Distribution of the Recombinant Coagulation Factor 125I-rFVIIa in Rats

Beeby, Tara L.; Chasseaud, L. F.; Taylor, Trevor; Thomsen, Morten B.

doi:10.1055/s-0038-1649606

Cited by 31 publications

(26 citation statements)

References 8 publications

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“…In addition to a high uptake of 18 F-FVIIai in the tumors, we noted an accumulation in the joint regions as previously described for 125 I-FVIIa in biodistribution studies in a rat model (32). Most likely this was due to a nonspecific interaction.…”

Section: Discussionsupporting

confidence: 83%

Quantitative PET Imaging of Tissue Factor Expression Using ¹⁸F-Labeled Active Site–Inhibited Factor VII

et al. 2015

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Tissue factor (TF) is upregulated in many solid tumors, and its expression is linked to tumor angiogenesis, invasion, metastasis, and prognosis. A noninvasive assessment of tumor TF expression status is therefore of obvious clinical relevance. Factor VII is the natural ligand to TF. Here we report the development of a new PET tracer for specific imaging of TF using an 18 F-labeled derivative of factor VII. Methods: Active site-inhibited factor VIIa (FVIIai) was obtained by inactivation with phenylalanine-phenylalanine-arginine-chloromethyl ketone. FVIIai was radiolabeled with N-succinimidyl 4-18 F-fluorobenzoate and purified. The corresponding product, 18 F-FVIIai, was injected into nude mice with subcutaneous human pancreatic xenograft tumors (BxPC-3) and investigated using small-animal PET/CT imaging 1, 2, and 4 h after injection. Ex vivo biodistribution was performed after the last imaging session, and tumor tissue was preserved for molecular analysis. A blocking experiment was performed in a second set of mice. The expression pattern of TF in the tumors was visualized by immunohistochemistry and the amount of TF in tumor homogenates was measured by enzyme-linked immunosorbent assay and correlated with the uptake of 18 F-FVIIai in the tumors measured in vivo by PET imaging. Results: The PET images showed high uptake of 18 F-FVIIai in the tumor regions, with a mean uptake of 2.5 ± 0.3 percentage injected dose per gram (%ID/g) (mean ± SEM) 4 h after injection of 7.3-9.3 MBq of 18 F-FVIIai and with an average maximum uptake in the tumors of 7.1 ± 0.7 %ID/g at 4 h. In comparison, the muscle uptake was 0.2 ± 0.01 %ID/g at 4 h. At 4 h, the tumors had the highest uptake of any organ. Blocking with FVIIai significantly reduced the uptake of 18 F-FVIIai from 2.9 ± 0.1 to 1.4 ± 0.1 %ID/g (P , 0.001). The uptake of 18 F-FVIIai measured in vivo by PET imaging correlated (r 5 0.72, P , 0.02) with TF protein level measured ex vivo. Conclusion: 18 F-FVIIai is a promising PET tracer for specific and noninvasive imaging of tumor TF expression. The tracer merits further development and clinical translation, with potential to become a companion diagnostics for emerging TF-targeted therapies.

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Section: Discussionsupporting

confidence: 83%

Quantitative PET Imaging of Tissue Factor Expression Using ¹⁸F-Labeled Active Site–Inhibited Factor VII

et al. 2015

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“…We demonstrated that the differences in clearance observed between rFVIIa:C and rFVII:Ag are explained by rFVIIa-AT complex formation. Prior studies suggest the liver is a major clearance organ for rFVIIa [10,11,21]. However, whether rFVIIa is cleared by the liver directly or in a complex is not known.…”

Section: Discussionmentioning

confidence: 99%

“…A few studies in animals have addressed the in vivo clearance mechanism of rFVIIa. For example, in rats, distribution studies suggest that rFVIIa is widely distributed in the body, with the highest rFVIIa concentrations observed in highly perfused organs, such as the liver [10]. Also in rats, histopathological examinations of the liver suggest that rFVIIa is cleared by hepatocytes and kuppfer cells via clathrin-mediated endocytosis [11].…”

Section: Introductionmentioning

confidence: 99%

Recombinant human factor VIIa (rFVIIa) cleared principally by antithrombin following intravenous administration in hemophilia patients

Agersø

Brophy

Pelzer

et al. 2011

Journal of Thrombosis and Haemostasis

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Summary. Objective: The objective of the present study was to evaluate the pharmacokinetics and the clearance pathways of rFVIIa after intravenous administration to hemophilia patients. Methods: Ten severe hemophilia patients were included in the study; all patients were intravenously administered a clinically relevant dose of 90 μg kg−1 (1.8 nmol kg−1) rFVIIa. Blood samples were collected consecutively to describe the pharmacokinetics of rFVIIa. All samples were analyzed using three different assays: a clot assay to measure the activity (FVIIa:C), an enzyme immunoassay (EIA) to measure the antigen levels (FVII:Ag), and an EIA (FVIIa‐AT) to measure the FVIIa antithrombin III (AT) complex. Pharmacokinetic parameters were evaluated both by use of standard non‐compartmental methods and by use of mixed effects methods. A population pharmacokinetic model was used to simultaneously model all three datasets. The total body clearance of rFVIIa:C was estimated to be 38 mL h−1 kg−1. The rFVII‐AT complex formation was responsible for 65% of the total rFVIIa:C clearance. The initial and the terminal half‐life of rFVIIa:C was estimated to be 0.6 and 2.6 h, respectively. The formation of rFVII‐AT complex was able to explain the difference observed between the rFVIIa:C and the rFVII:Ag concentration. The non‐compartmental analysis resulted in almost identical parameters.

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“…Thirdly, placental transfer of maternal FVII may account for the observed coagulopathy. However, a direct examination of maternal FVII levels in embryos failed to reveal such transfer, except when supraphysiological levels of maternal FVII were present (11,20). Additionally, the rescue of the intrauterine lethality associated with a TFPI deficiency by the additional loss of FVII suggests that any possible level of maternal FVII is insufficient to cause coagulopathy in these embryos (14).…”

mentioning

confidence: 99%

Combined factor VII/protein C deficiency results in intrauterine coagulopathy in mice

Chan

Cornelissen²,

Collen³

et al. 2000

J. Clin. Invest.

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Distribution of the Recombinant Coagulation Factor 125I-rFVIIa in Rats

Cited by 31 publications

References 8 publications

Quantitative PET Imaging of Tissue Factor Expression Using ¹⁸F-Labeled Active Site–Inhibited Factor VII

Quantitative PET Imaging of Tissue Factor Expression Using ¹⁸F-Labeled Active Site–Inhibited Factor VII

Recombinant human factor VIIa (rFVIIa) cleared principally by antithrombin following intravenous administration in hemophilia patients

Combined factor VII/protein C deficiency results in intrauterine coagulopathy in mice

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Distribution of the Recombinant Coagulation Factor 125I-rFVIIa in Rats

Cited by 31 publications

References 8 publications

Quantitative PET Imaging of Tissue Factor Expression Using 18F-Labeled Active Site–Inhibited Factor VII

Quantitative PET Imaging of Tissue Factor Expression Using 18F-Labeled Active Site–Inhibited Factor VII

Recombinant human factor VIIa (rFVIIa) cleared principally by antithrombin following intravenous administration in hemophilia patients

Combined factor VII/protein C deficiency results in intrauterine coagulopathy in mice

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Quantitative PET Imaging of Tissue Factor Expression Using ¹⁸F-Labeled Active Site–Inhibited Factor VII

Quantitative PET Imaging of Tissue Factor Expression Using ¹⁸F-Labeled Active Site–Inhibited Factor VII