The Fab Fragment of a Novel Anti-GPVI Monoclonal Antibody, OM4, Reduces In Vivo Thrombosis Without Bleeding Risk in Rats

Li, Haiquan; Lockyer, Simon; Concepcion, Alice; Gong, Xiaoqi; Takizawa, Hisao; Guertin, Moe; Matsumoto, Yutaka; Kambayashi, Jun-ichi; Tandon, Narendra N.; Liu, Yongge

doi:10.1161/atvbaha.107.140590

Cited by 56 publications

(36 citation statements)

References 29 publications

(35 reference statements)

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“…Furthermore preventing aggregation by blockade of the GPVI receptor, totally different from the P2Y 12 receptor, was similarly protective suggesting that the protection is likely to be a class effect. Although OM2 and cangrelor produce similar cardioprotection, anti-GPVI antibodies reportedly have a smaller bleeding risk than other platelet antagonists which may make them a more desirable clinical choice [12,13]. Our observations that GPVI antibody and P2Y 12 antagonists decrease infarct size are compatible with studies in genetically engineered mice in which interference with platelet aggregation by removing either G q [14], GPVI [15,16], or P-selectin [17] was accompanied by diminished infarction after ischemia/reperfusion.…”

Section: Discussionmentioning

confidence: 99%

Two Classes of Anti-Platelet Drugs Reduce Anatomical Infarct Size in Monkey Hearts

Yang

Liu

Cui

et al. 2013

Cardiovasc Drugs Ther

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Recent studies in rabbits have demonstrated that platelet P2Y12 receptor antagonists are cardioprotective, and that the mechanism is surprisingly not related to blockade of platelet aggregation but rather to triggering of the same signal transduction pathway seen in pre- and postconditioning. We wanted to determine whether this same cardioprotection could be documented in a primate model and whether the protection was limited to P2Y12 receptor antagonists or was a class effect. Thirty-one macaque monkeys underwent 90-min LAD occlusion/4-h reperfusion. The platelet P2Y12 receptor blocker cangrelor started just prior to reperfusion significantly decreased infarction by an amount equivalent to that seen with ischemic postconditioning (p<0.001). For any size of risk zone, infarct size in treated hearts was significantly smaller than that in control hearts. OM2, an investigational murine antibody against the primate collagen receptor glycoprotein (GP) VI, produced similar protection (p<0.01) suggesting a class effect. Both cangrelor and OM2 were quite effective at blocking platelet aggregation (94% and 97%, respectively). Thus in a primate model in which infarct size could be determined directly platelet anti-aggregatory agents are cardioprotective. The important implication of these investigations is that patients with acute myocardial infarction who are treated with platelet anti-aggregatory agents prior to revascularization may already be in a postconditioned state. This hypothesis may explain why in recent clinical trials postconditioningmimetic interventions which were so protective in animal models had at best only a modest effect.

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Section: Discussionmentioning

confidence: 99%

Two Classes of Anti-Platelet Drugs Reduce Anatomical Infarct Size in Monkey Hearts

Yang

Liu

Cui

et al. 2013

Cardiovasc Drugs Ther

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“…25,26 Additionally, the Fab fragment of a novel monoclonal antihuman GP VI antibody, OM4, inhibits thrombosis in vivo in a model of thrombosis in rats without the prolongation of bleeding time that is seen with anti-GP IIb/IIIa antibodies. 27 Further studies are needed to investigate whether OM4 and the other anti-GPVI antibodies can be developed for future clinical use.The α2β1 integrin, commonly referred to as GP Ia/IIa, VLA-2 or CD49b/CD29, also plays a role in the adhesion of platelets to collagen and for subsequent optimal activation. The expression level of α2β1, as that of GP VI, is controlled by silent polymorphisms and correlates with the in vitro rapidity in platelet adhesion and responsiveness to collagen.…”

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confidence: 99%

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confidence: 99%

Platelet receptors and signaling in the dynamics of thrombus formation

Rivera¹,

Lozano²,

et al. 2009

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Hemostasis and pathological thrombus formation are dynamic processes that require a co-ordinated series of events involving platelet membrane receptors, bidirectional intracellular signals, and release of platelet proteins and inflammatory substances. This review aims to summarize current knowledge in the key steps in the dynamics of thrombus formation, with special emphasis on the crucial participation of platelet receptors and signaling in this process. Initial tethering and firm adhesion of platelets to the exposed subendothelium is mediated by glycoprotein (GP) Ib/IX/V complex and collagen receptors, GP VI and α2β1 integrin, in the platelet surface, and by VWF and fibrillar collagen in the vascular site. Interactions between these elements are largely influenced by flow and trigger signaling events that reinforce adhesion and promote platelet activation. Thereafter, soluble agonists, ADP, thrombin, TxA2, produced/released at the site of vascular injury act in autocrine and paracrine mode to amplify platelet activation and to recruit circulating platelets to the developing thrombus. Specific interactions of these agonists with their G-protein coupled receptors generate inside-out signaling leading to conformational activation of integrins, in particular αIIbβ3, increasing their ligand affinity. Binding of αIIbβ3 to its ligands, mainly fibrinogen, supports processes such as clot retraction and platelet aggregation. Stabilization of thrombi is supported by the late wave of signaling events promoted by close contact between aggregated platelets. The best known contact-dependent signaling is outside-in signaling through αIIbβ3, but new ones are being clarified such as those mediated by interaction of Eph receptors with ephrins, or by Sema 4D and Gas-6 binding to their receptors. Finally, newly identified mechanisms appear to control thrombus growth, including back-shifting of activated integrins and actuation of compensatory molecules such as ESAM or PECAM-1. The expanding knowledge of thrombotic disease is expected to translate into the development of new drugs to help management and prevention of thrombosis.Key words: platelet, receptors, thrombus formation.Citation: Rivera J, Lozano ML, Navarro-Núñez L, Vicente V. Platelet receptors and signaling in the dynamics of thrombus formation. Haematologica 2009; 94:700-711. doi:10.3324/haematol.2008 This is an open-access paper. ABSTRACT Platelet receptors and signaling in the dynamics of thrombus formationJosé Rivera, María Luisa Lozano, Leyre Navarro-Núñez, and Vicente Vicente Unit of Hematology and Clinical Oncology, Centro Regional de Hemodonación, University of Murcia, Spain © F e r r a t a S t o r t i F o u n d a t i o nand metastasis, or immunological host defense. 1Internally, platelets contain a cytoskeleton, a dense tubular system, few mitochondrias, glycogen granules, dense (δ) and α storage granules and peroxisomes. The α-granules retain relevant proteins for the hemostatic function of platelets, such as von Willebrand factor (VWF), fibrinogen, P-selectin,...

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“…[57][58][59] In vitro experiments with human blood have also confirmed the efficacy of blocking GPVI with antibodies. 60,61 Thus, this may be a promising strategy to prevent occlusive thrombus formation in diseased vessels without causing a significant risk of bleeding.…”

Section: Arterioscler Thromb Vasc Biolmentioning

confidence: 80%

Targeting Glycoprotein VI and the Immunoreceptor Tyrosine-Based Activation Motif Signaling Pathway

Stegner

Haining

Nieswandt

2014

ATVB

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Abstract-Coronary artery thrombosis and ischemic stroke are often initiated by the disruption of an atherosclerotic plaque and consequent intravascular platelet activation. Thus, antiplatelet drugs are central in the treatment and prevention of the initial, and subsequent, vascular events. However, novel pharmacological targets for platelet inhibition remain an important goal of cardiovascular research because of the negative effect of existing antiplatelet drugs on primary hemostasis. One promising target is the platelet collagen receptor glycoprotein VI. Blockade or antibody-mediated depletion of this receptor in circulating platelets is beneficial in experimental models of thrombosis and thromboinflammatory diseases, such as stroke, without impairing hemostasis. In this review, we summarize the importance of glycoprotein VI and (hem)immunoreceptor tyrosine-based activation motif signaling in hemostasis, thrombosis, and thrombo-inflammatory processes and discuss the targeting strategies currently under development for inhibiting glycoprotein VI and its signaling. (Arterioscler Thromb Vasc Biol. 2014;34:1615-1620.)

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The Fab Fragment of a Novel Anti-GPVI Monoclonal Antibody, OM4, Reduces In Vivo Thrombosis Without Bleeding Risk in Rats

Cited by 56 publications

References 29 publications

Two Classes of Anti-Platelet Drugs Reduce Anatomical Infarct Size in Monkey Hearts

Two Classes of Anti-Platelet Drugs Reduce Anatomical Infarct Size in Monkey Hearts

Platelet receptors and signaling in the dynamics of thrombus formation

Targeting Glycoprotein VI and the Immunoreceptor Tyrosine-Based Activation Motif Signaling Pathway

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