Hot new technologies! We have waves of them in this business, and everyone talks about them, spends money looking at them, and does deals with small companies who are formed around them. But then reality sets in: only a few of these things march forward into the clinic, and even fewer emerge on the other side of the trials. Case in point: nanobodies. It seems like only yesterday that these were a big topic for people all across drug discovery, but the big startup in that field (Ablynx) was founded in 2001. And the first nanobody-based therapeutic (caplacizumab) was only approved earlier this year.
Those of you outside the field may be asking yourselves, so what’s a nanobody? Well, members of the camelid family (camels themselves, llamas, alpacas) went off in their own direction when it comes to immune response.
Instead of In addition to (edited to fix my own misunderstanding – DBL) generating full-sized antibody proteins with several domains, they make trimmed-down versions with only one (specifically, only the “heavy chain” part). A full-sized monoclonal antibody will weigh up around 150 kiloDaltons, but these can be about one-tenth that size (if you just narrow down to the variable region), and that allows them the chance to do some things that regular antibodies have a hard time with. Epitopes that just aren’t normally accessible can be targeted, there are better possibilities for blood-brain barrier and cell-membrane crossing, the cost of manufacturing could be lower, you could administer them by different routes, and so on. (I should note that sharks also have their own weirdo antibody alternatives, which are being looked at as well).
But as this article at Nature Reviews Drug Discovery details, all these advantages were still only possibilities, and had to be proven in the real world. What really kick-started the nanobody craze was intellectual property – many people saw these new proteins as a way to get around the heavy-duty licensing fees that the big players in monoclonal antibody generation were charging, with a specific example being the Roche-Genentech “Cabilly” patents that only expired in 2017. It’s safe to say that Shmuel Cabilly had no idea of what he was really kicking off when he filed the original application (from City of Hope hospital) in 1983 – the legal saga that resulted took so many bizarre turns and huge reversals (all the way up to the Supreme Court) that it’s the exact intellectual property equivalent of a crazed long-running soap opera, the kind with evil twins, fake deaths, and it-was-all-a-dream sequences. The “Cabilly II” patent (US 6331415) is surely high on the list of the most fee-generating biotech patents – from both directions – in industry history; a lot of people took cracks at it in court (at ferocious expense), but it continued to bring in vast amounts of licensing revenue ($840 million in its last year).
Avoiding all that was a very appealing prospect, but realizing the potential of nanobodies was, as they say, nontrivial. They tend to have shorter half-lives than their full-sized cousins (some of which are spectacularly long-lived after dosing), and their smaller size has an inevitable trade-off in potency. In a head-to-head competition against a monoclonal, they’re probably going to lose, unless you’ve got some specialized edge working for you. Which is what happened for a while – companies went after well-validated targets (in order not to have that risk at the same time as a new technology risk), but that meant running right into the traditional antibodies. Which didn’t go well.
And that’s why we have caplacizumab, actually – it targets von Willebrand factor, which is involved in thrombotic thrombocytopenic purpurea (TPP). Going after that with a monoclonal, it was thought, would run the risk of aggregating the protein in yet another way and making the disease even worse, and in this case the short half-life of the nanobody isn’t a problem (TPP patients are getting frequent plasma exchanges anyway). So after some detours and dead ends, nanobodies might finally be arriving, twenty years after they were a big buzzing deal. The NRDD article says that there are about a dozen ongoing projects in the area (as opposed to hundreds and hundreds of antibody projects in development), but if they can hit in areas where antibodies can’t, then that’ll be worthwhile.