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Editorials
10. Pos W, Sorvillo N, Fijnheer R, et al. Residues Arg568 and Phe592 con- tribute to an antigenic surface for anti-ADAMTS13 antibodies in the spacer domain. Haematologica. 2011;96(11):1670-1677.
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A new drug for an old concept: aptamer to von Willebrand factor for prevention of arterial and microvascular thrombosis
Agnès Veyradier1,2
1Hematology department, French National Reference Centre for Thrombotic Microangiopathies and von Willebrand disease, Hospital Lariboisière, AP-HP.Nord and 2EA3518 Saint-Louis Research Institute, Paris University, Paris, France.
E-mail: AGNÈS VEYRADIER - agnes.veyradier@aphp.fr doi:10.3324/haematol.2020.261081
Von Willebrand factor (VWF) is a large and complex multimeric glycoprotein essential for initiation of hemostasis after vascular injury. VWF is the media- tor of platelet adhesion to the subendothelial collagen matrix and of platelet aggregation, especially at high shear rates of blood flow present in the microcirculation and stenotic arteries.1 Platelet adhesion involves specific sequences of the A1 domain of VWF (VWF-A1) and the platelet receptor glycoprotein Ib (GPIb).1 The adhesive properties of VWF are proportional to both the size of its multimers and their shear-induced unfolding, which respectively determine the number of available VWF-A1 and their swift from a cryptic to an exposed status able to bind platelet GPIb.2 Physiologically, in order to prevent the spontaneous binding of VWF to platelets, VWF multimeric distribution is regulated by a specific-cleaving protease, ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 repeats, member 13).3 A defect in VWF (related to genetic mutations of VWF) causes a bleed- ing disorder named von Willebrand disease (VWD) while an excess of ultralarge multimers of VWF (UL VWF) (due to a severe deficiency in ADAMTS13 mostly mediated by specific auto-antibodies) causes a thrombotic microan- giopathy called thrombotic thrombocytopenic purpura (TTP).4 In addition, the interaction of VWF-A1 with platelet GPIb also contributes to arterial thrombosis present in ath- erosclerotic cardiovascular disease (ACD).5 Consequently, inhibiting the binding of VWF to GPIb by specifically tar- geting VWF-A1, is a rational approach to decrease both arterial and microvascular thrombosis by preventing the formation of further VWF- and platelet-rich thrombi2 in both acute ACD5 and acute TTP3, respectively.
In the 1990-2000s, two classes of anti-VWF-A1 therapeu- tic agents were developed for this purpose. On one hand, a humanized single-variable domain immunoglobulin (Nanobody®)6,7 has recently been approved and commer- cialized as caplacizumab (Cablivi TM) by Ablynx, a Sanofi company (Sanofi-Aventis, Paris, France) for the treatment of acute acquired TTP in adults, on the basis of positive results in phase II and III trials.8,9 On the other hand, several aptamers, consisting of single-stranded DNA or RNA
oligonucleotides with a specific and stable three-dimen- sional shape able to recognize their target with high affinity and specificity, were developed and tested in animal mod- els.10-12 However, only the historical anti-VWF-A1 aptamer, ARC1779, developed by Archemix (Cambridge, MA, USA), was investigated in ACD13-16 and TTP17-21 including limited phase II studies.16,19-21
In this issue of Haematologica, Sakai K and colleagues22 present the in vitro characterization of a recently developed novel aptamer to VWF-A1, TAGX-0004,23 using an elegant and extensive structural and functional investigation in both static and dynamic conditions (platelet aggregation, shear stress-induced platelet thrombus formation, study of binding to both wild-type VWF-A1 and 16 alanine-scan- ning VWF-A1 mutants using an electrophoresis mobility shift assay and surface plasmon resonance, and graphic analysis of three-dimensional (3D) structure models of VWF-A1). The authors show that, in vitro, TAGX-0004 is able to inhibit the binding of VWF-A1 to platelet GPIb bet- ter than the historical aptamer ARC1779 and as well as the Nanobody® caplacizumab. TAGX-0004 is thus presented as a new potential therapeutic option not only in acute TTP but also in various VWF-mediated thrombotic disorders such as acute coronary syndrome (ACS) and cerebral infarc- tion.
In terms of the biochemical properties, the comparison of TAGX-0004 with ARC1779 is solid because those aptamers were used as both monovalent entities with no polyethyl- ene glycol (PEG). The significantly higher affinity of TAGX- 0004 for VWF-A1 compared to ARC1779 is likely related to the presence of Ds, an artificial hydrophobic base, able to directly interact with a specific residue (F1366) within VWF-A1. Also, interestingly, the amino acid residues of VWF-A1 identified as binding sites for TAGX-0004 and ARC1779 by the current study did not totally overlap and some slight differences with the originally mapping of VWF-A1 binding sites for ARC1172/ARC1179 performed by Huang and colleagues24 were also observed. Regarding the similar in vitro affinity for VWF-A1 measured for both TAGX-0004 and caplacizumab, the authors mention that direct comparison of an affinity of monovalent entity with
haematologica | 2020; 105(11)