The BrainCAB tag carried an antibody from the blood into brain tissue in mice and newborn macaques
The BrainCAB tag carried an antibody from the blood into brain tissue in mice and newborn macaques
On August 26, Nature Chemical Biology published a study of BrainCAB, a brinzolamide-based tag. The tag can be attached to a protein or a short RNA or DNA strand in a single chemical step. It then binds to CA-IV, an enzyme on the blood-facing surface of brain vessels.
The blood-brain barrier is a layer of cells in the walls of brain vessels that selectively controls the passage of substances from the blood. Recognizing a target in the brain is not sufficient for a large antibody. The antibody must first cross this barrier.
BrainCAB grew out of a 2023 study from the same line of research. The researchers found that one of the adeno-associated viruses used to deliver genetic instructions into cells crosses the barrier with the help of CA-IV. In the new study, the authors tested whether the same enzyme could serve as a chemical address for nonviral cargo.
The researchers attached a brinzolamide derivative containing a reactive group to an antibody. In cells, the tagged antibody bound to human, mouse, and macaque CA-IV and entered the cells. In mice, seven days after a single intravenous dose, the concentration of the BrainCAB-tagged antibody in the whole brain was approximately eight times higher than that of the same antibody without the tag.
The authors separated capillary fragments, the smallest blood vessels in the brain, from the tissue between them. They detected the tagged antibody in this tissue. In mice with the Car4 gene, which encodes CA-IV, disabled, the tagged antibody did not accumulate in the brain. This control confirmed that transport depended on CA-IV.
In newborn macaques, the tagged antibody was detected in several brain regions and in the tissue between capillaries on the fifth and seventh days after a single intravenous dose of 20 mg/kg. In the primate experiments, each combination of condition and time point included one animal. The authors tested nanobodies, which are small antibody fragments, and small interfering RNA, which suppresses the activity of specific genes, in cell-based assays. Both types of cargo bound to CA-IV and entered the cells.
The animal experiments in the article focused on the antibody. BrainCAB carried this antibody from the blood vessels into brain tissue in mice and newborn macaques.