446
H. Jin
But, not all aptamers are so lucky. Pegnivacogin is an RNA aptamer that inhibits
coagulation factor IXa, this aptamer was conjugated with 40-kDa methoxy polyethylene glycol (mPEG) to increase its concentration and half-life in plasma. After
encouraging results from Phase 1 and 2a clinical trials [212, 214, 249], Pegnivacogin
entered a phase 2b clinical trial, RADAR trial [89]. Unfortunately, this successive trial
[89] was halted following three patient occurred the allergic-like reactions shortly
after pegnivacogin administration, one of them is fatal. Most of the patients that
experienced serious adverse events had the highest levels of anti-PEG antibodies.
The following study demonstrated pre-existing IgG anti-PEG antibodies correlated with allergic events, suggesting that the PEG moiety, and not the oligonucleotide, was the causative allergic agent [217, 218]. The results from the pegnivacogin clinical trial trigger vigilance to the possible safety concerns that can be
associated with the administration of PEGylated therapies.
Another phase 3 clinical trial named “the REG1 anticoagulation system versus
bivalirudin on outcomes after percutaneous coronary intervention (REGULATEPCI)” [216] provided further evidence that pegnivacogin can cause the allure effects,
a single intravenous bolus infusion of pegnivacogen (1 mg/kg), 0.6% of the patients
(10 out of 1,605) experienced a serious adverse event. The levels of pre-existing
IgG anti-PEG antibodies were associated with the severity of clinical manifestation
[218].
Except for the allergic evens, Moreno and co-workers [250] further validated
that pre-existed anti-PEG antibodies can directly inhibit a PEGylated aptamer’s
therapeutic effect. For example, anti-PEG antibodies are capable of inhibiting the
anticoagulant activity of pegnivacogin in vitro as well as in vivo.
To sum up, the good news for the field is the allergy has nothing to do with the
aptamer itself, while bioconjugation material such as PEG which is pervasively used
in everyday life in countless medical and commercial products may bring potential
hazards during the clinical applications. One option to conquer the challenge is to
find out more alternative moieties for avoiding renal clearance; another option is to
generate antibodies for PEG which are required for the advancement and approval
of many bona fide effectiveness.
14.5.3 Adapt to the Homeostasis of the Human Body
For aptamers to move from the laboratory to the clinic, one more thing to consider
is the homeostasis of the human body. In in vitro experiments, to achieve the
ideal results, extreme treatment conditions can be adopted for the aptamer, such
as changing the ion concentration, pH value, temperature, and osmotic pressure, but
the body temperature, the pH of body fluids, the ions between organ cells as well
as osmotic pressure are physiologically in the stable range. As we all know, human
body temperature is 36.2–37 °C, blood pH value is 7.35–7.45, extracellular sodium
ion concentration is around 145 mM, potassium ion concentration 1.5 mM, and the
plasma osmolality is about 300 mOsm/kgH 2 O.
H. Jin
But, not all aptamers are so lucky. Pegnivacogin is an RNA aptamer that inhibits
coagulation factor IXa, this aptamer was conjugated with 40-kDa methoxy polyethylene glycol (mPEG) to increase its concentration and half-life in plasma. After
encouraging results from Phase 1 and 2a clinical trials [212, 214, 249], Pegnivacogin
entered a phase 2b clinical trial, RADAR trial [89]. Unfortunately, this successive trial
[89] was halted following three patient occurred the allergic-like reactions shortly
after pegnivacogin administration, one of them is fatal. Most of the patients that
experienced serious adverse events had the highest levels of anti-PEG antibodies.
The following study demonstrated pre-existing IgG anti-PEG antibodies correlated with allergic events, suggesting that the PEG moiety, and not the oligonucleotide, was the causative allergic agent [217, 218]. The results from the pegnivacogin clinical trial trigger vigilance to the possible safety concerns that can be
associated with the administration of PEGylated therapies.
Another phase 3 clinical trial named “the REG1 anticoagulation system versus
bivalirudin on outcomes after percutaneous coronary intervention (REGULATEPCI)” [216] provided further evidence that pegnivacogin can cause the allure effects,
a single intravenous bolus infusion of pegnivacogen (1 mg/kg), 0.6% of the patients
(10 out of 1,605) experienced a serious adverse event. The levels of pre-existing
IgG anti-PEG antibodies were associated with the severity of clinical manifestation
[218].
Except for the allergic evens, Moreno and co-workers [250] further validated
that pre-existed anti-PEG antibodies can directly inhibit a PEGylated aptamer’s
therapeutic effect. For example, anti-PEG antibodies are capable of inhibiting the
anticoagulant activity of pegnivacogin in vitro as well as in vivo.
To sum up, the good news for the field is the allergy has nothing to do with the
aptamer itself, while bioconjugation material such as PEG which is pervasively used
in everyday life in countless medical and commercial products may bring potential
hazards during the clinical applications. One option to conquer the challenge is to
find out more alternative moieties for avoiding renal clearance; another option is to
generate antibodies for PEG which are required for the advancement and approval
of many bona fide effectiveness.
14.5.3 Adapt to the Homeostasis of the Human Body
For aptamers to move from the laboratory to the clinic, one more thing to consider
is the homeostasis of the human body. In in vitro experiments, to achieve the
ideal results, extreme treatment conditions can be adopted for the aptamer, such
as changing the ion concentration, pH value, temperature, and osmotic pressure, but
the body temperature, the pH of body fluids, the ions between organ cells as well
as osmotic pressure are physiologically in the stable range. As we all know, human
body temperature is 36.2–37 °C, blood pH value is 7.35–7.45, extracellular sodium
ion concentration is around 145 mM, potassium ion concentration 1.5 mM, and the
plasma osmolality is about 300 mOsm/kgH 2 O.