By Dan Wolak and Robert Thorne
Diseases of the central nervous system (CNS), such as stroke, brain cancer, and Alzheimer disease, are a serious threat affecting over 50 million Americans with an associated cost of over $750 billion per year, which is expected to grow significantly over the coming decades. Paradoxically, several pharmaceutical companies are reducing their CNS drug development pipelines in spite of this great need for neurotherapeutics, likely associated with the fact that CNS drug development lags compared to other indications, both in the approval timeline and in the approval percentage. While many factors have limited CNS drug development (e.g., off-target side effects, a shortage of biomarkers, and inherent CNS complexity), effective drug delivery to the brain arguably remains the major hurdle for both small molecules and biologics.
Systemic drug delivery to the brain is extremely limited by the blood-brain barrier, which blocks many small molecules and nearly all biologics from entering the brain. This suggests central delivery methods (e.g., infusions into the brain tissue or the cerebrospinal fluid) present important opportunities for many drugs to gain access to their target sites within the CNS. However, there is surprisingly little known about drug transport within the brain.
Through central delivery, biologics can access the CNS, but their transport may be limited by a “barrier beyond the barrier” as they must navigate the brain microenvironment. The brain extracellular spaces can hinder local distribution where drugs are forced to navigate winding, narrow pathways around cells to reach their target sites. Large molecules may be further limited by steric hindrance imposed by the narrow extracellular space width or by the effects of charge and/or binding from components of the extracellular matrix. To access deeper areas of the brain following central administration, biologics may be able to take advantage of larger compartments for transport involving the perivascular spaces of cerebral blood vessels.
Immunotherapy is an attractive strategy to treat a variety of disorders, from cancer to immune diseases, because monoclonal antibodies are an extremely versatile platform. Antibodies can be engineered to target a variety of highly specific epitopes with different affinities as well as reduced to smaller antigen binding units known as antibody fragments. Despite the success of immunotherapy in other indications, systemic applications of antibodies to treat CNS disorders (such as Alzheimer disease, Parkinson disease, and brain tumors) have yet to make it through clinical trials to approval. In many cases, poor antibody delivery and distribution have likely been limiting factors, although the precise reasons remain under debate.
We recently published our work studying the distribution of IgG within the brain microenvironment, and at this year’s AAPS National Biotechnology Conference we will present new findings investigating brain transport and distribution of antibody-based therapeutics following central delivery on Tuesday, May 17 from 12:45 pm–1:45 pm (Poster#: T2015). We have explored the effects that size and binding have on local distribution and have attempted to improve distribution by reversibly altering the extracellular spaces. We have also investigated the whole brain distribution of well-characterized tracers following infusion into the cerebrospinal fluid. By carefully defining the mechanisms of antibody transport in the brain, we hope to move these proteins one step closer to effective CNS immunotherapy in the clinic.