10 Aptamers for Thrombotic Diseases
295
aptamer 9.3t displayed high affinity for FIX and IXa and little binding to FVII,
X, XI, or protein C [59, 75]. Furthermore, aptamer PEG-9.3t effectively inhibited
FIXa-mediated FX activation and increased APTT in human plasma, which was
similar to the condition of hemophilia B patients. The antidote 5.2C could rapidly
and completely reverse the anticoagulant activity of aptamer 9.3t for a long time [74].
Furthermore, aptamer RB006 and its complementary agent RB007 were optimized
to resist degradation and clearance.
10.4.1 Preclinical Evaluation
Preclinical evaluation demonstrated that aptamer RB006 cross-reacted with FIX of a
variety of species of animals [74]. The aptamer could effectively prevent thrombosis
in animal models of injury. Bleeding caused by high doses of aptamer 9.3t derivatives could be controlled by the antidote in murine tail transection and arterial injury
models. Meanwhile, experiments of porcine models demonstrated that aptamer treatment dose-dependently increased the APTT values and whole blood clotting time
[76]. Furthermore, FIXa inhibition maintained circuit patency for 60 min when antidote was administrated in a porcine model of cardiopulmonary bypass, indicating
a durable reversal. Aptamer-antidote treatment inhibited thrombin generation and
inflammatory response more effectively compared to heparin-protamine in the pig
model [76, 3].
The REG1 anticoagulation system (Regado Biosciences, Inc. (NJ, USA)) is an
anti-FIXa aptamer-based inhibitor pair agent that is developed for treatment in the
settings of ACS, PCI, and open-heart surgery. REG1 is an anticoagulant-antidote pair
that is composed of the active aptamer named RB006 (pegnivacogin) and its active
control agent RB007 (anivamersen) [77]. Pegnivacogin is a 31-mer anti-FIXa RNA
aptamer with modification of 2
-fluoro, 2
-O-methyl, 3
-inverted deoxythymidine,
and 5
-end conjugation of 40 kDa PEG resistant to renal filtration and exonuclease
degradation [17]. Anivamersen, the active control antidote of pegnivacogin, is a
15-mer 2
-O-methyl RNA oligonucleotide which binds to pegnivacogin by Watson–
Crick base pairing to neutralize its anticoagulant effect (Fig. 10.5). The REG1 anticoagulation system can partially or fully reverse the anticoagulant effect in real time
according to clinical needs based on the anivamersen dosage [69]. The REG1 has
been widely evaluated in animal models and in phase 2 clinical trials as a potential
antithrombotic therapeutic in patients with coronary artery disease (CAD) or ACS
[78].
295
aptamer 9.3t displayed high affinity for FIX and IXa and little binding to FVII,
X, XI, or protein C [59, 75]. Furthermore, aptamer PEG-9.3t effectively inhibited
FIXa-mediated FX activation and increased APTT in human plasma, which was
similar to the condition of hemophilia B patients. The antidote 5.2C could rapidly
and completely reverse the anticoagulant activity of aptamer 9.3t for a long time [74].
Furthermore, aptamer RB006 and its complementary agent RB007 were optimized
to resist degradation and clearance.
10.4.1 Preclinical Evaluation
Preclinical evaluation demonstrated that aptamer RB006 cross-reacted with FIX of a
variety of species of animals [74]. The aptamer could effectively prevent thrombosis
in animal models of injury. Bleeding caused by high doses of aptamer 9.3t derivatives could be controlled by the antidote in murine tail transection and arterial injury
models. Meanwhile, experiments of porcine models demonstrated that aptamer treatment dose-dependently increased the APTT values and whole blood clotting time
[76]. Furthermore, FIXa inhibition maintained circuit patency for 60 min when antidote was administrated in a porcine model of cardiopulmonary bypass, indicating
a durable reversal. Aptamer-antidote treatment inhibited thrombin generation and
inflammatory response more effectively compared to heparin-protamine in the pig
model [76, 3].
The REG1 anticoagulation system (Regado Biosciences, Inc. (NJ, USA)) is an
anti-FIXa aptamer-based inhibitor pair agent that is developed for treatment in the
settings of ACS, PCI, and open-heart surgery. REG1 is an anticoagulant-antidote pair
that is composed of the active aptamer named RB006 (pegnivacogin) and its active
control agent RB007 (anivamersen) [77]. Pegnivacogin is a 31-mer anti-FIXa RNA
aptamer with modification of 2
-fluoro, 2
-O-methyl, 3
-inverted deoxythymidine,
and 5
-end conjugation of 40 kDa PEG resistant to renal filtration and exonuclease
degradation [17]. Anivamersen, the active control antidote of pegnivacogin, is a
15-mer 2
-O-methyl RNA oligonucleotide which binds to pegnivacogin by Watson–
Crick base pairing to neutralize its anticoagulant effect (Fig. 10.5). The REG1 anticoagulation system can partially or fully reverse the anticoagulant effect in real time
according to clinical needs based on the anivamersen dosage [69]. The REG1 has
been widely evaluated in animal models and in phase 2 clinical trials as a potential
antithrombotic therapeutic in patients with coronary artery disease (CAD) or ACS
[78].