Re-engineering biopharmaceuticals for delivery to brain with molecular Trojan horses.
Biopharmaceuticals, including recombinant proteins, monoclonal antibody therapeutics, and antisense or RNA interference drugs, cannot be developed as drugs for the brain, because these large molecules do not cross the blood-brain barrier (BBB). Biopharmaceuticals must be re-engineered to cross the BBB, and this is possible with genetically engineered molecular Trojan horses. A molecular Trojan horse is an endogenous peptide, or peptidomimetic monoclonal antibody (mAb), which enters brain from blood via receptor-mediated transport on endogenous BBB transporters. Recombinant neurotrophins, single chain Fv antibodies, or therapeutic enzymes may be re-engineered as IgG fusion proteins. The engineering of IgG-avidin fusion proteins enables the BBB delivery of biotinylated drugs. The IgG fusion proteins are new chemical entities that are dual or triple function molecules that bind multiple receptors. The fusion proteins are able both to enter the brain, by binding an endogenous BBB receptor, and to induce the desired pharmacologic effect in brain, by binding target receptors in the brain behind the BBB. The development of molecular Trojan horses for BBB drug delivery allows the re-engineering of biopharmaceuticals that, owing to the BBB problem, could not otherwise be developed as new drugs for the human brain.
Department of Medicine, University of California at Los Angeles, Los Angeles, California 90024, USA. wpardridge@mednet.ucla.edu
William M
WM
Pardridge
D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics* / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D004337:Drug Carriers / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D010455:Peptides / Q000235:genetics* / Q000378:metabolism*; D015202:Protein Engineering / Q000379:methods*
D000911:Antibodies, Monoclonal; D004337:Drug Carriers; D010455:Peptides