Functional characteristics of the novel, human-derived recombinant FVIII protein product, human-cl rhFVIII

Sandberg, Helena; Kannicht, Christoph; Stenlund, Peter; Dadaian, Marina; Oswaldsson, Ulla; Cordula, Carina; Walter, Olaf

doi:10.1016/j.thromres.2012.08.311

Cited by 70 publications

(86 citation statements)

References 36 publications

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“…macropinocytosis, 75 but is also in agreement with findings that a significant portion of FVIII:Ag present in rFVIII preparations is not able to associate with VWF. 54,[65][66][67][68] Delignat and co-workers reassessed these findings in a model of FVIII-deficient mice. The animals were treated by intravenous injection with rFVIII, which was either pre-incubated or not with a 50-fold molar excess of purified VWF.…”

Section: 70mentioning

confidence: 94%

“…It was suggested that this portion of rFVIII:Ag may trigger the specific immune response in patients. 54,[65][66][67][68] The exposed VWF-binding site on FVIII, incidentally, may be occupied by anionic phospholipids which were suggested to have additional implications for the immune response. 69,70 VWF inhibits uptake of FVIII in antigen presenting cells Qadura and colleagues were not able to confirm a protective effect of VWF in hemophilic mice, but found variant patterns of inflammatory mediators and of immune gene expression profiles in activated (CD11c + ) splenic dendritic cells (DCs) between pdFVIII-and rFVIII-treated hemophilic mice (type 1 vs. type 2 inflammatory response).…”

Section: Von Willebrand Factor Shields Fviii Epitopes From Recognitiomentioning

confidence: 99%

mentioning

confidence: 99%

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Alloantibodies to therapeutic factor VIII in hemophilia A: the role of von Willebrand factor in regulating factor VIII immunogenicity

Oldenburg¹,

Lacroix‐Desmazes

Lillicrap

2015

Haematologica

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The rising incidence of neutralizing antibodies (inhibitors) against therapeutic factor VIII prompted the conduct of studies to answer the question as to whether this rise is related to the introduction of recombinant factor VIII products. The present article summarizes current opinions and results of non-clinical and clinical studies on the immunogenic potential of recombinant compared to plasma-derived factor VIII concentrates. Numerous studies provided circumstantial evidence that von Willebrand factor, the natural chaperone protein present in plasma-derived factor VIII products, plays an important role in protecting exogenous factor VIII from uptake by antigen presenting cells and from recognition by immune effectors. However, the definite contribution of von Willebrand factor in reducing the inhibitor risk and in the achievement of immune tolerance is still under debate. ABSTRACTinhibitors in stable PTPs after switching treatment is consistently lower than in previously untreated patients (PUPs), 31,32 probably because many of them have developed some kind of cross-tolerance. Thus, the immunogenicity of a given FVIII concentrate in PTPs is relevant for PTPs only. However, in daily clinical practice, more situations that demand a decision between treatment options are related to PUPs, i.e. patients in their early years of life who are newly diagnosed with hemophilia A or who sustain their first bleeding episode. 27,33 Are inhibitor testing methods a critical confounder?One of the most cited arguments used to confute a higher incidence of inhibitors associated with rFVIII treatment is that the testing frequencies and methods used for the detection of inhibitors have increased and improved over time. These improvements coincide with the introduction of rFVIII, which might have favored the detection of borderline and transient inhibitors in rFVIII-treated patient groups. 23,31,34 In fact, in 1995, the so-called "Nijmegen" method, a modification of the till then most widely used "Bethesda assay", was launched. 35 However, despite the improvements made over recent years, the methods used to detect inhibitors have not yet been standardized, 28,36 and the classical Bethesda assay originally published in 1975 is still the most frequently used assay. 34,36 Furthermore, the major advantage of the Nijmegen modification of the Bethesda assay lies in the improvement in the test's specificity near the cut-off value. 28,35,37 Hence, the advent and use of the Nijmegen assay should have caused a decrease in the rate of false positive test results and, consequently, a decrease rather than an increase in the inhibitor incidence in studies dating back to the 1990s. On the other hand, it is very possible that the increased testing frequency in the last two decades had an impact on the reported incidence of inhibitors. Studies reporting on the incidence of high-responding inhibitors [> 5 Bethesda units (BU) per milliliter] (Figure 1) avoided potential bias from assay performance and testing frequencies, because high-res...

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Section: 70mentioning

confidence: 94%

Section: Von Willebrand Factor Shields Fviii Epitopes From Recognitiomentioning

confidence: 99%

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Alloantibodies to therapeutic factor VIII in hemophilia A: the role of von Willebrand factor in regulating factor VIII immunogenicity

Oldenburg¹,

Lacroix‐Desmazes

Lillicrap

2015

Haematologica

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“…24,43 Nuwiq Ò was approved in 2015 by the FDA, being the first fourth generation product. The cell cultivation is performed using a defined serum-free medium with no animal or human-derived supplementation; therefore, the risk for virus contamination in the final product is almost negligible.…”

Section: Recombinant Factor VIII Productsmentioning

confidence: 99%

Production of recombinant coagulation factors: Are humans the best host cells?

2017

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The main treatment option for Hemophilia A/B patients involves the administration of recombinant coagulation factors on-demand or in a prophylactic approach. Despite the safety and efficacy of this replacement therapy, the development of antibodies against the coagulation factor infused, which neutralize the procoagulant activity, is a severe complication. The production of recombinant coagulation factors in human cell lines is an efficient approach to avoid such complication. Human cell lines can produce recombinant proteins with post translation modifications more similar to their natural counterpart, reducing potential immunogenic reactions. This review provides a brief overview of the most important characteristics of recombinant FVIII and FIX products available on the market and the improvements that have recently been achieved by the production using human cell lines.

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“…Oprócz czynników krzepnięcia o przedłużonym działaniu w próbach klinicznych testuje się także zmodyfikowane białka o zbliżonym okresie biologicznego półtrwania do okresów półtrwania standardowych czynników krzepnięcia. Przykładem jest rFVIII produkowany w komórkach ludzkich (rFVIII-hcl, recombinant FVIII-human cell line), a zatem zachowujący wzór glikozylacji charakterystyczny dla natywnego czynnika VIII [13]. Potencjalną zaletą rFVIII-hcl ma być mniejsza immunogenność w porównaniu ze standardowymi rFVIII.…”

Section: Czynniki Krzepnięcia O Przedłużonym Okresie Biologicznego Póunclassified

Postępy w leczeniu chorych na hemofilie

Windyga

2015

Hematologia

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Functional characteristics of the novel, human-derived recombinant FVIII protein product, human-cl rhFVIII

Cited by 70 publications

References 36 publications

Alloantibodies to therapeutic factor VIII in hemophilia A: the role of von Willebrand factor in regulating factor VIII immunogenicity

Alloantibodies to therapeutic factor VIII in hemophilia A: the role of von Willebrand factor in regulating factor VIII immunogenicity

Production of recombinant coagulation factors: Are humans the best host cells?

Postępy w leczeniu chorych na hemofilie

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