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.

[1]  W. Pardridge,et al.  Human Insulin Receptor Monoclonal Antibody Undergoes High Affinity Binding to Human Brain Capillaries in Vitro and Rapid Transcytosis Through the Blood–Brain Barrier in Vivo in the Primate , 1995, Pharmaceutical Research.

[2]  C. Patlak,et al.  Intrathecal chemotherapy: brain tissue profiles after ventriculocisternal perfusion. , 1975, The Journal of pharmacology and experimental therapeutics.

[3]  W. Pardridge Re-engineering biopharmaceuticals for delivery to brain with molecular Trojan horses. , 2008, Bioconjugate chemistry.

[4]  N. Green Avidin. , 1975, Advances in protein chemistry.

[5]  H. Vinters,et al.  Enhanced neuroprotective effects of basic fibroblast growth factor in regional brain ischemia after conjugation to a blood-brain barrier delivery vector. , 2002, The Journal of pharmacology and experimental therapeutics.

[6]  W. Pardridge,et al.  Conjugation of brain-derived neurotrophic factor to a blood–brain barrier drug targeting system enables neuroprotection in regional brain ischemia following intravenous injection of the neurotrophin , 2001, Brain Research.

[7]  J. Murray-Rust,et al.  Distinct structural elements in GDNF mediate binding to GFRα1 and activation of the GFRα1–c‐Ret receptor complex , 1999 .

[8]  P. Lewczuk,et al.  Erythropoietin Therapy for Acute Stroke Is Both Safe and Beneficial , 2002, Molecular medicine.

[9]  Mark Stacy,et al.  Randomized controlled trial of intraputamenal glial cell line–derived neurotrophic factor infusion in Parkinson disease , 2006, Annals of neurology.

[10]  R. Sunahara,et al.  Human paraoxonases (PON1, PON2, and PON3) are lactonases with overlapping and distinct substrate specificitiess⃞s⃞ The online version of this article (available at http://www.jlr.org) contains additional text, figures, and references. Published, JLR Papers in Press, March 16, 2005. DOI 10.1194/jlr.M , 2005, Journal of Lipid Research.

[11]  I. Verma,et al.  Targeted delivery of proteins across the blood–brain barrier , 2007, Proceedings of the National Academy of Sciences.

[12]  J. Loike,et al.  Scavenger receptors in neurobiology and neuropathology: Their role on microglia and other cells of the nervous system , 2002, Glia.

[13]  W. Pardridge The blood-brain barrier: Bottleneck in brain drug development , 2005, NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics.

[14]  J. Jankovic,et al.  Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD , 2003, Neurology.

[15]  M. Radeke,et al.  Distribution of Intracerebral Ventricularly Administered Neurotrophins in Rat Brain and Its Correlation with Trk Receptor Expression , 1994, Experimental Neurology.

[16]  W. Pardridge,et al.  AGT-181: expression in CHO cells and pharmacokinetics, safety, and plasma iduronidase enzyme activity in Rhesus monkeys. , 2009, Journal of biotechnology.

[17]  T. Lieutaud,et al.  Characterization of the pharmacokinetics of human recombinant erythropoietin in blood and brain when administered immediately after lateral fluid percussion brain injury and its pharmacodynamic effects on IL-1beta and MIP-2 in rats. , 2008, Journal of neurotrauma.

[18]  C. P. Morris,et al.  Human alpha-L-iduronidase: cDNA isolation and expression. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[19]  J. Tolar,et al.  Targeting of the CNS in MPS-IH using a nonviral transferrin-alpha-L-iduronidase fusion gene product. , 2008, Molecular therapy : the journal of the American Society of Gene Therapy.

[20]  David J. Cummins,et al.  Peripheral anti-Aβ antibody alters CNS and plasma Aβ clearance and decreases brain Aβ burden in a mouse model of Alzheimer's disease , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[21]  G. Glenner,et al.  Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. , 1984, Biochemical and biophysical research communications.

[22]  W. Pardridge,et al.  Alzheimer's disease drug development and the problem of the blood-brain barrier , 2009, Alzheimer's & Dementia.

[23]  D. Eisenberg,et al.  alpha-L-iduronidase forms semi-crystalline spherulites with amyloid-like properties. , 2000, Acta crystallographica. Section D, Biological crystallography.

[24]  W. Pardridge,et al.  Selective transport of an anti-transferrin receptor antibody through the blood-brain barrier in vivo. , 1991, The Journal of pharmacology and experimental therapeutics.

[25]  J. Lile,et al.  GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. , 1993, Science.

[26]  P. Fitzpatrick,et al.  Lipoprotein Receptor Binding, Cellular Uptake, and Lysosomal Delivery of Fusions between the Receptor-associated Protein (RAP) and α-l-Iduronidase or Acid α-Glucosidase* , 2004, Journal of Biological Chemistry.

[27]  W. Pardridge,et al.  Blood-brain barrier transcytosis of insulin in developing rabbits , 1987, Brain Research.

[28]  Masako Wakitani,et al.  Enhanced Fc-dependent cellular cytotoxicity of Fc fusion proteins derived from TNF receptor II and LFA-3 by fucose removal from Asn-linked oligosaccharides. , 2006, Journal of biochemistry.

[29]  W. Pardridge,et al.  Engineering and expression of a chimeric transferrin receptor monoclonal antibody for blood–brain barrier delivery in the mouse , 2009, Biotechnology and bioengineering.

[30]  W. Pardridge,et al.  Genetic engineering of a lysosomal enzyme fusion protein for targeted delivery across the human blood‐brain barrier , 2008, Biotechnology and bioengineering.

[31]  W. Pardridge,et al.  Comparison of Blood-Brain Barrier Transport of Glial-Derived Neurotrophic Factor (GDNF) and an IgG-GDNF Fusion Protein in the Rhesus Monkey , 2009, Drug Metabolism and Disposition.

[32]  D. Holtzman,et al.  Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer's disease. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[33]  W. Pardridge,et al.  Imaging brain tumors by targeting peptide radiopharmaceuticals through the blood-brain barrier. , 1999, Cancer research.

[34]  A. Faden,et al.  Early neuronal expression of tumor necrosis factor-α after experimental brain injury contributes to neurological impairment , 1999, Journal of Neuroimmunology.

[35]  W. Pardridge Peptide drug delivery to the brain , 1991 .

[36]  W. Bradley A controlled trial of recombinant methionyl human BDNF in ALS , 1999, Neurology.

[37]  Stephen J. Victor,et al.  Fiblast (Trafermin) in Acute Stroke: Results of the European-Australian Phase II/III Safety and Efficacy Trial , 2002, Cerebrovascular Diseases.

[38]  B. Solomon,et al.  Disaggregation of Alzheimer β-amyloid by site-directed mAb , 1997 .

[39]  J. Murray-Rust,et al.  Distinct structural elements in GDNF mediate binding to GFRalpha1 and activation of the GFRalpha1-c-Ret receptor complex. , 1999, The EMBO journal.

[40]  W. Pardridge,et al.  Capillary Depletion Method for Quantification of Blood–Brain Barrier Transport of Circulating Peptides and Plasma Proteins , 1990, Journal of neurochemistry.

[41]  S. Rapoport Peptide Drug Delivery to the Brain , 1992, Neurology.

[42]  W. Pardridge,et al.  GDNF fusion protein for targeted‐drug delivery across the human blood–brain barrier , 2008, Biotechnology and bioengineering.

[43]  W. Pardridge,et al.  Imaging endogenous gene expression in brain cancer in vivo with 111In-peptide nucleic acid antisense radiopharmaceuticals and brain drug-targeting technology. , 2004, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[44]  J. Zivin Factors determining the therapeutic window for stroke , 1998, Neurology.

[45]  Robert L. Dufresne Brain Drug Targeting: The Future of Brain Drug Development , 2002 .

[46]  J. L. Smith,et al.  Crystal structure of core streptavidin determined from multiwavelength anomalous diffraction of synchrotron radiation. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[47]  Y. Itoyama,et al.  Reduction of ischemic brain injury by topical application of glial cell line-derived neurotrophic factor after permanent middle cerebral artery occlusion in rats. , 1998, Stroke.

[48]  D. Selkoe,et al.  LRP promotes endocytosis and degradation, but not transcytosis, of the amyloid-β peptide in a blood–brain barrier in vitro model , 2008, Neurobiology of Disease.

[49]  W. Pardridge,et al.  Palmitate and Cholesterol Transport Through the Blood‐Brain Barrier , 1980, Journal of neurochemistry.

[50]  W. Pardridge,et al.  Pharmacokinetics and Safety in Rhesus Monkeys of a Monoclonal Antibody-GDNF Fusion Protein for Targeted Blood-Brain Barrier Delivery , 2009, Pharmaceutical Research.

[51]  M. J. Coloma,et al.  Transport Across the Primate Blood-Brain Barrier of a Genetically Engineered Chimeric Monoclonal Antibody to the Human Insulin Receptor , 2000, Pharmaceutical Research.

[52]  B. Engelhardt,et al.  Targeting rat anti-mouse transferrin receptor monoclonal antibodies through blood-brain barrier in mouse. , 2000, The Journal of pharmacology and experimental therapeutics.

[53]  C. Masters,et al.  Amyloid plaque core protein in Alzheimer disease and Down syndrome. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[54]  W. Pardridge,et al.  Transport of [125I]transferrin through the rat blood-brain barrier , 1995, Brain Research.

[55]  R. Motter,et al.  Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease , 2000, Nature Medicine.

[56]  W. Pardridge,et al.  IgG-paraoxonase-1 fusion protein for targeted drug delivery across the human blood-brain barrier. , 2008, Molecular pharmaceutics.

[57]  W. Pardridge,et al.  Neuroprotection with noninvasive neurotrophin delivery to the brain. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[58]  Qing-hui Zhou,et al.  Pharmacokinetics and brain uptake of a genetically engineered bifunctional fusion antibody targeting the mouse transferrin receptor. , 2010, Molecular pharmaceutics.

[59]  H. Lee,et al.  Imaging Brain Amyloid of Alzheimer Disease in Vivo in Transgenic Mice with an Aβ Peptide Radiopharmaceutical , 2002, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[60]  M. Barinaga Neurotrophic factors enter the clinic. , 1994, Science.

[61]  R. Cecchelli,et al.  Low‐Density Lipoprotein Receptor on Endothelium of Brain Capillaries , 1989, Journal of neurochemistry.

[62]  Steven Warach,et al.  Early blood–brain barrier disruption in human focal brain ischemia , 2004, Annals of neurology.

[63]  W. Pardridge,et al.  Genetic engineering, expression, and activity of a chimeric monoclonal antibody-avidin fusion protein for receptor-mediated delivery of biotinylated drugs in humans. , 2008, Bioconjugate chemistry.

[64]  U. Bickel,et al.  In vivo demonstration of subcellular localization of anti-transferrin receptor monoclonal antibody-colloidal gold conjugate in brain capillary endothelium. , 1994, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[65]  Yi Ai,et al.  Point source concentration of GDNF may explain failure of phase II clinical trial , 2006, Experimental Neurology.

[66]  S. Jiao,et al.  Glial cell line-derived neurotrophic factor attenuates behavioural deficits and regulates nigrostriatal dopaminergic and peptidergic markers in 6-hydroxydopamine-lesioned adult rats: comparison of intraventricular and intranigral delivery , 1997, Neuroscience.

[67]  G. Bu,et al.  Efficient transfer of receptor-associated protein (RAP) across the blood-brain barrier , 2004, Journal of Cell Science.

[68]  H. Reiber,et al.  Protein transfer at the blood cerebrospinal fluid barrier and the quantitation of the humoral immune response within the central nervous system. , 1987, Clinica chimica acta; international journal of clinical chemistry.

[69]  B. Solomon,et al.  Disaggregation of Alzheimer beta-amyloid by site-directed mAb. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[70]  W. Pardridge,et al.  Central nervous system pharmacologic effect in conscious rats after intravenous injection of a biotinylated vasoactive intestinal peptide analog coupled to a blood-brain barrier drug delivery system. , 1996, The Journal of pharmacology and experimental therapeutics.

[71]  P. Janak,et al.  Glial Cell Line-Derived Neurotrophic Factor Mediates the Desirable Actions of the Anti-Addiction Drug Ibogaine against Alcohol Consumption , 2005, The Journal of Neuroscience.

[72]  W. Pardridge,et al.  Neuroprotection in Transient Focal Brain Ischemia After Delayed Intravenous Administration of Brain-Derived Neurotrophic Factor Conjugated to a Blood-Brain Barrier Drug Targeting System , 2001, Stroke.

[73]  W. Sly,et al.  Correction of murine mucopolysaccharidosis VII by a human beta-glucuronidase transgene. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[74]  W. Pardridge,et al.  Fusion antibody for Alzheimer's disease with bidirectional transport across the blood-brain barrier and abeta fibril disaggregation. , 2007, Bioconjugate chemistry.

[75]  P. Janak,et al.  GDNF and Addiction , 2005, Reviews in the neurosciences.

[76]  D. Scott,et al.  Activation of natural regulatory T cells by IgG Fc-derived peptide "Tregitopes". , 2008, Blood.

[77]  W. Pardridge,et al.  Tumor necrosis factor receptor-IgG fusion protein for targeted drug delivery across the human blood-brain barrier. , 2009, Molecular pharmaceutics.

[78]  R. Ridley,et al.  Continuous Low-Level Glial Cell Line-Derived Neurotrophic Factor Delivery Using Recombinant Adeno-Associated Viral Vectors Provides Neuroprotection and Induces Behavioral Recovery in a Primate Model of Parkinson's Disease , 2005, The Journal of Neuroscience.

[79]  S. Finklestein,et al.  Delayed Treatment with Intravenous Basic Fibroblast Growth Factor Reduces Infarct Size following Permanent Focal Cerebral Ischemia in Rats , 1995, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[80]  W. Pardridge,et al.  Humanization of anti‐human insulin receptor antibody for drug targeting across the human blood–brain barrier , 2007, Biotechnology and bioengineering.

[81]  W. Pardridge,et al.  Genetic engineering of IgG-glucuronidase fusion proteins , 2010, Journal of drug targeting.

[82]  P. Steeg,et al.  Uptake of ANG1005, A Novel Paclitaxel Derivative, Through the Blood-Brain Barrier into Brain and Experimental Brain Metastases of Breast Cancer , 2009, Pharmaceutical Research.