I admit to doing a spit-take when I saw the title of this article: Aptamers as Therapeutic Agents: Has the Initial Euphoria Subsided?. At this stage in the game, with only one aptamer therapeutic cleared and it having perennially weak sales, that question mark in the title seems more than a bit out of date. By at least a decade.
Aptamers are most commonly compared to monoclonal antibodies as a therapeutic platform. Both are large molecules, and both exhibit high-affinity, high-specificity binding to a range of targets. But one is a successful drug development platform, the other is not.
In contrast to the one cleared aptamer therapeutic, there are hundreds of monoclonals cleared for therapeutic use, many of which are billion-dollar drugs. No sign of the initial euphoria subsiding there.
For sure, monoclonals had a head start: the seminal paper disclosing the technology was published in 1975; the equivalent papers for aptamer technology were published in 1989. But that 14-year head start underestimates the true gap in drug development time and effort.
Although monoclonals were new in 1975, antibodies as therapeutic agents were not. Antibodies, in the form of anti-sera, were the first medicines developed by the scientific method (as opposed to trial and error). The rise of germ theory in the 1870s enabled the development not just of bacteriology, but immunology too: until the concept of specific disease-causing agents was established, it was impossible to conceive of specific host responses that might neutralize them. Immunology could never have developed under the humoral theories of disease that dominated both Eastern and Western medicine for millennia.
And from that beginning, some of the challenges of antibody therapeutics were evident. Although horse antisera against Corynebacter diphtheriae cut case fatality rates for diphtheria in half, they also triggered serious human anti-horse reactions in the patient.
Despite nearly a hundred years experience in dealing with host vs antibody reactions, the first monoclonal therapies, introduced in 1986, suffered similarly from human anti-mouse reactions, and their use was limited to desperate cases such as organ transplant rejection. It took another decade to develop humanized monoclonals that minimized host reactions.
That timeline–a hundred years of experience with antibody therapeutics followed by twenty years of development of monoclonals before they became mainstream drugs–provides a bit of perspective on just how hard it is to develop a new therapeutic platform. Thirty years to develop aptamer therapeutics does not seem quite so disappointing in that light.
But neither does it guarantee success. When I was at NeXagen (the original aptamer company) in the 90’s, I argued that we should focus our efforts on addressing diseases that were (1) acute, not chronic and (2) confined to organs with low clearance rates. I was wrong about (1) because I couldn’t imagine the acceptance of $100K courses of therapy that is routine today (many of them monoclonal therapies).
Argument (2) was validated by Macugen, an anti-VEGF aptamer that was intended to be a cancer therapeutic but repurposed to treat macular degeneration. Systemic administration as a cancer therapeutic was implausible because of the short serum half-life of the aptamer. But clearance of aptamers from the eye is much slower, requiring only monthly intra-ocular injections.
The prospects for using aptamers in systemic indications have taken a big step forward with the development of modifications that could increase their serum half-life by a factor of a hundred–from minutes to hours. Despite this advance (assuming it pans out), I’d still argue that directly competing with monoclonals is largely a losing proposition.
Despite having similar pharmacokinetics, Macugen got its butt kicked in the marketplace by a monoclonal antibody (Lucentis) also targeted to VEGF, largely due to inferior performance in clinical trials. This story is likely to repeat itself wherever an antibody can do what an aptamer does. The lead in technological development is just too great to overcome at this point. Except in rare cases where you just can’t raise a high-affinity antibody to a target, monoclonals are likely to win out over aptamers every time.
I argued in the 90s, and would still argue today, that aptamer technology should exploit its advantage in chemistry. Aptamers are synthetic molecules and reactive groups of just about any kind can be added to them at specific sites. The upshot is that aptamer-reactive group conjugates can be created that are far more reactive, and yet far more specific than the reactive group alone, enhancing their potency while reducing their toxicity.
My little group at NeXstar did a couple of proofs-of-concept, including creating a highly potent neutrophil elastase inhibitor that showed therapeutic activity in rat models of inflammatory lung disease. I have no idea if elastase inhibition is a plausible therapeutic mode for treating ARDS or other lung conditions. But surely there are other indications where coupling a small molecule to an aptamer would create a potent therapeutic–and have distinct advantages over monoclonal antibodies.
Yeah, after 30 years, I think we can conclude that the initial euphoria around aptamer therapeutics has subsided. But it is far from time to give up, either. Aptamer technology is still not ready to compete head-to-head with monoclonal technology. But it doesn’t have to. It just has to find some niches where both small molecules and monoclonals have failed, and use its strengths, which are mainly in chemistry, to fill those niches. Making aptamers that are basically nucleic acid versions of monoclonals is just never going to succeed.