Recombinant factor VIII Fc for the treatment of haemophilia A.
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ABSTRACT:
SUBMITTER: Hermans C
PROVIDER: S-EPMC8252769 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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.
| S-EPMC6234359 | biostudies-literature
Project description:BackgroundHemophilia A results from a deficiency in factor VIII activity. Current treatment regimens require frequent dosing, owing to the short half-life of FVIII. A recombinant FVIII-Fc fusion protein (rFVIIIFc) was molecularly engineered to increase the half-life of FVIII, by 1.5-2-fold, in several preclinical animal models and humans.ObjectiveTo perform a biochemical and functional in vitro characterization of rFVIIIFc, with existing FVIII products as comparators.Methods?rFVIIIFc was examined by utilizing a series of structural and analytic assays, including mass spectrometry following lysyl endopeptidase or thrombin digestion. rFVIIIFc activity was determined in both one-stage clotting (activated partial thromboplastin time) and chromogenic activity assays, in the context of the FXase complex with purified components, and in both in vitro and ex vivo rotational thromboelastometry (ROTEM) assays performed in whole blood.Results?rFVIIIFc contained the predicted primary structure and post-translational modifications, with an FVIII moiety that was similar to other recombinant FVIII products. The von Willebrand factor-binding and specific activity of rFVIIIFc were also found to be similar to those of other recombinant FVIII molecules. Both chromogenic and one-stage assays of rFVIIIFc gave similar results. Ex vivo ROTEM studies demonstrated that circulating rFVIIIFc activity was prolonged in mice with hemophilia A in comparison with B-domain-deleted or full-length FVIII. Clot parameters at early time points were similar to those for FVIII, whereas rFVIIIFc showed prolonged improvement of clot formation.Conclusions?rFVIIIFc maintains normal FVIII interactions with other proteins necessary for its activity, with prolonged in vivo activity, owing to fusion with the Fc region of IgG(1) .
| S-EPMC3588154 | biostudies-literature
Project description:IntroductionBAY 94-9027, a site-specifically PEGylated, B-domain-deleted recombinant factor VIII (FVIII) with extended half-life, demonstrated efficacy for bleed prevention and treatment in previously treated adolescents and adults with severe haemophilia A.AimTo assess BAY 94-9027 in children with severe haemophilia A.MethodsIn the two-part PROTECT VIII Kids study, boys <12 years with <1% FVIII and >50 exposure days (EDs) to FVIII were enrolled in two cohorts (<6 years; 6-<12 years) and treated with BAY 94-9027 prophylaxis twice-weekly, every 5 days, or every 7 days at physician discretion for ≥50 EDs (Part 1) or twice-weekly for 12-weeks (Part 2). Annualized bleeding rate (ABR) was a primary efficacy endpoint; FVIII inhibitor development was the primary safety variable.ResultsAt study completion, 25 patients had been treated twice-weekly, 28 in the every-5-day group, and 8 in the every-7-day group. Median ABR for all bleeds was 2.9 (Part 1) and 2.4 (Part 2) and similar in younger and older patients; median ABR for joint bleeds was 0 for both cohorts. In the last 90 days' treatment, median ABR was 0 for younger and older patients (Part 1). Of 149 reported bleeds, 93% were treated with ≤2 infusions. Twelve patients, the majority <6 years (n = 11), discontinued due to apparent loss of efficacy or hypersensitivity. No FVIII inhibitors developed.ConclusionsIn PROTECT VIII Kids, which allowed tailoring of prophylaxis to individual clinical response, BAY 94-9027 was efficacious for bleed prevention and treatment in previously treated children with severe haemophilia A.
| S-EPMC7317355 | biostudies-literature
Project description:Essentials Recombinant factor VIII (rFVIII) Fc fusion protein has a 1.5-fold longer half-life than rFVIII. Five orthogonal methods were used to characterize the structure of rFVIIIFc compared to rFVIII. The C-terminal Fc fusion does not perturb the structure of FVIII in rFVIIIFc. The FVIII and Fc components of rFVIIIFc are flexibly tethered and functionally independent.Background Fusion of the human IgG1 Fc domain to the C-terminal C2 domain of B-domain-deleted (BDD) factor VIII (FVIII) results in the recombinant FVIII Fc (rFVIIIFc) fusion protein, which has a 1.5-fold longer half-life in humans. Objective To assess the structural properties of rFVIIIFc by comparing its constituent FVIII and Fc elements with their respective isolated components, and evaluating their structural independence within rFVIIIFc. Methods rFVIIIFc and its isolated FVIII and Fc components were compared by the use of hydrogen-deuterium exchange mass spectrometry (HDX-MS). The structure of rFVIIIFc was also evaluated by the use of X-ray crystallography, small-angle X-ray scattering (SAXS), and electron microscopy (EM). The degree of steric interference by the appended Fc domain was assessed by EM and surface plasmon resonance (SPR). Results HDX-MS analysis of rFVIIIFc revealed that fusion caused no structural perturbations in FVIII or Fc. The rFVIIIFc crystal structure showed that the FVIII component is indistinguishable from published BDD FVIII structures. The Fc domain was not observed, indicating high mobility. SAXS analysis was consistent with an ensemble of rigid-body models in which the Fc domain exists in a largely extended orientation relative to FVIII. Binding of Fab fragments of anti-C2 domain antibodies to BDD FVIII was visualized by EM, and the affinities of the corresponding intact antibodies for BDD FVIII and rFVIIIFc were comparable by SPR analysis. Conclusions The FVIII and Fc components of rFVIIIFc are structurally indistinguishable from their isolated constituents, and show a high degree of structural independence, consistent with the functional comparability of rFVIIIFc and unmodified FVIII.
| S-EPMC5500164 | biostudies-literature
Project description:This phase 3 pivotal study evaluated the safety, efficacy, and pharmacokinetics of a recombinant FVIII Fc fusion protein (rFVIIIFc) for prophylaxis, treatment of acute bleeding, and perioperative hemostatic control in 165 previously treated males aged ?12 years with severe hemophilia A. The study had 3 treatment arms: arm 1, individualized prophylaxis (25-65 IU/kg every 3-5 days, n = 118); arm 2, weekly prophylaxis (65 IU/kg, n = 24); and arm 3, episodic treatment (10-50 IU/kg, n = 23). A subgroup compared recombinant FVIII (rFVIII) and rFVIIIFc pharmacokinetics. End points included annualized bleeding rate (ABR), inhibitor development, and adverse events. The terminal half-life of rFVIIIFc (19.0 hours) was extended 1.5-fold vs rFVIII (12.4 hours; P < .001). Median ABRs observed in arms 1, 2, and 3 were 1.6, 3.6, and 33.6, respectively. In arm 1, the median weekly dose was 77.9 IU/kg; approximately 30% of subjects achieved a 5-day dosing interval (last 3 months on study). Across arms, 87.3% of bleeding episodes resolved with 1 injection. Adverse events were consistent with those expected in this population; no subjects developed inhibitors. rFVIIIFc was well-tolerated, had a prolonged half-life compared with rFVIII, and resulted in low ABRs when dosed prophylactically 1 to 2 times per week.
| S-EPMC3894491 | biostudies-literature
Project description:The development of neutralizing antibodies (inhibitors) against factor VIII (FVIII) is a major complication of hemophilia A treatment. The sole clinical therapy to restore FVIII tolerance in patients with inhibitors remains immune tolerance induction (ITI) which is expensive, difficult to administer and not always successful. Although not fully understood, the mechanism of ITI is thought to rely on inhibition of FVIII-specific B cells (1). Its efficacy might therefore be improved through more aggressive B cell suppression. FcγRIIB is an inhibitory Fc receptor that down-regulates B cell signaling when cross-linked with the B cell receptor (BCR). We sought to investigate if recombinant FVIII Fc (rFVIIIFc), an Fc fusion molecule composed of FVIII and the Fc region of immunoglobulin G1 (IgG1) (2), is able to inhibit B cell activation more readily than FVIII. rFVIIIFc was able to bind FVIII-exposed and naïve B cells from hemophilia A mice as well as a FVIII-specific murine B cell hybridoma line (413 cells). An anti-FcγRIIB antibody and FVIII inhibited binding, suggesting that rFVIIIFc is able to interact with both FcγRIIB and the BCR. Furthermore, incubation of B cells from FVIII-exposed mice and 413 cells with rFVIIIFc resulted in increased phosphorylation of SH-2 containing inositol 5-phosphatase (SHIP) when compared to FVIII. B cells from FVIII-exposed hemophilia A mice also exhibited decreased extracellular signal-regulated kinase (ERK) phosphorylation when exposed to rFVIIIFc. These differences were absent in B cells from naïve, non-FVIII exposed hemophilic mice suggesting an antigen-dependent effect. Finally, rFVIIIFc was able to inhibit B cell calcium flux induced by anti-Ig F(ab)2. Our results therefore indicate that rFVIIIFc is able to crosslink FcγRIIB and the BCR of FVIII-specific B cells, causing inhibitory signaling in these cells.
| S-EPMC7025534 | biostudies-literature
Project description:Background and objectivesRecombinant factor IX Fc fusion protein (rFIXFc) is a clotting factor developed using monomeric Fc fusion technology to prolong the circulating half-life of factor IX. The objective of this analysis was to elucidate the pharmacokinetic characteristics of rFIXFc in patients with haemophilia B and identify covariates that affect rFIXFc disposition.MethodsPopulation pharmacokinetic analysis using NONMEM(®) was performed with clinical data from two completed trials in previously treated patients with severe to moderate haemophilia B. Twelve patients from a phase 1/2a study and 123 patients from a registrational phase 3 study were included in this population analysis.ResultsA three-compartment model was found to best describe the pharmacokinetics of rFIXFc. For a typical 73 kg patient, the clearance (CL), volume of the central compartment (V 1) and volume of distribution at steady state (V ss) were 2.39 dL/h, 71.4 dL and 198 dL, respectively. Because of repeat pharmacokinetic profiles at week 26 for patients in a subgroup, inclusion of inter-occasion variability (IOV) on CL and V 1 were evaluated and significantly improved the model. The magnitude of IOV on CL and V 1 were both low to moderate (<20 %) and less than the corresponding inter-individual variability. Body weight (BW) was found to be the only significant covariate for rFIXFc disposition. However, the impact of BW was limited, as the BW power exponents on CL and V 1 were 0.436 and 0.396, respectively.ConclusionThis is the first population pharmacokinetic analysis that systematically characterized the pharmacokinetics of long-lasting rFIXFc in patients with haemophilia B. The population pharmacokinetic model for rFIXFc can be utilized to evaluate and optimize dosing regimens for the treatment of patients with haemophilia B.
| S-EPMC3997831 | biostudies-literature
Project description:Current factor VIII (FVIII) products display a half-life (t(1/2)) of ? 8-12 hours, requiring frequent intravenous injections for prophylaxis and treatment of patients with hemophilia A. rFVIIIFc is a recombinant fusion protein composed of a single molecule of FVIII covalently linked to the Fc domain of human IgG(1) to extend circulating rFVIII t(1/2). This first-in-human study in previously treated subjects with severe hemophilia A investigated safety and pharmacokinetics of rFVIIIFc. Sixteen subjects received a single dose of rFVIII at 25 or 65 IU/kg followed by an equal dose of rFVIIIFc. Most adverse events were unrelated to study drug. None of the study subjects developed anti-rFVIIIFc antibodies or inhibitors. Across dose levels, compared with rFVIII, rFVIIIFc showed 1.54- to 1.70-fold longer elimination t(1/2), 1.49- to 1.56-fold lower clearance, and 1.48- to 1.56-fold higher total systemic exposure. rFVIII and rFVIIIFc had comparable dose-dependent peak plasma concentrations and recoveries. Time to 1% FVIII activity above baseline was ? 1.53- to 1.68-fold longer than rFVIII across dose levels. Each subject showed prolonged exposure to rFVIIIFc relative to rFVIII. Thus, rFVIIIFc may offer a viable therapeutic approach to achieve prolonged hemostatic protection and less frequent dosing in patients with hemophilia A. This trial was registered at www.clinicaltrials.gov as NCT01027377.
| S-EPMC3646317 | biostudies-literature
Project description:Although the primary reason for recombinant factor VIII Fc fusion protein (rFVIIIFc) development was to reduce treatment burden associated with routine prophylaxis, new evidence suggests additional benefits of Fc fusion technology in the treatment of people with haemophilia A. Preclinical research has been utilized to characterize the potential immunomodulatory properties of rFVIIIFc, including an ability to reduce inflammation and induce tolerance to factor VIII. This has since been expanded into clinical research in immune tolerance induction (ITI) with rFVIIIFc, results of which suggest the potential for rapid tolerization in first-time ITI patients and therapeutic benefit in patients undergoing rescue ITI. The potential for improved joint health through the anti-inflammatory properties of rFVIIIFc has also been suggested. In addition, a new avenue of research into the role of rFVIIIFc in promoting bone health in patients with haemophilia A, potentially through reduced osteoclast formation, has yielded encouraging results that support further study. This review summarizes the existing preclinical and clinical studies of immunomodulation and tolerization with rFVIIIFc, as well as studies in joint and bone health, to elucidate the potential benefits of rFVIIIFc in haemophilia A beyond the extension of factor VIII half-life.
| S-EPMC7818509 | biostudies-literature
Project description:Despite proven benefits, prophylactic treatment for hemophilia A is hampered by the short half-life of factor VIII. A recombinant factor VIII-Fc fusion protein (rFVIIIFc) was constructed to determine the potential for reduced frequency of dosing. rFVIIIFc has an ? 2-fold longer half-life than rFVIII in hemophilia A (HemA) mice and dogs. The extension of rFVIIIFc half-life requires interaction of Fc with the neonatal Fc receptor (FcRn). In FcRn knockout mice, the extension of rFVIIIFc half-life is abrogated, and is restored in human FcRn transgenic mice. The Fc fusion has no impact on FVIII-specific activity. rFVIIIFc has comparable acute efficacy as rFVIII in treating tail clip injury in HemA mice, and fully corrects whole blood clotting time (WBCT) in HemA dogs immediately after dosing. Furthermore, consistent with prolonged half-life, rFVIIIFc shows 2-fold longer prophylactic efficacy in protecting HemA mice from tail vein transection bleeding induced 24-48 hours after dosing. In HemA dogs, rFVIIIFc also sustains partial correction of WBCT 1.5- to 2-fold longer than rFVIII. rFVIIIFc was well tolerated in both species. Thus, the rescue of FVIII by Fc fusion to provide prolonged protection presents a novel pathway for FVIII catabolism, and warrants further investigation.
| S-EPMC3953019 | biostudies-literature