WO2010119704A1 - Antibodies that specifically bind to a beta oligomers and use thereof - Google Patents
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- WO2010119704A1 WO2010119704A1 PCT/JP2010/002771 JP2010002771W WO2010119704A1 WO 2010119704 A1 WO2010119704 A1 WO 2010119704A1 JP 2010002771 W JP2010002771 W JP 2010002771W WO 2010119704 A1 WO2010119704 A1 WO 2010119704A1
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- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
- G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
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- C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
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- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
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- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
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- G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
- G01N2333/4701—Details
- G01N2333/4709—Amyloid plaque core protein
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- G01N2800/00—Detection or diagnosis of diseases
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Abstract
Description
[NPL 2]Klein WL, Trends Neurosci. 24: 219-224, 2001
[NPL 3]Selkoe DJ, Science 298: 789-791, 2002
[NPL 4]Haass C et al.: Nat Rev Mol Cell Biol. 8: 101-12, 2007
[NPL 5]Lee EB, et al.: J. Biol. Chem. 281: 4292-4299, 2006
[1]An antibody that recognizes an isolated A beta tetramer as an antigen, wherein the antibody does not bind to an A beta monomer.
[2]The antibody of [1], which is any one of (1) to (99) below:
(1) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 530;
(2) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 532;
(3) an antibody that comprises the H chain of (1) and the L chain of (2);
(4) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 534;
(5) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 536;
(6) an antibody that comprises the H chain of (4) and the L chain of (5);
(7) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 538;
(8) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 540;
(9) an antibody that comprises the H chain of (7) and the L chain of (8);
(10) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 542;
(11) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 544;
(12) an antibody that comprises the H chain of (10) and the L chain of (11);
(13) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 546;
(14) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 548;
(15) an antibody that comprises the H chain of (13) and the L chain of (14);
(16) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 550;
(17) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 552;
(18) an antibody that comprises the H chain of (16) and the L chain of (17);
(19) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 554;
(20) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 556;
(21) an antibody that comprises the H chain of (19) and the L chain of (20);
(22) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 558;
(23) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 560;
(24) an antibody that comprises the H chain of (22) and the L chain of (23);
(25) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 562;
(26) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 564;
(27) an antibody that comprises the H chain of (25) and the L chain of (26);
(28) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 566;
(29) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 568;
(30) an antibody that comprises the H chain of (28) and the L chain of (29);
(31) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 570;
(32) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 572;
(33) an antibody that comprises the H chain of (31) and the L chain of (32);
(34) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 574;
(35) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 576;
(36) an antibody that comprises the H chain of (34) and the L chain of (35);
(37) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 578;
(38) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 580;
(39) an antibody that comprises the H chain of (37) and the L chain of (38);
(40) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 582;
(41) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 584;
(42) an antibody that comprises the H chain of (40) and the L chain of (41);
(43) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 586;
(44) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 588;
(45) an antibody that comprises the H chain of (43) and the L chain of (44);
(46) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 590;
(47) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 592;
(48) an antibody that comprises the H chain of (46) and the L chain of (47);
(49) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 594;
(50) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 596;
(51) an antibody that comprises the H chain of (49) and the L chain of (50);
(52) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 598;
(53) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 600;
(54) an antibody that comprises the H chain of (52) and the L chain of (53);
(55) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 602;
(56) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 604;
(57) an antibody that comprises the H chain of (55) and the L chain of (56);
(58) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 606;
(59) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 608;
(60) an antibody that comprises the H chain of (58) and the L chain of (59);
(61) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 610;
(62) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 612;
(63) an antibody that comprises the H chain of (61) and the L chain of (62);
(64) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 614;
(65) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 616;
(66) an antibody that comprises the H chain of (64) and the L chain of (65);
(67) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 618;
(68) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 620;
(69) an antibody that comprises the H chain of (67) and the L chain of (68);
(70) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 622;
(71) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 624;
(72) an antibody that comprises the H chain of (70) and the L chain of (71);
(73) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 626;
(74) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 628;
(75) an antibody that comprises the H chain of (73) and the L chain of (74);
(76) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 630;
(77) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 632;
(78) an antibody that comprises the H chain of (76) and the L chain of (77);
(79) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 634;
(80) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 636;
(81) an antibody that comprises the H chain of (79) and the L chain of (80);
(82) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 638;
(83) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 640;
(84) an antibody that comprises the H chain of (82) and the L chain of (83);
(85) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 642;
(86) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 644;
(87) an antibody that comprises the H chain of (85) and the L chain of (86);
(88) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 646;
(89) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 648;
(90) an antibody that comprises the H chain of (88) and the L chain of (89);
(91) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 650;
(92) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 652;
(93) an antibody that comprises the H chain of (91) and the L chain of (92);
(94) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 654;
(95) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 656;
(96) an antibody that comprises the H chain of (94) and the L chain of (95);
(97) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 658;
(98) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 660; and
(99) an antibody that comprises the H chain of (97) and the L chain of (98).
[3]The antibody of [1], which is any one of (1) to (200) below:
(1) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 6 as CDR1, the amino acid sequence of SEQ ID NO: 8 as CDR2, and the amino acid sequence of SEQ ID NO: 10 as CDR3;
(2) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 12 as CDR1, the amino acid sequence of SEQ ID NO: 14 as CDR2, and the amino acid sequence of SEQ ID NO: 16 as CDR3;
(3) an antibody that comprises the H chain of (1) and the L chain of (2);
(4) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 530 as VH;
(5) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 532 as VL;
(6) an antibody that comprises the H chain of (4) and the L chain of (5);
(7) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 22 as CDR1, the amino acid sequence of SEQ ID NO: 24 as CDR2, and the amino acid sequence of SEQ ID NO: 26 as CDR3;
(8) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 28 as CDR1, the amino acid sequence of SEQ ID NO: 30 as CDR2, and the amino acid sequence of SEQ ID NO: 32 as CDR3;
(9) an antibody that comprises the H chain of (7) and the L chain of (8);
(10) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 534 as VH;
(11) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 536 as VL;
(12) an antibody that comprises the H chain of (10) and the L chain of (11);
(13) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 38 as CDR1, the amino acid sequence of SEQ ID NO: 40 as CDR2, and the amino acid sequence of SEQ ID NO: 42 as CDR3;
(14) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 44 as CDR1, the amino acid sequence of SEQ ID NO: 46 as CDR2, and the amino acid sequence of SEQ ID NO: 48 as CDR3;
(15) an antibody that comprises the H chain of (13) and the L chain of (14);
(16) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 538 as VH;
(17) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 540 as VL;
(18) an antibody that comprises the H chain of (16) and the L chain of (17);
(19) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 54 as CDR1, the amino acid sequence of SEQ ID NO: 56 as CDR2, and the amino acid sequence of SEQ ID NO: 58 as CDR3;
(20) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 60 as CDR1, the amino acid sequence of SEQ ID NO: 62 as CDR2, and the amino acid sequence of SEQ ID NO: 64 as CDR3;
(21) an antibody that comprises the H chain of (19) and the L chain of (20);
(22) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 542 as VH;
(23) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 544 as VL;
(24) an antibody that comprises the H chain of (22) and the L chain of (23);
(25) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 70 as CDR1, the amino acid sequence of SEQ ID NO: 72 as CDR2, and the amino acid sequence of SEQ ID NO: 74 as CDR3;
(26) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 76 as CDR1, the amino acid sequence of SEQ ID NO: 78 as CDR2, and the amino acid sequence of SEQ ID NO: 80 as CDR3;
(27) an antibody that comprises the H chain of (25) and the L chain of (26);
(28) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 546 as VH;
(29) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 548 as VL;
(30) an antibody that comprises the H chain of (28) and the L chain of (29);
(31) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 86 as CDR1, the amino acid sequence of SEQ ID NO: 88 as CDR2, and the amino acid sequence of SEQ ID NO: 90 as CDR3;
(32) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 92 as CDR1, the amino acid sequence of SEQ ID NO: 94 as CDR2, and the amino acid sequence of SEQ ID NO: 96 as CDR3;
(33) an antibody that comprises the H chain of (31) and the L chain of (32);
(34) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 550 as VH;
(35) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 552 as VL;
(36) an antibody that comprises the H chain of (34) and the L chain of (35);
(37) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 102 as CDR1, the amino acid sequence of SEQ ID NO: 104 as CDR2, and the amino acid sequence of SEQ ID NO: 106 as CDR3;
(38) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 108 as CDR1, the amino acid sequence of SEQ ID NO: 110 as CDR2, and the amino acid sequence of SEQ ID NO: 112 as CDR3;
(39) an antibody that comprises the H chain of (37) and the L chain of (38);
(40) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 554 as VH;
(41) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 556 as VL;
(42) an antibody that comprises the H chain of (40) and the L chain of (41);
(43) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 118 as CDR1, the amino acid sequence of SEQ ID NO: 120 as CDR2, and the amino acid sequence of SEQ ID NO: 122 as CDR3;
(44) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 124 as CDR1, the amino acid sequence of SEQ ID NO: 126 as CDR2, and the amino acid sequence of SEQ ID NO: 128 as CDR3;
(45) an antibody that comprises the H chain of (43) and the L chain of (44);
(46) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 558 as VH;
(47) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 560 as VL;
(48) an antibody that comprises the H chain of (46) and the L chain of (47);
(49) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 134 as CDR1, the amino acid sequence of SEQ ID NO: 136 as CDR2, and the amino acid sequence of SEQ ID NO: 138 as CDR3;
(50) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 140 as CDR1, the amino acid sequence of SEQ ID NO: 142 as CDR2, and the amino acid sequence of SEQ ID NO: 144 as CDR3;
(51) an antibody that comprises the H chain of (49) and the L chain of (50);
(52) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 562 as VH;
(53) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 564 as VL;
(54) an antibody that comprises the H chain of (52) and the L chain of (53);
(55) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 150 as CDR1, the amino acid sequence of SEQ ID NO: 152 as CDR2, and the amino acid sequence of SEQ ID NO: 154 as CDR3;
(56) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 156 as CDR1, the amino acid sequence of SEQ ID NO: 158 as CDR2, and the amino acid sequence of SEQ ID NO: 160 as CDR3;
(57) an antibody that comprises the H chain of (55) and the L chain of (56);
(58) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 566 as VH;
(59) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 568 as VL;
(60) an antibody that comprises the H chain of (58) and the L chain of (59);
(61) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 166 as CDR1, the amino acid sequence of SEQ ID NO: 168 as CDR2, and the amino acid sequence of SEQ ID NO: 170 as CDR3;
(62) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 172 as CDR1, the amino acid sequence of SEQ ID NO: 174 as CDR2, and the amino acid sequence of SEQ ID NO: 176 as CDR3;
(63) an antibody that comprises the H chain of (61) and the L chain of (62);
(64) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 570 as VH;
(65) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 572 as VL;
(66) an antibody that comprises the H chain of (64) and the L chain of (65);
(67) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 182 as CDR1, the amino acid sequence of SEQ ID NO: 184 as CDR2, and the amino acid sequence of SEQ ID NO: 186 as CDR3;
(68) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 188 as CDR1, the amino acid sequence of SEQ ID NO: 190 as CDR2, and the amino acid sequence of SEQ ID NO: 192 as CDR3;
(69) an antibody that comprises the H chain of (67) and the L chain of (68);
(70) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 574 as VH;
(71) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 576 as VL;
(72) an antibody that comprises the H chain of (70) and the L chain of (71);
(73) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 198 as CDR1, the amino acid sequence of SEQ ID NO: 200 as CDR2, and the amino acid sequence of SEQ ID NO: 202 as CDR3;
(74) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 204 as CDR1, the amino acid sequence of SEQ ID NO: 206 as CDR2, and the amino acid sequence of SEQ ID NO: 208 as CDR3;
(75) an antibody that comprises the H chain of (73) and the L chain of (74);
(76) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 578 as VH;
(77) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 580 as VL;
(78) an antibody that comprises the H chain of (75) and the L chain of (76);
(79) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 214 as CDR1, the amino acid sequence of SEQ ID NO: 216 as CDR2, and the amino acid sequence of SEQ ID NO: 218 as CDR3;
(80) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 220 as CDR1, the amino acid sequence of SEQ ID NO: 222 as CDR2, and the amino acid sequence of SEQ ID NO: 224 as CDR3;
(81) an antibody that comprises the H chain of (79) and the L chain of (80);
(82) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 582 as VH;
(83) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 584 as VL;
(84) an antibody that comprises the H chain of (82) and the L chain of (83);
(85) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 230 as CDR1, the amino acid sequence of SEQ ID NO: 232 as CDR2, and the amino acid sequence of SEQ ID NO: 234 as CDR3;
(86) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 236 as CDR1, the amino acid sequence of SEQ ID NO: 238 as CDR2, and the amino acid sequence of SEQ ID NO: 240 as CDR3;
(87) an antibody that comprises the H chain of (85) and the L chain of (86);
(88) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 586 as VH;
(89) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 588 as VL;
(90) an antibody that comprises the H chain of (88) and the L chain of (89);
(91) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 246 as CDR1, the amino acid sequence of SEQ ID NO: 248 as CDR2, and the amino acid sequence of SEQ ID NO: 250 as CDR3;
(92) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 252 as CDR1, the amino acid sequence of SEQ ID NO: 254 as CDR2, and the amino acid sequence of SEQ ID NO: 256 as CDR3;
(93) an antibody that comprises the H chain of (91) and the L chain of (92);
(94) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 590 as VH;
(95) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 592 as VL;
(96) an antibody that comprises the H chain of (94) and the L chain of (95);
(97) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 262 as CDR1, the amino acid sequence of SEQ ID NO: 264 as CDR2, and the amino acid sequence of SEQ ID NO: 266 as CDR3;
(98) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 268 as CDR1, the amino acid sequence of SEQ ID NO: 270 as CDR2, and the amino acid sequence of SEQ ID NO: 272 as CDR3;
(99) an antibody that comprises the H chain of (97) and the L chain of (98);
(100) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 594 as VH;
(101) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 596 as VL;
(102) an antibody that comprises the H chain of (100) and the L chain of (101);
(103) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 278 as CDR1, the amino acid sequence of SEQ ID NO: 280 as CDR2, and the amino acid sequence of SEQ ID NO: 282 as CDR3;
(104) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 284 as CDR1, the amino acid sequence of SEQ ID NO: 286 as CDR2, and the amino acid sequence of SEQ ID NO: 288 as CDR3;
(105) an antibody that comprises the H chain of (103) and the L chain of (104);
(106) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 598 as VH;
(107) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 600 as VL;
(108) an antibody that comprises the H chain of (106) and the L chain of (107);
(109) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 294 as CDR1, the amino acid sequence of SEQ ID NO: 296 as CDR2, and the amino acid sequence of SEQ ID NO: 298 as CDR3;
(110) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 300 as CDR1, the amino acid sequence of SEQ ID NO: 302 as CDR2, and the amino acid sequence of SEQ ID NO: 304 as CDR3;
(111) an antibody that comprises the H chain of (109) and the L chain of (110);
(112) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 602 as VH;
(113) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 604 as VL;
(114) an antibody that comprises the H chain of (112) and the L chain of (113);
(115) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 310 as CDR1, the amino acid sequence of SEQ ID NO: 312 as CDR2, and the amino acid sequence of SEQ ID NO: 314 as CDR3;
(116) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 316 as CDR1, the amino acid sequence of SEQ ID NO: 318 as CDR2, and the amino acid sequence of SEQ ID NO: 320 as CDR3;
(117) an antibody that comprises the H chain of (115) and the L chain of (116);
(118) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 606 as VH;
(119) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 608 as VL;
(120) an antibody that comprises the H chain of (118) and the L chain of (119);
(121) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 326 as CDR1, the amino acid sequence of SEQ ID NO: 328 as CDR2, and the amino acid sequence of SEQ ID NO: 330 as CDR3;
(122) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 332 as CDR1, the amino acid sequence of SEQ ID NO: 334 as CDR2, and the amino acid sequence of SEQ ID NO: 336 as CDR3;
(123) an antibody that comprises the H chain of (121) and the L chain of (122);
(124) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 610 as VH;
(125) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 612 as VL;
(126) an antibody that comprises the H chain of (124) and the L chain of (125);
(127) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 342 as CDR1, the amino acid sequence of SEQ ID NO: 344 as CDR2, and the amino acid sequence of SEQ ID NO: 346 as CDR3;
(128) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 348 as CDR1, the amino acid sequence of SEQ ID NO: 350 as CDR2, and the amino acid sequence of SEQ ID NO: 352 as CDR3;
(129) an antibody that comprises the H chain of (127) and the L chain of (128);
(130) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 614 as VH;
(131) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 616 as VL;
(132) an antibody that comprises the H chain of (130) and the L chain of (131);
(133) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 358 as CDR1, the amino acid sequence of SEQ ID NO: 360 as CDR2, and the amino acid sequence of SEQ ID NO: 362 as CDR3;
(134) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 364 as CDR1, the amino acid sequence of SEQ ID NO: 366 as CDR2, and the amino acid sequence of SEQ ID NO: 368 as CDR3;
(135) an antibody that comprises the H chain of (133) and the L chain of (134);
(136) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 618 as VH;
(137) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 620 as VL;
(138) an antibody that comprises the H chain of (136) and the L chain of (137);
(139) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 374 as CDR1, the amino acid sequence of SEQ ID NO: 376 as CDR2, and the amino acid sequence of SEQ ID NO: 378 as CDR3;
(140) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 380 as CDR1, the amino acid sequence of SEQ ID NO: 382 as CDR2, and the amino acid sequence of SEQ ID NO: 384 as CDR3;
(141) an antibody that comprises the H chain of (139) and the L chain of (140);
(142) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 622 as VH;
(143) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 624 as VL;
(144) an antibody that comprises the H chain of (142) and the L chain of (143);
(145) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 390 as CDR1, the amino acid sequence of SEQ ID NO: 392 as CDR2, and the amino acid sequence of SEQ ID NO: 394 as CDR3;
(146) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 396 as CDR1, the amino acid sequence of SEQ ID NO: 398 as CDR2, and the amino acid sequence of SEQ ID NO: 400 as CDR3;
(147) an antibody that comprises the H chain of (145) and the L chain of (146);
(148) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 626 as VH;
(149) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 628 as VL;
(150) an antibody that comprises the H chain of (148) and the L chain of (149);
(151) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 406 as CDR1, the amino acid sequence of SEQ ID NO: 408 as CDR2, and the amino acid sequence of SEQ ID NO: 410 as CDR3;
(152) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 412 as CDR1, the amino acid sequence of SEQ ID NO: 414 as CDR2, and the amino acid sequence of SEQ ID NO: 416 as CDR3;
(153) an antibody that comprises the H chain of (151) and the L chain of (152);
(154) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 630 as VH;
(155) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 632 as VL;
(156) an antibody that comprises the H chain of (154) and the L chain of (155);
(157) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 422 as CDR1, the amino acid sequence of SEQ ID NO: 424 as CDR2, and the amino acid sequence of SEQ ID NO: 426 as CDR3;
(158) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 428 as CDR1, the amino acid sequence of SEQ ID NO: 430 as CDR2, and the amino acid sequence of SEQ ID NO: 432 as CDR3;
(159) an antibody that comprises the H chain of (157) and the L chain of (158);
(160) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 634 as VH;
(161) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 636 as VL;
(162) an antibody that comprises the H chain of (160) and the L chain of (161);
(163) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 438 as CDR1, the amino acid sequence of SEQ ID NO: 440 as CDR2, and the amino acid sequence of SEQ ID NO: 442 as CDR3;
(164) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 444 as CDR1, the amino acid sequence of SEQ ID NO: 446 as CDR2, and the amino acid sequence of SEQ ID NO: 448 as CDR3;
(165) an antibody that comprises the H chain of (163) and the L chain of (164);
(166) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 638 as VH;
(167) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 640 as VL;
(168) an antibody that comprises the H chain of (166) and the L chain of (167);
(169) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 454 as CDR1, the amino acid sequence of SEQ ID NO: 456 as CDR2, and the amino acid sequence of SEQ ID NO: 458 as CDR3;
(170) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 460 as CDR1, the amino acid sequence of SEQ ID NO: 462 as CDR2, and the amino acid sequence of SEQ ID NO: 464 as CDR3;
(171) an antibody that comprises the H chain of (169) and the L chain of (170);
(172) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 642 as VH;
(173) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 644 as VL;
(174) an antibody that comprises the H chain of (172) and the L chain of (173);
(175) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 470 as CDR1, the amino acid sequence of SEQ ID NO: 472 as CDR2, and the amino acid sequence of SEQ ID NO: 474 as CDR3;
(176) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 476 as CDR1, the amino acid sequence of SEQ ID NO: 478 as CDR2, and the amino acid sequence of SEQ ID NO: 480 as CDR3;
(177) an antibody that comprises the H chain of (175) and the L chain of (176);
(178) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 646 as VH;
(179) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 648 as VL;
(180) an antibody that comprises the H chain of (178) and the L chain of (179);
(181) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 486 as CDR1, the amino acid sequence of SEQ ID NO: 488 as CDR2, and the amino acid sequence of SEQ ID NO: 490 as CDR3;
(182) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 492 as CDR1, the amino acid sequence of SEQ ID NO: 494 as CDR2, and the amino acid sequence of SEQ ID NO: 496 as CDR3;
(183) an antibody that comprises the H chain of (181) and the L chain of (182);
(184) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 650 as VH;
(185) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 652 as VL;
(186) an antibody that comprises the H chain of (184) and the L chain of (185);
(187) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 502 as CDR1, the amino acid sequence of SEQ ID NO: 504 as CDR2, and the amino acid sequence of SEQ ID NO: 506 as CDR3;
(188) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 508 as CDR1, the amino acid sequence of SEQ ID NO: 510 as CDR2, and the amino acid sequence of SEQ ID NO: 512 as CDR3;
(189) an antibody that comprises the H chain of (187) and the L chain of (188);
(190) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 654 as VH;
(191) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 656 as VL;
(192) an antibody that comprises the H chain of (190) and the L chain of (191);
(193) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 518 as CDR1, the amino acid sequence of SEQ ID NO: 520 as CDR2, and the amino acid sequence of SEQ ID NO: 522 as CDR3;
(194) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 524 as CDR1, the amino acid sequence of SEQ ID NO: 526 as CDR2, and the amino acid sequence of SEQ ID NO: 528 as CDR3;
(195) an antibody that comprises the H chain of (193) and the L chain of (194);
(196) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 658 as VH;
(197) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 660 as VL;
(198) an antibody that comprises the H chain of (196) and the L chain of (197);
(199) an antibody that comprises one or more amino acid substitutions, deletions, additions, and/or insertions in the antibody of any one of (1) to (198), which has equivalent activity to the antibody of any one of (1) to (198); and
(200) an antibody that binds to the epitope bound by the antibody of any one of (1) to (198).
[4]The antibody of any one of [1]to [3], wherein the antibody is a chimeric antibody or a humanized antibody.
[5]An antigen-binding fragment of the antibody of any one of [1]to [4].
[6]A pharmaceutical composition comprising the antibody of any one of [1]to [4]or the antigen-binding fragment of [5], and a pharmaceutically acceptable carrier.
[7]The composition of [6], which comprises an agent against cognitive impairment, a therapeutic agent for Alzheimer's disease, an agent for suppressing the progression of Alzheimer's disease, an agent for suppressing senile plaque formation, an agent for suppressing A beta accumulation, an anti-neurotoxic agent, an agent for inhibiting A beta amyloid fibril formation, or an agent against synaptic toxicity.
[8]A method for detecting an A beta oligomer, which comprises the step of detecting an A beta oligomer contained in a sample using the antibody of any one of [1]to [4]or the antigen-binding fragment of [5].
[9]A method of diagnosing whether or not a subject is a possible Alzheimer's disease patient, which comprises using the antibody of any one of [1]to [4]or the antigen-binding fragment of [5], to detect an A beta oligomer in a sample collected from a subject.
[10]A method of diagnosing whether or not a subject is a possible Alzheimer's disease patient, which comprises the steps of:
(a) contacting a sample collected from a subject with the antibody of any one of [1]to [4]or the antigen-binding fragment of [5]; and
(b) measuring the amount of A beta oligomer in the sample,
wherein the subject is determined to be a possible Alzheimer's disease patient, when the amount measured in step (b) is higher than that of a healthy individual.
[11]A method of diagnosing whether or not a subject is a possible Alzheimer's disease patient, which comprises the steps of:
(a) contacting a sample collected from a subject with the antibody of any one of [1]to [4]or the antigen-binding fragment of [5], and an antibody that binds to an A beta monomer; and
(b) measuring the ratio of A beta oligomer to A beta monomer in the sample,
wherein the subject is determined to be a possible Alzheimer's disease patient, when the ratio measured in step (b) is higher than that of a healthy individual.
[12]The method of any one of [8]to [11], wherein the sample is blood or cerebrospinal fluid.
[13]A pharmaceutical agent for use in the method of any one of [8]to [12].
[14]A kit for use in the method of any one of [8]to [12].
Furthermore, the present invention provides the following:
[15]Use of the antibody of any one of [1]to [4]or the antigen-binding fragment of [5]in the production of an agent against cognitive impairment, a therapeutic agent for Alzheimer's disease, an agent for suppressing the progression of Alzheimer's disease, an agent for suppressing senile plaque formation, an agent for suppressing A beta accumulation, an anti-neurotoxic agent, an agent for inhibiting A beta amyloid fibril formation, or an agent against synaptic toxicity.
[16]The antibody of any one of [1]to [4]or the antigen-binding fragment of [5]for use in preventing and/or treating cognitive impairment.
[17]The antibody of any one of [1]to [4]or the antigen-binding fragment of [5]for use in preventing and/or treating Alzheimer's disease.
[18]The antibody of any one of [1]to [4]or the antigen-binding fragment of [5]for use in suppressing the progression of Alzheimer's disease.
[19]The antibody of any one of [1]to [4]or the antigen-binding fragment of [5]for use in suppressing senile plaque formation.
[20]The antibody of any one of [1]to [4]or the antigen-binding fragment of [5]for use in suppressing A beta accumulation.
[21]The antibody of any one of [1]to [4]or the antigen-binding fragment of [5]for use in neutralizing (suppressing) neurotoxicity.
[22]The antibody of any one of [1]to [4]or the antigen-binding fragment of [5]for use in inhibiting A beta amyloid fibril formation.
[23]The antibody of any one of [1]to [4]or the antigen-binding fragment of [5]for use in neutralizing (suppressing) synaptic toxicity.
[24]A method for preventing and/or treating cognitive impairment, which comprises the step of administering the antibody of any one of [1]to [4]or the antigen-binding fragment of [5]as an active ingredient.
[25]A method for preventing and/or treating Alzheimer's disease, which comprises the step of administering the antibody of any one of [1]to [4]or the antigen-binding fragment of [5]as an active ingredient.
[26]A method for suppressing the progression of Alzheimer's disease, which comprises the step of administering the antibody of any one of [1]to [4]or the antigen-binding fragment of [5]as an active ingredient.
[27]A method for suppressing senile plaque formation, which comprises the step of administering the antibody of any one of [1]to [4]or the antigen-binding fragment of [5]as an active ingredient.
[28]A method for suppressing A beta accumulation, which comprises the step of administering the antibody of any one of [1]to [4]or the antigen-binding fragment of [5]as an active ingredient.
[29]A method for neutralizing neurotoxicity, which comprises the step of administering the antibody of any one of [1]to [4]or the antigen-binding fragment of [5]as an active ingredient.
[30]A method for inhibiting A beta amyloid fibril formation, which comprises the step of administering the antibody of any one of [1]to [4]or the antigen-binding fragment of [5]as an active ingredient.
[31]A method for neutralizing synaptic toxicity, which comprises the step of administering the antibody of any one of [1]to [4]or the antigen-binding fragment of [5]as an active ingredient.
[32]Use of the antibody of any one of [1]to [4]or the antigen-binding fragment of [5]for preventing and/or treating cognitive impairment.
[33]Use of the antibody of any one of [1]to [4]or the antigen-binding fragment of [5]for preventing and/or treating Alzheimer's disease.
[34]Use of the antibody of any one of [1]to [4]or the antigen-binding fragment of [5]for suppressing the progression of Alzheimer's disease.
[35]Use of the antibody of any one of [1]to [4]or the antigen-binding fragment of [5]for suppressing senile plaque formation.
[36]Use of the antibody of any one of [1]to [4]or the antigen-binding fragment of [5]for suppressing A beta accumulation.
[37]Use of the antibody of any one of [1]to [4]or the antigen-binding fragment of [5]for neutralizing neurotoxicity.
[38]Use of the antibody of any one of [1]to [4]or the antigen-binding fragment of [5]for inhibiting A beta amyloid fibril formation.
[39]Use of the antibody of any one of [1]to [4]or the antigen-binding fragment of [5]for neutralizing (suppressing) synaptic toxicity.
As described above, the present inventors succeeded in obtaining antibodies that bind specifically to A beta oligomers but not to A beta monomers. That is, the present invention provides antibodies that bind to A beta oligomers but not to A beta monomers. The antibodies are preferably isolated or purified.
(1) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 530;
(2) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 532;
(3) an antibody that comprises the H chain of (1) and the L chain of (2);
(4) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 534;
(5) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 536;
(6) an antibody that comprises the H chain of (4) and the L chain of (5);
(7) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 538;
(8) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 540;
(9) an antibody that comprises the H chain of (7) and the L chain of (8);
(10) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 542;
(11) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 544;
(12) an antibody that comprises the H chain of (10) and the L chain of (11);
(13) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 546;
(14) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 548;
(15) an antibody that comprises the H chain of (13) and the L chain of (14);
(16) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 550;
(17) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 552;
(18) an antibody that comprises the H chain of (16) and the L chain of (17);
(19) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 554;
(20) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 556;
(21) an antibody that comprises the H chain of (19) and the L chain of (20);
(22) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 558;
(23) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 560;
(24) an antibody that comprises the H chain of (22) and the L chain of (23);
(25) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 562;
(26) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 564;
(27) an antibody that comprises the H chain of (25) and the L chain of (26);
(28) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 566;
(29) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 568;
(30) an antibody that comprises the H chain of (28) and the L chain of (29);
(31) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 570;
(32) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 572;
(33) an antibody that comprises the H chain of (31) and the L chain of (32);
(34) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 574;
(35) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 576;
(36) an antibody that comprises the H chain of (34) and the L chain of (35);
(37) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 578;
(38) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 580;
(39) an antibody that comprises the H chain of (37) and the L chain of (38);
(40) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 582;
(41) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 584;
(42) an antibody that comprises the H chain of (40) and the L chain of (41);
(43) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 586;
(44) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 588;
(45) an antibody that comprises the H chain of (43) and the L chain of (44);
(46) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 590;
(47) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 592;
(48) an antibody that comprises the H chain of (46) and the L chain of (47);
(49) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 594;
(50) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 596;
(51) an antibody that comprises the H chain of (49) and the L chain of (50);
(52) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 598;
(53) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 600;
(54) an antibody that comprises the H chain of (52) and the L chain of (53);
(55) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 602;
(56) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 604;
(57) an antibody that comprises the H chain of (55) and the L chain of (56);
(58) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 606;
(59) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 608;
(60) an antibody that comprises the H chain of (58) and the L chain of (59);
(61) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 610;
(62) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 612;
(63) an antibody that comprises the H chain of (61) and the L chain of (62);
(64) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 614;
(65) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 616;
(66) an antibody that comprises the H chain of (64) and the L chain of (65);
(67) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 618;
(68) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 620;
(69) an antibody that comprises the H chain of (67) and the L chain of (68);
(70) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 622;
(71) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 624;
(72) an antibody that comprises the H chain of (70) and the L chain of (71);
(73) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 626;
(74) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 628;
(75) an antibody that comprises the H chain of (73) and the L chain of (74);
(76) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 630;
(77) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 632;
(78) an antibody that comprises the H chain of (76) and the L chain of (77);
(79) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 634;
(80) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 636;
(81) an antibody that comprises the H chain of (79) and the L chain of (80);
(82) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 638;
(83) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 640;
(84) an antibody that comprises the H chain of (82) and the L chain of (83);
(85) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 642;
(86) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 644;
(87) an antibody that comprises the H chain of (85) and the L chain of (86);
(88) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 646;
(89) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 648;
(90) an antibody that comprises the H chain of (88) and the L chain of (89);
(91) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 650;
(92) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 652;
(93) an antibody that comprises the H chain of (91) and the L chain of (92);
(94) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 654;
(95) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 656;
(96) an antibody that comprises the H chain of (94) and the L chain of (95);
(97) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 658;
(98) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 660; and
(99) an antibody that comprises the H chain of (97) and the L chain of (98);
As mentioned above, "CDR1, CDR2, and CDR3" refers to CDR determined by a method well-known in the art (e.g., see Kabat, Elvin A., Sequences of proteins of immunological interest 5th ed., National Institutes of Health, 1991; Chothia et al, J Mol Biol 196:901-917,1987). It is a technical common knowledge in the art that the amino acid sequences of CDR1, CDR2, and CDR3 can be identified in amino acid sequences of regions including CDR1, CDR2, and CDR3, using a method well-known in the art. In the following embodiments, for each antibody, an example of the CDR amino acid sequence determined according to the definition by Kabat is shown.
AL-201 antibody:
(1) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 6 as CDR1, the amino acid sequence of SEQ ID NO: 8 as CDR2, and the amino acid sequence of SEQ ID NO: 10 as CDR3;
(2) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 12 as CDR1, the amino acid sequence of SEQ ID NO: 14 as CDR2, and the amino acid sequence of SEQ ID NO: 16 as CDR3;
(3) an antibody that comprises the H chain of (1) and the L chain of (2);
(4) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 530 as VH;
(5) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 532 as VL;
(6) an antibody that comprises the H chain of (4) and the L chain of (5);
AL-202 antibody:
(7) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 22 as CDR1, the amino acid sequence of SEQ ID NO: 24 as CDR2, and the amino acid sequence of SEQ ID NO: 26 as CDR3;
(8) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 28 as CDR1, the amino acid sequence of SEQ ID NO: 30 as CDR2, and the amino acid sequence of SEQ ID NO: 32 as CDR3;
(9) an antibody that comprises the H chain of (7) and the L chain of (8);
(10) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 534 as VH;
(11) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 536 as VL;
(12) an antibody that comprises the H chain of (10) and the L chain of (11);
AL-203 antibody:
(13) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 38 as CDR1, the amino acid sequence of SEQ ID NO: 40 as CDR2, and the amino acid sequence of SEQ ID NO: 42 as CDR3;
(14) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 44 as CDR1, the amino acid sequence of SEQ ID NO: 46 as CDR2, and the amino acid sequence of SEQ ID NO: 48 as CDR3;
(15) an antibody that comprises the H chain of (13) and the L chain of (14);
(16) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 538 as VH;
(17) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 540 as VL;
(18) an antibody that comprises the H chain of (16) and the L chain of (17);
AL-204 antibody:
(19) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 54 as CDR1, the amino acid sequence of SEQ ID NO: 56 as CDR2, and the amino acid sequence of SEQ ID NO: 58 as CDR3;
(20) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 60 as CDR1, the amino acid sequence of SEQ ID NO: 62 as CDR2, and the amino acid sequence of SEQ ID NO: 64 as CDR3;
(21) an antibody that comprises the H chain of (19) and the L chain of (20);
(22) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 542 as VH;
(23) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 544 as VL;
(24) an antibody that comprises the H chain of (22) and the L chain of (23);
AL-205 antibody:
(25) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 70 as CDR1, the amino acid sequence of SEQ ID NO: 72 as CDR2, and the amino acid sequence of SEQ ID NO: 74 as CDR3;
(26) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 76 as CDR1, the amino acid sequence of SEQ ID NO: 78 as CDR2, and the amino acid sequence of SEQ ID NO: 80 as CDR3;
(27) an antibody that comprises the H chain of (25) and the L chain of (26);
(28) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 546 as VH;
(29) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 548 as VL;
(30) an antibody that comprises the H chain of (28) and the L chain of (29);
AL-206 antibody:
(31) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 86 as CDR1, the amino acid sequence of SEQ ID NO: 88 as CDR2, and the amino acid sequence of SEQ ID NO: 90 as CDR3;
(32) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 92 as CDR1, the amino acid sequence of SEQ ID NO: 94 as CDR2, and the amino acid sequence of SEQ ID NO: 96 as CDR3;
(33) an antibody that comprises the H chain of (31) and the L chain of (32);
(34) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 550 as VH;
(35) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 552 as VL;
(36) an antibody that comprises the H chain of (34) and the L chain of (35);
AL-207 antibody:
(37) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 102 as CDR1, the amino acid sequence of SEQ ID NO: 104 as CDR2, and the amino acid sequence of SEQ ID NO: 106 as CDR3;
(38) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 108 as CDR1, the amino acid sequence of SEQ ID NO: 110 as CDR2, and the amino acid sequence of SEQ ID NO: 112 as CDR3;
(39) an antibody that comprises the H chain of (37) and the L chain of (38);
(40) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 554 as VH;
(41) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 556 as VL;
(42) an antibody that comprises the H chain of (40) and the L chain of (41);
AL-208 antibody:
(43) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 118 as CDR1, the amino acid sequence of SEQ ID NO: 120 as CDR2, and the amino acid sequence of SEQ ID NO: 122 as CDR3;
(44) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 124 as CDR1, the amino acid sequence of SEQ ID NO: 126 as CDR2, and the amino acid sequence of SEQ ID NO: 128 as CDR3;
(45) an antibody that comprises the H chain of (43) and the L chain of (44);
(46) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 558 as VH;
(47) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 560 as VL;
(48) an antibody that comprises the H chain of (46) and the L chain of (47);
AL-209 antibody:
(49) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 134 as CDR1, the amino acid sequence of SEQ ID NO: 136 as CDR2, and the amino acid sequence of SEQ ID NO: 138 as CDR3;
(50) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 140 as CDR1, the amino acid sequence of SEQ ID NO: 142 as CDR2, and the amino acid sequence of SEQ ID NO: 144 as CDR3;
(51) an antibody that comprises the H chain of (49) and the L chain of (50);
(52) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 562 as VH;
(53) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 564 as VL;
(54) an antibody that comprises the H chain of (52) and the L chain of (53);
AL-210 antibody:
(55) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 150 as CDR1, the amino acid sequence of SEQ ID NO: 152 as CDR2, and the amino acid sequence of SEQ ID NO: 154 as CDR3;
(56) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 156 as CDR1, the amino acid sequence of SEQ ID NO: 158 as CDR2, and the amino acid sequence of SEQ ID NO: 160 as CDR3;
(57) an antibody that comprises the H chain of (55) and the L chain of (56);
(58) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 566 as VH;
(59) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 568 as VL;
(60) an antibody that comprises the H chain of (58) and the L chain of (59);
AL-211 antibody:
(61) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 166 as CDR1, the amino acid sequence of SEQ ID NO: 168 as CDR2, and the amino acid sequence of SEQ ID NO: 170 as CDR3;
(62) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 172 as CDR1, the amino acid sequence of SEQ ID NO: 174 as CDR2, and the amino acid sequence of SEQ ID NO: 176 as CDR3;
(63) an antibody that comprises the H chain of (61) and the L chain of (62);
(64) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 570 as VH;
(65) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 572 as VL;
(66) an antibody that comprises the H chain of (64) and the L chain of (65);
AL-212 antibody:
(67) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 182 as CDR1, the amino acid sequence of SEQ ID NO: 184 as CDR2, and the amino acid sequence of SEQ ID NO: 186 as CDR3;
(68) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 188 as CDR1, the amino acid sequence of SEQ ID NO: 190 as CDR2, and the amino acid sequence of SEQ ID NO: 192 as CDR3;
(69) an antibody that comprises the H chain of (67) and the L chain of (68);
(70) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 574 as VH;
(71) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 576 as VL;
(72) an antibody that comprises the H chain of (70) and the L chain of (71);
AL-213 antibody:
(73) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 198 as CDR1, the amino acid sequence of SEQ ID NO: 200 as CDR2, and the amino acid sequence of SEQ ID NO: 202 as CDR3;
(74) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 204 as CDR1, the amino acid sequence of SEQ ID NO: 206 as CDR2, and the amino acid sequence of SEQ ID NO: 208 as CDR3;
(75) an antibody that comprises the H chain of (73) and the L chain of (74);
(76) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 578 as VH;
(77) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 580 as VL;
(78) an antibody that comprises the H chain of (75) and the L chain of (76);
AL-214 antibody:
(79) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 214 as CDR1, the amino acid sequence of SEQ ID NO: 216 as CDR2, and the amino acid sequence of SEQ ID NO: 218 as CDR3;
(80) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 220 as CDR1, the amino acid sequence of SEQ ID NO: 222 as CDR2, and the amino acid sequence of SEQ ID NO: 224 as CDR3;
(81) an antibody that comprises the H chain of (79) and the L chain of (80);
(82) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 582 as VH;
(83) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 584 as VL;
(84) an antibody that comprises the H chain of (82) and the L chain of (83);
AL-215 antibody:
(85) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 230 as CDR1, the amino acid sequence of SEQ ID NO: 232 as CDR2, and the amino acid sequence of SEQ ID NO: 234 as CDR3;
(86) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 236 as CDR1, the amino acid sequence of SEQ ID NO: 238 as CDR2, and the amino acid sequence of SEQ ID NO: 240 as CDR3;
(87) an antibody that comprises the H chain of (85) and the L chain of (86);
(88) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 586 as VH;
(89) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 588 as VL;
(90) an antibody that comprises the H chain of (88) and the L chain of (89);
AL-216 antibody:
(91) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 246 as CDR1, the amino acid sequence of SEQ ID NO: 248 as CDR2, and the amino acid sequence of SEQ ID NO: 250 as CDR3;
(92) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 252 as CDR1, the amino acid sequence of SEQ ID NO: 254 as CDR2, and the amino acid sequence of SEQ ID NO: 256 as CDR3;
(93) an antibody that comprises the H chain of (91) and the L chain of (92);
(94) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 590 as VH;
(95) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 592 as VL;
(96) an antibody that comprises the H chain of (94) and the L chain of (95);
AL-217 antibody:
(97) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 262 as CDR1, the amino acid sequence of SEQ ID NO: 264 as CDR2, and the amino acid sequence of SEQ ID NO: 266 as CDR3;
(98) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 268 as CDR1, the amino acid sequence of SEQ ID NO: 270 as CDR2, and the amino acid sequence of SEQ ID NO: 272 as CDR3;
(99) an antibody that comprises the H chain of (97) and the L chain of (98);
(100) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 594 as VH;
(101) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 596 as VL;
(102) an antibody that comprises the H chain of (100) and the L chain of (101);
AL-218 antibody:
(103) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 278 as CDR1, the amino acid sequence of SEQ ID NO: 280 as CDR2, and the amino acid sequence of SEQ ID NO: 282 as CDR3;
(104) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 284 as CDR1, the amino acid sequence of SEQ ID NO: 286 as CDR2, and the amino acid sequence of SEQ ID NO: 288 as CDR3;
(105) an antibody that comprises the H chain of (103) and the L chain of (104);
(106) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 598 as VH;
(107) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 600 as VL;
(108) an antibody that comprises the H chain of (106) and the L chain of (107);
AL-219 antibody:
(109) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 294 as CDR1, the amino acid sequence of SEQ ID NO: 296 as CDR2, and the amino acid sequence of SEQ ID NO: 298 as CDR3;
(110) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 300 as CDR1, the amino acid sequence of SEQ ID NO: 302 as CDR2, and the amino acid sequence of SEQ ID NO: 304 as CDR3;
(111) an antibody that comprises the H chain of (109) and the L chain of (110);
(112) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 602 as VH;
(113) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 604 as VL;
(114) an antibody that comprises the H chain of (112) and the L chain of (113);
AL-220 antibody:
(115) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 310 as CDR1, the amino acid sequence of SEQ ID NO: 312 as CDR2, and the amino acid sequence of SEQ ID NO: 314 as CDR3;
(116) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 316 as CDR1, the amino acid sequence of SEQ ID NO: 318 as CDR2, and the amino acid sequence of SEQ ID NO: 320 as CDR3;
(117) an antibody that comprises the H chain of (115) and the L chain of (116);
(118) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 606 as VH;
(119) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 608 as VL;
(120) an antibody that comprises the H chain of (118) and the L chain of (119);
AL-221 antibody:
(121) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 326 as CDR1, the amino acid sequence of SEQ ID NO: 328 as CDR2, and the amino acid sequence of SEQ ID NO: 330 as CDR3;
(122) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 332 as CDR1, the amino acid sequence of SEQ ID NO: 334 as CDR2, and the amino acid sequence of SEQ ID NO: 336 as CDR3;
(123) an antibody that comprises the H chain of (121) and the L chain of (122);
(124) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 610 as VH;
(125) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 612 as VL;
(126) an antibody that comprises the H chain of (124) and the L chain of (125);
AL-222 antibody:
(127) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 342 as CDR1, the amino acid sequence of SEQ ID NO: 344 as CDR2, and the amino acid sequence of SEQ ID NO: 346 as CDR3;
(128) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 348 as CDR1, the amino acid sequence of SEQ ID NO: 350 as CDR2, and the amino acid sequence of SEQ ID NO: 352 as CDR3;
(129) an antibody that comprises the H chain of (127) and the L chain of (128);
(130) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 614 as VH;
(131) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 616 as VL;
(132) an antibody that comprises the H chain of (130) and the L chain of (131);
AL-223 antibody:
(133) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 358 as CDR1, the amino acid sequence of SEQ ID NO: 360 as CDR2, and the amino acid sequence of SEQ ID NO: 362 as CDR3;
(134) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 364 as CDR1, the amino acid sequence of SEQ ID NO: 366 as CDR2, and the amino acid sequence of SEQ ID NO: 368 as CDR3;
(135) an antibody that comprises the H chain of (133) and the L chain of (134);
(136) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 618 as VH;
(137) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 620 as VL;
(138) an antibody that comprises the H chain of (136) and the L chain of (137);
AL-224 antibody:
(139) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 374 as CDR1, the amino acid sequence of SEQ ID NO: 376 as CDR2, and the amino acid sequence of SEQ ID NO: 378 as CDR3;
(140) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 380 as CDR1, the amino acid sequence of SEQ ID NO: 382 as CDR2, and the amino acid sequence of SEQ ID NO: 384 as CDR3;
(141) an antibody that comprises the H chain of (139) and the L chain of (140);
(142) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 622 as VH;
(143) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 624 as VL;
(144) an antibody that comprises the H chain of (142) and the L chain of (143);
AL-225 antibody:
(145) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 390 as CDR1, the amino acid sequence of SEQ ID NO: 392 as CDR2, and the amino acid sequence of SEQ ID NO: 394 as CDR3;
(146) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 396 as CDR1, the amino acid sequence of SEQ ID NO: 398 as CDR2, and the amino acid sequence of SEQ ID NO: 400 as CDR3;
(147) an antibody that comprises the H chain of (145) and the L chain of (146);
(148) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 626 as VH;
(149) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 628 as VL;
(150) an antibody that comprises the H chain of (148) and the L chain of (149);
AL-226 antibody:
(151) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 406 as CDR1, the amino acid sequence of SEQ ID NO: 408 as CDR2, and the amino acid sequence of SEQ ID NO: 410 as CDR3;
(152) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 412 as CDR1, the amino acid sequence of SEQ ID NO: 414 as CDR2, and the amino acid sequence of SEQ ID NO: 416 as CDR3;
(153) an antibody that comprises the H chain of (151) and the L chain of (152);
(154) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 630 as VH;
(155) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 632 as VL;
(156) an antibody that comprises the H chain of (154) and the L chain of (155);
AL-227 antibody:
(157) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 422 as CDR1, the amino acid sequence of SEQ ID NO: 424 as CDR2, and the amino acid sequence of SEQ ID NO: 426 as CDR3;
(158) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 428 as CDR1, the amino acid sequence of SEQ ID NO: 430 as CDR2, and the amino acid sequence of SEQ ID NO: 432 as CDR3;
(159) an antibody that comprises the H chain of (157) and the L chain of (158);
(160) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 634 as VH;
(161) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 636 as VL;
(162) an antibody that comprises the H chain of (160) and the L chain of (161);
AL-228 antibody:
(163) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 438 as CDR1, the amino acid sequence of SEQ ID NO: 440 as CDR2, and the amino acid sequence of SEQ ID NO: 442 as CDR3;
(164) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 444 as CDR1, the amino acid sequence of SEQ ID NO: 446 as CDR2, and the amino acid sequence of SEQ ID NO: 448 as CDR3;
(165) an antibody that comprises the H chain of (163) and the L chain of (164);
(166) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 638 as VH;
(167) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 640 as VL;
(168) an antibody that comprises the H chain of (166) and the L chain of (167);
AL-229 antibody:
(169) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 454 as CDR1, the amino acid sequence of SEQ ID NO: 456 as CDR2, and the amino acid sequence of SEQ ID NO: 458 as CDR3;
(170) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 460 as CDR1, the amino acid sequence of SEQ ID NO: 462 as CDR2, and the amino acid sequence of SEQ ID NO: 464 as CDR3;
(171) an antibody that comprises the H chain of (169) and the L chain of (170);
(172) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 642 as VH;
(173) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 644 as VL;
(174) an antibody that comprises the H chain of (172) and the L chain of (173);
AL-230 antibody:
(175) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 470 as CDR1, the amino acid sequence of SEQ ID NO: 472 as CDR2, and the amino acid sequence of SEQ ID NO: 474 as CDR3;
(176) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 476 as CDR1, the amino acid sequence of SEQ ID NO: 478 as CDR2, and the amino acid sequence of SEQ ID NO: 480 as CDR3;
(177) an antibody that comprises the H chain of (175) and the L chain of (176);
(178) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 646 as VH;
(179) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 648 as VL;
(180) an antibody that comprises the H chain of (178) and the L chain of (179);
AL-231 antibody:
(181) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 486 as CDR1, the amino acid sequence of SEQ ID NO: 488 as CDR2, and the amino acid sequence of SEQ ID NO: 490 as CDR3;
(182) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 492 as CDR1, the amino acid sequence of SEQ ID NO: 494 as CDR2, and the amino acid sequence of SEQ ID NO: 496 as CDR3;
(183) an antibody that comprises the H chain of (181) and the L chain of (182);
(184) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 650 as VH;
(185) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 652 as VL;
(186) an antibody that comprises the H chain of (184) and the L chain of (185);
AL-232 antibody:
(187) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 502 as CDR1, the amino acid sequence of SEQ ID NO: 504 as CDR2, and the amino acid sequence of SEQ ID NO: 506 as CDR3;
(188) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 508 as CDR1, the amino acid sequence of SEQ ID NO: 510 as CDR2, and the amino acid sequence of SEQ ID NO: 512 as CDR3;
(189) an antibody that comprises the H chain of (187) and the L chain of (188);
(190) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 654 as VH;
(191) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 656 as VL;
(192) an antibody that comprises the H chain of (190) and the L chain of (191);
AL-233 antibody:
(193) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 518 as CDR1, the amino acid sequence of SEQ ID NO: 520 as CDR2, and the amino acid sequence of SEQ ID NO: 522 as CDR3;
(194) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 524 as CDR1, the amino acid sequence of SEQ ID NO: 526 as CDR2, and the amino acid sequence of SEQ ID NO: 528 as CDR3;
(195) an antibody that comprises the H chain of (193) and the L chain of (194);
(196) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 658 as VH;
(197) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 660 as VL;
(198) an antibody that comprises the H chain of (196) and the L chain of (197);
(199) an antibody that comprises one or more amino acid substitutions, deletions, additions, and/or insertions in the antibody of any one of (1) to (198), which has equivalent activity to the antibody of any one of (1) to (198); and
(200) an antibody that binds to the epitope bound by the antibody of any one of (1) to (198).
AL-201 antibody:
An example of the VH in the above-mentioned "H chain having the amino acid sequence of SEQ ID NO: 6 (sequence of the AL-201antibody H-chain CDR1) as CDR1, the amino acid sequence of SEQ ID NO: 8 (sequence of the AL-201 antibody H-chain CDR2) as CDR2, and the amino acid sequence of SEQ ID NO: 10 (sequence of the AL-201 antibody H-chain CDR3) as CDR3"of (1) is a VH comprising the amino acid sequence of SEQ ID NO: 530 (sequence of the AL-201 antibody VH).
An example of the VH in the above-mentioned "H chain having the amino acid sequence of SEQ ID NO: 22 (sequence of the AL-202 antibody H-chain CDR1) as CDR1, the amino acid sequence of SEQ ID NO: 24 (sequence of the AL-202 antibody H-chain CDR2) as CDR2, and the amino acid sequence of SEQ ID NO: 26 (sequence of the AL-202 antibody H-chain CDR3) as CDR3"of (7) is a VH comprising the amino acid sequence of SEQ ID NO: 534 (sequence of the AL-202 antibody VH).
An example of the VH in the above-mentioned "H chain having the amino acid sequence of SEQ ID NO: 38 (sequence of the AL-203 antibody H-chain CDR1) as CDR1, the amino acid sequence of SEQ ID NO: 40 (sequence of the AL-203 antibody H-chain CDR2) as CDR2, and the amino acid sequence of SEQ ID NO: 42 (sequence of the AL-203 antibody H-chain CDR3) as CDR3"of (13) is a VH comprising the amino acid sequence of SEQ ID NO: 538 (sequence of the AL-203 antibody VH).
An example of the VH in the above-mentioned "H chain having the amino acid sequence of SEQ ID NO: 54 (sequence of the AL-204 antibody H-chain CDR1) as CDR1, the amino acid sequence of SEQ ID NO: 56 (sequence of the AL-204 antibody H-chain CDR2) as CDR2, and the amino acid sequence of SEQ ID NO: 58 (sequence of the AL-204 antibody H-chain CDR3) as CDR3"of (19) is a VH comprising the amino acid sequence of SEQ ID NO: 542 (sequence of the AL-204 antibody VH).
An example of the VH in the above-mentioned "H chain having the amino acid sequence of SEQ ID NO: 70 (sequence of the AL-205 antibody H-chain CDR1) as CDR1, the amino acid sequence of SEQ ID NO: 72 (sequence of the AL-205 antibody H-chain CDR2) as CDR2, and the amino acid sequence of SEQ ID NO: 74 (sequence of the AL-205 antibody H-chain CDR3) as CDR3"of (25) is a VH comprising the amino acid sequence of SEQ ID NO: 66, more preferably, a VH comprising the amino acid sequence of SEQ ID NO: 546 (sequence of the AL-205 antibody VH).
An example of the VH in the above-mentioned "H chain having the amino acid sequence of SEQ ID NO: 86 (sequence of the AL-206 antibody H-chain CDR1) as CDR1, the amino acid sequence of SEQ ID NO: 88 (sequence of the AL-206 antibody H-chain CDR2) as CDR2, and the amino acid sequence of SEQ ID NO: 90 (sequence of the AL-206 antibody H-chain CDR3) as CDR3"of (31) is a VH comprising the amino acid sequence of SEQ ID NO: 550 (sequence of the AL-206 antibody VH).
An example of the VH in the above-mentioned "H chain having the amino acid sequence of SEQ ID NO: 102 (sequence of the AL-207 antibody H-chain CDR1) as CDR1, the amino acid sequence of SEQ ID NO: 104 (sequence of the AL-207 antibody H-chain CDR2) as CDR2, and the amino acid sequence of SEQ ID NO: 106 (sequence of the AL-207 antibody H-chain CDR3) as CDR3"of (37) is a VH comprising the amino acid sequence of SEQ ID NO: 554 (sequence of the AL-207 antibody VH).
An example of the VH in the above-mentioned "H chain having the amino acid sequence of SEQ ID NO: 118 (sequence of the AL-208 antibody H-chain CDR1) as CDR1, the amino acid sequence of SEQ ID NO: 120 (sequence of the AL-208 antibody H-chain CDR2) as CDR2, and the amino acid sequence of SEQ ID NO: 122 (sequence of the AL-208 antibody H-chain CDR3) as CDR3"of (43) is a VH comprising the amino acid sequence of SEQ ID NO: 558 (sequence of the AL-208 antibody VH).
An example of the VH in the above-mentioned "H chain having the amino acid sequence of SEQ ID NO: 134 (sequence of the AL-209antibody H-chain CDR1) as CDR1, the amino acid sequence of SEQ ID NO: 136 (sequence of the AL-209 antibody H-chain CDR2) as CDR2, and the amino acid sequence of SEQ ID NO: 138 (sequence of the AL-209 antibody H-chain CDR3) as CDR3"of (49) is a VH comprising the amino acid sequence of SEQ ID NO: 562 (sequence of the AL-209 antibody VH).
An example of the VH in the above-mentioned "H chain having the amino acid sequence of SEQ ID NO: 150 (sequence of the AL-210 antibody H-chain CDR1) as CDR1, the amino acid sequence of SEQ ID NO: 152 (sequence of the AL-210 antibody H-chain CDR2) as CDR2, and the amino acid sequence of SEQ ID NO: 154 (sequence of the AL-210 antibody H-chain CDR3) as CDR3"of (55) is a VH comprising the amino acid sequence of SEQ ID NO: 566 (sequence of the AL-210 antibody VH).
An example of the VH in the above-mentioned "H chain having the amino acid sequence of SEQ ID NO: 166 (sequence of the AL-211 antibody H-chain CDR1) as CDR1, the amino acid sequence of SEQ ID NO: 168 (sequence of the AL-211 antibody H-chain CDR2) as CDR2, and the amino acid sequence of SEQ ID NO: 170 (sequence of the AL-211 antibody H-chain CDR3) as CDR3"of (61) is a VH comprising the amino acid sequence of SEQ ID NO: 570 (sequence of the AL-211 antibody VH).
An example of the VH in the above-mentioned "H chain having the amino acid sequence of SEQ ID NO: 182 (sequence of the AL-212 antibody H-chain CDR1) as CDR1, the amino acid sequence of SEQ ID NO: 184 (sequence of the AL-212 antibody H-chain CDR2) as CDR2, and the amino acid sequence of SEQ ID NO: 186 (sequence of the AL-212 antibody H-chain CDR3) as CDR3"of (67) is a VH comprising the amino acid sequence of SEQ ID NO: 574 (sequence of the AL-212 antibody VH).
An example of the VH in the above-mentioned "H chain having the amino acid sequence of SEQ ID NO: 198 (sequence of the AL-213 antibody H-chain CDR1) as CDR1, the amino acid sequence of SEQ ID NO: 200 (sequence of the AL-213 antibody H-chain CDR2) as CDR2, and the amino acid sequence of SEQ ID NO: 202 (sequence of the AL-213 antibody H-chain CDR3) as CDR3"of (73) is a VH comprising the amino acid sequence of SEQ ID NO: 578 (sequence of the AL-213 antibody VH).
An example of the VH in the above-mentioned "H chain having the amino acid sequence of SEQ ID NO: 214 (sequence of the AL-214 antibody H-chain CDR1) as CDR1, the amino acid sequence of SEQ ID NO: 216 (sequence of the AL-214 antibody H-chain CDR2) as CDR2, and the amino acid sequence of SEQ ID NO: 218 (sequence of the AL-214 antibody H-chain CDR3) as CDR3"of (79) is a VH comprising the amino acid sequence of SEQ ID NO: 582 (sequence of the AL-214 antibody VH).
An example of the VH in the above-mentioned "H chain having the amino acid sequence of SEQ ID NO: 230 (sequence of the AL-215 antibody H-chain CDR1) as CDR1, the amino acid sequence of SEQ ID NO: 232 (sequence of the AL-215 antibody H-chain CDR2) as CDR2, and the amino acid sequence of SEQ ID NO: 234 (sequence of the AL-215 antibody H-chain CDR3) as CDR3"of (85) is a VH comprising the amino acid sequence of SEQ ID NO: 586 (sequence of the AL-215 antibody VH).
An example of the VH in the above-mentioned "H chain having the amino acid sequence of SEQ ID NO: 246 (sequence of the AL-216 antibody H-chain CDR1) as CDR1, the amino acid sequence of SEQ ID NO: 248 (sequence of the AL-216 antibody H-chain CDR2) as CDR2, and the amino acid sequence of SEQ ID NO: 250 (sequence of the AL-216 antibody H-chain CDR3) as CDR3"of (91) is a VH comprising the amino acid sequence of SEQ ID NO: 590 (sequence of the AL-216 antibody VH).
An example of the VH in the above-mentioned "H chain having the amino acid sequence of SEQ ID NO: 262 (sequence of the AL-217 antibody H-chain CDR1) as CDR1, the amino acid sequence of SEQ ID NO: 264 (sequence of the AL-217 antibody H-chain CDR2) as CDR2, and the amino acid sequence of SEQ ID NO: 266 (sequence of the AL-217 antibody H-chain CDR3) as CDR3"of (97) is a VH comprising the amino acid sequence of SEQ ID NO: 594 (sequence of the AL-217 antibody VH).
An example of the VH in the above-mentioned "H chain having the amino acid sequence of SEQ ID NO: 278 (sequence of the AL-218 antibody H-chain CDR1) as CDR1, the amino acid sequence of SEQ ID NO: 280 (sequence of the AL-218 antibody H-chain CDR2) as CDR2, and the amino acid sequence of SEQ ID NO: 282 (sequence of the AL-218 antibody H-chain CDR3) as CDR3"of (103) is a VH comprising the amino acid sequence of SEQ ID NO: 598 (sequence of the AL-218 antibody VH).
An example of the VH in the above-mentioned "H chain having the amino acid sequence of SEQ ID NO: 294 (sequence of the AL-219 antibody H-chain CDR1) as CDR1, the amino acid sequence of SEQ ID NO: 296 (sequence of the AL-219 antibody H-chain CDR2) as CDR2, and the amino acid sequence of SEQ ID NO: 298 (sequence of the AL-219 antibody H-chain CDR3) as CDR3"of (109) is a VH comprising the amino acid sequence of SEQ ID NO: 602 (sequence of the AL-219 antibody VH).
An example of the VH in the above-mentioned "H chain having the amino acid sequence of SEQ ID NO: 310 (sequence of the AL-220 antibody H-chain CDR1) as CDR1, the amino acid sequence of SEQ ID NO: 312 (sequence of the AL-220 antibody H-chain CDR2) as CDR2, and the amino acid sequence of SEQ ID NO: 314 (sequence of the AL-220 antibody H-chain CDR3) as CDR3"of (115) is a VH comprising the amino acid sequence of SEQ ID NO: 606 (sequence of the AL-220 antibody VH).
An example of the VH in the above-mentioned "H chain having the amino acid sequence of SEQ ID NO: 326 (sequence of the AL-221 antibody H-chain CDR1) as CDR1, the amino acid sequence of SEQ ID NO: 328 (sequence of the AL-221 antibody H-chain CDR2) as CDR2, and the amino acid sequence of SEQ ID NO: 330 (sequence of the AL-221 antibody H-chain CDR3) as CDR3"of (121) is a VH comprising the amino acid sequence of SEQ ID NO: 610 (sequence of the AL-221 antibody VH).
An example of the VH in the above-mentioned "H chain having the amino acid sequence of SEQ ID NO: 342 (sequence of the AL-222 antibody H-chain CDR1) as CDR1, the amino acid sequence of SEQ ID NO: 344 (sequence of the AL-222 antibody H-chain CDR2) as CDR2, and the amino acid sequence of SEQ ID NO: 346 (sequence of the AL-222 antibody H-chain CDR3) as CDR3"of (127) is a VH comprising the amino acid sequence of SEQ ID NO: 614 (sequence of the AL-222 antibody VH).
An example of the VH in the above-mentioned "H chain having the amino acid sequence of SEQ ID NO: 358 (sequence of the AL-223 antibody H-chain CDR1) as CDR1, the amino acid sequence of SEQ ID NO: 360 (sequence of the AL-223 antibody H-chain CDR2) as CDR2, and the amino acid sequence of SEQ ID NO: 362 (sequence of the AL-223 antibody H-chain CDR3) as CDR3"of (133) is a VH comprising the amino acid sequence of SEQ ID NO: 618 (sequence of the AL-223 antibody VH).
An example of the VH in the above-mentioned "H chain having the amino acid sequence of SEQ ID NO: 374 (sequence of the AL-224 antibody H-chain CDR1) as CDR1, the amino acid sequence of SEQ ID NO: 376 (sequence of the AL-224 antibody H-chain CDR2) as CDR2, and the amino acid sequence of SEQ ID NO: 378 (sequence of the AL-224 antibody H-chain CDR3) as CDR3"of (139) is a VH comprising the amino acid sequence of SEQ ID NO: 622 (sequence of the AL-224 antibody VH).
An example of the VH in the above-mentioned "H chain having the amino acid sequence of SEQ ID NO: 390 (sequence of the AL-225 antibody H-chain CDR1) as CDR1, the amino acid sequence of SEQ ID NO: 392 (sequence of the AL-225 antibody H-chain CDR2) as CDR2, and the amino acid sequence of SEQ ID NO: 394 (sequence of the AL-225 antibody H-chain CDR3) as CDR3"of (145) is a VH comprising the amino acid sequence of SEQ ID NO: 626 (sequence of the AL-225 antibody VH).
An example of the VH in the above-mentioned "H chain having the amino acid sequence of SEQ ID NO: 406 (sequence of the AL-226 antibody H-chain CDR1) as CDR1, the amino acid sequence of SEQ ID NO: 408 (sequence of the AL-226 antibody H-chain CDR2) as CDR2, and the amino acid sequence of SEQ ID NO: 410 (sequence of the AL-226 antibody H-chain CDR3) as CDR3"of (151) is a VH comprising the amino acid sequence of SEQ ID NO: 630 (sequence of the AL-226 antibody VH).
An example of the VH in the above-mentioned "H chain having the amino acid sequence of SEQ ID NO: 422 (sequence of the AL-227 antibody H-chain CDR1) as CDR1, the amino acid sequence of SEQ ID NO: 424 (sequence of the AL-227 antibody H-chain CDR2) as CDR2, and the amino acid sequence of SEQ ID NO: 426 (sequence of the AL-227 antibody H-chain CDR3) as CDR3"of (157) is a VH comprising the amino acid sequence of SEQ ID NO: 634 (sequence of the AL-227 antibody VH).
An example of the VH in the above-mentioned "H chain having the amino acid sequence of SEQ ID NO: 438 (sequence of the AL-228 antibody H-chain CDR1) as CDR1, the amino acid sequence of SEQ ID NO: 440 (sequence of the AL-228 antibody H-chain CDR2) as CDR2, and the amino acid sequence of SEQ ID NO: 442 (sequence of the AL-228 antibody H-chain CDR3) as CDR3"of (163) is a VH comprising the amino acid sequence of SEQ ID NO: 638 (sequence of the AL-228 antibody VH).
An example of the VH in the above-mentioned "H chain having the amino acid sequence of SEQ ID NO: 454 (sequence of the AL-229 antibody H-chain CDR1) as CDR1, the amino acid sequence of SEQ ID NO: 456 (sequence of the AL-229 antibody H-chain CDR2) as CDR2, and the amino acid sequence of SEQ ID NO: 458 (sequence of the AL-229 antibody H-chain CDR3) as CDR3"of (169) is a VH comprising the amino acid sequence of SEQ ID NO: 642 (sequence of the AL-229 antibody VH).
An example of the VH in the above-mentioned "H chain having the amino acid sequence of SEQ ID NO: 470 (sequence of the AL-230 antibody H-chain CDR1) as CDR1, the amino acid sequence of SEQ ID NO: 472 (sequence of the AL-230 antibody H-chain CDR2) as CDR2, and the amino acid sequence of SEQ ID NO: 474 (sequence of the AL-230 antibody H-chain CDR3) as CDR3"of (175) is a VH comprising the amino acid sequence of SEQ ID NO: 646 (sequence of the AL-230 antibody VH).
An example of the VH in the above-mentioned "H chain having the amino acid sequence of SEQ ID NO: 486 (sequence of the AL-231 antibody H-chain CDR1) as CDR1, the amino acid sequence of SEQ ID NO: 488 (sequence of the AL-231 antibody H-chain CDR2) as CDR2, and the amino acid sequence of SEQ ID NO: 490 (sequence of the AL-231 antibody H-chain CDR3) as CDR3"of (181) is a VH comprising the amino acid sequence of SEQ ID NO: 650 (sequence of the AL-231 antibody VH).
An example of the VH in the above-mentioned "H chain having the amino acid sequence of SEQ ID NO: 502 (sequence of the AL-232 antibody H-chain CDR1) as CDR1, the amino acid sequence of SEQ ID NO: 504 (sequence of the AL-232 antibody H-chain CDR2) as CDR2, and the amino acid sequence of SEQ ID NO: 506 (sequence of the AL-232 antibody H-chain CDR3) as CDR3"of (187) is a VH comprising the amino acid sequence of SEQ ID NO: 654 (sequence of the AL-232 antibody VH).
An example of the VH in the above-mentioned "H chain having the amino acid sequence of SEQ ID NO: 518 (sequence of the AL-233 antibody H-chain CDR1) as CDR1, the amino acid sequence of SEQ ID NO: 520 (sequence of the AL-233 antibody H-chain CDR2) as CDR2, and the amino acid sequence of SEQ ID NO: 524 (sequence of the AL-233 antibody H-chain CDR3) as CDR3"of (193) is a VH comprising the amino acid sequence of SEQ ID NO: 658 (sequence of the AL-233 antibody VH).
the amino acid sequence and the nucleotide sequence of the H-chain variable region (VH) are shown in SEQ ID NO: 530 and SEQ ID NO: 529, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain variable region (VL) are shown in SEQ ID NO: 532 and SEQ ID NO: 531, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR1 are shown in SEQ ID NO: 6 and SEQ ID NO: 5, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR2 are shown in SEQ ID NO: 8 and SEQ ID NO: 7, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR3 are shown in SEQ ID NO: 10 and SEQ ID NO: 9, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR1 are shown in SEQ ID NO: 12 and SEQ ID NO: 11, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR2 are shown in SEQ ID NO: 14 and SEQ ID NO: 13, respectively; and
the amino acid sequence and the nucleotide sequence of the L-chain CDR3 are shown in SEQ ID NO: 16 and SEQ ID NO: 15 , respectively.
the amino acid sequence and the nucleotide sequence of the H-chain variable region (VH) are shown in SEQ ID NO: 534 and SEQ ID NO: 533, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain variable region (VL) are shown in SEQ ID NO: 536 and SEQ ID NO: 535, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR1 are shown in SEQ ID NO: 22 and SEQ ID NO: 21, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR2 are shown in SEQ ID NO: 24 and SEQ ID NO: 23, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR3 are shown in SEQ ID NO: 26 and SEQ ID NO: 25, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR1 are shown in SEQ ID NO: 28 and SEQ ID NO: 27, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR2 are shown in SEQ ID NO: 30 and SEQ ID NO: 29, respectively; and
the amino acid sequence and the nucleotide sequence of the L-chain CDR3 are shown in SEQ ID NO: 32 and SEQ ID NO: 31, respectively.
the amino acid sequence and the nucleotide sequence of the H-chain variable region (VH) are shown in SEQ ID NO: 538 and SEQ ID NO: 537, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain variable region (VL) are shown in SEQ ID NO: 540 and SEQ ID NO: 539, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR1 are shown in SEQ ID NO: 38 and SEQ ID NO: 37, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR2 are shown in SEQ ID NO: 40 and SEQ ID NO: 39, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR3 are shown in SEQ ID NO: 42 and SEQ ID NO: 41, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR1 are shown in SEQ ID NO: 44 and SEQ ID NO: 43, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR2 are shown in SEQ ID NO: 46 and SEQ ID NO: 45, respectively; and
the amino acid sequence and the nucleotide sequence of the L-chain CDR3 are shown in SEQ ID NO: 48 and SEQ ID NO: 47, respectively.
the amino acid sequence and the nucleotide sequence of the H-chain variable region (VH) are shown in SEQ ID NO: 542 and SEQ ID NO: 541, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain variable region (VL) are shown in SEQ ID NO: 544 and SEQ ID NO: 543, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR1 are shown in SEQ ID NO: 54 and SEQ ID NO: 53, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR2 are shown in SEQ ID NO: 56 and SEQ ID NO: 55, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR3 are shown in SEQ ID NO: 58 and SEQ ID NO: 57, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR1 are shown in SEQ ID NO: 60 and SEQ ID NO: 59, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR2 are shown in SEQ ID NO: 62 and SEQ ID NO: 61, respectively; and
the amino acid sequence and the nucleotide sequence of the L-chain CDR3 are shown in SEQ ID NO: 64 and SEQ ID NO: 63, respectively.
the amino acid sequence and the nucleotide sequence of the H-chain variable region (VH) are shown in SEQ ID NO: 546 and SEQ ID NO: 545, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain variable region (VL) are shown in SEQ ID NO: 548 and SEQ ID NO: 547, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR1 are shown in SEQ ID NO: 70 and SEQ ID NO: 69, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR2 are shown in SEQ ID NO: 72 and SEQ ID NO: 71, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR3 are shown in SEQ ID NO: 74 and SEQ ID NO: 73, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR1 are shown in SEQ ID NO: 76 and SEQ ID NO: 75, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR2 are shown in SEQ ID NO: 78 and SEQ ID NO: 77, respectively; and
the amino acid sequence and the nucleotide sequence of the L-chain CDR3 are shown in SEQ ID NO: 80 and SEQ ID NO: 79, respectively.
the amino acid sequence and the nucleotide sequence of the H-chain variable region (VH) are shown in SEQ ID NO: 550 and SEQ ID NO: 549, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain variable region (VL) are shown in SEQ ID NO: 552 and SEQ ID NO: 551, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR1 are shown in SEQ ID NO: 86 and SEQ ID NO: 85, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR2 are shown in SEQ ID NO: 88 and SEQ ID NO: 87, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR3 are shown in SEQ ID NO: 90 and SEQ ID NO: 89, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR1 are shown in SEQ ID NO: 92 and SEQ ID NO: 91, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR2 are shown in SEQ ID NO: 94 and SEQ ID NO: 93, respectively; and
the amino acid sequence and the nucleotide sequence of the L-chain CDR3 are shown in SEQ ID NO: 96 and SEQ ID NO: 95, respectively.
the amino acid sequence and the nucleotide sequence of the H-chain variable region (VH) are shown in SEQ ID NO: 554 and SEQ ID NO: 553, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain variable region (VL) are shown in SEQ ID NO: 556 and SEQ ID NO: 555, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR1 are shown in SEQ ID NO: 102 and SEQ ID NO: 101, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR2 are shown in SEQ ID NO: 104 and SEQ ID NO: 103, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR3 are shown in SEQ ID NO: 106 and SEQ ID NO: 105, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR1 are shown in SEQ ID NO: 108 and SEQ ID NO: 107, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR2 are shown in SEQ ID NO: 110 and SEQ ID NO: 109, respectively; and
the amino acid sequence and the nucleotide sequence of the L-chain CDR3 are shown in SEQ ID NO: 112 and SEQ ID NO: 111, respectively.
the amino acid sequence and the nucleotide sequence of the H-chain variable region (VH) are shown in SEQ ID NO: 558 and SEQ ID NO: 557, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain variable region (VL) are shown in SEQ ID NO: 560 and SEQ ID NO: 559, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR1 are shown in SEQ ID NO: 118 and SEQ ID NO: 117, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR2 are shown in SEQ ID NO: 120 and SEQ ID NO: 119, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR3 are shown in SEQ ID NO: 122 and SEQ ID NO: 121, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR1 are shown in SEQ ID NO: 124 and SEQ ID NO: 123, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR2 are shown in SEQ ID NO: 126 and SEQ ID NO: 125, respectively; and
the amino acid sequence and the nucleotide sequence of the L-chain CDR3 are shown in SEQ ID NO: 128 and SEQ ID NO: 127, respectively.
the amino acid sequence and the nucleotide sequence of the H-chain variable region (VH) are shown in SEQ ID NO: 562 and SEQ ID NO: 561, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain variable region (VL) are shown in SEQ ID NO: 564 and SEQ ID NO: 563, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR1 are shown in SEQ ID NO: 134 and SEQ ID NO: 133, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR2 are shown in SEQ ID NO: 136 and SEQ ID NO: 135, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR3 are shown in SEQ ID NO: 138 and SEQ ID NO: 137, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR1 are shown in SEQ ID NO: 140 and SEQ ID NO: 139, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR2 are shown in SEQ ID NO: 142 and SEQ ID NO: 141, respectively; and
the amino acid sequence and the nucleotide sequence of the L-chain CDR3 are shown in SEQ ID NO: 144 and SEQ ID NO: 143, respectively.
the amino acid sequence and the nucleotide sequence of the H-chain variable region (VH) are shown in SEQ ID NO: 566 and SEQ ID NO: 565, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain variable region (VL) are shown in SEQ ID NO: 568 and SEQ ID NO: 567, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR1 are shown in SEQ ID NO: 150 and SEQ ID NO: 149, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR2 are shown in SEQ ID NO: 152 and SEQ ID NO: 151, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR3 are shown in SEQ ID NO: 154 and SEQ ID NO: 153, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR1 are shown in SEQ ID NO: 156 and SEQ ID NO: 155, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR2 are shown in SEQ ID NO: 158 and SEQ ID NO: 157, respectively; and
the amino acid sequence and the nucleotide sequence of the L-chain CDR3 are shown in SEQ ID NO: 160 and SEQ ID NO: 159, respectively.
the amino acid sequence and the nucleotide sequence of the H-chain variable region (VH) are shown in SEQ ID NO: 570 and SEQ ID NO: 569, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain variable region (VL) are shown in SEQ ID NO: 572 and SEQ ID NO: 571, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR1 are shown in SEQ ID NO: 166 and SEQ ID NO: 165, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR2 are shown in SEQ ID NO: 168 and SEQ ID NO: 167, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR3 are shown in SEQ ID NO: 170 and SEQ ID NO: 169, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR1 are shown in SEQ ID NO: 172 and SEQ ID NO: 171, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR2 are shown in SEQ ID NO: 174 and SEQ ID NO: 173, respectively; and
the amino acid sequence and the nucleotide sequence of the L-chain CDR3 are shown in SEQ ID NO: 176 and SEQ ID NO: 175, respectively.
the amino acid sequence and the nucleotide sequence of the H-chain variable region (VH) are shown in SEQ ID NO: 574 and SEQ ID NO: 573, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain variable region (VL) are shown in SEQ ID NO: 576 and SEQ ID NO: 575, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR1 are shown in SEQ ID NO: 182 and SEQ ID NO: 181, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR2 are shown in SEQ ID NO: 184 and SEQ ID NO: 183, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR3 are shown in SEQ ID NO: 186 and SEQ ID NO: 185, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR1 are shown in SEQ ID NO: 188 and SEQ ID NO: 187, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR2 are shown in SEQ ID NO: 190 and SEQ ID NO: 189, respectively; and
the amino acid sequence and the nucleotide sequence of the L-chain CDR3 are shown in SEQ ID NO: 192 and SEQ ID NO: 191, respectively.
the amino acid sequence and the nucleotide sequence of the H-chain variable region (VH) are shown in SEQ ID NO: 578 and SEQ ID NO: 577, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain variable region (VL) are shown in SEQ ID NO: 580 and SEQ ID NO: 579, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR1 are shown in SEQ ID NO: 198 and SEQ ID NO: 197, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR2 are shown in SEQ ID NO: 200 and SEQ ID NO: 199, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR3 are shown in SEQ ID NO: 202 and SEQ ID NO: 201, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR1 are shown in SEQ ID NO: 204 and SEQ ID NO: 203, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR2 are shown in SEQ ID NO: 206 and SEQ ID NO: 205, respectively; and
the amino acid sequence and the nucleotide sequence of the L-chain CDR3 are shown in SEQ ID NO: 208 and SEQ ID NO: 207, respectively.
the amino acid sequence and the nucleotide sequence of the H-chain variable region (VH) are shown in SEQ ID NO: 582 and SEQ ID NO: 581, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain variable region (VL) are shown in SEQ ID NO: 584 and SEQ ID NO: 583, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR1 are shown in SEQ ID NO: 214 and SEQ ID NO: 213, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR2 are shown in SEQ ID NO: 216 and SEQ ID NO: 215, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR3 are shown in SEQ ID NO: 218 and SEQ ID NO: 217, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR1 are shown in SEQ ID NO: 220 and SEQ ID NO: 219, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR2 are shown in SEQ ID NO: 222 and SEQ ID NO: 221, respectively; and
the amino acid sequence and the nucleotide sequence of the L-chain CDR3 are shown in SEQ ID NO: 224 and SEQ ID NO: 223, respectively.
the amino acid sequence and the nucleotide sequence of the H-chain variable region (VH) are shown in SEQ ID NO: 586 and SEQ ID NO: 585, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain variable region (VL) are shown in SEQ ID NO: 588 and SEQ ID NO: 587, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR1 are shown in SEQ ID NO: 230 and SEQ ID NO: 229, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR2 are shown in SEQ ID NO: 232 and SEQ ID NO: 231, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR3 are shown in SEQ ID NO: 234 and SEQ ID NO: 233, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR1 are shown in SEQ ID NO: 236 and SEQ ID NO: 235, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR2 are shown in SEQ ID NO: 238 and SEQ ID NO: 237, respectively; and
the amino acid sequence and the nucleotide sequence of the L-chain CDR3 are shown in SEQ ID NO: 240 and SEQ ID NO: 239, respectively.
the amino acid sequence and the nucleotide sequence of the H-chain variable region (VH) are shown in SEQ ID NO: 590 and SEQ ID NO: 589, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain variable region (VL) are shown in SEQ ID NO: 592 and SEQ ID NO: 591, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR1 are shown in SEQ ID NO: 246 and SEQ ID NO: 245, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR2 are shown in SEQ ID NO: 248 and SEQ ID NO: 247, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR3 are shown in SEQ ID NO: 250 and SEQ ID NO: 249, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR1 are shown in SEQ ID NO: 252 and SEQ ID NO: 251, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR2 are shown in SEQ ID NO: 254 and SEQ ID NO: 253, respectively; and
the amino acid sequence and the nucleotide sequence of the L-chain CDR3 are shown in SEQ ID NO: 256 and SEQ ID NO: 255, respectively.
the amino acid sequence and the nucleotide sequence of the H-chain variable region (VH) are shown in SEQ ID NO: 594 and SEQ ID NO: 593, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain variable region (VL) are shown in SEQ ID NO: 596 and SEQ ID NO: 595, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR1 are shown in SEQ ID NO: 262 and SEQ ID NO: 261, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR2 are shown in SEQ ID NO: 264 and SEQ ID NO: 263, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR3 are shown in SEQ ID NO: 266 and SEQ ID NO: 265, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR1 are shown in SEQ ID NO: 268 and SEQ ID NO: 267, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR2 are shown in SEQ ID NO: 270 and SEQ ID NO: 269, respectively; and
the amino acid sequence and the nucleotide sequence of the L-chain CDR3 are shown in SEQ ID NO: 272 and SEQ ID NO: 271, respectively.
the amino acid sequence and the nucleotide sequence of the H-chain variable region (VH) are shown in SEQ ID NO: 598 and SEQ ID NO: 597, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain variable region (VL) are shown in SEQ ID NO: 600 and SEQ ID NO: 599, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR1 are shown in SEQ ID NO: 278 and SEQ ID NO: 277, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR2 are shown in SEQ ID NO: 280 and SEQ ID NO: 279, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR3 are shown in SEQ ID NO: 282 and SEQ ID NO: 281, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR1 are shown in SEQ ID NO: 284 and SEQ ID NO: 283, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR2 are shown in SEQ ID NO: 286 and SEQ ID NO: 285, respectively; and
the amino acid sequence and the nucleotide sequence of the L-chain CDR3 are shown in SEQ ID NO: 288 and SEQ ID NO: 287, respectively.
the amino acid sequence and the nucleotide sequence of the H-chain variable region (VH) are shown in SEQ ID NO: 602 and SEQ ID NO: 601, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain variable region (VL) are shown in SEQ ID NO: 604 and SEQ ID NO: 603, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR1 are shown in SEQ ID NO: 294 and SEQ ID NO: 293, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR2 are shown in SEQ ID NO: 296 and SEQ ID NO: 295, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR3 are shown in SEQ ID NO: 298 and SEQ ID NO: 297, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR1 are shown in SEQ ID NO: 300 and SEQ ID NO: 299, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR2 are shown in SEQ ID NO: 302 and SEQ ID NO: 301, respectively; and
the amino acid sequence and the nucleotide sequence of the L-chain CDR3 are shown in SEQ ID NO: 304 and SEQ ID NO: 303, respectively.
the amino acid sequence and the nucleotide sequence of the H-chain variable region (VH) are shown in SEQ ID NO: 606 and SEQ ID NO: 605, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain variable region (VL) are shown in SEQ ID NO: 608 and SEQ ID NO: 607, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR1 are shown in SEQ ID NO: 310 and SEQ ID NO: 309, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR2 are shown in SEQ ID NO: 312 and SEQ ID NO: 311, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR3 are shown in SEQ ID NO: 314 and SEQ ID NO: 313, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR1 are shown in SEQ ID NO: 316 and SEQ ID NO: 315, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR2 are shown in SEQ ID NO: 318 and SEQ ID NO: 317, respectively; and
the amino acid sequence and the nucleotide sequence of the L-chain CDR3 are shown in SEQ ID NO: 320 and SEQ ID NO: 319, respectively.
the amino acid sequence and the nucleotide sequence of the H-chain variable region (VH) are shown in SEQ ID NO: 610 and SEQ ID NO: 609, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain variable region (VL) are shown in SEQ ID NO: 612 and SEQ ID NO: 611, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR1 are shown in SEQ ID NO: 326 and SEQ ID NO: 325, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR2 are shown in SEQ ID NO: 328 and SEQ ID NO: 327, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR3 are shown in SEQ ID NO: 330 and SEQ ID NO: 329, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR1 are shown in SEQ ID NO: 332 and SEQ ID NO: 331, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR2 are shown in SEQ ID NO: 334 and SEQ ID NO: 333, respectively; and
the amino acid sequence and the nucleotide sequence of the L-chain CDR3 are shown in SEQ ID NO: 336 and SEQ ID NO: 335, respectively.
the amino acid sequence and the nucleotide sequence of the H-chain variable region (VH) are shown in SEQ ID NO: 614 and SEQ ID NO: 613, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain variable region (VL) are shown in SEQ ID NO: 616 and SEQ ID NO: 615, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR1 are shown in SEQ ID NO: 342 and SEQ ID NO: 341, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR2 are shown in SEQ ID NO: 344 and SEQ ID NO: 343, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR3 are shown in SEQ ID NO: 346 and SEQ ID NO: 345, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR1 are shown in SEQ ID NO: 348 and SEQ ID NO: 347, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR2 are shown in SEQ ID NO: 350 and SEQ ID NO: 349, respectively; and
the amino acid sequence and the nucleotide sequence of the L-chain CDR3 are shown in SEQ ID NO: 352 and SEQ ID NO: 351, respectively.
the amino acid sequence and the nucleotide sequence of the H-chain variable region (VH) are shown in SEQ ID NO: 618 and SEQ ID NO: 617, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain variable region (VL) are shown in SEQ ID NO: 620 and SEQ ID NO: 619, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR1 are shown in SEQ ID NO: 358 and SEQ ID NO: 357, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR2 are shown in SEQ ID NO: 360 and SEQ ID NO: 359, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR3 are shown in SEQ ID NO: 362 and SEQ ID NO: 361, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR1 are shown in SEQ ID NO: 364 and SEQ ID NO: 363, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR2 are shown in SEQ ID NO: 366 and SEQ ID NO: 365, respectively; and
the amino acid sequence and the nucleotide sequence of the L-chain CDR3 are shown in SEQ ID NO: 368 and SEQ ID NO: 367, respectively.
the amino acid sequence and the nucleotide sequence of the H-chain variable region (VH) are shown in SEQ ID NO: 622 and SEQ ID NO: 621, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain variable region (VL) are shown in SEQ ID NO: 624 and SEQ ID NO: 623, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR1 are shown in SEQ ID NO: 374 and SEQ ID NO: 373, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR2 are shown in SEQ ID NO: 376 and SEQ ID NO: 375, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR3 are shown in SEQ ID NO: 378 and SEQ ID NO: 377, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR1 are shown in SEQ ID NO: 380 and SEQ ID NO: 379, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR2 are shown in SEQ ID NO: 382 and SEQ ID NO: 381, respectively; and
the amino acid sequence and the nucleotide sequence of the L-chain CDR3 are shown in SEQ ID NO: 384 and SEQ ID NO: 383, respectively.
the amino acid sequence and the nucleotide sequence of the H-chain variable region (VH) are shown in SEQ ID NO: 626 and SEQ ID NO: 625, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain variable region (VL) are shown in SEQ ID NO: 628 and SEQ ID NO: 627, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR1 are shown in SEQ ID NO: 390 and SEQ ID NO: 389, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR2 are shown in SEQ ID NO: 392 and SEQ ID NO: 391, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR3 are shown in SEQ ID NO: 394 and SEQ ID NO: 393, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR1 are shown in SEQ ID NO: 396 and SEQ ID NO: 395, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR2 are shown in SEQ ID NO: 398 and SEQ ID NO: 397, respectively; and
the amino acid sequence and the nucleotide sequence of the L-chain CDR3 are shown in SEQ ID NO: 400 and SEQ ID NO: 399, respectively.
the amino acid sequence and the nucleotide sequence of the H-chain variable region (VH) are shown in SEQ ID NO: 630 and SEQ ID NO: 629, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain variable region (VL) are shown in SEQ ID NO: 632 and SEQ ID NO: 631, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR1 are shown in SEQ ID NO: 406 and SEQ ID NO: 405, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR2 are shown in SEQ ID NO: 408 and SEQ ID NO: 407, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR3 are shown in SEQ ID NO: 410 and SEQ ID NO: 409, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR1 are shown in SEQ ID NO: 412 and SEQ ID NO: 411, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR2 are shown in SEQ ID NO: 414 and SEQ ID NO: 413, respectively; and
the amino acid sequence and the nucleotide sequence of the L-chain CDR3 are shown in SEQ ID NO: 416 and SEQ ID NO: 415, respectively.
the amino acid sequence and the nucleotide sequence of the H-chain variable region (VH) are shown in SEQ ID NO: 634 and SEQ ID NO: 633, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain variable region (VL) are shown in SEQ ID NO: 636 and SEQ ID NO: 635, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR1 are shown in SEQ ID NO: 422 and SEQ ID NO: 421, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR2 are shown in SEQ ID NO: 424 and SEQ ID NO: 423, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR3 are shown in SEQ ID NO: 426 and SEQ ID NO: 425, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR1 are shown in SEQ ID NO: 428 and SEQ ID NO: 427, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR2 are shown in SEQ ID NO: 430 and SEQ ID NO: 429, respectively; and
the amino acid sequence and the nucleotide sequence of the L-chain CDR3 are shown in SEQ ID NO: 432 and SEQ ID NO: 431, respectively.
the amino acid sequence and the nucleotide sequence of the H-chain variable region (VH) are shown in SEQ ID NO: 638 and SEQ ID NO: 637, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain variable region (VL) are shown in SEQ ID NO: 640 and SEQ ID NO: 639, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR1 are shown in SEQ ID NO: 438 and SEQ ID NO: 437, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR2 are shown in SEQ ID NO: 440 and SEQ ID NO: 439, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR3 are shown in SEQ ID NO: 442 and SEQ ID NO: 441, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR1 are shown in SEQ ID NO: 444 and SEQ ID NO: 443, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR2 are shown in SEQ ID NO: 446 and SEQ ID NO: 445, respectively; and
the amino acid sequence and the nucleotide sequence of the L-chain CDR3 are shown in SEQ ID NO: 448 and SEQ ID NO: 447, respectively.
the amino acid sequence and the nucleotide sequence of the H-chain variable region (VH) are shown in SEQ ID NO: 642 and SEQ ID NO: 641, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain variable region (VL) are shown in SEQ ID NO: 644 and SEQ ID NO: 643, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR1 are shown in SEQ ID NO: 454 and SEQ ID NO: 453, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR2 are shown in SEQ ID NO: 456 and SEQ ID NO: 455, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR3 are shown in SEQ ID NO: 458 and SEQ ID NO: 457, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR1 are shown in SEQ ID NO: 460 and SEQ ID NO: 459, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR2 are shown in SEQ ID NO: 462 and SEQ ID NO: 461, respectively; and
the amino acid sequence and the nucleotide sequence of the L-chain CDR3 are shown in SEQ ID NO: 464 and SEQ ID NO: 463, respectively.
the amino acid sequence and the nucleotide sequence of the H-chain variable region (VH) are shown in SEQ ID NO: 646 and SEQ ID NO: 645, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain variable region (VL) are shown in SEQ ID NO: 648 and SEQ ID NO: 647, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR1 are shown in SEQ ID NO: 470 and SEQ ID NO: 469, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR2 are shown in SEQ ID NO: 472 and SEQ ID NO: 471, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR3 are shown in SEQ ID NO: 474 and SEQ ID NO: 473, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR1 are shown in SEQ ID NO: 476 and SEQ ID NO: 475, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR2 are shown in SEQ ID NO: 478 and SEQ ID NO: 477, respectively; and
the amino acid sequence and the nucleotide sequence of the L-chain CDR3 are shown in SEQ ID NO: 480 and SEQ ID NO: 479, respectively.
the amino acid sequence and the nucleotide sequence of the H-chain variable region (VH) are shown in SEQ ID NO: 650 and SEQ ID NO: 649, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain variable region (VL) are shown in SEQ ID NO: 652 and SEQ ID NO: 651, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR1 are shown in SEQ ID NO: 486 and SEQ ID NO: 485, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR2 are shown in SEQ ID NO: 488 and SEQ ID NO: 487, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR3 are shown in SEQ ID NO: 490 and SEQ ID NO: 489, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR1 are shown in SEQ ID NO: 492 and SEQ ID NO: 491, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR2 are shown in SEQ ID NO: 494 and SEQ ID NO: 493, respectively; and
the amino acid sequence and the nucleotide sequence of the L-chain CDR3 are shown in SEQ ID NO: 496 and SEQ ID NO: 495, respectively.
the amino acid sequence and the nucleotide sequence of the H-chain variable region (VH) are shown in SEQ ID NO: 654 and SEQ ID NO: 653, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain variable region (VL) are shown in SEQ ID NO: 656 and SEQ ID NO: 655, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR1 are shown in SEQ ID NO: 502 and SEQ ID NO: 501, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR2 are shown in SEQ ID NO: 504 and SEQ ID NO: 503, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR3 are shown in SEQ ID NO: 506 and SEQ ID NO: 505, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR1 are shown in SEQ ID NO: 508 and SEQ ID NO: 507, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR2 are shown in SEQ ID NO: 510 and SEQ ID NO: 509, respectively; and
the amino acid sequence and the nucleotide sequence of the L-chain CDR3 are shown in SEQ ID NO: 512 and SEQ ID NO: 511, respectively.
the amino acid sequence and the nucleotide sequence of the H-chain variable region (VH) are shown in SEQ ID NO: 658 and SEQ ID NO: 657, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain variable region (VL) are shown in SEQ ID NO: 660 and SEQ ID NO: 659, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR1 are shown in SEQ ID NO: 518 and SEQ ID NO: 517, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR2 are shown in SEQ ID NO: 520 and SEQ ID NO: 519, respectively;
the amino acid sequence and the nucleotide sequence of the H-chain CDR3 are shown in SEQ ID NO: 522 and SEQ ID NO: 521, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR1 are shown in SEQ ID NO: 524 and SEQ ID NO: 523, respectively;
the amino acid sequence and the nucleotide sequence of the L-chain CDR2 are shown in SEQ ID NO: 526 and SEQ ID NO: 525, respectively; and
the amino acid sequence and the nucleotide sequence of the L-chain CDR3 are shown in SEQ ID NO: 528 and SEQ ID NO: 527, respectively.
AL-201 antibody, AL-202 antibody, AL-203 antibody, AL-204 antibody, AL-205 antibody, AL-206 antibody, AL-207 antibody, AL-208 antibody, AL-209 antibody, AL-210 antibody, AL-211 antibody, AL-212 antibody, AL-213 antibody, AL-214 antibody, AL-215 antibody, AL-216 antibody, AL-217 antibody, AL-218 antibody, AL-219 antibody, AL-220 antibody, AL-221 antibody, AL-222 antibody, AL-223 antibody, AL-224 antibody, AL-225 antibody, AL-226 antibody, AL-227 antibody, AL-228 antibody, AL-229 antibody, AL-230 antibody, AL-231 antibody, AL-232 antibody, or AL-233 antibody,
is expressed as follows:
an antibody that has equivalent activity as an antibody comprising an H chain having the amino acid sequence of SEQ ID NO: a as CDR1, the amino acid sequence of SEQ ID NO: b as CDR2, and the amino acid sequence of SEQ ID NO: c as CDR3, wherein the "antibody that has equivalent activity" comprises an H chain having:
as CDR1, the amino acid sequence of SEQ ID NO: a, or an amino acid sequence with one or several amino acid substitutions, deletions, additions and/or insertions in the amino acid sequence of SEQ ID NO: a;
as CDR2, the amino acid sequence of SEQ ID NO: b, or an amino acid sequence with one or several amino acid substitutions, deletions, additions and/or insertions in the amino acid sequence of SEQ ID NO: b;
as CDR3, the amino acid sequence of SEQ ID NO: c, or an amino acid sequence with one or several amino acid substitutions, deletions, additions and/or insertions in the amino acid sequence of SEQ ID NO: c;
an antibody that has equivalent activity as an antibody comprising an L chain having the amino acid sequence of SEQ ID NO: d as CDR1, the amino acid sequence of SEQ ID NO: e as CDR2, and the amino acid sequence of SEQ ID NO: f as CDR3, wherein the "antibody that has equivalent activity" comprises an L chain having:
as CDR1, the amino acid sequence of SEQ ID NO: d, or an amino acid sequence with one or several amino acid substitutions, deletions, additions and/or insertions in the amino acid sequence of SEQ ID NO: d;
as CDR2, the amino acid sequence of SEQ ID NO: e, or an amino acid sequence with one or several amino acid substitutions, deletions, additions and/or insertions in the amino acid sequence of SEQ ID NO: e;
as CDR3, the amino acid sequence of SEQ ID NO: f, or an amino acid sequence with one or several amino acid substitutions, deletions, additions and/or insertions in the amino acid sequence of SEQ ID NO: f; or
an antibody that has equivalent activity as an antibody comprising an H chain having the amino acid sequence of SEQ ID NO: a as CDR1, the amino acid sequence of SEQ ID NO: b as CDR2, and the amino acid sequence of SEQ ID NO: c as CDR3, and an L chain having the amino acid sequence of SEQ ID NO: d as CDR1, the amino acid sequence of SEQ ID NO: e as CDR2, and the amino acid sequence of SEQ ID NO: f as CDR3, wherein the "antibody that has equivalent activity" comprises:
an H chain having:
as CDR1, the amino acid sequence of SEQ ID NO: a, or an amino acid sequence with one or several amino acid substitutions, deletions, additions and/or insertions in the amino acid sequence of SEQ ID NO: a;
as CDR2, the amino acid sequence of SEQ ID NO: b, or an amino acid sequence with one or several amino acid substitutions, deletions, additions and/or insertions in the amino acid sequence of SEQ ID NO: b;
as CDR3, the amino acid sequence of SEQ ID NO: c, or an amino acid sequence with one or several amino acid substitutions, deletions, additions and/or insertions in the amino acid sequence of SEQ ID NO: c
and
an L chain having:
as CDR1, the amino acid sequence of SEQ ID NO: d, or an amino acid sequence with one or several amino acid substitutions, deletions, additions and/or insertions in the amino acid sequence of SEQ ID NO: d;
as CDR2, the amino acid sequence of SEQ ID NO: e, or an amino acid sequence with one or several amino acid substitutions, deletions, additions and/or insertions in the amino acid sequence of SEQ ID NO: e;
as CDR3, the amino acid sequence of SEQ ID NO: f, or an amino acid sequence with one or several amino acid substitutions, deletions, additions and/or insertions in the amino acid sequence of SEQ ID NO: f.
an antibody that has equivalent activity as an antibody comprising an H chain having the amino acid sequence of SEQ ID NO: 6 as CDR1, the amino acid sequence of SEQ ID NO: 8 as CDR2, and the amino acid sequence of SEQ ID NO: 10 as CDR3, wherein the "antibody that has equivalent activity" comprises an H chain having:
as CDR1, the amino acid sequence of SEQ ID NO: 6, or an amino acid sequence with one or several amino acid substitutions, deletions, additions and/or insertions in the amino acid sequence of SEQ ID NO: 6;
as CDR2, the amino acid sequence of SEQ ID NO: 8, or an amino acid sequence with one or several amino acid substitutions, deletions, additions and/or insertions in the amino acid sequence of SEQ ID NO: 8;
as CDR3, the amino acid sequence of SEQ ID NO: 10, or an amino acid sequence with one or several amino acid substitutions, deletions, additions and/or insertions in the amino acid sequence of SEQ ID NO: 10;
an antibody that has equivalent activity as an antibody comprising an L chain having the amino acid sequence of SEQ ID NO: 12 as CDR1, the amino acid sequence of SEQ ID NO: 14 as CDR2, and the amino acid sequence of SEQ ID NO: 16 as CDR3, wherein the "antibody that has equivalent activity" comprises an L chain having:
as CDR1, the amino acid sequence of SEQ ID NO: 12, or an amino acid sequence with one or several amino acid substitutions, deletions, additions and/or insertions in the amino acid sequence of SEQ ID NO: 12;
as CDR2, the amino acid sequence of SEQ ID NO: 14, or an amino acid sequence with one or several amino acid substitutions, deletions, additions and/or insertions in the amino acid sequence of SEQ ID NO: 14;
as CDR3, the amino acid sequence of SEQ ID NO: 16, or an amino acid sequence with one or several amino acid substitutions, deletions, additions and/or insertions in the amino acid sequence of SEQ ID NO: 16; or
an antibody that has equivalent activity as an antibody comprising an H chain having the amino acid sequence of SEQ ID NO: 6 as CDR1, the amino acid sequence of SEQ ID NO: 8 as CDR2, and the amino acid sequence of SEQ ID NO: 10 as CDR3, and an L chain having the amino acid sequence of SEQ ID NO: 12 as CDR1, the amino acid sequence of SEQ ID NO: 14 as CDR2, and the amino acid sequence of SEQ ID NO: 16 as CDR3, wherein the "antibody that has equivalent activity" comprises:
an H chain having:
as CDR1, the amino acid sequence of SEQ ID NO: 6, or an amino acid sequence with one or several amino acid substitutions, deletions, additions and/or insertions in the amino acid sequence of SEQ ID NO: 6;
as CDR2, the amino acid sequence of SEQ ID NO: 8, or an amino acid sequence with one or several amino acid substitutions, deletions, additions and/or insertions in the amino acid sequence of SEQ ID NO: 8;
as CDR3, the amino acid sequence of SEQ ID NO: 10, or an amino acid sequence with one or several amino acid substitutions, deletions, additions and/or insertions in the amino acid sequence of SEQ ID NO: 10
and
an L chain having:
as CDR1, the amino acid sequence of SEQ ID NO: 12, or an amino acid sequence with one or several amino acid substitutions, deletions, additions and/or insertions in the amino acid sequence of SEQ ID NO: 12;
as CDR2, the amino acid sequence of SEQ ID NO: 14, or an amino acid sequence with one or several amino acid substitutions, deletions, additions and/or insertions in the amino acid sequence of SEQ ID NO: 14;
as CDR3, the amino acid sequence of SEQ ID NO: 16, or an amino acid sequence with one or several amino acid substitutions, deletions, additions and/or insertions in the amino acid sequence of SEQ ID NO: 16.
AL-201 antibody, AL-202 antibody, AL-203 antibody, AL-204 antibody, AL-205 antibody, AL-206 antibody, AL-207 antibody, AL-208 antibody, AL-209 antibody, AL-210 antibody, AL-211 antibody, AL-212 antibody, AL-213 antibody, AL-214 antibody, AL-215 antibody, AL-216 antibody, AL-217 antibody, AL-218 antibody, AL-219 antibody, AL-220 antibody, AL-221 antibody, AL-222 antibody, AL-223 antibody, AL-224 antibody, AL-225 antibody, AL-226 antibody, AL-227 antibody, AL-228 antibody, AL-229 antibody, AL-230 antibody, AL-231 antibody, AL-232 antibody, or AL-233 antibody
for "a" to "h".
an antibody that has equivalent activity as an antibody comprising an H chain having the amino acid sequence of SEQ ID NO: a as CDR1, the amino acid sequence of SEQ ID NO: b as CDR2, and the amino acid sequence of SEQ ID NO: c as CDR3, wherein the "antibody that has equivalent activity" comprises an H chain having:
as CDR1, the amino acid sequence of SEQ ID NO: a, or an amino acid sequence with one or several amino acid substitutions, deletions, additions and/or insertions in the amino acid sequence of SEQ ID NO: a;
as CDR2, the amino acid sequence of SEQ ID NO: b, or an amino acid sequence with one or several amino acid substitutions, deletions, additions and/or insertions in the amino acid sequence of SEQ ID NO: b;
as CDR3, the amino acid sequence of SEQ ID NO: c;
an antibody that has equivalent activity as an antibody comprising an L chain having the amino acid sequence of SEQ ID NO: d as CDR1, the amino acid sequence of SEQ ID NO: e as CDR2, and the amino acid sequence of SEQ ID NO: f as CDR3, wherein the "antibody that has equivalent activity" comprises an L chain having:
as CDR1, the amino acid sequence of SEQ ID NO: d, or an amino acid sequence with one or several amino acid substitutions, deletions, additions and/or insertions in the amino acid sequence of SEQ ID NO: d;
as CDR2, the amino acid sequence of SEQ ID NO: e, or an amino acid sequence with one or several amino acid substitutions, deletions, additions and/or insertions in the amino acid sequence of SEQ ID NO: e;
as CDR3, the amino acid sequence of SEQ ID NO: f; or
an antibody that has equivalent activity as an antibody comprising an H chain having the amino acid sequence of SEQ ID NO: a as CDR1, the amino acid sequence of SEQ ID NO: b as CDR2, and the amino acid sequence of SEQ ID NO: c as CDR3, and an L chain having the amino acid sequence of SEQ ID NO: d as CDR1, the amino acid sequence of SEQ ID NO: e as CDR2, and the amino acid sequence of SEQ ID NO: f as CDR3, wherein the "antibody that has equivalent activity" comprises:
an H chain having:
as CDR1, the amino acid sequence of SEQ ID NO: a, or an amino acid sequence with one or several amino acid substitutions, deletions, additions and/or insertions in the amino acid sequence of SEQ ID NO: a;
as CDR2, the amino acid sequence of SEQ ID NO: b, or an amino acid sequence with one or several amino acid substitutions, deletions, additions and/or insertions in the amino acid sequence of SEQ ID NO: b;
as CDR3, the amino acid sequence of SEQ ID NO: c
and
an L chain having:
as CDR1, the amino acid sequence of SEQ ID NO: d, or an amino acid sequence with one or several amino acid substitutions, deletions, additions and/or insertions in the amino acid sequence of SEQ ID NO: d;
as CDR2, the amino acid sequence of SEQ ID NO: e, or an amino acid sequence with one or several amino acid substitutions, deletions, additions and/or insertions in the amino acid sequence of SEQ ID NO: e;
as CDR3, the amino acid sequence of SEQ ID NO: f.
AL-201 antibody, AL-202 antibody, AL-203 antibody, AL-204 antibody, AL-205 antibody, AL-206 antibody, AL-207 antibody, AL-208 antibody, AL-209 antibody, AL-210 antibody, AL-211 antibody, AL-212 antibody, AL-213 antibody, AL-214 antibody, AL-215 antibody, AL-216 antibody, AL-217 antibody, AL-218 antibody, AL-219 antibody, AL-220 antibody, AL-221 antibody, AL-222 antibody, AL-223 antibody, AL-224 antibody, AL-225 antibody, AL-226 antibody, AL-227 antibody, AL-228 antibody, AL-229 antibody, AL-230 antibody, AL-231 antibody, AL-232 antibody, or AL-233 antibody
can be expressed as follows:
an antibody that has equivalent activity as an antibody comprising an H chain having VH comprising the amino acid sequence of SEQ ID NO: g, wherein the "antibody that has equivalent activity" comprises an H chain having VH comprising an amino acid sequence in which one or several amino acids are substituted, deleted, added, and/or inserted in the amino acid sequence of SEQ ID NO: g;
an antibody that has equivalent activity as an antibody comprising an L chain having VL comprising the amino acid sequence of SEQ ID NO: h, wherein the "antibody that has equivalent activity" comprises an H chain having VL comprising an amino acid sequence in which one or several amino acids are substituted, deleted, added, and/or inserted in the amino acid sequence of SEQ ID NO: h;
or
an antibody that has equivalent activity as an antibody comprising an H chain having VH comprising the amino acid sequence of SEQ ID NO: g and an L chain having VL comprising the amino acid sequence of SEQ ID NO: h, wherein the "antibody that has equivalent activity" comprises
an H chain having VH comprising the amino acid sequence of SEQ ID NO: g, or an amino acid sequence in which one or several amino acids are substituted, deleted, added, and/or inserted in the amino acid sequence of SEQ ID NO: g, and
an L chain having VL comprising the amino acid sequence of SEQ ID NO: h, or an amino acid sequence in which one or several amino acids are substituted, deleted, added, and/or inserted in the amino acid sequence of SEQ ID NO: h.
an antibody that has equivalent activity as an antibody comprising an H chain having VH comprising the amino acid sequence of SEQ ID NO: 530, wherein the "antibody that has equivalent activity" comprises an H chain having VH comprising an amino acid sequence in which one or several amino acids are substituted, deleted, added, and/or inserted in the amino acid sequence of SEQ ID NO: 530;
an antibody that has equivalent activity as an antibody comprising an L chain having VL comprising the amino acid sequence of SEQ ID NO: 532, wherein the "antibody that has equivalent activity" comprises an H chain having VL comprising an amino acid sequence in which one or several amino acids are substituted, deleted, added, and/or inserted in the amino acid sequence of SEQ ID NO: 532;
or
an antibody that has equivalent activity as an antibody comprising an H chain having VH comprising the amino acid sequence of SEQ ID NO: 530 and an L chain having VL comprising the amino acid sequence of SEQ ID NO: 532, wherein the "antibody that has equivalent activity" comprises
an H chain having VH comprising the amino acid sequence of SEQ ID NO: 530, or an amino acid sequence in which one or several amino acids are substituted, deleted, added, and/or inserted in the amino acid sequence of SEQ ID NO: 530, and
an L chain having VL comprising the amino acid sequence of SEQ ID NO: 532, or an amino acid sequence in which one or several amino acids are substituted, deleted, added, and/or inserted in the amino acid sequence of SEQ ID NO: 532.
AL-201 antibody, AL-202 antibody, AL-203 antibody, AL-204 antibody, AL-205 antibody, AL-206 antibody, AL-207 antibody, AL-208 antibody, AL-209 antibody, AL-210 antibody, AL-211 antibody, AL-212 antibody, AL-213 antibody, AL-214 antibody, AL-215 antibody, AL-216 antibody, AL-217 antibody, AL-218 antibody, AL-219 antibody, AL-220 antibody, AL-221 antibody, AL-222 antibody, AL-223 antibody, AL-224 antibody, AL-225 antibody, AL-226 antibody, AL-227 antibody, AL-228 antibody, AL-229 antibody, AL-230 antibody, AL-231 antibody, AL-232 antibody, or AL-233 antibody
can be expressed as follows:
an antibody that has equivalent activity as an antibody comprising an H chain having VH comprising the amino acid sequence of SEQ ID NO: a, wherein the "antibody that has equivalent activity" comprises an H chain having VH comprising an amino acid sequence in which one or several amino acids are substituted, deleted, added, and/or inserted in the amino acid sequence of SEQ ID NO: a, and the amino acid sequence of SEQ ID NO: b as CDR1, the amino acid sequence of SEQ ID NO: c as CDR2, and the amino acid sequence of SEQ ID NO: d as CDR3;
an antibody that has equivalent activity as an antibody comprising an L chain having VL comprising the amino acid sequence of SEQ ID NO: e, wherein the "antibody that has equivalent activity" comprises an L chain having VL comprising an amino acid sequence in which one or several amino acids are substituted, deleted, added, and/or inserted in the amino acid sequence of SEQ ID NO: e, and the amino acid sequence of SEQ ID NO: f as CDR1, the amino acid sequence of SEQ ID NO: g as CDR2, and the amino acid sequence of SEQ ID NO: h as CDR3;
or
an antibody that has equivalent activity as an antibody comprising an H chain having VH comprising the amino acid sequence of SEQ ID NO: a and VL comprising the amino acid sequence of SEQ ID NO: e, wherein the "antibody that has equivalent activity" comprises:
an H chain having VH comprising the amino acid sequence of SEQ ID NO: a, or an amino acid sequence in which one or several amino acids are substituted, deleted, added, and/or inserted in the amino acid sequence of SEQ ID NO: a, and the amino acid sequence of SEQ ID NO: b as CDR1, the amino acid sequence of SEQ ID NO: c as CDR2, and the amino acid sequence of SEQ ID NO: d as CDR3,
and
an L chain having VL comprising the amino acid sequence of SEQ ID NO: e, or an amino acid sequence in which one or several amino acids are substituted, deleted, added, and/or inserted in the amino acid sequence of SEQ ID NO: e, and the amino acid sequence of SEQ ID NO: f as CDR1, the amino acid sequence of SEQ ID NO: g as CDR2, and the amino acid sequence of SEQ ID NO: h as CDR3.
an antibody that has equivalent activity as an antibody comprising an H chain having VH comprising the amino acid sequence of SEQ ID NO: 530, wherein the "antibody that has equivalent activity" comprises an H chain having VH comprising an amino acid sequence in which one or several amino acids are substituted, deleted, added, and/or inserted in the amino acid sequence of SEQ ID NO: 530, and the amino acid sequence of SEQ ID NO: 6 as CDR1, the amino acid sequence of SEQ ID NO: 8 as CDR2, and the amino acid sequence of SEQ ID NO: 10 as CDR3;
an antibody that has equivalent activity as an antibody comprising an L chain having VL comprising the amino acid sequence of SEQ ID NO: 532, wherein the "antibody that has equivalent activity" comprises an L chain having VL comprising an amino acid sequence in which one or several amino acids are substituted, deleted, added, and/or inserted in the amino acid sequence of SEQ ID NO: 532, and the amino acid sequence of SEQ ID NO: 12 as CDR1, the amino acid sequence of SEQ ID NO: 14 as CDR2, and the amino acid sequence of SEQ ID NO: 16 as CDR3;
or
an antibody that has equivalent activity as an antibody comprising an H chain having VH comprising the amino acid sequence of SEQ ID NO: 530 and VL comprising the amino acid sequence of SEQ ID NO: 532, wherein the "antibody that has equivalent activity" comprises:
an H chain having VH comprising the amino acid sequence of SEQ ID NO: 530, or an amino acid sequence in which one or several amino acids are substituted, deleted, added, and/or inserted in the amino acid sequence of SEQ ID NO: 530, and the amino acid sequence of SEQ ID NO: 6 as CDR1, the amino acid sequence of SEQ ID NO: 8 as CDR2, and the amino acid sequence of SEQ ID NO: 10 as CDR3,
and
an L chain having VL comprising the amino acid sequence of SEQ ID NO: 532, or an amino acid sequence in which one or several amino acids are substituted, deleted, added, and/or inserted in the amino acid sequence of SEQ ID NO: 532, and the amino acid sequence of SEQ ID NO: 12 as CDR1, the amino acid sequence of SEQ ID NO: 14 as CDR2, and the amino acid sequence of SEQ ID NO: 16 as CDR3.
AL-201 antibody, AL-202 antibody, AL-203 antibody, AL-204 antibody, AL-205 antibody, AL-206 antibody, AL-207 antibody, AL-208 antibody, AL-209 antibody, AL-210 antibody, AL-211 antibody, AL-212 antibody, AL-213 antibody, AL-214 antibody, AL-215 antibody, AL-216 antibody, AL-217 antibody, AL-218 antibody, AL-219 antibody, AL-220 antibody, AL-221 antibody, AL-222 antibody, AL-223 antibody, AL-224 antibody, AL-225 antibody, AL-226 antibody, AL-227 antibody, AL-228 antibody, AL-229 antibody, AL-230 antibody, AL-231 antibody, AL-232 antibody, or AL-233 antibody,
the amino acid modifications are preferably conserved amino acid substitutions. Thus, in a preferred embodiment, in the antibodies described above, "conservative amino acid substitution" can be performed, instead of "substitution, deletion, addition, and/or insertion"
Methods for preparing a polypeptide having activity equivalent to that of a certain polypeptide that are well known to those skilled in the art include methods for introducing mutations into a polypeptide. For example, one skilled in the art can prepare an antibody having activity equivalent to that of an antibody of the present invention by introducing appropriate mutations into the antibody using site-directed mutagenesis (Hashimoto-Gotoh, T. et al. (1995) Gene 152, 271-275; Zoller, MJ, and Smith, M. (1983) Methods Enzymol. 100, 468-500; Kramer, W. et al. (1984) Nucleic Acids Res. 12, 9441-9456; Kramer W, and Fritz HJ (1987) Methods. Enzymol. 154, 350-367; Kunkel, TA (1985) Proc. Natl. Acad. Sci. USA. 82, 488-492; Kunkel (1988) Methods Enzymol. 85, 2763-2766) and such. Amino acid mutations may also occur naturally. The antibodies of the present invention also include an antibody that comprises an amino acid sequence with one or more amino acid mutations in the amino acid sequence of an antibody of the present invention, and which has activity equivalent to that of the antibody of the present invention.
AL-201 antibody, AL-202 antibody, AL-203 antibody, AL-204 antibody, AL-205 antibody, AL-206 antibody, AL-207 antibody, AL-208 antibody, AL-209 antibody, AL-210 antibody, AL-211 antibody, AL-212 antibody, AL-213 antibody, AL-214 antibody, AL-215 antibody, AL-216 antibody, AL-217 antibody, AL-218 antibody, AL-219 antibody, AL-220 antibody, AL-221 antibody, AL-222 antibody, AL-223 antibody, AL-224 antibody, AL-225 antibody, AL-226 antibody, AL-227 antibody, AL-228 antibody, AL-229 antibody, AL-230 antibody, AL-231 antibody, AL-232 antibody, and AL-233 antibody. These antibodies can be obtained by the method described in the Examples. Alternatively, the antibodies can be prepared based on their sequence information.
AL-201 antibody, AL-202 antibody, AL-203 antibody, AL-204 antibody, AL-205 antibody, AL-206 antibody, AL-207 antibody, AL-208 antibody, AL-209 antibody, AL-210 antibody, AL-211 antibody, AL-212 antibody, AL-213 antibody, AL-214 antibody, AL-215 antibody, AL-216 antibody, AL-217 antibody, AL-218 antibody, AL-219 antibody, AL-220 antibody, AL-221 antibody, AL-222 antibody, AL-223 antibody, AL-224 antibody, AL-225 antibody, AL-226 antibody, AL-227 antibody, AL-228 antibody, AL-229 antibody, AL-230 antibody, AL-231 antibody, AL-232 antibody, or AL-233 antibody;
and a constant region derived from human immunoglobulin. In a more preferred embodiment, humanized antibodies include antibodies comprise CDR derived from:
AL-201 antibody, AL-202 antibody, AL-203 antibody, AL-204 antibody, AL-205 antibody, AL-206 antibody, AL-207 antibody, AL-208 antibody, AL-209 antibody, AL-210 antibody, AL-211 antibody, AL-212 antibody, AL-213 antibody, AL-214 antibody, AL-215 antibody, AL-216 antibody, AL-217 antibody, AL-218 antibody, AL-219 antibody, AL-220 antibody, AL-221 antibody, AL-222 antibody, AL-223 antibody, AL-224 antibody, AL-225 antibody, AL-226 antibody, AL-227 antibody, AL-228 antibody, AL-229 antibody, AL-230 antibody, AL-231 antibody, AL-232 antibody, or AL-233 antibody;
and FR derived from human immunoglobulin, and a constant region derived from human immunoglobulin.
an antibody that comprises an H chain having VH comprising the amino acid sequence of SEQ ID NO: a, and CH of a human antibody;
an antibody that comprises an L chain having VL comprising the amino acid sequence of SEQ ID NO: b, and CL of a human antibody; or
an antibody that comprises an H chain having VH comprising the amino acid sequence of SEQ ID NO: a, and CH of a human antibody, and an L chain having VL comprising the amino acid sequence of SEQ ID NO: b, and CL of a human antibody.
an antibody that comprises an H chain having VH comprising the amino acid sequence of SEQ ID NO: 530, and CH of a human antibody;
an antibody that comprises an L chain having VL comprising the amino acid sequence of SEQ ID NO: 532, and CL of a human antibody; or
an antibody that comprises an H chain having VH comprising the amino acid sequence of SEQ ID NO: 530, and CH of a human antibody, and an L chain having VL comprising the amino acid sequence of SEQ ID NO: 532, and CL of a human antibody.
an antibody that comprises an H chain having CDR of VH comprising the amino acid sequence of SEQ ID NO: a, FR of VH of a human antibody, and CH of a human antibody;
an antibody that comprises an L chain having CDR of VL comprising the amino acid sequence of SEQ ID NO: b, FR of VL of a human antibody, and CL of a human antibody; or
an antibody that comprises an H chain having CDR of VH comprising the amino acid sequence of SEQ ID NO: a, FR of VH of a human antibody, and CH of a human antibody, and an L chain having CDR of VL comprising the amino acid sequence of SEQ ID NO: b, FR of VL of a human antibody, and CL of a human antibody.
an antibody that comprises an H chain having CDR of VH comprising the amino acid sequence of SEQ ID NO: 530, FR of VH of a human antibody, and CH of a human antibody;
an antibody that comprises an L chain having CDR of VL comprising the amino acid sequence of SEQ ID NO: 532, FR of VL of a human antibody, and CL of a human antibody; or
an antibody that comprises an H chain having CDR of VH comprising the amino acid sequence of SEQ ID NO: 530, FR of VH of a human antibody, and CH of a human antibody, and an L chain having CDR of VL comprising the amino acid sequence of SEQ ID NO: 532, FR of VL of a human antibody, and CL of a human antibody.
AL-201 antibody, AL-202 antibody, AL-203 antibody, AL-204 antibody, AL-205 antibody, AL-206 antibody, AL-207 antibody, AL-208 antibody, AL-209 antibody, AL-210 antibody, AL-211 antibody, AL-212 antibody, AL-213 antibody, AL-214 antibody, AL-215 antibody, AL-216 antibody, AL-217 antibody, AL-218 antibody, AL-219 antibody, AL-220 antibody, AL-221 antibody, AL-222 antibody, AL-223 antibody, AL-224 antibody, AL-225 antibody, AL-226 antibody, AL-227 antibody, AL-228 antibody, AL-229 antibody, AL-230 antibody, AL-231 antibody, AL-232 antibody, or AL-233 antibody.
AL-201 antibody, AL-202 antibody, AL-203 antibody, AL-204 antibody, AL-205 antibody, AL-206 antibody, AL-207 antibody, AL-208 antibody, AL-209 antibody, AL-210 antibody, AL-211 antibody, AL-212 antibody, AL-213 antibody, AL-214 antibody, AL-215 antibody, AL-216 antibody, AL-217 antibody, AL-218 antibody, AL-219 antibody, AL-220 antibody, AL-221 antibody, AL-222 antibody, AL-223 antibody, AL-224 antibody, AL-225 antibody, AL-226 antibody, AL-227 antibody, AL-228 antibody, AL-229 antibody, AL-230 antibody, AL-231 antibody, AL-232 antibody, or AL-233 antibody.
AL-201 antibody, AL-202 antibody, AL-203 antibody, AL-204 antibody, AL-205 antibody, AL-206 antibody, AL-207 antibody, AL-208 antibody, AL-209 antibody, AL-210 antibody, AL-211 antibody, AL-212 antibody, AL-213 antibody, AL-214 antibody, AL-215 antibody, AL-216 antibody, AL-217 antibody, AL-218 antibody, AL-219 antibody, AL-220 antibody, AL-221 antibody, AL-222 antibody, AL-223 antibody, AL-224 antibody, AL-225 antibody, AL-226 antibody, AL-227 antibody, AL-228 antibody, AL-229 antibody, AL-230 antibody, AL-231 antibody, AL-232 antibody, and AL-233 antibody. Memory deterioration has been shown to be related to synaptic dysfunction caused by soluble A beta oligomers (Klein WL, 2001, Trends Neurosci; and Selkoe DJ, 2002, Science). Excessive accumulation and deposition of A beta oligomers may trigger the complicated downstream cascades that cause Alzheimer's disease. Thus, therapeutic intervention using a composition comprising an antibody or antigen-binding fragment of the present invention and a pharmaceutically acceptable carrier could be effective for blocking the pathologic cascades, and thus this could enable the treatment of Alzheimer's disease (WO2009/051220, WO2009/099176,
- The above-described antibody or antigen-binding fragment of the present invention and a pharmaceutically acceptable carrier for use in preventing and/or treating cognitive impairment.
- The above-described antibody or antigen-binding fragment of the present invention for use in preventing and/or treating Alzheimer's disease.
- The above-described antibody or antigen-binding fragment of the present invention for use in suppressing the progression of Alzheimer's disease.
- The above-described antibody or antigen-binding fragment of the present invention for use in suppressing senile plaque formation.
- The above-described antibody or antigen-binding fragment of the present invention for use in suppressing A beta accumulation.
- The above-described antibody or antigen-binding fragment of the present invention for use in neutralizing (suppressing) neurotoxic activity.
- The above-described antibody or antigen-binding fragment of the present invention for use in inhibiting A beta amyloid fibril formation.
- The above-described antibody or antigen-binding fragment of the present invention for use in neutralizing (suppressing) synaptic toxicity.
- Use of the above-described antibody or antigen-binding fragment of the present invention for preventing and/or treating cognitive impairment.
- Use of the above-described antibody or antigen-binding fragment of the present invention for preventing and/or treating Alzheimer's disease.
- Use of the above-described antibody or antigen-binding fragment of the present invention for suppressing the progression of Alzheimer's disease.
- Use of the above-described antibody or antigen-binding fragment of the present invention for suppressing senile plaque formation.
- Use of the above-described antibody or antigen-binding fragment of the present invention for suppressing A beta accumulation.
- Use of the above-described antibody or antigen-binding fragment of the present invention for neutralizing (suppressing) neurotoxicity.
- Use of the above-described antibody or antigen-binding fragment of the present invention for inhibiting A beta amyloid fibril formation.
- Use of the above-described antibody or antigen-binding fragment of the present invention for neutralizing (suppressing) synaptic toxicity.
(a) contacting a sample collected from a subject with the antibody or antigen-binding fragment of the present invention; and
(b) measuring the amount of A beta oligomer in the sample,
wherein the subject is determined to be a possible Alzheimer's disease patient, when the amount measured in step (b) is higher than that of a healthy individual. Step (b) above can be alternatively expressed as "the step of detecting an A beta oligomer in the sample via the antibody or antigen-binding fragment of the present invention that has bound to an A beta oligomer in the sample".
(a) contacting a sample collected from a subject with an antibody or antigen-binding fragment of the present invention and an antibody or antigen-binding fragment that binds to an A beta monomer; and
(b) measuring the ratio of A beta oligomer to A beta monomer in the sample,
wherein the subject is determined to be a possible Alzheimer's disease patient, if the ratio measured in step (b) is higher than that of a healthy individual.
Preparation of antigens
Synthetic A beta1-42 (Peptide Institute, Inc., Osaka) was dissolved in distilled deionized water or 10 mM phosphate buffer, and incubated at 37degrees C for 18 hours. Then, the peptides were separated using a NuPAGE 4-12% Tris-Glycine Gel SDS-PAGE, and after visualization by CBB staining, just the A beta1-42 tetramer was excised without contamination of the A beta1-42 monomer. Antigen was prepared by finely crushing the gel containing the tetramer or extracting the tetramer from the gel.
BALB/c mice were immunized by injecting the antigen prepared by the method described above into their foot pads or abdominal cavities. Then, booster immunization was carried out six times. Hybridomas were prepared from inguinal lymph node cells or spleen cells by fusion with Sp2/O-Ag14 cells using Polyethylene Glycol 1500.
Hybridoma culture supernatants were added to ELISA plates immobilized with A beta oligomers and reacted. Color development was carried out using TMB solution after reacting with HRP-conjugated anti-mouse IgG antibody. A beta oligomers used in this method is A beta1-40 (HCl form) after one hour incubation or above-described extracted antigens of A beta1-42 tetramer.
Dot blot analysis was carried out for hybridomas that gave positive result for primary screening. In this analysis, 0.1 micro g/dot of three types of A beta; synthesized A beta 1-40 (TFA form) as A beta monomer, synthesized A beta1-40 (HCl form) after 1 hour incubation as A beta oligomer, and synthesized A beta1-42, were immobilized onto nitrocellulose membrane and used. The membrane was blocked with Tris Buffer containing 5% low-fat milk and 0.05% Tween-20, and reacted with hybridoma culture supernatants and detected with chemiluminescence kit (ECL) after reacting with HRP-conjugated anti-mouse IgG antibody.
Isotyping of purified immunoglobulins were carried out using a Serotec (Oxford, UK) Mouse Monoclonal Antibody Isotyping Test Kit.
RNAs were purified from hybridomas (1 x 106 cells) produced by the method described above using FastPure RNA Kit (TaKaRa, Japan). Using the RNAs as templates, cDNAs were synthesized using 5' RACE System (Invitrogen, USA) and primers specific to H chains or L chains of antibodies that are produced from each hybridomas. 3' side primer sequences that were used for cDNA syntheses are shown below.
H chain (G1) mIGC1Rv: AAGGCTTACAACCACAATCCCT (SEQ ID NO: 707)
H chain (G2a) mIGC2aRv: TGCTGGGCATTTGCATGGA (SEQ ID NO: 708)
H chain (G2b) mIGC2bRv: TGGGCATTTGTGACACTCC (SEQ ID NO: 709)
H chain (G3) mIGC3Rv: ACTGGGCTTGGGTATTCTAGG (SEQ ID NO: 710)
L chain (kappa) mIKCNRv1: GTCCAACTGTTCAGGACGCCATTTTGTCGTT (SEQ ID NO: 711)
L chain (lambda) mILCNRv1: TCCACAGTGTGACCTTCATGAGTGACC (SEQ ID NO: 712)
H chain mIGCNRv: ACAGGGATCCAGAGTTCCA (SEQ ID NO: 713)
L chain (kappa) mIKCNRv2: TAACTGCTCACTGGATGG (SEQ ID NO: 714)
L chain (lambda) mILCNRv2: AGTGTGGCCTTGTTAGTCTCGAGC (SEQ ID NO: 715)
SP6: CGCCAGGGTTTTCCCAGTCACGAC (SEQ ID NO: 718)
M13Rv: TCACACAGGAAACAGCTATGAC (SEQ ID NO: 719)
Anti-A beta antibody 6E10 was used as a control antibody to compare to the antibodies of the present invention. Anti-A beta antibody 6E10 (Covance Immuno-Technologies, Dedham, MA) is a mouse monoclonal antibody that recognizes a sequence in A beta1-16 as an epitope, and has no selectivity against A beta oligomer (binds to A beta monomer).
A beta oligomer antigens were prepared by diluting synthetic A beta1-40 (HCl form) at 0.1 mg/ml with PBS and incubating at 37degrees C for one hour. A beta monomer was prepared by diluting synthetic A beta1-40 (TFA form) at 0.1 mg/ml with PBS. First, 400 ng/well of A beta oligomer was immobilized onto 96-well immunopate and the plate was blocked with BSA. Next, antibodies of the present invention or a control anti-A beta antibody (6E10) were each mixed with serially-diluted A beta monomer or A beta oligomer at a range of 100 pg/ml to 100 micro g/ml and incubated for two hours, then each mixture was added to 96-well immunoplate and incubated at room temperature for ten minutes. Binding abilities of each antibodies to immobilized A beta oligomer were detected by reacting with HRP-conjugated anti-mouse IgG antibody and visualized by measuring absorbance at 450 nm using TMB solution. In the present method, two types of A beta1-40 (A beta1-40 monomer and A beta1-40 oligomer), which have the same sequence but have different structure and polymerization characters due to their structure, was compared as competitive substance. Accordingly, the method can compare the binding difference of the antibodies only derived from the existence of A beta1-40 polymerization, and thus can obtain extremely reliable results.
The analysis was carried out by Surface Plasmon Resonance (SPR) using Biacore 3000 (GE Healthcare Sciences). A beta oligomer was immobilized onto a sensor chip (CM5) as a ligand and antibodies of the present invention and control 6E10 antibody were used as analyte, kinetics analysis was carried out. Analysis was conducted at analyte antibodies at the following five concentrations: 1.25, 2.50, 5.00, 10.00, and 20.00 micro g/ml, and association rate constant (ka), dissociaton rate constant (kd), and dissociation constant (KD) was calculated using BiaEvaluation software. A beta oligomer used in the analysis was prepared by diluting synthetic A beta1-40 (HCl form) at 0.1 mg/ml with PBS and incubating at 37degrees C for one hour.
Human neuroblastoma cell (SH-SY5Y cell) was plated into 24-well plates at a density of 150,000 cells/well, and cultured for 24 hours in DMEM containing 10% FBS. Then, the medium was replaced a serum-free medium containing 12.5 micro M A beta1-42 in the presence or absence of antibodies and cells were cultured for another 24 hours. To determine the cytotoxicity induced by A beta1-42, LDH contents released into the medium from dead cells was determined using CytoTox96 Kit (manufactured by Promega).
A beta1-42 solution diluted to 12.5 micro M with cell culture medium was incubated in the presence or absence of antibodies of the present invention at 37degrees C for 24 hours. Then, the solutions were mixed with Thioflavin T (ThT) solution (5 micro M ThT, 50 mM Glycine-NaOH, pH8.5), ThT fluorescence intensity, which is correlated with A beta amyloid fibril contents,were determined using fluorescence spectrophotometer (RF-5300PC; Shimadzu Co., Kyoto, Japan). Excitation and emission wavelengths were set at 446 nm and 490 nm, respectively. Fluorescence intensity was measured immediately after the mixture was prepared.
Brain homogenates of Tg2576 or wild type mice were used for APP binding assay. The homogenates were electrophoresed in NuPAGE Tris-Glycine 4-12% gel and transferred to a PVDF membrane. The membrane was reacted to each antibody after blocking by PVDF blocking reagent (TOYOBO). The binding ability was detected by an HRP-conjugated anti-mouse IgG antibody and chemiluminescent reagent (Immobilon western, Millipore).
Selection of anti-A beta olilgomer antibodies
67 mice were immunized with A beta tetramer antigen and inguinal lympho node or spleen were isolated from each mice. Cells derived from each organs were fused with myeloma (Sp2/O-Ag14) and dispensed into seven plates of 96-well plate per mice and cultured. Hybridomas producing the antibodies of interest were selected by adding culture supernatant from the 96-well plate onto ELISA plates immobilized with A beta oligomer, and reacting them to analyze. As a result, 45 positive cells were selected from 45,024 wells ((67 mice) x (7 plates) x (96 wells)).
The variable region sequences were analyzed by the above-mentioned method, for 33 antibodies (i.e., AL-201 to AL-233) selected by the above dot blot analysis. As a result, the following nucleotide sequences of regions comprising VH CDR1, CDR2, and were obtained:
SEQ ID NO: 1(AL-201), SEQ ID NO: 17(AL-202), SEQ ID NO: 33(AL-203), SEQ ID NO: 49(AL-204), SEQ ID NO: 65(AL-205), SEQ ID NO: 81(AL-206), SEQ ID NO: 97(AL-207), SEQ ID NO: 113(AL-208), SEQ ID NO: 129(AL-209), SEQ ID NO: 145(AL-210), SEQ ID NO: 161(AL-211), SEQ ID NO: 177(AL-212), SEQ ID NO: 193(AL-213), SEQ ID NO: 209(AL-214), SEQ ID NO: 225(AL-215), SEQ ID NO: 241(AL-216), SEQ ID NO: 257(AL-217), SEQ ID NO: 273(AL-218), SEQ ID NO: 289(AL-219), SEQ ID NO: 305(AL-220), SEQ ID NO: 321(AL-221), SEQ ID NO: 337(AL-222), SEQ ID NO: 353(AL-223), SEQ ID NO: 369(AL-224), SEQ ID NO: 385(AL-225), SEQ ID NO: 401(AL-226), SEQ ID NO: 417(AL-227), SEQ ID NO: 433(AL-228), SEQ ID NO: 449(AL-229), SEQ ID NO: 465(AL-230), SEQ ID NO: 481(AL-231), SEQ ID NO: 497(AL-232), and SEQ ID NO: 513(AL-233). From the above nucleotide sequence, the following amino acid sequences were obtained:
SEQ ID NO: 2(AL-201), SEQ ID NO: 18(AL-202), SEQ ID NO: 34(AL-203), SEQ ID NO: 50(AL-204), SEQ ID NO: 66(AL-205), SEQ ID NO: 82(AL-206), SEQ ID NO: 98(AL-207), SEQ ID NO: 114(AL-208), SEQ ID NO: 130(AL-209), SEQ ID NO: 146(AL-210), SEQ ID NO: 162(AL-211), SEQ ID NO: 178(AL-212), SEQ ID NO: 194(AL-213), SEQ ID NO: 210(AL-214), SEQ ID NO: 226(AL-215), SEQ ID NO: 242(AL-216), SEQ ID NO: 258(AL-217), SEQ ID NO: 274(AL-218), SEQ ID NO: 290(AL-219), SEQ ID NO: 306(AL-220), SEQ ID NO: 322(AL-221), SEQ ID NO: 338(AL-222), SEQ ID NO: 354(AL-223), SEQ ID NO: 370(AL-224), SEQ ID NO: 386(AL-225), SEQ ID NO: 402(AL-226), SEQ ID NO: 418(AL-227), SEQ ID NO: 434(AL-228), SEQ ID NO: 450(AL-229), SEQ ID NO: 466(AL-230), SEQ ID NO: 482(AL-231), SEQ ID NO: 498(AL-232), and SEQ ID NO: 514(AL-233).
SEQ ID NO: 3(AL-201), SEQ ID NO: 19(AL-202), SEQ ID NO: 35(AL-203), SEQ ID NO: 51(AL-204), SEQ ID NO: 67(AL-205), SEQ ID NO: 83(AL-206), SEQ ID NO: 99(AL-207), SEQ ID NO: 115(AL-208), SEQ ID NO: 131(AL-209), SEQ ID NO: 147(AL-210), SEQ ID NO: 163(AL-211), SEQ ID NO: 179(AL-212), SEQ ID NO: 195(AL-213), SEQ ID NO: 211(AL-214), SEQ ID NO: 227(AL-215), SEQ ID NO: 243(AL-216), SEQ ID NO: 259(AL-217), SEQ ID NO: 275(AL-218), SEQ ID NO: 291(AL-219), SEQ ID NO: 307(AL-220), SEQ ID NO: 323(AL-221), SEQ ID NO: 339(AL-222), SEQ ID NO: 355(AL-223), SEQ ID NO: 371(AL-224), SEQ ID NO: 387(AL-225), SEQ ID NO: 403(AL-226), SEQ ID NO: 419(AL-227), SEQ ID NO: 435(AL-228), SEQ ID NO: 451(AL-229), SEQ ID NO: 467(AL-230), SEQ ID NO: 483(AL-231), SEQ ID NO: 499(AL-232), and SEQ ID NO: 515(AL-233). From the above nucleotide sequence, the following amino acid sequences were obtained:
SEQ ID NO: 4(AL-201), SEQ ID NO: 20(AL-202), SEQ ID NO: 36(AL-203), SEQ ID NO: 52(AL-204), SEQ ID NO: 68(AL-205), SEQ ID NO: 84(AL-206), SEQ ID NO: 100(AL-207), SEQ ID NO: 116(AL-208), SEQ ID NO: 132(AL-209), SEQ ID NO: 148(AL-210), SEQ ID NO: 164(AL-211), SEQ ID NO: 180(AL-212), SEQ ID NO: 196(AL-213), SEQ ID NO: 212(AL-214), SEQ ID NO: 228(AL-215), SEQ ID NO: 244(AL-216), SEQ ID NO: 260(AL-217), SEQ ID NO: 276(AL-218), SEQ ID NO: 292(AL-219), SEQ ID NO: 308(AL-220), SEQ ID NO: 324(AL-221), SEQ ID NO: 340(AL-222), SEQ ID NO: 356(AL-223), SEQ ID NO: 372(AL-224), SEQ ID NO: 388(AL-225), SEQ ID NO: 404(AL-226), SEQ ID NO: 420(AL-227), SEQ ID NO: 436(AL-228), SEQ ID NO: 452(AL-229), SEQ ID NO: 468(AL-230), SEQ ID NO: 484(AL-231), SEQ ID NO: 500(AL-232), and SEQ ID NO: 516(AL-233).
SEQ ID NO: 530(AL-201), SEQ ID NO: 534(AL-202), SEQ ID NO: 538(AL-203), SEQ ID NO: 542(AL-204), SEQ ID NO: 546(AL-205), SEQ ID NO: 550(AL-206), SEQ ID NO: 554(AL-207), SEQ ID NO: 558(AL-208), SEQ ID NO: 562(AL-209), SEQ ID NO: 566(AL-210), SEQ ID NO: 570(AL-211), SEQ ID NO: 574(AL-212), SEQ ID NO: 578(AL-213), SEQ ID NO: 582(AL-214), SEQ ID NO: 586(AL-215), SEQ ID NO: 590(AL-216), SEQ ID NO: 594(AL-217), SEQ ID NO: 598(AL-218), SEQ ID NO: 602(AL-219), SEQ ID NO: 606(AL-220), SEQ ID NO: 610(AL-221), SEQ ID NO: 614(AL-222), SEQ ID NO: 618(AL-223), SEQ ID NO: 622(AL-224), SEQ ID NO: 626(AL-225), SEQ ID NO: 630(AL-226), SEQ ID NO: 634(AL-227), SEQ ID NO: 638(AL-228), SEQ ID NO: 642(AL-229), SEQ ID NO: 646(AL-230), SEQ ID NO: 650(AL-231), SEQ ID NO: 654(AL-232), and SEQ ID NO: 658(AL-233). The nucleotide sequences corresponding to the above amino acid sequences are shown in the following sequence ID numbers:
SEQ ID NO: 529(AL-201), SEQ ID NO: 533(AL-202), SEQ ID NO: 537(AL-203), SEQ ID NO: 541(AL-204), SEQ ID NO: 545(AL-205), SEQ ID NO: 549(AL-206), SEQ ID NO: 553(AL-207), SEQ ID NO: 557(AL-208), SEQ ID NO: 561(AL-209), SEQ ID NO: 565(AL-210), SEQ ID NO: 569(AL-211), SEQ ID NO: 573(AL-212), SEQ ID NO: 577(AL-213), SEQ ID NO: 581(AL-214), SEQ ID NO: 585(AL-215), SEQ ID NO: 589(AL-216), SEQ ID NO: 593(AL-217), SEQ ID NO: 597(AL-218), SEQ ID NO: 601(AL-219), SEQ ID NO: 605(AL-220), SEQ ID NO: 609(AL-221), SEQ ID NO: 613(AL-222), SEQ ID NO: 617(AL-223), SEQ ID NO: 621(AL-224), SEQ ID NO: 625(AL-225), SEQ ID NO: 629(AL-226), SEQ ID NO: 633(AL-227), SEQ ID NO: 637(AL-228), SEQ ID NO: 641(AL-229), SEQ ID NO: 645(AL-230), SEQ ID NO: 649(AL-231), SEQ ID NO: 653(AL-232), and SEQ ID NO: 657(AL-233).
SEQ ID NO: 532(AL-201), SEQ ID NO: 536(AL-202), SEQ ID NO: 540(AL-203), SEQ ID NO: 544(AL-204), SEQ ID NO: 548(AL-205), SEQ ID NO: 552(AL-206), SEQ ID NO: 556(AL-207), SEQ ID NO: 560(AL-208), SEQ ID NO: 564(AL-209), SEQ ID NO: 568(AL-210), SEQ ID NO: 572(AL-211), SEQ ID NO: 576(AL-212), SEQ ID NO: 580(AL-213), SEQ ID NO: 584(AL-214), SEQ ID NO: 588(AL-215), SEQ ID NO: 592(AL-216), SEQ ID NO: 596(AL-217), SEQ ID NO: 600(AL-218), SEQ ID NO: 604(AL-219), SEQ ID NO: 608(AL-220), SEQ ID NO: 612(AL-221), SEQ ID NO: 616(AL-222), SEQ ID NO: 620(AL-223), SEQ ID NO: 624(AL-224), SEQ ID NO: 628(AL-225), SEQ ID NO: 632(AL-226), SEQ ID NO: 636(AL-227), SEQ ID NO: 640(AL-228), SEQ ID NO: 644(AL-229), SEQ ID NO: 648(AL-230), SEQ ID NO: 652(AL-231), SEQ ID NO: 656(AL-232), and SEQ ID NO: 660(AL-233). The nucleotide sequences corresponding to the above amino acid sequences are shown in the following sequence ID numbers:
SEQ ID NO: 531(AL-201), SEQ ID NO: 535(AL-202), SEQ ID NO: 539(AL-203), SEQ ID NO: 543(AL-204), SEQ ID NO: 547(AL-205), SEQ ID NO: 551(AL-206), SEQ ID NO: 555(AL-207), SEQ ID NO: 559(AL-208), SEQ ID NO: 563(AL-209), SEQ ID NO: 567(AL-210), SEQ ID NO: 571(AL-211), SEQ ID NO: 575(AL-212), SEQ ID NO: 579(AL-213), SEQ ID NO: 583(AL-214), SEQ ID NO: 587(AL-215), SEQ ID NO: 591(AL-216), SEQ ID NO: 595(AL-217), SEQ ID NO: 599(AL-218), SEQ ID NO: 603(AL-219), SEQ ID NO: 607(AL-220), SEQ ID NO: 611(AL-221), SEQ ID NO: 615(AL-222), SEQ ID NO: 619(AL-223), SEQ ID NO: 623(AL-224), SEQ ID NO: 627(AL-225), SEQ ID NO: 631(AL-226), SEQ ID NO: 635(AL-227), SEQ ID NO: 639(AL-228), SEQ ID NO: 643(AL-229), SEQ ID NO: 647(AL-230), SEQ ID NO: 651(AL-231), SEQ ID NO: 655(AL-232), and SEQ ID NO: 659(AL-233).
SEQ ID NO: 662(AL-213, AL-214), SEQ ID NO: 664(AL-207), SEQ ID NO: 667(AL-211, AL-212, AL-215, AL-218, AL-221, AL-222, AL-223, AL-225, AL-227, AL-228, AL-229, AL-231, AL-232), SEQ ID NO: 669(AL-209), SEQ ID NO: 671(AL-224), SEQ ID NO: 673(AL-201, AL-208, AL-216, AL-220), SEQ ID NO: 675(AL-202), SEQ ID NO: 677(AL-203, AL-204), SEQ ID NO: 679(AL-210, AL-217, AL-219, AL-226, AL-230), SEQ ID NO: 681(AL-233), SEQ ID NO: 683(AL-206), and SEQ ID NO: 685(AL-205). The nucleotide sequences encoding H-chain signal peptides of each antibody are shown in the following sequence ID numbers:
SEQ ID NO: 661(AL-213, AL-214), SEQ ID NO: 663(AL-207), SEQ ID NO: 665(AL-215, AL-227, AL-229), SEQ ID NO: 666(AL-211, AL-212, AL-218, AL-221, AL-222, AL-223, AL-225, AL-228, AL-231, AL-232), SEQ ID NO: 668(AL-209), SEQ ID NO: 670(AL-224), SEQ ID NO: 672(AL-201, AL-208, AL-216, AL-220), SEQ ID NO: 674(AL-202), SEQ ID NO: 676(AL-203, AL-204), SEQ ID NO: 678(AL-210, AL-217, AL-219, AL-226, AL-230), SEQ ID NO: 680(AL-233), SEQ ID NO: 682(AL-206), and SEQ ID NO: 684(AL-205).
SEQ ID NO: 687(AL-233), SEQ ID NO: 689(AL-206, AL-207, AL-208), SEQ ID NO: 691(AL-205), SEQ ID NO: 694(AL-203, AL-204), SEQ ID NO: 696(AL-228), SEQ ID NO: 698(AL-222), SEQ ID NO: 700(AL-210, AL-211, AL-212, AL-213, AL-214, AL-215, AL-216, AL-217, AL-218, AL-220, AL-221, AL-223, AL-224, AL-225, AL-226, AL-227, AL-229, AL-230, AL-231, AL-232), SEQ ID NO: 702(AL-201), SEQ ID NO: 704(AL-202), and SEQ ID NO: 706(AL-209). The nucleotide sequences encoding L-chain signal peptides of each antibody are shown in the following sequence ID numbers:
SEQ ID NO: 686(AL-233), SEQ ID NO: 688(AL-206, AL-207, AL-208), SEQ ID NO: 690(AL-205), SEQ ID NO: 692(AL-204), SEQ ID NO: 693(AL-203), SEQ ID NO: 695(AL-228), SEQ ID NO: 697(AL-222), SEQ ID NO: 699(AL-210, AL-211, AL-212, AL-213, AL-214, AL-215, AL-216, AL-217, AL-218, AL-220, AL-221, AL-223, AL-224, AL-225, AL-226, AL-227, AL-229, AL-230, AL-231, AL-232), SEQ ID NO: 701(AL-201), SEQ ID NO: 703(AL-202), and SEQ ID NO: 705(AL-209). The L-chain signal peptide sequence of AL-291 was not determined. An N-terminal portion of the L-chain signal peptide sequence of AL-228 was not determined.
Dot blot anlysis is a method for analyzing a reactivity against A beta monomer or oligomer immobilized onto nitrocellulose membtane. However, A betas are solubilized into fluids such as interstitial fluid, cerebral fluid, or blood. Then, the present analysis was carried out for investigating specific binding to A beta oligomers in solutions and difference of selectivity to A beta monomer. Competitive ELISA is a method for determining oligomer specificity by preliminarily reacting with antibodies to be measured and serially-diluted A beta monomer or oligomer in solutions, and carrying out ELISA by adding the solutions to a plate immobilized with A beta oligomer. When an antibody is an A beta oligomer-specific antibody, ELISA reaction decreases in an A beta oligomer concentration-dependent manner in a solution reacted with A beta oligomer, but does not decrease in a solution reacted with A beta monomer or decreases when A beta concentration becomes higher than the oligomer concentration. 19 antibodies were analyzed and the result shown in Fig. 2 was obtained. Eight antibodies (AL-213, 217, 220, 224, 225, 226, 229, and 233) showed high binding specificity even in the solution. Meanwhile, antibody that react with both A beta monomer and oligomer (6E10) used as a control showed equivalent ELISA reactivity against monomer and oligomer. IC50 and A beta oligomer selectivity over A beta monomer (A beta monomer IC50/A beta oligomer IC50) calculated by the competitive ELISA are shown in Table 2.
To investigate the binding ability of the antibodies of the present invention to A beta oligomer, affinity was analyzed (see Methods). From eight antibodies that exhibit high specificity by the competitive ELISA, three antibodies were analyzed and results shown in Fig. 3 was obtained. Calculated association rate constant (ka), dissociation rate constant (kd), and dissociation constant (KD) was shown in Table 3.
A beta oligomers cause cytotoxicity to neuronal cells. To assess whether the present anti-A beta oligomer antibodies neurtlize A beta-induced cytotoxicity, in vitro assay using human neuroblastoma cells (SH-SY5Y cells) was performed. Three kinds of anti-A beta oligomer antibodies (AL-217, AL-224 and AL-225) were examined. They neurtlized the A beta-induced cytotoxicity (Fig. 4). By contrast, non-A beta IgG which was used as a negative control antibody did not neurtlize the cytotoxicity. In the graphs, the value of Y axis indicates the relative rate to the cytotoxicity of A beta only (no antibody).
A beta monomers form fibrils as a result of multimerization when they are incubated in neutral pH buffer. To assess whether the present antibodies inhibit the fibril formation, an antibody and A beta were mixed and incubated for 24 hours and the mixture were measured by fluorescence of ThioflavinT which reflects the amount of fibrils. Three kinds fo anti-A beta oligomer antibodies (AL-217, AL-224 and AL-225) were examined. They inhibited formation of A beta fibrils compared to non-A beta IgG which was used as a negative control antibody (Fig. 5). In the graph, the values of Y axis indicates the relative rate to the fibril formation of A beta only (no antibody).
It is important for escape of side effect that anti-A beta antibodies do not bind APP which is a physiological protein expressed in a healthy body. Anti-A beta oligomer antibodies are expected not to bind to APP because they recognaize a conformational domain of A beta oligomer that does not present in APP. Therefore, the present inventor performed immunoblotting to assess whether the present anti-A beta oligomer antibodies do not bind to APP. Three antibodies (AL-217, AL-224 and AL-225) were examined, and the results showed that they do not bind to APP (Fig. 6).
Claims (14)
- An antibody that recognizes an isolated A beta tetramer as an antigen, wherein the antibody does not bind to an A beta monomer.
- The antibody of claim 1, which is any one of (1) to (99) below:
(1) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 530;
(2) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 532;
(3) an antibody that comprises the H chain of (1) and the L chain of (2);
(4) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 534;
(5) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 536;
(6) an antibody that comprises the H chain of (4) and the L chain of (5);
(7) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 538;
(8) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 540;
(9) an antibody that comprises the H chain of (7) and the L chain of (8);
(10) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 542;
(11) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 544;
(12) an antibody that comprises the H chain of (10) and the L chain of (11);
(13) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 546;
(14) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 548;
(15) an antibody that comprises the H chain of (13) and the L chain of (14);
(16) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 550;
(17) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 552;
(18) an antibody that comprises the H chain of (16) and the L chain of (17);
(19) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 554;
(20) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 556;
(21) an antibody that comprises the H chain of (19) and the L chain of (20);
(22) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 558;
(23) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 560;
(24) an antibody that comprises the H chain of (22) and the L chain of (23);
(25) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 562;
(26) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 564;
(27) an antibody that comprises the H chain of (25) and the L chain of (26);
(28) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 566;
(29) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 568;
(30) an antibody that comprises the H chain of (28) and the L chain of (29);
(31) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 570;
(32) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 572;
(33) an antibody that comprises the H chain of (31) and the L chain of (32);
(34) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 574;
(35) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 576;
(36) an antibody that comprises the H chain of (34) and the L chain of (35);
(37) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 578;
(38) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 580;
(39) an antibody that comprises the H chain of (37) and the L chain of (38);
(40) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 582;
(41) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 584;
(42) an antibody that comprises the H chain of (40) and the L chain of (41);
(43) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 586;
(44) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 588;
(45) an antibody that comprises the H chain of (43) and the L chain of (44);
(46) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 590;
(47) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 592;
(48) an antibody that comprises the H chain of (46) and the L chain of (47);
(49) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 594;
(50) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 596;
(51) an antibody that comprises the H chain of (49) and the L chain of (50);
(52) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 598;
(53) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 600;
(54) an antibody that comprises the H chain of (52) and the L chain of (53);
(55) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 602;
(56) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 604;
(57) an antibody that comprises the H chain of (55) and the L chain of (56);
(58) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 606;
(59) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 608;
(60) an antibody that comprises the H chain of (58) and the L chain of (59);
(61) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 610;
(62) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 612;
(63) an antibody that comprises the H chain of (61) and the L chain of (62);
(64) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 614;
(65) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 616;
(66) an antibody that comprises the H chain of (64) and the L chain of (65);
(67) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 618;
(68) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 620;
(69) an antibody that comprises the H chain of (67) and the L chain of (68);
(70) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 622;
(71) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 624;
(72) an antibody that comprises the H chain of (70) and the L chain of (71);
(73) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 626;
(74) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 628;
(75) an antibody that comprises the H chain of (73) and the L chain of (74);
(76) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 630;
(77) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 632;
(78) an antibody that comprises the H chain of (76) and the L chain of (77);
(79) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 634;
(80) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 636;
(81) an antibody that comprises the H chain of (79) and the L chain of (80);
(82) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 638;
(83) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 640;
(84) an antibody that comprises the H chain of (82) and the L chain of (83);
(85) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 642;
(86) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 644;
(87) an antibody that comprises the H chain of (85) and the L chain of (86);
(88) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 646;
(89) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 648;
(90) an antibody that comprises the H chain of (88) and the L chain of (89);
(91) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 650;
(92) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 652;
(93) an antibody that comprises the H chain of (91) and the L chain of (92);
(94) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 654;
(95) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 656;
(96) an antibody that comprises the H chain of (94) and the L chain of (95);
(97) an antibody that comprises an H chain having CDR1, CDR2, and CDR3, which are identified in VH comprising the amino acid sequence of SEQ ID NO: 658;
(98) an antibody that comprises an L chain having CDR1, CDR2, and CDR3, which are identified in VL comprising the amino acid sequence of SEQ ID NO: 660; and
(99) an antibody that comprises the H chain of (97) and the L chain of (98); - The antibody of claim 1, which is any one of (1) to (200) below:
(1) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 6 as CDR1, the amino acid sequence of SEQ ID NO: 8 as CDR2, and the amino acid sequence of SEQ ID NO: 10 as CDR3;
(2) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 12 as CDR1, the amino acid sequence of SEQ ID NO: 14 as CDR2, and the amino acid sequence of SEQ ID NO: 16 as CDR3;
(3) an antibody that comprises the H chain of (1) and the L chain of (2);
(4) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 530 as VH;
(5) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 532 as VL;
(6) an antibody that comprises the H chain of (4) and the L chain of (5);
(7) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 22 as CDR1, the amino acid sequence of SEQ ID NO: 24 as CDR2, and the amino acid sequence of SEQ ID NO: 26 as CDR3;
(8) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 28 as CDR1, the amino acid sequence of SEQ ID NO: 30 as CDR2, and the amino acid sequence of SEQ ID NO: 32 as CDR3;
(9) an antibody that comprises the H chain of (7) and the L chain of (8);
(10) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 534 as VH;
(11) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 536 as VL;
(12) an antibody that comprises the H chain of (10) and the L chain of (11);
(13) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 38 as CDR1, the amino acid sequence of SEQ ID NO: 40 as CDR2, and the amino acid sequence of SEQ ID NO: 42 as CDR3;
(14) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 44 as CDR1, the amino acid sequence of SEQ ID NO: 46 as CDR2, and the amino acid sequence of SEQ ID NO: 48 as CDR3;
(15) an antibody that comprises the H chain of (13) and the L chain of (14);
(16) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 538 as VH;
(17) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 540 as VL;
(18) an antibody that comprises the H chain of (16) and the L chain of (17);
(19) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 54 as CDR1, the amino acid sequence of SEQ ID NO: 56 as CDR2, and the amino acid sequence of SEQ ID NO: 58 as CDR3;
(20) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 60 as CDR1, the amino acid sequence of SEQ ID NO: 62 as CDR2, and the amino acid sequence of SEQ ID NO: 64 as CDR3;
(21) an antibody that comprises the H chain of (19) and the L chain of (20);
(22) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 542 as VH;
(23) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 544 as VL;
(24) an antibody that comprises the H chain of (22) and the L chain of (23);
(25) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 70 as CDR1, the amino acid sequence of SEQ ID NO: 72 as CDR2, and the amino acid sequence of SEQ ID NO: 74 as CDR3;
(26) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 76 as CDR1, the amino acid sequence of SEQ ID NO: 78 as CDR2, and the amino acid sequence of SEQ ID NO: 80 as CDR3;
(27) an antibody that comprises the H chain of (25) and the L chain of (26);
(28) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 546 as VH;
(29) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 548 as VL;
(30) an antibody that comprises the H chain of (28) and the L chain of (29);
(31) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 86 as CDR1, the amino acid sequence of SEQ ID NO: 88 as CDR2, and the amino acid sequence of SEQ ID NO: 90 as CDR3;
(32) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 92 as CDR1, the amino acid sequence of SEQ ID NO: 94 as CDR2, and the amino acid sequence of SEQ ID NO: 96 as CDR3;
(33) an antibody that comprises the H chain of (31) and the L chain of (32);
(34) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 550 as VH;
(35) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 552 as VL;
(36) an antibody that comprises the H chain of (34) and the L chain of (35);
(37) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 102 as CDR1, the amino acid sequence of SEQ ID NO: 104 as CDR2, and the amino acid sequence of SEQ ID NO: 106 as CDR3;
(38) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 108 as CDR1, the amino acid sequence of SEQ ID NO: 110 as CDR2, and the amino acid sequence of SEQ ID NO: 112 as CDR3;
(39) an antibody that comprises the H chain of (37) and the L chain of (38);
(40) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 554 as VH;
(41) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 556 as VL;
(42) an antibody that comprises the H chain of (40) and the L chain of (41);
(43) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 118 as CDR1, the amino acid sequence of SEQ ID NO: 120 as CDR2, and the amino acid sequence of SEQ ID NO: 122 as CDR3;
(44) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 124 as CDR1, the amino acid sequence of SEQ ID NO: 126 as CDR2, and the amino acid sequence of SEQ ID NO: 128 as CDR3;
(45) an antibody that comprises the H chain of (43) and the L chain of (44);
(46) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 558 as VH;
(47) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 560 as VL;
(48) an antibody that comprises the H chain of (46) and the L chain of (47);
(49) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 134 as CDR1, the amino acid sequence of SEQ ID NO: 136 as CDR2, and the amino acid sequence of SEQ ID NO: 138 as CDR3;
(50) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 140 as CDR1, the amino acid sequence of SEQ ID NO: 142 as CDR2, and the amino acid sequence of SEQ ID NO: 144 as CDR3;
(51) an antibody that comprises the H chain of (49) and the L chain of (50);
(52) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 562 as VH;
(53) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 564 as VL;
(54) an antibody that comprises the H chain of (52) and the L chain of (53);
(55) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 150 as CDR1, the amino acid sequence of SEQ ID NO: 152 as CDR2, and the amino acid sequence of SEQ ID NO: 154 as CDR3;
(56) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 156 as CDR1, the amino acid sequence of SEQ ID NO: 158 as CDR2, and the amino acid sequence of SEQ ID NO: 160 as CDR3;
(57) an antibody that comprises the H chain of (55) and the L chain of (56);
(58) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 566 as VH;
(59) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 568 as VL;
(60) an antibody that comprises the H chain of (58) and the L chain of (59);
(61) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 166 as CDR1, the amino acid sequence of SEQ ID NO: 168 as CDR2, and the amino acid sequence of SEQ ID NO: 170 as CDR3;
(62) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 172 as CDR1, the amino acid sequence of SEQ ID NO: 174 as CDR2, and the amino acid sequence of SEQ ID NO: 176 as CDR3;
(63) an antibody that comprises the H chain of (61) and the L chain of (62);
(64) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 570 as VH;
(65) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 572 as VL;
(66) an antibody that comprises the H chain of (64) and the L chain of (65);
(67) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 182 as CDR1, the amino acid sequence of SEQ ID NO: 184 as CDR2, and the amino acid sequence of SEQ ID NO: 186 as CDR3;
(68) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 188 as CDR1, the amino acid sequence of SEQ ID NO: 190 as CDR2, and the amino acid sequence of SEQ ID NO: 192 as CDR3;
(69) an antibody that comprises the H chain of (67) and the L chain of (68);
(70) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 574 as VH;
(71) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 576 as VL;
(72) an antibody that comprises the H chain of (70) and the L chain of (71);
(73) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 198 as CDR1, the amino acid sequence of SEQ ID NO: 200 as CDR2, and the amino acid sequence of SEQ ID NO: 202 as CDR3;
(74) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 204 as CDR1, the amino acid sequence of SEQ ID NO: 206 as CDR2, and the amino acid sequence of SEQ ID NO: 208 as CDR3;
(75) an antibody that comprises the H chain of (73) and the L chain of (74);
(76) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 578 as VH;
(77) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 580 as VL;
(78) an antibody that comprises the H chain of (75) and the L chain of (76);
(79) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 214 as CDR1, the amino acid sequence of SEQ ID NO: 216 as CDR2, and the amino acid sequence of SEQ ID NO: 218 as CDR3;
(80) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 220 as CDR1, the amino acid sequence of SEQ ID NO: 222 as CDR2, and the amino acid sequence of SEQ ID NO: 224 as CDR3;
(81) an antibody that comprises the H chain of (79) and the L chain of (80);
(82) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 582 as VH;
(83) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 584 as VL;
(84) an antibody that comprises the H chain of (82) and the L chain of (83);
(85) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 230 as CDR1, the amino acid sequence of SEQ ID NO: 232 as CDR2, and the amino acid sequence of SEQ ID NO: 234 as CDR3;
(86) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 236 as CDR1, the amino acid sequence of SEQ ID NO: 238 as CDR2, and the amino acid sequence of SEQ ID NO: 240 as CDR3;
(87) an antibody that comprises the H chain of (85) and the L chain of (86);
(88) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 586 as VH;
(89) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 588 as VL;
(90) an antibody that comprises the H chain of (88) and the L chain of (89);
(91) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 246 as CDR1, the amino acid sequence of SEQ ID NO: 248 as CDR2, and the amino acid sequence of SEQ ID NO: 250 as CDR3;
(92) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 252 as CDR1, the amino acid sequence of SEQ ID NO: 254 as CDR2, and the amino acid sequence of SEQ ID NO: 256 as CDR3;
(93) an antibody that comprises the H chain of (91) and the L chain of (92);
(94) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 590 as VH;
(95) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 592 as VL;
(96) an antibody that comprises the H chain of (94) and the L chain of (95);
(97) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 262 as CDR1, the amino acid sequence of SEQ ID NO: 264 as CDR2, and the amino acid sequence of SEQ ID NO: 266 as CDR3;
(98) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 268 as CDR1, the amino acid sequence of SEQ ID NO: 270 as CDR2, and the amino acid sequence of SEQ ID NO: 272 as CDR3;
(99) an antibody that comprises the H chain of (97) and the L chain of (98);
(100) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 594 as VH;
(101) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 596 as VL;
(102) an antibody that comprises the H chain of (100) and the L chain of (101);
(103) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 278 as CDR1, the amino acid sequence of SEQ ID NO: 280 as CDR2, and the amino acid sequence of SEQ ID NO: 282 as CDR3;
(104) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 284 as CDR1, the amino acid sequence of SEQ ID NO: 286 as CDR2, and the amino acid sequence of SEQ ID NO: 288 as CDR3;
(105) an antibody that comprises the H chain of (103) and the L chain of (104);
(106) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 598 as VH;
(107) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 600 as VL;
(108) an antibody that comprises the H chain of (106) and the L chain of (107);
(109) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 294 as CDR1, the amino acid sequence of SEQ ID NO: 296 as CDR2, and the amino acid sequence of SEQ ID NO: 298 as CDR3;
(110) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 300 as CDR1, the amino acid sequence of SEQ ID NO: 302 as CDR2, and the amino acid sequence of SEQ ID NO: 304 as CDR3;
(111) an antibody that comprises the H chain of (109) and the L chain of (110);
(112) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 602 as VH;
(113) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 604 as VL;
(114) an antibody that comprises the H chain of (112) and the L chain of (113);
(115) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 310 as CDR1, the amino acid sequence of SEQ ID NO: 312 as CDR2, and the amino acid sequence of SEQ ID NO: 314 as CDR3;
(116) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 316 as CDR1, the amino acid sequence of SEQ ID NO: 318 as CDR2, and the amino acid sequence of SEQ ID NO: 320 as CDR3;
(117) an antibody that comprises the H chain of (115) and the L chain of (116);
(118) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 606 as VH;
(119) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 608 as VL;
(120) an antibody that comprises the H chain of (118) and the L chain of (119);
(121) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 326 as CDR1, the amino acid sequence of SEQ ID NO: 328 as CDR2, and the amino acid sequence of SEQ ID NO: 330 as CDR3;
(122) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 332 as CDR1, the amino acid sequence of SEQ ID NO: 334 as CDR2, and the amino acid sequence of SEQ ID NO: 336 as CDR3;
(123) an antibody that comprises the H chain of (121) and the L chain of (122);
(124) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 610 as VH;
(125) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 612 as VL;
(126) an antibody that comprises the H chain of (124) and the L chain of (125);
(127) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 342 as CDR1, the amino acid sequence of SEQ ID NO: 344 as CDR2, and the amino acid sequence of SEQ ID NO: 346 as CDR3;
(128) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 348 as CDR1, the amino acid sequence of SEQ ID NO: 350 as CDR2, and the amino acid sequence of SEQ ID NO: 352 as CDR3;
(129) an antibody that comprises the H chain of (127) and the L chain of (128);
(130) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 614 as VH;
(131) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 616 as VL;
(132) an antibody that comprises the H chain of (130) and the L chain of (131);
(133) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 358 as CDR1, the amino acid sequence of SEQ ID NO: 360 as CDR2, and the amino acid sequence of SEQ ID NO: 362 as CDR3;
(134) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 364 as CDR1, the amino acid sequence of SEQ ID NO: 366 as CDR2, and the amino acid sequence of SEQ ID NO: 368 as CDR3;
(135) an antibody that comprises the H chain of (133) and the L chain of (134);
(136) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 618 as VH;
(137) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 620 as VL;
(138) an antibody that comprises the H chain of (136) and the L chain of (137);
(139) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 374 as CDR1, the amino acid sequence of SEQ ID NO: 376 as CDR2, and the amino acid sequence of SEQ ID NO: 378 as CDR3;
(140) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 380 as CDR1, the amino acid sequence of SEQ ID NO: 382 as CDR2, and the amino acid sequence of SEQ ID NO: 384 as CDR3;
(141) an antibody that comprises the H chain of (139) and the L chain of (140);
(142) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 622 as VH;
(143) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 624 as VL;
(144) an antibody that comprises the H chain of (142) and the L chain of (143);
(145) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 390 as CDR1, the amino acid sequence of SEQ ID NO: 392 as CDR2, and the amino acid sequence of SEQ ID NO: 394 as CDR3;
(146) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 396 as CDR1, the amino acid sequence of SEQ ID NO: 398 as CDR2, and the amino acid sequence of SEQ ID NO: 400 as CDR3;
(147) an antibody that comprises the H chain of (145) and the L chain of (146);
(148) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 626 as VH;
(149) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 628 as VL;
(150) an antibody that comprises the H chain of (148) and the L chain of (149);
(151) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 406 as CDR1, the amino acid sequence of SEQ ID NO: 408 as CDR2, and the amino acid sequence of SEQ ID NO: 410 as CDR3;
(152) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 412 as CDR1, the amino acid sequence of SEQ ID NO: 414 as CDR2, and the amino acid sequence of SEQ ID NO: 416 as CDR3;
(153) an antibody that comprises the H chain of (151) and the L chain of (152);
(154) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 630 as VH;
(155) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 632 as VL;
(156) an antibody that comprises the H chain of (154) and the L chain of (155);
(157) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 422 as CDR1, the amino acid sequence of SEQ ID NO: 424 as CDR2, and the amino acid sequence of SEQ ID NO: 426 as CDR3;
(158) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 428 as CDR1, the amino acid sequence of SEQ ID NO: 430 as CDR2, and the amino acid sequence of SEQ ID NO: 432 as CDR3;
(159) an antibody that comprises the H chain of (157) and the L chain of (158);
(160) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 634 as VH;
(161) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 636 as VL;
(162) an antibody that comprises the H chain of (160) and the L chain of (161);
(163) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 438 as CDR1, the amino acid sequence of SEQ ID NO: 440 as CDR2, and the amino acid sequence of SEQ ID NO: 442 as CDR3;
(164) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 444 as CDR1, the amino acid sequence of SEQ ID NO: 446 as CDR2, and the amino acid sequence of SEQ ID NO: 448 as CDR3;
(165) an antibody that comprises the H chain of (163) and the L chain of (164);
(166) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 638 as VH;
(167) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 640 as VL;
(168) an antibody that comprises the H chain of (166) and the L chain of (167);
(169) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 454 as CDR1, the amino acid sequence of SEQ ID NO: 456 as CDR2, and the amino acid sequence of SEQ ID NO: 458 as CDR3;
(170) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 460 as CDR1, the amino acid sequence of SEQ ID NO: 462 as CDR2, and the amino acid sequence of SEQ ID NO: 464 as CDR3;
(171) an antibody that comprises the H chain of (169) and the L chain of (170);
(172) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 642 as VH;
(173) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 644 as VL;
(174) an antibody that comprises the H chain of (172) and the L chain of (173);
(175) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 470 as CDR1, the amino acid sequence of SEQ ID NO: 472 as CDR2, and the amino acid sequence of SEQ ID NO: 474 as CDR3;
(176) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 476 as CDR1, the amino acid sequence of SEQ ID NO: 478 as CDR2, and the amino acid sequence of SEQ ID NO: 480 as CDR3;
(177) an antibody that comprises the H chain of (175) and the L chain of (176);
(178) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 646 as VH;
(179) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 648 as VL;
(180) an antibody that comprises the H chain of (178) and the L chain of (179);
(181) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 486 as CDR1, the amino acid sequence of SEQ ID NO: 488 as CDR2, and the amino acid sequence of SEQ ID NO: 490 as CDR3;
(182) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 492 as CDR1, the amino acid sequence of SEQ ID NO: 494 as CDR2, and the amino acid sequence of SEQ ID NO: 496 as CDR3;
(183) an antibody that comprises the H chain of (181) and the L chain of (182);
(184) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 650 as VH;
(185) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 652 as VL;
(186) an antibody that comprises the H chain of (184) and the L chain of (185);
(187) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 502 as CDR1, the amino acid sequence of SEQ ID NO: 504 as CDR2, and the amino acid sequence of SEQ ID NO: 506 as CDR3;
(188) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 508 as CDR1, the amino acid sequence of SEQ ID NO: 510 as CDR2, and the amino acid sequence of SEQ ID NO: 512 as CDR3;
(189) an antibody that comprises the H chain of (187) and the L chain of (188);
(190) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 654 as VH;
(191) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 656 as VL;
(192) an antibody that comprises the H chain of (190) and the L chain of (191);
(193) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 518 as CDR1, the amino acid sequence of SEQ ID NO: 520 as CDR2, and the amino acid sequence of SEQ ID NO: 522 as CDR3;
(194) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 524 as CDR1, the amino acid sequence of SEQ ID NO: 526 as CDR2, and the amino acid sequence of SEQ ID NO: 528 as CDR3;
(195) an antibody that comprises the H chain of (193) and the L chain of (194);
(196) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 658 as VH;
(197) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 660 as VL;
(198) an antibody that comprises the H chain of (196) and the L chain of (197);
(199) an antibody that comprises one or more amino acid substitutions, deletions, additions, and/or insertions in the antibody of any one of (1) to (198), which has equivalent activity to the antibody of any one of (1) to (198); and
(200) an antibody that binds to the epitope bound by the antibody of any one of (1) to (198). - The antibody of any one of claims 1 to 3, wherein the antibody is a chimeric antibody or a humanized antibody.
- An antigen-binding fragment of the antibody of any one of claims 1 to 4.
- A pharmaceutical composition comprising the antibody of any one of claims 1 to 4 or the antigen-binding fragment of claim 5, and a pharmaceutically acceptable carrier.
- The composition of claim 6, which comprises an agent against cognitive impairment, a therapeutic agent for Alzheimer's disease, an agent for suppressing the progression of Alzheimer's disease, an agent for suppressing senile plaque formation, an agent for suppressing A beta accumulation, an anti-neurotoxic agent, an agent for inhibiting A beta amyloid fibril formation, or an agent against synaptic toxicity.
- A method for detecting an A beta oligomer, which comprises the step of detecting an A beta oligomer contained in a sample using the antibody of any one of claims 1 to 4 or the antigen-binding fragment of claim 5.
- A method of diagnosing whether or not a subject is a possible Alzheimer's disease patient, which comprises using the antibody of any one of claims 1 to 4 or the antigen-binding fragment of claim 5, to detect an A beta oligomer in a sample collected from a subject.
- A method of diagnosing whether or not a subject is a possible Alzheimer's disease patient, which comprises the steps of:
(a) contacting a sample collected from a subject with the antibody of any one of claims 1 to 4 or the antigen-binding fragment of claim 5; and
(b) measuring the amount of A beta oligomer in the sample,
wherein the subject is determined to be a possible Alzheimer's disease patient, when the amount measured in step (b) is higher than that of a healthy individual. - A method of diagnosing whether or not a subject is a possible Alzheimer's disease patient, which comprises the steps of:
(a) contacting a sample collected from a subject with the antibody of any one of claims 1 to 4 or the antigen-binding fragment of claim 5, and an antibody that binds to an A beta monomer; and
(b) measuring the ratio of A beta oligomer to A beta monomer in the sample,
wherein the subject is determined to be a possible Alzheimer's disease patient, when the ratio measured in step (b) is higher than that of a healthy individual. - The method of any one of claims 8 to 11, wherein the sample is blood or cerebrospinal fluid.
- A pharmaceutical agent for use in the method of any one of claims 8 to 12.
- A kit for use in the method of any one of claims 8 to 12.
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2011544303A JP5812418B2 (en) | 2009-04-17 | 2010-04-16 | Antibody specifically binding to Aβ oligomer and use thereof |
DK10764291.0T DK2419447T3 (en) | 2009-04-17 | 2010-04-16 | ANTIBODIES THAT SPECIFICALLY BIND TO A BETA OLIGOMER AND USE THEREOF |
US13/264,671 US9090679B2 (en) | 2009-04-17 | 2010-04-16 | Antibodies that specifically bind to A beta oligomers and use thereof |
ES10764291.0T ES2641612T3 (en) | 2009-04-17 | 2010-04-16 | Antibodies that specifically bind to beta A oligomers and use thereof |
EP10764291.0A EP2419447B1 (en) | 2009-04-17 | 2010-04-16 | Antibodies that specifically bind to a beta oligomers and use thereof |
CN201080027272.0A CN102459335B (en) | 2009-04-17 | 2010-04-16 | Antibody of specific binding A beta oligomers and uses thereof |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
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US21298609P | 2009-04-17 | 2009-04-17 | |
US61/212,986 | 2009-04-17 | ||
US28254910P | 2010-02-26 | 2010-02-26 | |
US61/282,549 | 2010-02-26 |
Publications (1)
Publication Number | Publication Date |
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WO2010119704A1 true WO2010119704A1 (en) | 2010-10-21 |
Family
ID=42982376
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2010/002771 WO2010119704A1 (en) | 2009-04-17 | 2010-04-16 | Antibodies that specifically bind to a beta oligomers and use thereof |
Country Status (7)
Country | Link |
---|---|
US (1) | US9090679B2 (en) |
EP (1) | EP2419447B1 (en) |
JP (1) | JP5812418B2 (en) |
CN (1) | CN102459335B (en) |
DK (1) | DK2419447T3 (en) |
ES (1) | ES2641612T3 (en) |
WO (1) | WO2010119704A1 (en) |
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WO2023076998A1 (en) * | 2021-10-27 | 2023-05-04 | Atyr Pharma, Inc. | COMPOSITIONS AND METHODS COMPRISING ANTI-NRP2a ANTIBODIES |
WO2024027815A1 (en) * | 2022-08-05 | 2024-02-08 | 江苏恒瑞医药股份有限公司 | Antigen-binding molecule specifically binding to gucy2c and cd3 and pharmaceutical use thereof |
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EP2419447A4 (en) | 2014-02-26 |
CN102459335B (en) | 2015-11-25 |
JP5812418B2 (en) | 2015-11-11 |
EP2419447A1 (en) | 2012-02-22 |
ES2641612T3 (en) | 2017-11-10 |
US20120082667A1 (en) | 2012-04-05 |
EP2419447B1 (en) | 2017-08-23 |
JP2012524023A (en) | 2012-10-11 |
US9090679B2 (en) | 2015-07-28 |
DK2419447T3 (en) | 2017-09-25 |
CN102459335A (en) | 2012-05-16 |
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