Characterization of a panel of monoclonal antibodies toward mouse PAI-1 that exert a significant profibrinolytic effect in vivo

Craen, Britt Van De; Scroyen, Ilse; Abdelnabi, Rana; Brouwers, Els; Lijnen, H. Roger; Declerck, Paul; Gils, Ann

doi:10.1016/j.thromres.2011.01.011

Cited by 15 publications

(17 citation statements)

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“…In a model of thromboplastin-induced thromboembolism, which is well established for the evaluation of profibrinolytic agents, 17,18,23,32 the diabody was tested to determine an effective dose. Because of the extremely low baseline levels of PAI-1 in mice, endotoxemic mice were used in this type of acute model to obtain a potential contributing effect of PAI-1 inhibition.…”

Section: Resultsmentioning

confidence: 99%

“…[17][18][19] MA-TCK26D6 modulates TAFI/TAFIa by impairing activation mediated by thrombin and plasmin; however, it does not block the stronger activator, thrombin/thrombomodulin. 17 Interestingly this antibody also prevents the specific interaction of TAFIa on fibrin, but not on the other small proinflammatory substrates The online version of this article contains a data supplement.…”

Section: Introductionmentioning

confidence: 99%

“…The thromboprophylactic capacity of the diabody was evaluated in a well-established mouse model of venous thromboembolism. 17,18,23,24 In addition, the effect of the diabody on brain ischemia/reperfusion injury was assessed in a mechanical transient middle cerebral artery occlusion (tMCAo) model in which brain lesion and neurologic/motor outcome were measured. Furthermore, the profibrinolytic capacity was evaluated in 2 stroke models in which in situ clots are induced in the vascular lumen of the middle cerebral artery (MCA) via a thrombin-and a ferric chloride (FeCl 3 )-induced MCA occlusion (MCAo) model.…”

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confidence: 99%

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Innovative thrombolytic strategy using a heterodimer diabody against TAFI and PAI-1 in mouse models of thrombosis and stroke

Wyseure

Rubio

Denorme

et al. 2015

Blood

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• Early thrombolytic treatment with a bispecific inhibitor against TAFI and PAI-1 is effective without exogenous tPA.• Even at the highest dose tested, the bispecific inhibitor against TAFI and PAI-1 does not prolong bleeding time.Circulating thrombin-activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor-1 (PAI-1) are causal factors for thrombolytic failure. Therefore, we evaluated an antibody-engineered bispecific inhibitor against TAFI and PAI-1 (heterodimer diabody, Db-TCK26D6x33H1F7) in several mouse models of thrombosis and stroke. Prophylactic administration of the diabody (0.8 mg/kg) in a thromboplastin-induced model of thromboembolism led to decreased lung fibrin deposition. In a model of cerebral ischemia and reperfusion, diabody administration (0.8 mg/kg, 1 hour postocclusion) led to a mitigated cerebral injury with a 2.3-fold reduced lesion and improved functional outcomes. In a mouse model of thrombin-induced middle cerebral artery occlusion, the efficacy of the diabody was compared to the standard thrombolytic treatment with recombinant tissuetype plasminogen activator (tPA). Early administration of diabody (0.8 mg/kg) caused a twofold decrease in brain lesion size, whereas that of tPA (10 mg/kg) had a much smaller effect. Delayed administration of diabody or tPA had no effect on lesion size, whereas the combined administration of diabody with tPA caused a 1.7-fold decrease in lesion size. In contrast to tPA, the diabody did not increase accumulative bleeding. In conclusion, administration of a bispecific inhibitor against TAFI and PAI-1 results in a prominent profibrinolytic effect in mice without increased bleeding. (Blood. 2015;125(8):1325-1332 IntroductionPlasminogen activators are the only thrombolytic agents approved to rapidly revascularize a thrombosed vessel. Reperfusion of the ischemiaaffected organ leads to an improved outcome in patients when applied within the first hours after ischemic onset.1 Despite this evidence-based beneficial effect, current thrombolytic agents remain widely underutilized due to life-threatening side effects such as cerebral hemorrhages and possible neurotoxicity.2,3 For acute ischemic stroke, in particular, the only licensed treatment option consists of a high systemic dose of recombinant tissue-type plasminogen activator (tPA), which is actually given to ,10% of the patients. Therefore, there is an unmet clinical need to explore novel therapeutic avenues to enhance fibrinolysis without plasminogen activator-associated adverse effects. Endogenous intravascular fibrinolysis is driven on the release of tPA from the endothelium, which in turn enzymatically activates plasminogen into the fibrin-degrading enzyme, plasmin.4 This activation step is attenuated by circulating thrombin-activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor-1 (PAI-1). Activated TAFI (TAFIa; encoded by the CPB2 gene) eliminates C-terminal Lys exposed on partially degraded fibrin, which ultimately leads to a diminished efficiency and localizati...

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Innovative thrombolytic strategy using a heterodimer diabody against TAFI and PAI-1 in mouse models of thrombosis and stroke

Wyseure

Rubio

Denorme

et al. 2015

Blood

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“…In a recent study, the aim was to generate inhibitory anti-mPAI-1 mAbs reacting with the glycosylated form of mPAI-1 bound to vitronectin (Van De Craen et al, 2011). PAI-1 is secreted in an active but conformationally unstable form, which rapidly loses activity unless bound to vitronectin (Declerck et al, 1988).…”

Section: Monoclonal Antibodies Against Mpai-1mentioning

confidence: 99%

“…Five of the anti-mPAI-1 mAbs, reacting with epitopes conserved between the three species, were found to neutralize PAI-1 activity, even in the presence of a 33-fold molar excess of mouse vitronectin. In this neutralization assay, the inhibitory effect of the mAbs was determined as the ability of mPAI-1 to inhibit mtPA activity in the absence and presence of the antibodies (Figure 1) (Declerck et al, 1995b; Van De Craen et al, 2011). …”

Section: Monoclonal Antibodies Against Mpai-1mentioning

confidence: 99%

Inhibitory Monoclonal Antibodies against Mouse Proteases Raised in Gene-Deficient Mice Block Proteolytic Functions in vivo

Lund¹,

Rasch²,

Ingvarsen³

et al. 2012

Front. Pharmacol.

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Identification of targets for cancer therapy requires the understanding of the in vivo roles of proteins, which can be derived from studies using gene-targeted mice. An alternative strategy is the administration of inhibitory monoclonal antibodies (mAbs), causing acute disruption of the target protein function(s). This approach has the advantage of being a model for therapeutic targeting. mAbs for use in mouse models can be obtained through immunization of gene-deficient mice with the autologous protein. Such mAbs react with both species-specific epitopes and epitopes conserved between species. mAbs against proteins involved in extracellular proteolysis, including plasminogen activators urokinase plasminogen activator (uPA), tissue-type plasminogen activator (tPA), their inhibitor PAI-1, the uPA receptor (uPAR), two matrix metalloproteinases (MMP9 and MMP14), as well as the collagen internalization receptor uPARAP, have been developed. The inhibitory mAbs against uPA and uPAR block plasminogen activation and thereby hepatic fibrinolysis in vivo. Wound healing, another plasmin-dependent process, is delayed by an inhibitory mAb against uPA in the adult mouse. Thromboembolism can be inhibited by anti-PAI-1 mAbs in vivo. In conclusion, function-blocking mAbs are well-suited for targeted therapy in mouse models of different diseases, including cancer.

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PAI-1 production by reactive astrocytes drives tissue dysfibrinolysis in multiple sclerosis models

Lebas

Guérit

Picot

et al. 2022

Cell. Mol. Life Sci.

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Characterization of a panel of monoclonal antibodies toward mouse PAI-1 that exert a significant profibrinolytic effect in vivo

Cited by 15 publications

References 46 publications

Innovative thrombolytic strategy using a heterodimer diabody against TAFI and PAI-1 in mouse models of thrombosis and stroke

Innovative thrombolytic strategy using a heterodimer diabody against TAFI and PAI-1 in mouse models of thrombosis and stroke

Inhibitory Monoclonal Antibodies against Mouse Proteases Raised in Gene-Deficient Mice Block Proteolytic Functions in vivo

PAI-1 production by reactive astrocytes drives tissue dysfibrinolysis in multiple sclerosis models

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