The aptamer ARC1779 blocks von Willebrand factor–dependent platelet function in patients with thrombotic thrombocytopenic purpura ex vivo

Mayr, Florian; Knöbl, Paul; Jilma, Bernd; Siller‐Matula, Jolanta M.; Wagner, Patricia; Schaub, Robert G.; Gilbert, James C.; Jilma‐Stohlawetz, Petra

doi:10.1111/j.1537-2995.2009.02554.x

Cited by 51 publications

(44 citation statements)

References 38 publications

(41 reference statements)

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“…Today clinical trials are ongoing for two compounds targeting the protein partners of this complex (either VWF-A1 or GPIb␣) (7)(8)(9)(10)(11), and as anticipated, platelet function is dose-dependently inhibited, importantly without causing bleeding effects or interference with normal hemostasis. Recently, OS1, an 11-mer cysteine-constrained cyclic peptide, has been identified, and by targeting GPIb␣ it inhibits agonistinduced platelet aggregation by stabilizing the ␤-switch forming loop region in an alternative ␣-helical conformation (62,63).…”

Section: Discussionmentioning

confidence: 97%

“…Indeed, initial studies showed that Fab fragments of anti-GPIb␣ monoclonal antibodies (mAbs) that block VWF binding inhibited thrombus formation in vivo without significant prolongation of the bleeding time in non-human primates (4 -6). For other inhibitors of the GPIb␣-VWF interaction, such as the VWF-A1 binding aptamer ARC1779 (7)(8)(9) and the humanized bivalent Nanobody ALX-0081 (10,11), the antithrombotic potential and safety in initial human clinical trials has been indicated.…”

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confidence: 99%

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Identification of a Small Molecule That Modulates Platelet Glycoprotein Ib-von Willebrand Factor Interaction

Broos

Trekels

Jose

et al. 2012

Journal of Biological Chemistry

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Background:The size and/or protein nature of current von Willebrand factor (VWF)-glycoprotein (GP) Ib␣ inhibitors limits oral bioavailability and clinical development. Results: Through a rational approach, a small molecule was selected that modulates the VWF-GPIb interaction. Conclusion: Further chemical modifications will now allow full characterization and manipulation of the specific activity of the compound. Significance: Rational design allows for the identification of small molecules that interfere with protein-protein interactions.

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Section: Discussionmentioning

confidence: 97%

mentioning

confidence: 99%

Identification of a Small Molecule That Modulates Platelet Glycoprotein Ib-von Willebrand Factor Interaction

Broos

Trekels

Jose

et al. 2012

Journal of Biological Chemistry

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“…12 Dose response curves for ARC1779 indicate that the affinity of ARC1779 to the VWF A1 free domain is comparable between healthy volunteers, patients with TTP, or those with VWF disease. 12,13,25 This is an indicator that the capacity of ARC1779 is roughly comparable in subjects with normal, low or high multimer composition.…”

Section: Discussionmentioning

confidence: 99%

“…This high degree of specificity of ARC15105 is in good agreement with the high specificity of the predecessor ARC1779. 11,25 The investigated pegylated aptamer ARC15105 has been developed to provide a long-lasting inhibition of VWF after SC injection. Indeed, the formulation provided 98% bioavailability after SC injection, and the half-life is Ϸ65 hours.…”

Section: Discussionmentioning

confidence: 99%

ARC15105 Is a Potent Antagonist of Von Willebrand Factor Mediated Platelet Activation and Adhesion

Siller‐Matula

Merhi²,

Tanguay³

et al. 2012

ATVB

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Objective-We investigated the stability, pharmacokinetic, and pharmacodynamic profile of the 2 nd generation anti-von Willeband factor aptamer ARC15105. Methods and Results-Platelet plug formation was measured by collagen/adenosine diphosphate-induced closure time with the platelet function analyzer-100 and platelet aggregation by multiple electrode aggregometry. Platelet adhesion was measured on denuded porcine aortas and in a flow chamber. Aptamer stability was assessed by incubation in nuclease rich human, monkey, and rat serum for up to 72 hours. Pharmacokinetic and pharmacodynamic profiles were tested in cynomolgus monkeys after IV and SC administration. The median IC 100 and IC 50 to prolong collagen/ adenosine diphosphate-induced closure timewere 27 nmol/L and 12 nmol/L, respectively. ARC15105 (1.3 mol/L) completely inhibited ristocetin-induced platelet aggregation in whole blood (PϽ0.001), but also diminished collagen, ADP, arachidonic acid, and thrombin receptor activating peptide-induced platelet aggregation to some extent (PϽ0.05). ARC15105 (40 nmol/L) decreased platelet adhesion by Ͼ90% on denuded porcine aortas (PϽ0.001), which was comparable to the degree of inhibition obtained with abciximab. ARC15105 (100 nmol/L) also inhibited platelet adhesion to collagen under arterial shear in a flow chamber by Ͼ90% (PϽ0.001). The IV and SC terminal half-lives in cynomolgus monkeys were 67 and 65 hours, respectively, and the SC bioavailability was Ϸ98%. Allometric scaling estimates the human T 1/2 would be Ϸ217 hours. Pharmacodynamic analysis confirms that ARC15105 inhibits von Willeband factor activity Ͼ90% in blood samples taken 300 hours after a 20 mg/kg IV or SC dose in monkeys. VWF is required for normal hemostasis and mediates the adhesion of platelets to sites of vascular damage by binding to specific platelet membrane glycoproteins and constituents of exposed connective tissue. 3 VWF is also a carrier protein for blood clotting factor VIII and therefore stabilizes and prevents factor VIII from early inactivation. 4 It is released from endothelial cells and platelets following activation by a number of agents including thrombin. VWF plays a role in shear-dependent thrombogenesis, which occurs in stenotic coronary arteries or ruptured atherosclerotic plaque lesions. Conclusion-The 3Its levels are also heightened in patients, who experienced adverse cardiac events that are linked to a poorer prognosis. [5][6][7] Conventional therapy of myocardial infarction reduces platelet activation and aggregation, but mostly addresses receptors and targets other than VWF.8 Nevertheless, the central role of VWF in thrombogenesis made it a promising target in research on new antiplatelet therapies that specifically inhibit VWF, 9 like the anti-VWF aptamers. ARC1779 is an anti-VWF aptamer, which has been shown to potently and specifically inhibit excessive VWF activity in blood from patients with acute myocardial infarction (AMI), 10,11 and clinical proof of mechanism and concept has been demonstrated.12-14 ARC15105 is ...

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“…78 It has been proposed that the balance between ADAMTS13 activity and VWF can be restored, even in the presence of ADAMTS13 autoantibodies, using N-acetylcysteine, which reduces the VWF intra-A1 and intersubunit disulfide bonds, thereby altering the mean size and platelet adhesive function of VWF multimers in vitro and in vivo 79 ( Figure 3B). Alternatively, acute episodes of TTP might be attenuated by pharmacologic inhibition of the interaction of platelet GPIb with the A1 domain of VWF using an anti-VWF aptamer (eg, ARC1779) 80,81 or nanobody (eg, ALX-0081) [82][83][84] (Figure 3C). A continuous infusion of ARC1779 suppressed VWF activity and led to a rise in platelet counts in patients with hereditary TTP.…”

Section: Ttp: Autoantigen Functionmentioning

confidence: 99%

Antigen and substrate withdrawal in the management of autoimmune thrombotic disorders

Cines

McCrae

Zheng

et al. 2012

Blood

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The aptamer ARC1779 blocks von Willebrand factor–dependent platelet function in patients with thrombotic thrombocytopenic purpura ex vivo

Abstract: ARC1779 potently and specifically inhibits VWF activity and VWF-dependent PLT function. ARC1779 may be a promising novel therapeutic for the treatment of TTP.

Cited by 51 publications

References 38 publications

Identification of a Small Molecule That Modulates Platelet Glycoprotein Ib-von Willebrand Factor Interaction

Identification of a Small Molecule That Modulates Platelet Glycoprotein Ib-von Willebrand Factor Interaction

ARC15105 Is a Potent Antagonist of Von Willebrand Factor Mediated Platelet Activation and Adhesion

Antigen and substrate withdrawal in the management of autoimmune thrombotic disorders

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