The Drug Kingpins
Monoclonal antibodies (mAbs) are the undisputed drug kingpins. In 2013, the mAb market raked in $75 billion in combined sales, covering a whole range of indications from cancer and infectious disease, to autoimmune disorders, and even high cholesterol.
Despite the success, mAbs have one chink in their armor: they cannot enter cells due to their large size, hampering their range as therapeutics. To date, mAbs can only target proteins on the surface of cells, such as receptor proteins, or proteins circulating in the bloodstream, such as inflammatory cytokines. The development of cell-penetrating mAbs would open up a world of therapeutic targets and patient benefits.
Let’s review the fundamentals of therapeutic antibodies and explore a new type of therapeutic antibody that may be able to go where no antibody has gone before.
Antibodies are proteins naturally produced by our immune system to help defend against foreign invaders such as viruses and bacteria. Each antibody produced has a unique shape that enables it to recognize unique targets (antigens) which are typically proteins on the surface of pathogens. By binding to these pathogens, antibodies act as a flag to alert the rest of the immune system to attack.
Antibody therapeutics also rely on the ability of antibodies to interact with a specific target. Scientists have developed antibodies that recognize and bind proteins on the surface of tumor cells, thereby alerting the immune system to attack the tumor. Antibodies are also selected for their ability to inhibit (stop the activity of) a particular protein. For example, the breast cancer drug Herceptin (Genentech, South San Francisco) inhibits the activity of the growth factor receptor HER2 by preventing it from interacting with the growth factor HER2:
By developing antibodies that can enter cells, this inhibitory power can be used against targets inside of the cell. Let’s take a look at the newest contender.
Scientists at Ablynx (Ghent, Belgium) are developing a new type of therapeutic antibody from an unlikely source — camels and llamas, members of the biological family Camelidae. These antibodies are structurally and functionally very similar to human antibodies, with a few important differences that could add up to something big!
Like all antibodies, Camelidae antibodies work because they have a specific shape that enables them to recognize and bind to a specific target. However, they are a tenth the size of other mammalian antibodies — giving rise to the moniker “Nanobodies.” Nanobodies have the ability to recognize targets hidden inside of cells. Their small size may potentially also enable them to cross the challenging blood brain barrier, or penetrate the interior cells of tumors – two activities that conventional antibody therapies lack.
In addition to their small size, Nanobodies also exhibit a less complex structure overall. Because of this, they have been successfully produced in bacterial cells. If Nanobodies can be scaled-up, it would significantly reduce production costs as compared to standard antibody production in mammalian cells. Preliminary studies in mice also suggest that Nanobodies can be maintained in the stomach and intestine — opening up the possibility of oral delivery for some indications such as Crohn’s disease.
In The Clinic
We can expect to see the first Nanobodies on the market this year. In February of 2017, Ablynx submitted an application to the European Medicines Agency for the first of its Nanobody therapeutics, caplacizumab. Caplacizumab is being tested for the treatment for a rare disease known as acquired thrombotic thrombocytopenic purpura (aTTP), a blood-coagulation disorder that results in extensive microscopic clots forming in small blood vessels throughout the body. The disease is triggered by excess von Willebrand factor (vWF), a protein that initiates blood clotting. Caplacizumab inhibits vWF, thereby preventing clot formation.
The company has two more Nanobody products in Phase II clinical testing: Vobarilizumab, which reduces the activity of interleukin-6 (IL-6). IL-6 is a protein that stimulates the immune response; inhibiting the immune system may prove a useful treatment for autoimmune disorders. Vobarilizumab is being tested for the treatment of rheumatoid arthritis and lupus, in partnership with AbbVie (North Chicago IL). Next up is ALX-0171, which binds the fusion (F) protein on the surface of the respiratory syncytial virus (RSV). The F protein enables RSV to lock onto lung cells. ALX-0171 is expected to interfere with the interaction of F protein and lung cells, thereby preventing RSV infection.
In partnership with Boehringer Ingelheim (Ingelheim, Germany), Ablynx is also entering the oncology space with Phase I testing of a Nanobody that inhibits the vascular endothelial growth factor (VEGF) protein. VEGF is a growth factor secreted by tumor cells to encourage the growth of blood vessels into the tumor, a process called angiogenesis. By inhibiting VEGF and angiogenesis, the flow of blood and nutrients into the tumor is stopped, essentially starving the tumor. It is hoped that Nanobodies may be even better angiogenesis inhibitors than monoclonal antibodies have proven to be, due to their enhanced tumor-penetrating abilities.
As Nanobodies continue to be tested for safety and efficacy, a whole new kingdom of potential antibody targets may begin to emerge.