ferry into brain the therapeutic protein that is genetically fused to the receptor-specific Trojan horse protein. Monoclonal antibody Trojan horses that target the BBB insulin or transferrin receptor have been in drug development for over 10 years at ArmaGen, Inc., a biotechnology company in Los Angeles. ArmaGen has developed genetically engineered antibodies against both the insulin and transferrin receptors, and has fused to these antibodies different therapeutic proteins, including lysosomal enzymes, therapeutic antibodies, decoy receptors, and neurotrophins. These therapeutic proteins alone do not cross the BBB, but following genetic fusion to the Trojan horse antibody, the therapeutic protein penetrates the BBB at a rate comparable to small molecules. In 2015, ArmaGen will be the first to enter human clinical trials with the BBB Trojan horse fusion proteins that delivery protein drugs to the brain via the transcytosis pathway. The human diseases initially targeted by ArmaGen are lysosomal storage diseases that adversely affect the brain. Inherited diseases create a condition where a specific lysosomal enzyme is not produced, leading to serious brain conditions including mental retardation, behavioral problems, and then dementia. Although the missing enzyme can be manufactured by drug companies, the enzyme drug alone does not treat the brain, because the enzyme alone does not cross the BBB. ArmaGen has re-engineered the missing lysosomal enzyme as a Trojan horse-enzyme fusion protein that crosses the BBB. The first clinical trials of the new Trojan horse fusion protein technology will treat the brain in lysosomal storage disorders, including one of the mucopolysaccharidosis type I diseases, (MPSIH), also called Hurler syndrome, and MPS Type II, also called Hunter syndrome. Researchers at Genentech proposed the creation of a bispecific antibody that could bind the BBB membrane, induce receptor-mediated transcytosis, and release itself on the other side into the brain and CNS. They utilized a mouse bispecific antibody with two active sites performing different functions. One arm had a low-affinity anti-transferrin receptor binding site that induces transcytosis. A high-affinity binding site would result in the antibody not being able to release from the BBB membrane after transcytosis. This way, the amount of transported antibody is based on the concentration of antibody on either side of the barrier. The other arm had the previously developed high-affinity anti-BACE1 binding site that would inhibit BACE1 function and prevent amyloid plaque formation. Genentech was able to demonstrate in mouse models that the new bispecific antibody was able to reach