Comparative study of the sugar chains of factor VIII purified from human plasma and from the culture media of recombinant baby hamster kidney cells.

Hatori, Takashi; Furukawa, Kiyoshi; Esmon, P C; Fournel, Michael A.; Sawada, Shuzo; Kato, Miyoshi; Minaga, Takeyoshi; Kobata, Akira

doi:10.1016/s0021-9258(18)42401-5

Cited by 122 publications

(25 citation statements)

References 51 publications

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“…Plasma-derived (pd-) and recombinant (r-) FVIII products differ in the high number of identified FVIII glycoforms, and full length (FL) and B-domain-deleted (BDD) r-FVIII molecules substantially differ in the number of Nglycosylation sites. 17,18 FVIII bears terminal galactose (Gal) or N-acetylgalactosamine (GalNac) residues, and α2,6-linked sialic acid residues, 19 which have the ability to interact with the asialoglycoprotein receptor (ASGPR) in animal models. [20][21][22] Biochemical studies demonstrated that the ASGPR binds to FVIII with high affinity (K d $ 2 nM), particularly to the FVIII B domain through its N-linked oligosaccharide structures.…”

Section: Introductionmentioning

confidence: 99%

The Asialoglycoprotein Receptor Minor Subunit Gene Contributes to Pharmacokinetics of Factor VIII Concentrates in Hemophilia A

Lunghi

Morfini²,

Martinelli

et al. 2021

Thromb Haemost

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Background The asialoglycoprotein receptor (ASGPR) binds with high affinity factor VIII (FVIII) through its N-linked oligosaccharides. However, its contribution to the wide inter-individual variation of infused FVIII pharmacokinetics (PK) in Hemophilia A (HA) is unknown. Objective To investigate the variability in FVIII PK outcomes in relation to genetic variation in the ASGR2, encoding the ASGPR2 subunit. Patients/Methods Thirty‐two HA patients with FVIII:C ≤ 2 IU/dL underwent 66 single dose FVIII PKs. PK parameters were evaluated in relation to ASGR2 5’ untranslated region (5’UTR) polymorphisms, that were investigated by recombinant and white blood cell RT-PCR approaches. Results The 5’UTR polymorphisms determine a frequent and conserved haplotype (HT1) in a regulatory region. The HT1 homozygotes may differ in the amounts of alternatively spliced mRNA transcripts and thus ASGPR2 isoforms. Compared to the other ASGR2 genotypes, the c.-95TT homozygotes (n=9), showed three-fold longer Alpha HL (3.60 h, 95% CI 1.44-5.76, p=0.006), and the c.-95TC heterozygotes (n=17) showed 25% shorter MRT (18.5 h, 15.0-22.0, p=0.038) and 32% shorter Beta HL (13.5 h, 10.9-16.0, p=0.016). These differences were confirmed in patients (n=27) undergoing PKs (n=54) with full-length FVIII only. In different linear regression models, the contribution of the ASGR2 genotypes remained significant after adjustment by ABO genotypes and VWF:Ag levels, and explained 14% (MRT), 15-18% (Beta HL) and 22% (Alpha HL) of parameter variability. Conclusions Infused FVIII distribution was modulated by frequent ASGR2 genotypes, independently from and together with ABO and VWF antigen levels, which has potential implications for genetically tailored substitutive treatment in HA.

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Section: Introductionmentioning

confidence: 99%

The Asialoglycoprotein Receptor Minor Subunit Gene Contributes to Pharmacokinetics of Factor VIII Concentrates in Hemophilia A

Lunghi

Morfini²,

Martinelli

et al. 2021

Thromb Haemost

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“…Human‐cl rhFVIII is fully sulphated, ensuring high affinity for its carrier protein von Willebrand factor, and contains only human glycans . A combination of full sulphation and an absence of antigenic carbohydrate epitopes, which are present in rFVIII products derived from hamster cell lines , has the potential to minimize the intrinsic immunogenicity of Human‐cl rhFVIII . The Human‐cl rhFVIII production process is entirely free of additives of animal or human origin, and includes solvent/detergent and 20 nm nanofiltration steps, rendering the risk of pathogen transmission negligible .…”

Section: Introductionmentioning

confidence: 99%

Prophylaxis vs. on‐demand treatment with Nuwiq^® (Human‐cl rhFVIII) in adults with severe haemophilia A

Tiede

Oldenburg²,

Lissitchkov

et al. 2015

Haemophilia

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“…Glycosylation is considered one of the most important and conditioning processes influencing the biological activity, serum half-life and immunogenicity of FVIII. Already in 1992, it was observed that glycosylation profiles differed between plasma-derived and recombinant FVIII products (61). The major difference in the sugar chains of plasma-derived FVIII compared to recombinant FVIII was that some of the outer chains of the complex-type sugar chains of recombinant FVIII contain the Gala1-3Gal group.…”

Section: Post-translational Modifications and Cell Types For Manufacturing Of Recombinant Fviii Productsmentioning

confidence: 99%

Immune Responses to Plasma-Derived Versus Recombinant FVIII Products

2021

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The most severe side effect of hemophilia treatment is the inhibitor development occurring in 30% of patients, during the earliest stages of treatment with factor (F)VIII concentrates. These catastrophic immune responses rapidly inactivate the infused FVIII, rendering the treatment ineffective. This complication is associated with a substantial morbidity and mortality. The risk factors involved in the onset of the inhibitors are both genetic and environmental. The source of FVIII products, i.e. plasma-derived or recombinant FVIII products, is considered one of the most relevant factors for inhibitor development. Numerous studies in the literature report conflicting data on the different immunogenicity of the products. The SIPPET randomized trial showed an increased in the inhibitor rate in patients using recombinant FVIII products than those receiving plasma-derived products in the first exposure days. The SIPPET randomized trial showed an increase in the inhibitor rate in patients using recombinant FVIII products compared to those treated with plasma-derived products in the first days of exposure. The potential increase in the immunogenicity of recombinant products can be attributed to several factors such as: the different post-translational modification in different cell lines, the presence of protein aggregates, and the role played by the chaperon protein of FVIII, the von Willebrand factor, which modulates the uptake of FVIII by antigen presenting cells (APCs). Furthermore, the presence of non-neutralizing antibodies against FVIII has shown to be in increased inhibitor development as demonstrated in a sub-analysis of the SIPPET study. In addition, the presence of the specific subclasses of the immunoglobulins may also be an important biomarker to indicate whether the inhibitor will evolve into a persistent neutralizing antibody or a transient one that would disappear without any specific treatment. Recently, the availability of novel non-replacement therapies as well as emicizumab, administered by weekly subcutaneous infusion, have significantly changed the quality of life of patients with inhibitors showing a considerable reduction of the annual bleeding rate and in most patients the absence of bleeding. Although, these novel drugs improve patients' quality of life, they do not abolish the need to infuse FVIII during acute bleeding or surgery. Therefore, the issue of immunogenicity against FVIII still remains an important side effect of hemophilia treatment.

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Comparative study of the sugar chains of factor VIII purified from human plasma and from the culture media of recombinant baby hamster kidney cells.

Cited by 122 publications

References 51 publications

The Asialoglycoprotein Receptor Minor Subunit Gene Contributes to Pharmacokinetics of Factor VIII Concentrates in Hemophilia A

The Asialoglycoprotein Receptor Minor Subunit Gene Contributes to Pharmacokinetics of Factor VIII Concentrates in Hemophilia A

Prophylaxis vs. on‐demand treatment with Nuwiq^® (Human‐cl rhFVIII) in adults with severe haemophilia A

Immune Responses to Plasma-Derived Versus Recombinant FVIII Products

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Comparative study of the sugar chains of factor VIII purified from human plasma and from the culture media of recombinant baby hamster kidney cells.

Cited by 122 publications

References 51 publications

The Asialoglycoprotein Receptor Minor Subunit Gene Contributes to Pharmacokinetics of Factor VIII Concentrates in Hemophilia A

The Asialoglycoprotein Receptor Minor Subunit Gene Contributes to Pharmacokinetics of Factor VIII Concentrates in Hemophilia A

Prophylaxis vs. on‐demand treatment with Nuwiq® (Human‐cl rhFVIII) in adults with severe haemophilia A

Immune Responses to Plasma-Derived Versus Recombinant FVIII Products

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Product

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Prophylaxis vs. on‐demand treatment with Nuwiq^® (Human‐cl rhFVIII) in adults with severe haemophilia A