The important role of von Willebrand factor in platelet‐derived FVIII gene therapy for murine hemophilia A in the presence of inhibitory antibodies

Shi, Qizhen; Schroeder, Jocelyn A.; Kuether, Erin L.; Montgomery, Robert R.

doi:10.1111/jth.13001

Cited by 19 publications

(17 citation statements)

References 52 publications

(77 reference statements)

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“…26 The interaction between VWF and FVIII is critical in maintaining the clinical efficacy of platelet-derived FVIII gene therapy in HA mice in the presence of inhibitors. 27 How VWF affects FVIII immune responses in HA with a setting of preexisting anti-FVIII immunity is still uncertain and is not fully understood.…”

Section: Introductionmentioning

confidence: 99%

The impact of von Willebrand factor on factor VIII memory immune responses

et al. 2017

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Immune tolerance induction (ITI) with aggressive infusion of factor VIII (FVIII) is the current strategy used to eradicate FVIII inhibitors and restore normal FVIII pharmacokinetics in inhibitor patients. Whether the use of FVIII products containing von Willebrand factor (VWF) will affect the efficacy of ITI is still controversial. In this study, we explored the impact of VWF on FVIII memory immune responses in hemophilia A (HA) mice. A T-cell proliferation assay and cytokine profile analysis were used to study FVIII-primed CD4+ T cells. When CD4+ T cells from primed FVIIInull mice were restimulated with recombinant human FVIII (rhF8) plus recombinant human VWF (rhVWF) in vitro, the percentages of daughter CD4+ T cells were significantly decreased compared with the groups cultured with rhF8 only. Levels of interferon-γ and interleukin 10 were significantly lower in the rhF8 plus rhVWF groups than in the rhF8 groups. When memory B-cell pools from primed FVIIInull mice were cultured with rhF8 with or without rhVWF to induce differentiation of memory B cells into antibody-secreting cells (ASCs), the number of ASCs was significantly lower in the rhF8 plus VWF group than in the rhF8 group. When memory B-cell pools were transferred into NSGF8KO mice followed by rhF8 immunization with or without rhVWF, the titers of anti-F8 inhibitors and total immunoglobulin G were significantly higher in the rhF8 group than in the rhF8 plus rhVWF group, with an average difference of 2.23- and 2.04-fold. Together, our data demonstrate that VWF attenuates FVIII memory immune responses in HA mice.

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Section: Introductionmentioning

confidence: 99%

The impact of von Willebrand factor on factor VIII memory immune responses

et al. 2017

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“…In addition, it has been demonstrated that targeting FVIII expression to platelets results in FVIII storage together with VWF in platelet a-granules and corrects the murine hemophilia A phenotype even in the presence of high-titer anti-FVIII inhibitory antibodies (inhibitors). 47 …”

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confidence: 99%

Life in the shadow of a dominant partner: the FVIII-VWF association and its clinical implications for hemophilia A

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Montgomery

Pratt

et al. 2016

Blood

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A normal hemostatic response to vascular injury requires both factor VIII (FVIII) and von Willebrand factor (VWF). In plasma, VWF and FVIII normally circulate as a noncovalent complex, and each has a critical function in the maintenance of hemostasis. Furthermore, the interaction between VWF and FVIII plays a crucial role in FVIII function, immunogenicity, and clearance, with VWF essentially serving as a chaperone for FVIII. Several novel recombinant FVIII (rFVIII) therapies for hemophilia A have been in clinical development, which aim to increase the half-life of FVIII (∼12 hours) and reduce dosing frequency by utilizing bioengineering techniques including PEGylation, Fc fusion, and single-chain design. However, these approaches have achieved only moderate increases in halflife of 1.5-to 2-fold compared with marketed FVIII products. Clearance of PEGylated rFVIII, rFVIIIFc, and rVIII-SingleChain is still regulated to a large extent by interaction with VWF. Therefore, the half-life of VWF (∼15 hours) appears to be the limiting factor that has confounded attempts to extend the half-life of rFVIII. A greater understanding of the interaction between FVIII and VWF is required to drive novel bioengineering strategies for products that either prolong the survival of VWF or limit VWF-mediated clearance of FVIII. (Blood.

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“…In a murine model of haemophilia, the presence of pre‐existing FVIII inhibitory antibodies did not negate the therapeutic 2bF8 engraftment when efficient pre‐conditioning regimens had been employed . In the absence of VWF, however, levels of platelet‐derived FVIII were significantly decreased and its therapeutic efficacy was aborted in the presence of inhibitors .…”

Section: Targeting Cells That Synthesize Vwfmentioning

confidence: 96%

Novel investigations on the protective role of the FVIII/VWF complex in inhibitor development

et al. 2014

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Summary Development of inhibitory antibodies to infused factor VIII (FVIII) concentrates is the most serious unresolved complication of haemophilia A treatment. Systematic reviews suggest a twofold higher incidence of inhibitors with recombinant (rFVIII) vs. plasma‐derived (pdFVIII) FVIII products, but study methodologies vary widely. The lower immunogenicity of pdFVIII concentrates is believed to derive from the presence of von Willebrand factor (VWF) which acts as protector and chaperone for FVIII. Several novel investigations reinforce the protective role of the VWF/FVIII complex in inhibitor development. At the basic science level, numerous in vitro and in vivo experiments have demonstrated that VWF‐containing pdFVIII concentrates (pdFVIII/VWF) provide better protection against inhibitor neutralization than rFVIII products. Conformational aspects of the binding between VWF and FVIII are thought to prevent the ‘attack’ on FVIII by inhibitory antibodies. VWF/FVIII binding is 100% in pdFVIII products but only 80% in recombinant products and this ‘free’ FVIII may be a target for inhibitory antibodies. At the clinical level, newer strategies to prevent inhibitor development in previously untreated patients with severe haemophilia are under investigation. The concept of early prophylaxis (before the onset of a bleed) is convincing from a theoretical point of view but requires further evaluation. The Study on Inhibitors in Plasma‐Product Exposed Toddlers is specifically addressing the issue of relative immunogenicity between classes of FVIII product (recombinant vs. plasma‐derived). Currently nearing its target enrolment of 300 patients, this international randomized controlled trial is expected to provide some definitive answers about this ever‐present clinical dilemma.

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The important role of von Willebrand factor in platelet‐derived FVIII gene therapy for murine hemophilia A in the presence of inhibitory antibodies

Cited by 19 publications

References 52 publications

The impact of von Willebrand factor on factor VIII memory immune responses

The impact of von Willebrand factor on factor VIII memory immune responses

Life in the shadow of a dominant partner: the FVIII-VWF association and its clinical implications for hemophilia A

Novel investigations on the protective role of the FVIII/VWF complex in inhibitor development

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