“We Have Solved the Issue of Crossing the BBB”: What’s Next for Neurotherapeutics?

Therapeutic antibodies have transformed patient outcomes across cancer, autoimmune disorders, and rare diseases, but this success has yet to translate to central nervous system (CNS) disorders.

The blood–brain barrier (BBB), while essential to protecting the brain from unwanted guests, is a bottleneck for antibody therapies targeting neurological diseases. As a result of this biological gatekeeper, most traditional antibody therapies are unable to reach their targets in the brain in sufficient quantities.

Dr. Maarten Dewilde, an associate professor at KU Leuven, sat down with Technology Networks to discuss molecular engineering approaches that have proven effective in improving the transport of biologics to the brain and their retention in the CNS.

Dewilde’s research group focuses on exploiting receptor-mediated transcytosis (RMT) to increase brain permeability. “The BBB has developed methods to shuttle nutrients into the brain. For example, insulin does not enter the brain freely, and it’s not synthesized sufficiently by the brain, so the BBB has developed receptors that can grab insulin from the bloodstream,” said Dewilde.

“Our team has been researching RMT, whereby we are trying to bind antibodies to a receptor that normally shuttles nutrients into the brain, to increase the brain's permeability to biologics.”

In Dewilde’s opinion, targeting RMT is one of the more promising approaches for crossing the BBB, overcoming some of the issues associated with local injections into the brain.

“Direct injections come with some serious risks, such as risk of infection,” explained Dewilde. “Another major disadvantage is that the substance injected will not diffuse freely throughout the brain; it will diffuse only over a small distance.”

Every neuron in the brain is only a few micrometers from capillaries; therefore, crossing the BBB using RMT provides a much wider distribution of the therapy.

Designing molecules to cross the BBB

To harness RMT, researchers have re-engineered therapeutic antibodies into bispecific antibodies by fusing them with molecules that bind to receptors expressed on the BBB endothelium. Upon binding, the antibody-receptor complex is internalized via endocytosis, forming a vesicle that traverses the cell. The antibody is then released into the brain through exocytosis.

Endogenous ligands—natural molecules such as insulin that bind to BBB receptors—have been studied for their utility in transporting cargo across the BBB. “However, it’s better to work with something engineered to bind to a non-competitive site of the receptor to avoid interference with the endogenous function of the receptor,” stated Dewilde.

Whilst exploring antibodies that could efficiently deliver a therapeutic across the BBB, Dewilde and colleagues identified two nanobodies that bind to both human and non-human primate transferrin receptor (TfR). Preclinical studies suggested that the nanobodies can deliver biologicals into the brain in a humanized TfR mouse model.

Another approach being explored is the use of “vectorized antibodies,” whereby “you have the antibody in a virus that can cross the BBB spontaneously,” said Dewilde.

“A non-engineering technique is focused on using ultrasound on a local region of the brain,” continued Dewilde. Focused ultrasound was first reported in the 1940s and has since found application as a treatment for essential tremor in Parkinson’s disease. Combining low-intensity focused ultrasound with microbubbles can temporarily open junctions in the BBB, allowing for the passage of large therapeutic molecules. This technique can provide both spatial and temporal accuracy.

“The approach you use will depend on the application. For example, for Alzheimer’s disease, you may want a brain-wide distribution of the drug. However, if you’re trying to treat glioblastoma, where you need to treat a local tumor, a focused approach using the ultrasound method might work best,” Dewilde said.

From concept to the clinic

Translating these drug delivery strategies from preclinical research to clinical application has been a long road, but there is hope on the horizon. As Dewilde explained, “When we started this work, people were quite reluctant to make bispecific antibodies. It was a very complex process to get two chains to pair correctly and then to purify the product. Now, there are more than 100 bispecific antibodies in clinical development.”

Initial safety concerns had also held back the development of RMT-specific bispecific antibodies. “The first anti-transferrin antibodies showed hypercoagulability, because transferrin interacts with various clotting factors,” said Dewilde. “Now we see that we can circumvent this issue if we lower the affinity for the transferrin receptor via monovalent binding and by minimizing Fc effector function.”

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With development and coagulation issues now sorted, attention turns to ways to improve the half-life of drugs targeting the BBB.

“I believe we have solved the issue of crossing the BBB,” stated Dewilde. “The problem currently is the need for frequent administration when targeting only the transferrin receptor. TfR-targeting antibodies only have a half-life of a few days. This means that, especially for chronic disease, you need to reinject every two weeks, which is not very pleasant for the patient.”

Emerging technologies to improve brain retention

One approach for improving the half-life of antibody therapies is to target alternative receptors expressed in the BBB. CD98hc has been identified as a promising alternative, showing enhanced retention over TfR, making it ideal for sustained drug delivery.

Another strategy Dewilde and colleagues are working on is fusing a therapeutic antibody to an additional antibody-fragment targeting an abundant brain protein, myelin oligodendrocyte glycoprotein (MOG). “We observe that if you inject antibodies that target the anti-transferrin receptor and MOG, you have a much longer accumulation in the brain,” Dewilde said.

Roche has also developed a bispecific modular fusion protein, trontinemab, composed of a fully human monoclonal anti-amyloid-beta antibody with a fragment antigen-binding region that recognizes the TfR. Based on promising results from Phase 1 and 2 trials of trontinemab for early symptomatic Alzheimer’s disease, Roche has announced further Phase 3 trials, with planned completion in 2028.

Following its purchase of Aliada Therapeutics, AbbVie is also investing heavily in ALIA-1758, an anti-amyloid-beta antibody for the treatment of Alzheimer’s disease. Like trontinemab, ALIA-1758 utilizes a two-pronged approach consisting of an anti-pyroglutamate amyloid-beta antibody and transferrin-targeting technology. Currently in Phase 1 trials, the therapy, if successful, would enable once-monthly subcutaneous administration rather than intravenous infusions.

“Of course, it's not only about delivering antibodies to the brain; there have also been promising developments for antisense oligonucleotide [ASO] and siRNA delivery to the brain,” said Dewilde.

In studies with mice and macaques, Denali Therapeutics combined ASOs with a transferrin-targeting transport vehicle to successfully knock down select gene activity across the brain. This technology is the basis for Denali’s drug candidate, DNL628, which is currently in Phase 1b trials for the treatment of Alzheimer’s disease.

Alongside ASOs, Dewilde believes the development of nanotechnologies capable of carrying siRNAs to the brain could mark the next advancement in treating neurological disorders. “For siRNAs, it's known that if you can get them across the BBB, they will stay active for months. If you can make an siRNA therapeutic that can be delivered via systemic administration and travel across the BBB, that would be a major breakthrough,” Dewilde concluded.