Antithrombotic Efficacy of a Novel Murine Antihuman Factor IX Antibody in Rats

Feuerstein, Giora; Patel, Arun; Toomey, John R.; Bugelski, Peter J.; Church, William R.; Valocik, Richard E.; Koster, Paul F.; Baker, A. L.; Blackburn, Michael N.

doi:10.1161/01.atv.19.10.2554

Cited by 71 publications

(62 citation statements)

References 27 publications

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“…A bolus dose of 3.0 mg/kg had been shown previously to be an effective antithrombotic dose in rat models of arterial and venous thrombosis without a bleeding liability. 25,28,29 The pharmacodynamic effects of a bolus 3.0-mg/kg dose of SB 249417 lasted between 4 and 6 hours in rats with thromboembolic stroke, with peak factor IX inhibition (85Ϯ6%) at 1 hour after dosing comparable to that observed in naive animals ( Figure 2B). In rat safety pharmacology studies, the antibody did not affect cardiovascular or hemodynamic indices such as heart rate or blood pressure, nor were there any drug-related changes in body temperature or respiratory function (not shown).…”

Section: Factor IX Activitymentioning

confidence: 87%

“…tPA (alteplase recombinant Activase, Genentech Inc) was given at 10.0 mg/kg as a 10% bolus at the start of the infusion, followed by the remaining 90% over 30 minutes. SB 249417, a fully humanized factor IX-specific inhibitory monoclonal antibody described previously, 25 was given at 1.0, 2.0, or 3.0 mg/kg bolus at the start of the infusion, followed by saline. The dose range selected was based on the antibody effects on ex vivo factor IX activity.…”

Section: Dosingmentioning

confidence: 99%

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Inhibition of Factor IX(a) Is Protective in a Rat Model of Thromboembolic Stroke

Toomey

Valocik

Koster

et al. 2002

Stroke

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Background and Purpose-Although used clinically to prevent stroke, there are few examples of anticoagulant investigations in the treatment of acute thromboembolic stroke in animal models. The treatment of thromboembolic stroke in experimental models has been investigated almost exclusively around the use of tissue plasminogen activator (tPA). In this study, using a rat thromboembolic stroke model, we investigated the use of an inhibitory anti-factor IX(a) monoclonal antibody (SB 249417) for the treatment of thromboembolic stroke and compared its efficacy to that of tPA. Methods-Stroke was initiated by delivering 6 clots into the internal carotid artery. After 2, 4, or 6 hours, rats received either intravenous vehicle, 10.0 mg/kg tPA, or 1.0, 2.0, or 3.0 mg/kg SB 249417. At 24 hours after stroke, infarct volumes and neurological deficits were assessed. Results-Treatment with tPA 2, 4, or 6 hours after stroke reduced infarct volumes by 35% (PϭNS), 45%, and 39%, respectively. tPA treatment did not improve neurological deficits at any time point. Treatment with SB 249417 (3.0 mg/kg) 2, 4, or 6 hours after stroke reduced infarct volumes by 44%, 50%, and 13% (PϭNS), respectively. Neurological deficits were reduced by 49%, 42%, and 13% (PϭNS), respectively. Neither mortality nor hemorrhage was affected by either treatment. Conclusions-The data indicate that the inhibition of factor IX(a) within 4 hours of thromboembolic stroke produced a more favorable outcome than tPA. When treatment was initiated 6 hours after stroke, the benefits of factor IX(a) inhibition were lost, whereas tPA continued to suppress lesion development, albeit without a corresponding improvement in functional deficits. This study suggests that cerebral ischemia and the resultant perfusion deficit are exacerbated by the activation of blood coagulation and that anticoagulants like SB 249417 may find utility in the treatment of ischemic stroke. (Stroke. 2002;33:578-585.)

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Section: Factor IX Activitymentioning

confidence: 87%

Section: Dosingmentioning

confidence: 99%

Inhibition of Factor IX(a) Is Protective in a Rat Model of Thromboembolic Stroke

Toomey

Valocik

Koster

et al. 2002

Stroke

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“…15 Similar observations were reported with another anti-F.IX/IXa antibody in a similar model. 17,20 These different dose requirements may be related to the model-specific characteristics of coagulation initiation and propagation. For example, heparin is also less potent in the rat model, because smaller decreases in thrombus mass were observed at even larger prolongations in the APTT than those attained in the rabbit model.…”

Section: Discussionmentioning

confidence: 99%

“…15 Similar findings were reported with another anti-F.IX/IXa antibody, BC2, in rat models of arterial and venous thrombosis. 16,17 Although 10C12 was extremely potent in a guinea pig arterial thrombosis model, it was considerably less so in a rat, ferric chloride (FeCl 3 )-induced model of arterial thrombosis. 15 Because of this discrepancy in potency, it remained unclear whether this antibody was an unusually potent antithrombotic with a very broad safety margin or not.…”

mentioning

confidence: 99%

A Human Antibody That Inhibits Factor IX/IXa Function Potently Inhibits Arterial Thrombosis Without Increasing Bleeding

Refino¹,

Jeet²,

Deguzman³

et al. 2002

ATVB

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Abstract-10C12, a human antibody F(abЈ) 2 , which specifically binds to the ␥-carboxyglutamic acid domain of factor IX/factor IXa (F.IX/IXa), interferes with all known coagulation processes in which F.IX/IXa is involved. In a rabbit model of carotid artery injury, intravenous administration of 10C12 or heparin decreased thrombosis dose dependently. The dose that resulted in a 90% reduction of thrombus mass (ED 90 ) was a 30-g/kg bolus of 10C12 or a 100-U/kg bolus plus 1.0 U · kg Ϫ1 · min Ϫ1 infusion of heparin. Heparin, at and below the ED 90 , significantly prolonged coagulation times and cuticle bleeding times. In contrast, 10C12 had no effect on coagulation or bleeding times at doses up to 4 times the ED 90 . To further evaluate the effect of 10C12 on bleeding, it was compared with heparin in a novel model of blood loss. At the ED 90 of heparin, blood loss induced by a standardized injury to the vasculature of the rabbit tibia increased to more than 2 times that of saline controls. In contrast, the dose of 10C12 required to produce a similar increase in blood loss was more than 30 times the ED 90 . The antithrombotic potency and relative safety of this fully human antibody suggests that it may have therapeutic value for treatment of thrombotic disorders.

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“…sLA-LMWH can be added to a growing list of enzyme complex inhibitors, which include active site blocked f.Xa and f.IXa (51,52), f.IXa antibodies (53), and active site directed f.Xa inhibitors (54 -57). sLA-LMWH may have advantages over other agents because it simultaneously attenuates f.Xa and thrombin generation, with selectively greater inhibition of f.Xa generation by intrinsic tenase.…”

Section: Sla-lmwh Inhibits Intrinsic Tenase and Prothrombinasementioning

confidence: 99%

Hypersulfated Low Molecular Weight Heparin with Reduced Affinity for Antithrombin Acts as an Anticoagulant by Inhibiting Intrinsic Tenase and Prothrombinase

Anderson

Fredenburgh

Stafford

et al. 2001

Journal of Biological Chemistry

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In buffer systems, heparin and low molecular weight heparin (LMWH) directly inhibit the intrinsic factor Xactivating complex (intrinsic tenase) but have no effect on the prothrombin-activating complex (prothrombinase). Although chemical modification of LMWH, to lower its affinity for antithrombin (LA-LMWH) has no effect on its ability to inhibit intrinsic tenase, N-desulfation of LMWH reduces its activity 12-fold. To further explore the role of sulfation, hypersulfated LA-LMWH was synthesized (sLA-LMWH). sLA-LMWH is not only a 32-fold more potent inhibitor of intrinsic tenase than LA-LMWH; it also acquires prothrombinase inhibitory activity. A direct correlation between the extent of sulfation of LA-LMWH and its inhibitory activity against intrinsic tenase and prothrombinase is observed. In plasma-based assays of tenase and prothrombinase, sLA-LMWH produces similar prolongation of clotting times in plasma depleted of antithrombin and/or heparin cofactor II as it does in control plasma. In contrast, heparin has no effect in antithrombin-depleted plasma. When the effect of sLA-LMWH on various components of tenase and prothrombinase was examined, its inhibitory activity was found to be cofactor-dependent (factors Va and VIIIa) and phospholipid-independent. These studies reveal that sLA-LMWH acts as a potent antithrombin-independent inhibitor of coagulation by attenuating intrinsic tenase and prothrombinase.

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Antithrombotic Efficacy of a Novel Murine Antihuman Factor IX Antibody in Rats

Cited by 71 publications

References 27 publications

Inhibition of Factor IX(a) Is Protective in a Rat Model of Thromboembolic Stroke

Inhibition of Factor IX(a) Is Protective in a Rat Model of Thromboembolic Stroke

A Human Antibody That Inhibits Factor IX/IXa Function Potently Inhibits Arterial Thrombosis Without Increasing Bleeding

Hypersulfated Low Molecular Weight Heparin with Reduced Affinity for Antithrombin Acts as an Anticoagulant by Inhibiting Intrinsic Tenase and Prothrombinase

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