murine MFS aorta, Cetor® had no effect on aortic dilatation in MFS mice, indicating that complement inhibition is not a suitable treatment strategy in MFS.

Gene therapy for C1 esterase inhibitor deficiency in a Murine Model of Hereditary angioedema.

Hereditary angioedema (HAE) is a life-threatening, autosomal dominant disorder characterized by unpredictable, episodic swelling of the face, upper airway, oropharynx, extremities, genitalia, and gastrointestinal tract. Almost all cases of HAE are caused by mutations in the SERPING1 gene resulting in a deficiency in functional plasma C1 esterase inhibitor (C1EI), a serine protease inhibitor that normally inhibits proteases in the contact, complement, and fibrinolytic systems. Current treatment of HAE includes long-term prophylaxis with attenuated androgens or human plasma-derived C1EI and management of acute attacks with human plasma-derived or recombinant C1EI, bradykinin, and kallikrein inhibitors, each of which requires repeated administration. As an approach to effectively treat HAE with a single treatment, we hypothesized that a one-time intravenous administration of an adeno-associated virus (AAV) gene transfer vector expressing the genetic sequence of the normal human C1 esterase inhibitor (AAVrh.10hC1EI) would provide sustained circulating C1EI levels sufficient to prevent angioedema episodes. To study the efficacy of AAVrh.10hC1EI, we used CRISPR/Cas9 technology to create a heterozygote C1EI-deficient mouse model (S63±) that shares characteristics associated with HAE in humans including decreased plasma C1EI and C4 levels. Phenotypically, these mice have increased vascular permeability of skin and internal organs. Systemic administration of AAVrh.10hC1EI to the S63± mice resulted in sustained human C1EI activity levels above the predicted therapeutic levels and correction of the vascular leak in skin and internal organs. A single treatment with AAVrh.10hC1EI has the potential to provide long-term protection from angioedema attacks in affected individuals.

Human plasma-derived C1 esterase inhibitor for on-demand or prophylaxis treatment of patients with hereditary angioedema: intravenous and subcutaneous formulations

ABSTRACTIntroduction: Hereditary angioedema with C1 inhibitor (C1-INH) deficiency (C1-INH-HAE) is a rare disease in which patients have debilitating, unpredictable swelling attacks. Treatment approaches include prophylaxis therapies to prevent future attacks and on-demand therapies that reduce the duration and severity of an attack.Areas covered: This review summarizes the characteristics and efficacy and safety profiles of two formulations of human plasma-derived C1-INH concentrates, intravenous BERINERT® for on-demand treatment of attacks and subcutaneous HAEGARDA® for routine prophylaxis of attacks.Expert opinion: Intravenous C1-INH concentrates have long been used in the treatment of patients with C1-INH-HAE, and the recent approval of the subcutaneous formulation is a major advancement in prophylaxis therapy. Subcutaneous administration provides more stable and sustained trough C1-INH levels compared with intravenous administration. Pharmacokinetic modeling revealed a close relationship between trough functional C1-INH activity levels and the patient’s risk of experiencing an angioedema attack. The approved dose of subcutaneous C1-INH (60 IU/kg) provides clinically relevant and protective plasma levels of C1-INH throughout the dosing interval. The pharmacokinetic profile of the intravenous formulation consists of a rapid increase and high peak plasma levels of C1-INH, making intravenous administration well suited for the on-demand treatment of acute attacks.

Human plasma-derived C1 esterase inhibitor concentrate has limited effect on house dust mite-induced allergic lung inflammation in mice.

C1 esterase inhibitor (C1-INH) can inhibit multiple pathways (complement, contact-kinin, coagulation, and fibrinolysis) that are all implicated in the pathophysiology of asthma. We explored the effect of human plasma-derived C1-INH on allergic lung inflammation in a house dust mite (HDM) induced asthma mouse model by daily administration of C1-INH (15 U) during the challenge phase. NaCl and HDM exposed mice had comparable plasma C1-INH levels, while bronchoalveolar lavage fluid (BALF) levels were increased in HDM exposed mice coinciding with slightly reduced activation of complement (C5a). C1-INH treatment reduced Th2 response and enhanced HDM-specific IgG1. Influx of eosinophils in BALF or lung, pulmonary damage, mucus production, procoagulant response or plasma leakage in BALF was similar in both groups. In conclusion, C1-INH dampens Th2 responses during HDM induced allergic lung inflammation.

Self-administered C1 esterase inhibitor concentrates for the management of hereditary angioedema: usability and patient acceptance.

Hereditary angioedema (HAE) is a rare genetic disease characterized by episodic subcutaneous or submucosal swelling. The primary cause for the most common form of HAE is a deficiency in functional C1 esterase inhibitor (C1-INH). The swelling caused by HAE can be painful, disfiguring, and life-threatening. It reduces daily function and compromises the quality of life of affected individuals and their caregivers. Among different treatment strategies, replacement with C1-INH concentrates is employed for on-demand treatment of acute attacks and long-term prophylaxis. Three human plasma-derived C1-INH preparations are approved for HAE treatment in the US, the European Union, or both regions: Cinryze®, Berinert®, and Cetor®; however, only Cinryze is approved for long-term prophylaxis. Postmarketing studies have shown that home therapy (self-administered or administered by a caregiver) is a convenient and safe option preferred by many HAE patients. In this review, we summarize the role of self-administered plasma-derived C1-INH concentrate therapy with Cinryze at home in the prophylaxis of HAE.

Recombinant human C1 esterase inhibitor in the management of hereditary angioedema.

Hereditary angioedema (HAE), a rare autosomal dominant genetic disorder, is caused by a deficiency in functional C1 esterase inhibitor (C1-INH). This potentially life-threatening condition manifests as recurrent attacks of subcutaneous and submucosal swelling of the skin, gastrointestinal tract and larynx. The management of HAE includes treatment of acute episodes, short-term prophylaxis in preparation for exposure to known triggers and long-term prophylaxis to decrease the incidence and severity of HAE attacks. Four products are approved in the USA for the treatment of acute attacks of HAE, including one human plasma-derived C1-INH therapy, a recombinant human C1-INH product (rhC1-INH), a plasma kallikrein inhibitor and a bradykinin B2 receptor antagonist. In addition, one human plasma-derived C1-INH therapy and danazol are approved for prophylaxis of HAE attacks. rhC1-INH, extracted from the milk of transgenic rabbits, is a glycoprotein of 478 amino acids with an identical amino acid sequence to the endogenous human C1-INH protein. Population pharmacokinetic analysis of rhC1-INH supports an intravenous dosing strategy of 50 U/kg (maximum 4200 U). The safety and efficacy of rhC1-INH in the treatment of acute attacks in patients with HAE were demonstrated in three randomized, double-blind, placebo-controlled studies and two open-label extension studies. In a pilot prophylaxis study, weekly administration of rhC1-INH 50 U/kg for 8 weeks reduced the incidence of HAE attacks and was well tolerated. Administration of rhC1-INH has not been associated with the development of anti-drug antibodies or antibodies to anti-host-related impurities.

Successful use of daily intravenous infusion of C1 esterase inhibitor concentrate in the treatment of a hereditary angioedema patient with ascites, hypovolemic shock, sepsis, renal and respiratory failure

Hereditary angioedema (HAE) is a rare autosomal dominant disease most commonly associated with defects in C1 esterase inhibitor (C1-INH). HAE manifests as recurrent episodes of edema in various body locations. Atypical symptoms, such as ascites, acute respiratory distress syndrome, and hypovolemic shock, have also been reported. Management of HAE conventionally involves the treatment of acute attacks, as well as short- and long-term prophylaxis. Since attacks can be triggered by several factors, including stress and physical trauma, prophylactic therapy is recommended for patients undergoing surgery. Human plasma-derived C1-INH (pdC1-INH) concentrate is indicated for the treatment of both acute HAE attacks and pre-procedure prevention of HAE episodes in patients undergoing medical, dental, or surgical procedures. We report the first case of a patient with HAE who experienced an abdominal attack precipitated by a retroperitoneal bleed while being converted from warfarin to heparin in preparation for surgery. Subsequently, the patient had a protracted course in hospital with other complications, which included hypovolemic shock, ascites, severe sepsis from nosocomial pneumonia, renal and respiratory failure. Despite intensive interventions, the patient remained in a critical state for months; however, after a trial of daily intravenous infusion of pdC1-INH concentrate (Berinert®, CSL Behring GmbH, Marburg, Germany), clinical status improved, particularly renal function. Therefore, pdC1-INH concentrate may be an effective treatment option to consider for critically-ill patients with HAE.

The thrombogenicity of C1 esterase inhibitor (human): review of the evidence.

Thromboembolic events associated with human plasma-derived C1 esterase inhibitor (C1-INH) use in patients with hereditary angioedema (HAE) have been reported in the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System database. The purpose of this article is to review and assess the strength of available evidence regarding the thrombogenicity of human plasma-derived C1-INH. A PubMed search was conducted of English language articles from January 1990 to December 2013 reporting the thrombogenicity of C1-INH. Original research articles were selected if the following criteria were met: (1) C1-INH was the focus of the study and (2) the authors addressed the pro- or antithrombotic potential of C1-INH. Additional articles on the clinical use of C1-INH in disease states other than HAE were obtained using reference lists of selected articles. Pivotal studies and prescribing information for C1-INH products were also reviewed. Limited animal and clinical data suggest that C1-INH, particularly at high doses of up to 500 U/kg (compared with the U.S. FDA-approved 20-U/kg dose), may be prothrombotic. In contrast, C1-INH has been used in some patients with myocardial infarction, ischemic stroke, sepsis, and capillary leak syndrome at off-label supratherapeutic doses (up to 100 U/kg) without evidence of a thrombogenic effect. Based on our review, thromboembolic events reported with C1-INH use are rare and patients with HAE who experienced such events often have underlying thromboembolic risk factors.

Human Plasma-Derived C1 Esterase Inhibitor for the Treatment of Acute Antibody Mediated Rejection in Kidney Transplantation.

INTRODUCTION: Plasmapheresis (PP) and IVIg treatment of antibody mediated rejection (AMR) produces variable outcomes. We hypothesized that plasma derived C1 esterase inhibitor (C1 INH) would reduce injury during AMR protecting the graft from transplant glomerulopathy (tg). METHODS: This was a multi-center, prospective, randomized trial in 18 kidney transplant recipients with AMR. Subjects were randomized to receive C1 INH or placebo every other day for 2 weeks as add-on therapy to standard of care (SOC = plasmapheresis, IVIg and/or anti-CD20). Endpoints included safety, PK, and effect on renal function and histopathology at day 20 (n=18) and 3-6 months post treatment (n=14). RESULTS: No related serious adverse events were reported. Based on histopathology at 20 days, no differences were observed between treatment groups. Three of seven placebo and none of the C1 INH subjects (0/7) developed new tg at 3-6 months after treatment. Renal function trended towards more sustained improvement in the C1 INH cohort.Figure: No Caption available.The placebo subjects with long-term tg had C1 INH antigenic levels below baseline at end of study drug therapy although no corresponding association was seen on a chromogenic assay for C1 INH activity.Figure: No Caption available.CONCLUSIONS: Human plasma derived C1 INH is well tolerated and may be a useful adjunct to SOC for the prevention of tg after AMR. A larger scale randomized clinical trial is warranted. DISCLOSURE:Montgomery, R.: Grant/Research Support, Alexion, Genzyme, ViroPharma, Other, Astellas, Advisory Board, Gambro, Advisory Board, iPerian, Inc., Advisory Board. Racusen, L.: Grant/Research Support, ViroPharma. Shah, T.: Grant/Research Support, ViroPharma. Woodle, E.: Grant/Research Support, ViroPharma. Sommerer, C.: Grant/Research Support, ViroPharma. Fitts, D.: Employee, ViroPharma. Rockich, K.: Employee, ViroPharma. Uknis, M.: Employee, ViroPharma.

Pasteurized and Nanofiltered, Plasma-Derived C1 Esterase Inhibitor Concentrate for the Treatment of Hereditary Angioedema

Hereditary angioedema (HAE) is a relatively rare autosomal dominant disorder that is typically characterized by recurrent episodes of edema in various body locations. It is most commonly caused by an inherited deficiency of functionally active C1 esterase inhibitor (C1-INH). Replacement therapy with a human plasma-derived C1-INH concentrate is recommended for the treatment and prophylaxis of acute attacks of HAE due to C1-INH deficiency (HAE-C1-INH). This article will discuss the current therapies available for the treatment of HAE-C1-INH, latest treatment guidelines, results of several studies demonstrating the efficacy and safety of the plasma-derived, pasteurized and nanofiltered C1-INH concentrate Berinert(®) (CSL Behring GmBH, Marburg, Germany), and future perspectives for the treatment and management of HAE-C1-INH.

Home therapy with intravenous human C1‐inhibitor in children and adolescents with hereditary angioedema

C1-esterase inhibitor (C1-INH) replacement therapy is the treatment of choice for acute edema attacks in patients with hereditary angioedema (HAE). Our retrospective, observational study assessed the efficacy and safety of home therapy with a human plasma-derived C1-INH concentrate (pC1-INH) in 20 pediatric patients with HAE who had previously been treated with physician-based therapy. While on home therapy, 15 patients received on-demand treatment and five received individual replacement treatment (IRT). The switch to home therapy did not involve a significant increase in the dose of pC1-INH administered, but there was a significant increase in dosing frequency. Although only two patients were affected, the frequency of laryngeal attacks appeared to decrease on home therapy. All attacks, including laryngeal edema, were treated successfully during home therapy with pC1-INH. The mean annual number of days hospitalized was reduced from 3.8 during physician-based therapy to 0.11 during home therapy. No side effects or injection site complications were reported. The median time from onset of attack to administration of pC1-INH was reduced from 67.5 minutes during physician-based therapy to 15 minutes after switching to home therapy. The corresponding median time to initial symptom relief for all types of attack was reduced from 60 to 40 minutes. As in adults, home therapy with pC1-INH is effective and safe in the treatment of HAE attacks in pediatric patients; a larger, randomized study should ideally confirm our findings before this approach can be considered the standard of care for pediatric patients.