Relationships between factor VIII:Ag and factor VIII in recombinant and plasma‐derived factor VIII concentrates

Lin, Y.; Yang, Xi; Chevrier, Marie-Claire; Craven, Sharon; Barrowcliffe, T W; Lemieux, Réal; Ofosu, Frederick A.

doi:10.1111/j.1365-2516.2004.00957.x

Cited by 44 publications

(78 citation statements)

References 32 publications

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“…This observation reflects previous findings in FVIII-deficient mice. 6 The VWF used in our studies is a plasma-derived preparation that contains trace amounts 9 Our results demonstrate that the in vitro pre-incubation of rFVIII with VWF reduced its immunogenicity to the level achieved with pdFVIII. These data suggest that the immunogenicity of rFVIII is not due exclusively to the reduced ability of rFVIII to bind to VWF, but that other mechanisms must be implicated.…”

Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 73%

Comparison of the immunogenicity of different therapeutic preparations of human factor VIII in the murine model of hemophilia A

Delignat

Dasgupta²,

André³

et al. 2007

Haematologica

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Von Willebrand factor (VWF) has been proposed to reduce the immunogenicity of therapeutic factor VIII (FVIII) in patients with hemophilia A. Using FVIII-deficient mice, we compared the immunogenicity of different preparations of plasma-derived (pd) and recombinant (r) FVIII. Treatment of mice with pdFVIII induced significantly lower titers of FVIII inhibitors, as measured by ELISA and in vitro coagulation assays, compared with rFVIII. Furthermore, pre-incubation of rFVIII with excess VWF significantly reduced rFVIII immunogenicity. Our data confirm that pdFVIII induces lower levels of inhibitors than rFVIII, and that VWF is an immuno-chaperone molecule for FVIII. ABSTRACTH emophilia A is a rare genetic hemorrhagic disorder that affects 1 in 5,000-10,000 males. It results from the absence of endogenous pro-coagulant factor VIII (FVIII).1 The management of bleeding episodes involves the intravenous administration of therapeutic FVIII to restore normal hemostasis. Sources of therapeutic FVIII are either pools of plasma from healthy donors or recombinant molecules produced by genetic engineering. In up to 35% of cases, the administration of exogenous FVIII to patients with hemophilia A leads to the development of anti-FVIII alloantibodies that inhibit the pro-coagulant activity of FVIII.2 The occurrence of anti-FVIII antibodies, therefore, prevents further use of FVIII and is a major therapeutic challenge. Several risk factors associated with the development of FVIII inhibitors have been identified. 3,4 In particular, VWF has been proposed as a key chaperon molecule in reducing the immunogenicity of therapeutic FVIII in patients with hemophilia A. There is some evidence to suggest that the incidence of inhibitor development is lower when patients are treated with VWF-containing plasma-derived FVIII (pdFVIII) than when recombinant products without VWF are used. 5 In fact, studies in a murine model of hemophilia A have indicated that the immunogenicity of FVIII is reduced in the presence of VWF. 6We used the well-established model of FVIII-deficient mice to compare the immunogenicity of therapeutic preparations of pdFVIII and recombinant FVIII (rFVIII) that

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Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 73%

Comparison of the immunogenicity of different therapeutic preparations of human factor VIII in the murine model of hemophilia A

Delignat

Dasgupta²,

André³

et al. 2007

Haematologica

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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. …”

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confidence: 99%

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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“…More extensive pre-processing of plasma-derived FVIII possibly caused its lower signals as compared with those of the full size recombinant FVIII. Other characteristics include heterogeneity of full size FVIII due to the natural variability in the B-domain length and other properties, previously compared between various FVIII products (42)(43)(44)(45). A residual binding of both recombinant FVIII variants to the CR doublets non-active for plasma-derived FVIII was attributed to a nonspecific component.…”

Section: Expression Of Ldlr Fragments-mentioning

confidence: 98%

Mapping the Binding Region on the Low Density Lipoprotein Receptor for Blood Coagulation Factor VIII

Kurasawa

Shestopal

Karnaukhova

et al. 2013

Journal of Biological Chemistry

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Background: Low density lipoprotein receptor (LDLR) mediates clearance of blood coagulation factor VIII (FVIII). Results:The region of complement-type repeats 2-5 in LDLR was identified as the binding site for FVIII and for ␣-2-macroglobulin receptor-associated protein (RAP). Conclusion: Binding sites of LDLR for FVIII, and also for RAP, were characterized. Significance: This provides new data on LDLR structure and function and on FVIII catabolism.

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Relationships between factor VIII:Ag and factor VIII in recombinant and plasma‐derived factor VIII concentrates

Cited by 44 publications

References 32 publications

Comparison of the immunogenicity of different therapeutic preparations of human factor VIII in the murine model of hemophilia A

Comparison of the immunogenicity of different therapeutic preparations of human factor VIII in the murine model of hemophilia A

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

Mapping the Binding Region on the Low Density Lipoprotein Receptor for Blood Coagulation Factor VIII

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