Pharmacokinetics and Interspecies Scaling of Recombinant Human Factor VIII

Mordenti, Joyce; Osaka, Gary; Garcia, Kit; Thomsen, K; Ličko, Vojtech; Meng, Gloria

doi:10.1006/taap.1996.0008

Cited by 37 publications

(27 citation statements)

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“…Biphasic fVIII clearance in mice, observed in the present study, is in agreement with results of a previous study in which fVIII clearance in mice was described by the sum of two exponentials (45). The biphasic nature of fVIII clearance was also demonstrated for dogs (50) and humans (17).…”

Section: Discussionsupporting

confidence: 81%

Role of the Low Density Lipoprotein-related Protein Receptor in Mediation of Factor VIII Catabolism

Saenko

Yakhyaev

Mikhailenko

et al. 1999

Journal of Biological Chemistry

204

285

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In the present study, we found that catabolism of coagulation factor VIII (fVIII) is mediated by the low density lipoprotein receptor-related protein (LPR), a liver multiligand endocytic receptor. In a solid phase assay, fVIII was shown to bind to LRP (K d 116 nM). The specificity was confirmed by a complete inhibition of fVIII/ LRP binding by 39-kDa receptor-associated protein (RAP), an antagonist of all LRP ligands. The region of fVIII involved in its binding to LRP was localized within the A2 domain residues 484 -509, based on the ability of the isolated A2 domain and the synthetic A2 domain peptide 484 -509 to prevent fVIII interaction with LRP. Since vWf did not inhibit fVIII binding to LRP, we proposed that LRP receptor may internalize fVIII from its complex with vWf. Consistent with this hypothesis, mouse embryonic fibroblasts that express LRP, but not fibroblasts genetically deficient in LRP, were able to catabolize 125 I-fVIII complexed with vWf, which was not internalized by the cells. These processes could be inhibited by RAP and A2 subunit of fVIII, indicating that cellular internalization and degradation were mediated by interaction of the A2 domain of fVIII with LRP. In vivo studies of 125 I-fVIII⅐vWf complex clearance in mice demonstrated that RAP completely inhibited the fast phase of the biphasic 125 I-fVIII clearance that is responsible for removal of 60% of fVIII from circulation. Inhibition of the RAP-sensitive phase prolonged the half-life of 125 I-fVIII in circulation by 3.3-fold, indicating that LRP receptor plays an important role in fVIII clearance.The plasma glycoprotein factor VIII (fVIII) 1 functions as a cofactor for factor IXa in the factor X activation enzyme complex in the intrinsic pathway of blood coagulation, and its level is decreased or the protein is nonfunctional in patients with hemophilia A. The fVIII protein consists of a homologous A and C domains and a unique B domain which are arranged in the order A1-A2-B-A3-C1-C2 (1). It is processed to a series of Me 2ϩ -linked heterodimers produced by cleavage at the B-A3 junction (2), generating a light chain (LCh) which consists of an acidic region and A3, C1, and C2 domains and a heavy chain (HCh) which consists of the A1, A2, and B domains (Fig. 1).Transplantational studies both in animals and humans demonstrated that liver hepatocytes are the major fVIII-producing cells (3, 4). Immediately after release into circulation, fVIII binds with a high affinity (K d Ͻ 0.5 nM (5, 6)) to its carrier protein vWf to form a tight, noncovalent complex. The binding to vWf is required for maintenance of a normal fVIII level in circulation, since vWf stabilizes association of the LCh and HCh (7). This prevents fVIII from binding to phospholipid membranes (8), activation by factor Xa (9), and protein Ccatalyzed inactivation (10). vWf comprises a series of high molecular mass, disulfide-bonded multimers with molecular mass values as high as 2 ϫ 10 7 Da (11) and circulates in plasma at 10 g/ml or 50 nM assuming a molecular mass of 270 kDa for vW...

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Section: Discussionsupporting

confidence: 81%

Role of the Low Density Lipoprotein-related Protein Receptor in Mediation of Factor VIII Catabolism

Saenko

Yakhyaev

Mikhailenko

et al. 1999

Journal of Biological Chemistry

204

285

View full text Add to dashboard Cite

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“…Thus, although human antibody generation against the recombinant protein remains possible, these results suggest the risk is small. Extrapolation of the mouse data using allometric scaling suggests the ASN12 brain t1 ⁄ 2 of 24 h in the mouse brain would equate to a t1 ⁄ 2 of 8 days in the human (64). Therefore, a repeat i.v.…”

Section: Discussionmentioning

confidence: 99%

A Neuroprotective Brain-penetrating Endopeptidase Fusion Protein Ameliorates Alzheimer Disease Pathology and Restores Neurogenesis

Spencer¹,

Verma

Desplats

et al. 2014

Journal of Biological Chemistry

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Background: Development of new therapeutic approaches for Alzheimer disease (AD) is crucial. Results: A recombinant enzyme engineered to cross the blood-brain barrier treats the accumulation of A␤ in a mouse model. Conclusion: This study shows a therapy can improve the symptoms of AD while also increasing the population of new neurons. Significance: The enzyme could be delivered weekly or even monthly to patients.

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“…7 In the presence of VWF, FVIII half-life varies between 12 and 14 hours in humans 7,36 and about 1 hour in mice. 37 In VWF deficiency, however, FVIII half-life is only to 2 to 3 hours in humans 38 and less than 10 minutes in mice. 20 While FVIII clearance from the circulation seems to be driven by a particularly efficient process, the mechanism by which this occurs has remained poorly understood.…”

Section: Discussionmentioning

confidence: 99%

Elevated plasma factor VIII in a mouse model of low-density lipoprotein receptor–related protein deficiency

Bovenschen

Herz

Grimbergen

et al. 2003

Blood

108

134

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Pharmacokinetics and Interspecies Scaling of Recombinant Human Factor VIII

Cited by 37 publications

References 0 publications

Role of the Low Density Lipoprotein-related Protein Receptor in Mediation of Factor VIII Catabolism

Role of the Low Density Lipoprotein-related Protein Receptor in Mediation of Factor VIII Catabolism

A Neuroprotective Brain-penetrating Endopeptidase Fusion Protein Ameliorates Alzheimer Disease Pathology and Restores Neurogenesis

Elevated plasma factor VIII in a mouse model of low-density lipoprotein receptor–related protein deficiency

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