Leading the way across the blood–brain barrier
Precision matters: the importance of tissue-targeted therapeutic delivery
Over the past decade, advances in biomedical research have produced new therapeutic mechanisms that would have seemed like science fiction in the past. But the availability of novel therapies has uncovered another fundamental truth: delivering those novel therapies to the right tissue is just as critical as the therapy itself.
In oncology, this realization has driven major progress, as researchers have learned that precision delivery—controlling where a drug goes, how it gets there, and how long it lasts—can dramatically improve both efficacy and safety. These delivery-first principles, refined through decades of cancer R&D, are now being applied beyond cancer, informing how Biogen approaches therapeutic design in neurology and immunology, where tissue specificity is equally critical. Leveraging new techniques and a wealth of research knowledge, Biogen has taken on the task of solving one of the most complex delivery challenges in medicine: transporting therapies safely and effectively across the blood-brain barrier (BBB) and into the brain.
At Biogen, delivery is not approached as a single technology or one-off solution. Instead, the team at Biogen has built a comprehensive delivery toolbox a modular platform of strategies that can be tuned based on therapeutic modality, target tissue, and patient need. This approach allows scientists to engineer delivery with intention and control, selecting the right solution for each challenge. One of the most advanced applications of this toolbox is delivery across the BBB, where receptor-mediated transports led by transferring receptor (TfR) technologies, play a central role.
The challenge of central nervous system delivery, and why now is the time to tackle it
The BBB, a tightly regulated layer of cells, protects the brain against the entry of pathogens and toxins. It is a remarkable guardian of human brain health, but this same protector also prevents potential disease-altering medicines from reaching their targets.
For millions living with neurodegenerative conditions such as Alzheimer’s and Parkinson’s, this barrier remains a fundamental obstacle, and Biogen scientists are working to overcome it.
Using the brain’s own transport system
One promising way for drugs to cross the BBB is to work with the biology already in place. Within Biogen’s broader target-delivery toolbox, receptor-mediated transports have emerged as a powerful strategy. Among these, the transferrin receptor (TfR), which naturally transports iron into the brain, can be used as a gateway for therapies. While TfR-based approaches have attracted significant interest across the industry, Biogen has focused on applying systematic engineering and comparative design principles to develop a differentiated, scalable brain-delivery strategy.
Thanks to advances in medical science, progress has been made in using TfR as a target to allow CNS access for treatments. Adem Koksal, Ph.D., who leads Biogen's targeted delivery platforms is leading efforts to translate this biology into a scalable brain delivery strategy.
Over the past several years at Biogen, Adem and a cross-functional team of colleagues have built a systematic strategy to use BBB shuttles for rapid and precise transport across capillaries, reaching neurons and deeper regions of the brain.
Biogen’s teams have carefully crafted a collection of anti-TfR antibodies “designed to engage the transferrin receptor on brain endothelial cells and transport therapies into the brain in a controlled and predictable way,” explains Adem. This engineered toolbox approach allows scientists to match a specific shuttle to the therapeutic need.
Three key design parameters determine how effectively a shuttle can transport a therapy across the BBB. Each shuttle is tuned based on how tightly it binds the receptor (affinity), how many binding sites it uses (valency), and where it attaches (epitope). Together, these determine how safely and efficiently therapies reach their target.
Engineering a shuttle toolbox
Designing an effective shuttle requires balance. Adem explains that if affinity is too high, the therapeutic can get trapped and may degrade receptors. If affinity is too weak then the therapeutic may fail to cross the BBB at all. There are similar trade-offs when balancing valency.
Through systematic testing, the Biogen team identified a clear pattern. Brain delivery follows a bell-shaped curve, with a “sweet spot” range of binding strength that allows antibodies to cross the barrier efficiently. Similarly, valency and epitope add another layer that show different designs excel at different tasks. Some shuttles achieve higher short-term brain exposure, while others provide more sustained delivery over time with improved safety profiles.
This insight brings brain delivery from a trial-and-error approach into an engineering discipline with clear principles. To validate the success of this approach in delivering medicine into the brain, Biogen researchers carried out an experiment to see if engineered shuttles could deliver an antisense oligonucleotide (ASO) across the BBB in mice and achieve target mRNA knockdown in the brain.
The results demonstrated that mice treated with shuttled ASO had dramatically improved levels of ASO in their brains (yellow [bivalent] and green [monovalent] bars) compared with mice treated with non-shuttled treatment approaches, along with corresponding biological activity.1 Both monovalent and bivalent shuttles were effective when tuned to the right binding properties. This work, published in the journal Mabs, reinforces the potential of Biogen’s design-driven approach to translate into functional outcomes.
Biogen’s work in this space has revealed a critical insight: no single shuttle design works optimally for every therapeutic application. By creating a toolbox of optimized shuttles tailored to specific delivery needs, Biogen can match the antibody to the patient based on their individual needs.
Building on a legacy
Biogen’s shuttle toolbox has been initially developed to complement and advance the company’s ongoing leadership in Alzheimer’s disease. “Delivering therapies to the brain remains a critical scientific challenge in Alzheimer’s disease, as the brain’s protective barriers can limit how much medicine reaches its intended target,” said Sarah Kleinpeter, Biogen’s Head of Alzheimer's and Dementia Franchise. “Our work in molecular engineering to optimize this platform and toolbox will potentially help us improve brain exposure across multiple modalities and ultimately help address the complex biology of this debilitating disease.”
Looking to the future of targeted brain delivery
The Biogen team is already advancing beyond traditional TfR-based shuttles, exploring next-generation designs that target entirely different receptors. This could provide an alternative, free from reticulocyte depletion concerns. “It's not simply that our approach has led to a great toolbox, but also that we now know what that approach is when looking at other receptors,” Adem explains. “The next wave is about specific delivery to tissues and specific delivery to cell types.” As research progresses, targeting strategies will improve, leading to even more specific and efficient drug delivery. This may allow for lower therapeutic doses with maintained effectiveness and greater safety.
The expanding shuttle toolbox signals a shift in what’s possible for brain delivery. "The evolution of precision delivery is finally catching up with the complexity of neurological disease. For the first time, we’re seeing technologies that don’t just cross the blood–brain barrier, they do it with intention, control, and purpose. That’s how we translate scientific possibility into potential gains in efficacy and safety for patients," said Ross Jeggo, Head of Neurology Research at Biogen. Instead of working around the blood-brain barrier, Biogen is beginning to work with it—transforming a longstanding obstacle into a gateway for innovation.
1. Smith BA, et al. Balancing brain exposure, pharmacokinetics and safety of transferrin receptor antibodies for delivery of neuro-therapeutics. MAbs. 2025 Dec;17(1):2592422.