1,553
Views
45
CrossRef citations to date
0
Altmetric
Review

Re-engineering therapeutic antibodies for Alzheimer’s disease as blood-brain barrier penetrating bi-specific antibodies

Pages 1455-1468 | Received 25 Jun 2016, Accepted 25 Aug 2016, Published online: 07 Sep 2016

References

  • Han K, Ren M, Wick W, et al. Progression-free survival as a surrogate endpoint for overall survival in glioblastoma: a literature-based meta-analysis from 91 trials. Neuro Oncol. 2014 May;16(5):696–706. DOI:10.1093/neuonc/not236
  • Liu H-L, Hsu P-H, Lin C-Y, et al. Focused ultrasound enhances central nervous system delivery of bevacizumab for malignant glioma treatment. Radiology. 2016 May 18:152444. DOI:10.1148/radiol.2016152444
  • Cadavid D, Jurgensen S, Lee S. Impact of natalizumab on ambulatory improvement in secondary progressive and disabled relapsing-remitting multiple sclerosis. PLoS One. 2013;8(1):e53297. DOI:10.1371/journal.pone.0053297
  • Engelhardt B, Coisne C. Fluids and barriers of the CNS establish immune privilege by confining immune surveillance to a two-walled castle moat surrounding the CNS castle. Fluids Barriers CNS. 2011;8(1):4. DOI:10.1186/2045-8118-8-4
  • Pardridge WM. Targeted delivery of protein and gene medicines through the blood-brain barrier. Clin Pharmacol Ther. 2015 Apr;97(4):347–361. DOI:10.1002/cpt.18
  • Pardridge WM. Receptor-mediated peptide transport through the blood-brain barrier. Endocr Rev. 1986 Aug;7(3):314–330. DOI:10.1210/edrv-7-3-314
  • Pardridge WM, Buciak JL, Friden PM. Selective transport of an anti-transferrin receptor antibody through the blood-brain barrier in vivo. J Pharmacol Exp Ther. 1991 Oct;259(1):66–70.
  • Pardridge WM, Kang YS, Buciak JL, 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. Pharm Res. 1995 Jun;12(6):807–816.
  • Pardridge WM, Boado RJ. Reengineering biopharmaceuticals for targeted delivery across the blood-brain barrier. Methods Enzymol. 2012;503:269–292. DOI:10.1016/B978-0-12-396962-0.00011-2
  • Sengillo JD, Winkler EA, Walker CT, et al. Deficiency in mural vascular cells coincides with blood-brain barrier disruption in Alzheimer’s disease. Brain Pathol. 2013 May;23(3):303–310. DOI:10.1111/bpa.12004
  • Zhao Z, Nelson AR, Betsholtz C, et al. Establishment and dysfunction of the blood-brain barrier. Cell. 2015 Nov 19;163(5):1064–1078.
  • Ryu JK, McLarnon JG. A leaky blood-brain barrier, fibrinogen infiltration and microglial reactivity in inflamed Alzheimer’s disease brain. J Cell Mol Med. 2009 Sep;13(9A):2911–2925. DOI:10.1111/j.1582-4934.2008.00434.x
  • Hultman K, Strickland S, Norris EH. The APOE varepsilon4/varepsilon4 genotype potentiates vascular fibrin(ogen) deposition in amyloid-laden vessels in the brains of Alzheimer’s disease patients. J Cereb Blood Flow Metab. 2013 Aug;33(8):1251–1258. DOI:10.1038/jcbfm.2013.76
  • Halliday MR, Rege SV, Ma Q, et al. Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer’s disease. J Cereb Blood Flow Metab. 2016 Jan;36(1):216–227. DOI:10.1038/jcbfm.2015.44
  • Munoz DG, Erkinjuntti T, Gaytan-Garcia S, et al. Serum protein leakage in Alzheimer’s disease revisited. Ann N Y Acad Sci. 1997 Sep;26(826):173–189. DOI:10.1111/j.1749-6632.1997.tb48469.x
  • Harris NG, Gauden V, Fraser PA, et al. MRI measurement of blood-brain barrier permeability following spontaneous reperfusion in the starch microsphere model of ischemia. Magn Reson Imaging. 2002 Apr;20(3):221–230.
  • Montagne A, Barnes SR, Sweeney MD, et al. Blood-brain barrier breakdown in the aging human hippocampus. Neuron. 2015 Jan 21;85(2):296–302.
  • van de Haar HJ, Burgmans S, Jansen JF, et al. Blood-brain barrier leakage in patients with early Alzheimer disease. Radiology. 2016 May 31:152244. DOI:10.1148/radiol.2016152244
  • Schlageter NL, Carson RE, Rapoport SI. Examination of blood-brain barrier permeability in dementia of the Alzheimer type with [68Ga]EDTA and positron emission tomography. J Cereb Blood Flow Metab. 1987 Feb;7(1):1–8. DOI:10.1038/jcbfm.1987.1
  • Akoudad S, Wolters FJ, Viswanathan A, et al. Association of cerebral microbleeds with cognitive decline and dementia. JAMA Neurol. 2016 Aug 1;73(8):934–943.
  • Zlokovic BV. Cerebrovascular permeability to peptides: manipulations of transport systems at the blood-brain barrier. Pharm Res. 1995 Oct;12(10):1395–1406.
  • Frank HJ, Jankovic-Vokes T, Pardridge WM, et al. Enhanced insulin binding to blood-brain barrier in vivo and to brain microvessels in vitro in newborn rabbits. Diabetes. 1985 Aug;34(8):728–733.
  • Giddings SJ, Chirgwin J, Permutt MA. Evaluation of rat insulin messenger RNA in pancreatic and extrapancreatic tissues. Diabetologia. 1985 Jun;28(6):343–347.
  • Duffy KR, Pardridge WM. Blood-brain barrier transcytosis of insulin in developing rabbits. Brain Res. 1987 Sep 8;420(1):32–38.
  • Fishman JB, Rubin JB, Handrahan JV, et al. Receptor-mediated transcytosis of transferrin across the blood-brain barrier. J Neurosci Res. 1987;18(2):299–304. DOI:10.1002/jnr.490180206
  • Pardridge WM, Eisenberg J, Yang J. Human blood-brain barrier transferrin receptor. Metabolism. 1987 Sep;36(9):892–895.
  • Pardridge WM. Blood-brain barrier drug delivery of IgG fusion proteins with a transferrin receptor monoclonal antibody. Expert Opin Drug Deliv. 2015 Feb;12(2):207–222. DOI:10.1517/17425247.2014.952627
  • Lee HJ, Engelhardt B, Lesley J, et al. Targeting rat anti-mouse transferrin receptor monoclonal antibodies through blood-brain barrier in mouse. J Pharmacol Exp Ther. 2000 Mar;292(3):1048–1052.
  • Boado RJ, Zhang Y, Wang Y, et al. Engineering and expression of a chimeric transferrin receptor monoclonal antibody for blood-brain barrier delivery in the mouse. Biotechnol Bioeng. 2009Mar1;102(4):1251–1258. DOI:10.1002/bit.22135
  • Zhou Q-H, Boado RJ, Pardridge WM. Selective plasma pharmacokinetics and brain uptake in the mouse of enzyme fusion proteins derived from species-specific receptor-targeted antibodies. J Drug Target. 2012 Sep;20(8):715–719. DOI:10.3109/1061186X.2012.712132
  • Coloma MJ, Lee HJ, Kurihara A, et al. Transport across the primate blood-brain barrier of a genetically engineered chimeric monoclonal antibody to the human insulin receptor. Pharm Res. 2000 Mar;17(3):266–274.
  • Boado RJ, Zhang Y, Zhang Y, et al. Humanization of anti-human insulin receptor antibody for drug targeting across the human blood-brain barrier. Biotechnol Bioeng. 2007 Feb 1;96(2):381–391.
  • Ohtsuki S, Uchida Y, Kubo Y, et al. Quantitative targeted absolute proteomics-based ADME research as a new path to drug discovery and development: methodology, advantages, strategy, and prospects. J Pharm Sci. 2011 Sep;100(9):3547–3559. DOI:10.1002/jps.22612
  • Uchida Y, Ohtsuki S, Katsukura Y, et al. Quantitative targeted absolute proteomics of human blood-brain barrier transporters and receptors. J Neurochem. 2011 Apr;117(2):333–345. DOI:10.1111/j.1471-4159.2011.07208.x
  • Agarwal S, Uchida Y, Mittapalli RK, et al. Quantitative proteomics of transporter expression in brain capillary endothelial cells isolated from P-glycoprotein (P-gp), breast cancer resistance protein (Bcrp), and P-gp/Bcrp knockout mice. Drug Metab Dispos. 2012 Jun;40(6):1164–1169. DOI:10.1124/dmd.112.044719
  • Hoshi Y, Uchida Y, Tachikawa M, et al. Quantitative atlas of blood-brain barrier transporters, receptors, and tight junction proteins in rats and common marmoset. J Pharm Sci. 2013 Sep;102(9):3343–3355. DOI:10.1002/jps.23575
  • Triguero D, Buciak J, Pardridge WM. Capillary depletion method for quantification of blood-brain barrier transport of circulating peptides and plasma proteins. J Neurochem. 1990 Jun;54(6):1882–1888.
  • Greaves DR, Gordon S. The macrophage scavenger receptor at 30 years of age: current knowledge and future challenges. J Lipid Res. 2009 Apr;50(Suppl):S282–S286. DOI:10.1194/jlr.R800066-JLR200
  • Zlokovic BV. Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nat Rev Neurosci. 2011 Dec;12(12):723–738. DOI:10.1038/nrn3114
  • Tian X, Nyberg SPSS, Madsen J, et al. LRP-1-mediated intracellular antibody delivery to the central nervous system. Sci Rep. 2015;5:11990. DOI:10.1038/srep11990
  • Storck SE, Meister S, Nahrath J, et al. Endothelial LRP1 transports amyloid-beta(1-42) across the blood-brain barrier. J Clin Invest. 2016 Jan;126(1):123–136. DOI:10.1172/JCI81108
  • Demeule M, Currie JC, Bertrand Y, et al. Involvement of the low-density lipoprotein receptor-related protein in the transcytosis of the brain delivery vector angiopep-2. J Neurochem. 2008 Aug;106(4):1534–1544. DOI:10.1111/j.1471-4159.2008.05492.x
  • Pardridge WM. Drug transport across the blood-brain barrier. J Cereb Blood Flow Metab. 2012 Nov;32(11):1959–1972. DOI:10.1038/jcbfm.2012.126
  • Nazer B, Hong S, Selkoe DJ. LRP promotes endocytosis and degradation, but not transcytosis, of the amyloid-beta peptide in a blood-brain barrier in vitro model. Neurobiol Dis. 2008 Apr;30(1):94–102. DOI:10.1016/j.nbd.2007.12.005
  • Muruganandam A, Tanha J, Narang S, et al. Selection of phage-displayed llama single-domain antibodies that transmigrate across human blood-brain barrier endothelium. FASEB J. 2002 Feb;16(2):240–242. DOI:10.1096/fj.01-0343fje
  • Farrington GK, Caram-Salas N, Haqqani AS, et al. A novel platform for engineering blood-brain barrier-crossing bispecific biologics. FASEB J. 2014 Nov;28(11):4764–4778. DOI:10.1096/fj.14-253369
  • Webster CI, Caram-Salas N, Haqqani AS, et al. Brain penetration, target engagement, and disposition of the blood-brain barrier-crossing bispecific antibody antagonist of metabotropic glutamate receptor type 1. FASEB J. 2016 May;30(5):1927–1940. DOI:10.1096/fj.201500078
  • Haqqani AS, Caram-Salas N, Ding W, et al. Multiplexed evaluation of serum and CSF pharmacokinetics of brain-targeting single-domain antibodies using a NanoLC-SRM-ILIS method. Mol Pharm. 2013 May 6;10(5):1542–1556.
  • van der Mark VA, deWaart DR, Ho-Mok KS, et al. The lipid flippase heterodimer ATP8B1-CDC50A is essential for surface expression of the apical sodium-dependent bile acid transporter (SLC10A2/ASBT) in intestinal Caco-2 cells. Biochim Biophys Acta. 2014;1842:2378–2386. DOI:10.1016/j.bbadis.2014.09.003
  • Pardridge WM. Blood-brain barrier endogenous transporters as therapeutic targets: a new model for small molecule CNS drug discovery. Expert Opin Ther Targets. 2015;19(8):1059–1072. DOI:10.1517/14728222.2015.1042364
  • Boado RJ, Li JY, Nagaya M, et al. Selective expression of the large neutral amino acid transporter at the blood-brain barrier. Proc Natl Acad Sci. 1999;96:12079–12084.
  • Zuchero YJ, Chen X, Bien-Ly N, et al. Discovery of novel blood-brain barrier targets to enhance brain uptake of therapeutic antibodies. Neuron. 2016 Jan 6;89(1):70–82.
  • Fort J, Dela Ballina LR, Burghardt HE, et al. The structure of human 4F2hc ectodomain provides a model for homodimerization and electrostatic interaction with plasma membrane. J Biol Chem. 2007;282:31444–31452. DOI:10.1074/jbc.M704524200
  • Thomas FC, Taskar K, Rudraraju V, et al. Uptake of ANG1005, a novel paclitaxel derivative, through the blood-brain barrier into brain and experimental brain metastases of breast cancer. Pharm Res. 2009 Nov;26(11):2486–2494. DOI:10.1007/s11095-009-9964-5
  • Karkan D, Pfeifer C, Vitalis TZ, et al. A unique carrier for delivery of therapeutic compounds beyond the blood-brain barrier. PLoS One. 2008;3(6):e2469. DOI:10.1371/journal.pone.0002469
  • Deng D, Xu C, Sun P, et al. Crystal structure of the human glucose transporter GLUT1. Nature. 2014 Jun 5;510(7503):121–125.
  • Winkler EA, Nishida Y, Sagare AP, et al. GLUT1 reductions exacerbate Alzheimer’s disease vasculo-neuronal dysfunction and degeneration. Nat Neurosci. 2015 Apr;18(4):521–530. DOI:10.1038/nn.3966
  • Kubo Y, Ohtsuki S, Uchida Y, et al. Quantitative determination of luminal and abluminal membrane distributions of transporters in porcine brain capillaries by plasma membrane fractionation and quantitative targeted proteomics. J Pharm Sci. 2015 Sep;104(9):3060–3068. DOI:10.1002/jps.24398
  • Pardridge WM, Golden PL, Kang YS, et al. Brain microvascular and astrocyte localization of P-glycoprotein. J Neurochem. 1997 Mar;68(3):1278–1285.
  • Wang J-Z, Xiao N, Zhang Y-Z, et al. Mfsd2a-based pharmacological strategies for drug delivery across the blood-brain barrier. Pharmacol Res. 2016 Feb;104:124–131. DOI:10.1016/j.phrs.2015.12.024
  • Cornford EM, Braun LD, Oldendorf WH. Developmental modulations of blood-brain barrier permeability as an indicator of changing nutritional requirements in the brain. Pediatr Res. 1982 Apr;16(4 Pt 1):324–328.
  • Atwal JK, Chen Y, Chiu C, et al. A therapeutic antibody targeting BACE1 inhibits amyloid-beta production in vivo. Sci Transl Med. 2011 May 25;3(84):84ra43.
  • Bohrmann B, Baumann K, Benz J, et al. Gantenerumab: a novel human anti-Abeta antibody demonstrates sustained cerebral amyloid-beta binding and elicits cell-mediated removal of human amyloid-beta. J Alzheimers Dis. 2012;28(1):49–69. DOI:10.3233/JAD-2011-110977
  • Pardridge WM. CSF, blood-brain barrier, and brain drug delivery. Expert Opin Drug Deliv. 2016 Jul;13(7):963–975. DOI:10.1517/17425247.2016.1171315
  • Reiber H. Proteins in cerebrospinal fluid and blood: barriers, CSF flow rate and source-related dynamics. Restor Neurol Neurosci. 2003;21(3–4):79–96.
  • Urich E, Lazic SE, Molnos J, et al. Transcriptional profiling of human brain endothelial cells reveals key properties crucial for predictive in vitro blood-brain barrier models. PLoS One. 2012;7(5):e38149. DOI:10.1371/journal.pone.0038149
  • Pardridge WM, Triguero D, Yang J, et al. Comparison of in vitro and in vivo models of drug transcytosis through the blood-brain barrier. J Pharmacol Exp Ther. 1990 May;253(2):884–891.
  • Panza F, Solfrizzi V, Imbimbo BP, et al. Amyloid-directed monoclonal antibodies for the treatment of Alzheimer’s disease: the point of no return? Expert Opin Biol Ther. 2014 Oct;14(10):1465–1476. DOI:10.1517/14712598.2014.935332
  • Seubert P, Barbour R, Khan K, et al. Antibody capture of soluble Abeta does not reduce cortical Abeta amyloidosis in the PDAPP mouse. Neurodegener Dis. 2008;5(2):65–71. DOI:10.1159/000112834
  • Bard F, Fox M, Friedrich S, et al. Sustained levels of antibodies against Aβ in amyloid-rich regions of the CNS following intravenous dosing in human APP transgenic mice. Exp Neurol. 2012;238:38–43. DOI:10.1016/j.expneurol.2012.07.022
  • Boado RJ, Zhou QH, Lu JZ, et al. Pharmacokinetics and brain uptake of a genetically engineered bifunctional fusion antibody targeting the mouse transferrin receptor. Mol Pharm. 2010 Feb 1;7(1):237–244.
  • Greenblatt DJ, Sethy VH. Benzodiazepine concentrations in brain directly reflect receptor occupancy: studies of diazepam, lorazepam, and oxazepam. Psychopharmacology (Berl). 1990;102(3):373–378.
  • Sumbria RK, Zhou Q-H, Hui EK-W, et al. Pharmacokinetics and brain uptake of an IgG-TNF decoy receptor fusion protein following intravenous, intraperitoneal, and subcutaneous administration in mice. Mol Pharm. 2013;10:1425–1431. DOI:10.1021/mp400004a
  • Marvin JS, Zhu Z. Recombinant approaches to IgG-like bispecific antibodies. Acta Pharmacol Sin. 2005 Jun;26(6):649–658. DOI:10.1111/j.1745-7254.2005.00119.x
  • Yu YJ, Zhang Y, Kenrick M, et al. Boosting brain uptake of a therapeutic antibody by reducing its affinity for a transcytosis target. Sci Transl Med. 2011 May 25;3(84):84ra44.
  • Niewoehner J, Bohrmann B, Collin L, et al. Increased brain penetration and potency of a therapeutic antibody using a monovalent molecular shuttle. Neuron. 2014 Jan 8;81(1):49–60. DOI:10.1016/j.neuron.2013.10.061
  • Wu C, Ying H, Grinnell C, et al. Simultaneous targeting of multiple disease mediators by a dual-variable-domain immunoglobulin. Nat Biotechnol. 2007 Nov;25(11):1290–1297. DOI:10.1038/nbt1345
  • Boado RJ, Zhang Y, Zhang Y, et al. Fusion antibody for Alzheimer’s disease with bidirectional transport across the blood-brain barrier and abeta fibril disaggregation. Bioconjug Chem. 2007 Mar-Apr;18(2):447–455. DOI:10.1021/bc060349x
  • Coloma MJ, Morrison SL. Design and production of novel tetravalent bispecific antibodies. Nat Biotechnol. 1997;15(2):159–163. DOI:10.1038/nbt0297-159
  • Zhang Y, Pardridge WM. Mediated efflux of IgG molecules from brain to blood across the blood-brain barrier. J Neuroimmunol. 2001 Mar 1;114(1–2):168–172.
  • Zhang Y, Pardridge WM. Rapid transferrin efflux from brain to blood across the blood-brain barrier. J Neurochem. 2001 Mar;76(5):1597–1600.
  • Cserr HF, Cooper DN, Suri PK, et al. Efflux of radiolabeled polyethylene glycols and albumin from rat brain. Am J Physiol. 1981 Apr;240(4):F319–F328.
  • Schlachetzki F, Zhu C, Pardridge WM. Expression of the neonatal Fc receptor (FcRn) at the blood-brain barrier. J Neurochem. 2002 Apr;81(1):203–206.
  • De Groot AS, Moise L, McMurry JA, et al. Activation of natural regulatory T cells by IgG Fc-derived peptide “Tregitopes”. Blood. 2008 Oct 15;112(8):3303–3311.
  • Sumbria RK, Hui EK, Lu JZ, et al. Disaggregation of amyloid plaque in brain of Alzheimer’s disease transgenic mice with daily subcutaneous administration of a tetravalent bispecific antibody that targets the transferrin receptor and the Abeta amyloid peptide. Mol Pharm. 2013Sep3;10(9):3507–3513. DOI:10.1021/mp400348n
  • Boado RJ, Lu JZ, Hui EK-W, et al. IgG-single chain Fv fusion protein therapeutic for Alzheimer’s disease: expression in CHO cells and pharmacokinetics and brain delivery in the Rhesus monkey. Biotechnol Bioeng. 2010;105:627–635. DOI:10.1002/bit.22576
  • Zhou QH, Boado RJ, Hui EK, et al. Chronic dosing of mice with a transferrin receptor monoclonal antibody-glial-derived neurotrophic factor fusion protein. Drug Metab Dispos. 2011 Jul;39(7):1149–1154. DOI:10.1124/dmd.111.038349
  • Yu YJ, Atwal JK, Zhang Y, et al. Therapeutic bispecific antibodies cross the blood-brain barrier in nonhuman primates. Sci Transl Med. 2014 Nov 5;6(261):261ra154. DOI:10.1126/scitranslmed.3009835
  • Walus LR, Pardridge WM, Starzyk RM, et al. Enhanced uptake of rsCD4 across the rodent and primate blood-brain barrier after conjugation to anti-transferrin receptor antibodies. J Pharmacol Exp Ther. 1996 May;277(2):1067–1075.
  • Cucchiaroni ML, Viscomi MT, Bernardi G, et al. Metabotropic glutamate receptor 1 mediates the electrophysiological and toxic actions of the cycad derivative beta-N-Methylamino-L-alanine on substantia nigra pars compacta DAergic neurons. J Neurosci. 2010 Apr 14;30(15):5176–5188.
  • El-Kouhen O, Lehto SG, Pan JB, et al. Blockade of mGluR1 receptor results in analgesia and disruption of motor and cognitive performances: effects of A-841720, a novel non-competitive mGluR1 receptor antagonist. Br J Pharmacol. 2006 Nov;149(6):761–774. DOI:10.1038/sj.bjp.0706877
  • Sehlin D, Fang XT, Cato L, et al. Antibody-based PET imaging of amyloid beta in mouse models of Alzheimer’s disease. Nat Commun. 2016;7:10759. DOI:10.1038/ncomms10759
  • Wong DF, Rosenberg PB, Zhou Y, et al. In vivo imaging of amyloid deposition in Alzheimer disease using the radioligand 18F-AV-45 (florbetapir [corrected] F 18). J Nucl Med. 2010 Jun;51(6):913–920. DOI:10.2967/jnumed.109.069088
  • Bedse G, Di Domenico F, Serviddio G, et al. Aberrant insulin signaling in Alzheimer’s disease: current knowledge. Front Neurosci. 2015;9:204. DOI:10.3389/fnins.2015.00204
  • Morris CM, Candy JM, Kerwin JM, et al. Transferrin receptors in the normal human hippocampus and in Alzheimer’s disease. Neuropathol Appl Neurobiol. 1994 Oct;20(5):473–477.
  • Black RS, Sperling RA, Safirstein B, et al. A single ascending dose study of bapineuzumab in patients with Alzheimer disease. Alzheimer Dis Assoc Disord. 2010 Apr-Jun;24(2):198–203. DOI:10.1097/WAD.0b013e3181c53b00
  • Segaert S. Etanercept, improved dosage schedules and combinations in the treatment of psoriasis: an update. J Inflamm Res. 2009;2:29–36.
  • Pepinsky RB, Silvian L, Berkowitz SA, et al. Improving the solubility of anti-LINGO-1 monoclonal antibody Li33 by isotype switching and targeted mutagenesis. Protein Sci. 2010 May;19(5):954–966. DOI:10.1002/pro.372
  • Lawand NB, Saade NE, El-Agnaf OM, et al. Targeting alpha-synuclein as a therapeutic strategy for Parkinson’s disease. Expert Opin Ther Targets. 2015;19(10):1351–1360. DOI:10.1517/14728222.2015.1062877
  • Marques AR, Teixeira E, Diamond J, et al. Detection of human mammaglobin mRNA in serial peripheral blood samples from patients with non-metastatic breast cancer is not predictive of disease recurrence. Breast Cancer Res Treat. 2009 Mar;114(2):223–232. DOI:10.1007/s10549-008-0002-9
  • Kinoshita M, McDannold N, Jolesz FA, et al. Noninvasive localized delivery of Herceptin to the mouse brain by MRI-guided focused ultrasound-induced blood-brain barrier disruption. Proc Natl Acad Sci U S A. 2006 Aug 1;103(31):11719–11723.
  • Ben-Nathan D, Huitinga I, Lustig S, et al. West Nile virus neuroinvasion and encephalitis induced by macrophage depletion in mice. Arch Virol. 1996;141(3–4):459–469.
  • Oliphant T, Engle M, Nybakken GE, et al. Development of a humanized monoclonal antibody with therapeutic potential against West Nile virus. Nat Med. 2005 May;11(5):522–530. DOI:10.1038/nm1240

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.