Rational design of a fully active, long-acting PEGylated factor VIII for hemophilia A treatment

2012 ◽  
Vol 2012 ◽  
pp. 73-75
Author(s):  
J.A. Stockman
Keyword(s):  
Factor Viii ◽  
Rational Design ◽  
Hemophilia A ◽  
Long Acting

Rational design of a fully active, long-acting PEGylated factor VIII for hemophilia A treatment

Blood ◽  
2010 ◽  
Vol 116 (2) ◽  
pp. 270-279 ◽  
Author(s):  
Baisong Mei ◽  
Clark Pan ◽  
Haiyan Jiang ◽  
Hendri Tjandra ◽  
Jonathan Strauss ◽  
...  
Keyword(s):  
Factor Viii ◽  
Rational Design ◽  
Hemophilia A ◽  
Treatment Options ◽  
Pharmacokinetic Studies ◽  
Functional Assay ◽  
Coagulation Activity ◽  
Long Acting

Abstract A long-acting factor VIII (FVIII) as a replacement therapy for hemophilia A would significantly improve treatment options for patients with hemophilia A. To develop a FVIII with an extended circulating half-life, but without a reduction in activity, we have engineered 23 FVIII variants with introduced surface-exposed cysteines to which a polyethylene glycol (PEG) polymer was specifically conjugated. Screening of variant expression level, PEGylation yield, and functional assay identified several conjugates retaining full in vitro coagulation activity and von Willebrand factor (VWF) binding.PEGylated FVIII variants exhibited improved pharmacokinetics in hemophilic mice and rabbits. In addition, pharmacokinetic studies in VWF knockout mice indicated that larger molecular weight PEG may substitute for VWF in protecting PEGylated FVIII from clearance in vivo. In bleeding models of hemophilic mice, PEGylated FVIII not only exhibited prolonged efficacy that is consistent with the improved pharmacokinetics but also showed efficacy in stopping acute bleeds comparable with that of unmodified rFVIII. In summary site-specifically PEGylated FVIII has the potential to be a long-acting prophylactic treatment while being fully efficacious for on-demand treatment for patients with hemophilia A.

scholarly journals Low dose long-acting factor VIII prophylaxis in pediatric and young adult patients with hemophilia A: Short-term single-center experience from a developing country

2021 ◽  
Vol 0 ◽  
pp. 1-6
Author(s):  
Shailendra Prasad Verma ◽  
Anil Kumar Tripathi ◽  
Geeta Suri Sharma ◽  
Nidhish Kumar ◽  
Rashmi Kushwaha
Keyword(s):  
Young Adult ◽  
Adverse Events ◽  
Factor Viii ◽  
Low Dose ◽  
Hemophilia A ◽  
Adult Patients ◽  
Severe Hemophilia ◽  
Emergency Visits ◽  
Episodic Treatment ◽  
Long Acting

Objectives: High dose factor prophylaxis in hemophilia has been proven to prevent joint bleeds in the western world effectively. We look for a cost-effective and feasible way for Indian patients to reduce the dose and frequency of factor infusion. Data on prophylaxis with a low dose, long-acting factor infusion twice a week dosing schedule is limited. The purpose was to study the efficacy and safety of long-acting factor VIII (Eloctate) for secondary/ tertiary prophylaxis in pediatric and young adult patients with moderate and severe hemophilia A. Materials and Methods: Thirty-eight patients with moderate and severe hemophilia A with an age range from 1 to 25 years were included in the study. During the initial 4 months, they received therapeutic doses of ELOCTATE (Factor VIII with Fc Fusion Protein) on an episodic basis after a clinical bleed. In the next 4 months, they received prophylactic intravenous ELOCTATE at the dose of 20 units/kg body weight twice a week. Annual bleeding rates (ABR), school absenteeism, emergency visits, joint scores, and adverse events were compared during both periods. Results: The total number of joint bleeds during the episodic treatment and prophylaxis period was 608 and 67, respectively. ABR was 47.9 during the episodic treatment period and 5.3 during prophylaxis showing an 88.9% reduction in joint bleeds. School/college absenteeism and emergency visits were significantly reduced during prophylaxis. No significant adverse events were noted during prophylaxis. Conclusion: Low dose, twice a week, and long-acting recombinant factor VIII-Fc (Eloctate) prophylaxis can be a reasonable options for patients with hemophilia A in developing countries.

T Lymphocyte Proliferative Responses Induced by Recombinant Factor VIII in Hemophilia A Patients with Inhibitors

1996 ◽  
Vol 76 (01) ◽  
pp. 017-022 ◽  
Author(s):  
Sylvia T Singer ◽  
Joseph E Addiego ◽  
Donald C Reason ◽  
Alexander H Lucas
Keyword(s):  
T Lymphocytes ◽  
Factor Viii ◽  
Cellular Proliferation ◽  
Mononuclear Cells ◽  
Hemophilia A ◽  
Normal Subjects ◽  
Normal Male ◽  
Cell Fractionation ◽  
Severe Hemophilia ◽  
Human Factor Viii

SummaryIn this study we sought to determine whether factor VUI-reactive T lymphocytes were present in hemophilia A patients with inhibitor antibodies. Peripheral blood mononuclear cells (MNC) were obtained from 12 severe hemophilia A patients having high titer inhibitors, 4 severe hemophilia A patients without inhibitors and 5 normal male subjects. B cell-depleted MNC were cultured in serum-free medium in the absence or presence of 2 µg of recombinant human factor VIII (rFVIII) per ml, and cellular proliferation was assessed after 5 days of culture by measuring 3H-thymidine incorporation. rFVIII induced marked cellular proliferation in cultures of 4 of 12 inhibitor-positive hemophilia patients: fold increase over background (stimulation index, SI) of 7.8 to 23.3. The remaining 8 inhibitor-positive patients, the 4 hemophilia patients without inhibitors and the 5 normal subjects, all had lower proliferative responses to rFVIII, SI range = 1.6 to 6.0. As a group, the inhibitor-positive subjects had significantly higher proliferative responses to rFVIII than did the inhibitor-negative and normal subjects (p < 0.05 by t-test). Cell fractionation experiments showed that T lymphocytes were the rFVIII-responsive cell type, and that monocytes were required for T cell proliferation. Thus, rFVIII-reactive T lymphocytes are present in the peripheral circulation of some inhibitor-positive hemophilia A patients. These T cells may recognize FVIII in an antigen-specific manner and play a central role in the regulation of inhibitor antibody production

Treatment of Hemophilia A with a Highly Purified Factor VIII Concentrate Prepared by Anti-FVIIIc Immunoaffinity Chromatography

1992 ◽  
Vol 67 (01) ◽  
pp. 019-027 ◽  
Author(s):  
Joseph E Addiego ◽  
Edward Gomperts ◽  
Liu Shu-Len ◽  
Patricia Bailey ◽  
Suzanne G Courter ◽  
...  
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Virus Transmission ◽  
Human Albumin ◽  
Immunoaffinity Chromatography ◽  
Exchange Chromatography ◽  
Pharmacokinetic Studies ◽  
Enveloped Viruses ◽  
Clinically Significant ◽  
Detergent Mixture

SummaryTo reduce the risk of pathogenic virus transmission associated with the therapeutic administration of plasma-derived antihemophilic factor (FVIIIc), a process utilizing anti-FVIIIc immunoaffinity chromatography to isolate FVIIIc has been developed. In addition, the starting cryoprecipitate solution has been treated with an organic solvent/detergent mixture to inactivate lipid-enveloped viruses. A final ion exchange chromatography step is used to further remove contaminants, e.g., anti-FVIIIc antibody, potentially leached with FVIIIc during the immunoaffinity step. The purified FVTII is stabilized for lyophili-zation and storage by the addition of human albumin. The monoclonal anti-FVIIIc antibody used in the immunoaffinity step of the process is not detectable in the final preparation. Viral reduction studies performed at specific steps of the process demonstrate that 11 logs of human immunodeficiency virus (HIV) and greater than 4-5 logs of other lipid-enveloped viruses are inactivated within the first 30 s of exposure to the solvent/ detergent mixture and 4-5 logs of various model viruses, e. g. Endomyocarditis virus (EMC), are physically removed during washing of the immunoaffinity column. The lyophilized product is reconstituted using sterile water in a matter of seconds.The pharmacokinetics of Hemofil® M were compared to those obtained using a standard heat-treated concentrate (Hemofil® CT) in five severe factor VIII deficient hemophiliacs in a randomized, cross-over study. No statistically significant differences were observed in mean half life (p >0.6) or median recovery (p = 0.4) between the two preparations. No clinically significant adverse effects were observed in patients receiving either FVIII preparation.In addition, 43 patients at 18 different centers underwent pharmacokinetic studies, with a nominal dose of 50 u/kg FVIIIc Hemofil® M. The mean recovery was 103.6%, and the t 1/2 was 14.6 h. The recovery of FVIII in this group was as expected, providing an increase of assayed FVIII of approximately 2% per unit of FVTII/kg infused.Clinical trials using Hemofil® M have been initiated in 124 hemophilia A patients. The safety and efficacy of Hemofil® M has been established. To date, 0 of 60 patients tested have seroconverted to HIV. None of the previously untreated patients show clinical or laboratory evidence of Non-A, Non-B hepatitis (NANB), with 21 patients remaining negative as far as presence of antibodies to the Hepatitis C virus (a-HCV negative) at least 6 months after the initial infusion. There is no evidence of neoantigenicity, evidenced by seroconversion to murine antibody. An 8.7% (2 of 23) prevalence of anti-FVIIIc inhibitor development has been observed in previously untreated patients with FVIIIc⩽3%, receiving only the monoclonally purified solvent/ detergent treated FVIII concentrate while on study and on poststudy surveillance. All patients demonstrated clinical hemostasis following product use for either on demand bleeding or surgical prophylaxis.

A Survey of the Effectiveness of Prothrombin Complex Concentrates in Controlling Hemorrhage in Patients with Hemophilia and Anti-Factor VIII Antibodies

1980 ◽  
Vol 44 (01) ◽  
pp. 039-042 ◽  
Author(s):  
Philip M Blatt ◽  
Doris Ménaché ◽  
Harold R Roberts
Keyword(s):  
Factor Viii ◽  
Ad Hoc ◽  
Hemophilia A ◽  
Working Party ◽  
International Committee ◽  
Factor Ix ◽  
Prothrombin Complex Concentrates ◽  
Factor Viii Concentrates

SummaryThe treatment of patients with hemophilia A and anti-Factor VIII antibodies is difficult. Between July 1977 and June 1978, a survey was carried out by an ad hoc working party of the subcommittee on Factor IX concentrates of the International Committee on Thrombosis and Hemostasis to assess the effectiveness of Prothrombin Complex Concentrates in controlling hemorrhage in these patients. The results are presented in this paper and, although subjective, support the view that these concentrates are not as effective in patients with inhibitors as Factor VIII concentrates are in patients without inhibitors.

Investigations on the Nature of Hemophilia A

1963 ◽  
Vol 09 (01) ◽  
pp. 030-052 ◽  
Author(s):  
Eberhard Mammen
Keyword(s):  
Factor Viii ◽  
Human Plasma ◽  
Barium Sulfate ◽  
Freeze Drying ◽  
Room Temperature ◽  
Hemophilia A ◽  
Normal Human Plasma ◽  
Normal Human ◽  
And Storage ◽  
Prothrombin Activation

SummaryIn this paper an inhibitor is described that is found in hemophilic plasma and serum different from any till now described inhibitor. The inhibitor only inhibits prothrombin activation in the “intrinsic clotting systems”. This inhibitor is probably not present in normal human plasma or serum. It is destroyed by ether and freeze drying, is labile to acid and storage at room temperature. It is stable upon dialysis and has not been adsorbed on barium sulfate, aluminum hydroxide or kaolin. It precipitates at 50% v/v saturation with alcohol. The nature of this inhibitor seems to be a protein or lipoprotein.Factor VIII was isolated from hemophilic plasma. The amount isolated was the same as from normal plasma and the activity properties were not different. Hemophiliacs have normal amounts of factor VIII.

Sign in / Sign up

Export Citation Format

Share Document