Transcytosis

Transcytosis (also known as cytopempsis)

Pharmaceutical companies, such as

Molecules are transported across an epithelial or endothelial barrier by one of two routes: 1) a transcellular route through the intracellular compartment of the cell, or 2) a paracellular route through the extracellular space between adjacent cells.^[18] The transcellular route is also called transcytosis. Transcytosis can be receptor-mediated and consists of three steps: 1) receptor-mediated endocytosis of the molecule on one side of the cell, e.g. the luminal side; 2) movement of the molecule through the intracellular compartment typically within the endosomal system; and 3) exocytosis of the molecule to the extracellular space on the other side of the cell, e.g. the abluminal side.

Transcytosis may be either unidirectional or bidirectional. Unidirectional transcytosis may occur selectively in the luminal to abluminal direction, or in the reverse direction, in the abluminal to luminal direction.

Transcytosis is prominent in brain microvascular peptide and protein transport,^[19] because the brain microvascular endothelium, which forms the blood-brain barrier (BBB) in vivo, expresses unique, epithelial-like, high-resistance tight junctions.^[20] The brain endothelial tight junctions virtually eliminate the paracellular pathway of solute transport across the microvascular endothelial wall in brain. In contrast, the endothelial barrier in peripheral organs does not express tight junctions, and solute movement through the paracellular pathway is prominent at the endothelial barrier in organs other than the brain or spinal cord.^[21]

Receptor-mediated transcytosis, or RMT, across the BBB is a potential pathway for drug delivery to the brain, particularly for biologic drugs such as recombinant proteins.^[22] The non-transportable drug, or therapeutic protein, is genetically fused to a transporter protein. The transporter protein may be an endogenous peptide, or peptidomimetic monoclonal antibody, which undergoes RMT across the BBB via transport on brain endothelial receptors such as the insulin receptor or transferrin receptor. The transporter protein acts as a molecular Trojan horse to 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.^[23] 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