Reengineering biopharmaceuticals for targeted delivery across the blood-brain barrier.
Recombinant protein therapeutics cannot enter brain drug development because these large molecule drugs do not cross the blood-brain barrier (BBB). However, recombinant proteins can be reengineered as BBB-penetrating IgG fusion proteins, where the IgG part is a genetically engineered monoclonal antibody (MAb) against an endogenous BBB receptor, such as the human insulin receptor (HIR) or the transferrin receptor (TfR). The IgG binds the endogenous insulin receptor or TfR to trigger transport across the BBB and acts as a molecular Trojan horse (MTH) to ferry into brain the fused protein therapeutic. The most potent MTH to date is a MAb against the HIR, designated the HIRMAb, which is active in humans and Old World primates, such as the Rhesus monkey. There is no known MAb against the mouse insulin receptor. For drug delivery in the mouse, protein therapeutics are fused to a chimeric MAb against the mouse TfR, designated the cTfRMAb. The HIRMAb or cTfRMAb Trojan horses have been engineered and expressed as fusion proteins with multiple classes of protein therapeutics, including lysosomal enzymes, neurotrophins, decoy receptors, single chain Fv therapeutic antibodies, and avidin. The pharmacokinetic (PK) properties of the IgG fusion proteins differ from that of typical MAb drugs and resemble the PK profiles of small molecules due to rapid uptake by peripheral tissues, as well as brain. The brain uptake of the IgG fusion proteins, 2-3% of injected dose/brain, is comparable to the brain uptake of small molecules. The IgG fusion proteins have been administered chronically in mouse models, and the immune response is low titer and has no effect on the fusion protein clearance from blood or brain uptake in vivo. The BBB MTH technology enables the reengineering of a wide spectrum of recombinant protein therapeutics for targeted drug delivery to the brain.
Department of Medicine, UCLA, Los Angeles, California, USA.
William M
WM
Pardridge
Ruben J
RJ
Boado
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D015703:Antigens, CD / Q000737:chemistry / Q000276:immunology; D001812:Blood-Brain Barrier / Q000737:chemistry* / Q000276:immunology; D001921:Brain / Q000187:drug effects / Q000276:immunology; D003001:Cloning, Molecular; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D007109:Immunity; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D051379:Mice; D010957:Plasmids / Q000737:chemistry / Q000235:genetics; D015202:Protein Engineering / Q000379:methods*; D011972:Receptor, Insulin / Q000737:chemistry / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D007074:Immunoglobulin G; D011993:Recombinant Fusion Proteins; C435941:INSR protein, human; D011972:Receptor, Insulin