Novel amyloid-beta specific scFv and VH antibody fragments from human and mouse phage display antibody libraries.
Anti-amyloid immunotherapy has been proposed as an appropriate therapeutic approach for Alzheimer's disease (AD). Significant efforts have been made towards the generation and assessment of antibody-based reagents capable of preventing and clearing amyloid aggregates as well as preventing their synaptotoxic effects. In this study, we selected a novel set of human anti-amyloid-beta peptide 1-42 (Abeta1-42) recombinant monoclonal antibodies in a single chain fragment variable (scFv) and a single-domain (VH) format. We demonstrated that these antibody fragments recognize in a specific manner amyloid-beta deposits in APP/Tg mouse brains, inhibit toxicity of oligomeric Abeta1-42 in neuroblastoma cell cultures in a concentration-dependent manner and reduced amyloid deposits in APP/Tg2576 mice after intracranial administration. These antibody fragments recognize epitopes in the middle/C-terminus region of Abeta, which makes them strong therapeutic candidates due to the fact that most of the Abeta species found in the brains of AD patients display extensive N-terminus truncations/modifications.
Medecigo
M
M
Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México (UNAM), México DF, Mexico.
Manoutcharian
K
K
Vasilevko
V
V
Govezensky
T
T
Munguia
M E
ME
Becerril
B
B
Luz-Madrigal
A
A
Vaca
L
L
Cribbs
D H
DH
Gevorkian
G
G
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017104:Bacteriophage M13 / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D001666:Binding Sites, Antibody / Q000235:genetics; D045744:Cell Line, Tumor; D000939:Epitopes / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology*; D019151:Peptide Library; D017434:Protein Structure, Tertiary / Q000235:genetics; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D057127:Single-Chain Antibodies / Q000096:biosynthesis / Q000737:chemistry* / Q000235:genetics
D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal; D000939:Epitopes; D007143:Immunoglobulin Heavy Chains; D010446:Peptide Fragments; D019151:Peptide Library; D011994:Recombinant Proteins; D057127:Single-Chain Antibodies; C075222:amyloid beta-protein (1-42)
Nat Med. 2000 Aug;6(8):916-9
10932230
Nat Med. 2005 May;11(5):556-61
15834427
J Neurosci. 2003 Sep 17;23(24):8532-8
13679422
Neurology. 2005 May 10;64(9):1553-62
15883316
J Neurochem. 2008 Feb;104(4):859-74
17986215
Nature. 2000 Dec 21-28;408(6815):979-82
11140685
J Alzheimers Dis. 2006;9(3 Suppl):425-32
16914881
Appl Microbiol Biotechnol. 2007 Nov;77(1):13-22
17704915
Lancet Neurol. 2008 Sep;7(9):805-11
18667360
J Physiol. 2006 Apr 15;572(Pt 2):477-92
16469784
Curr Opin Drug Discov Devel. 2008 Sep;11(5):675-87
18729019
Nature. 1999 Jul 8;400(6740):173-7
10408445
Neurobiol Dis. 2009 Feb;33(2):213-20
19028582
Neurobiol Dis. 2004 Oct;17(1):114-21
15350972
Proc Natl Acad Sci U S A. 2001 Apr 10;98(8):4764-9
11296304
FEBS J. 2005 May;272(10):2591-601
15885107
J Neurosci. 2009 Jun 24;29(25):7957-65
19553436
Trends Biotechnol. 2003 Nov;21(11):484-90
14573361
Nat Rev Neurosci. 2007 Jul;8(7):499-509
17551515
J Neurosci. 2002 Sep 15;22(18):7873-8
12223540
Brain Pathol. 2008 Oct;18(4):548-61
18422760
J Alzheimers Dis. 2008 Dec;15(4):555-69
19096156
J Neurosci. 2008 Dec 24;28(52):14156-64
19109498
Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19232-7
18042730
J Neurochem. 2007 Jun;101(5):1172-84
17286590
Mol Immunol. 2009 Feb;46(4):695-704
18930548
Nat Biotechnol. 2005 Sep;23(9):1126-36
16151406
Nat Med. 2008 Aug;14(8):837-42
18568035
J Infect Dis. 2007 Jan 1;195(1):149-57
17152019
Nat Rev Mol Cell Biol. 2007 Feb;8(2):101-12
17245412
Neurobiol Dis. 2006 Sep;23(3):502-11
16766200
J Neurosci. 2006 May 17;26(20):5340-6
16707786
J Neurosci. 2007 Nov 14;27(46):12721-31
18003852
J Mol Biol. 2009 Apr 3;387(3):584-606
19361429
Annu Rev Neurosci. 2008;31:175-93
18352830
Nat Neurosci. 2005 Jan;8(1):79-84
15608634
J Clin Invest. 2006 Jan;116(1):193-201
16341263
J Neuroimmunol. 2003 Dec;145(1-2):12-7
14644026
J Neurosci. 2005 Jun 29;25(26):6213-20
15987951
J Neuroimmunol. 2000 Jul 1;106(1-2):23-31
10814779
J Mol Biol. 2008 Dec 26;384(4):917-28
18929576
Am J Pathol. 2004 Jul;165(1):283-97
15215183
Science. 1996 Oct 4;274(5284):99-102
8810256
Virol J. 2007 Sep 18;4:88
17877803
J Neurosci. 2002 Aug 1;22(15):6331-5
12151510
J Neurosci Res. 2002 Nov 15;70(4):599-610
12404514
Science. 2002 Nov 15;298(5597):1379
12434053
J Mol Biol. 2002 Mar 15;317(1):73-83
11916379
Ann Neurol. 1999 Dec;46(6):860-6
10589538
J Neurosci. 2008 Apr 2;28(14):3555-66
18385314
FEBS Lett. 2005 May 9;579(12):2564-8
15862291
Biotechnol Adv. 2009 Jul-Aug;27(4):502-20
19374944
J Neurosci. 2005 Jan 19;25(3):629-36
15659599
J Neuroimmunol. 2009 Aug 18;213(1-2):39-46
19545911
Clin Exp Immunol. 2002 Sep;129(3):453-63
12197886
Lancet. 2008 Jul 19;372(9634):216-23
18640458
J Neural Transm (Vienna). 2002 Jul;109(7-8):1081-7
12111445