Biopharmaceutical drug targeting to the brain.
Biopharmaceuticals are large molecule drugs that do not cross the blood-brain barrier (BBB). The limiting factor in the drug development of biopharmaceuticals as new drugs for the human brain is the engineering of effective brain drug targeting technology platforms. Recombinant proteins, enzymes, and monoclonal antibodies can be re-engineered for transport across the human BBB with the molecular Trojan horse technology. The most active BBB molecular Trojan horse is a monoclonal antibody to the human insulin receptor. The genetic engineering of IgG fusion proteins has been demonstrated for neurotrophic factors, decoy receptors, therapeutic enzymes, single chain Fv antibodies, and avidin. The IgG fusion proteins are not toxic on repeated administration in high doses to primates and do not interfere with glycemic control in plasma or brain. IgG fusion proteins contain amino acid sequences that induce immune tolerance, and show low immunogenicity in primates. The IgG fusion proteins are new bifunctional biopharmaceuticals that are both targeted to brain via transport on endogenous BBB receptors, and exert pharmacological effects in brain at the cognate receptor, ligand, or enzyme substrate.
Pardridge
William M
WM
Department of Medicine, UCLA, Los Angeles, CA 90024, USA. wpardridge@mednet.ucla.edu
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D016503:Drug Delivery Systems; D015195:Drug Design; D004798:Enzymes / Q000008:administration & dosage / Q000493:pharmacokinetics; D006801:Humans; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics; D013678:Technology, Pharmaceutical / Q000379:methods
D000911:Antibodies, Monoclonal; D004798:Enzymes; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins