Drugs & Aging

, Volume 33, Issue 10, pp 685–697 | Cite as

Antibody-Based Drugs and Approaches Against Amyloid-β Species for Alzheimer’s Disease Immunotherapy

  • Jing Liu
  • Bin Yang
  • Jun Ke
  • Wenjia Li
  • Wen-Chen Suen
Review Article


Alzheimer’s disease (AD), one of the most devastating diseases for the older population, has become a major healthcare burden in the increasingly aging society worldwide. Currently, there are still only symptomatic treatments available on the market, just to slow down disease progression. In the past decades, extensive research focusing on the development of immunotherapy using monoclonal antibodies (mAbs) as potential “disease-modifying drugs” has shown promise in inhibiting or clearing the formation of toxic amyloid-β (Aβ) species, the suspected causative agents of AD. As a result, these potential life-saving drugs can break the amyloid cascade, cease neurodegeneration, and prevent further reduction in cognitive and physical function. In this review, we first describe the polymorphisms of Aβ species, comprising three different pools, including monomers, soluble oligomers, and insoluble fibrils, with each pool encompassing multiple structures of Aβ aggregation. A comprehensive review on their toxicities follows in relation to the characterized epitopes of anti-Aβ mAb candidates under development. We then present the outcomes of these mAbs in clinical or pre-clinical trials and conclude by providing a summary of other novel and promising antibody-based immunotherapeutic approaches that deserve more attention for the effective treatment of AD in the future.


Tg2576 Mouse Amyloid Plaque Cerebral Amyloid Angiopathy Vasogenic Edema 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Compliance with Ethical Standards


This work was funded by the Guangdong province special plan for introducing innovative R&D teams (201101Y0104990178, China).

Conflict of interest

All authors (Jing Liu, Bin Yang, Jun Ke, Wenjia Li, and Wen-Chen Suen) are employees of Sunshine Lake Pharma Co. which has an interest in the development of therapeutic agents for Alzheimer’s disease and concur with this submission.


  1. 1.
    Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi HM. Forecasting the global burden of Alzheimer’s disease. Alzheimer’s Dement J Alzheimer’s Assoc. 2007;3:186–91.CrossRefGoogle Scholar
  2. 2.
    Alzheimer’s disease—global drug forecast and market analysis to 2023. GlobalData PharmaPoint. Reference code: GDHC010EPIDR. Publication data: May 2015.Google Scholar
  3. 3.
    Geldmacher DS. Treatment guidelines for Alzheimer’s disease: redefining perceptions in primary care. Prim Care Companion J Clin Psychiatry. 2007;9:113–21.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Pozueta J, Lefort R, Shelanski ML. Synaptic changes in Alzheimer’s disease and its models. Neuroscience. 2013;251:51–65.PubMedCrossRefGoogle Scholar
  5. 5.
    Hane F, Tran G, Attwood SJ, Leonenko Z. Cu(2+) affects amyloid-beta (1–42) aggregation by increasing peptide-peptide binding forces. PLoS One. 2013;8:e59005.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Fu HJ, Liu B, Frost JL, Lemere CA. Amyloid-beta immunotherapy for Alzheimer’s disease. CNS Neurol Disord Drug Targets. 2010;9:197–206.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO. Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med. 2003;9:448–52.PubMedCrossRefGoogle Scholar
  8. 8.
    Kayed R, Lasagna-Reeves CA. Molecular mechanisms of amyloid oligomers toxicity. J Alzheimer’s Dis. 2013;33(Suppl 1):S67–78.Google Scholar
  9. 9.
    Goure WF, Krafft GA, Jerecic J, Hefti F. Targeting the proper amyloid-beta neuronal toxins: a path forward for Alzheimer’s disease immunotherapeutics. Alzheimers Res Ther. 2014;6:42.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Cole SL, Vassar R. The Alzheimer’s disease beta-secretase enzyme, BACE1. Mol Neurodegener. 2007;2:22.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Hamley IW. The amyloid beta peptide: a chemist’s perspective. Role in Alzheimer’s and fibrillization. Chem Rev. 2012;112:5147–92.PubMedCrossRefGoogle Scholar
  12. 12.
    Dong X, Chen W, Mousseau N, Derreumaux P. Energy landscapes of the monomer and dimer of the Alzheimer’s peptide Abeta(1–28). J Chem Phys. 2008;128:125108.PubMedCrossRefGoogle Scholar
  13. 13.
    Burdick D, Soreghan B, Kwon M, Kosmoski J, Knauer M, Henschen A, et al. Assembly and aggregation properties of synthetic Alzheimer’s A4/beta amyloid peptide analogs. J Biol Chem. 1992;267:546–54.PubMedGoogle Scholar
  14. 14.
    Jang S, Shin S. Computational study on the structural diversity of amyloid beta peptide (abeta(10–35)) oligomers. J Phys Chem B. 2008;112:3479–84.PubMedCrossRefGoogle Scholar
  15. 15.
    Miller Y, Ma B, Nussinov R. Polymorphism of Alzheimer’s Abeta17–42 (p3) oligomers: the importance of the turn location and its conformation. Biophys J. 2009;97:1168–77.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Tjernberg LO, Callaway DJ, Tjernberg A, Hahne S, Lilliehook C, Terenius L, et al. A molecular model of Alzheimer amyloid beta-peptide fibril formation. J Biol Chem. 1999;274:12619–25.PubMedCrossRefGoogle Scholar
  17. 17.
    Miller Y, Ma B, Nussinov R. Polymorphism in Alzheimer Abeta amyloid organization reflects conformational selection in a rugged energy landscape. Chem Rev. 2010;110:4820–38.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, et al. Diffusible, nonfibrillar ligands derived from Abeta1–42 are potent central nervous system neurotoxins. Proc Natl Acad Sci. 1998;95:6448–53.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Zhang Y, Lyubchenko YL. The structure of misfolded amyloidogenic dimers: computational analysis of force spectroscopy data. Biophys J. 2014;107:2903–10.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Spencer RK, Li H, Nowick JS. X-ray crystallographic structures of trimers and higher-order oligomeric assemblies of a peptide derived from Abeta(17–36). J Am Chem Soc. 2014;136:5595–8.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Du J, Murphy RM. Characterization of the interaction of beta-amyloid with transthyretin monomers and tetramers. Biochemistry. 2010;49:8276–89.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Barrera Guisasola EE, Gutierrez LJ, Andujar SA, Angelina E, Rodriguez AM, Enriz RD. Pentameric models as alternative molecular targets for the design of new antiaggregant agents. Curr Protein Pept Sci. 2016;17:156–68.PubMedCrossRefGoogle Scholar
  23. 23.
    Tran L, Basdevant N, Prevost C, Ha-Duong T. Structure of ring-shaped Abeta42 oligomers determined by conformational selection. Sci Rep. 2016;6:21429.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Strodel B, Lee JW, Whittleston CS, Wales DJ. Transmembrane structures for Alzheimer’s Abeta(1–42) oligomers. J Am Chem Soc. 2010;132:13300–12.PubMedCrossRefGoogle Scholar
  25. 25.
    Gessel MM, Wu C, Li H, Bitan G, Shea JE, Bowers MT. Abeta(39–42) modulates Abeta oligomerization but not fibril formation. Biochemistry. 2012;51:108–17.PubMedCrossRefGoogle Scholar
  26. 26.
    Sherman MA, Lesne SE. Detecting abeta*56 oligomers in brain tissues. Methods Mol Biol. 2011;670:45–56.PubMedCrossRefGoogle Scholar
  27. 27.
    Barghorn S, Nimmrich V, Striebinger A, Krantz C, Keller P, Janson B, et al. Globular amyloid beta-peptide oligomer—a homogenous and stable neuropathological protein in Alzheimer’s disease. J Neurochem. 2005;95:834–47.PubMedCrossRefGoogle Scholar
  28. 28.
    Hepler RW, Grimm KM, Nahas DD, Breese R, Dodson EC, Acton P, et al. Solution state characterization of amyloid beta-derived diffusible ligands. Biochemistry. 2006;45:15157–67.PubMedCrossRefGoogle Scholar
  29. 29.
    Caughey B, Lansbury PT. Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annu Rev Neurosci. 2003;26:267–98.PubMedCrossRefGoogle Scholar
  30. 30.
    Hoshi M, Sato M, Matsumoto S, Noguchi A, Yasutake K, Yoshida N, et al. Spherical aggregates of beta-amyloid (amylospheroid) show high neurotoxicity and activate tau protein kinase I/glycogen synthase kinase-3beta. Proc Natl Acad Sci. 2003;100:6370–5.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Walsh DM, Hartley DM, Kusumoto Y, Fezoui Y, Condron MM, Lomakin A, et al. Amyloid beta-protein fibrillogenesis. Structure and biological activity of protofibrillar intermediates. J Biol Chem. 1999;274:25945–52.PubMedCrossRefGoogle Scholar
  32. 32.
    Meyer-Luehmann M, Spires-Jones TL, Prada C, Garcia-Alloza M, de Calignon A, Rozkalne A, et al. Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer’s disease. Nature. 2008;451:720–4.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Tu S, Okamoto S, Lipton SA, Xu H. Oligomeric Abeta-induced synaptic dysfunction in Alzheimer’s disease. Mol Neurodegener. 2014;9:48.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Klyubin I, Betts V, Welzel AT, Blennow K, Zetterberg H, Wallin A, et al. Amyloid beta protein dimer-containing human CSF disrupts synaptic plasticity: prevention by systemic passive immunization. J Neurosci. 2008;28:4231–7.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Martins IC, Kuperstein I, Wilkinson H, Maes E, Vanbrabant M, Jonckheere W, et al. Lipids revert inert Abeta amyloid fibrils to neurotoxic protofibrils that affect learning in mice. EMBO J. 2008;27:224–33.PubMedCrossRefGoogle Scholar
  36. 36.
    Lacor PN, Buniel MC, Furlow PW, Clemente AS, Velasco PT, Wood M, et al. Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer’s disease. J Neurosci. 2007;27:796–807.PubMedCrossRefGoogle Scholar
  37. 37.
    Lashuel HA, Hartley D, Petre BM, Walz T, Lansbury PT Jr. Neurodegenerative disease: amyloid pores from pathogenic mutations. Nature. 2002;418:291.PubMedCrossRefGoogle Scholar
  38. 38.
    Ono K, Condron MM, Teplow DB. Structure-neurotoxicity relationships of amyloid beta-protein oligomers. Proc Natl Acad Sci. 2009;106:14745–50.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Morozova OA, Gupta S, Colby DW. Prefibrillar huntingtin oligomers isolated from HD brain potently seed amyloid formation. FEBS Lett. 2015;589:1897–903.PubMedCrossRefGoogle Scholar
  40. 40.
    Walker LC, Jucker M. Neurodegenerative diseases: expanding the prion concept. Annu Rev Neurosci. 2015;38:87–103.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Lee HG, Zhu X, Castellani RJ, Nunomura A, Perry G, Smith MA. Amyloid-beta in Alzheimer disease: the null versus the alternate hypotheses. J Pharmacol Exp Ther. 2007;321:823–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Mandrekar-Colucci S, Landreth GE. Microglia and inflammation in Alzheimer’s disease. CNS Neurol Disord Drug Targets. 2010;9:156–67.PubMedCrossRefGoogle Scholar
  43. 43.
    Spangenberg EE, Green KN. Inflammation in Alzheimer’s disease: lessons learned from microglia-depletion models. Brain Behav Immun. 2016. doi: 10.1016/j.bbi.2016.07.003.PubMedGoogle Scholar
  44. 44.
    Kuperstein I, Broersen K, Benilova I, Rozenski J, Jonckheere W, Debulpaep M, et al. Neurotoxicity of Alzheimer’s disease Abeta peptides is induced by small changes in the Abeta42 to Abeta40 ratio. EMBO J. 2010;29:3408–20.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Morrone CD, Liu M, Black SE, McLaurin J. Interaction between therapeutic interventions for Alzheimer’s disease and physiological Abeta clearance mechanisms. Front Aging Neurosci. 2015;7:64.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Paul S, Planque S, Nishiyama Y. Beneficial catalytic immunity to abeta peptide. Rejuvenation Res. 2010;13:179–87.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Lichtlen P, Mohajeri MH. Antibody-based approaches in Alzheimer’s research: safety, pharmacokinetics, metabolism, and analytical tools. J Neurochem. 2008;104:859–74.PubMedCrossRefGoogle Scholar
  48. 48.
    Robert R, Lefranc MP, Ghochikyan A, Agadjanyan MG, Cribbs DH, Van Nostrand WE, et al. Restricted V gene usage and VH/VL pairing of mouse humoral response against the N-terminal immunodominant epitope of the amyloid beta peptide. Mol Immunol. 2010;48:59–72.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Solomon B, Koppel R, Frankel D, Hanan-Aharon E. Disaggregation of Alzheimer beta-amyloid by site-directed mAb. Proc Natl Acad Sci. 1997;94:4109–12.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Bard F, Cannon C, Barbour R, Burke RL, Games D, Grajeda H, et al. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med. 2000;6:916–9.PubMedCrossRefGoogle Scholar
  51. 51.
    Sil S, Ghosh A, Ghosh T. Impairment of blood brain barrier is related with the neuroinflammation induced peripheral immune status in intracerebroventricular colchicine injected rats: an experimental study with mannitol. Brain Res. 2016;1646:278–86.PubMedCrossRefGoogle Scholar
  52. 52.
    Kerchner GA, Boxer AL. Bapineuzumab. Expert Opin Biol Ther. 2010;10:1121–30.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Racke MM, Boone LI, Hepburn DL, Parsadainian M, Bryan MT, Ness DK, et al. Exacerbation of cerebral amyloid angiopathy-associated microhemorrhage in amyloid precursor protein transgenic mice by immunotherapy is dependent on antibody recognition of deposited forms of amyloid beta. J Neurosci. 2005;25:629–36.PubMedCrossRefGoogle Scholar
  54. 54.
    DiFrancesco JC, Longoni M, Piazza F. Anti-Abeta autoantibodies in amyloid related imaging abnormalities (ARIA): candidate biomarker for immunotherapy in Alzheimer’s disease and cerebral amyloid angiopathy. Front Neurol. 2015;6:207.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Miles LA, Crespi GA, Doughty L, Parker MW. Bapineuzumab captures the N-terminus of the Alzheimer’s disease amyloid-beta peptide in a helical conformation. Sci Rep. 2013;3:1302.PubMedPubMedCentralGoogle Scholar
  56. 56. A service of the U.S. National Institutes of Health. Accessed 09 Sep 2016.
  57. 57.
    Bagyinszky E, Youn YC, An SS, Kim S. The genetics of Alzheimer’s disease. Clin Interv Aging. 2014;9:535–51.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Wildsmith KR, Holley M, Savage JC, Skerrett R, Landreth GE. Evidence for impaired amyloid beta clearance in Alzheimer’s disease. Alzheimers Res Ther. 2013;5:33.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Vandenberghe R, Rinne JO, Boada M, Katayama S, Scheltens P, Vellas B, et al. Bapineuzumab for mild to moderate Alzheimer’s disease in two global, randomized, phase 3 trials. Alzheimers Res Ther. 2016;8:18.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Wisniewski T, Goni F. Immunotherapeutic approaches for Alzheimer’s disease. Neuron. 2015;85:1162–76.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Delnomdedieu M, Duvvuri S, Li DJ, Atassi N, Lu M, Brashear HR, et al. First-In-Human safety and long-term exposure data for AAB-003 (PF-05236812) and biomarkers after intravenous infusions of escalating doses in patients with mild to moderate Alzheimer’s disease. Alzheimers Res Ther. 2016;8:12.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Moreth J, Mavoungou C, Schindowski K. Passive anti-amyloid immunotherapy in Alzheimer’s disease: what are the most promising targets? Immun Ageing. 2013;10:18.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Leyhe T, Andreasen N, Simeoni M, Reich A, von Arnim CA, Tong X, et al. Modulation of beta-amyloid by a single dose of GSK933776 in patients with mild Alzheimer’s disease: a phase I study. Alzheimers Res Ther. 2014;6:19.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Volz C, Pauly D. Antibody therapies and their challenges in the treatment of age-related macular degeneration. Eur J Pharm Biopharm. 2015;95:158–72.PubMedCrossRefGoogle Scholar
  65. 65.
    DeMattos RB, Bales KR, Cummins DJ, Dodart JC, Paul SM, Holtzman DM. 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. Proc Natl Acad Sci. 2001;98:8850–5.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Karran E, Hardy J. A critique of the drug discovery and phase 3 clinical programs targeting the amyloid hypothesis for Alzheimer disease. Ann Neurol. 2014;76:185–205.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Lundkvist J, Halldin MM, Sandin J, Nordvall G, Forsell P, Svensson S, et al. The battle of Alzheimer’s Disease—the beginning of the future unleashing the potential of academic discoveries. Front Pharmacol. 2014;5:102.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med. 2014;370:311–21.PubMedCrossRefGoogle Scholar
  69. 69.
    Siemers ER, Sundell KL, Carlson C, Case M, Sethuraman G, Liu-Seifert H, et al. Phase 3 solanezumab trials: secondary outcomes in mild Alzheimer’s disease patients. Alzheimer’s Dement J Alzheimer’s Assoc. 2016;12:110–20.CrossRefGoogle Scholar
  70. 70.
    Wilcock DM, Alamed J, Gottschall PE, Grimm J, Rosenthal A, Pons J, et al. Deglycosylated anti-amyloid-beta antibodies eliminate cognitive deficits and reduce parenchymal amyloid with minimal vascular consequences in aged amyloid precursor protein transgenic mice. J Neurosci. 2006;26:5340–6.PubMedCrossRefGoogle Scholar
  71. 71.
    Miyoshi I, Fujimoto Y, Yamada M, Abe S, Zhao Q, Cronenberger C, et al. Safety and pharmacokinetics of PF-04360365 following a single-dose intravenous infusion in Japanese subjects with mild-to-moderate Alzheimer’s disease: a multicenter, randomized, double-blind, placebo-controlled, dose-escalation study. Int J Clin Pharmacol Ther. 2013;51:911–23.PubMedCrossRefGoogle Scholar
  72. 72.
    Bogstedt A, Groves M, Tan K, Narwal R, McFarlane M, Hoglund K. Development of immunoassays for the quantitative assessment of amyloid-beta in the presence of therapeutic antibody: application to pre-clinical studies. J Alzheimer’s Dis. 2015;46:1091–101.CrossRefGoogle Scholar
  73. 73.
    Bohrmann B, Baumann K, Benz J, Gerber F, Huber W, Knoflach F, 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 Alzheimer’s Dis. 2012;28:49–69.Google Scholar
  74. 74.
    Shughrue PJ, Acton PJ, Breese RS, Zhao WQ, Chen-Dodson E, Hepler RW, et al. Anti-ADDL antibodies differentially block oligomer binding to hippocampal neurons. Neurobiol Aging. 2010;31:189–202.PubMedCrossRefGoogle Scholar
  75. 75.
    Lambert MP, Velasco PT, Chang L, Viola KL, Fernandez S, Lacor PN, et al. Monoclonal antibodies that target pathological assemblies of Abeta. J Neurochem. 2007;100:23–35.PubMedCrossRefGoogle Scholar
  76. 76.
    Kayed R, Canto I, Breydo L, Rasool S, Lukacsovich T, Wu J, et al. Conformation dependent monoclonal antibodies distinguish different replicating strains or conformers of prefibrillar Abeta oligomers. Mol Neurodegener. 2010;5:57.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Sarsoza F, Saing T, Kayed R, Dahlin R, Dick M, Broadwater-Hollifield C, et al. A fibril-specific, conformation-dependent antibody recognizes a subset of Abeta plaques in Alzheimer disease, Down syndrome and Tg2576 transgenic mouse brain. Acta Neuropathol. 2009;118:505–17.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Kayed R, Head E, Thompson JL, McIntire TM, Milton SC, Cotman CW, et al. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science. 2003;300:486–9.PubMedCrossRefGoogle Scholar
  79. 79.
    Morgado I, Wieligmann K, Bereza M, Ronicke R, Meinhardt K, Annamalai K, et al. Molecular basis of beta-amyloid oligomer recognition with a conformational antibody fragment. Proc Natl Acad Sci. 2012;109:12503–8.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Perchiacca JM, Ladiwala AR, Bhattacharya M, Tessier PM. Structure-based design of conformation- and sequence-specific antibodies against amyloid beta. Proc Natl Acad Sci. 2012;109:84–9.PubMedCrossRefGoogle Scholar
  81. 81.
    Westwood M, Lawson ADG. Opportunities for conformation-selective antibodies in amyloid-related diseases. Antibodies 2015;4:170–96.CrossRefGoogle Scholar
  82. 82.
    Kayed R, Head E, Sarsoza F, Saing T, Cotman CW, Necula M, et al. Fibril specific, conformation dependent antibodies recognize a generic epitope common to amyloid fibrils and fibrillar oligomers that is absent in prefibrillar oligomers. Mol Neurodegener. 2006;2:99–119.Google Scholar
  83. 83.
    Larson ME, Lesne SE. Soluble Abeta oligomer production and toxicity. J Neurochem. 2012;120(Suppl 1):125–39.PubMedCrossRefGoogle Scholar
  84. 84.
    Barghorn S, Striebinger A, Giaisi S, Koehler A, Ebert U, Hillen H. Abeta-oligomer selective antibody A-887755 exhibits a favorable profile for Alzheimer’s disease immunotherapy compared to Abeta-peptide unselective antibodies. Alzheimer’s Dementia. 2009;5:424.CrossRefGoogle Scholar
  85. 85.
    Adolfsson O, Pihlgren M, Toni N, Varisco Y, Buccarello AL, Antoniello K, et al. An effector-reduced anti-beta-amyloid (Abeta) antibody with unique abeta binding properties promotes neuroprotection and glial engulfment of Abeta. J Neurosci. 2012;32:9677–89.PubMedCrossRefGoogle Scholar
  86. 86.
    Cummings J. Cho W, Ward M, Friesenhahn M, Brunstein F, Honigberg L, et al. A randomized, double-blind, placebo-controlled phase 2 study to evaluate the efficacy and safety of crenezumab in patients with mild to moderate Alzheimer’s disease. In: Alzheimer’s association international conference 2014, Copenhagen, Presentation number: O4-11-062014.Google Scholar
  87. 87.
    Demattos RB, Lu J, Tang Y, Racke MM, Delong CA, Tzaferis JA, et al. A plaque-specific antibody clears existing beta-amyloid plaques in Alzheimer’s disease mice. Neuron. 2012;76:908–20.PubMedCrossRefGoogle Scholar
  88. 88.
    Sehlin D, Englund H, Simu B, Karlsson M, Ingelsson M, Nikolajeff F, et al. Large aggregates are the major soluble Abeta species in AD brain fractionated with density gradient ultracentrifugation. PLoS One. 2012;7:e32014.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Lannfelt L, Moller C, Basun H, Osswald G, Sehlin D, Satlin A, et al. Perspectives on future Alzheimer therapies: amyloid-beta protofibrils—a new target for immunotherapy with BAN2401 in Alzheimer’s disease. Alzheimers Res Ther. 2014;6:16.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Tucker S, Moller C, Tegerstedt K, Lord A, Laudon H, Sjodahl J, et al. The murine version of BAN2401 (mAb158) selectively reduces amyloid-beta protofibrils in brain and cerebrospinal fluid of tg-ArcSwe mice. J Alzheimer’s Disease. 2015;43:575–88.Google Scholar
  91. 91.
    Logovinsky V, Satlin A, Lai R, Swanson C, Kaplow J, Osswald G, et al. Safety and tolerability of BAN2401 - a clinical study in Alzheimer’s disease with a protofibril selective Abeta antibody. Alzheimers Res Ther. 2016;8:14.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Nerelius C, Laudon H, Sigvrdson J. Improved Aβ protofibril binding antibodies. WIPO Patent Application WO/2016/005466. International Publication Data, 14 Jan 2016.Google Scholar
  93. 93.
    Bruhns P, Iannascoli B, England P, Mancardi DA, Fernandez N, Jorieux S, et al. Specificity and affinity of human Fcgamma receptors and their polymorphic variants for human IgG subclasses. Blood. 2009;113:3716–25.PubMedCrossRefGoogle Scholar
  94. 94.
    Hillen H, Barghorn S, Striebinger A, Labkovsky B, Muller R, Nimmrich V, et al. Generation and therapeutic efficacy of highly oligomer-specific beta-amyloid antibodies. J Neurosci. 2010;30:10369–79.PubMedCrossRefGoogle Scholar
  95. 95.
    Krafft GA, Hefti F, Goure WF, Jerecic J, Iverson K. ACU-193: A drug candidate antibody that selectively targets soluble Abeta oligomers. Alzheimer’s Dementia. 2013;9:326.CrossRefGoogle Scholar
  96. 96.
    Neurimmune. RTM™ Technology Platform. Accessed 08 Sep 2016.
  97. 97.
    Thierry B, Paul HW, Thomas E, Kenneth R, Joseph A, Fang Q, et al. A method of reducing brain amyloid plaques using anti-Aβ antibodies. WIPO Patent Application WO/2014/089500. International Publication Data, 12 June 2014.Google Scholar
  98. 98.
    Sevigny J, Chiao P, Bussiere T, Weinreb PH, Williams L, Maier M, et al. The antibody aducanumab reduces Abeta plaques in Alzheimer’s disease. Nature. 2016;537:50–6.PubMedCrossRefGoogle Scholar
  99. 99.
    Biogen Presents New Data from Phase 1B Study of Investigational Alzheimer’s Disease Treatment Aducanumab (BIIB037) at Alzheimer’s Association International Conference® 2015. Available 22 July 2015.Google Scholar
  100. 100.
    Lannfelt L, Relkin NR, Siemers ER. Amyloid-ss-directed immunotherapy for Alzheimer’s disease. J Intern Med. 2014;275:284–95.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Jia Q, Deng Y, Qing H. Potential therapeutic strategies for Alzheimer’s disease targeting or beyond beta-amyloid: insights from clinical trials. BioMed Res Int. 2014;2014:837157.PubMedPubMedCentralGoogle Scholar
  102. 102.
    Relkin N. Clinical trials of intravenous immunoglobulin for Alzheimer’s disease. J Clin Immunol. 2014;34(Suppl 1):S74–9.PubMedCrossRefGoogle Scholar
  103. 103.
    Blennow K, de Leon MJ, Zetterberg H. Alzheimer’s disease. Lancet. 2006;368:387–403.PubMedCrossRefGoogle Scholar
  104. 104.
    da Rocha MD, Viegas FP, Campos HC, Nicastro PC, Fossaluzza PC, Fraga CA, et al. The role of natural products in the discovery of new drug candidates for the treatment of neurodegenerative disorders II: Alzheimer’s disease. CNS Neurol Disord Drug Targets. 2011;10:251–70.PubMedCrossRefGoogle Scholar
  105. 105.
    Dias KS, Viegas C Jr. Multi-target directed drugs: a modern approach for design of new drugs for the treatment of Alzheimer’s disease. Curr Neuropharmacol. 2014;12:239–55.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Yu YJ, Zhang Y, Kenrick M, Hoyte K, Luk W, Lu Y, et al. Boosting brain uptake of a therapeutic antibody by reducing its affinity for a transcytosis target. Sci Transl Med. 2011;3:84ra44.Google Scholar
  107. 107.
    Gadkar K, Yadav DB, Zuchero JY, Couch JA, Kanodia J, Kenrick MK, et al. Mathematical PKPD and safety model of bispecific TfR/BACE1 antibodies for the optimization of antibody uptake in brain. Eur J Pharm Biopharm. 2016;101:53–61.PubMedCrossRefGoogle Scholar
  108. 108.
    Miller TW, Messer A. Intrabody applications in neurological disorders: progress and future prospects. Mol Ther. 2005;12:394–401.PubMedCrossRefGoogle Scholar
  109. 109.
    de Marco A. Recombinant antibody production evolves into multiple options aimed at yielding reagents suitable for application-specific needs. Microb Cell Fact. 2015;14:125.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    LaFerla FM, Tinkle BT, Bieberich CJ, Haudenschild CC, Jay G. The Alzheimer’s A beta peptide induces neurodegeneration and apoptotic cell death in transgenic mice. Nat Genet. 1995;9:21–30.PubMedCrossRefGoogle Scholar
  111. 111.
    Paganetti P, Calanca V, Galli C, Stefani M, Molinari M. beta-site specific intrabodies to decrease and prevent generation of Alzheimer’s Abeta peptide. J Cell Biol. 2005;168:863–8.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Moran N. Mouse platforms jostle for slice of humanized antibody market. Nat Biotechnol. 2013;31:267–8.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Biopharmaceutical DivisionHEC R&D Center, Sunshine Lake Pharma Co., LtdDongguanChina

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