Reduction of Factor VIII Inhibitor Titers During Immune Tolerance Induction With Recombinant Factor VIII-Fc Fusion Protein

Groomes, Charles L.; Gianferante, David M.; Crouch, Gary; Parekh, Dina S.; Scott, David W.; Lieuw, Kenneth

doi:10.1002/pbc.25874

Cited by 30 publications

(27 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, epitopes in the Fc fragment are known to upregulate regulatory T cells, which can result in tipping the balance towards tolerance over immunogenicity . These data are consistent with prior case reports in which 4 patients had been successfully treated with rFVIIIFc for inhibitors and with the case series described here.…”

Section: Discussionsupporting

confidence: 92%

Recombinant factor VIII Fc fusion protein for immune tolerance induction in patients with severe haemophilia A with inhibitors—A retrospective analysis

et al. 2018

View full text Add to dashboard Cite

Introduction Immune tolerance induction (ITI) is the gold standard for eradication of factor VIII inhibitors in severe haemophilia A; however, it usually requires treatment for extended periods with associated high burden on patients and healthcare resources. Aim Review outcomes of ITI with recombinant factor VIII Fc fusion protein (rFVIIIFc) in patients with severe haemophilia A and high‐titre inhibitors. Methods Multicentre retrospective chart review of severe haemophilia A patients treated with rFVIIIFc for ITI. Results Of 19 patients, 7 were first‐time ITI and 12 were rescue ITI. Of 7 first‐time patients, 6 had at least 1 high‐risk feature for ITI failure. Four of 7 first‐time patients were tolerized in a median of 7.8 months. The remaining 3 patients continue on rFVIIIFc ITI. Of 12 rescue patients, 7 initially achieved a negative Bethesda titre (≤0.6) in a median of 3.3 months, 1 had a decrease in Bethesda titre and continues on rFVIIIFc ITI and 4 have not demonstrated a decrease in Bethesda titre. Of these 4, 3 continue on rFVIIIFc ITI and 1 switched to bypass therapy alone. Two initially responsive patients transitioned to other factors due to recurrence. Overall, 16 of 19 patients remain on rFVIIIFc (prophylaxis or ITI). For those still undergoing ITI, longer follow‐up is needed to determine final outcomes. No adverse events reported. Conclusions Recombinant factor VIII Fc fusion protein demonstrated rapid time to tolerization in high‐risk first‐time ITI patients. For rescue ITI, rFVIIIFc showed therapeutic benefit in some patients who previously failed ITI with other products. These findings highlight the need to further evaluate the use of rFVIIIFc for ITI.

show abstract

Section: Discussionsupporting

confidence: 92%

Recombinant factor VIII Fc fusion protein for immune tolerance induction in patients with severe haemophilia A with inhibitors—A retrospective analysis

et al. 2018

View full text Add to dashboard Cite

show abstract

“…It has been reported that rFVIIIFc could reduce inhibitor titers in inhibitor-positive HemA patients in recent case reports. 11,12 In addition, a retrospective chart review reported that rFVIIIFc achieved rapid time to tolerization in high-risk first-time ITI patients. 13 In preclinical animal studies, decreased levels of inhibitor formation after rFVIIIFc treatment of HemA mice was reported, compared with rFVIII treatment.…”

Section: Introductionmentioning

confidence: 99%

Recombinant factor VIII Fc fusion protein drives regulatory macrophage polarization

Kis-Tóth¹,

Rajani²,

Simpson³

et al. 2018

Blood Advances

View full text Add to dashboard Cite

The main complication of replacement therapy with factor in hemophilia A (HemA) is the formation of inhibitors (neutralizing anti–factor VIII [FVIII] antibodies) in ∼30% of severe HemA patients. Because these inhibitors render replacement FVIII treatment essentially ineffective, preventing or eliminating them is of top priority in disease management. The extended half-life recombinant FVIII Fc fusion protein (rFVIIIFc) is an approved therapy for HemA patients. In addition, it has been reported that rFVIIIFc may induce tolerance to FVIII more readily than FVIII alone in HemA patients that have developed inhibitors. Given that the immunoglobulin G1 Fc region has the potential to interact with immune cells expressing Fc receptors (FcRs) and thereby affect the immune response to rFVIII, we investigated how human macrophages, expressing both FcRs and receptors reported to bind FVIII, respond to rFVIIIFc. We show herein that rFVIIIFc, but not rFVIII, uniquely skews macrophages toward an alternatively activated regulatory phenotype. rFVIIIFc initiates signaling events that result in morphological changes, as well as a specific gene expression and metabolic profile that is characteristic of the regulatory type Mox/M2-like macrophages. Further, these changes are dependent on rFVIIIFc-FcR interactions. Our findings elucidate mechanisms of potential immunomodulatory properties of rFVIIIFc.

show abstract

“…The recent fusion of FVIII with a human IgG 1 Fc has created a therapeutic FVIII with extended half-life due to recycling of the protein via the neonatal Fc receptor (FcRn) (143). Initial pre-clinical and clinical studies (144)(145)(146)(147) have suggested that FVIII-Fc may also lower the incidence of inhibitor development and increase ITI success rates (148). A recent study based on retrospective chart review indicated that patients receiving FVIII-Fc for ITI tolerized faster than with standard ITI protocols utilizing non-Fc fusion products, and several patients receiving "rescue ITI, " i.e., who had failed an earlier ITI regimen, became tolerized during ITI with FVIII-Fc and were able to resume standard replacement therapy (149).…”

Section: Fviii-fc Fusion Proteinsmentioning

confidence: 99%

Tolerating Factor VIII: Recent Progress

et al. 2020

Self Cite

View full text Add to dashboard Cite

Development of neutralizing antibodies against biotherapeutic agents administered to prevent or treat various clinical conditions is a longstanding and growing problem faced by patients, medical providers and pharmaceutical companies. The hemophilia A community has deep experience with attempting to manage such deleterious immune responses, as the lifesaving protein drug factor VIII (FVIII) has been in use for decades. Hemophilia A is a bleeding disorder caused by genetic mutations that result in absent or dysfunctional FVIII. Prophylactic treatment consists of regular intravenous FVIII infusions. Unfortunately, 1/4 to 1/3 of patients develop neutralizing anti-FVIII antibodies, referred to clinically as "inhibitors," which result in a serious bleeding diathesis. Until recently, the only therapeutic option for these patients was "Immune Tolerance Induction," consisting of intensive FVIII administration, which is extraordinarily expensive and fails in ∼30% of cases. There has been tremendous recent progress in developing novel potential clinical alternatives for the treatment of hemophilia A, ranging from encouraging results of gene therapy trials, to use of other hemostatic agents (either promoting coagulation or slowing down anti-coagulant or fibrinolytic pathways) to "bypass" the need for FVIII or supplement FVIII replacement therapy. Although these approaches are promising, there is widespread agreement that preventing or reversing inhibitors remains a high priority. Risk profiles of novel therapies are still unknown or incomplete, and FVIII will likely continue to be considered the optimal hemostatic agent to support surgery and manage trauma, or to combine with other therapies. We describe here recent exciting studies, most still pre-clinical, that address FVIII immunogenicity and suggest novel interventions to prevent or reverse inhibitor development. Studies of FVIII uptake, processing and presentation on antigen-presenting cells, epitope mapping, and the roles of complement, heme, von Willebrand factor, glycans, and the microbiome in FVIII immunogenicity are elucidating mechanisms of primary and secondary immune responses and suggesting additional novel targets. Promising tolerogenic therapies include development of FVIII-Fc fusion proteins, nanoparticle-based therapies, oral tolerance, and engineering of regulatory or cytotoxic T cells to render them FVIII-specific. Importantly, these studies are highly applicable to other scenarios where establishing immune tolerance to a defined antigen is a clinical priority.

show abstract

Reduction of Factor VIII Inhibitor Titers During Immune Tolerance Induction With Recombinant Factor VIII-Fc Fusion Protein

Cited by 30 publications

References 25 publications

Recombinant factor VIII Fc fusion protein for immune tolerance induction in patients with severe haemophilia A with inhibitors—A retrospective analysis

Recombinant factor VIII Fc fusion protein for immune tolerance induction in patients with severe haemophilia A with inhibitors—A retrospective analysis

Recombinant factor VIII Fc fusion protein drives regulatory macrophage polarization

Tolerating Factor VIII: Recent Progress

Contact Info

Product

Resources

About