Biodistribution of the recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in rats

Herzog, Eva; Harris, Stephen; Henson, Claire; McEwen, Andrew; Schenk, Sabrina; Nolte, Marc W.; Pragst, Ingo; Dickneite, Gerhard; Schulte, Stefan; Zollner, Sabine

doi:10.1016/j.thromres.2014.02.010

Cited by 26 publications

(35 citation statements)

References 34 publications

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“…In part, the success of mAb therapeutics has sparked efforts to harness the favorable pharmacokinetic properties of the antibody scaffold by fusing the fragment-crystallizable domain (Fc) of an IgG with novel biologic proteins (Korth-Bradley et al, 2000;Fast et al, 2009;Herzog et al, 2014). However, the absorption, distribution, metabolism, and excretion of mAb-based proteins are complicated owing to interactions with the pharmacological target(s) (e.g., target-mediated drug disposition), the potential influence of antidrug antibodies, and interactions with Fc receptors.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Near Infrared Fluorescent Labeling of Monoclonal Antibodies as a Tool for Tissue Distribution

et al. 2014

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The pharmacokinetic (PK) behavior of monoclonal antibodies (mAbs) is influenced by target-mediated drug disposition, off-target effects, antidrug antibody-mediated clearance, and interaction with fragmentcrystallizable domain (Fc) receptors such as neonatal Fc receptor. All of these interactions hold the potential to impact mAb biodistribution. Near infrared (NIR) fluorescent probes offer an approach complementary to radionuclides to characterize drug disposition. Notably, the use of IRDye800 (IR800; LI-COR, Lincoln, NE) as a protein-labeling agent in preclinical work holds the potential for quantitative tissue analysis. Here, we tested the utility of the IR800 dye as a quantitative mAb tracer during pharmacokinetic analysis in both plasma and tissues using a model mouse monoclonal IgG1 (8C2) labeled with £1.5 molecules of IR800. The plasma PK parameters derived from a mixture of IR800-8C2 and 8C2 dosed intravenously to C57BL/6 mice at 8 mg/kg exhibited a large discrepancy in exposure depending on the method of quantitation [CL plasma = 8.4 ml/d per kilogram (NIR fluorescence detection) versus 2.5 ml/d per kilogram (enzyme-linked immunosorbent assay)]. The disagreement between measurements suggests that the PK of 8C2 is altered by addition of the IR800 dye. Additionally, direct fluorescence analysis of homogenized tissues revealed several large differences in IR800-8C2 tissue uptake when compared with a previously published study using [125 I]8C2, most notably an over 4-fold increase in liver concentration. Finally, the utility of IR800 in combination with whole body imaging was examined by comparison of IR800-8C2 levels observed in animal sagittal cross-sections to those measured in homogenized tissues. Our results represent the first PK analysis in both mouse plasma and tissues of an IR800-mAb conjugate and suggest that mAb disposition is significantly altered by IR800 conjugation to 8C2.

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Section: Introductionmentioning

confidence: 99%

Evaluation of Near Infrared Fluorescent Labeling of Monoclonal Antibodies as a Tool for Tissue Distribution

et al. 2014

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“…rIX-FP has demonstrated improved pharmacokinetics (PK) and prolonged pharmacodynamic activity, when compared with rFIX in preclinical studies [9][10][11] and in earlier clinical trials. 12,13 The improved PK profile of rIX-FP may allow patients to be injected less frequently while maintaining a circulating FIX level high enough to minimize the occurrence of spontaneous bleeding episodes.…”

Section: Introductionmentioning

confidence: 99%

Long-acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial

Santagostino

Martinowitz

Lissitchkov

et al. 2016

Blood

172

284

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• rIX-FP maintains mean trough of 20 and 12 IU/dL FIX activity with 40 IU/kg weekly and 75 IU/kg every 2 weeks prophylaxis, respectively. • Weekly and 14-day prophylaxis regimens with rIX-FP were well tolerated and provided low bleeding rates and target joint improvement.A global phase 3 study evaluated the pharmacokinetics, efficacy, and safety of recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in 63 previously treated male patients (12-61 years) with severe hemophilia B (factor IX [FIX] activity £2%). The study included 2 groups: group 1 patients received routine prophylaxis once every 7 days for 26 weeks, followed by either 7-, 10-, or 14-day prophylaxis regimen for a mean of 50, 38, or 51 weeks, respectively; group 2 patients received on-demand treatment of bleeding episodes for 26 weeks and then switched to a 7-day prophylaxis regimen for a mean of 45 weeks. The mean terminal half-life of rIX-FP was 102 hours, 4.3-fold longer than previous FIX treatment. Patients maintained a mean trough of 20 and 12 IU/dL FIX activity on prophylaxis with rIX-FP 40 IU/kg weekly and 75 IU/kg every 2 weeks, respectively. There was 100% reduction in median annualized spontaneous bleeding rate (AsBR) and 100% resolution of target joints when subjects switched from on-demand to prophylaxis treatment with rIX-FP (P < .0001). The median AsBR was 0.00 for all prophylaxis regimens. Overall, 98.6% of bleeding episodes were treated successfully, including 93.6% that were treated with a single injection. No patient developed an inhibitor, and no safety concerns were identified. These results indicate rIX-FP is safe and effective for preventing and treating bleeding episodes in patients with hemophilia B at dosing regimens of 40 IU/kg weekly and 75 IU/kg every 2 weeks. This trial was registered at www.clinicaltrials.gov as

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“…Current knowledge on the specific extravascular interactions of EHL FIX products, including their tissue distribution and binding affinity to subendothelial collagen IV, remains limited . Direct in vivo tissue distribution of rIX‐FP (rFIX genetically fused to recombinant albumin via a cleavable linker) has been assessed in rats, and compared with that of rFIX and albumin using radioactive labelling and quantitative whole‐body autoradiography . While both [ 3 H]‐labelled rIX‐FP and albumin showed prolonged tissue and plasma retention, the tissue distribution profile of [ 3 H]‐rIX‐FP was similar to that of [ 3 H]‐rFIX, both penetrating predominantly into bone and well‐perfused tissues.…”

Section: Interactions Of Fixmentioning

confidence: 99%

“…While both [ 3 H]‐labelled rIX‐FP and albumin showed prolonged tissue and plasma retention, the tissue distribution profile of [ 3 H]‐rIX‐FP was similar to that of [ 3 H]‐rFIX, both penetrating predominantly into bone and well‐perfused tissues. This suggests that albumin fusion does not affect the distribution pattern of rIX‐FP, but that this is determined by the FIX moiety . Indeed, it is of interest to note that rIX‐FP follows the same neonatal Fc receptor (FcRn)‐recycling route as albumin, indicating that this pathway contributes to its half‐life extension …”

Section: Interactions Of Fixmentioning

confidence: 99%

Phenotypic characterization of haemophilia B – Understanding the underlying biology of coagulation factor IX

Tjärnlund-Wolf

Lassila

2019

Haemophilia

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Haemophilia B is a recessive, X‐linked bleeding disorder due to inherited deficiency in vitamin K‐dependent coagulation factor IX (FIX). FIX activity levels, as a basis for the definition of disease severity, do not clearly correlate with bleeding phenotype, likely due to the multiple steps regulating coagulation. Timely, with the availability of extended half‐life products and successful steps in gene therapy, haemophilia B therapy is in an active developmental phase. Therefore, increased knowledge of the factors contributing to the variation of haemostatic and clinical outcome and response to therapy is welcomed. FIX acts at the crossroads of both the extrinsic and intrinsic pathways, and on the platelet procoagulant membrane at the site of vascular injury, and therefore, FIX biology is targeted for multiple effectors and regulators. The synthesis, cellular and molecular interactions, and elimination routes of FIX are not as well studied as for FVIII. The specific roles of magnesium in both platelet adhesion and FIX activation, and of vascular collagen at the haemostatic site of platelet adhesion and FIX residence are of particular interest. Biochemical and translational research on these issues should improve our understanding of the mechanisms involved, leading to the development of relevant assays that measure both haemostasis and treatment response. The latter is becoming increasingly important in the new era of haemophilia management and ultimately may lead to improved treatment strategies individually tailored to a patient's needs and cost‐efficiency.

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Biodistribution of the recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in rats

Abstract: The prolonged plasma and tissue retention of rIX-FP achieved by albumin fusion may allow a reduction in dosing frequency leading to increased therapeutic compliance and convenience.

Cited by 26 publications

References 34 publications

Evaluation of Near Infrared Fluorescent Labeling of Monoclonal Antibodies as a Tool for Tissue Distribution

Evaluation of Near Infrared Fluorescent Labeling of Monoclonal Antibodies as a Tool for Tissue Distribution

Long-acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial

Phenotypic characterization of haemophilia B – Understanding the underlying biology of coagulation factor IX

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