A novel transport vehicle (TV) that binds to the transferrin receptor (TfR) could facilitate the transport of large biotherapeutics from the blood into the brain, according to two new studies recently published in Science Translational Medicine. The approach could aid the treatment of a range of CNS disorders.

The blood–brain barrier (BBB) restricts the transport of large molecules between the blood and brain tissue, and poses a challenge for the delivery of therapeutics to the brain. TfR is natively expressed on brain endothelial cells and transports transferrin across the BBB.

Antibodies engineered to bind to TfR have been used to transport protein therapeutics from the blood into the brain. However, these approaches either incorporated TfR binding into one of the antigen-binding fragment (Fab) arms of the antibody, which precluded bivalent or bispecific binding of the therapeutic molecule, or required a TfR-binding molecule to be connected to the antibody via a peptide linker. The new studies aimed to address these issues.

In the first study, led by Mihalis Kariolis and Y. Joy Yu Zuchero, researchers engineered an antibody fragment crystallizable (Fc) domain to contain a binding site for human TfR (hTfR); they referred to the resulting molecule as a TV. “By designing the platform this way, the TV retains the structure and function of a native Fc domain,” explains Kariolis. “Furthermore, because it is built from an Fc domain, it readily accommodates various fusion partners including proteins, enzymes, oligonucleotides or Fab arms.”

As a proof of concept, the TV was fused to the Fab arms of an antibody to β-secretase 1 (BACE1), a putative therapeutic target for Alzheimer disease. The resulting molecule, called an antibody transport vehicle (ATV), was tested in mice that express the apical domain of hTfR. The mice were treated intravenously with ATV–BACE1 or non-TfR-binding anti-BACE1. After 24 h, the brain concentration of ATV–BACE1 was nearly 40-fold higher than that of anti-BACE1. The TV approach was also used to deliver BACE1 antibodies into the brains of non-human primates. “This shows that a large molecule can be administered intravenously and successfully delivered throughout the brain,” notes Zuchero.

In the second study, led by Kariolis and Anastasia Henry, the TV was fused to iduronate 2-sulfatase (IDS) to generate ETV–IDS. Recombinant IDS is used to treat the lysosomal storage disorder Hunter syndrome, which causes the accumulation of glycosaminoglycans (GAGs) in body tissues. However, IDS cannot cross the BBB and does not address the CNS manifestations of the disease.

When ETV–IDS or IDS alone were intravenously administered to IDS-knockout mice that express the apical domain of hTfR, brain uptake of ETV–IDS was greater than that of IDS alone. IDS alone reduced GAG accumulation in peripheral tissues only, whereas ETV–IDS reduced GAG accumulation in peripheral tissues and the brain. “To our knowledge, this is the first demonstration that a BBB-penetrant enzyme replacement therapy effectively traffics to critical CNS cell types within the brain,” says Henry. “ETV–IDS is entering clinical trials and we expect data later this year, which may serve as a proof-of-concept of the TV platform in humans.”