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Targeting Glycoprotein VI for Thromboembolic Disorders

2019; Lippincott Williams & Wilkins; Volume: 39; Issue: 5 Linguagem: Inglês

10.1161/atvbaha.119.312621

1524-4636

Frederik Denorme, Matthew T. Rondina,

Antiplatelet Therapy and Cardiovascular Diseases

HomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 39, No. 5Targeting Glycoprotein VI for Thromboembolic Disorders Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBTargeting Glycoprotein VI for Thromboembolic DisordersAll Gain With No Pain? Frederik Denorme and Matthew T. Rondina Frederik DenormeFrederik Denorme From the Molecular Medicine Program, University of Utah, Salt Lake City (F.D., M.T.R.) Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Belgium (F.D.) and Matthew T. RondinaMatthew T. Rondina Correspondence to Matthew T. Rondina, MD, University of Utah Health Sciences Center Eccles Institute of Human Genetics, 15 N 2030 E, Bldg 533, Suite 4220, Salt Lake City, Utah 84112. Email E-mail Address: [email protected] From the Molecular Medicine Program, University of Utah, Salt Lake City (F.D., M.T.R.) Department of Internal Medicine, University of Utah, Salt Lake City (M.T.R.) George E. Wahlen VAMC Department of Internal Medicine and GRECC, Salt Lake City, Utah (M.T.R.). Originally published24 Apr 2019https://doi.org/10.1161/ATVBAHA.119.312621Arteriosclerosis, Thrombosis, and Vascular Biology. 2019;39:839–840This article is a commentary on the followingSafety and Tolerability, Pharmacokinetics, and Pharmacodynamics of ACT017, an Antiplatelet GPVI (Glycoprotein VI) FabIn this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Voors-Pette et al1 report results of their first-in-human, phase one clinical trial using ACT017, a therapeutic antibody to platelet GPVI (glycoprotein VI). In healthy volunteers, ACT017 dose-dependently inhibited collagen-induced platelet aggregation without affecting template bleeding times. Combined with the absence of serious adverse events and consistent pharmacokinetic/pharmacodynamic properties, the road is paved for further clinical development of this promising antithrombotic drug.See accompanying article on page 956Platelet adhesion and activation at sites of vascular injury is a multistep process involving multiple platelet receptor-ligand interactions. GPVI plays a central role in this process, as it allows platelets to bind to exposed subendothelial collagen. The GPVI-collagen interaction subsequently induces intracellular signaling, ultimately leading to platelet activation.2 Intriguingly, despite an essential role in the formation of a stable platelet thrombus, no overt bleeding phenotype was observed either in GPVI deficient mice3 or in patients with a congenital GPVI deficiency.4 However, in some patients with anti-GPVI autoantibodies, bleeding complications have been reported, although bleeding in these patients were mainly attributed to concomitant GPVI deficiency and thrombocytopenia.5 In light of this, it is encouraging that in this clinical trial, ACT017 treatment did not affect platelet count or GPVI expression at any of the doses or timepoints tested.The observations from mice and patients with a GPVI deficiency have put forward targeting GPVI as an attractive antithrombotic strategy without the apparent risk of bleeding complications. The latter is highly relevant in the setting of stroke, where even small intracranial hemorrhages can have detrimental clinical consequences. Emerging and established data demonstrate that platelets have a dual role in the setting of ischemic stroke. Undeniably, platelets are key players in pathological thrombus formation, causing cerebral vessel occlusion and ischemia/reperfusion injury.6 Nevertheless, however, platelets are also essential to maintain vascular integrity after thrombus resolution and subsequent reperfusion of the ischemic brain. This duality of platelet functions in stroke was elegantly shown by 2 independent research groups who depleted platelets in a mouse model ischemic stroke. In both studies, platelet depletion prevented ischemic stroke brain injury; however, this was accompanied by hemorrhagic transformations in the brain.7,8Preclinical studies on the involvement of platelet receptor-ligand interactions in acute stroke have revealed that interfering with early steps of platelet adhesion (via anti-GPIb antibodies) and activation (via anti-GPVI antibodies) limits infarct progression, without increasing the risk of intracranial bleeding.9 In contrast, inhibiting platelet aggregation (via anti-GPIIb/IIIa antibodies) not only failed to protect mice from an ischemic stroke but also increased mortality rates and induced significant intracranial hemorrhages.9 Notably, Kraft et al10 subsequently confirmed these findings in aged and comorbid mice. In this study, GPVI inhibition conferred protection from stroke in aged mice, mice with diabetes mellitus, and hypertensive mice. In addition, in all these models, GPVI inhibition resulted in smaller cerebral infarcts, better functional outcomes, and reduced intracerebral hemorrhage rates compared with mice treated with inhibitors of GPIIb/IIIa. It is noteworthy that the harm of GPIIb/IIIa inhibition in these experimental murine models recapitulates adverse outcomes clinical studies of stroke. In patients with stroke, GPIIb/IIIa inhibitors (which effectively prevent thrombosis) are associated with a significantly increased risk of intracranial hemorrhage.11 Whether strategies targeting GPVI will be safer in the clinical setting of stroke remains to be seen, although the preclinical stroke data are promising.In parallel to direct targeting of GPVI by ACT017, an indirect GPVI-targeting strategy has also advanced into clinical trials (Figure). Revacept is a soluble dimeric GPVI-Fc fusion protein which acts as a competitive inhibitor of GPVI by irreversibly binding to exposed vascular collagen.12 Similar to ACT017, Revacept induced specific, dose-related inhibition of collagen-induced platelet aggregation while preserving general hemostasis in healthy individuals.12 As Revacept technically only works at sites of vascular injury, it was initially expected to have a smaller risk of bleeding complications. However, in an ex vivo model of human, atherosclerotic plaque–induced platelet aggregation, Revacept was found to be less effective than antibodies directly targeting GPVI.13 This was attributed to platelets adhering at Revacept-free segments of collagen fibers, subsequently recruiting and activating additional platelets.How both strategies targeting GPVI will compare in a real-life thrombotic settings remains to be seen and warrants additional clinical investigation. Yet, the safe profile of both compounds in healthy volunteers and the absence of bleeding complications in patients with a genetic deficiency of GPVI is encouraging for further development of GPVI-targeted antithrombotic strategies.Download figureDownload PowerPointFigure. Antithrombotic therapies are targeting platelet GP (glycoprotein) receptors. Clinically approved inhibitors targeting integrin αIIbβ3 (eg, GPIIb/IIIa) are listed in the top left. While these drugs are effective at preventing thrombosis, they are also associated with an increased bleeding risk in many patients. These bleeding complications may limit their use in the setting of ischemic stroke. In contrast, targeting GPVI may offer effective protection from thrombosis, without increasing bleeding risk. Blocking GPVI function can be achieved either by antibodies directly targeting the GPVI receptor (ACT017) or, indirectly, by preventing GPVI from binding to collagen that may be exposed on areas of damaged endothelium (Revacept).AcknowledgmentsWe thank Diana Lim for her excellent creativity and assistance with creating the figure.Sources of FundingF. Denorme is a postdoctoral fellow of the Fonds voor Wetenschappelijk Onderzoek Vlaanderen (FWO, 12U7818N).DisclosuresNone.FootnotesCorrespondence to Matthew T. Rondina, MD, University of Utah Health Sciences Center Eccles Institute of Human Genetics, 15 N 2030 E, Bldg 533, Suite 4220, Salt Lake City, Utah 84112. Email matthew.[email protected]utah.eduReferences1. Voors-Pette C, Lebozec K, Dogterom P, Jullien L, Billiald P, Ferlan P, Renaud L, Favre-Bulle O, Avenard G, Machacek M, Plétan Y, Jandrot-Perrus M. Safety and tolerability, pharmacokinetics, and pharmacodynamics of ACT017, an antiplatelet GPVI (glycoprotein VI) Fab: first-in-human healthy volunteer trial.Arterioscler Thromb Vasc Biol. 2019; 39:956–964. doi: 10.1161/ATVBAHA.118.312314LinkGoogle Scholar2. Rayes J, Watson SP, Nieswandt B. Functional significance of the platelet immune receptors GPVI and CLEC-2.J Clin Invest. 2019; 129:12–23. doi: 10.1172/JCI122955CrossrefMedlineGoogle Scholar3. Kato K, Kanaji T, Russell S, Kunicki TJ, Furihata K, Kanaji S, Marchese P, Reininger A, Ruggeri ZM, Ware J. The contribution of glycoprotein VI to stable platelet adhesion and thrombus formation illustrated by targeted gene deletion.Blood. 2003; 102:1701–1707. doi: 10.1182/blood-2003-03-0717CrossrefMedlineGoogle Scholar4. Matus V, Valenzuela G, Sáez CG, Hidalgo P, Lagos M, Aranda E, Panes O, Pereira J, Pillois X, Nurden AT, Mezzano D. An adenine insertion in exon 6 of human GP6 generates a truncated protein associated with a bleeding disorder in four Chilean families.J Thromb Haemost. 2013; 11:1751–1759. doi: 10.1111/jth.12334CrossrefMedlineGoogle Scholar5. Arthur JF, Dunkley S, Andrews RK. Platelet glycoprotein VI-related clinical defects.Br J Haematol. 2007; 139:363–372. doi: 10.1111/j.1365-2141.2007.06799.xCrossrefMedlineGoogle Scholar6. De Meyer SF, Denorme F, Langhauser F, Geuss E, Fluri F, Kleinschnitz C. Thromboinflammation in stroke brain damage.Stroke. 2016; 47:1165–1172. doi: 10.1161/STROKEAHA.115.011238LinkGoogle Scholar7. Goerge T, Ho-Tin-Noe B, Carbo C, Benarafa C, Remold-O'Donnell E, Zhao BQ, Cifuni SM, Wagner DD. Inflammation induces hemorrhage in thrombocytopenia.Blood. 2008; 111:4958–4964. doi: 10.1182/blood-2007-11-123620CrossrefMedlineGoogle Scholar8. Morowski M, Vögtle T, Kraft P, Kleinschnitz C, Stoll G, Nieswandt B. Only severe thrombocytopenia results in bleeding and defective thrombus formation in mice.Blood. 2013; 121:4938–4947. doi: 10.1182/blood-2012-10-461459CrossrefMedlineGoogle Scholar9. Kleinschnitz C, Pozgajova M, Pham M, Bendszus M, Nieswandt B, Stoll G. Targeting platelets in acute experimental stroke: impact of glycoprotein Ib, VI, and IIb/IIIa blockade on infarct size, functional outcome, and intracranial bleeding.Circulation. 2007; 115:2323–2330. doi: 10.1161/CIRCULATIONAHA.107.691279LinkGoogle Scholar10. Kraft P, Schuhmann MK, Fluri F, Lorenz K, Zernecke A, Stoll G, Nieswandt B, Kleinschnitz C. Efficacy and safety of platelet glycoprotein receptor blockade in aged and comorbid mice with acute experimental stroke.Stroke. 2015; 46:3502–3506. doi: 10.1161/STROKEAHA.115.011114LinkGoogle Scholar11. Ciccone A, Motto C, Abraha I, Cozzolino F, Santilli I. Glycoprotein IIb-IIIa inhibitors for acute ischaemic stroke.Cochrane Database Syst Rev. 2014; 3:CD005208.Google Scholar12. Ungerer M, Rosport K, Bültmann A, Piechatzek R, Uhland K, Schlieper P, Gawaz M, Münch G. Novel antiplatelet drug revacept (Dimeric Glycoprotein VI-Fc) specifically and efficiently inhibited collagen-induced platelet aggregation without affecting general hemostasis in humans.Circulation. 2011; 123:1891–1899. doi: 10.1161/CIRCULATIONAHA.110.980623LinkGoogle Scholar13. Jamasbi J, Megens RT, Bianchini M, et al. Differential inhibition of human atherosclerotic plaque-induced platelet activation by dimeric GPVI-Fc and anti-GPVI antibodies: functional and imaging studies.J Am Coll Cardiol. 2015; 65:2404–2415. doi: 10.1016/j.jacc.2015.03.573CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Spaetgens B, Nagy M and ten Cate H (2022) Antiplatelet Therapy in Patients With COVID-19—More Is Less?, JAMA, 10.1001/jama.2021.23866, 327:3, (223), Online publication date: 18-Jan-2022. Tullemans B, Karel M, Léopold V, ten Brink M, Baaten C, Maas S, Vos A, Eble J, Nijziel M, Vorst E, Cosemans J, Heemskerk J, Claushuis T and Kuijpers M (2021) Comparison of inhibitory effects of irreversible and reversible Btk inhibitors on platelet function, eJHaem, 10.1002/jha2.269, 2:4, (685-699), Online publication date: 1-Nov-2021. Gupta S and Brass L (2020) Glycoprotein VI Blockade, Arteriosclerosis, Thrombosis, and Vascular Biology, 40:9, (1964-1966), Online publication date: 1-Sep-2020. Gianazza E, Brioschi M, Baetta R, Mallia A, Banfi C and Tremoli E (2020) Platelets in Healthy and Disease States: From Biomarkers Discovery to Drug Targets Identification by Proteomics, International Journal of Molecular Sciences, 10.3390/ijms21124541, 21:12, (4541) Montague S, Lim Y, Lee W and Gardiner E (2020) Imaging Platelet Processes and Function—Current and Emerging Approaches for Imaging in vitro and in vivo, Frontiers in Immunology, 10.3389/fimmu.2020.00078, 11 Related articlesSafety and Tolerability, Pharmacokinetics, and Pharmacodynamics of ACT017, an Antiplatelet GPVI (Glycoprotein VI) FabChristine Voors-Pette, et al. Arteriosclerosis, Thrombosis, and Vascular Biology. 2019;39:956-964 May 2019Vol 39, Issue 5 Advertisement Article InformationMetrics © 2019 American Heart Association, Inc.https://doi.org/10.1161/ATVBAHA.119.312621PMID: 31017825 Originally publishedApril 24, 2019 Keywordsthrombosisplatelet aggregationglycoproteinscollagenEditorialsPDF download Advertisement SubjectsPlatelets