Fukuta et al.
Development of blood-brain barrier-penetrating antibodies for neutralizing tick-borne encephalitis virus in the brain. mSphere. 2025;10(1):e00184-25. doi:10.1128/msphere.00184-25
There is currently no approved treatment for tick-borne encephalitis (TBE); patients with severe illness receive only supportive care. Previous studies have shown that TBE-specific monoclonal antibodies provide protective activity in murine models (e.g., Snapshot 49/2023).
The blood-brain barrier (BBB) is a highly selective interface that separates blood vessels from brain parenchyma, preventing harmful agents and microorganisms from entering the central nervous system (CNS) via the bloodstream. However, this protective function also restricts the delivery of therapeutic agents, including brain-targeted drug delivery systems (DDSs) for anti-TBE virus molecules such as monoclonal antibodies. To address this limitation, a 29–amino acid peptide derived from the rabies virus glycoprotein (RVG), which binds to the nicotinic acetylcholine receptor, has been investigated as a brain-targeted DDS for TBE virus–neutralizing antibodies.
In this approach, RVG was genetically fused to the C-terminus of the heavy chain of monoclonal antibodies. The resulting recombinant antibodies retained neutralizing activity in plaque reduction assays, although activity was somewhat reduced compared with non-fused counterparts. The RVG-fused antibodies interacted with the receptor via the RVG peptide and were able to cross the BBB in vivo. When administered intraperitoneally to mice infected with TBE virus seven days post-infection, RVG-fused antibodies significantly reduced viral titers in brain tissue compared with non-fused antibodies.
These findings demonstrate the therapeutic potential of BBB-penetrating, RVG-fused antibodies for TBE even after viral invasion of the CNS.