Therapeutic bispecific antibodies cross the blood-brain barrier in nonhuman primates

Bispecific antibodies engineered to both bind to the primate transferrin receptor and inhibit β-secretase are taken up by the nonhuman primate brain and reduce brain β-amyloid. A Two-Pronged Approach for Central Nervous System Therapeutics The brain has been considered off-limits to antibody therapies because of the blood-brain barrier (BBB), which protects the brain from circulating toxins while selectively transporting essential molecules into the brain. Efforts to use natural transport mechanisms to deliver antibody therapies into the brain have been successful in rodents. Whether a similar approach can be used in primates, including humans, remains unknown. Using bispecific antibodies with one arm binding to the transferrin receptor and the other to an Alzheimer’s disease drug target, we show that therapeutic antibodies can effectively and safely cross the BBB and enter the primate brain, thus paving the way for antibody therapeutics to treat central nervous system diseases in humans. Using therapeutic antibodies that need to cross the blood-brain barrier (BBB) to treat neurological disease is a difficult challenge. We have shown that bispecific antibodies with optimized binding to the transferrin receptor (TfR) that target β-secretase (BACE1) can cross the BBB and reduce brain amyloid-β (Aβ) in mice. Can TfR enhance antibody uptake in the primate brain? We describe two humanized TfR/BACE1 bispecific antibody variants. Using a human TfR knock-in mouse, we observed that anti-TfR/BACE1 antibodies could cross the BBB and reduce brain Aβ in a TfR affinity–dependent fashion. Intravenous dosing of monkeys with anti-TfR/BACE1 antibodies also reduced Aβ both in cerebral spinal fluid and in brain tissue, and the degree of reduction correlated with the brain concentration of anti-TfR/BACE1 antibody. These results demonstrate that the TfR bispecific antibody platform can robustly and safely deliver therapeutic antibody across the BBB in the primate brain.