title: Single-chain fragment variable passive immunotherapies for neurodegenerative diseases.
abstract: Accumulation of misfolded proteins has been implicated in a variety of neurodegenerative diseases including prion diseases, Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). In the past decade, single-chain fragment variable (scFv) -based immunotherapies have been developed to target abnormal proteins or various forms of protein aggregates including Aβ, SNCA, Htt, and PrP proteins. The scFvs are produced by fusing the variable regions of the antibody heavy and light chains, creating a much smaller protein with unaltered specificity. Because of its small size and relative ease of production, scFvs are promising diagnostic and therapeutic reagents for protein misfolded diseases. Studies have demonstrated the efficacy and safety of scFvs in preventing amyloid protein aggregation in preclinical models. Herein, we discuss recent developments of these immunotherapeutics. We review efforts of our group and others using scFv in neurodegenerative disease models. We illustrate the advantages of scFvs, including engineering to enhance misfolded conformer specificity and subcellular targeting to optimize therapeutic action.
authors.affiliation: Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA. hjf8@georgetown.edu.
authors.forename: Liang
authors.initials: L
authors.lastname: Huang
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Su
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Federoff
mesh_terms: D016229:Amyloid beta-Peptides / Q000276:immunology; D006801:Humans; D000071058:Huntingtin Protein; D007116:Immunization, Passive; D009419:Nerve Tissue Proteins / Q000276:immunology; D019636:Neurodegenerative Diseases / Q000628:therapy*; D011328:Prions / Q000276:immunology; D057127:Single-Chain Antibodies / Q000276:immunology / Q000627:therapeutic use*; D051844:alpha-Synuclein / Q000276:immunology
chemical_list: D016229:Amyloid beta-Peptides; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D011328:Prions; C497604:SNCA protein, human; D057127:Single-Chain Antibodies; D051844:alpha-Synuclein
references.citation: J Immunol Methods. 1998 Jul 1;216(1-2):165-81
references.pmid: 9760222
references.citation: MAbs. 2012 Nov-Dec;4(6):686-93
references.pmid: 22929188
references.citation: Protein Eng Des Sel. 2009 Mar;22(3):199-208
references.pmid: 18927231
references.citation: J Biol Chem. 2012 Apr 13;287(16):12858-66
references.pmid: 22362783
references.citation: PLoS One. 2008;3(12):e3872
references.pmid: 19060956
references.citation: Nat Rev Neurosci. 2013 Jan;14(1):38-48
references.pmid: 23254192
references.citation: Nature. 2001 Aug 16;412(6848):739-43
references.pmid: 11507642
references.citation: Nat Rev Genet. 2010 Apr;11(4):247-58
references.pmid: 20177426
references.citation: Biotechnol Bioeng. 2010 Feb 15;105(3):627-35
references.pmid: 19816967
references.citation: J Neurochem. 2007 Jun;101(6):1516-26
references.pmid: 17542810
references.citation: Mol Immunol. 2008 Jan;45(1):144-51
references.pmid: 17576014
references.citation: Prion. 2007 Jan-Mar;1(1):26-31
references.pmid: 19172113
references.citation: Appl Biochem Biotechnol. 2013 Jan;169(1):159-69
references.pmid: 23160949
references.citation: J Immunol Methods. 1999 Dec 10;231(1-2):177-89
references.pmid: 10648937
references.citation: Proc Natl Acad Sci U S A. 2002 Jan 22;99(2):1002-7
references.pmid: 11792860
references.citation: Cold Spring Harb Perspect Med. 2012 Aug 01;2(8):
references.pmid: 22908195
references.citation: Prog Neurobiol. 2011 Jun;94(1):1-19
references.pmid: 21439347
references.citation: Biochemistry. 2004 Mar 16;43(10):2871-8
references.pmid: 15005622
references.citation: Neurobiol Dis. 2005 Jun-Jul;19(1-2):47-56
references.pmid: 15837560
references.citation: Biochem J. 2009 Mar 15;418(3):507-15
references.pmid: 19000036
references.citation: Adv Protein Chem. 2001;57:229-72
references.pmid: 11447692
references.citation: Expert Rev Anti Infect Ther. 2007 Aug;5(4):613-30
references.pmid: 17678425
references.citation: Mol Psychiatry. 1998 Nov;3(6):493-9
references.pmid: 9857974
references.citation: Proc Natl Acad Sci U S A. 2001 Apr 10;98(8):4764-9
references.pmid: 11296304
references.citation: J Biol Chem. 2003 Oct 10;278(41):40186-97
references.pmid: 12885775
references.citation: J Infect Dis. 2006 Sep 1;194(5):702-9
references.pmid: 16897671
references.citation: FEBS Lett. 2008 Feb 20;582(4):517-22
references.pmid: 18230361
references.citation: Proc Natl Acad Sci U S A. 2000 Oct 10;97(21):11455-9
references.pmid: 11027345
references.citation: J Neuropathol Exp Neurol. 2010 Oct;69(10):1078-85
references.pmid: 20838238
references.citation: Mol Ther. 2010 Aug;18(8):1471-81
references.pmid: 20551911
references.citation: J Clin Pathol. 2013 May;66(5):362-6
references.pmid: 23526599
references.citation: Nat Chem Biol. 2011 May 29;7(7):453-60
references.pmid: 21623356
references.citation: Clin Dev Immunol. 2012;2012:980250
references.pmid: 22474489
references.citation: Brain Res Mol Brain Res. 2004 Feb 5;121(1-2):141-5
references.pmid: 14969746
references.citation: PLoS One. 2011;6(12):e29199
references.pmid: 22216210
references.citation: Am J Pathol. 2005 Oct;167(4):1033-42
references.pmid: 16192638
references.citation: J Mol Biol. 2006 Oct 13;363(1):75-97
references.pmid: 16962610
references.citation: J Neurosci. 2007 Aug 22;27(34):9220-32
references.pmid: 17715357
references.citation: J Mol Biol. 2009 Jan 9;385(1):299-311
references.pmid: 18992254
references.citation: Biochemistry. 2004 Jun 8;43(22):6959-67
references.pmid: 15170333
references.citation: Int J Biochem Cell Biol. 2012 Sep;44(9):1541-54
references.pmid: 22713792
references.citation: PLoS Pathog. 2007 Aug 31;3(8):e125
references.pmid: 17784787
references.citation: N Engl J Med. 2001 May 17;344(20):1516-26
references.pmid: 11357156
references.citation: J Biol Chem. 2012 Apr 20;287(17):14023-39
references.pmid: 22356913
references.citation: Eur J Immunol. 1996 Dec;26(12):2801-6
references.pmid: 8977271
references.citation: FEBS Lett. 1997 Mar 24;405(2):224-8
references.pmid: 9089295
references.citation: Am J Pathol. 2000 Aug;157(2):401-10
references.pmid: 10934145
references.citation: Exp Neurol. 2012 Nov;238(1):1-11
references.pmid: 22200539
references.citation: Nature. 2005 Sep 8;437(7056):257-61
references.pmid: 16148934
references.citation: Nature. 2003 Mar 6;422(6927):80-3
references.pmid: 12621436
references.citation: J Mol Biol. 2006 Apr 21;358(1):57-66
references.pmid: 16516231
references.citation: Nature. 1997 Aug 28;388(6645):839-40
references.pmid: 9278044
references.citation: Alzheimers Dement. 2007 Jul;3(3):186-91
references.pmid: 19595937
references.citation: J Alzheimers Dis. 2011;24 Suppl 2:223-32
references.pmid: 21460436
references.citation: Eur J Biochem. 1988 Sep 1;176(1):21-30
references.pmid: 3138115
references.citation: Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13363-83
references.pmid: 9811807
references.citation: BMC Biotechnol. 2007 Jul 02;7:38
references.pmid: 17605808
references.citation: Arch Med Res. 2012 Nov;43(8):600-8
references.pmid: 23159715
references.citation: Biochim Biophys Acta. 2011 Dec;1814(12):1703-12
references.pmid: 21979582
references.citation: Prog Neurobiol. 2012 May;97(2):190-204
references.pmid: 22120646
references.citation: FEBS Lett. 2009 Feb 4;583(3):579-84
references.pmid: 19162022
references.citation: Acta Biochim Biophys Sin (Shanghai). 2013 Jun;45(6):442-51
references.pmid: 23557632
references.citation: J Virol. 2011 May;85(9):4538-46
references.pmid: 21345946
references.citation: J Comp Neurol. 2009 Jul 1;515(1):4-14
references.pmid: 19399901
references.citation: Science. 2001 Oct 5;294(5540):178-82
references.pmid: 11546838
references.citation: Neurobiol Dis. 2006 Sep;23(3):502-11
references.pmid: 16766200
references.citation: J Neuropathol Exp Neurol. 1996 Mar;55(3):259-72
references.pmid: 8786384
references.citation: J Mol Biol. 2008 Mar 14;377(1):136-47
references.pmid: 18237741
references.citation: J Immunol Methods. 1997 Feb 14;201(1):35-55
references.pmid: 9032408
references.citation: Neurobiol Dis. 2010 Oct;40(1):130-4
references.pmid: 20399860
references.citation: Neuron. 2010 Jan 14;65(1):66-79
references.pmid: 20152114
references.citation: Nature. 2003 Dec 18;426(6968):884-90
references.pmid: 14685248
references.citation: J Alzheimers Dis. 2004 Aug;6(4):435-42; discussion 443-9
references.pmid: 15345814
references.citation: Neurotoxicology. 2010 Sep;31(5):598-602
references.pmid: 20430055
references.citation: Biologicals. 2007 Mar;35(1):31-4
references.pmid: 16580230
references.citation: Curr Med Chem. 2008;15(13):1336-49
references.pmid: 18537613
references.citation: Appl Biochem Biotechnol. 2010 Mar;160(6):1808-21
references.pmid: 19597999
references.citation: J Biol Chem. 2005 Jan 7;280(1):685-94
references.pmid: 15513919
references.citation: Protein Eng. 1993 Nov;6(8):989-95
references.pmid: 8309948
references.citation: J Mol Biol. 2007 May 11;368(4):1132-44
references.pmid: 17391701
references.citation: J Struct Biol. 2000 Jun;130(2-3):300-9
references.pmid: 10940234
references.citation: J Gen Virol. 2008 Aug;89(Pt 8):2055-2061
references.pmid: 18632978
references.citation: Neurobiol Aging. 2009 Mar;30(3):364-76
references.pmid: 17686552
references.citation: Cell Mol Neurobiol. 2011 Oct;31(7):999-1008
references.pmid: 21516351
references.citation: Cold Spring Harb Perspect Biol. 2011 Jun 01;3(6):
references.pmid: 21441583
references.citation: Mol Ther. 2005 Sep;12(3):394-401
references.pmid: 15964243
references.citation: Science. 2002 Nov 15;298(5597):1379
references.pmid: 12434053
references.citation: IUBMB Life. 2010 May;62(5):334-9
references.pmid: 20209636
references.citation: J Mol Med (Berl). 2003 Nov;81(11):678-99
references.pmid: 12942175
references.citation: Cell. 1993 Jul 2;73(7):1339-47
references.pmid: 8100741
references.citation: J Exp Med. 2012 May 7;209(5):889-93
references.pmid: 22566400
references.citation: Brain Res. 2012 Oct 2;1476:183-202
references.pmid: 22560500
references.citation: Ann Neurol. 2013 Feb;73(2):155-69
references.pmid: 23225525
references.citation: Protein Pept Lett. 2004 Jun;11(3):213-28
references.pmid: 15182223
references.citation: Mol Immunol. 2007 Mar;44(8):1888-96
references.pmid: 17140664
references.citation: Cell. 1983 Nov;35(1):57-62
references.pmid: 6414721
references.citation: Protein Expr Purif. 2012 May;83(1):21-9
references.pmid: 22387083
references.citation: J Mol Recognit. 1996 Sep-Dec;9(5-6):738-45
references.pmid: 9174966
references.citation: Brain Res. 2012 Jan 13;1432:95-113
references.pmid: 22153624
references.citation: Mol Ther. 2004 Dec;10(6):1023-31
references.pmid: 15564134
references.citation: J Alzheimers Dis. 2010;21(4):1065-75
references.pmid: 21504118
references.citation: Biochemistry. 2001 Jul 3;40(26):7812-9
references.pmid: 11425308
references.citation: J Neurosci. 2005 Jan 19;25(3):629-36
references.pmid: 15659599
references.citation: Prion. 2013 Mar-Apr;7(2):114-6
references.pmid: 23154635
references.citation: Hum Antibodies. 2000;9(4):207-14
references.pmid: 11341174
references.citation: Neurology. 1998 Aug;51(2 Suppl 2):S2-9
references.pmid: 9711973
references.citation: Arch Biochem Biophys. 2012 Oct 15;526(2):132-8
references.pmid: 22475448
references.citation: Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):10962-6
references.pmid: 7902575
references.citation: Prion. 2012 Sep-Oct;6(4):383-90
references.pmid: 22842862
references.citation: Microbiol Immunol. 2010 Feb;54(2):112-21
references.pmid: 20377745
references.citation: Nat Rev Neurol. 2013 Feb;9(2):98-105
references.pmid: 23247613
references.citation: J Virol. 2005 Jul;79(13):8330-8
references.pmid: 15956578
references.citation: Mol Immunol. 2009 Feb;46(4):532-40
references.pmid: 18973947
references.citation: Hum Mol Genet. 2012 Mar 1;21(5):1138-44
references.pmid: 22100763
references.citation: Proc Natl Acad Sci U S A. 2005 Aug 9;102(32):11563-8
references.pmid: 16061794
references.citation: J Neurosci. 2006 Nov 15;26(46):11923-8
references.pmid: 17108166
references.citation: Mol Ther. 2008 Mar;16(3):481-6
references.pmid: 18180775
references.citation: PLoS One. 2011 Jan 20;6(1):e15783
references.pmid: 21283753
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3498-503
references.pmid: 14993615
references.citation: Neurobiol Dis. 2013 Aug;56:74-8
references.pmid: 23607939
references.citation: Proc Natl Acad Sci U S A. 2012 Feb 28;109(9):3213-9
references.pmid: 22315428