RE:RE:RE:NEW DRUG PASSES BBB ?
Irregardless (god, I love that word)....
Here ya go:
Clinical Applications of Transcytosis
Pharmaceutical companies, such as Lundbeck, are currently exploring the use of transcytosis as a mechanism for transporting therapeutic drugs across the human blood–brain barrier (BBB). Exploiting the body’s own transport mechanism can help to overcome the high selectivity of the BBB which typically blocks the uptake of most therapeutic antibodies into the brain and Central Nervous System (CNS). The pharmaceutical company Genentech, after having synthesized a therapeutic antibody that effectively inhibited BACE1 enzymatic function, experienced problems transferring adequate, efficient levels of the antibody within the brain. BACE1 is the enzyme which processes amyloid precursor proteins into amyloid-ß peptides, including the species that aggregate to form amyloid plaques associated with Alzheimer's disease.
Molecules are transported across an epithelial or endothelial barrier by one of two routes: 1) a trans-cellular route through the intra-cellular compartment of the cell, or 2) a para-cellular route through the extra-cellular space between adjacent cells.[17] The trans-cellular 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,[18] because the brain microvascular endothelium, which forms the blood-brain barrier (BBB) in vivo, expresses unique, epithelial-like, high resistance tight junctions.[19] The brain endothelial tight junctions virtually eliminate the para-cellular 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 para-cellular pathway is prominent at the endothelial barrier in organs other than the brain or spinal cord.[20]
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.[21] 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.[22] 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 Mucopolysaccharidosis (MPS) Type I, also called Hurlers 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 therapeutic levels in the brain.
[23] Genentech’s method of disguising and transporting the therapeutic antibody by attaching it to a receptor-mediated transcytosis activator has been referred to as the "Trojan Horse" method