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G. Yang and Y. Huang
6.3.2 ARC19499 Targeting TFPI
Tissue factor pathway inhibitor (TFPI) is a single-chain polypeptide with a relative
molecular mass of 34–40 kD. TFPI inhibits thrombin production by forming the
S protein/TFPI complex and negatively regulates the coagulation cascade reaction.
High-affinity-specific antagonistic aptamer ARC19499 (BAX499) of TFPI is a 32
nt-modified RNA. ARC19499 competitively binds to TFPI cofactor protein S to form
TFPI/ARC19499 complex, which effectively neutralizes the inhibitory effect of TFPI
on thrombin formation [58, 59], selectively increases thrombin production, shortens
prothrombin dilution time (PT), and mediates prothrombin in vivo and in vitro [60].
The results showed that ARC19499 improved the coagulation parameters of patients
with different degrees of hemophilia A/B and acquired hemophilia [61–63]. In 2010,
ARC19499 entered a phase 1 clinical trials to evaluate its safety and efficacy in
hemophiliacs; however, the study was terminated without further results [64].
6.3.3 ARC1779 Targeting vWF
von Willebrand factor (vWF) is a polysaccharide protein containing three main functional domains, which bind coagulation factor VIII, platelet receptor glycoprotein
Ib, and heparin, respectively, and play an important role in coagulation [65]. The
aptamer ARC1779 targeting to vWF is a 39 nt DNA aptamer (K D = ∼2 nM).
ARC1779 specifically identified the A1 domain of vWF and blocked its interaction
with platelet receptor glycoprotein Ib, leading to the reduction of platelet aggregation
and thrombosis in arterial bed, so as to achieve antithrombotic activity. ARC1779 has
potential therapeutic value in the treatment of von vle hemophilia-related diseases,
including stroke, myocardial ischemia, thrombocytopenic purpura (TTP), and so on
[66]. The results of phase 1 and phase 2 clinical trials demonstrated that ARC1779
had good pharmacokinetics, pharmacodynamics, and safety in healthy people and
patients with thrombocytopenic purpura (TTP) [58, 59]. However, Archemix, the
developer of ARC1779, has terminated a phase 2 clinical study of PCI postsurgical
patients with acute myocardial infarction (AMI), and no further evaluation results
have been released [49, 60].
Further, the researchers continued to attempt to screen novel vWF aptamer with
optimize performance. ARC15105 is another vwf-a1 domain adaptor optimized on
the basis of ARC1779, adding 40-kDa PEG at the 5
end to reduce renal clearance
and extend the half-life. ARC15105 exhibited high inhibition of vWF but low specificity when compared to ARC1779 [67]. The results of platelet adherence test (PAdT)
showed that the inhibition rate of 40 nmol/l ARC15105 on platelet adhesion reached
93%. In the rat platelet aggregation model induced by five agonists including lystoxetine, ARC15105 showed a higher inhibition effect on platelet aggregation than that
of ARC1779. In 2019, the novel DNA aptamer AGX-0004 [68] and RNA aptamer
DTRI-031 [69] of vWF-A1 domain were identified.
G. Yang and Y. Huang
6.3.2 ARC19499 Targeting TFPI
Tissue factor pathway inhibitor (TFPI) is a single-chain polypeptide with a relative
molecular mass of 34–40 kD. TFPI inhibits thrombin production by forming the
S protein/TFPI complex and negatively regulates the coagulation cascade reaction.
High-affinity-specific antagonistic aptamer ARC19499 (BAX499) of TFPI is a 32
nt-modified RNA. ARC19499 competitively binds to TFPI cofactor protein S to form
TFPI/ARC19499 complex, which effectively neutralizes the inhibitory effect of TFPI
on thrombin formation [58, 59], selectively increases thrombin production, shortens
prothrombin dilution time (PT), and mediates prothrombin in vivo and in vitro [60].
The results showed that ARC19499 improved the coagulation parameters of patients
with different degrees of hemophilia A/B and acquired hemophilia [61–63]. In 2010,
ARC19499 entered a phase 1 clinical trials to evaluate its safety and efficacy in
hemophiliacs; however, the study was terminated without further results [64].
6.3.3 ARC1779 Targeting vWF
von Willebrand factor (vWF) is a polysaccharide protein containing three main functional domains, which bind coagulation factor VIII, platelet receptor glycoprotein
Ib, and heparin, respectively, and play an important role in coagulation [65]. The
aptamer ARC1779 targeting to vWF is a 39 nt DNA aptamer (K D = ∼2 nM).
ARC1779 specifically identified the A1 domain of vWF and blocked its interaction
with platelet receptor glycoprotein Ib, leading to the reduction of platelet aggregation
and thrombosis in arterial bed, so as to achieve antithrombotic activity. ARC1779 has
potential therapeutic value in the treatment of von vle hemophilia-related diseases,
including stroke, myocardial ischemia, thrombocytopenic purpura (TTP), and so on
[66]. The results of phase 1 and phase 2 clinical trials demonstrated that ARC1779
had good pharmacokinetics, pharmacodynamics, and safety in healthy people and
patients with thrombocytopenic purpura (TTP) [58, 59]. However, Archemix, the
developer of ARC1779, has terminated a phase 2 clinical study of PCI postsurgical
patients with acute myocardial infarction (AMI), and no further evaluation results
have been released [49, 60].
Further, the researchers continued to attempt to screen novel vWF aptamer with
optimize performance. ARC15105 is another vwf-a1 domain adaptor optimized on
the basis of ARC1779, adding 40-kDa PEG at the 5
end to reduce renal clearance
and extend the half-life. ARC15105 exhibited high inhibition of vWF but low specificity when compared to ARC1779 [67]. The results of platelet adherence test (PAdT)
showed that the inhibition rate of 40 nmol/l ARC15105 on platelet adhesion reached
93%. In the rat platelet aggregation model induced by five agonists including lystoxetine, ARC15105 showed a higher inhibition effect on platelet aggregation than that
of ARC1779. In 2019, the novel DNA aptamer AGX-0004 [68] and RNA aptamer
DTRI-031 [69] of vWF-A1 domain were identified.