Targeted inhibition of activated protein C by a non-active-site inhibitory antibody to treat hemophilia

Zhao, Xiao‐Fan; Wilmen, Andreas; Wang, Dongli; Wang, Xinquan; Bauzon, Maxine; Kim, Jiyun; Lindén, Lars; Li, Liang; Egner, Ursula; Marquardt, Tobias; Moosmayer, Dieter; Tebbe, Jan; Glück, Julian M.; Ellinger, P.; Mclean, Kirk; Yuan, Shujun; Yegneswaran, Subramanian; Jiang, Xiaoqiao; Evans, Vince; Gu, Jianming; Schneider, Doug; Zhu, Ying; Xu, Yifan; Mallari, Cornell; Hesslein, Ashley; Wang, Yan; Schmidt, Nicole; Gutberlet, Katrin; Ruehl-Fehlert, Christine; Freyberger, Alexius; Hermiston, Terry; Patel, Chandra; Sim, Derek; Mosnier, Laurent O.; Laux, Volker

doi:10.1038/s41467-020-16720-9

Cited by 26 publications

(24 citation statements)

References 47 publications

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“…This feature distinguishes super FVa from approaches using anti-APC antibodies with long half-lives to curb bleeding. 42 In contrast to enzymatic prohemostatics such as rhFVIIa (Novo7, NovoNordisk), 71,72 super FVa is a nonenzymatic cofactor with restricted function at sites of active injury and dependent on the endogenous generation of FXa, thereby exhibiting a presumably low thrombogenic risk. Our current observations would support this concept because super FVa normalized, rather than enhanced, coagulation.…”

Section: Discussionmentioning

confidence: 99%

“…37,38,40,41 Growing evidence in humans and animal models suggests that excessive APC anticoagulation can exacerbate bleeding. 27,28,42,43 As a cofactor in the prothrombinase complex, FVa enhances the rate of thrombin generation approximately 10,000-fold. [44][45][46] APC rapidly inactivates FVa via proteolytic cleavage at Arg506 followed by a slower cleavage at Arg306.…”

Section: Introductionmentioning

confidence: 99%

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An engineered activated factor V for the prevention and treatment of acute traumatic coagulopathy and bleeding in mice

et al. 2022

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Acute traumatic coagulopathy (ATC) occurs in ≈30% of trauma patients and is associated with increased mortality. Excessive generation of activated protein C (APC) and hyperfibrinolysis are believed to be driving forces for ATC. Two mouse models were used to investigate whether an engineered activated FV variant (superFVa) that is resistant to inactivation by APC and contains a stabilizing A2-A3 domain disulfide bond, is able to reduce traumatic bleeding and normalize hemostasis parameters in ATC. First, ATC was induced by the combination of trauma and shock. ATC was characterized by APTT prolongation and reductions of FV, FVIII, and fibrinogen, but not FII and FX. Administration of superFVa normalized the APTT, returned FV and FVIII clotting activity levels to their normal range, and reduced APC and thrombin-antithrombin (TAT) levels, indicating improved hemostasis. Next, a liver laceration model was used where ATC develops as the consequence of severe bleeding. SuperFVa prophylaxis prior to liver laceration reduced bleeding, prevented APTT prolongation, depletion of FV and FVIII, and excessive generation of APC. Thus, prophylactic administration of superFVa prevented the development of ATC. SuperFVa intervention started after the development of ATC stabilized bleeding, reversed the prolonged APTT, returned FV and FVIII levels to their normal range, and reduced TAT levels that were increased by ATC. In summary, superFVa prevented ATC and traumatic bleeding when administered prophylactically, and superFVa stabilized bleeding and reversed abnormal hemostasis parameters when administered while ATC was in progress. Thus, superFVa may be an attractive strategy to intercept ATC and mitigate traumatic bleeding.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

An engineered activated factor V for the prevention and treatment of acute traumatic coagulopathy and bleeding in mice

et al. 2022

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“…CD137 is a costimulating molecule that acts on the activation of T cells, regulating the activity of these cells in physiological and pathological processes [ 108 ]. Wang was one of the authors of a study that tested two types of mAbs for the treatment of hemophilia [ 109 ], and Zhang participated in a study whose objective was to evaluate the performance of monoclonal antibody 7C6 in marking MICA/B a3, a domain present in tumor cells, potentiating the activity of antitumor CIK cells [ 110 ]. Other studies of the main authors cited and other researchers are given in Table 3 .…”

Section: Resultsmentioning

confidence: 99%

Technological Advancements in Monoclonal Antibodies

Santos-Neto

Oliveira

Hodel

et al. 2021

The Scientific World Journal

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Biopharmaceuticals are innovative solutions that have revolutionized the treatment of important chronic diseases and malignancies. The approval of biosimilar products has become a complex and balanced process, and there are versions of drugs with established biosimilarity that can offer a more accessible treatment option to patients. The objective of this work was to identify the advancement of these technologies by means of patent and article analysis based on technological and scientific prospection. In patent document recovery, Derwent Innovation Index (DWPI) and PatentInspiration databases were used. The research was based on the search of the selected terms in the title, summary, and claims of the documents through a search strategy containing IPC code and keywords. In articles recovery, the Web of Science tool was used in the search of scientific publications dated from the last 5 years. The search resulted in a total of 2295 individual patent documents and 467 families using DWPI database, 769 individual patents and 205 families using PatentInspiration, and 2602 articles using Web of Science database. Additionally, this work describes the number of organizations that contribute to this area, where they are, how much development they have undergone, and the inventors/authors involved. Based on the number of publications registered, there is an important prominence for scientific research in mAbs. In terms of innovation, it is expected that several therapeutic drugs are already under regulatory review, which will allow drugs to be approved over the next few years and will thus generate a continuous flow of new products based on immunotherapies, mAbs, and biosimilar drugs. These drugs have become essential weapons for the treatment of significant diseases, and the increasing trend in the number of related scientific and technological publications contributes to making these therapies available to the greatest number of people.

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“…6 D). Notably, recombinant activated protein C (APC), a component of the natural anticoagulant system, has been applied in the treatment of sepsis due to its potent anti-inflammatory activity for endothelial cells [ 128 , 129 ], but the severe bleeding tendency with APC due to the decomposition of procoagulant co-factors Va and VIIIa prevent its clinical application. Recently, Lee et al designed a protein nanocage (TFMG) composed of short ferritin (sFn), γ-Carboxyglutamic Acid of Protein C (PC-Gla), PAR-1-activating peptide (TRAP), and a matrix metalloproteinase (MMP)-2 cleavage site, where sFn acts as a skeleton structure, inserting PC-Gla at the C-terminus and TRAP in the N-terminus [ 130 ].…”

Section: Inflammation Regulationmentioning

confidence: 99%

Nanotherapies for sepsis by regulating inflammatory signals and reactive oxygen and nitrogen species: New insight for treating COVID-19

et al. 2021

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SARS-CoV-2 has caused up to 127 million cases of COVID-19. Approximately 5% of COVID-19 patients develop severe illness, and approximately 40% of those with severe illness eventually die, corresponding to more than 2.78 million people. The pathological characteristics of COVID-19 resemble typical sepsis, and severe COVID-19 has been identified as viral sepsis. Progress in sepsis research is important for improving the clinical care of these patients. Recent advances in understanding the pathogenesis of sepsis have led to the view that an uncontrolled inflammatory response and oxidative stress are core factors. However, in the traditional treatment of sepsis, it is difficult to achieve a balance between the inflammation, pathogens (viruses, bacteria, and fungi), and patient tolerance, resulting in high mortality of patients with sepsis. In recent years, nanomaterials mediating reactive oxygen and nitrogen species (RONS) and the inflammatory response have shown previously unattainable therapeutic effects on sepsis. Despite these advantages, RONS and inflammatory response-based nanomaterials have yet to be extensively adopted as sepsis therapy. To the best of our knowledge, no review has yet discussed the pathogenesis of sepsis and the application of nanomaterials. To help bridge this gap, we discuss the pathogenesis of sepsis related to inflammation and the overproduction RONS, which activate pathogen-associated molecular pattern (PAMP)-pattern recognition receptor (PRR) and damage-associated molecular pattern (DAMP)-PRR signaling pathways. We also summarize the application of nanomaterials in the treatment of sepsis. As highlighted here, this strategy could synergistically improve the therapeutic efficacy against both RONS and inflammation in sepsis and may prolong survival. Current challenges and future developments for sepsis treatment are also summarized.

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Targeted inhibition of activated protein C by a non-active-site inhibitory antibody to treat hemophilia

Cited by 26 publications

References 47 publications

An engineered activated factor V for the prevention and treatment of acute traumatic coagulopathy and bleeding in mice

An engineered activated factor V for the prevention and treatment of acute traumatic coagulopathy and bleeding in mice

Technological Advancements in Monoclonal Antibodies

Nanotherapies for sepsis by regulating inflammatory signals and reactive oxygen and nitrogen species: New insight for treating COVID-19

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