Alzheimer’s monoclonal antibodies have an Achilles' heel: They struggle to get past the blood-brain barrier, requiring high doses which make them cost-prohibitive. Here’s how drugmakers are trying to overcome the challenge.
When ancient Greek soldiers laid their mythical siege upon the city of Troy, they struggled to break through the city’s impenetrable walls. To finally take the city, the soldiers constructed a giant “Trojan horse” as an offering to the goddess Athena — and hid inside the structure. The people of Troy brought the Trojan horse inside, sealing their fate.
Like the walls surrounding the city of Troy, the blood-brain barrier is a protective barrier that’s difficult to penetrate. It is selective about what types of molecules gain entry and keeps toxins and other harmful substances away from the brain. Since antibody-based drugs like Leqembi and Kisunla are very large molecules, they struggle getting past the blood-brain barrier, requiring high doses that make the drugs more expensive. Scientists are using brain transporters that act like a Trojan horse, tricking the blood-brain barrier into letting the monoclonal antibody through.
“With the existing, the current generation of approved treatments for Alzheimer’s, like lecanemab (Leqembi) and donanemab (Kisunla), only a tiny fraction of the administered drug actually reaches the brain, so that limits the ability of these drugs to clear amyloid,” Robert Alexander, MD, chief scientific officer at the Alzheimer’s Prevention Initiative at Banner Alzheimer’s Institute, told Being Patient.
While the research into these methods is still in the early stages, it may make these and future treatments safer and less expensive.
How to fool the blood-brain barrier
The idea of tricking the blood-brain barrier is nothing new.
“There’s been a long history of trying to overcome the blood brain barrier as a barrier to drug delivery in brain diseases,” Howard Fillit, MD, chief scientific officer of the Alzheimer’s Drug Discovery Foundation told Being Patient.
In 2022, after failing to improve cognitive outcomes in clinical trials, Roche discontinued the development of their anti-amyloid drug gantenerumab. However, it may gain new life after a makeover — Roche attached a protein they call a “Brainshuttle” onto the antibody calling the new entity trontinemab.
“There’s a receptor on the blood brain barrier called the transferrin receptor,” Fillit said. The transferrin receptor attaches to iron in the bloodstream, which is important for healthy brain function, and brings it into the brain. “In this case, the monoclonal antibodies were engineered so that they would not only bind amyloid and get rid of the amyloid, but they would also bind the transferrin receptor.”
The Brainshuttle attached to the antibody increases the concentration of antibody that gets to the brain. In early trials, it has also led to faster clearance of beta-amyloid at lower doses and far fewer side effects, like ARIA — brain swelling and brain bleeding.
Alexander said we aren’t sure why the rates of ARIA are lower and it isn’t clear if the effects will replicate in larger trials.
Other companies, including Denali Therapeutics, AbbVie, and BioArctic, are developing similar add-ons to monoclonal antibodies that could help them bypass the blood-brain barrier using the transferrin receptor.
How far along are brain transporters?
Monoclonal antibodies with brain transporters are not so far off. In fact, Roche may file with the FDA for accelerated regulatory approval of trontinemab in the coming years.
“It’s been proven already that we can overcome the chemistry challenges in engineering these antibodies,” Fillit said. “This is a major advance in our ability to develop drugs for central nervous system neurodegenerative disease.”
He added that the Brainshuttle and similar technologies will be key as drug companies are developing subcutaneous versions of monoclonal antibodies that can be injected under the skin at home, like insulin or Ozempic.
In the future, Fillit thinks that some biotech companies might license the use of their brain transporter to a company developing monoclonal antibodies for amyloid as well as other targets, speeding up drug development.
Subcutaneous injection combined with brain transporters could open the door for patients to receive multiple monoclonal antibodies at home. Since a lower dose of the drug is needed, and the drug no longer needs to be infused at a specialist clinic bringing down the cost of treatment.
Good to hear things are moving on in the treatment of this dreadful disease. My mum died after some years living with dementia. I now have it in its early stages! Any progress is very welcome.