Antibody-mediated inhibition of FXIIa blocks downstream bradykinin generation

Cao, Helen; Biondo, Mark; Lioe, Hadi; Busfield, Samantha J.; Rayzman, Veronika; Nieswandt, Bernhard; Bork, Konrad; Harrison, Leonard C.; Auyeung, Priscilla; Farkas, Henriette; Pelzing, Matthias; Dower, Steven K.; Wilson, Michael J.; Nash, Andrew D.; Nolte, Marc W.; Panousis, Con

doi:10.1016/j.jaci.2018.06.014

Cited by 33 publications

(34 citation statements)

References 9 publications

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“…45,46 Strategies to inhibit FXII focus on knock down of FXII with small interfering RNA molecules (siRNAs) or ASOs, aptamers that bind to FXII and/or FXIIa and block FXI activation, and monoclonal antibodies that inhibit FXIIa or bind to FXI and block its activation by FXIIa (Table 1). 40,[47][48][49][50][51][52][53] Development of potent and specific small molecule inhibitors is more difficult for FXIIa than for FXIa because FXIIa has an open active site cleft. 54 The mode of administration of FXI or FXII inhibitors differs depending on the agent.…”

Section: Strategies To Inhibit Fxi and Fxiimentioning

confidence: 99%

Novel antithrombotic strategies for treatment of venous thromboembolism

Weitz

Chan

2020

Blood

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Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), is the third most common cause of vascular death after heart attack and stroke. Anticoagulation therapy is the cornerstone of VTE treatment. Despite such therapy, up to 50% of patients with DVT develop postthrombotic syndrome, and up to 4% of patients with PE develop chronic thromboembolic pulmonary hypertension. Therefore, better therapies are needed. Although direct oral anticoagulants are more convenient and safer than warfarin for VTE treatment, bleeding remains the major side effect, particularly in cancer patients. Factor XII and factor XI have emerged as targets for new anticoagulants that may be safer. To reduce the complications of VTE, attenuation of thrombin activatable fibrinolysis inhibitor activity is under investigation in PE patients to enhance endogenous fibrinolysis, whereas blockade of leukocyte interaction with the vessel wall is being studied to reduce the inflammation that contributes to postthrombotic syndrome in DVT patients. Focusing on these novel antithrombotic strategies, this article explains why safer anticoagulants are needed, provides the rationale for factor XII and XI as targets for such agents, reviews the data on the factor XII– and factor XI–directed anticoagulants under development, describes novel therapies to enhance fibrinolysis and decrease inflammation in PE and DVT patients, respectively, and offers insights into the opportunities for these novel VTE therapies.

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Section: Strategies To Inhibit Fxi and Fxiimentioning

confidence: 99%

Novel antithrombotic strategies for treatment of venous thromboembolism

Weitz

Chan

2020

Blood

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“…The antibody inhibitor garadacimab entered phase II clinical trials in October 2018 as a preventative treatment in hereditary angioedema (HAE) https://www.clinicaltrials.gov/ct2/ show/NCT03712228 [68]. In this study, subjects were treated with either garadacimab at 75 mg, 200 mg, 600 mg, or a placebo to determine the efficacy, PK effects, and safety.…”

Section: Garadacimab (Aka Csl312)mentioning

confidence: 99%

Drugs in phase I and II clinical development for the prevention of stroke in patients with atrial fibrillation

Bentley

Hardy

Scott

et al. 2021

Expert Opinion on Investigational Drugs

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Introduction: Atrial fibrillation is the most frequently diagnosed cardiac arrhythmia globally and is associated with ischemic stroke and heart failure. Patients with atrial fibrillation are typically prescribed long-term anticoagulants in the form of either vitamin K antagonists or non-vitamin K antagonist oral anticoagulants; however, both carry a potential risk of adverse bleeding. Areas Covered: This paper sheds light on emerging anticoagulant agents which target clotting factors XI and XII, or their activated forms -XIa and XIIa, respectively, within the intrinsic coagulation pathway. The authors examined data available on PubMed, Scopus, and the clinical trials registry of the United States National Library of Medicine (www.clinicaltrials.gov). Expert Opinion: Therapies targeting factors XI or XII can yield anticoagulant efficacy with the potential to reduce adverse bleeding. Advantages for targeting factor XI or XII include a wider therapeutic window and reduced bleeding. Long-term follow-up studies and a greater understanding of the safety and efficacy are required. Atrial fibrillation is a chronic disease and therefore the development of oral formulations is key.

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“…A humanized anti-FXIIa monoclonal antibody is in development for use in multiple indications including subcutaneous HAE-C1-INH therapy. 58,59 A randomized, placebo-controlled, parallel-arm, phase II study is currently ongoing to investigate the clinical efficacy, pharmacokinetics, and safety of CSL312 prophylaxis to prevent attacks in adult patients.…”

Section: Factor XII Antibodiesmentioning

confidence: 99%

Hereditary angioedema in children and adolescents – A consensus update on therapeutic strategies for German‐speaking countries

Wahn

Aberer

Aygören‐Pürsün

et al. 2020

Pediatric Allergy Immunology

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Background/Methods: At a consensus meeting in August 2018, pediatricians and dermatologists from German-speaking countries discussed the therapeutic strategy for the treatment of pediatric patients with type I and II hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH) for Germany, Austria, and Switzerland, taking into account the current marketing approval status. HAE-C1-INH is a rare disease that usually presents during childhood or adolescence with intermittent episodes of potentially life-threatening angioedema. Diagnosis as early as possible and an optimal management of the disease are important to avoid ineffective therapies and to properly treat swelling attacks. This article provides recommendations for developing appropriate treatment strategies in the management of HAE-C1-INH in pediatric patients in German-speaking countries. An overview of available drugs in this age-group is provided, together with their approval status, and study results obtained in adults and pediatric patients. Results/Conclusion: Currently, plasma-derived C1 inhibitor concentrates have the broadest approval status and are considered the best available option for on-demand treatment of HAE-C1-INH attacks and for short-and long-term prophylaxis across all pediatric age-groups in German-speaking countries. For on-demand treatment of children aged 2 years and older, recombinant C1-INH and bradykinin-receptor antagonist icatibant are alternatives. For long-term prophylaxis in adolescents, the parenteral kallikrein inhibitor lanadelumab has recently been approved and can be recommended due to proven efficacy and safety. | 975 WAHN et Al.

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Antibody-mediated inhibition of FXIIa blocks downstream bradykinin generation

Abstract: , and ERDF. Z.D. was supported by a fellowship from Fondation Française pour la Recherche contre le My elome et les Gammapathies monoclonales (F.F.R.M.G.

Cited by 33 publications

References 9 publications

Novel antithrombotic strategies for treatment of venous thromboembolism

Novel antithrombotic strategies for treatment of venous thromboembolism

Drugs in phase I and II clinical development for the prevention of stroke in patients with atrial fibrillation

Hereditary angioedema in children and adolescents – A consensus update on therapeutic strategies for German‐speaking countries

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