更新于：2024-11-01

Factor XIIa x KLKB1 x FXIa

更新于：2024-11-01

基本信息

关联

项与 Factor XIIa x KLKB1 x FXIa 相关的药物

Ir CPI

靶点

Factor XIIa x Factor XIa x KLKB1

作用机制

Factor XIIa抑制剂 [+2]

在研机构

Bioxodes SA

原研机构

Free University of Brussels

在研适应症

脑出血 [+1]

非在研适应症-

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

项与 Factor XIIa x KLKB1 x FXIa 相关的临床试验

NCT05970224 / Recruiting临床2期

A Phase IIa, Randomized, Open-label, Proof-of-Concept Study to Evaluate Safety, Tolerability and Efficacy of Ir-CPI in Patients With Spontaneous Intracerebral Haemorrhage

The purpose of the study is to provide a first assessment of safety, tolerability and efficacy of Ir-CPI, administered on top of standard-of-care, on secondary brain injury in patients with spontaneous intracerebral haemorrhage.

开始日期2023-11-17

申办/合作机构

Bioxodes SA

NCT04653766 / Completed临床1期

A Phase I, Double Blind, Placebo Controlled, Single Ascending Dose Study of Intravenously Administered Ir-CPI to Evaluate Pharmacokinetics, Pharmacodynamics, Safety and Tolerability in Healthy Male Volunteers

The purpose of this First-in-Human study is to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of Ir-CPI, a novel dual inhibitor of FXIIa and FXIa, following IV administration of single ascending doses in healthy male volunteers.

开始日期2019-09-12

申办/合作机构

Bioxodes SA

100 项与 Factor XIIa x KLKB1 x FXIa 相关的临床结果

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100 项与 Factor XIIa x KLKB1 x FXIa 相关的转化医学

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0 项与 Factor XIIa x KLKB1 x FXIa 相关的专利（医药）

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项与 Factor XIIa x KLKB1 x FXIa 相关的文献（医药）

2023-01-01·Frontiers in immunology

Citrullination of C1-inhibitor as a mechanism of impaired complement regulation in rheumatoid arthritis.

Article

作者: Kapetanovic, Meliha C ; Fromell, Karin ; Nilsson, Sara C ; Enghild, Jan J ; Bielecka, Ewa ; Blom, Anna M ; Ekdahl, Kristina N ; Scavenius, Carsten ; Nilsson, Bo ; Eikrem, David ; Vogt, Leonie M ; Martin, Myriam ; Potempa, Jan

BackgroundDysregulated complement activation, increased protein citrullination, and production of autoantibodies against citrullinated proteins are hallmarks of rheumatoid arthritis (RA). Citrullination is induced by immune cell-derived peptidyl-Arg deiminases (PADs), which are overactivated in the inflamed synovium. We characterized the effect of PAD2- and PAD4-induced citrullination on the ability of the plasma-derived serpin C1-inhibitor (C1-INH) to inhibit complement and contact system activation.MethodsCitrullination of the C1-INH was confirmed by ELISA and Western blotting using a biotinylated phenylglyoxal probe. C1-INH-mediated inhibition of complement activation was analyzed by C1-esterase activity assay. Downstream inhibition of complement was studied by C4b deposition on heat-aggregated IgGs by ELISA, using pooled normal human serum as a complement source. Inhibition of the contact system was investigated by chromogenic activity assays for factor XIIa, plasma kallikrein, and factor XIa. In addition, autoantibody reactivity to native and citrullinated C1-INH was measured by ELISA in 101 RA patient samples.ResultsC1-INH was efficiently citrullinated by PAD2 and PAD4. Citrullinated C1-INH was not able to bind the serine protease C1s and inhibit its activity. Citrullination of the C1-INH abrogated its ability to dissociate the C1-complex and thus inhibit complement activation. Consequently, citrullinated C1-INH had a decreased capacity to inhibit C4b deposition via the classical and lectin pathways. The inhibitory effect of C1-INH on the contact system components factor XIIa, plasma kallikrein, and factor XIa was also strongly reduced by citrullination. In RA patient samples, autoantibody binding to PAD2- and PAD4-citrullinated C1-INH was detected. Significantly more binding was observed in anti-citrullinated protein antibody (ACPA)-positive than in ACPA-negative samples.ConclusionCitrullination of the C1-INH by recombinant human PAD2 and PAD4 enzymes impaired its ability to inhibit the complement and contact systems in vitro. Citrullination seems to render C1-INH more immunogenic, and citrullinated C1-INH might thus be an additional target of the autoantibody response observed in RA patients.

2021-02-01·Journal of Thrombosis and Haemostasis2区 · 医学

Dual inhibition of factor XIIa and factor XIa as a therapeutic approach for safe thromboprotection

2区 · 医学

Review

作者: Godfroid, Edmond ; Demoulin, Stéphanie ; Hermans, Cédric

Clinical practice shows that a critical unmet need in the field of medical device-associated thrombosis prevention is the availability of an anticoagulant therapy without hemorrhagic risk. In the quest for new drugs that are at least as effective as those currently available, while avoiding bleeding complications, molecules that target nearly every step of the coagulation pathway have been developed. Among these molecules, inhibitors of factor XII (FXII) or factor XI (FXI) are promising alternatives as deficiencies in these factors protect against thrombosis without causing spontaneous hemorrhage, as revealed by epidemiological and preclinical data. Ixodes ricinus-contact phase inhibitor (Ir-CPI), a new anticoagulant candidate with an innovative mechanism of action could be this ideal anticoagulant agent for safe prevention from clotting on medical devices. This protein, which selectively binds to FXIIa, FXIa, and plasma kallikrein and inhibits the reciprocal activation of FXII, prekallikrein, and FXI in human plasma, was shown to prevent thrombosis in an ovine cardiopulmonary bypass system associated with cardiac surgeries. Furthermore, as opposed to unfractionated heparin, Ir-CPI appears to be devoid of bleeding risk. This review outlines the rationale for targeting upstream coagulation factors in order to prevent medical device-associated thrombosis; examines the novel approaches under development; and focuses on Ir-CPI, which shows promising properties in the field of thrombosis prevention.

2020-01-01·TH Open

Lisinopril-Induced Angioedema in a Patient with Plasma Prekallikrein Deficiency

作者: Rivera, Stefanie ; Dasgupta, Swapan K. ; Thiagarajan, Perumal

AbstractAngiotensin-converting enzyme (ACE) inhibitors are extensively prescribed to treat patients with hypertension, congestive heart failure, and diabetic nephropathy. A small fraction of these patients (approximately 0.7%) develop angioedema, manifested by swelling of the lips and oropharynx. Angioedema of oropharynx is a medical emergency that can lead to asphyxiation and death. The angioedema is due to bradykinin generated from high molecular weight kininogen by kallikrein, which is derived from plasma prekallikrein by action of the factor XIIa, factor Xia, or prolylcarboxypeptidase. Bradykinin induces vasodilation and increased vascular permeability. ACE is the major degrading enzyme of bradykinin in the intravascular department. ACE inhibitors inhibit the proteolytic inactivation of bradykinin. We report a patient with oropharyngeal angioedema associated with an ACE inhibitor with complete absence of plasma prekallikrein due to homozygous mutation (Ser97PhefsTer173).