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K. Sakai et al.
binding sites to the target. On the other hand, two aptamers used in this study were formed as monovalent. It is known that the direct comparison of an affinity of monovalent entity with an avidity of bivalent entity is not straightforward. Nevertheless, it is intriguing that TAGX- 0004 has shown a comparable inhibitory effect against caplacizumab in the studies we performed, and how the bivalent form of TAGX-0004, which is not available though, behaves in the same experiments.
Treatment with caplacizumab has demonstrated a rapid decrease of VWF ristocetin cofactor assay in patients with aTTP and the levels of VWF antigen and factor VIII were also transiently reduced with caplacizumab treatment compared with placebo due to an increased clearance of the caplacizumab-VWF complex.11 Whether or not TAGX- 0004 demonstrates an equivalent effect is still to be stud- ied using an in vivo model. Nevertheless, judging from the binding ability of TAGX-0004 to plasma-derived human VWF confirmed with EMSA (data not shown), it is likely
that the aptamer shows a similar effect as caplacizumab in aTTP patients.
In conclusion, we confirmed the potency of TAGX-0004 to prevent platelet thrombus formation in vitro. Epitope mapping of the binding sites of TAGX-0004 compared with ARC1779 and caplacizumab provided us with infor- mation on each molecule’s efficacy and characteristics. Caplacizumab is now coming into use as a first-line ther- apy for aTTP. However, there are still challenges to be overcome with this agent, such as bleeding adverse events and high cost.31 TAGX-0004 has the potential to overcome these problems and could be developed as a promising drug not only for aTTP, but also for various VWF-mediat- ed thrombotic disorders such as acute coronary syndrome and cerebral infarction.
Funding
This work was supported by research grants from the Ministry of Health, Labour, and Welfare of Japan.
References
1. Sadler JE. Biochemistry and genetics of von Willebrand factor. Annu Rev Biochem. 1998;67:395-424.
2. Ruggeri ZM. Von Willebrand factor, platelets and endothelial cell interactions. J Thromb Haemost. 2003;1(7):1335-1342.
3. Montalescot G, Philippe F, Ankri A, et al. Early increase of von Willebrand factor pre- dicts adverse outcome in unstable coronary artery disease: beneficial effects of enoxa- parin. French Investigators of the ESSENCE Trial. Circulation. 1998;98(4):294-299.
4. Ray KK, Morrow DA, Gibson CM, Murphy S, Antman EM, Braunwald E. Predictors of the rise in vWF after ST eleva- tion myocardial infarction: implications for treatment strategies and clinical outcome: An ENTIRE-TIMI 23 substudy. Eur Heart J. 2005;26(5):440-446.
5. Bath PM, Blann A, Smith N, Butterworth RJ. Von Willebrand factor, P-selectin and fibrinogen levels in patients with acute ischaemic and haemorrhagic stroke, and their relationship with stroke sub-type and functional outcome. Platelets. 1998;9(3- 4):155-159.
6. Moake JL, Rudy CK, Troll JH, et al. Unusually large plasma factor VIII:von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura. N Engl J Med. 1982;307(23):1432- 1435.
7. Gragnano F, Sperlongano S, Golia E, et al. The role of von Willebrand factor in vascu- lar inflammation: from pathogenesis to tar- geted therapy. Mediators Inflamm. 2017;2017:5620314.
8. Siller-Matula JM, Krumphuber J, Jilma B. Pharmacokinetic, pharmacodynamic and clinical profile of novel antiplatelet drugs targeting vascular diseases. Br J Pharmacol. 2010;159(3):502-517.
9. Bae ON. Targeting von Willebrand factor as a novel anti-platelet therapy; application of ARC1779, an Anti-vWF aptamer, against thrombotic risk. Arch Pharm Res. 2012; 35(10):1693-1699.
10. Matsui T, Hori A, Hamako J, et al. Mutant botrocetin-2 inhibits von Willebrand factor- induced platelet agglutination. J Thromb Haemost. 2017;15(3):538-548.
11. Peyvandi F, Scully M, Kremer Hovinga JA,
et al. Caplacizumab for acquired thrombot- ic thrombocytopenic purpura. N Engl J Med. 2016;374(6):511-522.
12. Scully M, Cataland SR, Peyvandi F, et al. Caplacizumab treatment for acquired thrombotic thrombocytopenic purpura. N Engl J Med. 2019;380(4):335-346.
13. Cataland SR, Peyvandi F, Mannucci PM, et al. Initial experience from a double-blind, placebo-controlled, clinical outcome study of ARC1779 in patients with thrombotic thrombocytopenic purpura. Am J Hematol. 2012;87(4):430-432.
14. Matsunaga KI, Kimoto M, Hirao I. High- affinity DNA aptamer generation targeting von Willebrand factor A1-domain by genetic alphabet expansion for systematic evolution of ligands by exponential enrich- ment using two types of libraries com- posed of five different bases. J Am Chem Soc. 2017;139(1):324-334.
15. Hosokawa K, Ohnishi T, Kondo T, et al. A novel automated microchip flow-chamber system to quantitatively evaluate thrombus formation and antithrombotic agents under blood flow conditions. J Thromb Haemost. 2011;9(10):2029-2037.
21. Huang RH, Fremont DH, Diener JL, Schaub RG, Sadler JE. A structural explanation for the antithrombotic activity of ARC1172, a DNA aptamer that binds von Willebrand factor domain A1. Structure. 2009;17(11): 1476-1484.
22. Furlan M, Robles R, Galbusera M, et al. von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Engl J Med. 1998;339(22):1578-1584.
23. Tsai HM, Lian EC. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic pur- pura. N Engl J Med. 1998;339(22):1585- 1594.
24. Gragoudas ES, Adamis AP, Cunningham ET, Jr., Feinsod M, Guyer DR, Group VISiONCT. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med. 2004;351(27):2805-2816.
25. Gomez-Outes A, Suarez-Gea ML, Lecumberri R, Rocha E, Pozo-Hernandez C, Vargas-Castrillon E. New parenteral anticoagulants in development. Ther Adv Cardiovasc Dis. 2011;5(1):33-59.
26. Vavalle JP, Cohen MG. The REG1 anticoag- ulation system: a novel actively controlled factor IX inhibitor using RNA aptamer technology for treatment of acute coronary syndrome. Future Cardiol. 2012;8(3):371-
16. Hirao I, Kimoto M, Mitsui T, et al. An
unnatural hydrophobic base pair system: site-specific incorporation of nucleotide
analogs into DNA and RNA. Nat Methods. 2006;3(9):729-735. 382.
17. Yamashige R, Kimoto M, Takezawa Y, et al. Highly specific unnatural base pair systems as a third base pair for PCR amplification. Nucleic Acids Res. 2012;40(6):2793-2806.
18. Diener JL, Daniel Lagasse HA, Duerschmied D, et al. Inhibition of von Willebrand factor-mediated platelet activa- tion and thrombosis by the anti-von Willebrand factor A1-domain aptamer ARC1779. J Thromb Haemost. 2009; 7(7):1155-1162.
19. Huizinga EG, Tsuji S, Romijn RA, et al. Structures of glycoprotein Ibalpha and its complex with von Willebrand factor A1 domain. Science. 2002;297(5584):1176- 1179.
20. Matsushita T, Meyer D, Sadler JE. Localization of von willebrand factor-bind- ing sites for platelet glycoprotein Ib and botrocetin by charged-to-alanine scanning mutagenesis. J Biol Chem. 2000;275(15): 11044-11049.
27. Ponce AT, Hong KL. A mini-review: clinical development and potential of aptamers for thrombotic events treatment and monitor- ing. Biomedicines. 2019;7(3):55.
28. Gilbert JC, DeFeo-Fraulini T, Hutabarat RM, et al. First-in-human evaluation of anti von Willebrand factor therapeutic aptamer ARC1779 in healthy volunteers. Circulation. 2007;116(23):2678-2686.
29. Nimjee SM, White RR, Becker RC, Sullenger BA. Aptamers as therapeutics. Annu Rev Pharmacol Toxicol. 2017; 6(57):61-79.
30. Chen Y, Roberts JR, Orje JN, et al. Identification of a VWFA1 mutation atten- uating thrombus growth but not platelet adhesion. Blood. 2017;130(Suppl_1):547.
31. Mazepa MA, Masias C, Chaturvedi S. How targeted therapy disrupts the treatment paradigm for acquired TTP - the risks, ben- efits and unknowns. Blood. 2019;134(5): 415-420.
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