Aptamers???!!! WTH??!!!
Well that was my first impression when I heard this words from my lecturer and trust me, this is the whole class impression. Weird and sounds so alien to me, it is actually approx. 40kD oligonucleotide, a RNA based, and I must say, highly specific, ( target oriented).
We were asked to debate about this and the topic is : Aptamer Vs. Monoclonal antibodies. After a very long competitive debate, our lecturer didn't really announce the winner, but he just gave us hints where he rules out the pros and cons of both agents and leaves for us to find out. But, I heard form his opinion, most of the pro goes to Aptamer.
I was the 3rd speaker in the team and my points are related to the application of Aptamers.
This is the debate:
Good evening honorable judge Mr
Prasad , opponents and friends. I’m Adibah as the 3rd speaker would
like to continue supporting aptamers by explaining the application of aptamers.
Ladies and gentleman, for your
information, Aptamers are currently being developed as agents for a wide array
of application including diagnostic, delivery tools, therapeutics, and
biosensor.
In December 2004, FDA had
approved the first aptamer drug called
Pegaptanib and currently marketed by Pfizer and Eyetech as Macugen to treat
age-related macular degeneration (AMD) by
targeting vascular endothelial growth factors (VEGF), ,where pegaptanib will
specifically binds to VEGF165, a protein that plays role in angiogenesis
(formation of new blood vessels). A phase 2 clinical trial also investigated
pegaptanib in treatment of diabetic retinopathy and found improve vision and
reduce macular edema.
·
Route of administration: intravitreous
injection, implantable devices that delivers small but potent intraocularly.
·
But ranibizumab binds to all isoforms of human
VEGFA .
·
To increase aptamer stability is through the use
of enantiomeric forms known as Spiegelmers where it enhance nuclease
resistance.
Most advance aptamer is the
anticancer aptamer named AS1411 formerly known as AGRO100, which currently pass
the phase 1 clinical trials. AGRO100 is the 1st aptamer to be tested
in humans for treatment of cancer, and 67% patients exhibited a stable disease
profile after Phase 1 trial. The drug was administered intravenously and
toxicity was assessed. Of the 17 cancer patients under study, more than half
exhibited a stable disease profile after 2 months treatment. The most important
thing is absence of side effects that will
distinguish apatmers from other drugs that target the malingnant growth. Now UK
company planning to start Phase2 trials for renal cancer and acute myeloid
leukaemia.
Next candidate for anticancer
that show potential is tenascin-C aptamer (TTA1). Tenascin C is expressed on
many solid tumours such as glioblastoma, breast, lung, colorectal cancer which
make this aptamer wide therapeutic application. TTA1 aptamer also is rapidly
cleared by the renal system with half-life less than 2 minutes which gives it
advantage as an imaging agent or as a delivery tool.
Aptamers as an anti-HIV
As we all know that there are
only limited drug therapy for HIV, and we are thirsty to have new drugs for
HIV. And the discovery of aptamer give hopes in this field because it has excellent potential due to its small
molecule, aptamers has become the eligible candidate or major weapon to fight
HIV-1. The drug target the reverse
transcription reaction (anti-RT aptamer) and surface glycoprotein for HIV1.
But small is not enough because
the development of resistant or mutant species of HIV. So to overcome this, a
new approach is proposed where the use of oligonucleotide base strategies (antisense,
RNAi, aptamer).
Ladies and gentleman, Aptamers also
can work as an anti clotting agent where….
ARC1779 binds to A1 domain of von
willebrand factor and inhibit the capacity to bind to platelet membrane
glycoprotein 1b receptors thereby show/possessed antithrombotic effects without
significant anticoagulant. Currently in Phase 2 clinical trials for thrombotic
microangiopathies and in pts with carotid artery disease.
Aptamers as an excellent
diagnostic tools.
As Aptamer can be synthesized in
the laboratory, it is very convenient to tag them with fluorescent molecules.
In the past, diagnostic test was monopoly by antibodies; enzyme-linked immunosorbent
assays (ELISA). However, it has recently been shown that a combination use of
three aptamers targeting MutS, which is a protein involved in DNA repair, was
able to detect the protein over a fivefold variation in the concentration
range, something which antibodies have been unable to cover until now.
Aptamer as delivery tools
Aptamer also are being utilized
to deliver toxins, radioisotopes, chemotherapeutics agent. Deliver by aptamer
give : First. Targeted delivery will reduce harmful side effects associated with
the injury to normal cells and tissues. Second, the amount of drug required to
elicit response may significantly decrease with targeted delivery. For example
cardiotoxicity associated with anthracyclines is common in chemotherapy.
Targeted delivery of chemotherapies is one approach to avoid damage to healthy
tissue. Several chemotherapy has been conjugated with aptamers, including
doxorubicin and cisplatin.
As for the radioisotopes,
The main advantages using aptamer
for radioimaging/therapy is because its favorable pharmacokinetics that is
rapid renal clearance and their equisite affinity and specificity for targets.
Future candidates of aptamers
with therapeutic potential for treating diseases such as treatment of
arthritis, decrease in stress and pain, anti-allergic , control of myasthenia
gravis, myocardial ischemia, and anti inflammatory.
Lastly I would say that it is too
early to anticipate the commercial success that aptamers will achieve. Even the
first therapeutic monoclonal antibody (muromomab-CD3) could reach the market
only after almost century of research in the laboratory. Aptamers have been the
fast sprinters, with the first drug being launched within fifteen years of the
technology being developed. Whether this is a race between the hare and the
tortoise or if this is a unique case where history does not repeat itself, only
time will tell.
References:
- Shiping Song, et al, Aptamer-based biosensors, Trends in Analytical Chemistry, Vol. 27, No. 2, 2008
- William James, Aptamers, Encyclopedia of Analytical Chemistry, 2000
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