ANTIBODY WHICH BINDS TO MYELIN OLIGODENDROCYTE GLYCOPROTEIN

Abstract

The invention relates to an antibody which binds to myelin oligodendrocyte glycoprotein (MOG), an antibody fragment thereof, a hybridoma which produces the antibody or the antibody fragment, a nucleic acid containing a nucleotide sequence which encodes the antibody or the antibody fragment, a transformant cell containing a vector containing the nucleic acid, a method for producing the antibody or the antibody fragment, a composition containing the antibody or the antibody fragment and a method for detecting or measuring an antigen that is present in the brain, a method for diagnosing or treating a brain disease, a method for improving the property of an antibody of accumulating in the brain and a method for increasing the amount of an antibody in the brain which use the antibody or the antibody fragment.

Description

TECHNICAL FIELD

[0001] The present invention relates to an antibody which binds to myelin oligodendrocyte glycoprotein (MOG), an antibody fragment thereof, a hybridoma which produces the antibody or the antibody fragment, a nucleic acid containing a nucleotide sequence which encodes the antibody or the antibody fragment, a transformant cell containing a vector containing the nucleic acid, a method for producing the antibody or the antibody fragment, a composition containing the antibody or the antibody fragment and a method for detecting or measuring an antigen that is present in the brain, a method for diagnosing or treating a brain disease, a method for improving the property of an antibody of accumulating in the brain and a method for increasing the amount of an antibody in the brain which use the antibody or the antibody fragment.

BACKGROUND ART

[0002] Since the approval of a mouse anti-CD3 antibody, muromonab-CD3 (OKT3) as the first antibody drug by FDA in 1986, many antibody drugs have been developed. In 1994, a chimeric antibody, abciximab, in which a variable region of a mouse antibody and a constant region of a human antibody are linked to reduce the antigenicity of the mouse antibody, has been approved.

[0003] To further reduce the antigenicity, humanized antibody technique in which a complementarity determining region (CDR below), which plays an important role in binding to an antigen, of a variable region of a mouse antibody is inserted to the frame work region (FR below) of a human antibody has been developed, and a humanized anti-CD20 antibody, dacizumab has been approved in 1997.

[0004] Moreover, phage display technique using a human antibody sequence library has been used, and a fully human anti-TNF a antibody, adalimumab, which is the first antibody using the phage display technique that has been approved, has been approved in 2002. Sixty or more antibody drugs targeting antigens such as CD20, CD52, TNF a, HER2 and EGFR have already been approved (NPL 1).

[0005] In this manner, antibodies are a widely recognized drug format. Most of the antibody drugs that have been approved so far are those for cancers and immune diseases, which account for about 75% or more of all the antibody drugs.

[0006] The importance of biologics such as antibodies is increasing also in the treatment of central nervous system diseases, and it is reported that a monoclonal antibody to amyloid .beta. is studied in Alzheimer's disease and that neurotrophic factors (brain-derived neurotrophic factor BDNF and glial-derived neurotrophic factor GDNF) having neuroprotective effect exhibit neuroprotective effect in central nervous system diseases in an animal model (NPL 2).

[0007] However, when an antibody is peripherally administered, the amount sent to the central nervous system is lower than those to the other organs, and the antibody migration rate (the ratio of the concentration in the cerebrospinal fluid (CSF) to the serum concentration) is reported to be 0.1-0.3% (NPLs 3-5).

[0008] A reason why the drug delivery amount decreases in the central nervous system including the brain and the bone marrow is the mechanism which is called the blood brain barrier (BBB) and which limits the transportation of a substance between the tissue liquids of the blood and the brain. The blood brain barrier has a physical/nonspecific control mechanism due to the intercellular adhesion of the vascular endothelial cells and a substrate-specific efflux mechanism due to efflux transporters. The blood brain barrier protects the central nervous system from foreign matters or drugs and plays an important role in maintaining the homeostasis.

[0009] However, due to the existence of the blood brain barrier, the effective concentration of drug administration is not easily obtained in the central nervous system, and the drug development is difficult. For example, although enzyme replacement therapy is conducted by intravenously administering .alpha.-L-iduronidase to Hurler syndrome (mucopolysaccharidosis-I) or iduronate-2-sulfatase to Hunter syndrome (mucopolysaccharidosis-II), the enzymes do not pass through the blood brain barrier due to their high molecular weights, and no efficacy on conditions in the central nervous system has been found (NPLs 6-9). Moreover, it is reported that side effects such as production of a neutralizing antibody are caused because a certain amount of a recombinant enzyme is continuously administered regularly (NPL 10).

[0010] Moreover, attempts to directly administer biologics into the medullary cavity or the brain have been made to increase the concentration in the brain. For example, a method of administering iduronate-2-sulfatase into the brain of patients with Hunter syndrome (mucopolysaccharidosis-II) to prevent the progress of brain disorder of the patients is reported (PTL 1). However, direct administration into the medullary cavity or the brain is highly invasive (NPL 11).

[0011] Therefore, various delivery techniques have been studied to increase the concentrations of substances with high molecular weights such as biologics in the brain. For example, methods for allowing a substance with a high molecular weight to pass through the blood brain barrier through endocytosis by binding the substance and a membrane protein which is expressed in the brain vascular endothelial cells and by forming a complex of the substance with a high molecular weight and the membrane protein are reported.

[0012] Most of the reported techniques use receptor-mediated transcytosis (RMT below), and the target receptors expressed in the brain vascular endothelium are, for example, transferrin receptors, insulin receptors, insulin-like growth factor receptors and the low-density lipoprotein receptor family (LDLRf).

[0013] Techniques for passing the blood brain barrier through a transferrin receptor by producing a fused protein of an anti-transferrin receptor antibody and a nerve growth factor are reported. Reported techniques using an anti-transferrin receptor antibody are bispecific antibodies of an anti-transferrin receptor antibody and an anti-beta secretase (BACE1) antibody (PTLs 2 and 3 and NPLs 12 and 13) and fused antibodies obtained by fusing a monovalent anti-transferrin receptor antibody to the carboxyl terminus of an anti-amyloid .beta. antibody (PTL 4 and NPL 14).

[0014] It is reported that, regarding the brain delivery using a bispecific antibody of an anti-transferrin receptor antibody and an anti-BACE1 antibody, the amount of the antibody taken into the brain increases to about four times the amount of the control when the antibody is administered to a mouse at 20 mg/kg body weight (NPL 13).

[0015] Furthermore, a technique for allowing a drug to pass through the blood brain barrier by encapsulating the drug with a liposome having an anti-transferrin receptor antibody on its surface is reported. It is reported that the amount taken into the rat brain increases to about two to five times when an anti-rat transferrin receptor antibody fused to immunomicelle is used (NPL 9).

[0016] Techniques for passing through the blood brain barrier through an insulin receptor by producing a fused protein of a neurotrophic factor, an enzyme or an anti-amyloid antibody fused to the carboxyl terminus of an anti-insulin receptor antibody are reported (NPLs 16-19).

[0017] It is reported that when a fused antibody of a labeled anti-human insulin receptor antibody and GDNF is administered to a rhesus monkey, the amount taken into the brain after two hours is about 15 times compared to that of GDNF (NPL 17).

[0018] However, because transferrin receptors and insulin receptors are expressed not only in the brain vascular endothelial cells but also in the whole body including the liver and the like, a drug is delivered also to the liver and the like as the amount of the drug delivered to the central nervous system increases in these techniques (NPL 20). Moreover, because the antigen is expressed in the whole body, the half-life of the antibody in the blood is short (NPL 12).

[0019] Moreover, it is reported that an antibody (Fc5) to TMEM30A, which is an antigen expressed in the brain vascular endothelial membrane, shows an RMT-like activity (PTL 5 and NPLs 21 and 22). Fc5 is an antibody of a variable domain of heavy chain of heavy chain antibody (VHH below) of a single domain derived from llama, and it is shown in an in vitro BBB model and in a rat in vivo model that the amount of Fc5 fused with human Fc delivered to the brain is higher than that of the control IgG.

[0020] It is reported that the CSF exposure of a Fc5-derived single chain antibody (scFv) fused with a metabotropic glutamate receptor type I (mGluRI below) antibody is higher than that of a control single chain antibody fused with a mGluRI antibody in a rat model, but the increase in the amount is around five times (NPL 23).

[0021] It is also reported that an IgG antibody is rapidly discharged from the brain to the circulating blood by neonatal Fc receptor (FcRn) (NPLs 24 and 25), and for example, the half-life of IgG in the brain after the administration into the brain is as short as 48 minutes in rats (NPL 24).

[0022] MOG is a protein belonging to the immunoglobulin superfamily and constitutes myelin. Whole human MOG consists of 218 amino acids, and human MOG is expressed in the outermost layer of myelin in the central nervous system and plays a role in the cell adhesion and the cell surface interaction (NPLs 26-28).

[0023] MOG is considered as a candidate of an autoantigen in inflammatory diseases in which the glial cells in the central nerves are attacked by the autoimmunity, such as multiple sclerosis (MS) (NPLs 29 and 30). It is reported that, although the concentrations of anti-MOG antibodies in the serum are low in MS patients, anti-MOG antibodies are detected also in the central nerves (NPL 29).

[0024] As a reason for this, it is reported that the blood brain barrier breaks due to leakage of humoral factors and entry of inflammatory cells in pathological conditions such as MS and that antibodies easily migrate to the central nervous system (NPLs 30 and 31). It is also reported that autoantibodies are produced locally in the central nervous system due to B cells and plasma cells infiltrated to the central nervous system (NPLs 30, 32 and 33).

[0025] Experimental autoimmune encephalomyelitis (EAE) and MS have many pathological conditions in common, and thus EAE is a model used for studying the pathological conditions of MS. It is reported that EAE can be induced by immunizing an animal with MOG protein or peptide (NPL 34).

[0026] It is also reported that the EAE score deteriorates when an anti-MOG antibody is administered to an animal in which EAE has been induced (NPLs 29 and 35). However, the EAE score reaches its peak one to two days (NPL 29) or four days (NPL 35) after the administration of the antibody, and the deterioration is temporal. On the other hand, it is also reported that EAE does not develop even when an anti-MOG antibody alone is administered to a normal animal (NPLs 36 and 37).

CITATION LIST

Patent Literature

[0027] PTL 1: International Publication No. 2012/023623

[0028] PTL 2: International Publication No. 2016/081640

[0029] PTL 3: International Publication No. 2016/081643

[0030] PTL 4: International Publication No. 2014/033074

[0031] PTL 5: Canadian Patent No. 2623841

Non Patent Literature

[0031]

[0032] NPL 1: Kyla R R. and Richard C C., Biotechnol Adv, pii: S0734-9750 (16), 30091-X, 2016

[0033] NPL 2: Pardridge W M., Bioconjugate Chem., 19, 1327-1338, 2008

[0034] NPL 3: Wang W., et al., Clin. pharmacol. Ther., 84, 548-558, 2008

[0035] NPL 4: Garg A., et al., AAPSJ., 11, 553-557, 2009

[0036] NPL 5: Kaj B., et al., Arch. Neurol., 69 (8), 1002-1010, 2012

[0037] NPL 6: Wraith J E. et al., J. Pediatr. 144 (5), 581-588, 2004

[0038] NPL 7: Muenzer J. et al., Genet Med. 8 (8), 465-473, 2006

[0039] NPL 8: Document attached to intravenous infusion 2.9 mg of Aldurazyme (registered trademark) (July, 2016, 8th edition)

[0040] NPL 9: Document attached to intravenous infusion 6 mg of Elaprase (registered trademark) (July, 2016, 6th edition)

[0041] NPL 10: Brooks, D. A. et al., Trends Mol. Med. 9, 450-453, 2003

[0042] NPL 11: Sorrentino N C. et al., Pediatr Endocrinol Rev. 1, 630-638, 2016

[0043] NPL 12: Couch J A., et al., Science Translational Medicine, 5, 183ra57, 2013

[0044] NPL 13: Yu Y J., et al., Science Translational Medicine, 6, 261ra154, 2014

[0045] NPL 14: Niewoehner J., et al., Neuron. 81, 49-60, 2014

[0046] NPL 15: Jun Y., et al., Macromol. Biosci. 12, 1209-1219, 2012

[0047] NPL 16: Pardridge W M. and Boado R J., Methods in Enzymology, 503, 269-292, 2012

[0048] NPL 17: Boado R J., et al., Drug Metab. Dispos., 37 (12), 2299-2304, 2009

[0049] NPL 18: Boado R J., et al., J. Pharmacol. Exp. Ther., 333 (3), 961-969, 2010

[0050] NPL 19: Boado R J., et al., Bioconjugate Chem., 1, 97-104, 2012

[0051] NPL 20: Yun Zhang. et al., J. Pharmacol. Exp. Ther., 313 (3), 1075-1081, 2005

[0052] NPL 21: Abulrob A., et al., J. Neuyrochem., 95 (4), 1201-1214, 2005

[0053] NPL 22: Farrington G K., et al., FASEB J., 28, 4764-4778, 2014

[0054] NPL 23: Webster C I., et al., FASEB J., 30, 1927-1940, 2016

[0055] NPL 24: Zhang Y., et al., J. Neuroimmunol., 114(1-2), 168-172, 2001

[0056] NPL 25: Philip R C., et al., Brain Research, 1534, 13-21, 2013

[0057] NPL 26: Brunner C., et al., J. Neurochem, 52, 296-394, 1989

[0058] NPL 27: Pham-Dinh D., et al., Proc. Natl. Acad. Sci. USA, 90, 7990-7994, 1993

[0059] NPL 28: Gardinier M V., et al., J. Neurosci. Res., 33, 177-187, 1992

[0060] NPL 29: Eduard Urich, et al., PNAS, 103, 18697-18702, 2006

[0061] NPL 30: Markus Reindl, et al., Brain, 122, 2047-2056, 1999

[0062] NPL 31: Shimizu F., et al., Nihon Rinsho. 72(11), 1949-1954, 2014

[0063] NPL 32: Nese Sinmaz., et al., Ann. N.Y. Acad. Sci., 1351, 22-38, 2015

[0064] NPL 33: F. J. Quintana, Neurology, 78, 532-539, 2012

[0065] NPL 34: Ralf Gold., et al., Brain, 129, 1953-1971, 2006

[0066] NPL 35: Margaret M., et al., J. Neuroimmunology, 125, 114-124, 2002

[0067] NPL 36: G. Locatelli, et al., Nature Neuro Scienence, 15(4), 543-551, 2012

[0068] NPL 37: H J Schluesener, et al., J. Immunol., 139, 4016-4021, 1987

SUMMARY OF INVENTION

Technical Problem

[0069] Although it is disclosed in NPLs 29 and 35 that an anti-MOG antibody is detected in the brain when the antibody is administered to an EAE model, there is no report on an anti-MOG antibody which can be detected in the brain when the anti-MOG antibody is peripherally administered to a normal animal.

[0070] The invention relates to a myelin oligodendrocyte glycoprotein (MOG)-binding molecule which binds to MOG and methods using the molecule. Specifically, an object is to provide an antibody which binds to MOG, an antibody fragment thereof, a hybridoma which produces the antibody or the antibody fragment, a nucleic acid containing a nucleotide sequence which encodes the antibody or the antibody fragment, a transformant cell containing a vector containing the nucleic acid, a method for producing the antibody or the antibody fragment, a composition containing the antibody or the antibody fragment and a method for detecting or measuring an antigen that is present in the brain, a method for diagnosing or treating a brain disease, a method for improving the property of an antibody of accumulating in the brain and a method for increasing the amount of an antibody in the brain which use the antibody or the antibody fragment.

Solution to Problem

[0071] As means for solving the problems, the invention provides a MOG-binding molecule which binds to MOG and methods using the molecule and specifically provides an antibody or an antibody fragment thereof.

[0072] That is, the invention relates to (1) to (22) below.

[0073] (1) An antibody which binds to myelin oligodendrocyte glycoprotein (referred to as MOG below) or an antibody fragment thereof.

[0074] (2) The antibody or the antibody fragment according to (1), wherein the antibody has a property of accumulating in a brain.

[0075] (3) The antibody or the antibody fragment according to (1) or (2), wherein the antibody is selected from the group consisting of (a) to (r) below,

[0076] (a) an antibody in which the amino acid sequences of complementarity determining regions (CDRs below) 1 to 3 of a heavy chain variable region (referred to as VH below) contain the amino acid sequences of SEQ ID NOs: 4, 5 and 6, respectively, and in which the amino acid sequences of CDRs 1 to 3 of a light chain variable region (VL) contain the amino acid sequences of SEQ ID NOs: 10, 11 and 12, respectively,

[0077] (b) an antibody in which the amino acid sequences of CDRs 1 to 3 of VH contain the amino acid sequences of SEQ ID NOs: 16, 17 and 18, respectively, and in which the amino acid sequences of CDRs 1 to 3 of VL contain the amino acid sequences of SEQ ID NOs: 22, 23 and 24, respectively,

[0078] (c) an antibody in which the amino acid sequences of CDRs 1 to 3 of VH contain the amino acid sequences of SEQ ID NOs: 28, 29 and 30, respectively, and in which the amino acid sequences of CDRs 1 to 3 of VL contain the amino acid sequences of SEQ ID NOs: 34, 35 and 36, respectively,

[0079] (d) an antibody fragment in which the amino acid sequences of CDRs 1 to 3 of a heavy chain variable region of a heavy chain antibody (referred to as VHH below) contain the amino acid sequences of SEQ ID NOs: 40, 41 and 42, respectively,

[0080] (e) an antibody in which the amino acid sequences of CDRs 1 to 3 of VH contain the amino acid sequences of SEQ ID NOs: 153, 154 and 155, respectively, and in which the amino acid sequences of CDRs 1 to 3 of VL contain the amino acid sequences of SEQ ID NOs: 158, 159 and 160, respectively,

[0081] (f) an antibody in which the amino acid sequences of CDRs 1 to 3 of VH contain the amino acid sequences of SEQ ID NOs: 163, 164 and 165, respectively, and in which the amino acid sequences of CDRs 1 to 3 of VL contain the amino acid sequences of SEQ ID NOs: 168, 169 and 170, respectively,

[0082] (g) an antibody in which the amino acid sequences of CDRs 1 to 3 of VH contain the amino acid sequences of SEQ ID NOs: 173, 174 and 175, respectively, and in which the amino acid sequences of CDRs 1 to 3 of VL contain the amino acid sequences of SEQ ID NOs: 178, 179 and 180, respectively,

[0083] (h) an antibody in which the amino acid sequences of CDRs 1 to 3 of VH contain the amino acid sequences of SEQ ID NOs: 183, 184 and 185, respectively, and in which the amino acid sequences of CDRs 1 to 3 of VL contain the amino acid sequences of SEQ ID NOs: 188, 189 and 190, respectively,

[0084] (i) an antibody in which the amino acid sequences of CDRs 1 to 3 of VH contain the amino acid sequences of SEQ ID NOs: 193, 194 and 195, respectively, and in which the amino acid sequences of CDRs 1 to 3 of VL contain the amino acid sequences of SEQ ID NOs: 198, 199 and 200, respectively,

[0085] (j) an antibody in which the amino acid sequences of CDRs 1 to 3 of VH contain the amino acid sequences of SEQ ID NOs: 203, 204 and 205, respectively, and in which the amino acid sequences of CDRs 1 to 3 of VL contain the amino acid sequences of SEQ ID NOs: 208, 209 and 210, respectively,

[0086] (k) an antibody in which the amino acid sequences of CDRs 1 to 3 of VH contain the amino acid sequences of SEQ ID NOs: 213, 214 and 215, respectively, and in which the amino acid sequences of CDRs 1 to 3 of VL contain the amino acid sequences of SEQ ID NOs: 218, 219 and 220, respectively,

[0087] (l) an antibody in which the amino acid sequences of CDRs 1 to 3 of VH contain the amino acid sequences of SEQ ID NOs: 223, 224 and 225, respectively, and in which the amino acid sequences of CDRs 1 to 3 of VL contain the amino acid sequences of SEQ ID NOs: 228, 229 and 230, respectively,

[0088] (m) an antibody in which the amino acid sequences of CDRs 1 to 3 of VH contain the amino acid sequences of SEQ ID NOs: 233, 234 and 235, respectively, and in which the amino acid sequences of CDRs 1 to 3 of VL contain the amino acid sequences of SEQ ID NOs: 238, 239 and 240, respectively,

[0089] (n) an antibody in which the amino acid sequences of CDRs 1 to 3 of VH contain the amino acid sequences of SEQ ID NOs: 243, 244 and 245, respectively, and in which the amino acid sequences of CDRs 1 to 3 of VL contain the amino acid sequences of SEQ ID NOs: 248, 249 and 250, respectively,

[0090] (o) an antibody which competes in binding to MOG with at least one of the antibodies described in (a) to (n),

[0091] (p) an antibody which binds to an epitope containing an epitope to which any one of the antibodies described in (a) to (n) binds,

[0092] (q) an antibody which binds to the same epitope as an epitope to which any one of the antibodies described in (a) to (n) binds and

[0093] (r) an antibody which contains an amino acid sequence having homology of 85% or higher to the amino acid sequence of any one of the antibodies described in (a) to (n).

[0094] (4) The antibody or the antibody fragment according to any one of (1) to (3), wherein the antibody is selected from the group consisting of (a) to (n), (o1) to (o22) and (p) below,

[0095] (a) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 3 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 9,

[0096] (b) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 15 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 21,

[0097] (c) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 27 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 33,

[0098] (d) an antibody fragment in which the amino acid sequence of VHH contains the amino acid sequence of SEQ ID NO: 39,

[0099] (e) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 152 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 157,

[0100] (f) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 162 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 167,

[0101] (g) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 172 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 177,

[0102] (h) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 182 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 187,

[0103] (i) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 192 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 197,

[0104] (j) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 202 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 207,

[0105] (k) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 212 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 217,

[0106] (l) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 222 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 227,

[0107] (m) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 232 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 237,

[0108] (n) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 242 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 247,

[0109] (o1) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 252 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 254,

[0110] (o2) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 256 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 258,

[0111] (o3) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 260 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 262,

[0112] (o4) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 264 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 266,

[0113] (o5) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 268 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 270,

[0114] (o6) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 272 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 274,

[0115] (o7) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 276 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 278,

[0116] (o8) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 280 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 282,

[0117] (o9) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 284 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 286,

[0118] (o10) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 288 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 290,

[0119] (o11) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 292 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 294,

[0120] (o12) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 296 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 298,

[0121] (o13) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 300 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 302,

[0122] (o14) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 304 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 306,

[0123] (o15) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 308 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 310,

[0124] (o16) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 312 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 314,

[0125] (o17) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 316 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 318,

[0126] (o18) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 320 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 322,

[0127] (o19) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 324 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 326,

[0128] (o20) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 328 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 330,

[0129] (o21) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 332 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 334,

[0130] (o22) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 336 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 338 and

[0131] (p) an antibody which contains an amino acid sequence having homology of 85% or higher to the amino acid sequence of any one of the antibodies described in (a) to (n) and (o1) to (o22).

[0132] (5) The antibody or the antibody fragment according to any one of (1) to (4), wherein the antibody or the antibody fragment is a bispecific antibody.

[0133] (6) The bispecific antibody according to (5), wherein the bispecific antibody binds to MOG and an antigen that is present in a brain.

[0134] (7) The bispecific antibody according to (5) or (6), wherein the bispecific antibody contains an antigen binding site which binds to MOG and an antigen binding site which binds to an antigen that is present in a brain.

[0135] (8) The antibody fragment according to any one of (1) to (7) which is selected from the group consisting of Fab, Fab', F(ab')2, a single chain antibody (scFv), a dimerized V region (diabody), a disulfide-stabilized V region (dsFv), VHH and, a peptide containing CDR.

[0136] (9) The antibody and the antibody fragment according to any one of (1) to (8), wherein the antibody is a genetically recombinant antibody.

[0137] (10) The antibody and the antibody fragment according to any one of (1) to (9), wherein the antibody is selected from the group consisting of a mouse antibody, a rat antibody, a rabbit antibody, an alpaca antibody, a camel antibody, a llama antibody, a chimeric antibody, a humanized antibody, and a human antibody.

[0138] (11) A fused antibody or a fused antibody fragment which is obtained by binding at least one selected from the group consisting of (a) to (c) below to the antibody which binds to MOG according to any one of (1) to (10) or the antibody fragment thereof,

[0139] (a) a hydrophilic polymer,

[0140] (b) an amphipathic polymer, and

[0141] (c) a functional molecule.

[0142] (12) A hybridoma which produces the antibody according to any one of (1) to (11).

[0143] (13) A nucleic acid which contains a nucleotide sequence which encodes the antibody according to any one of (1) to (11).

[0144] (14) A transformant cell which contains a vector containing the nucleic acid according to (13).

[0145] (15) A method for producing the antibody or the antibody fragment according to any one of (1) to (11), including culturing the hybridoma according to (12) or the transformant cell according to (14) and collecting the antibody or the antibody fragment according to any one of (1) to (11) from a culture solution.

[0146] (16) A composition which contains the antibody or the antibody fragment according to any one of (1) to (11).

[0147] (17) The composition according to (16), wherein the composition is a composition for detecting or measuring an antigen that is present in a brain.

[0148] (18) The composition according to (16), wherein the composition is a composition for diagnosing or treating a brain disease.

[0149] (19) A method for detecting or measuring an antigen that is present in a brain using the antibody or the antibody fragment according to any one of (1) to (11) or the composition according to (16).

[0150] (20) A method for diagnosing or treating a brain disease using the antibody or the antibody fragment according to any one of (1) to (11) or the composition according to (16).

[0151] (21) A method for improving the property of accumulating in the brain of an antibody, an antibody fragment thereof, a fused antibody or a fused antibody fragment using the antibody, the antibody fragment, the fused antibody or the fused antibody fragment according to any one of (1) to (11) or the composition according to (16).

[0152] (22) A method for increasing the amount of an antibody, the amount of an antibody fragment thereof, the amount of a fused antibody or the amount of a fused antibody fragment in a brain using the antibody, the antibody fragment, the fused antibody or the fused antibody fragment according to any one of (1) to (11) or the composition according to (16).

Advantageous Effects of Invention

[0153] The MOG-binding molecule of the invention improves the property of the binding molecule itself of accumulating in the brain by specifically binding to MOG, and the MOG-binding molecule can also be applied to the treatment of brain diseases because another molecule which is modified by the MOG-binding molecule is delivered and kept in the brain. A specific MOG-binding molecule of the invention is an antibody. The antibody or the antibody fragment of the invention relates to an antibody which binds to MOG in the brain and thus has a property of accumulating in the brain. Accordingly, the antibody or the antibody fragment of the invention can be used for a composition for detecting or measuring an antigen that is present in the brain (MOG, or MOG and another antigen that is present in the brain), a composition for diagnosing a brain disease and a pharmaceutical composition for treating a brain disease.

BRIEF DESCRIPTION OF DRAWINGS

[0154] FIG. 1 shows the results of analysis by ELISA of the affinities to rMOG-FLAG_Fc of phage clones displaying scFv that binds to MOG. The vertical axis shows the absorbance relative to rMOG-FLAG_Fc, and the horizontal axis shows the names of the scFv antibodies displayed by the phage clones.

[0155] FIG. 2 shows the results of analysis using a flow cytometer of the affinities of anti-MOG antibodies to HEK cells, rat MOG/HEK cells, mouse MOG/HEK cells, cynomolgus monkey MOG/HEK cells or human MOG/HEK cells. The vertical axis shows the number of cells, and the horizontal axis shows the fluorescence intensity. A dotted line indicates a histogram of the affinity of an anti-AVM antibody used as a negative control, and a solid line indicates a histogram of the affinity of a MOG antibody.

[0156] FIGS. 3A and 3B show the results of evaluation of the rat brain migration properties of anti-MOG antibodies. FIG. 3A shows the antibody concentrations in the serum four days after administering the antibodies to rats. The vertical axis shows the antibody concentration (ng/mL), and the horizontal axis shows the administered antibodies. FIG. 3B shows the antibody concentrations in the brain tissues four days after administering the antibodies to rats. The vertical axis shows the antibody amount per brain weight (ng/g brain), and the horizontal axis shows the administered antibodies. In both figures, the white bars show the results of an anti-AVM antibody used as a negative control, and the black bars show the results of the anti-MOG antibodies.

[0157] FIGS. 4A and 4B show the results of evaluation of the rat brain migration property of an anti-MOG antibody. FIG. 4A shows the antibody concentrations in the serum four days and 10 days after administering the antibodies to rats. The vertical axis shows the antibody concentration (ng/mL), and the horizontal axis shows the period (day) after the administration of the antibodies. FIG. 4B shows the antibody concentrations in the brain tissues four days and 10 days after administering the antibodies to rats. The vertical axis shows the antibody amount per brain weight (ng/g brain), and the horizontal axis shows the period (day) after the administration of the antibodies. In both figures, the plots with white diamond markers show the results of an anti-AVM antibody used as a negative control. The plots with white square markers show the results of an anti-transferrin receptor antibody, OX26 antibody, and the plots with black triangle markers show the results of the anti-MOG antibody, MOG01 antibody.

[0158] FIG. 5 shows the results of analysis using a flow cytometer of the affinities of bispecific antibodies to HEK293F cells, rat MOG/HEK293F cells or human MOG/HEK293F cells. The vertical axis shows the number of cells, and the horizontal axis shows the fluorescence intensity. A dotted line indicates a histogram of the affinity of an anti-AVM antibody used as a negative control, and a solid line indicates a histogram of the affinity of a bispecific antibody.

[0159] FIG. 6 shows the results of analysis using a flow cytometer of the affinities of bispecific antibodies to human breast cancer cell line, SK-BR-3. The vertical axis shows the number of cells, and the horizontal axis shows the fluorescence intensity. A dotted line indicates a histogram of the affinity of an anti-AVM antibody used as a negative control, and a solid line indicates a histogram of the affinity of a bispecific antibody.

[0160] FIGS. 7A and 7B show the results of evaluation of the rat brain migration properties of bispecific antibodies which bind to MOG. FIG. 7A shows the antibody concentrations in the serum 10 days after administering the antibodies to rats. The vertical axis shows the antibody concentration (ng/mL), and the horizontal axis shows the bispecific antibodies used.

[0161] FIG. 7B shows the antibody concentrations in the brain tissues 10 days after administering the antibodies to rats. The vertical axis shows the antibody amount per brain weight (ng/g brain), and the horizontal axis shows the bispecific antibodies used.

[0162] FIGS. 8A and 8B show the results of evaluation of the mouse brain migration property of an anti-MOG01 antibody. FIG. 8A shows the antibody concentrations in the serum 3, 6, 10, 14, 21 and 28 days after administering the antibodies to mice. The vertical axis shows the antibody concentration (ng/mL), and the horizontal axis shows the time (day).

[0163] FIG. 8B shows the antibody concentrations in the brain tissues 3, 6, 10, 14, 21 and 28 days after administering the antibodies to mice. The vertical axis shows the antibody concentration (ng/g brain), and the horizontal axis shows the time (day). In both figures, the plots with white circle markers show the results of an anti-AVM antibody used as a negative control, and the plots with black square markers show the results of MOG01 scFv-hG4PE.

[0164] FIGS. 9A to 9C show the results of evaluation of the mouse brain migration property imaging of an anti-MOG01 antibody. FIG. 9A shows the measurement data of the fluorescence intensities in the brain six days after administering an Alexa FluorR 488-labeled anti-AVM antibody as a negative control and an Alexa FluorR 488-labeled anti-MOG01 antibody to mice, and FIG. 9B shows the measurement data of the fluorescence intensities in the brain after 14 days. FIG. 9C shows the values obtained by correcting the fluorescence amounts in the brain after six days and 14 days using the fluorescence intensities of the administered antibodies. The vertical axis shows the fluorescence amount in brain/fluorescence amount of administered antibody (%), and the horizontal axis shows the administered antibodies.

[0165] FIGS. 10A to 10C show the structures of bispecific antibodies which bind to AVM and MOG. FIG. 10A shows the structure of AVM-MOG01 IgG4PE(R409K) antibody, and

[0166] FIG. 10B shows the structure of AVM IgG4PE(R409K) MOG01 Fab antibody. FIG. 10C shows the structure of AVM IgG4PE(R409K)_MOG01sscFv antibody.

[0167] FIGS. 11A and 11B show the structures of bispecific antibodies which bind to AVM and MOG. FIG. 11A shows the structure of AVM IgG4PE(R409K)_MOG01dscFv antibody, AVM IgG4PE(R409K)_MOG01dscFv2 antibody and AVM IgG4PE(R409K)_MOG01dscFv4 antibody, and FIG. 11B shows the structure of AVM IgG4PE(R409K)_MOG01dscFv3 antibody and AVM IgG4PE(R409K)_MOG01dscFv5 antibody to AVM IgG4PE(R409K)_MOG01dscFv11 antibody.

[0168] FIGS. 12A to 12C show the results of analysis using a flow cytometer of the affinities of bispecific antibodies to human MOG/L929 cells. The vertical axis shows the average fluorescence intensity, and the horizontal axis shows the antibody concentration. In FIG. 12A, the plot with white circle markers shows the results of AVM IgG4PE(R409K) antibody (negative control), and the plot with black square markers shows the results of AVM-MOG01 IgG4PE(R409K) antibody. In FIG. 12B, the plot with white circle markers shows the results of AVM IgG4PE(R409K)_AVMsscFv antibody (negative control), and the plot with black square markers shows the results of AVM IgG4PE(R409K)_MOG01sscFv antibody. In FIG. 12C, the plot with white circle markers shows the results of AVM IgG4PE(R409K)_AVM Fab antibody (negative control), and the plot with black square markers shows the results of AVM IgG4PE(R409K)_MOG01 Fab antibody.

[0169] FIGS. 13A and 13B show the results of analysis using a flow cytometer of the affinities of bispecific antibodies to human MOG/L929 cells. The vertical axis shows the average fluorescence intensity, and the horizontal axis shows the antibody concentration. In FIG. 13A, the plot with white square markers shows the results of AVM IgG4PE(R409K)_MOG01dscFv antibody, the plot with white circle markers shows the results of AVM IgG4PE(R409K)_MOG01dscFv2 antibody, and the plot with white triangle markers shows the results of AVM IgG4PE(R409K)_MOG01dscFv4 antibody. In FIG. 13B, the plot with white diamond markers shows the results of AVM IgG4PE(R409K)_MOG01dscFv3 antibody, the plot with black diamond markers shows the results of AVM IgG4PE(R409K)_MOG01dscFv5 antibody, the plot with white circle markers shows the results of AVM IgG4PE(R409K)_MOG01dscFv6 antibody, the plot with black circle markers shows the results of AVM IgG4PE(R409K)_MOG01dscFv7 antibody, the plot with white triangle markers shows the results of AVM IgG4PE(R409K)_MOG01dscFv8 antibody, the plot with black triangle markers shows the results of AVM IgG4PE(R409K)_MOG01dscFv9 antibody, the plot with white square markers shows the results of AVM IgG4PE(R409K)_MOG01dscFv10 antibody, and the plot with black square markers shows the results of AVM IgG4PE(R409K)_MOG01dscFv11 antibody.

[0170] FIGS. 14A and 14B show the results of evaluation of the mouse brain migration properties of bispecific antibodies. The vertical axis shows the antibody concentration, and the horizontal axis shows the bispecific antibodies used. FIGS. 14A and 14B show the antibody concentrations in the serum and in the brain tissues, respectively, 10 days after the administration of AVM IgG4PE(R409K) antibody (negative control) and AVM-MOG01 IgG4PE(R409K) antibody.

[0171] FIGS. 15A and 15B show the results of evaluation of the mouse brain migration properties of bispecific antibodies. The vertical axis shows the antibody concentration, and the horizontal axis shows the bispecific antibodies used. FIGS. 15A and 15B show the antibody concentrations in the serum and in the brain tissues, respectively, 10 days after the administration of AVM IgG4PE(R409K)_AVMsscFv antibody (negative control) and AVM IgG4PE(R409K)_MOG01sscFv antibody.

[0172] FIGS. 16A and 16B show the results of evaluation of the mouse brain migration properties of bispecific antibodies. The vertical axis shows the antibody concentration, and the horizontal axis shows the bispecific antibodies used. FIGS. 16A and 16B show the antibody concentrations in the serum and in the brain tissues, respectively, 10 days after the administration of AVM IgG4PE(R409K)_AVM Fab antibody (negative control) and AVM IgG4PE(R409K)_MOG01 Fab antibody.

[0173] FIGS. 17A to 17D show the results of evaluation of the mouse brain migration properties of bispecific antibodies. The vertical axis shows the antibody concentration, and the horizontal axis shows the bispecific antibodies used. The negative control corresponding to AVM IgG4PE(R409K)_MOG01dscFv antibody is AVM IgG4PE(R409K)_AVMdscFv antibody, and the negative control corresponding to AVM IgG4PE(R409K)_MOG01dscFv3 antibody is AVM IgG4PE(R409K)_AVMdscFv3 antibody. The negative control corresponding to AVM IgG4PE(R409K)_MOG01dscFv5 antibody is AVM IgG4PE(R409K)_AVMdscFv5 antibody. FIG. 17A shows the antibody concentrations in the serum 10 days after the administration of the antibodies. FIG. 17B shows the antibody concentrations in the brain tissues 10 days after the administration of the antibodies. FIG. 17C shows the antibody concentrations in the serum 28 days after the administration of the antibodies. FIG. 17D shows the antibody concentrations in the brain tissues 28 days after the administration of the antibodies.

[0174] FIG. 18 shows the amino acid sequences of scFv of clones similar to a MOG antibody and shows clones similar to MOG301 antibody.

[0175] FIG. 19 shows the amino acid sequences of scFv of clones similar to a MOG antibody and shows clones similar to MOG303 antibody.

[0176] FIG. 20 shows the amino acid sequences of scFv of clones similar to a MOG antibody and shows clones similar to MOG307 antibody.

[0177] FIG. 21 shows the amino acid sequences of scFv of clones similar to a MOG antibody and shows clones similar to MOG310 antibody.

[0178] FIGS. 22A and 22B show the amino acid sequences of scFv of clones similar to MOG antibodies. FIG. 22A shows a clone similar to MOG329 antibody, and FIG. 22B shows a clone similar to MOG456 antibody.

[0179] FIG. 23 shows the results of analysis using a flow cytometer of the affinities of anti-MOG antibodies to Expi293F cells. The vertical axis shows the number of cells, and the horizontal axis shows the fluorescence intensity. A dotted line indicates a histogram of the affinity of an anti-AVM antibody used as a negative control, and a solid line indicates a histogram of the affinity of a MOG antibody.

[0180] FIG. 24 shows the results of analysis using a flow cytometer of the affinities of anti-MOG antibodies to mouse MOG/Expi293F cells. The vertical axis shows the number of cells, and the horizontal axis shows the fluorescence intensity. A dotted line indicates a histogram of the affinity of an anti-AVM antibody used as a negative control, and a solid line indicates a histogram of the affinity of a MOG antibody.

[0181] FIG. 25 shows the results of analysis using a flow cytometer of the affinities of anti-MOG antibodies to human MOG/Expi293F cells. The vertical axis shows the number of cells, and the horizontal axis shows the fluorescence intensity. A dotted line indicates a histogram of the affinity of an anti-AVM antibody used as a negative control, and a solid line indicates a histogram of the affinity of a MOG antibody.

[0182] FIG. 26 shows the results of analysis using a flow cytometer of the affinity of an enzyme-fused antibody, MOG01 IgG4PE(R409K)-ASM to human MOG/L929 cells. The vertical axis shows the average fluorescence intensity, and the horizontal axis shows the antibody concentration.

[0183] FIG. 27 shows the results of analysis by ELISA method of the affinities of anti-ASM antibodies (manufactured by LSBio) to MOG01 IgG4PE(R409K)-ASM and AVM IgG4PE(R409K)-ASM. The vertical axis shows the absorbance, and the horizontal axis shows the names of the immobilized antibodies. MOG01 IgG4PE and AVM IgG4PE were used as negative controls. The bars shaded with thin lines show the data of the anti-ASM antibodies at 5 .mu.g/mL, and the bars shaded with thick lines show the data of the anti-ASM antibodies at 1 .mu.g/mL. The white bars show the data of the anti-ASM antibodies at 0.2 .mu.g/mL.

[0184] FIGS. 28A and 28B show the results of evaluation of the mouse brain migration properties of enzyme-fused antibodies, MOG01 IgG4PE(R409K)-ASM and AVM IgG4PE(R409K)-ASM. The vertical axis shows the antibody concentration, and the horizontal axis shows the enzyme-fused antibodies used. FIG. 28A shows the antibody concentrations in the serum 10 days after the administration of the antibodies. FIG. 28B shows the antibody concentrations in the brain tissues 10 days after the administration of the antibodies.

DESCRIPTION OF EMBODIMENTS

[0185] The invention relates to an antigen-binding molecule which binds to myelin-oligodendrocyte glycoprotein (referred to as MOG below). More specifically, the invention relates to an antibody which binds to MOG or an antibody fragment thereof.

[0186] The MOG-binding molecule of the invention may be a molecule of any state as long as the molecule specifically binds to MOG and accumulates in the brain, and the MOG-binding molecule may be any of molecules such as proteins, nucleic acids and synthetic organic low-molecular-weight compounds/high-molecular-weight compounds. Specifically, the MOG-binding molecule may be any of recombinant proteins, antibodies, aptamers, low-molecular-weight compounds obtained by screening low-molecular-weight molecules and the like, but an antibody and an antibody fragment thereof are preferable. The MOG-binding molecule is preferably a molecule which binds to an extracellular region of MOG.

[0187] MOG is a protein belonging to the immunoglobulin superfamily and constitutes myelin. Whole human MOG, for example, consists of 218 amino acids, and human MOG is expressed in the outermost layer of myelin in the central nervous system and plays a role in the cell adhesion and the cell surface interaction.

[0188] The kinds of animal of MOG to which the MOG-binding molecule of the invention binds are mouse, rat, cynomolgus monkey, human and/or the like but are not particularly limited to these kinds, and an appropriate animal kind can be selected depending on the use of the antibody. For example, when the antibody of the invention is used for a pharmaceutical use for humans, the antibody is preferably an antibody which binds to at least human MOG.

[0189] In the invention, human MOG is a polypeptide which contains the amino acid sequence of SEQ ID NO: 78 or the amino acid sequence of NCBI accession No. AAB08088, a polypeptide which has the amino acid sequence of SEQ ID NO: 78 or the amino acid sequence of NCBI accession No. AAB08088, wherein one or more amino acids are deleted, substituted or added, and which has a function of human MOG, a polypeptide which has an amino acid sequence having homology of 60% or higher, preferably 80% or higher, further preferably 90% or higher, most preferably 95% or higher to the amino acid sequence of SEQ ID NO: 78 or the amino acid sequence of NCBI accession No. AAB08088 and which has a function of human MOG or the like.

[0190] The polypeptide which has the amino acid sequence of SEQ ID NO: 78 or the amino acid sequence of NCBI accession No. AAB08088, wherein one or more amino acids are deleted, substituted or added, can be obtained by introducing a site-specific mutation for example to DNA that encodes a polypeptide containing the amino acid sequence of SEQ ID NO: 78 using the site-directed mutagenesis [Molecular Cloning, A Laboratory Manual, Second Edition, Cold Spring Harbor Laboratory Press (1989), Current Protocols in Molecular Biology, John Wiley & Sons (1987-1997), Nucleic acids Research, 10, 6487 (1982), Proc. Natl. Acad. Sci. USA, 79, 6409 (1982), Gene, 34, 315 (1985), Nucleic Acids Research, 13, 4431 (1985) and Proc. Natl. Acad. Sci. USA, 82, 488 (1985)] or the like.

[0191] The number of amino acids that are deleted, substituted or added is not particularly limited but is preferably one to tens, for example, 1 to 20, more preferably one to a few, for example, one to five amino acids.

[0192] The same applies to the amino acid sequence of mouse MOG [SEQ ID NO: 74 and NCBI accession No. NP 034944], the amino acid sequence of rat MOG [SEQ ID NO: 68 and NCBI accession No. AAA41628] and the amino acid sequence of cynomolgus monkey MOG [SEQ ID NO: 76 and NCBI accession No. NP 001271785].

[0193] Genes which encode human MOG are the nucleotide sequence of SEQ ID NO: 77 and the nucleotide sequence of NCBI accession No. U64564. A gene containing DNA which has the nucleotide sequence of SEQ ID NO: 77 or the nucleotide sequence of NCBI accession No. U64564, wherein one or more bases are deleted, substituted or added, and which encodes a polypeptide having a function of MOG, a gene containing DNA which has a nucleotide sequence having homology of at least 60% or higher to the nucleotide sequence of SEQ ID NO: 77 or the nucleotide sequence of NCBI accession No. U64564, preferably a nucleotide sequence having homology of 80% or higher or further preferably a nucleotide sequence having homology of 95% or higher and which encodes a polypeptide having a function of MOG, a gene which contains DNA that hybridizes with DNA containing the nucleotide sequence of SEQ ID NO: 77 or the nucleotide sequence of NCBI accession No. U64564 under stringent conditions and which encodes a polypeptide having a function of MOG and another gene are also included as the genes that encode MOG in the invention.

[0194] The DNA that hybridizes under stringent conditions means hybridizable DNA that is obtained by a colony hybridization method, a plaque hybridization method, a southern blot hybridization method, a DNA microarray method or the like using DNA containing the nucleotide sequence of SEQ ID NO: 77 or the nucleotide sequence of NCBI accession No. U64564 as a probe.

[0195] Specifically, it is possible to exemplify DNA that can be identified by washing a filter or a glass slide under the condition of 65.degree. C. using a SSC solution of the concentration of 0.1 to 2 times (the composition of the SSC solution with the concentration of 1 time is 150 mmol/L sodium chloride and 15 mmol/L sodium citrate), after performing hybridization [Molecular Cloning, A Laboratory Manual, Second Edition, Cold Spring Harbor Laboratory Press (1989), Current Protocols in Molecular Biology, John Wiley & Sons (1987-1997) and DNA Cloning 1: Core Techniques, A Practical Approach, Second Edition, Oxford University, (1995)] at 65.degree. C. in the presence of 0.7 to 1.0 mol/L sodium chloride using a filter or a glass slide on which DNA derived from a hybridized colony or plaque or a PCR product or DNA oligo having the sequence is fixed.

[0196] Examples of the hybridizable DNA include DNA having homology of at least 60% or higher to the nucleotide sequence of SEQ ID NO: 77 or the nucleotide sequence of NCBI accession No. U64564, preferably DNA having homology of 80% or higher and further preferably DNA having homology of 95% or higher.

[0197] The same applies to the nucleotide sequence of mouse MOG [SEQ ID NO: 73 and NCBI accession No. NM010814], the nucleotide sequence of rat MOG [SEQ ID NO: 67 and NCBI accession No. M99485] and the nucleotide sequence of cynomolgus monkey MOG [SEQ ID NO: 75 and NCBI accession No. NM001284856].

[0198] The function of MOG is involvement in the cell adhesion, the cell surface interaction and the like on myelin.

[0199] Genetic polymorphism is often recognized in a nucleotide sequence of a gene that encodes a protein of a eukaryote. The genes that encode MOG in the invention also include genes in which small scale mutations arise in the nucleotide sequences by such polymorphism in the genes used in the invention.

[0200] A value of homology in the invention may be a value calculated using a homology detection program known to those skilled in the art unless particularly specified. Regarding a nucleotide sequence, there are a value calculated using a default parameter of BLAST [J. Mol. Biol., 215, 403 (1990)] and the like. Regarding an amino acid sequence, there are a value calculated using a default parameter of BLAST2 [Nucleic Acids Res., 25, 3389 (1997), Genome Res., 7, 649 (1997) and http://www.ncbi.nlm.nih.gov/Education/BLASTinfo/information3.htmL] and the like.

[0201] Regarding the default parameters, G (Cost to open gap) is 5 for a nucleotide sequence and 11 for an amino acid sequence, -E (Cost to extend gap) is 2 for a nucleotide sequence and 1 for an amino acid sequence, -q (Penalty for nucleotide mismatch) is -3, -r (reward for nucleotide match) is 1, -e (expect value) is 10, -W (wordsize) is 11 residues for a nucleotide sequence and 3 residues for an amino acid sequence, -y [Dropoff (X) for blast extensions in bits] is 20 for the blastn and 7 for programs other than the blastn, -X (X dropoff value for gapped alignment in bits) is 15, and -Z (final X dropoff value for gapped alignment in bits) is 50 for the blastn and 25 for programs other than the blastn (http://www.ncbi.nlm.nih.gov/blast/htmL/blastcgihelp.htmL).

[0202] A polypeptide containing a partial sequence of the amino acid sequence of any of the MOG kinds can be produced by a method known to those skilled in the art. Specifically, the polypeptide can be produced by deleting a part of DNA that encodes the amino acid sequence of any of the MOG kinds and culturing a transformant into which an expression vector including the DNA has been introduced. In addition, a polypeptide having the amino acid sequence of any of the MOG kinds in which one or more amino acids are deleted, substituted or added can be obtained by the same method as above.

[0203] Furthermore, a polypeptide that has the amino acid sequence of any of the MOG kinds or a polypeptide having the amino acid sequence of any of the MOG kinds in which one or more amino acids are deleted, substituted or added can be produced also using a chemical synthesis method such as a fluorenylmethyloxycarbonyl (Fmoc) method or a t-butyloxycarbonyl (tBoc) method.

[0204] In the invention, the extracellular region of human MOG is the amino acid sequence of from position 30 to position 154 or from position 232 to position 247 in the amino acid sequence of SEQ ID NO: 78 or NCBI accession No. AAB08088 and is preferably the amino acid sequence of from position 30 to position 154.

[0205] The extracellular region of mouse MOG is the amino acid sequence of from position 30 to position 157 or from position 232 to position 247 in the amino acid sequence of SEQ ID NO: 74 or NCBI accession No. NP_034944 and is preferably the amino acid sequence of from position 30 to position 157. The extracellular region of rat MOG is the amino acid sequence of from position 28 to position 155 or from position 230 to 245 in the amino acid sequence of SEQ ID NO: 68 or NCBI accession No. AAA41628 and is preferably the amino acid sequence of from position 28 to position 155.

[0206] The extracellular region of cynomolgus monkey MOG is the amino acid sequence of from position 30 to position 154 or from position 232 to position 247 in the amino acid sequence of SEQ ID NO: 76 or NCBI accession No. NP_001271785 and is preferably the amino acid sequence of from position 30 to position 154.

[0207] That the antibody of the invention binds to an extracellular region of MOG can be confirmed by measuring the affinity of the antibody of the invention to MOG-expressing cells or a recombinant MOG protein using ELISA, flow cytometry, surface plasmon resonance method or the like. Moreover, binding of the antibody can be confirmed also using a combination of known immunological detection methods [Monoclonal Antibodies-Principles and practice, Third edition, Academic Press (1996), Antibodies-A Laboratory Manual, Cold Spring Harbor Laboratory (1988) and A manual for monoclonal antibody experiments, Kodansha scientific books (1987)] and the like.

[0208] The MOG-binding molecule of the invention is a molecule which specifically binds to MOG in the brain and which thus has a property of accumulating in the brain, and for example, the antibody is an antibody which binds to MOG in the brain and which thus has a property of accumulating in the brain. Moreover, the antibody of the invention is an antibody which passes through the blood brain barrier in the brain from the peripheral part, migrates to the brain and binds to MOG in the brain when peripherally administered to an animal and which thus has a property of accumulating in the brain. The antibody of the invention is preferably an antibody having an excellent property of accumulating in the brain or an antibody having an improved property of accumulating in the brain.

[0209] In the invention, the property of accumulating in the brain is a property of a subject of accumulating in the brain when the subject is administered to an animal to be tested. That is, the property means that the concentration in the brain (or the amount in the brain) of the subject increases or that the subject exists at a certain detectable concentration due to at least any one cause selected from an increase in the migration into the brain, an increase in the accumulation in the brain, a decrease in the migration to outside from the brain, a decrease in the discharge to outside from the brain and a decrease in the decomposition in the brain.

[0210] In the invention, that the property of accumulating in the brain is excellent, that the property of accumulating in the brain is high or that the property of accumulating in the brain is improved means that the concentration in the brain (or the amount in the brain) of the subject increases or that the subject exists in the brain at a certain concentration (amount) which is detectable for a long time when the subject is administered to an animal to be tested, as compared to a control after a same period (day) after the administration.

[0211] The phenomena are caused by at least any one of an increase in the migration of the subject into the brain, an increase in the accumulation in the brain, a decrease in the migration to outside from the brain, a decrease in the discharge to outside from the brain and a decrease in the decomposition in the brain as compared to a control.

[0212] In the invention, that the property of accumulating in the brain is excellent, that the property of accumulating in the brain is high or that the property of accumulating in the brain is improved means, for example, that, when the subject is administered to an animal to be tested, the concentration (amount) of the subject in the brain is higher than that of a control 1 to 10 days after the administration, preferably 2 to 10 days or 3 to 10 days, more preferably 4 to 10 days after the administration or that the peak of the concentration in the brain (or the amount in the brain) of the subject is seen on day 4 or later after the administration, preferably on day 5 or later, day 6 or later, day 7 or later, day 8 or later or day 9 or later, more preferably on day 10 or later after the administration.

[0213] The antibody having an excellent property of accumulating in the brain, the antibody having a high property of accumulating in the brain or the antibody having an improved property of accumulating in the brain may be any antibody as long as the antibody is an antibody whose antibody concentration (antibody amount) in the brain is higher than that of a control antibody or an antibody having the characteristic of existing in the brain for a long time.

[0214] Examples include antibodies having the characteristic that the migration rate to the brain and/or the accumulation rate in the brain are higher than those of a control antibody, the characteristic that the migration rate to outside from the brain, the discharge rate and/or the decomposition rate in the brain are lower and the characteristic that the migration rate to the brain and/or the accumulation rate in the brain are higher than the migration rate to outside from the brain, the discharge rate and/or the decomposition rate in the brain.

[0215] Accordingly, the antibody or the antibody fragment of the invention is, for example an antibody or an antibody fragment thereof whose antibody concentration (or the antibody amount) in the brain is higher than that of a control antibody after a same period (day) after the administration when the antibody or the antibody fragment is administered to an animal or an antibody or an antibody fragment thereof which can exist in the brain for a long time.

[0216] The change in the antibody concentration (or the antibody amount) in the brain may be any change, and examples include a case in which the antibody concentration gradually decreases after the antibody concentration in the brain once reaches its peak during the measurement period, a case in which after the antibody concentration in the brain reaches its peak, the antibody concentration is maintained, a case in which the antibody concentration in the brain continues to increase after the administration of the antibody or another case.

[0217] The antibody or the antibody fragment of the invention is, for example, an antibody whose antibody concentration or antibody amount in the brain is higher than that of a control antibody on day 4 or day 10 after the administration to a rat, an antibody whose antibody concentration or antibody amount in the brain is maintained or increases from day 4 to day 10 after the administration to a rat, an antibody whose existence in the brain can be clearly confirmed on day 10 or later after the administration to a rat or another antibody but is not limited to these examples.

[0218] The control antibody may be any antibody as long as the control antibody is an antibody of the same species or subclass as that of the antibody to be tested, but for example, an anti-avermectin (AVM) antibody and the like can be used.

[0219] In the invention, the term "in the brain" is, for example, in the brain parenchyma, in a cerebral ventricle, in the cerebrospinal fluid or the like but is not limited to these examples.

[0220] In the invention, the method for administering an antibody to an animal is, for example, intravenous administration, intraventricular administration, intraperitoneal administration, subcutaneous administration, intradermal administration, nasal administration, intrathecal administration or the like but is not limited to these methods.

[0221] In the invention, the method for measuring the property of an antibody of accumulating in the brain is, for example, a method of collecting brain tissues several days after administering the antibody to an animal, measuring the antibody concentration of the supernatant obtained after homogenization and centrifugation and calculating the antibody amount per unit brain weight, a method of detecting the antibody using a known immunological method using the collected brain tissues, a method of administering the antibody which has been labeled to an animal and detecting the antibody by an in vivo imaging system sequentially or another method.

[0222] The antibody of the invention may be an antibody selected from the group consisting of (a) to (q) below,

[0223] (a) an antibody in which the amino acid sequences of CDRs 1 to 3 of VH are the amino acid sequences of SEQ ID NOs: 4, 5 and 6, respectively, and in which the amino acid sequences of CDRs 1 to 3 of VL contain the amino acid sequences of SEQ ID NOs: 10, 11 and 12, respectively,

[0224] (b) an antibody in which the amino acid sequences of CDRs 1 to 3 of VH are the amino acid sequences of SEQ ID NOs: 16, 17 and 18, respectively, and in which the amino acid sequences of CDRs 1 to 3 of VL contain the amino acid sequences of SEQ ID NOs: 22, 23 and 24, respectively,

[0225] (c) an antibody in which the amino acid sequences of CDRs 1 to 3 of VH are the amino acid sequences of SEQ ID NOs: 28, 29 and 30, respectively, and in which the amino acid sequences of CDRs 1 to 3 of VL contain the amino acid sequences of SEQ ID NOs: 34, 35 and 36, respectively,

[0226] (d) an antibody fragment in which the amino acid sequences of CDRs 1 to 3 of VHH contain the amino acid sequences of SEQ ID NOs: 40, 41 and 42, respectively,

[0227] (e) an antibody in which the amino acid sequences of CDRs 1 to 3 of VH contain the amino acid sequences of SEQ ID NOs: 153, 154 and 155, respectively, and in which the amino acid sequences of CDRs 1 to 3 of VL contain the amino acid sequences of SEQ ID NOs: 158, 159 and 160, respectively,

[0228] (f) an antibody in which the amino acid sequences of CDRs 1 to 3 of VH contain the amino acid sequences of SEQ ID NOs: 163, 164 and 165, respectively, and in which the amino acid sequences of CDRs 1 to 3 of VL contain the amino acid sequences of SEQ ID NOs: 168, 169 and 170, respectively,

[0229] (g) an antibody in which the amino acid sequences of CDRs 1 to 3 of VH contain the amino acid sequences of SEQ ID NOs: 173, 174 and 175, respectively, and in which the amino acid sequences of CDRs 1 to 3 of VL contain the amino acid sequences of SEQ ID NOs: 178, 179 and 180, respectively,

[0230] (h) an antibody in which the amino acid sequences of CDRs 1 to 3 of VH contain the amino acid sequences of SEQ ID NOs: 183, 184 and 185, respectively, and in which the amino acid sequences of CDRs 1 to 3 of VL contain the amino acid sequences of SEQ ID NOs: 188, 189 and 190, respectively,

[0231] (i) an antibody in which the amino acid sequences of CDRs 1 to 3 of VH contain the amino acid sequences of SEQ ID NOs: 193, 194 and 195, respectively, and in which the amino acid sequences of CDRs 1 to 3 of VL contain the amino acid sequences of SEQ ID NOs: 198, 199 and 200, respectively,

[0232] (j) an antibody in which the amino acid sequences of CDRs 1 to 3 of VH contain the amino acid sequences of SEQ ID NOs: 203, 204 and 205, respectively, and in which the amino acid sequences of CDRs 1 to 3 of VL contain the amino acid sequences of SEQ ID NOs: 208, 209 and 210, respectively,

[0233] (k) an antibody in which the amino acid sequences of CDRs 1 to 3 of VH contain the amino acid sequences of SEQ ID NOs: 213, 214 and 215, respectively, and in which the amino acid sequences of CDRs 1 to 3 of VL contain the amino acid sequences of SEQ ID NOs: 218, 219 and 220, respectively,

[0234] (l) an antibody in which the amino acid sequences of CDRs 1 to 3 of VH contain the amino acid sequences of SEQ ID NOs: 223, 224 and 225, respectively, and in which the amino acid sequences of CDRs 1 to 3 of VL contain the amino acid sequences of SEQ ID NOs: 228, 229 and 230, respectively,

[0235] (m) an antibody in which the amino acid sequences of CDRs 1 to 3 of VH contain the amino acid sequences of SEQ ID NOs: 233, 234 and 235, respectively, and in which the amino acid sequences of CDRs 1 to 3 of VL contain the amino acid sequences of SEQ ID NOs: 238, 239 and 240, respectively,

[0236] (n) an antibody in which the amino acid sequences of CDRs 1 to 3 of VH contain the amino acid sequences of SEQ ID NOs: 243, 244 and 245, respectively, and in which the amino acid sequences of CDRs 1 to 3 of VL contain the amino acid sequences of SEQ ID NOs: 248, 249 and 250, respectively,

[0237] (o) an antibody which competes in binding to MOG with at least one of the antibodies described in (a) to (n),

[0238] (p) an antibody which binds to an epitope containing an epitope to which any one of the antibodies described in (a) to (n) binds and

[0239] (q) an antibody which binds to the same epitope as an epitope to which any one of the antibodies described in (a) to (n) binds.

[0240] As the antibody of the invention, an antibody having amino acid sequences of CDRs 1 to 3 of VH and CDRs 1 to 3 of VL of an antibody having homology of 85% or higher, preferably 90% or higher to the amino acid sequences of CDRs 1 to 3 of VH and CDRs 1 to 3 of VL of any one of the antibodies described in (a) to (n) is included. The homology of 90% or higher is more preferably homology of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or the like.

[0241] In the invention, embodiments of the antibodies described in (a) to (n) include human anti-MOG monoclonal antibodies, MOG01 antibody, MOG09 antibody and MOG14 antibody and an alpaca anti-MOG monoclonal VHH antibody, iMOG-3Rim1-S32 antibody. In addition, embodiments include a human chimeric antibody of iMOG-3Rim1-S32, a humanized antibody of iMOG-3Rim1-S32 and the like.

[0242] In the invention, the antibody of (o) is a second antibody which inhibits binding of a first antibody and MOG, wherein the antibody described in any of (a) to (n) is the first antibody.

[0243] In the invention, the antibody of (p) is a second antibody which binds to a second epitope containing a first epitope, wherein the antibody described in any of (a) to (n) is a first antibody, and the epitope to which the first antibody binds is the first epitope.

[0244] Moreover, the antibody of (q) of the invention is a second antibody which binds to a first epitope, wherein the antibody described in any of (a) to (n) is a first antibody, and the epitope to which the first antibody binds is the first epitope.

[0245] Furthermore, the antibody of the invention may be specifically an antibody selected from the group consisting of (a) to (n) and (o1) to (o22) below,

[0246] (a) an antibody in which the amino acid sequence of VH is the amino acid sequence of SEQ ID NO: 3 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 9,

[0247] (b) an antibody in which the amino acid sequence of VH is the amino acid sequence of SEQ ID NO: 15 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 21,

[0248] (c) an antibody in which the amino acid sequence of VH is the amino acid sequence of SEQ ID NO: 27 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 33,

[0249] (d) an antibody fragment in which the amino acid sequence of VHH contains the amino acid sequence of SEQ ID NO: 39,

[0250] (e) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 152 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 157,

[0251] (f) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 162 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 167,

[0252] (g) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 172 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 177,

[0253] (h) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 182 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 187,

[0254] (i) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 192 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 197,

[0255] (j) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 202 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 207,

[0256] (k) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 212 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 217,

[0257] (l) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 222 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 227,

[0258] (m) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 232 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 237,

[0259] (n) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 242 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 247,

[0260] (o1) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 252 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 254,

[0261] (o2) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 256 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 258,

[0262] (o3) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 260 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 262,

[0263] (o4) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 264 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 266,

[0264] (o5) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 268 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 270,

[0265] (o6) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 272 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 274,

[0266] (o7) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 276 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 278,

[0267] (o8) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 280 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 282,

[0268] (o9) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 284 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 286,

[0269] (o10) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 288 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 290,

[0270] (o11) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 292 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 294,

[0271] (o12) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 296 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 298,

[0272] (o13) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 300 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 302,

[0273] (o14) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 304 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 306,

[0274] (o15) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 308 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 310,

[0275] (o16) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 312 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 314,

[0276] (o17) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 316 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 318,

[0277] (o18) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 320 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 322,

[0278] (o19) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 324 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 326,

[0279] (o20) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 328 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 330,

[0280] (o21) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 332 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 334 and (o22) an antibody in which the amino acid sequence of VH contains the amino acid sequence of SEQ ID NO: 336 and in which the amino acid sequence of VL contains the amino acid sequence of SEQ ID NO: 338.

[0281] As the antibody of the invention, an antibody having amino acid sequences of VH and VL of an antibody having homology of 85% or higher, preferably 90% or higher to the amino acid sequences of VH and VL of any one of the antibodies described in (a) to (n) and (o1) to (o22) is included. The homology of 90% or higher is more preferably homology of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or the like.

[0282] In the invention, embodiments of the antibodies described in (a) to (n) and (o1) to (o22) include human anti-MOG monoclonal antibodies, MOG01 antibody, MOG09 antibody and MOG14 antibody and an alpaca anti-MOG monoclonal VHH antibody, iMOG-3Rim1-S32 antibody. In addition, embodiments include an iMOG-3Rim1-S32 human chimeric antibody, an iMOG-3Rim1-S32 humanized antibody and the like.

[0283] In the invention, the EU index refers to the position of an amino acid residue according to Sequences of Proteins of Immunological Interest, Fifth edition (1991). The positions of the amino acid residues shown below are all the positions of the amino acid residues according to the EU index unless particularly described.

[0284] An antibody molecule is also called an immunoglobulin (referred to as Ig below), and its basic structure is a tetramer having two polypeptides called heavy chains (referred to as H chains below) and two polypeptides called light chains (referred to as L chains below).

[0285] Each H chain is composed of a H chain variable region (also referred to as VH) and a H chain constant region (also referred to as CH) from the N-terminus side, and each L chain is composed of a L chain variable region (also referred to as VL) and a L chain constant region (also referred to as CL) from the N-terminus side.

[0286] For CH, .alpha., .delta., .epsilon., .gamma. and .mu. chains are known for each subclass. CH is further composed of a CH1 domain, a hinge domain, a CH2 domain and a CH3 domain from the N-terminus side.

[0287] A domain is a functional structural unit which constitutes a polypeptide of an antibody molecule. The CH2 domain and the CH3 domain are together called a Fc (Fragment, crystallizable) region or simply Fc. For CL, Ca, chain and CK chain are known.

[0288] The subclasses of antibody in which CH is .alpha., .delta., .epsilon., .gamma. and .mu. chains are called IgA, IgD, IgE, IgG and IgM, respectively. There are sometimes isotypes for a subclass of an antibody depending on the animal. In human, there are isotypes IgA1 and IgA2 for IgA, and there are isotypes IgG1, IgG2, IgG3 and IgG4 for IgG.

[0289] The CH1 domain, the hinge domain, the CH2 domain, the CH3 domain and the Fc region in the invention can be identified by the positions of the amino acid residues from the N-terminus according to the EU index.

[0290] Specifically, CH1 is identified as the amino acid sequence of from position 118 to position 215 according to the EU index, and the hinge is identified as the amino acid sequence of from position 216 to position 230 according to the EU index. CH2 is identified as the amino acid sequence of from position 231 to position 340 according to the EU index, and CH3 is identified as the amino acid sequence of from position 341 to position 447 according to the EU index. The Fc region is identified as the amino acid sequence of from position 231 to position 447 according to the EU index.

[0291] As the antibody of the invention, a polyclonal antibody, a monoclonal antibody and an oligoclonal antibody are all included. A polyclonal antibody is a group of antibody molecules that are secreted by antibody-producing cells of different clones. A monoclonal antibody is an antibody that is secreted by antibody-producing cells of a single clone and recognizes only one epitope (also called an antigenic determinant). The amino acid sequences (primary sequences) of same monoclonal antibodies are the same. An oligoclonal antibody is a group of antibody molecules in which different monoclonal antibodies are mixed.

[0292] The monoclonal antibody of the invention may be an antibody that is produced from a hybridoma or a genetically recombinant antibody that is produced by a transformant transformed with an expression vector containing the antibody genes.

[0293] The epitope may be a single amino acid sequence, a three-dimensional structure made of an amino acid sequence, an amino acid sequence modified after translation, a three-dimensional structure made of an amino acid sequence modified after translation which the monoclonal antibody recognizes and binds to or the like.

[0294] The amino acid sequence modified after translation may be an O-linked glycan in which sugar chains are attached to Tyr and Ser having OH substituents, an N-linked glycan in which sugar chains are attached to Gln and Asn having NH.sub.2 substituents or a tyrosine sulfated amino acid sequence in which a sulfuric acid molecule is attached to Tyr having OH substituents.

[0295] The epitope of MOG to which the antibody of the invention binds can be identified by an antibody-binding test using a deletion variant of MOG in which some domains are lost, a mutant in which some domains are replaced with domains derived from another protein, a partial peptide fragment of MOG or the like. The antibody-binding test can also be conducted using cells expressing the deletion variant or the mutant.

[0296] Alternatively, the epitope of MOG to which the antibody of the invention binds can also be identified by adding the antibody of the invention to peptide fragments of MOG obtained by decomposition using a protease and conducting epitope mapping using a known mass spectrometry.

[0297] As the antibody of the invention, genetically recombinant antibodies of a mouse antibody, a rat antibody, a hamster antibody, a rabbit antibody, a llama antibody, a camel antibody, an alpaca antibody, a chimeric antibody, a humanized antibody (also called a "Complementarity Determining Region (CDR)-inserted antibody"), a human antibody and the like are also included.

[0298] In the invention, the chimeric antibody is an antibody in which VH and VL are derived from a different animal kind from that of CH and CL. An antibody composed of VH and VL of an antibody of an animal other than human (a non-human animal) and CH and CL of a human antibody is called a human chimeric antibody, and an antibody composed of VH and VL of an antibody of an animal other than mouse and CH and CL of a mouse antibody is called a mouse chimeric antibody. Other chimeric antibodies are named in the same manner.

[0299] As the non-human animal, any animal such as mouse, rat, hamster, rabbit, llama, camel or alpaca can be used as long as a hybridoma can be produced or an antibody phage library can be produced.

[0300] A hybridoma is a cell which is obtained by cell fusion of a B cell obtained by immunizing a non-human animal with an antigen and a myeloma cell derived from a mouse or the like and which produces a monoclonal antibody having a desired antigen specificity.

[0301] An antibody phage library is a library produced by cloning the genes of immunoglobulin variable regions to a phage and expressing an antigen-binding molecule on its surface. The phages used are M13 phage and the like but are not particularly limited.

[0302] The antigen-binding molecule which is displayed on a phage may be in any form but is preferably an antibody fragment such as scFv, Fab or VHH.

[0303] In the invention, the antibody phage library may be any library of an immune library, a naive library and a synthetic library.

[0304] An immune library is an antibody phage library which is constructed based on the antibody genes derived from lymphocytes of an animal immunized with an antigen or a patient. A naive library is an antibody phage library which is constructed based on the antibody genes derived from lymphocytes of a normal animal or a healthy human. A synthetic library is a library in which CDRs of a V gene in genome DNA or a reconstructed functional V gene are replaced with oligonucleotides that encode any amino acid sequences of appropriate lengths.

[0305] As a method for producing a chimeric antibody, a method for producing a human chimeric antibody is described below. Other chimeric antibodies can also be produced by the same method.

[0306] A human chimeric antibody can be produced by obtaining cDNAs that encode VH and VL from a hybridoma derived from a non-human animal cell producing a monoclonal antibody, inserting the cDNAs into an expression vector for animal cells having DNA that encodes CH and CL of a human antibody, thereby constructing a human chimeric antibody expression vector, introducing the vector to an animal cell and expressing the antibody.

[0307] A human chimeric antibody can also be produced by cloning the genes that encode VH and VL from an antibody phage library derived from a non-human animal, inserting the genes into an expression vector for animal cells having DNA that encodes CH and CL of a human antibody, thereby constructing a human chimeric antibody expression vector, introducing the vector to an animal cell and expressing the antibody.

[0308] A humanized antibody is an antibody in which the amino acid sequences of CDRs of VH and VL of an antibody of a non-human animal are implanted to the corresponding CDRs of VH and VL of a human antibody. The region other than the CDRs of VH and VL is called a framework region (referred to as FR below).

[0309] A humanized antibody can be produced by constructing cDNA that encodes the amino acid sequence of VH formed from the amino acid sequences of CDRs of VH of an antibody of a non-human animal and the amino acid sequence of FR of VH of any human antibody and cDNA that encodes the amino acid sequence of VL formed from the amino acid sequences of CDRs of VL of an antibody of a non-human animal and the amino acid sequence of FR of VL of any human antibody, inserting the cDNAs to an expression vector for animal cells having DNA that encodes CH and CL of a human antibody, thereby constructing a humanized antibody expression vector, introducing the vector to an animal cell and expressing the antibody.

[0310] A human antibody is originally an antibody that naturally exists in the human body, but antibodies obtained from a human antibody phage library and a human antibody-producing transgenic animal and the like are also included.

[0311] A human antibody can be obtained by immunizing a mouse having a human immunoglobulin gene (Tomizuka K. et al., Proc Natl Acad Sci USA. 97, 722-7, 2000.) with a desired antigen. A human antibody can be obtained also without immunization by selecting a human antibody having a desired binding activity using a phage display library obtained by amplifying antibody genes from human-derived B cells (Winter G. et al., Annu Rev Immunol. 12:433-55. 1994).

[0312] Moreover, a human antibody can be obtained by producing cells which produce a human antibody having a desired binding activity by immortalizing human B cells using EB virus (Rosen A. et al., Nature 267, 52-54.1977).

[0313] A human antibody phage library is a library in which antibody fragments such as Fab, scFv and VHH are expressed on the surface of phages by inserting an antibody gene produced from lymphocytes of a human (a healthy individual or a patient) to phage genes. It is possible to collect phages on which antibody fragments having a desired antigen binding activity are expressed using binding activity to a substrate to which an antigen is fixed as an index from the library. The antibody fragments can be further converted to a human antibody molecule formed from two whole H chains and two whole L chains using the genetic engineering technique.

[0314] A human antibody-producing transgenic animal is an animal in which a human antibody gene is incorporated into the chromosomes of the host animal. Specifically, a human antibody-producing transgenic animal can be produced by introducing a human antibody gene to mouse ES cells, implanting the ES cells to an early embryo of another mouse and then causing development.

[0315] A human antibody can be produced from a human antibody-producing transgenic animal by culturing a human antibody-producing hybridoma obtained by a general hybridoma production method performed for mammals other than human, producing and accumulating the human antibody in the culture and purifying the antibody from the culture.

[0316] The antibody of the invention includes a heavy chain antibody composed of heavy chains only. Heavy chain antibodies are an antibody obtained from a Camelidae animal such as llama, camel and alpaca and a genetically recombinant antibody produced based on the antibody.

[0317] In the invention, the antibody fragment is a fragment of an antibody which has an antigen binding activity. Examples include Fab, Fab', F(ab').sub.2, single chain Fv (scFv), diabody, dsFv, a peptide containing CDRs, VHH and the like. The antibody fragment of the invention also includes any antibody fragment as long as the antibody fragment contains a partial fragment of an antibody and has a MOG binding activity, such as an antibody fragment obtained by fusing the whole or a part of a constant region or Fc of an antibody to the antibody fragment or an antibody fragment containing a constant region or Fc.

[0318] Fab is an antibody fragment which has an antigen binding activity and a molecular weight of approximately fifty thousand and in which about a half of the H chain in the N-terminus side and the entire L chain are linked to each other through disulfide bonds (S--S bonds) (cleaved at the 224th amino acid residue in the H chain), of the fragments obtained by treating IgG antibody with a protease, papain.

[0319] F(ab').sub.2 is an antibody fragment which has an antigen binding activity and a molecular weight of approximately hundred thousand and which is slightly larger than the one in which Fabs are bound through the S--S bond in the hinge region (cleaved at the 234th amino acid residue in the H chain), of the fragments obtained by treating IgG with a protease, pepsin.

[0320] Fab' is an antibody fragment which has an antigen binding activity and a molecular weight of approximately fifty thousand and in which the S--S bond in the hinge region of the above F(ab').sub.2 is cleaved.

[0321] scFv is a VH-P-VL or VL-P-VH polypeptide in which one VH and one VL are linked using an appropriate peptide linker (P) such as a linker peptide of any number of connected linkers each having four Gly residues and one Ser residue (G4S) and is an antibody fragment having an antigen binding activity.

[0322] Diabody is an antibody fragment in which scFvs having same or different antigen binding specificities form a dimer and is an antibody fragment having a divalent antigen binding activity to a same antigen or specific antigen binding activities to different antigens.

[0323] dsFv is a fragment in which polypeptides obtained by substituting one amino acid residue in VH and that in VL with cysteine residues are bound through the S--S bond between the cysteine residues.

[0324] A peptide containing CDR is composed of and contains at least one or more regions of CDRs of VH or VL. In a peptide containing CDRs, the CDRs can be bound directly or through an appropriate peptide linker.

[0325] Production can be performed by constructing DNA that encodes CDRs of VH and VL of the antibody of the invention, inserting the DNA into an expression vector for a prokaryote or an expression vector for a eukaryote and introducing the expression vector into a prokaryote or a eukaryote for expression. In addition, a peptide containing CDR can also be produced by a chemical synthesis method such as the Fmoc method or the tBoc method.

[0326] VHH is a variable region of a heavy chain antibody and is also called a nanobody.

[0327] The antibody fragment of the invention includes any antibody fragment as long as the antibody fragment contains any of the antibody fragments described above or a partial fragment thereof and has a MOG binding activity.

[0328] In the invention, an antibody having one antigen binding site or an antibody fragment thereof is called a monovalent antibody. The formats of a monovalent antibody are the formats of an antibody having one antigen binding site or an antibody fragment thereof described in International Publication No. 2014/054804, International Publication No. 2011/090754, International Publication No. 2007/048037, International Publication No. 2012/116927 and the like and other formats.

[0329] In the invention, an antibody of one molecule which binds to three or more different antigens or epitopes or an antibody fragment thereof is called a multispecific antibody. In the invention, an antibody of one molecule which binds to two different antigens or epitopes or an antibody fragment thereof is called a bispecific antibody.

[0330] The formats of a multispecific antibody or a bispecific antibody are the formats described in International Publication No. 2009/131239, International Publication No. 2014/054804, International Publication No. 01/077342, US Patent Application Publication No. 2007/0071675, International Publication No. 2007/024715, Wu et al., [Nature Biotechnology, 2007, 25(11), p. 1290-1297], Labrijn et al., [PNAS 2013, vol. 110, no. 13, p 5145-5150], Jong et al., [http://dx.doi.org/10.1371/journal.pbio.1002344], Kontermann et al., [mAbs 2012, vol. 4, issue2, p 182-197], Spiess et al., [Molecular Immunology 67 (2015) 95-106], Ridgway et al., [Protein engineering, 1996 vol. 9 no. 7 pp 617-621, International Publication No. 2009/080251, International Publication No. 2010/151792, International Publication No. 2014/033074 and the like and other formats.

[0331] The bispecific antibody may be specifically any of the bispecific antibodies described below and the like.

[0332] (1) A bispecific antibody in which amino acid modifications S354C/T366W are introduced to CH3 of one of the two heavy chains of an antibody (heavy chain A) and in which amino acid modifications Y349C/T366S/L368A/Y407V are introduced to CH3 of the other heavy chain (heavy chain B).

[0333] (2) A bispecific antibody in which an antibody fragment is fused to a C-terminus of an antibody.

[0334] (3) A bispecific antibody in which an antibody fragment is fused to a N-terminus of an antibody.

[0335] The bispecific antibody described in (1) may be a bispecific antibody in which the antigen binding site containing VH of heavy chain A binds to MOG and in which the antigen binding site containing VH of heavy chain B binds to an antigen that is present in the brain or one in which the bindings are the other way around.

[0336] The bispecific antibody described in (2) may be any bispecific antibody of a bispecific antibody in which an antibody fragment is bound to the C-terminus of one of the two heavy chains constituting the antibody and a bispecific antibody in which antibody fragments are bound to both of the two heavy chains. Moreover, an appropriate linker may be between the C-terminus of the heavy chain of the antibody and the antibody fragment.

[0337] The antibody fragment(s) that the bispecific antibody described in (2) has is preferably scFv, Fab, VHH or the like but is not particularly limited to these fragments.

[0338] The bispecific antibody described in (2) may be a bispecific antibody in which the antigen binding site at the N-terminus binds to MOG and in which the antigen binding site at the C-terminus binds to an antigen that is present in the brain or one in which the bindings are the other way around.

[0339] The bispecific antibody described in (3) is a bispecific antibody in which an antibody fragment is bound to the N-terminus of at least any one of the two heavy chains or the light chains constituting the antibody. Moreover, an appropriate linker may be between the N-terminus of the heavy chain and/or the light chain of the antibody and the antibody fragment. The antibody fragment that the bispecific antibody described in (3) has is preferably scFv, Fab, VHH or the like but is not particularly limited to these fragments.

[0340] The bispecific antibody described in (3) is a bispecific antibody having a structure VH.sub.1-CH1-VH.sub.2-CH1-hinge-CH2-CH3 from the N-terminus of a heavy chain, a bispecific antibody which has the heavy chain structure and in which VH.sub.1 and VH.sub.2 each form an antigen binding site with VL or the like. The VLs with which VH.sub.1 and VH.sub.2 form antigen binding sites may have a same amino acid sequence or different amino acid sequences.

[0341] In the invention, the multispecific antibody or the bispecific antibody may be any antibody as long as the antibody is a multispecific antibody or a bispecific antibody which binds to MOG. Of such antibodies, a multispecific antibody or a bispecific antibody which binds to MOG and an antigen that is present in the brain is preferable, and a multispecific antibody or a bispecific antibody containing an antigen binding site which binds to MOG and an antigen binding site which binds to an antigen that is present in the brain is more preferable.

[0342] In the invention, the antigen that is present in the brain is a protein, a sugar chain, a lipid or the like and is preferably a protein of these antigens.

[0343] Examples of the protein that is present in the brain include MOG, Prion, 5T4, AFP, ADAM-10, ADAM-12, ADAM17, AFP, AXL, BSG, C5, C5R, CA9, CA72-4, CCL11, CCL2, CCR1, CCR4, CCR5, CCR6, CD2, CD3E, CD4, CD5, CD6, CD8, CD11, CD18, CD19, CD20, CD22, CD24, CD25, CD29, CD30, CD32B, CD33, CD37, CD38, CD40, CD40LG, CD44, CD47, CD52, CD55SC1, CD56, CD66E, CD71, CD72, CD74, CD79a, CD79b, CD80, CD86, CD95, CD98, CD137, CD147, CD138, CD168, CD200, CD248, CD254, CD257, CDH3, CEA, CEACAM1, CEACAM5, CEACAM6, CEACAM8, Claudin3, Claudin4, c-Met, CS-1, CSF2RA, CSPG-4, CTLA4, CRF-1, Cripto, CXCR4, CXCR5, DLL4, DR4, DR5, ED-B, EFNA2, EGFR, EGFRvIII, ETBR, ENPP3, EPCAM, EphA2, ERBB2, ERBB3, ERBB4, FAP.alpha., FAS, Fc.gamma.RI, FCER2, FGFR1, FGFR2, FGFR3, FGFR4, FLT1, FOLH1, FOLR1, GDF2, GFR, GLP1R, glypican-3, GPNMB, GRP78, HB-EGF, HGF, HLA-DR.beta., ICAM1, IFNA1, IFNA1, IgE, IgE-Fc, IGF1R, IL10, IL12B, IL13, IL15, IL17A, IL1A, IL1B, IL2RA, IL4, IL5, IL5RA, IL6, IL6R, IL9, IL2Ra, IL2RI3, IL2Ry, INSR, ITGA2, ITGA2B2, ITGB3, ITGA4, ITGB7, ITGA5, ITGAL, ITGAV, ITGB3, ITGB2, KDR, L1CAM, mesothelin, MMP14, MMP15, MST1R, MSTN, MUC1, MUC4, MUC16, MUCSAC, myostatin, NECTIN4, NGF, NOTCH, NRG1, NRP, OX40, OX40L, PDGFA, PDGFB, PDGFRA, PDGFRB, PD1, PDL1, PSCA, SLAM7, SLC44A4, TAG-72, TCR, TGFB1, TGFB2, TGFBR, TNF, TNFR, TNFRSF10A, TNFRSF10B, TNFRSF12A, TNFSF13, TNFSF14, TNFSF2, TNFSF7, TRAILR2, TRKA, TRKB, TRKC, VEGF, VEGFR, VLA-4, CGRP, alpha-synuclein, TDP-43, Tau, FUS, Amyloid-beta (A.beta.), APP, BACE1, Presenilin, LINGO-1, Nogo, polyQ, androgen receptor, huntingtin, ataxin 1, ataxin 2, RGMA, Phospho-Tau, Phospho-alpha-synuclein and the like, but the protein is not limited to these proteins.

[0344] Examples of the sugar chain that is present in the brain include Lewis-x, Lewis-y, CD15 and the like, but the sugar chain is not limited to these sugar chain.

[0345] Examples of the lipid that is present in the brain include GD1a, GD2, GD3, GM1, GM2, GM3, phosphatidylserine and the like, but the lipid is not limited to these lipids.

[0346] The antibody or the antibody fragment of the invention also includes an antibody containing any amino acid that is modified after translation. Examples of the modification after translation include deletion of the lysine residue at the C-terminus of a H chain (lysine clipping), conversion of the glutamine residue at the N-terminus of a polypeptide into pyroglutamine (puroGlu) and the like [Beck et al, Analytical Chemistry, 85, 715-736(2013)].

[0347] An amino acid residue in the Fc region of the antibody or the antibody fragment of the invention may be modified. Examples of the amino acid modification in the Fc region include amino acid modification for stabilizing the antibody or regulating the half-life in the blood and the like. Specific examples of the amino acid modification in the Fc region include those in International Publication No. 2006/033386, International Publication No. 2006/075668, International Publication No. 2011/122011, International Publication No. 2009/125825 and the like.

[0348] The antibody or the antibody fragment of the invention also includes a fused antibody or a fused antibody fragment in which an antibody or an antibody fragment is modified. The method for modifying an antibody is not particularly limited, and any method which can modify a desired amino acid residue and a sugar chain can be used.

[0349] Examples include chemical modification using chemical reaction [Introduction to Antibody Engineering, Chijinshokan Co., Ltd. (1994); and Kolb et al., Angew Chem Int Ed Engl. 40. 2004-21, 2001], modification by the genetic engineering technique in which a recombinant protein expression vector is introduced to an appropriate host cell for expression using genetic recombination technology and the like.

[0350] In the invention, examples of the molecule which modifies the antibody or the antibody fragment include a hydrophilic polymer, an amphipathic polymer, a functional molecule and the like. Examples of the hydrophilic polymer and the amphipathic polymer include a polyoxyalkylene, a molecule containing a polyol or a polysaccharide and the like.

[0351] Examples of the polyoxyalkylene include linear or branched chain polyethylene glycol (referred to as PEG below), polypropylene glycol, polypropylene ethylene glycol and the like.

[0352] Examples of the molecule containing a polyol or a polysaccharide include homo- or hetero-polysaccharides such as amylose, dextran, pullulan or glycogen composed of linear or branched chain polyglycerol and the like.

[0353] The molecular weight of the molecule containing a hydrophilic polymer or an amphipathic polymer is not particularly limited but is preferably 100 Da or more, preferably for example 100 Da to 100 kDa.

[0354] Examples of the functional molecule include an antigen-binding molecule, a fragment thereof, a drug, a bioactive peptide, a bioactive protein, a nucleic acid, a radiolabeling compound, a sugar chain, a lipid, a fluorescent compound and the like. A molecule which has double specificity as a result of modification with a functional molecule such as an antigen-binding molecule is a bispecific antibody.

[0355] Examples of the antigen-binding molecule include an antibody, a receptor, a ligand and the like.

[0356] The fragment of the antigen-binding molecule may be any fragment as long as the fragment is a fragment of the antigen-binding molecule and has an antigen binding activity.

[0357] Examples of the drug include anti-cancer drugs such as alkylating agents, nitrosoureas, antimetabolites, antiviral agents, antibiotics, plant alkaloids, topoisomerase inhibitors, tubulin polymerization inhibitors, hormonal therapy agents, hormone antagonists, aromatase inhibitors, P-glycoprotein inhibitors, platinum complex derivatives, M cycle inhibitor or kinase inhibitors [Clinical oncology, Cancer and chemotherapy (1996)], anti-inflammatory agents such as steroids such as hydrocortisone or prednisone, nonsteroidal drugs such as aspirin or indomethacin, immune modulating drugs such as gold thiomalate or penicillamine, immunosuppressive drugs such as cyclophosphamide or azathioprine, antihistamine drugs such as chlorpheniramine maleate or clemastine [Inflammation and anti-inflammatory therapy, Ishiyaku Pub, Inc. (1982)] and the like.

[0358] Examples of the anti-cancer drugs include mertansine, emtansine, amifostine (Ethyol), cisplatin, dacarbazine (DTIC), dactinomycin, mechlorethamine (nitrogen mustard), streptozocin, cyclophosphamide, ifosfamide, carmustine (BCNU), lomustine (CCNU), doxorubicin (Adriamycin), epirubicin, gemcitabine (Gemzar), daunorubicin, procarbazine, mitomycin, cytarabine, etoposide, 5-fluorouracil, fluorouracil, vinblastine, vincristine, bleomycin, daunomycin, peplomycin, estramustine, paclitaxel (Taxol), docetaxel (Taxotere), Aldesleukin, asparaginase, busulfan, carboplatin, oxaliplatin, nedaplatin, cladribine, camptothecin, 7-ethyl-10-hydroxycamptothecin (SN38), floxuridine, fludarabine, hydroxyurea, idarubicin, mesna, irinotecan (CPT-11), nogitecan, mitoxantrone, topotecan, leuprolide, megestrol, melphalan, mercaptopurine, hydroxycarbamide, plicamycin, mitotane, pegaspargase, pentostatin, pipobroman, streptozocin, tamoxifen, goserelin, leuprorelin, flutamide, teniposide, testolactone, thioguanine, thiotepa, uracil mustard, vinorelbine, chlorambucil, hydrocortisone, prednisolone, methylprednisolone, vindesine, nimustine, semustine, capecitabine, Tomudex, azacitidine, UFT, oxaloplatin, gefitinib (Iressa), imatinib (STI571), erlotinib, FMS-like tyrosine kinase 3 (Flt3) inhibitor, vascular endothelial growth factor receptor (VEGFR) inhibitor, fibroblast growth factor receptor (FGFR) inhibitor, epidermal growth factor receptor (EGFR) inhibitor such as Tarceva, radicicol, 17-allylamino-17-demethoxygeldanamycin, rapamycin, amsacrine, all-trans retinoic acid, thalidomide, lenalidomide, anastrozole, fadrozole, letrozole, exemestane, gold thiomalate, D-penicillamine, bucillamine, azathioprine, mizoribine, cyclosporine, rapamycin, hydrocortisone, bexarotene (Targretin), tamoxifen, dexamethasone, progestins, estrogens, anastrozole (Arimidex), Leuplin, Aspirin, indomethacin, celecoxib, azathioprine, penicillamine, gold thiomalate, chlorpheniramine maleate, chloropheniramine, clemastine, tretinoin, bexarotene, arsenic, bortezomib, allopurinol, calicheamicin, ibritumomab tiuxetan, targretin, ozogamine, clarithromycin, leucovorin, ketoconazole, aminoglutethimide, suramin, methotrexate, maytansinoid, derivatives thereof and the like.

[0359] Examples of the method for binding the drug and the antibody or the antibody fragment include a method of binding the drug to an amino group of the antibody through glutaraldehyde, a method of binding an amino group of the drug to a carboxyl group of the antibody through water-soluble carbodiimide and the like in addition to the above method.

[0360] Examples of the bioactive peptide or the bioactive protein include interferon (referred to as IFN below)-.alpha., IFN-.beta., interleukin (referred to as IL below)-2, IL-12, IL-15, IL-18, IL-21, IL-23, granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), macrophage colony stimulating factor (M-CSF), cytokines or growth factors which activate immunocompetent cells such as NK cells, macrophages or neutrophils, proteases such as hydrase, lyase and isomerase, enzymes such as acid sphingomyelinase, toxins including bacterial toxins and phytotoxins such as ricin, diphtheria toxin or ONTAK, antimicrobial peptides having cytomembrane-damaging activity, peptides having cytomembrane-binding affinity or permeability to cytomembrane, derivatives thereof and the like.

[0361] The nucleic acid may be any molecule as long as it is a molecule in which nucleotides or molecules having equivalent function to that of nucleotides are polymerized, and examples include siRNA, microRNA, antisense RNA, DNA aptamers and the like.

[0362] The radiolabeling compound may be any nuclide that is used for applications for diagnoses or treatment, and examples include .sup.3H, .sup.14C, .sup.32P, .sup.33P, .sup.35S, .sup.51Cr, .sup.57CO, .sup.18F, .sup.153Gd, .sup.159Gd, .sup.64Cu, .sup.68Ge, .sup.166Ho, .sup.115In, .sup.113In, .sup.112In, .sup.111In, .sup.131I, .sup.125I, .sup.123I, .sup.140La, .sup.177Lu, .sup.54Mn, .sup.99Mo, .sup.103Pd, .sup.142Pr, .sup.149Pm, .sup.186Re, .sup.188Re, .sup.211At, .sup.105Rh, .sup.97Ru, .sup.153Sm, .sup.47Sc, .sup.75Se, .sup.85Sr, .sup.99Tc, .sup.201Ti, .sup.22 Sn, .sup.117Sn, .sup.133Xe, .sup.169Yb, .sup.175Yb, .sup.90Y, .sup.90Y, .sup.65Zn, and compounds containing the nuclides.

[0363] The radiolabeling compound can be directly bound to the antibody by the chloramine T method or the like. In addition, a substance that chelates the radiolabeling compound may be bound to the antibody. Examples of the chelating agent include DOTA, PA-DOTA, TRITA, DTPA and the like, and an antibody modified with the chelating agent and a modified antibody which is labeled with the radiolabeling compound through the chelating agent are also included in the antibody of the invention.

[0364] Examples of the sugar chain include monosaccharides, disaccharides or oligosaccharides such as fucose, mannose, glucose, allose, aldose, gulose, idose, galactose, talose, ribose, arabinose, xylose, lyxose, erythose, erythrose, threose, cellobiose, maltose, isomaltose, lactose, lipoarabinomannan, Lewis X trisaccharide and sialyl-Lewis X tetrasaccharide and the like. Moreover, the sugar chain may be a natural product containing a sugar chain known as immunoadjuvant and may be .beta.(1.fwdarw.3) glucan (lentinan or schizophyllan), .alpha.-galactosylceramide (KRN7000) or the like.

[0365] Examples of the lipid include simple lipids (neutral lipids), which are esters of fatty acids and alcohols and analogues thereof. Examples include fats (for example, triacylglycerol), wax (for example, fatty acid esters of higher alcohols), sterol esters, cholesterol esters, fatty acid esters and the like of vitamins, complex lipids having a polar group such as phosphoric acid, saccharide, sulfuric acid or amine in addition to a fatty acid and an alcohol such as phospholipids (for example, glycerophospholipids, sphingophospholipids and the like) and glycolipids (for example, glyceroglycolipids, sphingoglycolipids and the like), derived lipids which are lipid-soluble compounds of compounds produced by hydrolysis of simple lipids and complex lipids such as fatty acids, higher alcohols, lipid-soluble vitamins, steroids and carbohydrates and the like.

[0366] Examples of the fluorescent compound include fluorescent dyes such as fluorescein series like fluorescein isothiocyanate (FITC), rhodamine series, Cy3, Cy5, eosine series, Alexa Fluor series and NBD series, light-emitting substances such as acridinium esters or lophine, fluorescent proteins such as green fluorescent protein (GFP) and the like.

[0367] The antibody or the antibody fragment of the invention can be bound to the hydrophilic polymer, the amphipathic polymer or the functional molecule directly or through an appropriate linker. Examples of the linker include esters, disulfides, hydrazones, dipeptides and the like.

[0368] When a fused antibody or a fused antibody fragment is produced by modifying the antibody or the antibody fragment of the invention by the genetic engineering technique, a fused antibody or a fused antibody fragment can be produced by linking cDNA encoding a protein to cDNA encoding an antibody to construct DNA that encodes the fused antibody or the fused antibody fragment, inserting the DNA into an expression vector for a prokaryote or a eukaryote, introducing the expression vector into a prokaryote or a eukaryote and expressing the fused antibody or the fused antibody fragment.

[0369] The composition of the invention may be any composition as long as the composition contains the antibody or the antibody fragment of the invention. The composition may contain an appropriate carrier or an additive such as a stabilizing agent in addition to the antibody or the antibody fragment.

[0370] Examples of the composition of the invention includes a composition for detection or measurement containing the antibody or the antibody fragment of the invention and the like. Examples of the composition of the invention include a pharmaceutical composition (a therapeutic agent) containing the antibody or the antibody fragment of the invention as an active ingredient and the like, and pharmaceutical formulation with a desired dosage form is prepared together with a pharmacologically acceptable carrier.

[0371] In the invention, the composition for detection or measurement may be any composition as long as the composition contains the antibody or the antibody fragment of the invention and can detect or measure an antigen to which the antibody or the antibody fragment of the invention specifically binds. The antigen to which the antibody or the antibody fragment of the invention specifically binds is MOG, MOG and an antigen that is present in the brain or the like.

[0372] The antibody or the antibody fragment of the invention has a property of binding to MOG in the brain and accumulating in the brain when administered to an animal. Therefore, when the composition for detection or measurement containing the antibody or the antibody fragment is used, the antibody can be maintained in the brain, or the antibody concentration in the brain can be improved. Thus, MOG or MOG and an antigen that is present in the brain can be detected or measured for a long time, and/or MOG or MOG and an antigen that is present in the brain can also be detected or measured with high sensitivity.

[0373] For example, when the composition for detection or measurement is a composition containing a bispecific antibody which binds to MOG and an antigen that is present in the brain, MOG and the antigen in the brain, to which the bispecific antibody binds, can be detected or measured for a long time, and/or MOG and the antigen that is present in the brain can be detected or measured with high sensitivity.

[0374] Moreover, for example, when the composition for detection or measurement is a composition containing a fused antibody or a fused antibody fragment which is labeled with a radiolabeling compound or a fluorescent dye and which binds to MOG, MOG can be detected or measured for a long time, and/or MOG can be detected or measured with high sensitivity.

[0375] The pharmaceutical composition (therapeutic agent) containing the antibody of the invention may be a therapeutic agent for any disease as long as the antigen to which the antibody or the antibody fragment of the invention specifically binds is expressed in the disease but is preferably a therapeutic agent for a brain disease.

[0376] Examples of the brain disease include Alzheimer's disease, the prodromal stage of Alzheimer's disease, Huntington disease, Parkinson's disease, brain tumors, multiple sclerosis, muscular dystrophy, amyotrophic lateral sclerosis, multiple system atrophy, progressive supranuclear palsy, nigrostriatal degeneration, olivopontocerebellar atrophy, bulbospinal muscular atrophy, spinocerebellar degeneration, cerebrovascular disease, epilepsy, migraine, hyperactivity disorder, Creutzfeldt-Jakob disease, corticobasal degeneration, lysosomal storage disease, depression, dystonia and the like.

[0377] The antibody of the invention has a property of binding to MOG in the brain and accumulating in the brain when administered to an animal. Therefore, when the therapeutic agent containing the antibody or the antibody fragment is used, the antibody or the antibody fragment can be maintained in the brain for a long time, and the antibody concentration in the brain can be improved. Thus, therapeutic effects on the diseases can be exhibited.

[0378] For example, when the therapeutic agent is a therapeutic agent containing a bispecific antibody which binds to MOG and an antigen that is present in the brain, a therapeutic effect on a brain disease related to the antigen in the brain, to which the bispecific antibody binds, can be exhibited.

[0379] Moreover, for example, when the therapeutic agent is a fused antibody or a fused antibody fragment which is modified with a low molecular weight drug and which binds to MOG, a therapeutic effect on a brain disease targeted by the low molecular weight drug can be exhibited. At this point, the therapeutic effect is preferably higher when the therapeutic agent of the invention is used compared to the effect of the low molecular weight drug alone.

[0380] The therapeutic agent containing the antibody or the antibody fragment of the invention may be an agent that contains only the antibody or the antibody fragment as an active ingredient, but the agent is generally desirably mixed with one or more pharmacologically acceptable carriers and provided as medicinal formulation that is produced by any method known in the technical field of pharmaceutical science.

[0381] As the route of administration, it is preferable to use the most effective route for the treatment, and examples include oral administration or parenteral administration such as intraoral, airway, intrarectal, subcutaneous, intradermal, intramuscular, intraventricular, intraspinal cord, intranasal, intraperitoneal or intravenous administration. Intravenous or intraventricular administration or the like is particularly preferable. Examples of the form of administration include a spray, a capsule, a tablet, a powder, a granule, a syrup, an emulsion, a suppository, an injection, an ointment, a tape and the like.

[0382] The dose or the frequency of administration varies according to the desired therapeutic effect, administration method, treatment period, age, body weight and the like but is usually 10 .mu.g/kg to 20 mg/kg per day for adult.

[0383] The invention also includes a method for keeping an antibody in the brain, a method for improving the property of an antibody of accumulating in the brain and a method for increasing the antibody concentration (or the antibody amount) in the brain which use the antibody or the antibody fragment of the invention.

[0384] The invention also relates to a peptide which binds to MOG, a nucleic acid containing a nucleotide sequence which encodes the peptide, a transformant cell which contains a vector containing the nucleic acid, a method for producing the peptide including culturing the transformant cell and collecting the peptide from the culture solution, a composition containing the peptide or a method for detecting or measuring an antigen that is present in the brain, a method for diagnosing or treating a brain disease, a method for improving the property of a peptide of accumulating in the brain or a method for increasing the peptide amount in the brain that uses the peptide or the composition.

[0385] The peptide of the invention includes a fused peptide obtained by modifying a peptide.

[0386] The definitions of the terms related to the peptide which binds to MOG and the like are the same as the definitions of the terms described for the antibody which binds to MOG and the like above unless particularly described.

[0387] The method for producing the antibody or the antibody fragment of the invention, the method for treating a disease, the method for diagnosing a disease and the like are specifically explained below.

1. Production Method of Antibody

(l) Preparation of Antigen

[0388] MOG as an antigen or a MOG-expressing cell can be obtained by introducing an expression vector containing cDNA that encodes the full length of MOG or a partial length thereof to E. coli, yeast, insect cells, animal cells or the like. In addition, MOG can also be obtained by purifying MOG from an animal cell line, an animal cell or an animal tissue of various kinds and the like in which MOG is expressed in a large amount.

[0389] In addition, the animal cell line, the animal cell, the animal tissue and the like can also be used as they are as an antigen. Furthermore, a synthetic peptide having a partial sequence of MOG can be prepared using a chemical synthesis method such as the Fmoc method or the tBoc method and used as an antigen.

[0390] A known tag such as FLAG or His may be added to the C-terminus or the N-terminus of MOG or the synthetic peptide having a partial sequence of MOG.

[0391] MOG used in the invention can be produced using the method described in Molecular Cloning, A Laboratory Manual, Second Edition, Cold Spring Harbor Laboratory Press (1989), Current Protocols In Molecular Biology, John Wiley & Sons (1987-1997) or the like or another method by expressing DNA that encodes MOG in a host cell for example by the following method.

[0392] First, a recombinant vector is produced by inserting the full-length cDNA containing the part that encodes MOG into downstream of a promoter in an appropriate expression vector. A DNA fragment of an appropriate length which contains the part that encodes the polypeptide and which is prepared based on the full-length cDNA may be used in place of the full-length cDNA. Next, a transformant that produces the polypeptide can be obtained by introducing the obtained recombinant vector into a host cell suitable for the expression vector.

[0393] As the expression vector, any vector can be used as long as it can replicate autonomously or can be inserted into a chromosome in a host cell to be used and which contains a suitable promoter in the position that enables the transcription of DNA that encodes the polypeptide. As the host cell, any cell, such as a microorganism belonging to the genus Escherichia such as E. coli, yeast, an insect cell or an animal cell, can be used as long as it enables the expression of a target gene.

[0394] In a case where a prokaryote such as E. coli is used as a host cell, the expression vector is preferably a vector that can replicate autonomously in the prokaryote and that contains a promoter, a ribosomal binding sequence, DNA containing the part encoding human MOG and a transcription termination sequence. In addition, the transcription termination sequence is not essentially needed for the expression vector, but the transcription termination sequence is preferably placed immediately after the structural gene. Furthermore, the recombinant vector may contain a gene controlling the promoter.

[0395] As the expression vector, it is preferable to use a plasmid in which the distance between the Shine-Dalgarno sequence (also called SD sequence) that is a ribosomal binding sequence and the initiation codon is appropriately adjusted (to, for example, 6 to 18 nucleotides).

[0396] In addition, regarding the nucleotide sequence of DNA that encodes MOG, a nucleotide can be substituted in a manner that the codon becomes optimum for the expression in a host, which enables the enhancement in the production rate of target MOG.

[0397] As the expression vector, any vector can be used as long as it can exhibit its function in a host cell to be used. Examples thereof include pBTrp2, pBTac1 and pBTac2 (manufactured by Roche Diagnostics K.K.), pKK233-2 (manufactured by Pharmacia), pSE280 (manufactured by Invitrogen), pGEMEX-1 (manufactured by Promega Corporation), pQE-8 (manufactured by QIAGEN), pKYP10 (JP-A-S58-110600), pKYP200 [Agricultural Biological Chemistry, 48, 669 (1984)], pLSA1 [Agric. Biol. Chem., 53, 277 (1989)], pGEL1 [Proc. Natl. Acad. Sci. USA, 82, 4306 (1985)], pBluescript II SK(-) (manufactured by Stratagene Corporation), pTrs30 [prepared from Escherichia coli JM109/pTrS30 (FERM BP-5407)], pTrs32 [prepared from Escherichia coli JM109/pTrS32 (FERM BP-5408)], pGHA2 [prepared from Escherichia coli IGHA2 (FERM BP-400), JP-A-560-221091], pGKA2 [prepared from Escherichia coli IGKA2 (FERM BP-6798), JP-A-560-221091], pTerm2 (U.S. Pat. Nos. 4,686,191, 4,939,094 and United States Patent No. 160,735), pSupex, pUB110, pTPS, pC194, pEG400 [J. Bacteriol., 172, 2392 (1990)], pGEX (manufactured by Pharmacia), pET System (manufactured by Novagen), pME18SFL3 and the like.

[0398] As the promoter, any promoter may be used as long as it can exhibit its function in a host cell to be used. Examples thereof include promoters such as a trp promoter (Ptrp), a lac promoter, a PL promoter, a PR promoter or a T7 promoter, which are derived from E. coli, a phage or the like. In addition, examples thereof also include promoters such as a tandem promoter with two tandemly arrayed Ptrps, a tac promoter, a lacT7 promoter or a let I promoter, which are artificially designed and altered.

[0399] Examples of the host cell include E. coli XL1-Blue, E. coli XL2-Blue, E. coli DH1, E. coli MC1000, E. coli KY3276, E. coli W1485, E. coli JM109, E. coli HB101, E. coli No. 49, E. coli W3110, E. coli NY49, E. coli DH5.alpha. and the like.

[0400] As a method for introducing a recombinant vector into a host cell, any method can be used as long as it is a method by which DNA is introduced into a host cell to be used. Examples thereof include a method using calcium ions [Proc. Natl. Acad. Sci. USA, 69, 2110 (1972), Gene, 17, 107 (1982) and Molecular & General Genetics, 168, 111 (1979)].

[0401] In a case of using an animal cell as a host, as the expression vector, any vector can be used as long as it can exhibit its function in the animal cell. Examples thereof include pcDNAI, pCDM8 (manufactured by Funakoshi Co., Ltd.), pAGE107 [JP-A-H3-22979; and Cytotechnology, 3, 133 (1990)], pAS3-3 (JP-A-H2-227075), pCDM8 [Nature, 329, 840 (1987)], pcDNAI/Amp (manufactured by Invitrogen), pcDNA3.1 (manufactured by Invitrogen), pREP4 (manufactured by Invitrogen), pAGE103 [J. Biochemistry, 101, 1307 (1987)], pAGE210, pME18SFL3, pKANTEX93 (International Publication No. 97/10354), N5KG1val (U.S. Pat. No. 6,001,358), INPEP4 (manufactured by Biogen-IDEC), pCI (manufactured by Promega Corporation), a transposon vector (International Publication No. 2010/143698) and the like.

[0402] As the promoter, any promoter can be used as long as it can exhibit its function in the animal cell. Examples thereof include a promoter of cytomegalovirus (CMV) immediate early (IE) gene, an early promoter of SV40, a retroviral promoter, a metallothionein promoter, a heat-shock promoter, a SR.alpha. promoter, a promoter of Moloney murine leukemia virus or an enhancer. In addition, an enhancer of human CMV IE gene may be used together with the promoter.

[0403] Examples of the host cell include a human leukemia cell Namalwa, a monkey cell COS, a Chinese hamster ovary cell CHO [Journal of Experimental Medicine, 108, 945 (1958); Proc. Natl. Acad. Sci. USA, 60, 1275 (1968); Genetics, 55, 513 (1968); Chromosoma, 41, 129 (1973); Methods in Cell Science, 18, 115 (1996); Radiation Research, 148, 260 (1997); Proc. Natl. Acad. Sci. USA, 77, 4216 (1980); Proc. Natl. Acad. Sci., 60, 1275 (1968); Cell, 6, 121 (1975); and Molecular Cell Genetics, Appendix I, II (pp. 883-900)]; a CHO cell which lacks dihydrofolate reductase gene (referred to as dhfr below) (CHO/DG44 cell) [Proc. Natl. Acad. Sci. USA, 77,4216(1980)], CHO-K1 (ATCC CCL-61), DUkXB11 (ATCC CCL-9096), Pro-5 (ATCC CCL-1781), CHO-S(Life Technologies, Cat #11619), Pro-3, a rat myeloma cell YB2/3HL.P2.G11.16Ag.20 (also called YB2/0), a mouse myeloma cell NSO, a mouse myeloma cell SP2/0-Ag14, a Syrian hamster cell BHK, HBT5637 (JP-A-S63-000299) and the like.

[0404] As a method for introducing an expression vector into a host cell, any method can be used as long as it is a method by which DNA is introduced into an animal cell. Examples thereof include the electroporation [Cytotechnology, 3, 133 (1990)], the calcium phosphate transfection method (JP-A-H2-227075), the lipofection [Proc. Natl. Acad. Sci. USA, 84, 7413 (1987)] and the like.

[0405] MOG can be produced by culturing a transformant derived from a microorganism, an animal cell or the like having the expression vector into which DNA that encodes MOG has been introduced and which is obtained as above in a medium, generating and accumulating MOG in the culture solution and then collecting MOG from the culture solution. A method of culturing the transformant in a medium can be performed according to a usual method used for a host culture.

[0406] In a case of expression in the cells derived from a eukaryote, MOG added with sugars or sugar chains can be obtained.

[0407] When culturing a microorganism that has been transformed by an expression vector using an inducible promoter, an inducer may be added to the medium if necessary. For example, isopropyl-.beta.-D-thiogalactopyranoside or the like may be added to the medium for a case of culturing a microorganism that has been transformed by an expression vector using a lac promoter, and indoleacrylic acid or the like may be added to the medium for a case of culturing a microorganism that has been transformed by an expression vector using a trp promoter.

[0408] Examples of the medium in which the transfectant obtained using an animal cell as a host is cultured include RPMI 1640 Medium [The Journal of the American Medical Association, 199, 519 (1967)], Eagle's MEM Medium [Science, 122, 501 (1952)], Dulbecco's Modified MEM Medium [Virology, 8, 396 (1959)], Medium 199 [Proc. Soc. Exp. Biol. Med., 73, 1 (1950)], Iscove's Modified Dulbecco's Medium (IMDM), which are generally used, or a medium in which fetal bovine serum (FBS) or the like is added to such a medium. Culture is usually performed under the conditions of pH 6 to 8 and 30 to 40.degree. C. in the presence of 5% CO.sub.2 for 1 to 7 days. In addition, during the culture, antibiotics such as kanamycin or penicillin may be added to the medium, if necessary.

[0409] Examples of the method for expressing a gene that encodes MOG include a method such as secretory production or fused protein expression [Molecular Cloning, A Laboratory Manual, Second Edition, Cold Spring Harbor Laboratory Press (1989)] in addition to direct expression.

[0410] Examples of the method for producing MOG include a method of producing in a host cell, a method of secretion out of a host cell and a method of producing on the outer membrane of a host cell. An appropriate method can be selected by changing the host cell to be used or the structure of MOG to be produced.

[0411] In a case where MOG is produced in a host cell or on the outer membrane of a host cell, MOG can be actively secreted outside the host cell using the method by Paulson et al. [J. Biol. Chem., 264, 17619 (1989)], the method by Lowe et al. [Proc. Natl. Acad. Sci., USA, 86, 8227 (1989) and Genes Develop., 4, 1288 (1990)] or the method described in JP-A-HOS-336963, International Publication No. 94/23021 or the like. In addition, the amount of production of MOG can also be increased using the gene amplification using dihydrofolate reductase gene or the like (JP-A-H2-227075).

[0412] Obtained MOG can be isolated and purified as follows for example. In a case where MOG is expressed in the cells in a dissolved state, the cells are collected by centrifugation after completing culture and suspended in an aquatic buffer solution, followed by crushing of the cells using an ultrasonic crusher, a French press, a Manton Gaulin homogenizer, a Dyno mill or the like, and therefore cell-free extract is obtained. A purified sample can be obtained from a supernatant obtained by centrifugation of the cell-free extract using a method such as a general method for isolation and purification of proteins, that is, a solvent extraction method, a salting-out method using ammonium sulfate or the like, a desalting method, a precipitation method using an organic solvent, anion-exchange chromatography using a resin such as Diethylaminoethyl (DEAE)-Sepharose or DIAION HPA-75 (manufactured by Mitsubishi Chemical Corporation), cation-exchange chromatography using a resin such as S-Sepharose FF (manufactured by Pharmacia), hydrophobic interaction chromatography method using a resin such as Butyl Sepharose or Phenyl Sepharose, a gel filtration method using molecular decoration, affinity chromatography, a chromatofocusing method, electrophoresis such as isoelectric focusing electrophoresis and the like alone or in combination.

[0413] In a case where MOG forms an insoluble complex and expressed in the cells, the cells are collected and then crushed in the same manner as above, followed by centrifugation, and then an insoluble complex of MOG is collected as a precipitated fraction. The collected insoluble complex of MOG is solubilized with a protein denaturant. A purified sample of the polypeptide can be obtained by the same method for isolation and purification as above, after returning MOG back to the normal three-dimensional structure through dilution or dialysis of the solubilized solution.

[0414] In a case where MOG or a derivative thereof such as a sugar-modified complex is extracellularly secreted, MOG or the derivative thereof such as a sugar-modified complex can be collected in a culture supernatant. By subjecting the culture to procedures using a method such as centrifugation as in the same manner as above, thereby obtaining a soluble fraction, and then using the same method for isolation and purification as above, a purified sample can be obtained from the soluble fraction.

[0415] In addition, MOG used in the invention can be produced also by a chemical synthesis method such as the Fmoc method or the tBoc method. MOG can be also chemically synthesized using a peptide synthesizer manufactured by Advanced Chemtech,

[0416] PerkinElmer, Inc., Pharmacia, Protein Technology Instrument, Inc., Shinseserubega Co., Perceptive, Shimadzu Corporation or the like.

(2) Immunization of Animal and Preparation of Antibody-Producing Cell for Fusion

[0417] By immunizing a 3- to 20-week old animal such as a mouse, a rat, a rabbit or a hamster with the antigen obtained in (1), antibody-producing cells are collected from the spleen, lymph nodes or peripheral blood of the animal. In addition, an animal such as a llama, an alpaca or a camel can also be used as the animal to be immunized.

[0418] Immunization is performed by administering the antigen for example together with an appropriate adjuvant such as Freund's complete adjuvant, aluminum hydroxide gel or Bordetella pertussis vaccine subcutaneously, intravenously or intraperitoneally to the animal. In a case where the antigen is a partial peptide, a conjugate of the antigen with a carrier protein such as BSA (bovine serum albumin) or KLH (Keyhole Limpet hemocyanin) is produced and used as an immunogen.

[0419] When a mouse or a rat is immunized, the administration of the antigen is performed 5 to 10 times every 1 to 2 weeks after the first administration. On the 3rd to 7th day after each administration, the blood is collected from a venous plexus of the fundus of the eye, and the antibody valency of the serum is measured using an enzyme immunoassay method [Antibodies--A Laboratory Manual, Cold Spring Harbor Laboratory (1988)] or the like. An animal in which the serum exhibited sufficient antibody valency with respect to the antigen used for the immunization is used as a supply source for the antibody-producing cells for fusion.

[0420] On the 3.sup.rd to 7.sup.th day after a final administration of the antigen, tissues including the antibody-producing cells such as the spleen are extracted from the immunized animal, and the antibody-producing cells are collected. In a case of using the spleen cells, the spleen is shredded and loosened, followed by centrifugation, and then erythrocytes are removed. The antibody-producing cells for fusion are thus obtained.

[0421] Other animals to be immunized can also be immunized by the same method, and antibody-producing cells can be obtained. Appropriate conditions for the interval of immunizations and the period between the final immunization and the collection of the tissues can be determined depending on the kind of the animal to be immunized.

(3) Preparation of Myeloma Cells

[0422] As the myeloma cells, established cells obtained from a mouse are used, and for example, a 8-azaguanine resistant mouse (BALB/c derived) myeloma cell line, P3-X63Ag8-U1 (P3-U1) [Current Topics in Microbiology and Immunology, 18, 1 (1978)], P3-NS1/1-Ag41 (NS-1) [European J. Immunology, 6, 511 (1976)], SP2/0-Ag14(SP-2) [Nature, 276, 269 (1978)], P3-X63-Ag8653 (653) [J. Immunology, 123, 1548 (1979)], P3-X63-Ag8(X63) [Nature, 256, 495(1975)] or the like is used.

[0423] The myeloma cells are subjected to subculturing with a normal medium [RPMI1640 medium supplemented with glutamine, 2-mercaptoethanol, gentamicin, FBS and 8-azaguanine] and subjected to subculturing with a normal medium 3 to 4 days before the cell fusion, and 2.times.10.sup.7 or more cells are acquired on the day of the fusion.

(4) Cell Fusion and Preparation of Monoclonal Antibody-Producing Hybridoma

[0424] The antibody-producing cells for fusion obtained in (2) and the myeloma cells obtained in (3) are thoroughly washed with the Minimum Essential Medium (MEM) or PBS (disodium phosphate 1.83 g, monopotassium phosphate 0.21 g, salt 7.65 g, distilled water 1 liter, pH 7.2), mixed at cell numbers of antibody-producing cells for fusion: myeloma cells of 5:1 to 10:1 and centrifuged, and then the supernatant is removed.

[0425] After the precipitated cell clusters are loosened thoroughly, a mixture of polyethylene glycol-1000 (PEG-1000), MEM and dimethylsulfoxide is added thereto while stirring at 37.degree. C. Furthermore, 1 to 2 mL of MEM is added thereto every 1 to 2 minutes for several times, and then MEM is added so that the total amount becomes 50 mL.

[0426] After centrifugation, the supernatant is removed. The precipitated cell clusters are loosened gently, and then the cells are suspended gently in the HAT medium [normal medium supplemented with hypoxanthine, thymidine and aminopterin]. This suspension is cultured in a 5% CO.sub.2 incubator at 37.degree. C. for 7 to 14 days.

[0427] After culturing, a part of the culture supernatant is taken, and cell clusters which react with MOG and which do not react with antigens other than MOG are selected by a method for selecting a hybridoma such as the binding assay described below. Next, after cloning by the limiting dilution method, a hybridoma which stably shows potent antibody valency is selected as a monoclonal antibody-producing hybridoma.

(5) Preparation of Purified Monoclonal Antibody

[0428] The monoclonal antibody-producing hybridoma obtained in (4) is intraperitoneally injected into an 8- to 10-week old mouse or nude mouse which has been treated by pristane treatment [by intraperitoneally administering 2,6,10,14-tetramethylpentadecane (Pristane) 0.5 mL and breeding for 2 weeks]. In 10 to 21 days, the hybridoma becomes an ascites tumor.

[0429] The ascites are collected from this mouse, and the solid is removed by centrifugation. Then, by salting out with 40 to 50% ammonium sulfate and purifying by caprylic acid precipitation method, a DEAE-Sepharose column, a protein A-column or a gel filtration column, an IgG or IgM fraction is collected to obtain a purified monoclonal antibody.

[0430] Moreover, the monoclonal antibody-producing hybridoma obtained in (4) is cultured in RPMI1640 medium supplemented with 10% FBS or the like, and then the supernatant is removed by centrifugation. The hybridoma is suspended in Hybridoma SFM medium and cultured for 3 to 7 days.

[0431] A purified monoclonal antibody can also be obtained by centrifuging the obtained cell suspension, purifying from the obtained supernatant by a protein A-column or a protein G-column and collecting an IgG fraction. In this regard, 5% Daigo's GF21 can be added to Hybridoma SFM medium.

[0432] The subclass of the antibody is determined by the enzyme immunoassay method using a subclass typing kit. The protein mass is determined by the Lowry method or by calculating from the absorbance at 280 nm.

(6) Selection of Antibody

[0433] The antibody is selected for example by measuring the affinity of the antibody to MOG-expressing cells using flow cytometry as shown below. The MOG-expressing cells may be any cells as long as MOG is expressed on the cell surface, and examples include animal cells, an animal cell line, the MOG forcibly-expressing cell line obtained in (1) and the like.

[0434] After dispensing the MOG-expressing cells to a plate such as a 96-well plate, the substances to be tested such as serum, culture supernatants of hybridomas or purified antibodies are dispensed as the first antibodies and reacted. The cells after the reaction are thoroughly washed with PBS containing 1 to 10% bovine serum albumin (BSA) (referred to as BSA-PBS below) or the like, and an anti-immunoglobulin antibody labeled with a fluorescent reagent or the like is then dispensed as the second antibody and reacted. After thoroughly washing with BSA-PBS or the like, the fluorescence amounts of the labeled antibody are measured using a flow cytometer, and an antibody which specifically reacts with the MOG-expressing cells is thus selected.

[0435] Moreover, the antibody can also be selected by measuring the affinity of the monoclonal antibody to MOG-expressing cells, a MOG protein or the like using ELISA or surface plasmon resonance described below. The MOG protein may be a protein composed of some domains of MOG or a protein to which a tag such as GST is added.

[0436] In ELISA, after dispensing the MOG-expressing cells or the MOG protein to a plate such as a 96-well plate, the wells are blocked with BSA-PBS, and the substances to be tested such as serum, culture supernatants of hybridomas or purified antibodies are dispensed as the first antibodies and reacted. Next, after thoroughly washing with PBS or the like, an anti-immunoglobulin antibody labeled with a fluorescent reagent or the like is dispensed as the second antibody and reacted.

[0437] Then, after thoroughly washing with PBS or the like, a chromogenic reagent is added. At the end, the chromogenic reaction is stopped with a solution for stopping the reaction, and the absorbances of the wells are measured with a microplate reader. An antibody which specifically reacts with the MOG-expressing cells or the MOG protein is thus selected.

[0438] In surface plasmon resonance, using a known protocol, the affinity of an antibody which binds to MOG can be measured by immobilizing the antibody on an appropriate sensor chip and using a MOG protein as the analyte.

[0439] Using the affinity of the antibody obtained, an antibody having desired affinity to a MOG protein can be selected. The affinity of an antibody which binds to MOG can also be measured by immobilizing a MOG protein on a sensor chip and using the antibody as the analyte.

[0440] In addition, an antibody which competes in binding to MOG with the antibody of the invention can be obtained by adding an antibody to be tested to the assay system using flow cytometry or ELISA described above and reacting. That is, by selecting an antibody which inhibits binding of the antibody of the invention and MOG when the antibody to be tested is added by screening, an antibody that competes with the antibody of the invention in binding to the amino acid sequence of MOG or the three-dimensional structure thereof can be obtained.

[0441] An antibody which binds to an epitope containing the epitope to which the antibody of the invention binds can be obtained by identifying the epitope of an antibody obtained by the screening method described above by a known method, producing a synthetic peptide containing the identified epitope, a synthetic peptide which mimics the three-dimensional structure of the epitope or the like and immunizing.

[0442] An antibody which binds to the same epitope as the epitope to which the antibody of the invention binds can be obtained by identifying the epitope of an antibody obtained by the screening method described above, producing a partial synthetic peptide of the identified epitope, a synthetic peptide which mimics the three-dimensional structure of the epitope or the like and immunizing.

(7) Acquisition of Antibody by Phage Display Method

(7-1) Production Method of Antibody Phage Library

[0443] In the invention, as the antibody phage library, an immune library, a naive library and a synthetic library can be used. The methods for producing the libraries are described below.

[0444] Lymphocytes derived from an animal immunized by the same method as that of (1) or a patient are collected for an immune library, and lymphocytes derived from a normal animal or a healthy human are collected for a naive library. RNA is extracted from the lymphocytes, and cDNA is synthesized by reverse transcription reaction.

[0445] A fragment of an antibody gene amplified by PCR using the cDNA as a template is inserted to a phagemid vector, and E. coli is transformed by the phagemid vector. When the obtained transformant is infected with a helper phage, an antibody phage library of the antibody gene can be obtained.

[0446] With respect to a synthetic library, CDR of a V gene in the genome DNA or a reconstructed functional V gene is substituted with an oligonucleotide that encodes any amino acid sequence of an appropriate length, and E. coli is transformed by a phagemid vector into which the V gene has been inserted. When the obtained transformant is infected with a helper phage, an antibody phage library can be obtained.

[0447] As the cDNA derived from lymphocytes and the antibody phage library, those which are commercially available can also be used.

[0448] As the phagemid vector, pCANTAB 5E (Amersham Pharmacia Biotech Inc.), pUC118/pUC119 vector (TaKaRa), pBlueScript II Phagemid Vector (Agilent Technologies), pKSTV-02 (Miyazaki et al, J. Biochem. 2015; 1) and the like can be used.

[0449] As the helper phage, M13K07 helper phage (Invitrogen), VCSM13 Interference Resistant Helper Phage (Agilent Technologies), R408 Interference Resistant Helper Phage (Agilent Technologies) and the like can be used.

[0450] A phage vector can also be used for phage display. There are a peptide phage library in which filamentous bacteriophage g3p is a displayed molecule (manufactured by New England Biolabs and the like), a method in which g7p, g8p or g9p is a displayed molecule and the like.

[0451] Moreover, phage display using T7 phage can also be used. A display system for T7 phage is T7 Select vector (Novagen) or the like.

(7-2) Selection of Antibody Phage Clone

[0452] An antibody phage clone can be selected from the antibody phage libraries produced in (7-1) using the ELISA method shown below.

[0453] MOG is immobilized in an immuno tube, and the tube is blocked with a blocking buffer. The antibody phage libraries produced in (7-1) are added to the wells of the tube and reacted. Next, the wells are washed, and a fluorescently labeled anti-phage antibody is added and reacted. Then, the wells are washed again, and a chromogenic solution is added. Then, the chromogenic reaction is stopped with a solution for stopping the reaction, and the absorbances of the wells are measured with a microplate reader. In this manner, an antibody phage clone which binds to MOG is selected.

2. Production of Genetically Recombinant Antibody

[0454] As examples for producing a genetically recombinant antibody, methods for producing a human chimeric antibody and a humanized antibody are described below. Genetically recombinant mouse antibody, rat antibody, rabbit antibody, hamster antibody, camel antibody, llama antibody, alpaca antibody and human antibody, chimeric antibodies, a heavy chain antibody and the like can also be produced by the same method.

(1) Construction of Expression Vector for Genetically Recombinant Antibody

[0455] An expression vector for a genetically recombinant antibody is an expression vector for animal cells in which DNA that encodes CH and CL of a human antibody has been incorporated and can be constructed by cloning DNAs that encode CH and CL of a human antibody into an expression vector for animal cells.

[0456] As the C region of a human antibody, CH and CL of any human antibody can be used. For example, CH of yl subclass and CL of x class of a human antibody and the like are used. As the DNAs that encode CH and CL of the human antibody, cDNA is used, but chromosomal DNA consisting of exons and introns can also be used.

[0457] As the expression vector for animal cells, any vector can be used as long as it is capable of incorporating and expressing a gene that encodes the C region of a human antibody. For example, pAGE107 [Cytotechnol., 3, 133 (1990)], pAGE103 [J. Biochem., 101, 1307 (1987)], pHSG274 [Gene, 27, 223 (1984)], pKCR [Proc. Natl. Acad. Sci. USA, 78, 1527 (1981)], pSG1bd2-4 [Cytotechnol., 4, 173 (1990)], pSE1UK1Sed1-3 [Cytotechnol., 13, 79 (1993)] and the like are used.

[0458] The promoter and the enhancer of the expression vector for animal cells are the early promoter of SV40 [J. Biochem., 101, 1307 (1987)], the Moloney murine leukemia virus LTR [Biochem. Biophys. Res. Commun., 149, 960 (1987)] or the promoter of immunoglobulin H chain [Cell, 41, 479 (1985)] and the enhancer [Cell, 33, 717 (1983)] or the like.

[0459] As the expression vector for the genetically recombinant antibody, an expression vector for a genetically recombinant antibody of a type in which the antibody H chains and L chains are on the same vector (tandem type) [J. Immunol. Methods, 167, 271 (1994)] is used from the viewpoints of ease of construction of the expression vector for the genetically recombinant antibody, ease of introduction into animal cells, balanced expression levels of the antibody H chains and L chains in animal cells and the like, but a type in which the antibody H chains and L chains are on different vectors can also be used. As the tandem type expression vector for a genetically recombinant antibody, pKANTEX93 (International Publication No. 97/10354), pEE18 [Hybridoma, 17, 559 (1998)] and the like are used.

(2) Acquisition of cDNA Encoding V Region of Antibody Derived from Animal Other Than Human and Analysis of Amino Acid Sequence

[0460] cDNA that encodes VH and VL of a non-human antibody can be obtained, and the amino acid sequence can be analyzed as follows.

(2-1) When Antibody is Obtained by Hybridoma Method

[0461] mRNA is extracted from hybridoma cells producing a non-human antibody, and cDNA is synthesized. The synthesized cDNA is cloned into a vector such as a phage or a plasmid to produce a cDNA library.

[0462] Recombinant phages or recombinant plasmids having cDNAs that encode VH or VL are isolated from the libraries using DNAs that encode the C region and the V region of the non-human antibody as probes. The entire nucleotide sequences of VH or VL of the target non-human antibody on the recombinant phages or the recombinant plasmids are determined, and then the entire amino acid sequences of VH or VL are deduced from the nucleotide sequences.

[0463] As the animal other than human which produces the hybridoma cells producing the non-human antibody, a mouse, a rat, a hamster, a rabbit, a llama, a camel, an alpaca or the like is used, but any animal can be used as long as hybridoma cells can be produced.

[0464] For the preparation of total RNA from hybridoma cells, the guanidine thiocyanate-cesium trifluoroacetate method [Methods in Enzymol., 154, 3 (1987)], a kit such as RNA easy Kit (manufactured by QIAGEN) or the like is used.

[0465] To prepare mRNA from total RNA, oligo (dT) immobilized cellulose column chromatography [Molecular Cloning, A Laboratory Manual, Second Edition, Cold Spring Harbor Laboratory Press (1989)], a kit such as Oligo-dT30<Super> mRNA Purification (registered trademark) Kit (manufactured by Takara Bio Inc.) or the like is used. Furthermore, mRNA can also be prepared from hybridoma cells using a kit such as Fast Track mRNA Isolation (registered trademark) Kit (manufactured by Invitrogen) or QuickPrep mRNA Purification (registered trademark) Kit (manufactured by Pharmacia).

[0466] For the synthesis of cDNA and the production of a cDNA library, a known method [Molecular Cloning, A Laboratory Manual, Second Edition, Cold Spring Harbor Laboratory Press (1989) and Current Protocols in Molecular Biology, Supplement 1, John Wiley & Sons (1987-1997)], a kit such as SuperScript Plasmid System for cDNA Synthesis and Plasmid Cloning (manufactured by Invitrogen) or ZAP-cDNA Synthesis (registered trademark) Kit (manufactured by Stratagene) or the like is used.

[0467] When a cDNA library is produced, any vector capable of incorporating the cDNA can be used as a vector into which the cDNA synthesized using mRNA extracted from the hybridoma cells as a template is incorporated. For example, ZAP Express [Strategies, 5, 58 (1992)], pBluescript II SK (+) [Nucleic Acids Research, 17, 9494 (1989)], .lamda.ZAPII (manufactured by Stratagene), .lamda.gt 10 and .lamda.gt 11 [DNA Cloning: A Practical Approach, I, 49 (1985)], Lambda Blue Mid (manufactured by Clontech Laboratories, Inc.), .lamda.ExCell, pT7T3-18U (manufactured by Pharmacia), pCD2 [Mol. Cell. Biol., 3, 280 (1983)], pUC18 [Gene, 33, 103 (1985)] or the like is used.

[0468] Any Escherichia coli can be used as Escherichia coli into which a cDNA library constructed by a phage or a plasmid vector is introduced as long as the cDNA library can be introduced, expressed and maintained. For example, XL1-Blue MRF' [Strategies, 5, 81 (1992)], C600 [Genetics, 39, 440 (1954)], Y1088, Y1090 [Science, 222, 778 (1983)], NM522 [J. Mol. Biol., 166, 1 (1983)], K802 [J. Mol. Biol., 16, 118 (1966)], JM105 [Gene, 38, 275 (1985)] or the like is used.

[0469] For the selection of the cDNA clone that encodes VH or VL of the non-human antibody from the cDNA libraries, a colony hybridization method using an isotope- or fluorescently labeled probe, the plaque hybridization method [Molecular Cloning, A Laboratory Manual, Second Edition, Cold Spring Harbor Laboratory Press (1989)] or the like is used.

[0470] In addition, the cDNA that encodes VH or VL can also be prepared by preparing primers and performing the polymerase chain reaction method [referred to as PCR method below, Molecular Cloning, A Laboratory Manual, Second Edition, Cold Spring Harbor Laboratory Press (1989) and Current Protocols in Molecular Biology, Supplement 1, John Wiley & Sons (1987-1997)] using the cDNA synthesized from mRNA or a cDNA library as a template.

[0471] The selected cDNA is cleaved with an appropriate restriction enzyme or the like and then cloned into a plasmid such as pBluescript SK (-) (manufactured by Stratagene), and the nucleotide sequence of the cDNA is determined by a commonly used nucleotide sequence analysis method or the like. For the nucleotide sequence analysis method, for example, after performing a reaction such as the dideoxy method [Proc. Natl. Acad. Sci. USA, 74, 5463 (1977)], an automatic nucleotide sequence analyzer such as ABI PRISM3700 (manufactured by PE Biosystems) or A.L.F. DNA sequencer (manufactured by Pharmacia) or the like is used.

(2-2) When Antibody is Obtained by Phage Display Method

[0472] The entire nucleotide sequences of VH or VL are determined from the plasmid vectors of the selected phage clones using DNAs that encode the vector region or the V region as probes, and then the entire amino acid sequences of VH or VL can be deduced from the nucleotide sequences.

[0473] In both of the hybridoma method and the phage display method, by deducing the entire amino acid sequences of VH and VL from the determined nucleotide sequences and comparing with the entire amino acid sequences of VH and VL of a known antibody [Sequences of Proteins of Immunological Interest, US Dept. Health and Human Services (1991)], it is confirmed whether the obtained cDNA encodes the complete amino acid sequences of VH and VL of an antibody containing a secretion signal sequence.

[0474] Regarding the complete amino acid sequences of VH and VL of the antibody containing a secretion signal sequence, by comparing with the entire amino acid sequences of VH and VL of a known antibody [Sequences of Proteins of Immunological Interest, US Dept. Health and Human Services (1991)], the length of the secretion signal sequence and the N-terminus amino acid sequence can be deduced, and the subgroup to which they belong can be found.

[0475] In addition, the amino acid sequences of the CDRs of VH and VL can also be determined by comparing with the amino acid sequences of VH and VL of a known antibody [Sequences of Proteins of Immunological Interest, US Dept. Health and Human Services (1991)].

[0476] Furthermore, using the obtained complete amino acid sequences of VH and VL, it is possible to confirm whether the complete amino acid sequences of VH and VL are new by carrying out homology search by the BLAST method [J. Mol. Biol., 215, 403 (1990)] or the like using any database such as SWISS-PROT or PIR-Protein.

(3) Construction of Human Chimeric Antibody Expression Vector

[0477] By cloning cDNAs that encode VH and VL of a non-human antibody in the upstream of the respective genes that encode CH and CL of a human antibody in the expression vector for a genetically recombinant antibody obtained in (1), a human chimeric antibody expression vector can be constructed.

[0478] In order to link the 3' terminus sides of the cDNAs that encode VH or VL of the non-human antibody with the respective 5' terminus sides of CH or CL of the human antibody, cDNAs of VH and VL in which the nucleotide sequences of the linking parts are designed to encode an appropriate amino acid and to become an appropriate restriction enzyme recognition sequence are produced.

[0479] The produced cDNAs of VH and VL are cloned in the upstream of the respective genes that encode CH or CL of the human antibody in the expression vector for a genetically recombinant antibody obtained in (1) in a manner that they are expressed in an appropriate form, and therefore a human chimeric antibody expression vector is constructed.

[0480] In addition, each of the cDNAs that encode VH or VL of the non-human antibody can be amplified by the PCR method using synthetic DNA having an appropriate restriction enzyme recognition sequence at both ends and cloned into the expression vector for a genetically recombinant antibody obtained in (1).

(4) Construction of cDNA Encoding V Region of Humanized Antibody

[0481] A cDNA that encodes VH or VL of a humanized antibody can be constructed as follows.

[0482] Amino acid sequences of the FRs of VH and VL of a human antibody for the insertion of the amino acid sequences of the CDRs of VH and VL of a non-human antibody are selected. Any amino acid sequences derived from a human antibody can be used as the selected amino acid sequences of the FRs.

[0483] For example, an amino acid sequence of FR of a human antibody registered in a database such as Protein Data Bank, a common amino acid sequence of the subgroups of FR of a human antibody [Sequences of Proteins of Immunological Interest, US Dept. Health and Human Services (1991)] or the like is used. In order to suppress a decrease in binding activity of the antibody, an amino acid sequence of FR having as high homology (at least 60% or more) as possible to the amino acid sequence of the FR of VH or VL of the original antibody is selected.

[0484] Next, the amino acid sequences of the CDRs of the original antibody are inserted to the respective selected amino acid sequences of the FRs of VH and VL of the human antibody, and the amino acid sequences of VH and VL of a humanized antibody are designed. By converting the designed amino acid sequences into DNA sequences in consideration of the use frequency of codons found in the nucleotide sequences of the antibody genes [Sequences of Proteins of Immunological Interest, US Dept. Health and Human Services (1991)], DNA sequences encoding the amino acid sequences of VH and VL of a humanized antibody are designed.

[0485] Based on the designed DNA sequences, several synthetic DNAs having lengths of around 100 bases are synthesized, and the PCR reaction is carried out using the DNAs. In this case, due to the reaction efficiency of the PCR reaction and the synthesizable lengths of DNAs, 6 synthetic DNAs are preferably designed for each of the VH and VL.

[0486] Furthermore, by introducing an appropriate restriction enzyme recognition sequence at the 5' or 3' terminus of the synthetic DNAs located at both ends, cDNA that encodes VH or VL of a humanized antibody can be easily cloned into the expression vector for a genetically recombinant antibody obtained in (1).

[0487] After the PCR reaction, the amplified products are each cloned into a plasmid such as pBluescript SK (-) (manufactured by Stratagene), and the nucleotide sequences are determined by the same method as the method described in (2). A plasmid having the DNA sequence that encodes the amino acid sequence of VH or VL of a desired humanized antibody is thus obtained.

[0488] Alternatively, the entire VH and the entire VL each synthesized as a long chain DNA based on the designed DNA sequences can also be used instead of the PCR amplified products. Moreover, by introducing an appropriate restriction enzyme recognition sequence at both ends of the synthesized long chain DNAs, cDNAs that encode VH and VL of the humanized antibody can be easily cloned into the expression vector for a genetically recombinant antibody obtained in (1).

(5) Modification of Amino Acid Sequence of V Region of Humanized Antibody

[0489] When only the CDRs of VH and VL of a non-human antibody are merely inserted into the FRs of VH and VL of a human antibody, the antigen binding activity of the humanized antibody is lower than that of the original non-human antibody [BIO/TECHNOLOGY, 9, 266 (1991)].

[0490] In a humanized antibody, by identifying the amino acid residues directly related to antigen binding, the amino acid residues interacting with the amino acid residues of the CDRs and the amino acid residues which maintain the three-dimensional structure of the antibody and which are indirectly related to antigen binding, in the amino acid sequences of the FRs of VH and VL of a human antibody, and by substituting these amino acid residues with the amino acid residues of the original non-human antibody, the lowered antigen binding activity can be increased.

[0491] In order to identify the amino acid residues of FR related to the antigen binding activity, the three-dimensional structure of the antibody can be constructed and analyzed using X-ray crystallography [J. Mol. Biol., 112, 535 (1977)], computer modeling [Protein Engineering, 7, 1501 (1994)] or the like. Furthermore, a humanized antibody having necessary antigen binding activity can be obtained by producing various types of variants for each antibody and repeatedly examining their correlation with the antigen binding activities and through trial and error.

[0492] Amino acid residues of the FRs of VH and VL of a human antibody can be modified by carrying out the PCR reaction described in (4) using synthetic DNA for the modification. The nucleotide sequence of the amplified product after the PCR reaction is determined, and whether the intended modification has been carried out is confirmed by the method described in (2).

(6) Construction of Expression Vector for Humanized Antibody

[0493] By cloning the cDNAs that encode VH and VL of the constructed genetically recombinant antibody in the upstream of the respective genes that encode CH and CL of the human antibody in the expression vector for a genetically recombinant antibody obtained in (1), an expression vector for a humanized antibody can be constructed.

[0494] For example, the cDNAs are cloned in the upstream of the respective genes that encode CH and CL of the human antibody in the expression vector for a genetically recombinant antibody obtained in (1) in a manner that the cDNAs are expressed in an appropriate form by introducing an appropriate restriction enzyme recognition sequence at the 5' or 3' terminus of the synthetic DNAs located at both ends of the synthetic DNAs used for constructing the VH and VL of the humanized antibody obtained in (4) and (5).

(7) Transient Expression of Genetically Recombinant Antibody

[0495] By transiently expressing genetically recombinant antibodies using the expression vectors of a genetically recombinant antibody obtained in (3) and (6) or modified expression vectors thereof, the antigen binding activities of the produced various human chimeric antibodies and humanized antibodies can be efficiently evaluated.

[0496] As a host cell into which an expression vector is introduced, any cell can be used as long as it is a host cell capable of expressing a genetically recombinant antibody, but for example, COS-7 cells [American Type Culture Collection (ATCC) number: CRL1651] are used [Methods in Nucleic Acids Res., CRC press, 283 (1991)].

[0497] For introduction of an expression vector into COS-7 cells, the DEAE-dextran method [Methods in Nucleic Acids Res., CRC press (1991)], the lipofection method [Proc. Natl. Acad. Sci. USA, 84, 7413 (1987)] or the like is used.

[0498] After the introduction of the expression vector, the expression level and the antigen binding activity of the genetically recombinant antibody in a culture supernatant are measured using the enzyme immunoassay method [Monoclonal Antibodies-Principles and practice, Third edition, Academic Press (1996), Antibodies-A Laboratory Manual, Cold Spring Harbor Laboratory (1988) and A manual for monoclonal antibody experiments, Kodansha scientific books (1987)] or the like.

(8) Acquisition of Stable Expression Transformant of Genetically Recombinant Antibody and Preparation of Genetically Recombinant Antibody

[0499] By introducing the expression vector for a genetically recombinant antibody obtained in (3) or (6) into an appropriate host cell, a transformant stably expressing the genetically recombinant antibody can be obtained.

[0500] For the introduction of the expression vector into a host cell, the electroporation method [JP-A-H2-257891 and Cytotechnology, 3, 133 (1990)] or the like is used.

[0501] As the host cell into which the expression vector for a genetically recombinant antibody is introduced, any cell can be used as long as it is a host cell capable of expressing the genetically recombinant antibody. For example, CHO-K1 (ATCC CCL-61), DUKXB11 (ATCC CCL-9096), Pro-5 (ATCC CCL-1781), CHO-S(Life Technologies, Cat #11619), rat myeloma cells YB2/3HL.P2.G11.16Ag.20 (ATCC No. CRL1662, also called YB2/0), mouse myeloma cells NSO, mouse myeloma cells SP2/0-Ag14 (ATCC No. CRL1581), mouse P3X63-Ag8.653 cells (ATCC No. CRL1580), CHO cells in which the dihydrofolate reductase gene (referred to as dhfr below) is deficient (CHO/DG44 cells) [Proc. Natl. Acad. Sci. USA, 77, 4216 (1980)] and the like are used.

[0502] In addition, a host cell in which the activity of a protein such as enzymes related to intracellular synthesis of sugar nucleotide GDP-fucose, a protein such as enzymes related to glycosylation modification in which the 1-position of fucose is .alpha.-bonded to the 6-position of N-acetylglucosamine at the reducing terminus of a N-glycoside-linked complex type sugar chain, a protein related to intracellular transport of sugar nucleotide GDP-fucose to the Golgi body or the like is reduced or lost, for example, CHO cells in which the a1,6-fucosyltransferase gene is deficient (International Publication No. 2005/035586 and International Publication No. 02/31140), Lec13 having lectin resistance [Somatic Cell and Molecular genetics, 12, 55 (1986)] and the like can also be used.

[0503] After the introduction of the expression vector, a transformant stably expressing a genetically recombinant antibody is selected by culturing the transformant in a medium for animal cell culture containing a drug such as G418 sulfate (referred to as G418 below) (JP-A-H2-257891).

[0504] As the medium for animal cell culture, RPMI 1640 medium (manufactured by Invitrogen), GIT medium (manufactured by Nippon Pharmaceutical Co., Ltd.), EX-CELL 301 medium (manufactured by Jay Earl H., Inc.), IMDM medium (manufactured by Invitrogen), Hybridoma-SFM medium (manufactured by Invitrogen), a medium in which various additives such as FBS are added to any of these media or the like is used.

[0505] A genetically recombinant antibody is expressed and accumulated in a culture supernatant by culturing the obtained transformant in the medium. The expression level and the antigen binding activity of the genetically recombinant antibody in the culture supernatant can be measured by the ELISA method or the like. In addition, the expression level of the genetically recombinant antibody produced by the transformant can be increased using the dhfr gene amplification system (JP-A-H2-257891) or the like.

[0506] The genetically recombinant antibody is purified using a protein A-column from the culture supernatant of the transformant [Monoclonal Antibodies--Principles and practice, Third edition, Academic Press (1996) and Antibodies--A Laboratory Manual, Cold Spring Harbor Laboratory (1988)]. In addition, a method used for purifying proteins, such as gel filtration, ion exchange chromatography and ultrafiltration, can also be combined.

[0507] The molecular weights of the H chains, the L chains or the whole antibody molecule of the purified genetically recombinant antibody can be measured using polyacrylamide gel electrophoresis [Nature, 227, 680 (1970)], western blotting method [Monoclonal Antibodies-Principles and practice, Third edition, Academic Press (1996) and Antibodies--A Laboratory Manual, Cold Spring Harbor Laboratory (1988)] or the like.

(9) Production Method of Antibody Fragment

[0508] The antibody fragment of the invention can be produced according to a known method. The antibody fragment of the invention may be produced by cleaving an antibody produced according to the method described in (1) to (8) using an enzyme or the like or may be produced by the genetic engineering technique after preparing a nucleotide sequence which encodes a desired antibody fragment.

(10) Production Method of Monovalent Antibody

[0509] In the invention, a monovalent antibody can be produced by the method described in International Publication No. 2014/054804, International Publication No. 2011/090754, International Publication No. 2007/048037, International Publication No. 2012/116927 or the like or another method.

(11) Production Method of Bispecific Antibody or Multispecific Antibody

[0510] The bispecific antibody or the multispecific antibody of the invention can be produced according to the production method of the antibody described above. For example, the bispecific antibody or the multispecific antibody can be produced using the method described in International Publication No. 2009/131239, International Publication No. 2014/054804, International Publication No. 01/077342, US Patent Application Publication No. 2007/0071675, International Publication No. 2007/024715, Wu et al., [Nature Biotechnology, 2007, 25(11), p. 1290-1297], Labrijn et al., [PNAS 2013, vol. 110, no. 13, p 5145-5150], Jong et al., [http://dx.doi.org/10.1371/journal.pbio.1002344], Kontermann et al., [mAbs 2012, vol. 4, issue2, p 182-197], Spiess et al., [Molecular Immunology 67 (2015) 95-106], Ridgway et al., [Protein engineering, 1996 vol. 9 no. 7 pp 617-621, International Publication No. 2009/080251, International Publication No. 2010/151792, International Publication No. 2014/033074 or the like.

[0511] For example, an expression vector of a bispecific antibody in which scFv that binds to MOG is fused to the C-terminus of an IgG antibody that binds to an antigen that is present in the brain can be produced by the method described below, and the bispecific antibody can be produced according to the expression method of the antibody and the purification method of the antibody described above. In addition, a bispecific antibody in which an antibody fragment is fused to the C-terminus of an antibody can also be produced by the same methods.

[0512] A gene fragment of a CH1-Hinge-CH2-CH3-linker domain is amplified by the PCR method using a synthetic gene of a heavy chain constant region of an IgG antibody which binds to an antigen that is present in the brain as a template. Next, using the nucleotide sequence of an antibody which binds to MOG as a template, the nucleotide sequence of a scFv domain in which VH and VL of the antibody are linked with an appropriate linker is prepared using the PCR method or the like. The two domains are linked by the PCR method or the like, and the obtained gene fragment is inserted to an appropriate vector such as pCI vector.

[0513] Moreover, a gene fragment of a light chain domain (VL and CL) of an IgG antibody which binds to an antigen that is present in the brain and a gene fragment of VH of the antibody are amplified by the PCR method using appropriate templates and are inserted into the appropriate position of the vector.

[0514] In addition, the bispecific antibody of the invention can also be produced by binding an antigen binding site containing an antibody fragment to an IgG antibody by a chemical method.

3. Evaluation of Activity of Antibody or Antibody Fragment Thereof

[0515] In the invention, the activity of an antibody or an antibody fragment thereof can be evaluated as follows.

(1) Binding Activity to MOG

[0516] The binding activity of the antibody or the antibody fragment of the invention to MOG is measured using flow cytometry, ELISA or surface plasmon resonance detection described in 1-(6) above or the like. Moreover, the binding activity can also be measured using a fluorescent antibody method [Cancer Immunol. Immunother., 36, 373 (1993)].

[0517] Also when the antibody or the antibody fragment of the invention is a monovalent antibody which binds to MOG, the binding activity of the monovalent antibody to MOG can be measured by the same method. Also when the antibody or the antibody fragment of the invention is a bispecific antibody or a multispecific antibody which binds to MOG and an antigen that is present in the brain, the binding activity of the bispecific antibody or the multispecific antibody to MOG or the antigen that is present in the brain can be measured by the same method.

(2) Measurement Method of Property of Accumulating in Brain

[0518] The property of the antibody or the antibody fragment of the invention of accumulating in the brain can be measured by the method described below.

[0519] A method of collecting brain tissues several days after administering the antibody or the antibody fragment to an animal, homogenizing the brain tissues, measuring the concentration of the antibody or the antibody fragment in the supernatant after centrifugation and calculating the amount of the antibody or the antibody fragment per unit brain weight, a method of detecting the presence of the antibody or the antibody fragment by a known immunological method using the collected brain tissues or the like is used. Moreover, a method of administering the antibody or the antibody fragment to which a pharmacologically acceptable label has been attached to an animal and detecting the presence of the antibody or the antibody fragment by in vivo imaging system sequentially or the like is used.

[0520] As the animal used, an animal suitable for the use of the antibody or the antibody fragment of the invention can be selected.

(3) Measurement Method of ADCC and CDC

[0521] The CDC or the ADCC of the antibody or the antibody fragment of the invention to human MOG-expressing cells or cells in which MOG and the antigen that is present in the brain are expressed can be measured by a known measurement method [Cancer Immunol. Immunother., 36, 373(1993); and Current protocols in Immunology, Chapter7. Immunologic studies in humans, Editor, John E, Coligan et al., John Wiley & Sons, Inc., (1993)].

4. Method for Controlling Effector Activity of Antibody or Antibody Fragment

[0522] As the method for controlling the effector activity of the antibody or the antibody fragment of the invention, a method for controlling the amount of a1,6-fucose (also called a core fucose) binding to N-acetylglucosamine (GlcNAc) present on the reducing terminal of the N-linked complex sugar chain that bind to the 297.sup.th asparagine (Asn) in the Fc region of the antibody or the antibody fragment containing Fc (International Publication No. 2005/035586, International Publication No. 2002/31140 and International Publication No. 00/61739), a method for controlling by modifying an amino acid residue in the Fc region of the antibody or the antibody fragment and the like are known. The effector activity of the antibody or the antibody fragment of the invention can be controlled using any of the methods.

[0523] The effector activity refers to the antibody-dependent activity that is caused through the Fc region of the antibody or the antibody fragment, and ADCC, CDC, Antibody-dependent phagocytosis (ADP) that is caused by phagocytes such as macrophages or dendritic cells and the like are known.

[0524] As the method for measuring the effector activity, for example, the effector activity can be measured by mixing the target cells, human peripheral blood mononuclear cells (PBMCs) as the effector and a target cell-specific antibody or an antibody fragment thereof, incubating the mixture for around four hours and then measuring the released lactate dehydrogenase (LDH) as an index of the cytotoxicity. In addition, the effector activity can also be measured by .sup.51Cr-release method, flow cytometry method or the like.

[0525] The effector activity of an antibody or an antibody fragment containing Fc can be increased or decreased by controlling the core fucose content of the N-linked complex sugar chain of Fc of the antibody. Regarding the method for reducing the amount of fucose that binds to the N-linked complex sugar chain binding to Fc of the antibody or the antibody fragment, an antibody or an antibody fragment thereof to which fucose is not bound can be obtained by expressing the antibody or the antibody fragment using CHO cells in which the a1,6-fucosyltransferase gene is deficient. An antibody or an antibody fragment thereof to which fucose is not bound has high ADCC.

[0526] On the other hand, as the method for increasing the amount of fucose that binds to the N-linked complex sugar chain binding to Fc of the antibody or the antibody fragment, an antibody or an antibody fragment thereof to which fucose is bound can be obtained by expressing the antibody or the antibody fragment using host cells into which the a1,6-fucosyltransferase gene has been introduced. An antibody or an antibody fragment thereof to which fucose is bound has lower ADCC than that of an antibody or an antibody fragment thereof to which fucose is not bound.

[0527] Moreover, by modifying an amino acid residue in the Fc region of the antibody or the antibody fragment, the ADCC or the CDC can be increased or reduced. For example, the CDC of the antibody or the antibody fragment can be increased using the amino acid sequence of the Fc region described in US Patent Application Publication No. 2007/0148165.

[0528] Furthermore, the ADCC or the CDC can be increased or decreased by the amino acid modifications described in U.S. Pat. No. 6,737,056, 7,297,775 or U.S. Pat. No. 7,317,091.

[0529] The antibody or the antibody fragment of the invention also includes an antibody or an antibody fragment thereof whose half-life in the blood is controlled by controlling the reactivity with Fc receptor, for example through the amino acid modifications described in JP-A-2013-165716, JP-A-2012-021004 or the like in accordance with the amino acid modifications or the sugar chain modifications in the constant region contained in the antibody or the antibody fragment.

[0530] Moreover, when a combination of the above methods is applied to one antibody or an antibody fragment thereof, an antibody or an antibody fragment thereof whose effector activity and the half-life in the blood are controlled can be obtained.

5. Method for Treating Disease Using Antibody or Antibody Fragment of Invention

[0531] The antibody or the antibody fragment of the invention can be used for treating a brain disease of an animal in which MOG is expressed in the brain.

[0532] Examples of the brain disease include Alzheimer's disease, the prodromal stage of Alzheimer's disease, Huntington disease, Parkinson's disease, brain tumors, multiple sclerosis, muscular dystrophy, amyotrophic lateral sclerosis, multiple system atrophy, progressive supranuclear palsy, nigrostriatal degeneration, olivopontocerebellar atrophy, bulbospinal muscular atrophy, spinocerebellar degeneration, cerebrovascular disease, epilepsy, migraine, hyperactivity disorder, Creutzfeldt-Jakob disease, corticobasal degeneration, lysosomal storage disease, depression, dystonia and the like.

[0533] The brain disease that the antibody or the antibody fragment of the invention can treat differs with the antigen to which the antibody or the antibody fragment of the invention binds, the kind of the molecule which modifies the antibody or the antibody fragment in the fused antibody or the fused antibody fragment of the invention and the like.

[0534] The therapeutic agent containing the antibody or the antibody fragment of the invention may contain only the antibody or the antibody fragment as an active ingredient, but the agent is generally mixed with one or more pharmacologically acceptable carriers and provided as medicinal formulation that is produced by a method known in the technical field of pharmaceutical science.

[0535] Examples of the route of administration include oral administration or parenteral administration such as intraoral, airway, intrarectal, subcutaneous, intramuscular, intraventricular, intraperitoneal, intradermal, intranasal, intrathecal or intravenous administration. Examples of the form of administration include a spray, a capsule, a tablet, a powder, a granule, a syrup, an emulsion, a suppository, an injection, an ointment, a tape and the like.

[0536] Formulations suitable for oral administration are emulsions, syrups, capsules, tablets, powders, granules and the like.

[0537] Liquid preparations such as emulsions or syrups are produced using water, sugars such as sucrose, sorbitol or fructose, glycols such as polyethylene glycol or propylene glycol, oils such as sesame oil, olive oil or soybean oil, preservatives such as p-hydroxybenzoic acid esters, flavors such as strawberry flavor or peppermint or the like as an additive.

[0538] The capsules, the tablets, the powders, the granules and the like are produced using excipients such as lactose, glucose, sucrose or mannitol, disintegrating agents such as starch or sodium alginate, lubricants such as magnesium stearate or talc, binders such as polyvinyl alcohol, hydroxypropyl cellulose or gelatin, surfactants such as a fatty acid ester, plasticizers such as glycerin or the like as an additive.

[0539] Formulations suitable for parenteral administration are injections, suppositories, sprays and the like. The injections are produced using a salt solution, a glucose solution, a carrier formed of a mixture of these solutions or the like. The suppositories are produced using carriers such as cocoa butter, hydrogenated fats or carboxylic acids.

[0540] The sprays are produced using a carrier which does not stimulate the oral and respiratory mucosa of a recipient and which enables dispersion of the antibody or the antibody fragment of the invention as fine particles and easy absorption or the like. As the carrier, for example, lactose, glycerin or the like is used. In addition, it can also be produced as an aerosol or a dry powder. Furthermore, also for the above parenteral preparations, the components exemplified as the additives for the formulations suitable for oral administration can also be added.

6. Method for Detecting or Measuring Antigen Present in Brain or Method for Diagnosing Disease Using Antibody or Antibody Fragment of Invention

[0541] Using the antibody or the antibody fragment of the invention, MOG or MOG and an antigen that is present in the brain can be detected or measured. Moreover, by detecting or measuring MOG or MOG and an antigen that is present in the brain, a brain disease of an animal in which MOG is expressed in the brain can be diagnosed.

[0542] Examples of the brain disease include Alzheimer's disease, the prodromal stage of Alzheimer's disease, Huntington disease, Parkinson's disease, brain tumors, multiple sclerosis, muscular dystrophy, amyotrophic lateral sclerosis, multiple system atrophy, progressive supranuclear palsy, nigrostriatal degeneration, olivopontocerebellar atrophy, bulbospinal muscular atrophy, spinocerebellar degeneration, cerebrovascular disease, epilepsy, migraine, hyperactivity disorder, Creutzfeldt-Jakob disease, corticobasal degeneration, lysosomal storage disease, depression, dystonia and the like. The brain disease that the antibody or the antibody fragment of the invention can diagnose differs with the antigen to which the antibody or the antibody fragment of the invention binds, the kind of the molecule which modifies the antibody or the antibody fragment in the fused antibody or the fused antibody fragment of the invention and the like.

[0543] The brain disease of an animal in which MOG is expressed in the brain can be diagnosed for example by detecting or measuring MOG that is present in the brain of the patient or the patient animal by an immunological method. Moreover, the brain disease can be diagnosed by detecting MOG that is expressed or present in the cells in the brain of the patient or the patient animal using an immunological method such as flow cytometry.

[0544] When a monovalent antibody which binds to MOG is used as the antibody or the antibody fragment of the invention, MOG in the brain can be measured by the same method as that described above. When a bispecific antibody or a multispecific antibody which binds to MOG and an antigen that is present in the brain is used as the antibody or the antibody fragment of the invention, MOG in the brain or the antigen that is present in the brain can be detected or measured by the same method as that described above.

[0545] The immunological method is a method of detecting or measuring the amount of an antibody or the amount of an antigen using a labeled antigen, antibody or the like. For example, the radioactive material labeled immune antibody method, the enzyme immunoassay method, the fluorescence immunoassay method, the luminescence immunoassay method, the western blotting method, the physicochemical method or the like is used.

[0546] In the radioactive material labeled immune antibody method, for example, the antibody or the antibody fragment of the invention is reacted with an antigen, cells expressing an antigen or the like and then reacted with an anti-immunoglobulin antibody or an antibody fragment thereof subjected to radiolabeling, followed by measurement with a scintillation counter or the like.

[0547] In the enzyme immunoassay method, for example, the antibody or the antibody fragment of the invention is reacted with an antigen, cells expressing an antigen or the like and then reacted with an anti-immunoglobulin antibody or an antibody fragment thereof subjected to labeling with an enzyme or the like, followed by addition of a substrate and measurement of the absorbance of the reaction solution with an absorptiometer. For example, a sandwich ELISA method or the like is used. As a labeling substance used in the enzyme immunoassay method, a known [Enzyme Immunoassay Method, Igaku-Shoin Ltd. (1987)] enzyme label can be used.

[0548] For example, alkaline phosphatase label, peroxidase label, luciferase label, biotin label or the like is used. The sandwich ELISA method is a method in which after binding an antibody to a solid phase, a target antigen to be detected or to be measured is trapped, and then a second antibody is reacted with the trapped antigen.

[0549] In the ELISA method, two kinds of antibodies which recognize the antigen to be detected or measured and which have different antigen recognition sites are prepared, and among these, a first antibody is adsorbed on a plate (for example, a 96-well plate) in advance, followed by labeling the second antibody with a fluorescent substance such as FITC, an enzyme such as peroxidase, biotin or the like.

[0550] The plate on which the first antibody is adsorbed is allowed to react with cells or a lysate thereof, tissues or a lysate thereof, a cell culture supernatant, serum, pleural effusion, ascites, intraocular fluid or the like separated from the living body and then to react with the second antibody, followed by the detection reaction according to the labeling material. From a calibration curve prepared by serially diluting the antigen of a known concentration, the antigen concentration in the test sample is calculated.

[0551] As the antibodies used in the sandwich ELISA method, either a polyclonal antibody or a monoclonal antibody may be used. Antibody fragments such as Fab, Fab' and F(ab).sub.2 may be used instead of the antibodies. The combination of the two kinds of antibodies used in the sandwich ELISA method may be a combination of monoclonal antibodies or antibody fragments thereof which recognize different epitopes or may be a combination of a polyclonal antibody, a monoclonal antibody and antibody fragments thereof.

[0552] In the fluorescence immunoassay method, measurement is carried out by the method described in documents [Monoclonal Antibodies-Principles and practice, Third edition, Academic Press (1996) and A manual for monoclonal antibody experiments, Kodansha scientific books (1987)] or the like. As the labeling substance used in the fluorescence immunoassay method, a known [Fluorescent Antibody Method, Soft Science (1983)] fluorescent label can be used. For example, FITC, RITC or the like is used.

[0553] In the luminescence immunoassay method, measurement is carried out by the method described in a document [Bioluminescence and Chemiluminescence, Clinical Test 42, Hirokawa-Shoten Ltd. (1998)] or the like. As the labeling substance used in the luminescence immunoassay method, a known luminescent label is used, and an acridinium ester, a lophine or the like is used.

[0554] In the western blotting method, measurement is carried out by after fractionating antigens, cells expressing an antigen or the like by SDS (sodium dodecyl sulfate)--PAGE (polyacrylamide gel) [Antibodies--A Laboratory Manual Cold Spring Harbor Laboratory (1988)], blotting the gel on a polyvinylidene fluoride (PVDF) membrane or a nitrocellulose membrane, reacting an antibody or an antibody fragment that recognizes the antigen with the membrane, further reacting it with an anti-mouse IgG antibody or a binding fragment subjected to labeling with a fluorescent substance such as FITC, labeling with an enzyme such as peroxidase, biotin labeling or the like and then visualizing the label. An example is shown below.

[0555] Cells or tissues expressing a polypeptide having the amino acid sequence of MOG are lysed, and 0.1 to 30 .mu.g as a protein amount per lane is subjected to electrophoresis by the SDS-PAGE method under reducing conditions. The electrophoresed proteins are transferred to a PVDF membrane and reacted with PBS containing 1 to 10% BSA (referred to as BSA-PBS below) for 30 minutes at room temperature to perform blocking operation.

[0556] The antibody or the antibody fragment of the invention is reacted therewith, and the membrane is washed with PBS containing 0.05 to 0.1% Tween-20 (referred to as Tween-PBS below) and reacted with a goat anti-mouse IgG labeled with peroxidase for 2 hours at room temperature.

[0557] By washing with Tween-PBS and detecting a band to which the antibody or the antibody fragment of the invention is bound using ECL Western Blotting Detection Reagents (manufactured by Amersham) or the like, the polypeptide having the amino acid sequence of MOG is detected.

[0558] As the antibody or the antibody fragment used for detection by western blotting, an antibody or an antibody fragment thereof capable of binding to a polypeptide that does not retain the natural three-dimensional structure is used.

[0559] The physicochemical method is carried out, for example, by binding MOG, which is the antigen, with the antibody or the antibody fragment of the invention to form an aggregate and detecting the aggregate. As another physicochemical method, a capillary tube method, a one-dimensional immunodiffusion method, an immunoturbidimetric method, a latex immunoturbidimetric method [Outline of Clinical Examination Method, KANEHARA & Co., LTD. (1998)] or the like can also be used.

[0560] In the latex immunoturbidimetric method, when a carrier such as a polystyrene latex having a particle size of approximately 0.1 to 1 .mu.m sensitized with an antibody or an antigen is used to cause the antigen-antibody reaction with a corresponding antigen or antibody, the scattered light is increased in a reaction solution, and the transmitted light is decreased. The antigen concentration and the like in the test sample are measured by detecting this change as absorbance or integrating sphere turbidity.

[0561] For detection or measurement of cells expressing MOG, a known immunological detection method can be used, but of known methods, the immunoprecipitation method, the immunocytostaining method, the immunohistochemical staining method, the fluorescent antibody staining method or the like is preferably used.

[0562] In the immunoprecipitation method, after reacting cells expressing MOG or the like with the antibody or the antibody fragment of the invention, a carrier having specific binding ability to an immunoglobulin such as Protein G-Sepharose is added thereto, and therefore an antigen-antibody complex is precipitated. Alternatively, the method can also be carried out by the following method.

[0563] The antibody or the antibody fragment of the invention described above is immobilized on a 96-well plate for ELISA and then blocked with BSA-PBS. When the antibody is an antibody which is not purified such as a hybridoma culture supernatant for example, the hybridoma culture supernatant is dispensed and bound after immobilizing anti-mouse immunoglobulin, anti-rat immunoglobulin, protein-A, protein-G or the like on a 96-well plate for ELISA in advance and blocking the plate with BSA-PBS.

[0564] Next, after discarding BSA-PBS and thoroughly washing with PBS, lysates of cells or tissues expressing human MOG are reacted therewith. Immunoprecipitates are extracted from the plate after thoroughly washing with a sample buffer for SDS-PAGE and detected by the above western blotting.

[0565] The immunocytostaining method or the immunohistochemical staining method is a method in which cells, tissues or the like expressing an antigen are treated with a surfactant, methanol or the like in order to improve passing of the antibody in some cases, then reacted with the antibody of the invention and further reacted with an anti-immunoglobulin antibody or a binding fragment thereof subjected to fluorescent labeling with FITC or the like, labeling with an enzyme such as peroxidase, biotin labeling or the like and in which the label is then visualized and observed with a microscope.

[0566] In addition, detection can be carried out by the fluorescent antibody staining method in which a fluorescently-labeled antibody is reacted with cells and analyzed with a flow cytometer [Monoclonal Antibodies--Principles and practice, Third edition, Academic Press (1996) and A manual for monoclonal antibody experiments, Kodansha scientific books (1987)]. In particular, the antibody or the antibody fragment of the invention can detect cells in which the antigen is expressed and retains the natural three-dimensional structure by the fluorescent antibody staining method.

[0567] In addition, when the FMAT 8100 HTS system (manufactured by Applied Biosystems) or the like of the fluorescent antibody staining methods is used, the amount of an antigen or the amount of an antibody can be measured without separating the formed antibody-antigen complex from the free antibody or antigen that is not involved in formation of the antibody-antigen complex.

[0568] Hereinafter, the invention will be explained in more detail by Examples, but the invention is not limited to the following Examples.

EXAMPLES

[Example 1] Acquisition of Anti-MOG Antibodies

(l) Acquisition of Antibodies Using Human Antibody Phage Libraries

[0569] A VH gene fragment and a VL gene fragment were amplified from human PBMC-derived cDNA by PCR. The VH gene fragment and the VL gene fragment were inserted to a phagemid vector pCANTAB 5E (manufactured by Amersham Pharmacia Biotech), and a plasmid was obtained by transforming Escherichia coli TG1 (manufactured by Lucigen).

[0570] The obtained plasmid was infected with M13K07 Helper Phage (manufactured by Invitrogen), and a human antibody M13 phage library of the VH gene and the VL gene was thus obtained.

[0571] Using the human antibody M13 phage libraries, anti-rat MOG (rMOG) monoclonal antibodies were obtained using the phage display method described below. rMOG-FLAG_Fc of Example 4 described below was immobilized on a MAXISORP STARTUBE (manufactured by NUNC), and the sites to which rMOG-FLAG_Fc was not bound were blocked using SuperBlock Blocking Buffer (manufactured by Thermo Fisher Scientific Inc.).

[0572] A human antibody M13 phage library was reacted with the tube at room temperature for an hour, and the phage was eluted with 0.1 M Gly-HCl (pH 2.2) after washing with PBS or PBS containing 0.1% Tween 20 (referred to as PBS-T below). The eluate was neutralized by adding Tris-HCl (pH 8.5). TG1 competent cells were infected with the eluted phage, and the phage was amplified.

[0573] Then, the reaction with rMOG-FLAG_Fc immobilized on a MAXISORP STARTUBE was conducted again, and washing and elution were conducted. This procedure was repeated, and phages displaying scFv which specifically binds to rMOG-FLAG_Fc were concentrated. The concentrated phages were monocloned, and three clones having affinity to rMOG-FLAG_Fc were selected by ELISA.

[0574] In ELISA, rMOG-FLAG_Fc was immobilized on MAXISORP (manufactured by NUNC), and the sites to which rMOG-FLAG_Fc was not bound were blocked using SuperBlock Blockig Buffer (manufactured by Thermo Fisher Scientific Inc.). As the negative control, a plate in which FLAG_Fc was immobilized was also prepared.

[0575] The phage clones were added to separate wells and reacted at room temperature for 30 minutes, and then the wells were washed with PBS-T. Subsequently, a solution obtained by diluting horseradish peroxidase-labeled anti-M13 antibody (manufactured by GE Healthcare) with PBS-T containing 10% Block Ace (manufactured by Dainippon Pharma Co., Ltd.) was added to the wells, and the plates were incubated at room temperature for 30 minutes.

[0576] After washing the microplates three times with PBS-T, a TMB chromogenic substrate solution (manufactured by DAKO) was added, and the plates were incubated at room temperature. The chromogenic reaction was stopped by adding 0.5 M sulfuric acid to the wells, and the absorbances at the wavelength of 450 nm (reference wavelength of 570 nm) were measured with a microplate reader (manufactured by Molecular Devices). The results obtained are shown in FIG. 1.

[0577] As shown in FIG. 1, it could be confirmed that the three phage clones all bind to rMOG-FLAG_Fc. On the other hand, none of the phage clones bound to FLAG_Fc (data not shown).

[0578] The sequences of the clones which bound to rMOG-FLAG_Fc were analyzed, and anti-MOG antibody phagemid vectors, pCANTAB_MOG01, pCANTAB_MOG09 and pCANTAB_MOG14 were obtained.

[0579] In the following paragraphs, the names of the anti-MOG scFv antibodies displayed by the phages expressed using pCANTAB_MOG01, pCANTAB_MOG09 and pCANTAB_MOG14 are referred to as MOG01 antibody, MOG09 antibody and MOG14 antibody, respectively. The nucleotide sequences which encode VH or VL of the anti-MOG scFv antibodies, and the amino acid sequences deduced from the nucleotide sequences are shown in Table 1.

TABLE-US-00001 TABLE 1 Sequence Information of Anti-MOG scFv Antibodies (MOG01 Antibody, MOG09 Antibody and MOG14 Antibody) Clone Name MOG01 MOG09 MOG14 Nucleotide sequence encoding VH SEQ ID NO: 1 SEQ ID NO: 13 SEQ ID NO: 25 (including signal sequence) Amino acid sequence of VH SEQ ID NO: 2 SEQ ID NO: 14 SEQ ID NO: 26 (including signal sequence) Amino acid sequence of VH SEQ ID NO: 3 SEQ ID NO: 15 SEQ ID NO: 27 (excluding signal sequence) Amino acid sequence of HCDR1 SEQ ID NO: 4 SEQ ID NO: 16 SEQ ID NO: 28 Amino acid sequence of HCDR2 SEQ ID NO: 5 SEQ ID NO: 17 SEQ ID NO: 29 Amino acid sequence of HCDR3 SEQ ID NO: 6 SEQ ID NO: 18 SEQ ID NO: 30 Nucleotide sequence encoding VL SEQ ID NO: 7 SEQ ID NO: 19 SEQ ID NO: 31 (including signal sequence) Amino acid sequence of VL SEQ ID NO: 8 SEQ ID NO: 20 SEQ ID NO: 32 (including signal sequence) Amino acid sequence of VL SEQ ID NO: 9 SEQ ID NO: 21 SEQ ID NO: 33 (excluding signal sequence) Amino acid sequence of LCDR1 SEQ ID NO: 10 SEQ ID NO: 22 SEQ ID NO: 34 Amino acid sequence of LCDR2 SEQ ID NO: 11 SEQ ID NO: 23 SEQ ID NO: 35 Amino acid sequence of LCDR3 SEQ ID NO: 12 SEQ ID NO: 24 SEQ ID NO: 36

(2) Acquisition of Antibodies Using Alpaca Antibody Libraries

[0580] An emulsion of rMOG-FLAG_Fc and complete adjuvant for the first immunization and an emulsion of rMOG-FLAG_Fc and incomplete adjuvant for the second and third immunization were produced as immunogens, and an alpaca was immunized.

[0581] Lymphocytes (2.times.10.sup.7 cells) were collected from the blood (50 mL) of the immunized alpaca, and RNA was extracted from the obtained cells using RNA IsoPlus (manufactured by TAKARA). After synthesizing cDNA by reverse transcription reaction using SuperScript (registered trademark) III First-Strand Synthesis System for RT-PC (manufactured by Invitrogen), VHH gene was amplified using primers specific to alpaca IgG2 (Short hinge-heavy chain antibody) and IgG3 (Long hinge-heavy chain antibody).

[0582] The VHH gene fragment was inserted to a phagemid vector pKSTV-02 (described in Miyazaki et al, J. Biochem. 2015; 1), and Escherichia coli TG1 was transformed by electroporation using a MicroPulser electroporator (manufactured by BioRad) (the IgG2 titer of the transformant was 2.6.times.10.sup.7, and the IgG3 titer was 3.2.times.10.sup.7).

[0583] The obtained transformant was infected with M13K07 Helper Phage (manufactured by Invitrogen), and an alpaca antibody M13 phage library of the VHH gene was thus obtained.

[0584] Using the alpaca antibody M13 phage libraries, anti-MOG antibodies were obtained using the biopanning method described below. rMOG-GST (4 .mu.g/2 mL) was immobilized on an immuno tube, and the sites to which rMOG-GST was not bound were blocked using 0.5% BSA.

[0585] The alpaca antibody M13 phage library was reacted with the tube at room temperature for an hour, and the phage was eluted with 0.1 M Gly-HCl (pH 2.7) after washing with PBS-T. The eluant was neutralized by adding Tris-HCl (pH 9.1). Escherichia coli TG1 was infected with the eluted phage, and then the phage was amplified. Then, the reaction with rMOG-GST immobilized on an immuno tube was conducted again, and washing and elution were conducted.

[0586] The procedure was repeated three times for IgG2 and twice for IgG3, and phages displaying VHH which specifically binds to rMOG-GST were concentrated. From the concentrated phages, 96 phage clones displaying VHH of IgG2 and 96 phage clones displaying VHH of IgG3 were monocloned, and clones having affinity to rMOG-GST were selected by ELISA.

[0587] In ELISA, rMOG-GST was immobilized (50 ng/50 .mu.L) on MAXISORP (manufactured by NUNC), and the sites to which rMOG-GST was not bound were blocked using 0.5% BSA. The phage clones were added to separate wells and reacted at room temperature for an hour, and then the wells were washed five times with PBS-T.

[0588] Subsequently, 50 .mu.L of a biotinylated anti-M13 phage antibody (manufactured by Abcam) and horseradish peroxidase-labeled streptavidin (manufactured by Vector) were added to the wells, and the plate was incubated at room temperature for an hour.

[0589] After washing the microplate with PBS-T, a TMB chromogenic substrate solution (manufactured by CALBIOCHEM) was added to the wells, and the plate was incubated at room temperature. The chromogenic reaction was stopped by adding 1 M hydrochloric acid to the wells, and the absorbances at the wavelength of 450 nm (reference wavelength of 570 nm) were measured with a microplate reader (Model 680XR, manufactured by BioRad).

[0590] The sequences of the clones which bound to rMOG-GST were analyzed, and an anti-MOG VHH antibody, iMOG-3Rim1-S32 antibody was obtained. The nucleotide sequence encoding VHH of iMOG-3Rim1-S32 antibody and the amino acid sequence deduced from the nucleotide sequence are shown in Table 2.

TABLE-US-00002 TABLE 2 Sequence Information of Anti-MOG VHH Antibody (iMOG-3Rim1-S32 Antibody) Clone Name iMOG-3Rim1-S32 Nucleotide sequence encoding SEQ ID NO: 37 VHH (including signal sequence) Amino acid sequence of VHH SEQ ID NO: 38 (including signal sequence) Amino acid sequence of VHH SEQ ID NO: 39 (excluding signal sequence) Amino acid sequence of CDR1 SEQ ID NO: 40 Amino acid sequence of CDR2 SEQ ID NO: 41 Amino acid sequence of CDR3 SEQ ID NO: 42

[Example 2] Construction of Antibody Expression Vectors

(l) Construction of Anti-MOG Antibody Expression Vectors

[0591] To produce anti-MOG antibodies of human IgG type, expression vectors for anti-MOG antibodies in which the DNA sequences encoding the amino acid sequences of the variable regions of the human antibody phage library-derived anti-MOG scFv antibodies obtained in Example 1 were incorporated into a nucleotide sequence encoding the amino acid sequence of a constant region of human IgG antibody were produced by the method described below.

[0592] A nucleotide sequence encoding the lambda chain constant region of human IgG was synthesized and inserted to the BglII-EcoRI site of N5KG4PE vector (described in International Publication No. 2002/088186), and N5LG4PE vector was thus produced.

[0593] Expression vectors obtained by inserting nucleotide sequences encoding the amino acid sequences of VH and VL of MOG01 antibody and MOG09 antibody into N5LG4PE were named N5LG4PE_MOG01 and N5LG4PE_MOG09, respectively. Moreover, an expression vector obtained by inserting nucleotide sequences encoding the amino acid sequences of VH and VL of MOG14 antibody into N5KG4PE vector was named N5KG4PE_MOG14.

(1-1)_MOG01 Antibody Expression Vector N5LG4PE_MOG01

[0594] Using phagemid vector pCANTAB_MOG01 as a template and using primer 1 (SEQ ID NO: 43) and primer 2 (SEQ ID NO: 44) and KOD plus DNA Polymerase (manufactured by Toyobo Co., Ltd.), a gene fragment of the VL region was amplified by PCR. In the PCR, 30 cycles of reaction of 30 seconds at 94.degree. C., 30 seconds at 58.degree. C. and 45 seconds at 68.degree. C. were conducted. The PCR described in Example 2 was conducted under the conditions unless particularly described.

[0595] Using the PCR product as a template and using primer 3 (SEQ ID NO: 45) and primer 2 (SEQ ID NO: 44) and KOD plus DNA Polymerase (manufactured by Toyobo Co., Ltd.), a signal sequence was added to the gene fragment of the VL region by PCR.

[0596] The obtained gene fragment was inserted to the BglII-BlpI site of N5LG4PE vector, and N5LG4PE_MOG01VL was obtained. Next, using pCANTAB_MOG01 as a template and using primer 4 (SEQ ID NO: 46) and primer 5 (SEQ ID NO: 47) and KOD plus DNA Polymerase (manufactured by Toyobo Co., Ltd.), a gene fragment of the VH region was amplified by PCR.

[0597] Using the PCR product as a template and using primer 6 (SEQ ID NO: 48) and primer 5 (SEQ ID NO: 47) and KOD plus DNA Polymerase (manufactured by Toyobo Co., Ltd.), a signal sequence was added to the gene fragment of the VH region by PCR. The obtained gene fragment was inserted to the SalI-NheI site of N5LG4PE_MOG01VL vector, and N5LG4PE_MOG01 was obtained.

(1-2)_MOG09 Antibody Expression Vector N5LG4PE_MOG09

[0598] N5LG4PE_MOG09 was produced by the same method as that of (1-1). A phagemid vector pCANTAB_MOG09 was used as a template. Primer 7 (SEQ ID NO: 49) and primer 8 (SEQ ID NO: 50) were used to amplify a gene fragment of the VL region, and primer 3 (SEQ ID NO: 45) and primer 8 (SEQ ID NO: 50) were used to add a signal sequence to the gene fragment of the VL region. Primer 9 (SEQ ID NO: 51) and primer 10 (SEQ ID NO: 52) were used to amplify a gene fragment of the VH region, and primer 6 (SEQ ID NO: 48) and primer 10 (SEQ ID NO: 52) were used to add a signal sequence to the gene fragment of the VH region.

(1-3)_MOG14 Antibody Expression Vector N5KG4PE_MOG14

[0599] N5KG4PE_MOG14 was produced by the same method as that of (1-1). A phagemid vector pCANTAB_MOG14 was used as a template. Primer 11 (SEQ ID NO: 53) and primer 12 (SEQ ID NO: 54) were used to amplify a gene fragment of the VL region, and primer 3 (SEQ ID NO: 45) and primer 12 (SEQ ID NO: 54) were used to add a signal sequence to the gene fragment of the VL region. The obtained gene fragment of the VL region to which the signal sequence was added was inserted to the BglII-BsiWI site of N5KG4PE vector, and N5KG4PE_MOG14VL was obtained.

[0600] Next, pCANTAB_MOG14 was used as a template. Primer 13 (SEQ ID NO: 55) and primer 14 (SEQ ID NO: 56) were used to amplify a gene fragment of the VH region, and primer 6 (SEQ ID NO: 48) and primer 14 (SEQ ID NO: 56) were used to add a signal sequence to the gene fragment of the VH region. The obtained gene fragment of the VH region to which the signal sequence was added was inserted to the SalI-NheI site of N5KG4PE_MOG14VL, and N5KG4PE_MOG14 was obtained.

(1-4) iMOG-3Rim1-S32 Antibody Expression Vector N5G4PEFc_iMOG-3Rim1-S32

[0601] A sequence obtained by adding a signal sequence to the gene encoding the Fc region of human IgG4PE was synthesized, and a gene fragment of human Fc region was amplified by PCR using primer 25 (SEQ ID NO: 79) and primer 26 (SEQ ID NO: 80) and KOD plus DNA Polymerase (manufactured by Toyobo Co., Ltd.).

[0602] In the PCR, 30 cycles of reaction of 30 seconds at 94.degree. C., 30 seconds at 58.degree. C. and 60 seconds at 68.degree. C. were conducted. The obtained Fc gene fragment was inserted to the BglII-BamHI site of N5KG4PE vector, and N5G4PEFc vector was produced.

[0603] An expression vector obtained by inserting a nucleotide sequence encoding the amino acid sequence of VHH of iMOG-3Rim1-S32 to N5G4PEFc was named N5G4PEFc_iMOG-3Rim1-S32. The VHH-Fc expression vector was produced by the method described below.

[0604] The nucleotide sequence of VHH of iMOG-3Rim1-S32 was synthesized, and a gene fragment of the VHH region was amplified by PCR using primer 15 (SEQ ID NO: 57) and primer 16 (SEQ ID NO: 58) and KOD plus DNA Polymerase (manufactured by Toyobo Co., Ltd.). In the PCR, 30 cycles of reaction of 30 seconds at 94.degree. C., 30 seconds at 58.degree. C. and 60 seconds at 68.degree. C. were conducted. The obtained VHH gene fragment was inserted to the EcoRI-BglII site of N5G4PEFc vector, and N5G4PEFc_iMOG-3Rim1-S32 was obtained.

(2) Anti-Avermectin Antibody Expression Vector N5LG4PE_AVM

[0605] As a negative control antibody, a chimeric anti-Avermectin (AVM) antibody was produced by the same method as that of (1-1). An expression vector obtained by inserting nucleotide sequences encoding the amino acid sequences of VH and VL of an AVM antibody to N5LG4PE was named N5LG4PE_AVM.

[0606] An SD rat was immunized with AVM, and an anti-AVM antibody-producing hybridoma was established by a general method. The variable region of the anti-AVM antibody derived from the hybridoma was used as a template. Primer 29 (SEQ ID NO: 83) and primer 30 (SEQ ID NO: 84) were used to amplify a gene fragment of the VL region, and primer 3 (SEQ ID NO: 45) and primer 30 (SEQ ID NO: 84) were used to add a signal sequence to the gene fragment of the VL region.

[0607] Primer 31 (SEQ ID NO: 85) and primer 32 (SEQ ID NO: 86) were used to amplify a gene fragment of the VH region, and primer 6 (SEQ ID NO: 48) and primer 32 (SEQ ID NO: 86) were used to add a signal sequence to the gene fragment of the VH region.

(3) Anti-Rat Transferrin Receptor Antibody OX26 Antibody Expression Vector N5KG4PE(R409K)_OX26

[0608] As a positive control antibody of an anti-rat transferrin receptor antibody, the anti-rat transferrin receptor antibody, OX26 antibody described in [Protein Engineering, 12, 787-796, 1999] was produced. An expression vector obtained by inserting nucleotide sequences encoding the amino acid sequences of VH and VL of OX26 antibody to N5KG4PE (R409K) (described in International Publication No. 2002/088186) was produced by the same method as that of (1-1) and named N5KG4PE(R409K)_OX26.

[0609] The gene encoding the amino acid sequence of VL of OX26 antibody was synthesized and used as a template. Primer 40 (SEQ ID NO: 94) and primer 41 (SEQ ID NO: 95) were used to amplify a gene fragment of the VL region, and primer 42 (SEQ ID NO: 96) and primer 43 (SEQ ID NO: 97) were used to amplify a gene fragment of the VH region.

[Example 3] Construction of Bispecific Antibody Expression Vectors

(l) Production of Vector Expressing Bispecific Antibody Binding to Her2 and MOG

[0610] A vector expressing a bispecific antibody binding to HER2 and MOG, pCI-Trastuzumab-hKG4PE(R409K)_MOG01scFv was produced by the following method. In the bispecific antibody, scFv of an anti-MOG antibody is fused to the C-terminuses of the two H chains of IgG of an anti-HER2 antibody.

[0611] Using a synthetic gene of the heavy chain constant region as a template and using primer 17 (SEQ ID NO: 59) and primer 18 (SEQ ID NO: 60) and KOD plus DNA Polymerase (manufactured by Toyobo Co., Ltd.), a gene fragment of the CH1-Hinge-CH2-CH3-linker region was amplified by PCR.

[0612] In the PCR, 30 cycles of reaction of 30 seconds at 94.degree. C., 30 seconds at 58.degree. C. and two minutes at 68.degree. C. were conducted. Using a phagemid vector pCANTAB_MOG01 as a template and using primer 19 (SEQ ID NO: 61) and primer 20 (SEQ ID NO: 62) and KOD plus DNA Polymerase (manufactured by Toyobo Co., Ltd.), a gene fragment of the scFv region (referred to as MOG01scFv below) was amplified by PCR.

[0613] In the PCR, 30 cycles of reaction of 30 seconds at 94.degree. C., 30 seconds at 58.degree. C. and 90 seconds at 68.degree. C. were conducted. Next, using the CH1-Hinge-CH2-CH3 region and the MOG01scFv region as templates and using primer 17 (SEQ ID NO: 59) and primer 20 (SEQ ID NO: 62) and KOD plus DNA Polymerase (manufactured by Toyobo Co., Ltd.), CH1-Hinge-CH2-CH3-MOG01scFv was amplified.

[0614] In the PCR, 30 cycles of reaction of 30 seconds at 94.degree. C., 30 seconds at 58.degree. C. and two minutes at 68.degree. C. were conducted. The obtained gene fragment was inserted to pCI vector (manufactured by Promega Corporation), and pCI-hG4PE(R409K)_MOG01scFv vector was produced.

[0615] The gene encoding the amino acid sequence of VL of an anti-HER2 antibody (Trastuzumab) (described in International Publication No. 1999/57134) was synthesized and used as a template, and a gene fragment of the VL region was amplified by PCR using primer 21 (SEQ ID NO: 63) and primer 22 (SEQ ID NO: 64) and KOD plus DNA Polymerase (manufactured by Toyobo Co., Ltd.).

[0616] In the PCR, 30 cycles of reaction of 30 seconds at 94.degree. C., 30 seconds at 58.degree. C. and 45 seconds at 68.degree. C. were conducted. Using N5KG4PE vector (described in International Publication No. 2002/088186) as a template and using primer 27 (SEQ ID NO: 81) and primer 28 (SEQ ID NO: 82) and KOD plus DNA Polymerase (manufactured by Toyobo Co., Ltd.), a gene fragment of the CL region was amplified by PCR.

[0617] In the PCR, 30 cycles of reaction of 30 seconds at 94.degree. C., 30 seconds at 58.degree. C. and 45 seconds at 68.degree. C. were conducted. Using the obtained gene fragments VL and CL as templates and using primer 21 (SEQ ID NO: 63) and primer 28 (SEQ ID NO: 82) and KOD plus DNA Polymerase (manufactured by Toyobo Co., Ltd.), a gene fragment was amplified by PCR.

[0618] In the PCR, 30 cycles of reaction of 30 seconds at 94.degree. C., 30 seconds at 58.degree. C. and 90 seconds at 68.degree. C. were conducted. The obtained gene fragment was inserted to pCI-hG4PE(R409K)_MOG01scFv, and pCI-TrastuzumabVL-hKG4PE(R409K)_MOG01scFv was obtained.

[0619] Next, the gene encoding the amino acid sequence of VH of Trastuzumab was synthesized and used as a template, and a gene fragment of the VH region was amplified by PCR using primer 23 (SEQ ID NO: 65) and primer 24 (SEQ ID NO: 66) and KOD plus DNA Polymerase (manufactured by Toyobo Co., Ltd.). In the PCR, 30 cycles of reaction of 30 seconds at 94.degree. C., 30 seconds at 58.degree. C. and 45 seconds at 68.degree. C. were conducted.

[0620] The obtained gene fragment was inserted to pCI-TrastuzumabVL-hKG4PE(R409K)_MOG01scFv, and pCI-Trastuzumab-hKG4PE(R409K)_MOG01scFv was obtained.

(2) Production of Vector Expressing Bispecific Antibody Binding to AVM and MOG

[0621] Moreover, a vector expressing a bispecific antibody binding to AVM and MOG, pCI-AVM-hLG4PE(R409K)_MOG01scFv was produced by the method described below. In the bispecific antibody, scFv of an anti-MOG antibody is fused to the C-terminus of IgG of an anti-AVM antibody.

[0622] Using N5LG4PE_AVM as a template and using primer 33 (SEQ ID NO: 87) and primer 34 (SEQ ID NO: 88) and KOD plus DNA Polymerase (manufactured by Toyobo Co., Ltd.), a gene fragment of the AVM light chain region was amplified by PCR. In the PCR, 30 cycles of reaction of 30 seconds at 94.degree. C., 30 seconds at 58.degree. C. and 60 seconds at 68.degree. C. were conducted.

[0623] Using N5LG4PE_AVM as a template and using primer 35 (SEQ ID NO: 89) and primer 32 (SEQ ID NO: 86) and KOD plus DNA Polymerase (manufactured by Toyobo Co., Ltd.), a gene fragment of the AVM VH region was amplified by PCR.

[0624] In the PCR, 30 cycles of reaction of 30 seconds at 94.degree. C., 30 seconds at 58.degree. C. and 45 seconds at 68.degree. C. were conducted. The obtained gene fragment was inserted to pCI-hG4PE(R409K)_MOG01scFv produced above, and pCI-AVM-hLG4PE(R409K)_MOG01scFv was obtained.

(3) Production of Vector Expressing Antibody in which scFv of Anti-AVM Antibody is Fused to C-Terminus of IgG of Anti-AVM Antibody

[0625] As a negative control antibody, a vector expressing an antibody in which scFv of an anti-AVM antibody is fused to the C-terminus of IgG of an anti-AVM antibody was named pCI-AVM-hLG4PE(R409K)_AVM scFv.

[0626] Using a synthetic gene of the heavy chain constant region as a template and using primer 36 (SEQ ID NO: 90) and primer 37 (SEQ ID NO: 91) and KOD plus DNA Polymerase (manufactured by Toyobo Co., Ltd.), a gene fragment of the CH1-Hinge-CH2-CH3-linker region was amplified by PCR.

[0627] In the PCR, 30 cycles of reaction of 30 seconds at 94.degree. C., 30 seconds at 58.degree. C. and two minutes at 68.degree. C. were conducted. Using a synthetic gene of AVM scFv as a template and using primer 38 (SEQ ID NO: 92) and primer 39 (SEQ ID NO: 93) and KOD plus DNA Polymerase (manufactured by Toyobo Co., Ltd.), a gene fragment of the scFv region was amplified by PCR.

[0628] In the PCR, 30 cycles of reaction of 30 seconds at 94.degree. C., 30 seconds at 58.degree. C. and 90 seconds at 68.degree. C. were conducted. Next, using the CH1-Hinge-CH2-CH3 region and the AVM scFv region as templates and using primer 36 (SEQ ID NO: 90) and primer 39 (SEQ ID NO: 93) and KOD plus DNA Polymerase (manufactured by Toyobo Co., Ltd.), CH1-Hinge-CH2-CH3-AVM scFv was amplified. In the PCR, 30 cycles of reaction of 30 seconds at 94.degree. C., 30 seconds at 58.degree. C. and two minutes at 68.degree. C. were conducted.

[0629] The obtained gene fragment was inserted to the NheI-BamHI site of pCI-AVM-hLG4PE(R409K)_MOG01scFv, and pCI-AVM-hLG4PE(R409K)_AVM scFv was obtained.

Example 4

Production of Soluble MOG Antigen and Soluble HER2 Antigen

(1) Production of Extracellular Domain Protein of Rat MOG to Which FLAG-Fc is Bound

[0630] As a soluble antigen of rat MOG, an extracellular domain protein of MOG to which FLAG-Fc was added at the C-terminus was produced by the method described below. The nucleotide sequence encoding rMOG is shown in SEQ ID NO: 67, and the amino acid sequence deduced from the nucleotide sequence is shown in SEQ ID NO: 68.

[0631] A gene sequence of the extracellular domain of MOG was synthesized and inserted to the BglII-XbaI site of INPEP4 (manufactured by IDEC) vector to which FLAG-Fc had been inserted, and a plasmid vector INPEP4 rMOG-FLAG-Fc expressing the extracellular domain of MOG to which FLAG-Fc was added at the C-terminus was thus produced. The nucleotide sequence of rMOG-FLAG-Fc is shown in SEQ ID NO: 69, and the amino acid sequence deduced from the nucleotide sequence is shown in SEQ ID NO: 70.

[0632] INPEP4_rMOG-FLAG-Fc was introduced to suspension 293 cells using Expi293 (trademark) Expression System (manufactured by Thermo Fisher Scientific Inc.), and the cells were cultured to express the protein in a transient expression system. The culture supernatant was collected four days after the introduction of the vector and filtered through a membrane filter having a pore size of 0.22 .mu.m (manufactured by Millipore Corporation.).

[0633] The MOG-FLAG-Fc protein in the culture supernatant was affinity-purified using Protein A resin (MabSelect SuRe, manufactured by GE Healthcare BioSciences). A phosphate buffer solution was used as a washing solution.

[0634] The protein adsorbed on the Protein A was eluted with 20 mM sodium citrate and 50 mM NaCl buffer solution (pH 3.4) and collected in a tube containing 1 M Tris-HCl Buffer Solution (pH 8.0).

[0635] Next, the solvent of the eluate was replaced with PBS by ultrafiltration using VIVASPIN (manufactured by Sartrius stealin) and a NAP column (manufactured by GE Healthcare BioSciences), and then filtration sterilization with a membrane filter having a pore size of 0.22 .mu.m (Millex-GV, manufactured by Millipore Corporation) was conducted. The concentration of the purified MOG-FLAG-Fc protein in the solution was measured from the absorbance at 280 nm.

(2) Production of Extracellular Domain Protein of MOG to Which GST is Bound

[0636] As a soluble antigen of rat MOG, an extracellular domain protein of MOG to which GST was added at the C-terminus was produced by the method described below.

[0637] A gene sequence of the extracellular domain of MOG was synthesized and inserted to the BglII-KpnI site of N5 vector (manufactured by IDEC) to which GST had been inserted, and a plasmid vector N5 rMOG-GST expressing the extracellular domain of MOG to which GST was added at the C-terminus was thus produced. The nucleotide sequence of rMOG-GST is shown in SEQ ID NO: 71, and the amino acid sequence deduced from the nucleotide sequence is shown in SEQ ID NO: 72.

[0638] As a soluble antigen of human HER2, an extracellular domain protein of HER2 to which GST was added at the C-terminus was produced by the method described below. A gene sequence of the extracellular domain of HER2 was synthesized and inserted to the BglII-KpnI site of N5 vector (manufactured by IDEC) to which GST had been inserted, and a plasmid vector N5 hHER2-GST expressing the extracellular domain of HER2 to which GST was added at the C-terminus was thus produced. The nucleotide sequence of hHER2-GST is shown in SEQ ID NO: 71, and the amino acid sequence deduced from the nucleotide sequence is shown in SEQ ID NO: 72.

[0639] N5_rMOG-GST and N5 hHER2-GST were introduced to suspension 293 cells using Expi293 (trademark) Expression System (manufactured by Thermo Fisher Scientific Inc.), and the cells were cultured to express the proteins in a transient expression system. The culture supernatants were collected four days after the introduction of the vectors and filtered through a membrane filter having a pore size of 0.22 .mu.m (manufactured by Millipore Corporation).

[0640] The proteins in the culture supernatants were affinity-purified using Glutathione Sepharose 4B (manufactured by GE Healthcare BioSciences). A phosphate buffer solution was used as a washing solution. The proteins adsorbed on the Glutathione Sepharose 4B were eluted with 50 mM Tris-HCl and 10 mM reduced glutatione (pH 8.0).

[0641] Next, the solvents of the solutions were replaced with PBS by ultrafiltration using VIVASPIN (manufactured by Sartrius stealin) and a NAP column (manufactured by GE Healthcare BioSciences), and then filtration sterilization with a membrane filter having a pore size of 0.22 .mu.m (Millex-GV, manufactured by Millipore Corporation) was conducted. The concentrations of the purified rMOG-GST protein and the hHER2-GST protein in the solutions were measured from the absorbances at 280 nm.

[Example 5] Production of Membrane MOG Antigen Expression Vectors

[0642] The entire gene sequences of rat MOG (rMOG), mouse MOG (mMOG), monkey MOG (cMOG) and human MOG (hMOG) were synthesized, and the gene sequences were each inserted to the BamHI-NotI site of pEF6/V5-His (manufactured by Thermo Fisher Scientific Inc.) vector. Plasmid vectors for expressing MOG in the membrane, pEF6_rMOG, pEF6_mMOG, pEF6_cMOG and pEF6 hMOG were thus produced.

[0643] The nucleotide sequence encoding mMOG is shown in SEQ ID NO: 73, and the amino acid sequence deduced from the nucleotide sequence is shown in SEQ ID NO: 74. The nucleotide sequence encoding cMOG is shown in SEQ ID NO: 75, and the amino acid sequence deduced from the nucleotide sequence is shown in SEQ ID NO: 76. The nucleotide sequence encoding hMOG is shown in SEQ ID NO: 77, and the amino acid sequence deduced from the nucleotide sequence is shown in SEQ ID NO: 78.

[Example 6] Preparation of Antibodies

[0644] The antibody expression plasmid vectors produced in Example 2 and Example 3 were introduced to suspension 293 cells using Expi293.TM. Expression System (manufactured by Thermo Fisher Scientific Inc.), and the cells were cultured to express the antibodies in a transient expression system.

[0645] The culture supernatants were collected four days after the introduction of the vectors and filtered through a membrane filter having a pore size of 0.22 pa (manufactured by Millipore Corporation). The proteins in the culture supernatants were affinity-purified using Protein A resin (MabSelect SuRe, manufactured by GE Healthcare BioSciences). A phosphate buffer solution was used as a washing solution. The antibodies adsorbed on the Protein A were eluted with 20 mM sodium citrate and 50 mM NaCl buffer solution (pH 3.4) and collected in tubes containing 1 M Tris-HCl Buffer Solution (pH 8.0).

[0646] Next, the solvents of the eluates were replaced with PBS by ultrafiltration using VIVASPIN (manufactured by Sartrius stealin) and a NAP column (manufactured by GE Healthcare BioSciences), and then filtration sterilization with a membrane filter having a pore size of 0.22 pa (Millex-GV, manufactured by Millipore Corporation) was conducted. The absorbances of the antibody solutions at 280 nm were measured, and the concentrations of the purified antibodies were calculated by converting the concentration 1 mg/mL to 1.40 Optimal density.

[0647] The anti-MOG human IgG antibodies expressed using the anti-MOG antibody expression vectors, N5LG4PE_MOG01, N5LG4PE_MOG09, N5KG4PE_MOG14 and N5G4PEFc_iMOG-3Rim1-S32 described in Example 2 are referred to as MOG01 antibody, MOG09 antibody, MOG14 antibody and iMOG-3Rim1-S32 antibody, respectively.

[0648] The antibodies obtained by expressing using the bispecific antibody expression vectors, pCI-AVM-hLG4PE(R409K)_AVM scFv, pCI-AVM-hLG4PE(R409K)_MOG01scFv and pCI-Trastuzumab-hKG4PE(R409K)_MOG01scFv produced in Example 3 were named AVM IgG4PE(R409K)_AVM dscFv antibody, AVM IgG4PE(R409K)_MOG01dscFv antibody and Trastuzumab IgG4PE(R409K)_MOG01scFv antibody, respectively.

[Example 7] Evaluation of Affinities of Anti-MOG Antibodies to MOG Using Flow Cytometer

[0649] Binding of the anti-MOG antibodies, MOG01 antibody, MOG09 antibody, MOG14 antibody and iMOG-3Rim1-S32 antibody obtained in Example 6 to MOG were evaluated by the fluorescence activated cell sorting (FACS) method according to the following procedures.

[0650] The membrane MOG antigen expression vectors produced in Example 5 were introduced to suspension 293 cells using FreeStyle (trademark) 293 Expression System (manufactured by Thermo Fisher Scientific Inc.), and the cells were cultured to express the membrane antigens in a transient expression system. Using the cells, the reactivities of the anti-MOG antibodies were analyzed by the method described below.

[0651] rMOG/HEK293F, mMOG/HEK293F, cMOG/HEK293 and hMOG/HEK293 cells were suspended in a Staining Buffer (SB) of PBS containing 0.1% NaN.sub.3 and 1% FBS each at a concentration of 5.times.10.sup.5 cells/mL and dispensed to a round-bottom 96-well plate (manufactured by Becton Dickinson).

[0652] After centrifugation (2000 rpm, 4.degree. C., two minutes), the supernatants were removed, and the antibodies obtained in Example 6 at 10 .mu.g/mL were added to the pellets. After suspending the pellets, the plate was left to stand at ice temperature for 30 minutes. The supernatants were removed after further centrifugation (2000 rpm, 4.degree. C., two minutes), and the pellets were washed with SB. Then, 1 .mu.g/mL RPE fluorescently labeled goat anti-human antibody (manufactured by Southern Bioblot) was added, and the plate was incubated at ice temperature for 30 minutes.

[0653] After washing with SB, the cells were suspended in SB, and the fluorescence intensities of the cells were measured using a flow cytometer FACS CANTO II (manufactured by Becton Dickinson). The results obtained are shown in FIG. 2. As the negative control, an anti-AVM antibody was used.

[0654] As shown in FIG. 2, MOG01 antibody, MOG09 antibody, MOG14 antibody and iMOG-3Rim1-S32 antibody, which are anti-MOG antibodies, all showed binding activity to rMOG/HEK293F cells and mMOG/HEK293F cells. Moreover, MOG01 antibody and MOG14 antibody both showed binding activity also to cMOG/HEK293 cells and hMOG/HEK293 cells.

[0655] Accordingly, it was elucidated that anti-MOG human IgG antibodies, MOG01 and MOG14 recognize and bind to not only rat and mouse MOG but also cynomolgus monkey and human MOG.

[Example 8] Evaluation of Affinities of Anti-MOG Antibodies to MOG by Surface Plasmon Resonance Detection

[0656] The affinities of the anti-MOG antibodies, MOG01 antibody, MOG09 antibody, MOG14 antibody and iMOG-3Rim1-S32 antibody obtained in Example 6 to rat MOG were measured using Biacore T-100 (GE Healthcare).

[0657] The antibodies were immobilized on CMS sensor chips using a Human antibody Capture kit, and the binding abilities were evaluated using rMOG-GST produced in Example 4 as an analyte. The obtained sensorgrams were analyzed with BIA evaluation software, and the dissociation constants (KD values) were thus calculated. The results obtained are shown in Table 3.

TABLE-US-00003 TABLE 3 ka (1/Ms) kd (1/s) KD (M) MOG01 1.4E+05 9.5E-04 6.6E-09 MOG09 9.0E+03 1.9E-07 2.1E-11 MOG14 4.7E+03 1.9E-04 4.0E-08 iMOG-3Rim1-S32 1.4E+06 8.4E-04 6.2E-10

[0658] As shown in Table 3, the dissociation constants (KD values) of the anti-MOG antibodies were 2.1.times.10.sup.-11 (M) to 4.0.times.10.sup.-8 (M), and it was elucidated that all the antibodies show excellent affinity. The dissociation rate constant kd of MOG09 antibody was outside the measurement range of the device, and the KD value could not be determined as a unique value.

[Example 9] Evaluation of Rat Brain Migration Properties of Anti-MOG Antibodies

[0659] An antibody was administered to the tail vein (i.v.) of a rat, and then blood was collected from the tail vein. On the same day of the blood collection, the brain tissues were collected after whole body perfusion under anesthesia with pentobarbital, and the weight was measured. A buffer solution was added to the collected brain tissues, and the brain tissues were homogenized. After centrifugation, the antibody solution eluted in the supernatant was collected. While the volume was measured, the antibody concentration was measured with AlphaLISA (manufactured by PerkinElmer, Inc.). The antibody amount per unit brain weight was calculated.

[0660] With respect to the anti-MOG antibodies, MOG01 antibody, MOG14 antibody and iMOG-3Rim1-S32 antibody and the anti-AVM antibody as a negative control, MOG01 antibody and MOG14 antibody were administered at an amount of 1 mg/kg body weight, and iMOG-3Rim1-S32 antibody was administered at an amount of 5 mg/kg body weight. The antibody concentrations in the serum and the antibody amounts per unit brain weight in the brain tissues four days after the administration of the antibodies are shown in FIGS. 3A and 3B.

[0661] As shown in FIGS. 3A and 3B, it was shown that the antibody concentrations in the serum of all the anti-MOG antibodies did not change as compared to that of the negative control (AVM) but that the antibody amounts in the brain increased to 5-10 times.

[0662] With respect to the anti-MOG antibody, MOG01 antibody, the anti-transferrin receptor antibody, OX26 antibody and the anti-AVM antibody as a negative control, the antibody concentrations in the serum and the antibody amounts per unit brain weight in the brain tissues four days and 10 days after the administration of the antibodies at an amount of 5 mg/kg body weight are shown in FIGS. 4A and 4B.

[0663] As shown in FIG. 4A, the antibody concentration of OX26 antibody in the serum was the lowest of the evaluated antibodies after four days and was equal to or lower than the detection sensitivity after 10 days, and thus the dynamics of the antibody in the blood was poor. The antibody concentration in the serum of MOG01 antibody, which is an anti-MOG antibody, did not change largely four days and 10 days after the administration, and the antibody concentration was equivalent to that of the negative control. This suggests that the half-life of MOG01 antibody in the blood is equivalent to that of the negative control.

[0664] Moreover, as shown in FIG. 4B, with respect to the antibody amounts in the brain, the antibody amount of the negative control was the lowest of the evaluated antibodies four days after the administration, and the antibody amount further decreased after 10 days although it was a slight decrease.

[0665] The antibody amount of OX26 antibody rapidly decreased between four days and 10 days after the administration, and the antibody amount 10 days after the administration was not higher than that of the negative control. On the other hand, the antibody amount of MOG01 antibody increased between four days and 10 days after the administration. The antibody amount four days after the administration was about 2.5 times the amount of the negative control, and the antibody amount 10 days after the administration was about 10 times the amount of the negative control.

[0666] The above results show that, while the anti-MOG antibody, MOG01 antibody shows an antibody concentration equal to that of the negative control in the serum, MOG01 antibody can increase its amount in the brain to about 2.5 times the amount of the negative control four days after the administration and to about 10 times the amounts of the negative control and OX26 antibody 10 days after the administration.

[Example 10] Evaluation of Affinities of Bispecific Antibodies of MOG to MOG or HER2 Using Flow Cytometer

[0667] Binding to MOG or HER2 of the bispecific antibody binding to MOG and Her2, Trastuzumab IgG4PE(R409K)_MOG01 dscFv antibody, the bispecific antibody binding to MOG and AVM, AVM IgG4PE(R409K)_MOG01 dscFv antibody and the antibody binding to AVM, AVM IgG4PE(R409K)_AVM dscFv antibody obtained in Example 6 was evaluated by the fluorescence activated cell sorting (FACS) method according to the following procedures.

[0668] The membrane MOG antigen expression vectors produced in Example 5 were introduced to suspension 293 cells using FreeStyle (trademark) 293 Expression System (manufactured by Thermo Fisher Scientific Inc.), and the cells were cultured to express the membrane antigens in a transient expression system.

[0669] HEK293F cells, rMOG/HEK293F cells, hMOG/HEK293F cells and human breast cancer cell line SK-BR-3 cells were suspended in a Staining Buffer (SB) of PBS containing 0.1% NaN.sub.3 and 1% FBS each at a concentration of 5.times.10.sup.5 cells/mL and dispensed to a round-bottom 96-well plate (manufactured by Becton Dickinson).

[0670] After centrifugation (2000 rpm, 4.degree. C., two minutes), the supernatants were removed, and the antibodies obtained in Example 6 at 10 .mu.g/mL were added to the pellets. After suspending the pellets, the plate was left to stand at ice temperature for 30 minutes. The supernatants were removed after further centrifugation (2000 rpm, 4.degree. C., two minutes), and the pellets were washed with SB. Then, 1 .mu.g/mL RPE fluorescently labeled goat anti-human antibody (manufactured by Southern Bioblot) was added, and the plate was incubated at ice temperature for 30 minutes.

[0671] After washing with SB, the cells were suspended in SB, and the fluorescence intensities of the cells were measured with a flow cytometer FACS CANTO II (manufactured by Becton Dickinson). As the negative control, 10 .mu.g/mL anti-AVM antibody was used. The results of the analysis of the affinities to HEK293F cells, rMOG/HEK293F cells and hMOG/HEK293 cells are shown in FIG. 5.

[0672] From FIG. 5, binding of AVM IgG4PE(R409K)_MOG01 dscFv antibody and Trastuzumab IgG4PE(R409K)_MOG01 dscFv antibody to rMOG/HEK293F cells and hMOG/HEK293 cells can be observed. Thus, it was shown that the antibodies maintain the affinities to rat MOG and human MOG also in the form of bispecific antibody.

[0673] The results of the analysis of the affinities to human breast cancer cell line SK-BR-3 cells are shown in FIG. 6. It is known that HER2 is expressed in the cells.

[0674] From FIG. 6, it was shown that Trastuzumab IgG4PE(R409K)_MOG01 dscFv antibody maintains the affinity to HER2 also in the form of bispecific antibody.

[Example 11] Evaluation of Affinities of Bispecific Antibodies of MOG to MOG by Surface Plasmon Resonance Detection

[0675] The affinities of the bispecific antibodies of MOG to MOG were measured by the same method as that of Example 8, and the results are shown in Table 4.

TABLE-US-00004 TABLE 4 Antibody Name ka (1/Ms) kd (1/s) KD (M) AVM IgG4PE(R409K)_MOG01 dscFv 2.3E+04 4.6E-03 2.0E-07 Trastuzumab IgG4PE(R409K)_MOG01 2.4E+08 2.5E+01 1.0E-07 dscFv

[0676] As shown in Table 4, the dissociation constant (KD value) of the bispecific antibody, AVM IgG4PE(R409K)_MOG01 dscFv antibody was 2.0.times.10.sup.-7 (M), and that of Trastuzumab IgG4PE(R409K)_MOG01 dscFv antibody was 1.0.times.10.sup.-7 (M). It was elucidated that both bispecific antibodies of MOG show excellent affinity.

[0677] The association rate constant ka and the dissociation rate constant kd of Trastuzumab IgG4PE(R409K)_MOG01 dscFv antibody were outside the measurement ranges of the device, and the KD value could not be determined as a unique value.

[Example 12] Evaluation of Affinity of Bispecific Antibody of MOG to HER2 by Surface Plasmon Resonance Detection

[0678] The affinity of the bispecific antibody binding to MOG and HER2, Trastuzumab IgG4PE(R409K)_MOG01 dscFv antibody to HER2 was measured using Biacore T-100 (GE Healthcare).

[0679] The antibody was immobilized on a CMS sensor chip using a Human antibody Capture kit, and the binding ability of the MOG-Her2 bispecific antibody was evaluated using HER2-GST produced in Example 4 as an analyte. The obtained sensorgram was analyzed with BIA evaluation software, and the dissociation constant (KD value) was thus calculated. The results are shown in Table 5.

TABLE-US-00005 TABLE 5 Antibody Name ka (1/Ms) kd (1/s) KD (M) Trastuzumab IgG4PE(R409K)_MOG01 4.7E+04 1.8E-04 3.7E-09 dscFv

[0680] As shown in Table 5, the dissociation constant (KD value) of Trastuzumab IgG4PE(R409K)_MOG01 dscFv antibody to HER2 was 3.7.times.10.sup.-9 (M), and it was elucidated that this is an antibody showing excellent affinity.

[Example 13] Evaluation of Rat Brain Migration Properties of Bispecific Antibodies of MOG

[0681] The rat brain migration properties of the bispecific antibodies, AVM IgG4PE(R409K)_MOG01 dscFv antibody, Trastuzumab IgG4PE(R409K)_MOG01 dscFv antibody and AVM IgG4PE(R409K)_AVM dscFv antibody was evaluated by the same method as that of Example 9. The antibody concentrations in the serum and the antibody amounts per unit brain weight in the brain tissues 10 days after the administration of the antibodies at an amount of 5 mg/kg body weight are shown in FIGS. 7A and 7B.

[0682] As shown in FIG. 7A, as compared to AVM IgG4PE(R409K)_AVM dscFv antibody, which is the negative control of the bispecific antibodies, the antibody concentrations in the serum of AVM IgG4PE(R409K)_MOG01 dscFv antibody and Trastuzumab IgG4PE(R409K)_MOG01 dscFv antibody were not different.

[0683] On the other hand, as shown in FIG. 7B, it was shown that, as compared to AVM IgG4PE(R409K)_AVM dscFv antibody, which is the negative control of the bispecific antibodies, the antibody amounts of AVM IgG4PE(R409K)_MOG01 dscFv antibody and Trastuzumab IgG4PE(R409K)_MOG01 dscFv antibody in the brain increased to about 10 times.

[0684] The above results show that while the bispecific antibodies which bind to MOG can increase the antibody amount in the brain to about 10 times the value of the bispecific antibody which does not bind to MOG, the half-lives in the blood do not change.

[Example 14] Evaluation of Mouse Brain Migration Property of Anti-MOG01 Antibody

(1) Measurement of Antibody Amount

[0685] Several days after administering the antibody to the tail vein (i.v.) of a mouse at 35 nmol/kg, blood was collected from the tail vein. On the same day of the blood collection, the brain tissues were collected after whole body perfusion under anesthesia with pentobarbital, and the weight was measured. A buffer solution was added to the collected brain tissues, and the brain tissues were homogenized. After centrifugation, the antibody solution eluted in the supernatant was collected. While the volume was measured, the antibody concentration was measured with AlphaLISA (manufactured by PerkinElmer, Inc.). The antibody amount per unit brain weight was calculated.

[0686] With respect to the anti-MOG01 human IgG antibody and an anti-AVM human IgG antibody as the negative control, the antibody concentrations in the serum and the antibody amounts per unit brain weight in the brain tissues 3, 6, 10, 14, 21 and 28 days after the administration of the antibodies are shown in FIGS. 8A and 8B, respectively.

[0687] As shown in FIG. 8A, the antibody concentrations of the anti-MOG01 human IgG antibody in the serum were not different from those of the negative control. On the other hand, as shown in FIG. 8B, it was shown that the antibody amount in the brain can be increased to several ten times over 28 days.

(2) Imaging Analysis

[0688] The anti-MOG01 human IgG antibody and the anti-AVM human IgG antibody as the negative control were labeled with Alexa FluorR 488 Protein Labeling Kit (manufactured by Molecular Probes). The labeled antibodies are referred to as AF488-MOG01 IgG4PE antibody and AF488-AVM IgG4PE antibody.

[0689] Several days after administering the labeled antibodies to the tail veins (i.v.) of mice at 10 mg/kg, Tomato lectin was administered, and the blood was collected from the cheeks of the mice. The brain tissues were collected after the blood collection and after whole body perfusion under anesthesia with pentobarbital, and the fluorescence intensities were measured with IVIS Spectrum (manufactured by PerkinElmer, Inc.). The brain images after six days are shown in FIG. 9A, and the brain images after 14 days are shown in FIG. 9B. The fluorescence amounts in the brain corrected with the fluorescence intensities of the administered antibodies are shown in FIG. 9C.

[0690] As shown in FIGS. 9A to 9C, it was shown that the anti-MOG01 antibody can increase the antibody amount to several ten times over the entire brain as compared to the negative control.

[Example 15] Construction of Bispecific Antibody Expression Vectors

[0691] Vectors expressing bispecific antibodies which have any of the structures described in FIGS. 10A to 10C and FIGS. 11A and 11B and which bind to AVM and MOG were produced by the following method. The names of the bispecific antibodies and the names of the antibody expression vectors are shown in Table 6, and the names of the antibody expression vectors, the nucleotide sequences of the antibodies and the amino acid sequences deduced from the nucleotide sequences are shown in Table 7.

TABLE-US-00006 TABLE 6 Name of Bispecific Antibody Name of Antibody Expression Vector AVM-MOG01 IgG4PE(R409K) antibody pCI-AVM-hLG4PE(R409K/S354C/T366W)-FLAG tag pCI-MOG01-hLG4PE(R409K/Y349C/T366S/L368A/Y407V)-His tag AVM IgG4PE(R409K)_MOG01 Fab antibody pCI-AVM-hLG4PE(R409K)-linker-MOG01VL-CL pCI-MOG01VH-CH AVM IgG4PE(R409K)_MOG01 sscFv antibody pCI-AVM-hLG4PE(R409K/S354C/T366W)-linker-MOG01scFv-FLAG tag pCI-AVM-hLG4PE(R409K/Y349C/T366S/L368A/Y407V)-His tag AVM IgG4PE(R409K)_MOG01dscFv2 antibody pCI-AVM-hLG4PE(R409K)_MOG01scFv2 AVM IgG4PE(R409K)_MOG01dscFv3 antibody pCI-AVM-hLG4PE(R409K)_MOG01scFv3 AVM IgG4PE(R409K)_MOG01dscFv4 antibody pCI-AVM-hLG4PE(R409K)_MOG01scFv4 AVM IgG4PE(R409K)_MOG01dscFv5 antibody pCI-AVM-hLG4PE(R409K)_MOG01scFv5 AVM IgG4PE(R409K)_MOG01dscFv6 antibody pCI-AVM-hLG4PE(R409K)_MOG01scFv6 AVM IgG4PE(R409K)_MOG01dscFv7 antibody pCI-AVM-hLG4PE(R409K)_MOG01scFv7 AVM IgG4PE(R409K)_MOG01dscFv8 antibody pCI-AVM-hLG4PE(R409K)_MOG01scFv8 AVM IgG4PE(R409K)_MOG01dscFv9 antibody pCI-AVM-hLG4PE(R409K)_MOG01scFv9 AVM IgG4PE(R409K)_MOG01dscFv10 antibody pCI-AVM-hLG4PE(R409K)_MOG01scFv10 AVM IgG4PE(R409K)_MOG01dscFv11 antibody pCI-AVM-hLG4PE(R409K)_MOG01scFv11

TABLE-US-00007 TABLE 7 Nucleotide Sequence of Heavy Chain Amino Acid Sequence of Light Chain Antibody Sequence Heavy Chain Antibody Antibody (excluding signal Sequence (excluding Name of Antibody Expression Vector Sequence sequence) signal sequence) pCI-AVM-hLG4PE(R409K/S354C/T366W)-FLAG tag AVM SEQ ID NO: 108 SEQ ID NO: 109 pCI-MOG01-hLG4PE(R409K/Y349C/T366S/L368A/Y407V)-His tag MOG01 SEQ ID NO: 110 SEQ ID NO: 111 pCI-AVM-hLG4PE(R409K)-linker-MOG01VL-CL AVM SEQ ID NO: 112 SEQ ID NO: 113 pCI-MOG01VH-CH None SEQ ID NO: 114 SEQ ID NO: 115 pCI-AVM-hLG4PE(R409K/S354C/T366W)-linker-MOG01scFv-FLAG AVM SEQ ID NO: 116 SEQ ID NO: 117 pCI-AVM-hLG4PE(R409K/Y349C/T366S/L368A/Y407V)-His tag AVM SEQ ID NO: 118 SEQ ID NO: 119 pCI-AVM-hLG4PE(R409K)_MOG01scFv2 AVM SEQ ID NO: 120 SEQ ID NO: 121 pCI-AVM-hLG4PE(R409K)_MOG01scFv3 AVM SEQ ID NO: 122 SEQ ID NO: 123 pCI-AVM-hLG4PE(R409K)_MOG01scFv4 AVM SEQ ID NO: 124 SEQ ID NO: 125 pCI-AVM-hLG4PE(R409K)_MOG01scFv5 AVM SEQ ID NO: 126 SEQ ID NO: 127 pCI-AVM-hLG4PE(R409K)_MOG01scFv6 AVM SEQ ID NO: 128 SEQ ID NO: 129 pCI-AVM-hLG4PE(R409K)_MOG01scFv7 AVM SEQ ID NO: 130 SEQ ID NO: 131 pCI-AVM-hLG4PE(R409K)_MOG01scFv8 AVM SEQ ID NO: 132 SEQ ID NO: 133 pCI-AVM-hLG4PE(R409K)_MOG01scFv9 AVM SEQ ID NO: 134 SEQ ID NO: 135 pCI-AVM-hLG4PE(R409K)_MOG01scFv10 AVM SEQ ID NO: 136 SEQ ID NO: 137 pCI-AVM-hLG4PE(R409K)_MOG01scFv11 AVM SEQ ID NO: 138 SEQ ID NO: 139

(1) Construction of Bispecific Antibody Expression Vectors Related to Structure in FIG. 10A

[0692] (1-1) Construction of pCI-AVM-hLG4PE(R409K/S354C/T366W)-FLAG tag Vector

[0693] A gene fragment of the CH1-Hinge-CH2-CH3(R409K/S354C/T366W) region was amplified by PCR using a synthetic gene as a template and inserted to the NheI-BamHI site of pCI-AVM-hLG4PE(R409K)_AVMscFv, and pCI-AVM-hLG4PE(R409K/S354C/T366W)-FLAG tag vector was produced.

(1-2) Construction of pCI-MOG01-hLG4PE(R409K/Y349C/T366S/L368A/Y407V)-His tag Vector

[0694] A gene fragment of the CH1-Hinge-CH2-CH3(R409K/Y349C/T366S/L368A/Y407V)-His tag region was amplified by PCR using a synthetic gene as a template. Moreover, a gene fragment of the MOG01 light chain region and a gene fragment of the MOG01 VH region were amplified by PCR using N5LG4PE_MOG01 as a template. The obtained gene fragments were inserted to pCI vector (manufactured by Promega Corporation), and pCI-MOG01-hLG4PE(R409KN349C/T366S/L368A/Y407V)-His tag vector was produced.

(2) Construction of Bispecific Antibody Expression Vectors Related to Structure in FIG. 10B

[0695] (2-1) Construction of pCI-AVM-hLG4PE(R409K)-linker-MOG01VL-CL Vector

[0696] A gene fragment of the CH1-Hinge-CH2-CH3-linker-MOG01VL-CL region was amplified by PCR using a synthetic gene as a template and inserted to the NheI-BamHI site of pCI-AVM-hLG4PE(R409K)_AVMscFv, and pCI-AVM-hLG4PE(R409K)-linker-MOG01VL-CL vector was produced.

(2-2) Construction of pCI-MOG01VH-CH Vector

[0697] A gene fragment of the MOG01VH-CH region was amplified by PCR using a synthetic gene as a template and inserted to pCI vector (manufactured by Promega Corporation), and pCI-MOG01VH-CH vector was produced.

(3) Construction of Bispecific Antibody Expression Vectors Related to Structure in FIG. 10C

[0698] (3-1) Construction of pCI-AVM-hLG4PE(R409K/S354C/T366W)-linker-MOG01scFv-FLAG Tag Vector

[0699] A gene fragment of the CH1-Hinge-CH2-CH3(R409K/S354C/T366W)-linker region was amplified by PCR using a synthetic gene as a template. Moreover, a gene fragment of the linker-MOG01scFv region was amplified by PCR using MOG01scFv as a template. Furthermore, a gene fragment of the linker-MOG01scFv-FLAG tag region was amplified by PCR using the PCR product as a template. The gene fragments of the CH1-Hinge-CH2-CH3(R409K/S354C/T366W)-linker region and the linker-MOG01scFv-FLAG tag region were inserted to the NheI-BamHI site of pCI-AVM-hLG4PE(R409K)_AVM scFv, and pCI-AVM-hLG4PE(R409K/S354C/T366W)-linker-MOG01scFv-FLAG tag vector was produced.

(3-2) Construction of pCI-AVM-hLG4PE(R409KN349C/T366S/L368A/Y407V)-His Tag Vector

[0700] A gene fragment of the CH1-Hinge-CH2-CH3(R409K/Y349C/T366S/L368A/Y407V)-His tag region was amplified by PCR using a synthetic gene as a template and inserted to the NheI-BamHI site of pCI-AVM-hLG4PE(R409K)_AVMscFv, and pCI-AVM-hLG4PE(R409K/Y349C/T366S/L368A/Y407V)-His tag vector was produced.

(4) Construction of Vectors Expressing Bispecific Antibodies Having Structures in FIGS. 11A and 11B

[0701] (4-1) Construction of pCI-AVM-hLG4PE(R409K)_MOG01scFv Vector

[0702] A gene fragment of the CH1-Hinge-CH2-CH3-linker region was amplified by PCR using a synthetic gene as a template. Moreover, a gene fragment of the VH region and the VL region of MOG01 was amplified by PCR using MOG01scFv as a template. The gene fragment of the CH1-Hinge-CH2-CH3-linker region and the gene fragment of the VH region and the VL region of MOG01 were inserted to the NheI-BamHI site of pCI-AVM-hLG4PE(R409K)_AVMscFv, and pCI-AVM-hLG4PE(R409K)_MOG01scFv2 vector was produced.

[0703] In the same manner, pCI-AVM-hLG4PE(R409K)_MOG01scFv3 vector, pCI-AVM-hLG4PE(R409K)_MOG01scFv4 vector, pCI-AVM-hLG4PE(R409K)_MOG01scFv5 vector, pCI-AVM-hLG4PE(R409K)_MOG01scFv6 vector, pCI-AVM-hLG4PE(R409K)_MOG01scFv7 vector, pCI-AVM-hLG4PE(R409K)_MOG01scFv8 vector, pCI-AVM-hLG4PE(R409K)_MOG01scFv9 vector, pCI-AVM-hLG4PE(R409K)_MOG01scFv10 vector and pCI-AVM-hLG4PE(R409K)_MOG01scFv11 vector were produced.

(5) Construction of Vectors Expressing Antibodies as Negative Controls

[0704] The antibodies as the negative controls were produced by the following method. The names of the antibodies and the names of the antibody expression vectors are shown in Table 8, and the names of the antibody expression vectors, the nucleotide sequences of the antibodies and the amino acid sequences deduced from the nucleotide sequences are shown in Table 9.

TABLE-US-00008 TABLE 8 Name of Negative Control Antibody Name of Antibody Expression Vector AVM IgG4PE(R409K) antibody pCI-AVM-hLG4PE(R409K) AVM IgG4PE(R409K)_AVM Fab antibody pCI-AVM-hLG4PE(R409K)-linker-AVMVL-CL pCI-AVMVH-CH AVM IgG4PE(R409K)_AVMsscFv antibody pCI-AVM-hLG4PE(R409K/S354C/T366W)-linker-AVMscFv-FLAG tag pCI-AVM-hLG4PE(R409K/Y349C/T366S/L368A/Y407V)-His tag AVM IgG4PE(R409K)_AVMdscFv3 antibody pCI-AVM-hLG4PE(R409K)_AVMscFv3 AVM IgG4PE(R409K)_AVMdscFv5 antibody pCI-AVM-hLG4PE(R409K)_AVMscFv5

TABLE-US-00009 TABLE 9 Nucleotide Sequence of Amino Acid Sequence of Light Chain Heavy Chain Antibody Heavy Chain Antibody Antibody Sequence (excluding Sequence (excluding Name of Antibody Expression Vector Sequence signal sequence) signal sequence) pCI-AVM-hLG4PE(R409K)-linker-AVMVL-CL AVM SEQ ID NO: 140 SEQ ID NO: 141 pCI-AVMVH-CH None SEQ ID NO: 142 SEQ ID NO: 143 pCI-AVM-hLG4PE(R409K/S354C/T366W)-linker-AVMscFv-FLAG tag AVM SEQ ID NO: 144 SEQ ID NO: 145 pCI-AVM-hLG4PE(R409K)_AVMscFv3 AVM SEQ ID NO: 146 SEQ ID NO: 147 pCI-AVM-hLG4PE(R409K)_AVMscFv5 AVM SEQ ID NO: 148 SEQ ID NO: 149

(2-1) Production of pCI-AVM-hLG4PE(R409K) Vector

[0705] A gene fragment of the VH region, the VL region and the antibody constant region of AVM was amplified by PCR using a synthetic gene as a template and inserted to pCI vector (manufactured by Promega Corporation), and pCI-AVM-hLG4PE(R409K) vector was produced.

(2-2) Production of pCI-AVM-hLG4PE(R409K)-linker-AVMVL-CL Vector

[0706] A gene fragment of the CH1-Hinge-CH2-CH3-linker-AVMVL-CL region was amplified by PCR using a synthetic gene as a template and inserted to the NheI-BamHI site of pCI-AVM-hLG4PE(R409K)_AVM scFv, and pCI-AVM-hLG4PE(R409K)-linker-AVMVL-CL vector was produced.

(2-3) Construction of pCI-AVMVH-CH Vector

[0707] A gene fragment of the AVMVH-CH region was amplified by PCR using a synthetic gene as a template and inserted to pCI vector (manufactured by Promega Corporation), and pCI-AVMVH-CH vector was produced.

(2-4) Construction of pCI-AVM-hLG4PE(R409K/S354C/T366W)-linker-AVMscFv-FLAG Tag Vector

[0708] A gene fragment of the CH1-Hinge-CH2-CH3(R409K/S354C/T366W)-linker region was amplified by PCR using a synthetic gene as a template. Moreover, a gene fragment of the linker-AVMscFv-FLAG tag region was amplified by PCR using N5LG4PE_AVM as a template. The gene fragments of the CH1-Hinge-CH2-CH3(R409K/S354C/T366W)-linker region and the linker-AVMscFv-FLAG tag region were inserted to the NheI-BamHI site of pCI-AVM-hLG4PE(R409K)_AVM scFv, and pCI-AVM-hLG4PE(R409K/S354C/T366W)-linker-AVMscFv-FLAG tag vector was produced.

(2-5) Construction of pCI-AVM-hLG4PE(R409K)_AVMscFv Vector

[0709] A gene fragment of the CH1-Hinge-CH2-CH3-linker region was amplified by PCR using a synthetic gene as a template. Moreover, a gene fragment of the VH region and the VL region of AVM was amplified by PCR using N5LG4PE_AVM as a template. The gene fragment of the CH1-Hinge-CH2-CH3-linker region and the gene fragment of the VH region and the VL region of AVM were inserted to the NheI-BamHI site of pCI-AVM-hLG4PE(R409K)_AVMscFv, and pCI-AVM-hLG4PE(R409K)_AVMscFv3 vector and pCI-AVM-hLG4PE(R409K)_AVMscFv5 vector were produced.

[Example 16] Preparation of Bispecific Antibodies

[0710] By the method described in Example 6, AVM IgG4PE(R409K)_MOG01 Fab antibody, AVM IgG4PE(R409K)_MOG01dscFv2 antibody, AVM IgG4PE(R409K)_MOG01dscFv3 antibody, AVM IgG4PE(R409K)_MOG01dscFv4 antibody, AVM IgG4PE(R409K)_MOG01dscFv5 antibody, AVM IgG4PE(R409K)_MOG01dscFv6 antibody, AVM IgG4PE(R409K)_MOG01 dscFv7 antibody, AVM IgG4PE(R409K)_MOG01dscFv8 antibody, AVM IgG4PE(R409K)_MOG01dscFv9 antibody, AVM IgG4PE(R409K)_MOG01dscFv10 antibody, AVM IgG4PE(R409K)_MOG01dscFv11 antibody, AVM IgG4PE(R409K)_AVM Fab antibody, AVM IgG4PE(R409K)_AVMdscFv3 antibody and AVM IgG4PE(R409K)_AVMdscFv5 antibody were prepared.

[0711] AVM-MOG01 IgG4PE(R409K) antibody, AVM IgG4PE(R409K)_MOG01sscFv antibody and AVM IgG4PE(R409K)_AVMsscFv antibody were prepared by the method described below. The antibody expression plasmid vectors were introduced to suspension 293 cells using Expi293 (trademark) Expression System (manufactured by Thermo Fisher Scientific Inc.), and the cells were cultured to express the antibodies in a transient expression system.

[0712] The culture supernatants were collected four days after the introduction of the vectors and filtered through a membrane filter having a pore size of 0.22 .mu.m (manufactured by Millipore Corporation). The proteins in the culture supernatants were affinity-purified with His tag using Ni Sepharose resin (manufactured by GE Healthcare BioSciences). A 20 mM Imidazole-phosphate buffer solution was used as a washing solution.

[0713] The antibodies adsorbed on the Ni Sepharose resin were eluted with a 500 mM Imidazole-phosphate buffer solution. Next, the solvents of the eluates were replaced with PBS by ultrafiltration using VIVASPIN (manufactured by Sartrius stealin) and a NAP column (manufactured by GE Healthcare BioSciences).

[0714] The proteins after the His tag purification were affinity-purified using FLAG antibody affinity gel (manufactured by Sigma-Aldrich Co. LLC.). A phosphate buffer solution was used as a washing solution. The antibodies adsorbed on the FLAG antibody affinity gel were eluted with 20 mM sodium citrate and 50 mM NaCl buffer solution (pH 3.4) and collected in tubes containing 1 M Tris-HCl Buffer Solution (pH 8.0).

[0715] Next, the solvents of the eluates were replaced with PBS by ultrafiltration using VIVASPIN (manufactured by Sartrius stealin) and a NAP column (manufactured by GE Healthcare BioSciences), and then filtration sterilization with a membrane filter having a pore size of 0.22 .mu.m (Millex-GV, manufactured by Millipore Corporation) was conducted. The absorbances of the antibody solutions at 280 nm were measured, and the concentrations of the purified antibodies were calculated.

[Example 17] Evaluation of Affinities of Bispecific Antibodies to MOG Using Flow Cytometer

[0716] Binding of the bispecific antibodies and the negative control antibodies obtained in Example 6 and Example 16 to MOG was evaluated by the fluorescence activated cell sorting (FACS) method according to the following procedures.

[0717] pEF6_hMOG obtained in Example 5 was introduced to mouse connective tissue-derived fibroblast L929 cells [American Type Culture Collection (ATCC) No.: CCL-1] using HilyMax (manufactured by Dojindo Laboratories). The gene-transfected cells were selected using an antibiotic substance, Blasticidin (manufactured by Invitrogen) and then cloned by the limiting dilution method. Using the L929 cells expressing hMOG on the cell surface (abbreviated as hMOG/L929 below), the reactivities of the bispecific antibodies were analyzed by the method described below.

[0718] The hMOG/L929 cells were suspended in a Staining Buffer (SB) of PBS containing 0.1% NaN.sub.3 and 1% FBS and dispensed to a round-bottom 96-well plate (manufactured by Becton Dickinson). After centrifugation (2000 rpm, 4.degree. C., two minutes), the supernatants were removed, and the MOG01 bispecific antibodies obtained in Example 6 and Example 16 were added to the pellets. After suspending the pellets, the plate was left to stand at ice temperature for 30 minutes. The supernatants were removed after further centrifugation (2000 rpm, 4.degree. C., two minutes), and the pellets were washed with SB. Then, 1 .mu.g/mL RPE fluorescently labeled goat anti-human antibody (manufactured by Southern Biotech) was added, and the plate was incubated at ice temperature for 30 minutes. After washing with SB, the cells were suspended in SB, and the fluorescence intensities of the cells were measured with a flow cytometer FACS CANTO II (manufactured by Becton Dickinson). The results are shown in FIGS. 12A to 12C and FIGS. 13A and 13B.

[0719] As shown in FIGS. 12A to 12C and FIGS. 13A and 13B, it was confirmed that all the bispecific antibodies have affinity to MOG. In particular, it was elucidated that the affinities of AVM IgG4PE(R409K)_MOG01Fab antibody [FIG. 10B and FIG. 12C], AVM IgG4PE(R409K)_MOG01dscFv3 antibody, AVM IgG4PE(R409K)_MOG01dscFv5 antibody, AVM IgG4PE(R409K)_MOG01dscFv6 antibody, AVM IgG4PE(R409K)_MOG01dscFv7 antibody, AVM IgG4PE(R409K)_MOG01 dscFv8 antibody, AVM IgG4PE(R409K)_MOG01dscFv9 antibody, AVM IgG4PE(R409K)_MOG01dscFv10 antibody and AVM IgG4PE(R409K)_MOG01dscFv11 antibody [FIG. 11B and FIG. 13B] are high.

[Example 18] Evaluation of Affinities of Bispecific Antibodies to MOG by Surface Plasmon Resonance Detection

[0720] Binding of the bispecific antibodies obtained in Example 6 and Example 16 to MOG was evaluated by the same method as that of Example 8. The results obtained are shown in Table 10 and Table 11.

TABLE-US-00010 TABLE 10 Antibody Name ka (1/Ms) kd (1/s) KD (M) AVM-MOG01 IgG4PE(R409K) 1.3E+05 1.6E-03 1.2E-08 antibody AVM IgG4PE(R409K)_MOG01sscFv 5.1E+04 1.0E-02 2.0E-07 antibody AVM IgG4PE(R409K)_MOG01 Fab 1.0E+05 3.5E-03 3.4E-08 antibody

TABLE-US-00011 TABLE 11 Antibody Name ka (1/Ms) kd (1/s) KD (M) AVM IgG4PE(R409K)_MOG01dscFv 2.4E+04 4.9E-03 2.0E-07 antibody AVM IgG4PE(R409K)_MOG01dscFv3 1.7E+05 2.2E-03 1.3E-08 antibody AVM IgG4PE(R409K)_MOG01dscFv5 2.0E+05 4.8E-03 2.4E-08 antibody

[0721] As shown in Table 10 and Table 11, the dissociation constants (KD values) of the bispecific antibodies of MOG were 1.2.times.10.sup.-8 (M) to 2.0.times.10.sup.-7 (M), and it was elucidated that all the antibodies show excellent affinity.

[0722] In particular, it was elucidated that the affinities of AVM-MOG01 IgG4PE(R409K) antibody [FIG. 10A], AVM IgG4PE(R409K)_MOG01Fab antibody [FIG. 10B], AVM IgG4PE(R409K)_MOG01dscFv3 antibody and AVM IgG4PE(R409K)_MOG01dscFv5 antibody [FIG. 11B] are high.

[Example 19] Evaluation of Mouse Brain Migration Properties of Bispecific Antibodies

[0723] The mouse brain migration properties of the bispecific antibodies and the negative control antibodies obtained in Example 6 and Example 16 were evaluated by the method of Example 14.

[0724] AVM-MOG01 IgG4PE(R409K) antibody, AVM IgG4PE(R409K)_MOG01sscFv antibody and AVM IgG4PE(R409K)_MOG01 Fab antibody were administered at 5 mg/kg, and the antibody concentrations in the serum and the antibody amounts per unit brain weight in the brain tissues after 10 days are shown in FIG. 14A to FIG. 16B.

[0725] As shown in FIG. 14A, FIG. 15A and FIG. 16A, the antibody concentrations of all the MOG01 modified antibodies in the serum were not different from those of the negative controls. On the other hand, as shown in FIG. 14B, FIG. 15B and FIG. 16B, it was shown that the antibody amounts in the brain increase to about eight times in the case of AVM-MOG01 IgG4PE(R409K) antibody, about 12 times in the case of AVM IgG4PE(R409K)_MOG01sscFv antibody and about 30 times in the case of AVM IgG4PE(R409K)_MOG01 Fab antibody as compared to those of the negative controls.

[0726] The above results show that while the bispecific antibodies which bind to MOG can increase the antibody amount in the brain as compared to those of the negative control antibodies which do not bind to MOG, the half-lives in the blood do not change.

[0727] AVM IgG4PE(R409K)_MOG01dscFv antibody, AVM IgG4PE(R409K)_MOG01dscFv3 antibody and AVM IgG4PE(R409K)_MOG01dscFv5 antibody were administered at 5 mg/kg, and the antibody concentrations in the serum and the antibody amounts per unit brain weight in the brain tissues after 10 days and after 28 days are shown in FIGS. 17A to 17D.

[0728] As shown in FIGS. 17A and 17C, the antibody concentrations of all the bispecific antibodies in the serum were not different from those of the negative controls. On the other hand, as shown in FIGS. 17B and 17D, it was shown that the antibody amounts in the brain of AVM IgG4PE(R409K)_MOG01dscFv antibody, AVM IgG4PE(R409K)_MOG01dscFv3 antibody and AVM IgG4PE(R409K)_MOG01dscFv5 antibody can be increased to several ten times over 28 days. Moreover, as shown in FIG. 17D, when the antibody amounts in the brain were high after 28 days, the affinities of the bispecific antibodies to MOG were also high (Table 11). It was elucidated that there is a correlation between the MOG binding activity and the antibody amount in the brain.

[Example 20] Acquisition of Novel MOG Antibodies Showing Higher Affinity to MOG than Anti-MOG01 Antibody

(1) Production of Extracellular Domain Proteins of Soluble Human MOG Antigen and Soluble Mouse MOG Antigen to Which FLAG-Fc is Bound

[0729] Plasmid vectors, INPEP4 hMOG-FLAG-Fc and INPEP4 mMOG-FLAG-Fe, which each express an extracellular domain protein of MOG to which FLAG-Fc was added at the C-terminus, as soluble antigens of human MOG and mouse MOG were produced by the method described in Example 4. The nucleotide sequence of hMOG-FLAG-Fc is shown in SEQ ID NO: 100, and the amino acid sequence deduced from the nucleotide sequence is shown in SEQ ID NO: 101. The nucleotide sequence of mMOG-FLAG-Fc is shown in SEQ ID NO: 102, and the amino acid sequence deduced from the nucleotide sequence is shown in SEQ ID NO: 103. The extracellular domain proteins of MOG to which FLAG-Fc was bound were obtained by transiently expressing and purifying the proteins by the method described in Example 4.

(2) Production of Extracellular Domain Proteins of MOG to Which GST is Bound

[0730] Plasmid vectors, N5 hMOG-GST and N5 mMOG-GST, which each express an extracellular domain protein of MOG to which GST was added at the C-terminus, as soluble antigens of human MOG and mouse MOG were produced by the method described in Example 4. The nucleotide sequence of hMOG-GST is shown in SEQ ID NO: 104, and the amino acid sequence deduced from the nucleotide sequence is shown in SEQ ID NO: 105. The nucleotide sequence of mMOG-GST is shown in SEQ ID NO: 106, and the amino acid sequence deduced from the nucleotide sequence is shown in SEQ ID NO: 107. The extracellular domain proteins of MOG to which GST was bound were obtained by transiently expressing and purifying the proteins by the method described in Example 4.

(3) Acquisition of Anti-MOG Antibodies from Human Antibody-Producing Mice

[0731] hMOG-GST and mMOG-GST were mixed with pertussis vaccine and Alumgel and intraperitoneally or intradermally administered to human antibody-producing mice (Ishida & Lonberg, IBC's 11th Antibody Engineering, Abstract 2000; Ishida, I. et al., Cloning & Stem Cells 4, 85-96 (2002) and Ishida Isao (2002) Experimental Medicine 20, 6, 846-851).

[0732] After the first immunization, the mice were immunized with hMOG-GST and mMOG-GST three times. The individuals immunized by intraperitoneal administration were dissected four days after the final immunization, and the spleens were taken. After removing the red blood cells using a reagent for removing red blood cells (manufactured by Sigma Co. LLC.), the spleens were frozen with CELLBANKER 1 (manufactured by Nippon Zenyaku Kogyo Co., Ltd.). The individuals immunized by intradermal administration were dissected, and the axillary lymph nodes were taken. After removing the red blood cells using a reagent for removing red blood cells, the axillary lymph nodes were frozen with CELLBANKER 1. RNAs were extracted from the obtained spleen cells and the cells of the axillary lymph nodes using an RNeasy Plus Mini kit (manufactured by QIAGEN), and cDNAs were synthesized with a SMARTer RACE cDNA amplification kit (manufactured by Clontech Laboratories, Inc.). Human antibody-producing mouse-derived phage libraries were produced using the synthesized cDNAs by the method described in Example 1.

[0733] Anti-human MOG monoclonal antibodies were obtained using the human antibody-producing mouse-derived phage libraries by the phage display method. The phage display method and cloning ELISA were conducted using hMOG-FLAG_Fc and mMOG-FLAG_Fc by the methods described in Example 1.

[0734] The sequences of the clones which bound to hMOG-FLAG_Fc, mMOG-FLAG_Fc and hMOG/Expi293F cells were analyzed, and anti-MOG antibody phagemid vectors, pCANTAB_MOG301, pCANTAB_MOG303, pCANTAB_MOG307, pCANTAB_MOG310, pCANTAB_MOG312, pCANTAB_MOG326, pCANTAB_MOG329, pCANTAB_MOG446, pCANTAB_MOG456 and pCANTAB_MOG473 were obtained.

[0735] In the following paragraphs, the names of the anti-MOG scFv antibodies displayed by the phages expressed using pCANTAB_MOG301, pCANTAB_MOG303, pCANTAB_MOG307, pCANTAB_MOG310, pCANTAB_MOG312, pCANTAB_MOG326, pCANTAB_MOG329, pCANTAB_MOG446, pCANTAB_MOG456 and pCANTAB_MOG473 are referred to as MOG301 antibody, MOG303 antibody, MOG307 antibody, MOG310 antibody, MOG312 antibody, MOG326 antibody, MOG329 antibody, MOG446 antibody, MOG456 antibody and MOG473 antibody, respectively.

[0736] The nucleotide sequences which encode VH or VL of the anti-MOG antibodies and the amino acid sequences deduced from the nucleotide sequences are shown in Table 12.

TABLE-US-00012 TABLE 12 Clone Name MOG301 MOG303 MOG307 MOG310 MOG312 MOG326 MOG329 MOG446 MOG456 MOG473 Nucleotide sequence SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID encoding VH (excluding NO: 151 NO: 161 NO: 171 NO: 181 NO: 191 NO: 201 NO: 211 NO: 221 NO: 231 NO: 241 signal sequence) Amino acid sequence SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID of VH (excluding NO: 152 NO: 162 NO: 172 NO: 182 NO: 192 NO: 202 NO: 212 NO: 222 NO: 232 NO: 242 signal sequence) Amino acid sequence of SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID HCDR1 NO: 153 NO: 163 NO: 173 NO: 183 NO: 193 NO: 203 NO: 213 NO: 223 NO: 233 NO: 243 Amino acid sequence of SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID HCDR2 NO: 154 NO: 164 NO: 174 NO: 184 NO: 194 NO: 204 NO: 214 NO: 224 NO: 234 NO: 244 Amino acid sequence of SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID HCDR3 NO: 155 NO: 165 NO: 175 NO: 185 NO: 195 NO: 205 NO: 215 NO: 225 NO: 235 NO: 245 Nucleotide sequence SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID encoding VL (excluding NO: 156 NO: 166 NO: 176 NO: 186 NO: 196 NO: 206 NO: 216 NO: 226 NO: 236 NO: 246 signal sequence) Amino acid sequence SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID of VL (excluding NO: 157 NO: 167 NO: 177 NO: 187 NO: 197 NO: 207 NO: 217 NO: 227 NO: 237 NO: 247 signal sequence) Amino acid sequence of SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID LCDR1 NO: 158 NO: 168 NO: 178 NO: 188 NO: 198 NO: 208 NO: 218 NO: 228 NO: 238 NO: 248 Amino acid sequence of SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID LCDR2 NO: 159 NO: 169 NO: 179 NO: 189 NO: 199 NO: 209 NO: 219 NO: 229 NO: 239 NO: 249 Amino acid sequence of SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID LCDR3 NO: 160 NO: 170 NO: 180 NO: 190 NO: 200 NO: 210 NO: 220 NO: 230 NO: 240 NO: 250

[0737] Moreover, clones having similar sequences having homology of 91 to 93% to that of MOG301 antibody (MOG426 and MOG428), clones having similar sequences having homology of 85 to 95% to that of MOG303 antibody (MOG313, MOG314, MOG315, MOG331, MOG357 and MOG476), clones having similar sequences having homology of 97 to 99% to that of MOG307 antibody (MOG323, MOG341, MOG354 and MOG355), clones having similar sequences having homology of 85 to 98% to that of MOG310 antibody (MOG308, MOG316, MOG319, MOG320, MOG338, MOG352, MOG359 and MOG478), a clone having a similar sequence having homology of 85% to that of MOG329 antibody (MOG470) and a clone having a similar sequence having homology of 84% to that of MOG456 antibody (MOG418) were obtained by the phage display method using MOG affinity as an index. Because it was confirmed that these similar clones bind to hMOG-FLAG_Fc, mMOG-FLAG_Fc and hMOG/Expi293F cells, it was elucidated that antibody clones having high homology to the amino acid sequences of the antibody clones are also antibodies having MOG binding activity.

[0738] The nucleotide sequences which encode VH or VL of the similar clones and the amino acid sequences deduced from the nucleotide sequences are shown in Table 13, and comparisons of the amino acid sequences of the similar clones are shown in FIG. 18 to FIG. 22B.

TABLE-US-00013 TABLE 13 Name of Nucleotide sequence Amino acid sequence of Nucleotide sequence Amino acid sequence Representative Name of encoding VH (excluding VH (excluding signal encoding VL (excluding of VL (excluding signal Clone Similar Clone signal sequence) sequence) signal sequence) sequence) MOG301 MOG426 SEQ ID NO: 251 SEQ ID NO: 252 SEQ ID NO: 253 SEQ ID NO: 254 MOG428 SEQ ID NO: 255 SEQ ID NO: 256 SEQ ID NO: 257 SEQ ID NO: 258 MOG303 MOG313 SEQ ID NO: 259 SEQ ID NO: 260 SEQ ID NO: 261 SEQ ID NO: 262 MOG314 SEQ ID NO: 263 SEQ ID NO: 264 SEQ ID NO: 265 SEQ ID NO: 266 MOG315 SEQ ID NO: 267 SEQ ID NO: 268 SEQ ID NO: 269 SEQ ID NO: 270 MOG331 SEQ ID NO: 271 SEQ ID NO: 272 SEQ ID NO: 273 SEQ ID NO: 274 MOG357 SEQ ID NO: 275 SEQ ID NO: 276 SEQ ID NO: 277 SEQ ID NO: 278 MOG476 SEQ ID NO: 279 SEQ ID NO: 280 SEQ ID NO: 281 SEQ ID NO: 282 MOG307 MOG323 SEQ ID NO: 283 SEQ ID NO: 284 SEQ ID NO: 285 SEQ ID NO: 286 MOG341 SEQ ID NO: 287 SEQ ID NO: 288 SEQ ID NO: 289 SEQ ID NO: 290 MOG354 SEQ ID NO: 291 SEQ ID NO: 292 SEQ ID NO: 293 SEQ ID NO: 294 MOG355 SEQ ID NO: 295 SEQ ID NO: 296 SEQ ID NO: 297 SEQ ID NO: 298 MOG310 MOG308 SEQ ID NO: 299 SEQ ID NO: 300 SEQ ID NO: 301 SEQ ID NO: 302 MOG316 SEQ ID NO: 303 SEQ ID NO: 304 SEQ ID NO: 305 SEQ ID NO: 306 MOG319 SEQ ID NO: 307 SEQ ID NO: 308 SEQ ID NO: 309 SEQ ID NO: 310 MOG320 SEQ ID NO: 311 SEQ ID NO: 312 SEQ ID NO: 313 SEQ ID NO: 314 MOG338 SEQ ID NO: 315 SEQ ID NO: 316 SEQ ID NO: 317 SEQ ID NO: 318 MOG352 SEQ ID NO: 319 SEQ ID NO: 320 SEQ ID NO: 321 SEQ ID NO: 322 MOG359 SEQ ID NO: 323 SEQ ID NO: 324 SEQ ID NO: 325 SEQ ID NO: 326 MOG478 SEQ ID NO: 327 SEQ ID NO: 328 SEQ ID NO: 329 SEQ ID NO: 330 MOG329 MOG470 SEQ ID NO: 331 SEQ ID NO: 332 SEQ ID NO: 333 SEQ ID NO: 334 MOG456 MOG418 SEQ ID NO: 335 SEQ ID NO: 336 SEQ ID NO: 337 SEQ ID NO: 338

[Example 21] Production of Anti-MOG scFv-Fc Antibodies

[0739] A gene fragment of the scFv region was amplified by PCR using a phagemid vector pCANTAB_MOG01 as a template. A gene fragment of the Hinge-CH2-CH3 region was amplified by PCR using a synthetic gene of the heavy chain constant region as a template. The obtained gene fragments were inserted to N5KG4PE vector (described in International Publication No. 2002/088186), and N5-MOG01 scFv-hG4PE vector was produced.

[0740] A gene fragment of the scFv region was amplified by PCR using a phagemid vector pCANTAB_MOG301 as a template. A gene fragment of the Hinge-CH2-CH3 region was amplified by PCR using a synthetic gene of the heavy chain constant region as a template. The obtained gene fragments were inserted to pCI vector (manufactured by Promega Corporation), and pCI-MOG301 scFv-hG4PE(R409K) vector was produced.

[0741] By the same method, antibody expression vectors to which gene fragments of the scFv regions of the anti-MOG antibodies shown in Table 12 were inserted were produced and named pCI-MOG303 scFv-hG4PE(R409K), pCI-MOG307 scFv-hG4PE(R409K), pCI-MOG310 scFv-hG4PE(R409K), pCI-MOG312 scFv-hG4PE(R409K), pCI-MOG326 scFv-hG4PE(R409K), pCI-MOG329 scFv-hG4PE(R409K), pCI-MOG446 scFv-hG4PE(R409K), pCI-MOG456 scFv-hG4PE(R409K) and pCI-MOG473 scFv-hG4PE(R409K).

[0742] The produced anti-MOG antibody expression vectors were prepared by the method described in Example 6. Antibodies were expressed using the anti-MOG antibody expression vectors, pCI-MOG301 scFv-hG4PE(R409K), pCI-MOG303 scFv-hG4PE(R409K), pCI-MOG307 scFv-hG4PE(R409K), pCI-MOG310 scFv-hG4PE(R409K), pCI-MOG312 scFv-hG4PE(R409K), pCI-MOG326 scFv-hG4PE(R409K), pCI-MOG329 scFv-hG4PE(R409K), pCI-MOG446 scFv-hG4PE(R409K), pCI-MOG456 scFv-hG4PE(R409K) and pCI-MOG473 scFv-hG4PE(R409K), and MOG301 scFv-hG4PE(R409K) antibody, MOG303 scFv-hG4PE(R409K) antibody, MOG307 scFv-hG4PE(R409K) antibody, MOG310 scFv-hG4PE(R409K) antibody, MOG312 scFv-hG4PE(R409K) antibody, MOG326 scFv-hG4PE(R409K) antibody, MOG329 scFv-hG4PE(R409K) antibody, MOG446 scFv-hG4PE(R409K) antibody, MOG456 scFv-hG4PE(R409K) antibody and MOG473 scFv-hG4PE(R409K) antibody were obtained, respectively.

[Example 22] Evaluation of Affinities of Anti-MOG Antibodies to MOG Using Flow Cytometer

[0743] Binding of the anti-MOG antibodies obtained in Example 21 to MOG was evaluated by the same method as that of Example 7. The results are shown in FIGS. 23 to 25.

[0744] As shown in FIGS. 23 to 25, MOG01 scFv-hG4PE, MOG301 scFv-hG4PE(R409K), MOG303 scFv-hG4PE(R409K), MOG307 scFv-hG4PE(R409K), MOG310 scFv-hG4PE(R409K), MOG312 scFv-hG4PE(R409K), MOG326 scFv-hG4PE(R409K), MOG329 scFv-hG4PE(R409K), MOG446 scFv-hG4PE(R409K), MOG456 scFv-hG4PE(R409K) and MOG473 scFv-hG4PE(R409K) all showed binding activity to hMOG/Expi293F cells and mMOG/Expi293F cells.

[Example 23] Evaluation of Affinities of Anti-MOG Antibodies to MOG by Surface Plasmon Resonance Detection

[0745] Binding of MOG01 scFv-hG4PE, MOG301 scFv-hG4PE(R409K), MOG303 scFv-hG4PE(R409K), MOG307 scFv-hG4PE(R409K), MOG329 scFv-hG4PE(R409K), MOG446 scFv-hG4PE(R409K), MOG456 scFv-hG4PE(R409K) and MOG473 scFv-hG4PE(R409K) obtained in Example 21 to human MOG and mouse MOG was evaluated by the same method as that of Example 8. hMOG-GST and mMOG-GST were used as analytes. The results of evaluation of the affinities to human MOG are shown in Table 14, and the results of evaluation of the affinities to mouse MOG are shown in Table 15.

TABLE-US-00014 TABLE 14 Reactivity to human MOG Antibody Name ka (1/Ms) kd (1/s) KD (M) MOG01 scFv-hG4PE 4.1E+06 1.5E-02 3.6E-09 MOG301 scFv-hG4PE(R409K) 1.1E+06 1.8E-04 1.8E-10 MOG303 scFv-hG4PE(R409K) 9.1E+05 1.6E-04 1.7E-10 MOG307 scFv-hG4PE(R409K) 1.6E+05 1.4E-04 8.9E-10 MOG329 scFv-hG4PE(R409K) 1.6E+06 2.1E-04 1.3E-10 MOG446 scFv-hG4PE(R409K) 1.9E+05 1.7E-04 8.7E-10 MOG456 scFv-hG4PE(R409K) 1.0E+06 2.6E-04 2.5E-10 MOG473 scFv-hG4PE(R409K) 1.5E+06 1.5E-04 1.0E-10 ka of MOG01 was outside the measurement range.

TABLE-US-00015 TABLE 15 Reactivity to mouse MOG Antibody Name ka (1/Ms) kd (1/s) KD (M) MOG01 scFv-hG4PE 5.9E+06 4.0E-02 6.9E-09 MOG301 scFv-hG4PE(R409K) 4.9E+05 2.1E-04 4.3E-10 MOG303 scFv-hG4PE(R409K) 1.1E+06 2.1E-04 1.9E-10 MOG307 scFv-hG4PE(R409K) 1.6E+05 1.5E-04 9.6E-10 MOG329 scFv-hG4PE(R409K) 1.1E+06 2.3E-04 2.2E-10 MOG446 scFv-hG4PE(R409K) 1.2E+05 3.7E-04 3.2E-09 MOG456 scFv-hG4PE(R409K) 7.6E+05 3.9E-04 5.2E-10 MOG473 scFv-hG4PE(R409K) 7.6E+05 3.7E-04 4.9E-10

[0746] As shown in Table 14 and Table 15, the dissociation constants (KD values) of the anti-MOG antibodies to human MOG were 1.0.times.10.sup.-1.degree. (M) to 3.6.times.10.sup.-9 (M), and the dissociation constants (KD values) to mouse MOG were 1.9.times.10.sup.-1.degree. (M) to 6.9.times.10.sup.-9 (M). It was thus elucidated that all the antibodies show excellent affinity. The association rate constant ka of MOG01 scFv-hG4PE was outside the measurement range of the device, and the KD value could not be determined as a unique value.

[Example 24] Production of Enzyme-Fused Antibodies

[0747] Enzyme-fused antibodies in which acid sphingomyelinase (ASM) was fused to the C-terminus of anti-MOG01IgG antibody or anti-AVMIgG antibody were produced by the method described below. The vector expressing the antibody in which ASM was fused to the C-terminus of anti-MOG01IgG antibody was named pCI-MOG01-hLG4PE(R409K) ASM, and the vector expressing the antibody in which ASM was fused to the C-terminus of anti-AVMIgG antibody was named pCI-AVM-hLG4PE(R409K) ASM.

[0748] A gene fragment of the linker-ASM region was amplified by PCR using a synthetic gene of ASM shown in SEQ ID NO: 150 as a template. Moreover, a gene fragment of the CH1-Hinge-CH2-CH3(R409K) region was synthesized by PCR using a synthetic gene as a template. A gene fragment of the MOG01 light chain region and a gene fragment of the MOG01 VH region were amplified by PCR using N5LG4PE_MOG01 as a template.

[0749] The obtained gene fragments were inserted to pCI vector (manufactured by Promega Corporation), and pCI-MOG01-hLG4PE(R409K) ASM vector was produced. A gene fragment of the CH2-CH3 region was amplified by PCR using a synthetic gene as a template. The gene fragments of the CH2-CH3 region and the linker-ASM region were inserted to the PmlI-BamHI site of pCI-AVM-hLG4PE(R409K) vector, and pCI-AVM-hLG4PE(R409K)_ASM was produced.

[0750] pCI-MOG01-hLG4PE(R409K)_ASM and pCI-AVM-hLG4PE(R409K)_ASM were expressed and purified by the method shown in Example 6. The antibody obtained by expression using pCI-MOG01-hLG4PE(R409K)_ASM was named MOG01 IgG4PE(R409K)-ASM, and the antibody obtained by expression using pCI-AVM-hLG4PE(R409K)_ASM was named AVM IgG4PE(R409K)-ASM.

[Example 25] Evaluation of Activities of Enzyme-Fused Antibodies

[0751] The affinity of MOG01 IgG4PE(R409K)-ASM to MOG-expressing cells was examined by the same method as that of Example 23, and the results are shown in FIG. 26. Moreover, the affinity to MOG soluble antigen was examined by the same method as that of Example 8. As a result, the dissociation constant (KD value) of MOG01 IgG4PE(R409K)-ASM was 2.9.times.10.sup.-9 (M), and excellent affinity was observed.

[0752] That an anti-ASM antibody (manufactured by LSBio) binds to produced MOG01 IgG4PE(R409K)-ASM and AVM IgG4PE(R409K)-ASM was confirmed by the ELISA method shown below.

[0753] In the ELISA, MOG01 IgG4PE(R409K)-ASM and AVM IgG4PE(R409K)-ASM were immobilized (100 ng/50 .mu.L) on MAXISORP (manufactured by NUNC), and the sites to which MOG01 IgG4PE(R409K)-ASM and AVM IgG4PE(R409K)-ASM were not bound were blocked using SuperBlock Blocking Buffer (manufactured by Thermo Fisher Scientific Inc.). As a negative control, a plate on which anti-MOG01IgG antibody and anti-AVMIgG antibody were immobilized (50 ng/50 .mu.L) was also prepared. The anti-ASM antibody which was diluted to a concentration of 0.2, 1 or 5 .mu.g/mL with PBS-T was added to the wells and reacted at room temperature for an hour, and then the wells were washed with PBS-T.

[0754] Next, a solution obtained by diluting horseradish peroxidase-labeled anti-Mouse Immunoglobulins antibody (manufactured by Dako) with PBS-T was added to the wells and reacted at room temperature for an hour. A TMB chromogenic substrate solution (manufactured by DAKO) was added, and the plates were incubated at room temperature. The chromogenic reaction was stopped by adding 2 M hydrochloric acid to the wells, and the absorbances at the wavelength of 450 nm (reference wavelength of 570 nm) were measured. The results obtained are shown in FIG. 27.

[0755] As shown in FIG. 27, it was shown that the anti-ASM antibody recognized and bound to the produced ASM-fused antibodies. Moreover, as a result of measurement of the sphingomyelinase activities of produced MOG01 IgG4PE(R409K)-ASM and AVM IgG4PE(R409K)-ASM using a sphingomyelinase activity measurement kit (manufactured by Echelon Biosciences), it was confirmed that the produced ASM-fused antibodies had enzymatic activities.

[0756] From the above results, it was confirmed that the enzyme-fused antibody obtained by fusing an enzyme to a MOG antibody maintains both the antigen binding activity and the enzymatic activity.

[Example 26] Evaluation of Mouse Brain Migration Properties of Enzyme-Fused Antibodies

[0757] The mouse brain migration properties of the ASM-fused antibodies obtained in Example 24 were evaluated by the same method as that of Example 14. The antibody concentrations in the serum and the antibody amounts per unit brain weight in the brain tissues 10 days after administering the ASM-fused antibodies at 5 mg/kg are shown in FIGS. 28A and 28B.

[0758] As shown in FIGS. 28A and 28B, the antibody concentration of MOG01 IgG4PE(R409K)-ASM in the serum was not different from that of AVM IgG4PE(R409K)-ASM. On the other hand, it was shown that the antibody amount of MOG01 IgG4PE(R409K)-ASM in the brain increased to about 58 times the amount of AVM IgG4PE(R409K)-ASM.

[0759] The invention has been explained in detail using the specific aspects, but it is obvious for those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the invention. The present application is based on a Japanese patent application filed on Dec. 26, 2016 (patent application No. 2016-251106), which is incorporated by reference in its entirety.

SEQUENCE LISTING FREE TEXT

[0760] Definition of SEQ ID NO: 3-artificial sequence: amino acid sequence of VH of MOG01 excluding signal sequence

[0761] Definition of SEQ ID NO: 4-artificial sequence: amino acid sequence of HCDR1 of MOG01

[0762] Definition of SEQ ID NO: 5-artificial sequence: amino acid sequence of HCDR2 of MOG01

[0763] Definition of SEQ ID NO: 6-artificial sequence: amino acid sequence of HCDR3 of MOG01

[0764] Definition of SEQ ID NO: 9-artificial sequence: amino acid sequence of VL of MOG01 excluding signal sequence

[0765] Definition of SEQ ID NO: 10-artificial sequence: amino acid sequence of LCDR1 of MOG01

[0766] Definition of SEQ ID NO: 11-artificial sequence: amino acid sequence of LCDR2 of MOG01

[0767] Definition of SEQ ID NO: 12-artificial sequence: amino acid sequence of LCDR3 of MOG01

[0768] Definition of SEQ ID NO: 15-artificial sequence: amino acid sequence of VH of MOG09 excluding signal sequence

[0769] Definition of SEQ ID NO: 16-artificial sequence: amino acid sequence of HCDR1 of MOG09

[0770] Definition of SEQ ID NO: 17-artificial sequence: amino acid sequence of HCDR2 of MOG09

[0771] Definition of SEQ ID NO: 18-artificial sequence: amino acid sequence of HCDR3 of MOG09

[0772] Definition of SEQ ID NO: 21-artificial sequence: amino acid sequence of VL of MOG09 excluding signal sequence

[0773] Definition of SEQ ID NO: 22-artificial sequence: amino acid sequence of LCDR1 of MOG09

[0774] Definition of SEQ ID NO: 23-artificial sequence: amino acid sequence of LCDR2 of MOG09

[0775] Definition of SEQ ID NO: 24-artificial sequence: amino acid sequence of LCDR3 of MOG09

[0776] Definition of SEQ ID NO: 27-artificial sequence: amino acid sequence of VH of MOG14 excluding signal sequence

[0777] Definition of SEQ ID NO: 28-artificial sequence: amino acid sequence of HCDR1 of MOG14

[0778] Definition of SEQ ID NO: 29-artificial sequence: amino acid sequence of HCDR2 of MOG14

[0779] Definition of SEQ ID NO: 30-artificial sequence: amino acid sequence of HCDR3 of MOG14

[0780] Definition of SEQ ID NO: 33-artificial sequence: amino acid sequence of VL of MOG14 excluding signal sequence

[0781] Definition of SEQ ID NO: 34-artificial sequence: amino acid sequence of LCDR1 of MOG14

[0782] Definition of SEQ ID NO: 35-artificial sequence: amino acid sequence of LCDR2 of MOG14

[0783] Definition of SEQ ID NO: 36-artificial sequence: amino acid sequence of LCDR3 of MOG14

[0784] Definition of SEQ ID NO: 37-artificial sequence: nucleotide sequence of VHH of iMOG 3Rim1_S32 including signal sequence

[0785] Definition of SEQ ID NO: 38-artificial sequence: amino acid sequence of synthetic construct

[0786] Definition of SEQ ID NO: 39-artificial sequence: amino acid sequence of VHH of iMOG 3Rim1_S32 excluding signal sequence

[0787] Definition of SEQ ID NO: 40-artificial sequence: amino acid sequence of CDR1 of iMOG 3Rim1 S32

[0788] Definition of SEQ ID NO: 41-artificial sequence: amino acid sequence of CDR2 of iMOG 3Rim1 S32

[0789] Definition of SEQ ID NO: 42-artificial sequence: amino acid sequence of CDR3 of iMOG 3Rim1 S32

[0790] Definition of SEQ ID NO: 43-artificial sequence: nucleotide sequence of primer 1

[0791] Definition of SEQ ID NO: 44-artificial sequence: nucleotide sequence of primer 2

[0792] Definition of SEQ ID NO: 45-artificial sequence: nucleotide sequence of primer 3

[0793] Definition of SEQ ID NO: 46-artificial sequence: nucleotide sequence of primer 4

[0794] Definition of SEQ ID NO: 47-artificial sequence: nucleotide sequence of primer 5

[0795] Definition of SEQ ID NO: 48-artificial sequence: nucleotide sequence of primer 6

[0796] Definition of SEQ ID NO: 49-artificial sequence: nucleotide sequence of primer 7

[0797] Definition of SEQ ID NO: 50-artificial sequence: nucleotide sequence of primer 8

[0798] Definition of SEQ ID NO: 51-artificial sequence: nucleotide sequence of primer 9

[0799] Definition of SEQ ID NO: 52-artificial sequence: nucleotide sequence of primer 10

[0800] Definition of SEQ ID NO: 53-artificial sequence: nucleotide sequence of primer 11

[0801] Definition of SEQ ID NO: 54-artificial sequence: nucleotide sequence of primer 12

[0802] Definition of SEQ ID NO: 55-artificial sequence: nucleotide sequence of primer 13

[0803] Definition of SEQ ID NO: 56-artificial sequence: nucleotide sequence of primer 14

[0804] Definition of SEQ ID NO: 57-artificial sequence: nucleotide sequence of primer 15

[0805] Definition of SEQ ID NO: 58-artificial sequence: nucleotide sequence of primer 16

[0806] Definition of SEQ ID NO: 59-artificial sequence: nucleotide sequence of primer 17

[0807] Definition of SEQ ID NO: 60-artificial sequence: nucleotide sequence of primer 18

[0808] Definition of SEQ ID NO: 61-artificial sequence: nucleotide sequence of primer 19

[0809] Definition of SEQ ID NO: 62-artificial sequence: nucleotide sequence of primer 20

[0810] Definition of SEQ ID NO: 63-artificial sequence: nucleotide sequence of primer 21

[0811] Definition of SEQ ID NO: 64-artificial sequence: nucleotide sequence of primer 22

[0812] Definition of SEQ ID NO: 65-artificial sequence: nucleotide sequence of primer 23

[0813] Definition of SEQ ID NO: 66-artificial sequence: nucleotide sequence of primer 24

[0814] Definition of SEQ ID NO: 69-artificial sequence: nucleotide sequence of rMOG-FLAG-Fc

[0815] Definition of SEQ ID NO: 70-artificial sequence: amino acid sequence of synthetic construct

[0816] Definition of SEQ ID NO: 71-artificial sequence: nucleotide sequence of rMOG-GST

[0817] Definition of SEQ ID NO: 72-artificial sequence: amino acid sequence of synthetic construct

[0818] Definition of SEQ ID NO: 79-artificial sequence: nucleotide sequence of primer 25

[0819] Definition of SEQ ID NO: 80-artificial sequence: nucleotide sequence of primer 26

[0820] Definition of SEQ ID NO: 81-artificial sequence: nucleotide sequence of primer 27

[0821] Definition of SEQ ID NO: 82-artificial sequence: nucleotide sequence of primer 28

[0822] Definition of SEQ ID NO: 83-artificial sequence: nucleotide sequence of primer 29

[0823] Definition of SEQ ID NO: 84-artificial sequence: nucleotide sequence of primer 30

[0824] Definition of SEQ ID NO: 85-artificial sequence: nucleotide sequence of primer 31

[0825] Definition of SEQ ID NO: 86-artificial sequence: nucleotide sequence of primer 32

[0826] Definition of SEQ ID NO: 87-artificial sequence: nucleotide sequence of primer 33

[0827] Definition of SEQ ID NO: 88-artificial sequence: nucleotide sequence of primer 34

[0828] Definition of SEQ ID NO: 89-artificial sequence: nucleotide sequence of primer 35

[0829] Definition of SEQ ID NO: 90-artificial sequence: nucleotide sequence of primer 36

[0830] Definition of SEQ ID NO: 91-artificial sequence: nucleotide sequence of primer 37

[0831] Definition of SEQ ID NO: 92-artificial sequence: nucleotide sequence of primer 38

[0832] Definition of SEQ ID NO: 93-artificial sequence: nucleotide sequence of primer 39

[0833] Definition of SEQ ID NO: 94-artificial sequence: nucleotide sequence of primer 40

[0834] Definition of SEQ ID NO: 95-artificial sequence: nucleotide sequence of primer 41

[0835] Definition of SEQ ID NO: 96-artificial sequence: nucleotide sequence of primer 42

[0836] Definition of SEQ ID NO: 97-artificial sequence: nucleotide sequence of primer 43

[0837] Definition of SEQ ID NO: 98-artificial sequence: nucleotide sequence of hHER2-GST

[0838] Definition of SEQ ID NO: 99-artificial sequence: amino acid sequence of synthetic construct

[0839] Definition of SEQ ID NO: 100-artificial sequence: nucleotide sequence of hMOG-FLAG-Fc (including signal sequence)

[0840] Definition of SEQ ID NO: 101-artificial sequence: amino acid sequence of hMOG-FLAG-Fc (including signal sequence)

[0841] Definition of SEQ ID NO: 102-artificial sequence: nucleotide sequence of mMOG-FLAG-Fc (including signal sequence)

[0842] Definition of SEQ ID NO: 103-artificial sequence: amino acid sequence of mMOG-FLAG-Fc (including signal sequence)

[0843] Definition of SEQ ID NO: 104-artificial sequence: nucleotide sequence of hMOG-GST (including signal sequence)

[0844] Definition of SEQ ID NO: 105-artificial sequence: amino acid sequence of hMOG-GST (including signal sequence)

[0845] Definition of SEQ ID NO: 106-artificial sequence: nucleotide sequence of mMOG-GST (including signal sequence)

[0846] Definition of SEQ ID NO: 107-artificial sequence: amino acid sequence of mMOG-GST (including signal sequence)

[0847] Definition of SEQ ID NO: 108-artificial sequence: nucleotide sequence of antibody sequence of pCI-AVM-hLG4PE(R409K/S354C/T366W)-FLAG tag (excluding signal sequence)

[0848] Definition of SEQ ID NO: 109-artificial sequence: amino acid sequence of antibody sequence of pCI-AVM-hLG4PE(R409K/S354C/T366W)-FLAG tag (excluding signal sequence)

[0849] Definition of SEQ ID NO: 110-artificial sequence: nucleotide sequence of antibody sequence of pCI-MOG01-hLG4PE(R409K/Y349C/T366S/L368A/Y407V)-His tag (excluding signal sequence)

[0850] Definition of SEQ ID NO: 111-artificial sequence: amino acid sequence of antibody sequence of pCI-MOG01-hLG4PE(R409K/Y349C/T366S/L368A/Y407V)-His tag (excluding signal sequence)

[0851] Definition of SEQ ID NO: 112-artificial sequence: nucleotide sequence of antibody sequence of pCI-AVM-hLG4PE(R409K)-linker-MOG01VL-CL (excluding signal sequence)

[0852] Definition of SEQ ID NO: 113-artificial sequence: amino acid sequence of antibody sequence of pCI-AVM-hLG4PE(R409K)-linker-MOG01VL-CL (excluding signal sequence)

[0853] Definition of SEQ ID NO: 114-artificial sequence: nucleotide sequence of antibody sequence of pCI-MOG01VH-CH (excluding signal sequence)

[0854] Definition of SEQ ID NO: 115-artificial sequence: amino acid sequence of antibody sequence of pCI-MOG01VH-CH (excluding signal sequence)

[0855] Definition of SEQ ID NO: 116-artificial sequence: nucleotide sequence of antibody sequence of pCI-AVM-hLG4PE(R409K/S354C/T366W)-linker-MOG01scFv-FLAG tag (excluding signal sequence)

[0856] Definition of SEQ ID NO: 117-artificial sequence: amino acid sequence of antibody sequence of pCI-AVM-hLG4PE(R409K/S354C/T366W)-linker-MOG01scFv-FLAG tag (excluding signal sequence)

[0857] Definition of SEQ ID NO: 118-artificial sequence: nucleotide sequence of antibody sequence of pCI-AVM-hLG4PE(R409K/Y349C/T366S/L368A/Y407V)-His tag (excluding signal sequence)

[0858] Definition of SEQ ID NO: 119-artificial sequence: amino acid sequence of antibody sequence of pCI-AVM-hLG4PE(R409K/Y349C/T366S/L368A/Y407V)-His tag (excluding signal sequence)

[0859] Definition of SEQ ID NO: 120-artificial sequence: nucleotide sequence of antibody sequence of pCI-AVM-hLG4PE(R409K)_MOG01scFv2 (excluding signal sequence)

[0860] Definition of SEQ ID NO: 121-artificial sequence: amino acid sequence of antibody sequence of pCI-AVM-hLG4PE(R409K)_MOG01scFv2 (excluding signal sequence)

[0861] Definition of SEQ ID NO: 122-artificial sequence: nucleotide sequence of antibody sequence of pCI-AVM-hLG4PE(R409K)_MOG01scFv3 (excluding signal sequence)

[0862] Definition of SEQ ID NO: 123-artificial sequence: amino acid sequence of antibody sequence of pCI-AVM-hLG4PE(R409K)_MOG01scFv3 (excluding signal sequence)

[0863] Definition of SEQ ID NO: 124-artificial sequence: nucleotide sequence of antibody sequence of pCI-AVM-hLG4PE(R409K)_MOG01scFv4 (excluding signal sequence)

[0864] Definition of SEQ ID NO: 125-artificial sequence: amino acid sequence of antibody sequence of pCI-AVM-hLG4PE(R409K)_MOG01scFv4 (excluding signal sequence)

[0865] Definition of SEQ ID NO: 126-artificial sequence: nucleotide sequence of antibody sequence of pCI-AVM-hLG4PE(R409K)_MOG01scFv5 (excluding signal sequence)

[0866] Definition of SEQ ID NO: 127-artificial sequence: amino acid sequence of antibody sequence of pCI-AVM-hLG4PE(R409K)_MOG01scFv5 (excluding signal sequence)

[0867] Definition of SEQ ID NO: 128-artificial sequence: nucleotide sequence of antibody sequence of pCI-AVM-hLG4PE(R409K)_MOG01scFv6 (excluding signal sequence)

[0868] Definition of SEQ ID NO: 129-artificial sequence: amino acid sequence of antibody sequence of pCI-AVM-hLG4PE(R409K)_MOG01scFv6 (excluding signal sequence)

[0869] Definition of SEQ ID NO: 130-artificial sequence: nucleotide sequence of antibody sequence of pCI-AVM-hLG4PE(R409K)_MOG01scFv7 (excluding signal sequence)

[0870] Definition of SEQ ID NO: 131-artificial sequence: amino acid sequence of antibody sequence of pCI-AVM-hLG4PE(R409K)_MOG01scFv7 (excluding signal sequence)

[0871] Definition of SEQ ID NO: 132-artificial sequence: nucleotide sequence of antibody sequence of pCI-AVM-hLG4PE(R409K)_MOG01scFv8 (excluding signal sequence)

[0872] Definition of SEQ ID NO: 133-artificial sequence: amino acid sequence of antibody sequence of pCI-AVM-hLG4PE(R409K)_MOG01scFv8 (excluding signal sequence)

[0873] Definition of SEQ ID NO: 134-artificial sequence: nucleotide sequence of antibody sequence of pCI-AVM-hLG4PE(R409K)_MOG01scFv9 (excluding signal sequence)

[0874] Definition of SEQ ID NO: 135-artificial sequence: amino acid sequence of antibody sequence of pCI-AVM-hLG4PE(R409K)_MOG01scFv9 (excluding signal sequence)

[0875] Definition of SEQ ID NO: 136-artificial sequence: nucleotide sequence of antibody sequence of pCI-AVM-hLG4PE(R409K)_MOG01scFv10 (excluding signal sequence)

[0876] Definition of SEQ ID NO: 137-artificial sequence: amino acid sequence of antibody sequence of pCI-AVM-hLG4PE(R409K)_MOG01scFv10 (excluding signal sequence)

[0877] Definition of SEQ ID NO: 138-artificial sequence: nucleotide sequence of antibody sequence of pCI-AVM-hLG4PE(R409K)_MOG01scFv11 (excluding signal sequence)

[0878] Definition of SEQ ID NO: 139-artificial sequence: amino acid sequence of antibody sequence of pCI-AVM-hLG4PE(R409K)_MOG01scFv11 (excluding signal sequence)

[0879] Definition of SEQ ID NO: 140-artificial sequence: nucleotide sequence of antibody sequence of pCI-AVM-hLG4PE(R409K)-linker-AVMVL-CL (excluding signal sequence)

[0880] Definition of SEQ ID NO: 141-artificial sequence: amino acid sequence of antibody sequence of pCI-AVM-hLG4PE(R409K)-linker-AVMVL-CL (excluding signal sequence)

[0881] Definition of SEQ ID NO: 142-artificial sequence: nucleotide sequence of antibody sequence of pCI-AVMVH-CH (excluding signal sequence)

[0882] Definition of SEQ ID NO: 143-artificial sequence: amino acid sequence of antibody sequence of pCI-AVMVH-CH (excluding signal sequence)

[0883] Definition of SEQ ID NO: 144-artificial sequence: nucleotide sequence of antibody sequence of pCI-AVM-hLG4PE(R409K/S354C/T366W)-linker-AVMscFv-FLAG tag (excluding signal sequence)

[0884] Definition of SEQ ID NO: 145-artificial sequence: amino acid sequence of antibody sequence of pCI-AVM-hLG4PE(R409K/S354C/T366W)-linker-AVMscFv-FLAG tag (excluding signal sequence)

[0885] Definition of SEQ ID NO: 146-artificial sequence: nucleotide sequence of antibody sequence of pCI-AVM-hLG4PE(R409K)_AVMscFv3 (excluding signal sequence)

[0886] Definition of SEQ ID NO: 147-artificial sequence: amino acid sequence of antibody sequence of pCI-AVM-hLG4PE(R409K)_AVMscFv3 (excluding signal sequence)

[0887] Definition of SEQ ID NO: 148-artificial sequence: nucleotide sequence of antibody sequence of pCI-AVM-hLG4PE(R409K)_AVMscFv5 (excluding signal sequence)

[0888] Definition of SEQ ID NO: 149-artificial sequence: amino acid sequence of antibody sequence of pCI-AVM-hLG4PE(R409K)_AVMscFv5 (excluding signal sequence) Definition of SEQ ID NO: 150-artificial sequence: nucleotide sequence of Acid Sphingomyelinase (ASM)

[0889] Definition of SEQ ID NO: 151-artificial sequence: nucleotide sequence encoding VH (excluding signal sequence) of MOG301

[0890] Definition of SEQ ID NO: 152-artificial sequence: amino acid sequence of VH (excluding signal sequence) of MOG301

[0891] Definition of SEQ ID NO: 153-artificial sequence: amino acid sequence of HCDR1 of MOG301

[0892] Definition of SEQ ID NO: 154-artificial sequence: amino acid sequence of HCDR2 of MOG301

[0893] Definition of SEQ ID NO: 155-artificial sequence: amino acid sequence of HCDR3 of MOG301

[0894] Definition of SEQ ID NO: 156-artificial sequence: nucleotide sequence encoding VL (excluding signal sequence) of MOG301

[0895] Definition of SEQ ID NO: 157-artificial sequence: amino acid sequence of VL (excluding signal sequence) of MOG301

[0896] Definition of SEQ ID NO: 158-artificial sequence: amino acid sequence of LCDR1 of MOG301

[0897] Definition of SEQ ID NO: 159-artificial sequence: amino acid sequence of LCDR2 of MOG301

[0898] Definition of SEQ ID NO: 160-artificial sequence: amino acid sequence of LCDR3 of MOG301

[0899] Definition of SEQ ID NO: 161-artificial sequence: nucleotide sequence encoding VH (excluding signal sequence) of MOG303

[0900] Definition of SEQ ID NO: 162-artificial sequence: amino acid sequence of VH (excluding signal sequence) of MOG303

[0901] Definition of SEQ ID NO: 163-artificial sequence: amino acid sequence of HCDR1 of MOG303

[0902] Definition of SEQ ID NO: 164-artificial sequence: amino acid sequence of HCDR2 of MOG303

[0903] Definition of SEQ ID NO: 165-artificial sequence: amino acid sequence of HCDR3 of MOG303

[0904] Definition of SEQ ID NO: 166-artificial sequence: nucleotide sequence encoding VL (excluding signal sequence) of MOG303

[0905] Definition of SEQ ID NO: 167-artificial sequence: amino acid sequence of VL (excluding signal sequence) of MOG303

[0906] Definition of SEQ ID NO: 168-artificial sequence: amino acid sequence of LCDR1 of MOG303

[0907] Definition of SEQ ID NO: 169-artificial sequence: amino acid sequence of LCDR2 of MOG303

[0908] Definition of SEQ ID NO: 170-artificial sequence: amino acid sequence of LCDR3 of MOG303

[0909] Definition of SEQ ID NO: 171-artificial sequence: nucleotide sequence encoding VH (excluding signal sequence) of MOG307

[0910] Definition of SEQ ID NO: 172-artificial sequence: amino acid sequence of VH (excluding signal sequence) of MOG307

[0911] Definition of SEQ ID NO: 173-artificial sequence: amino acid sequence of HCDR1 of MOG307

[0912] Definition of SEQ ID NO: 174-artificial sequence: amino acid sequence of HCDR2 of MOG307

[0913] Definition of SEQ ID NO: 175-artificial sequence: amino acid sequence of HCDR3 of MOG307

[0914] Definition of SEQ ID NO: 176-artificial sequence: nucleotide sequence encoding VL (excluding signal sequence) of MOG307

[0915] Definition of SEQ ID NO: 177-artificial sequence: amino acid sequence of VL (excluding signal sequence) of MOG307

[0916] Definition of SEQ ID NO: 178-artificial sequence: amino acid sequence of LCDR1 of MOG307

[0917] Definition of SEQ ID NO: 179-artificial sequence: amino acid sequence of LCDR2 of MOG307

[0918] Definition of SEQ ID NO: 180-artificial sequence: amino acid sequence of LCDR3 of MOG307

[0919] Definition of SEQ ID NO: 181-artificial sequence: nucleotide sequence encoding VH (excluding signal sequence) of MOG310

[0920] Definition of SEQ ID NO: 182-artificial sequence: amino acid sequence of VH (excluding signal sequence) of MOG310

[0921] Definition of SEQ ID NO: 183-artificial sequence: amino acid sequence of HCDR1 of MOG310

[0922] Definition of SEQ ID NO: 184-artificial sequence: amino acid sequence of HCDR2 of MOG310

[0923] Definition of SEQ ID NO: 185-artificial sequence: amino acid sequence of HCDR3 of MOG310

[0924] Definition of SEQ ID NO: 186-artificial sequence: nucleotide sequence encoding VL (excluding signal sequence) of MOG310

[0925] Definition of SEQ ID NO: 187-artificial sequence: amino acid sequence of VL (excluding signal sequence) of MOG310

[0926] Definition of SEQ ID NO: 188-artificial sequence: amino acid sequence of LCDR1 of MOG310

[0927] Definition of SEQ ID NO: 189-artificial sequence: amino acid sequence of LCDR2 of MOG310

[0928] Definition of SEQ ID NO: 190-artificial sequence: amino acid sequence of LCDR3 of MOG310

[0929] Definition of SEQ ID NO: 191-artificial sequence: nucleotide sequence encoding VH (excluding signal sequence) of MOG312

[0930] Definition of SEQ ID NO: 192-artificial sequence: amino acid sequence of VH (excluding signal sequence) of MOG312

[0931] Definition of SEQ ID NO: 193-artificial sequence: amino acid sequence of HCDR1 of MOG312

[0932] Definition of SEQ ID NO: 194-artificial sequence: amino acid sequence of HCDR2 of MOG312

[0933] Definition of SEQ ID NO: 195-artificial sequence: amino acid sequence of HCDR3 of MOG312

[0934] Definition of SEQ ID NO: 196-artificial sequence: nucleotide sequence encoding VL (excluding signal sequence) of MOG312

[0935] Definition of SEQ ID NO: 197-artificial sequence: amino acid sequence of VL (excluding signal sequence) of MOG312

[0936] Definition of SEQ ID NO: 198-artificial sequence: amino acid sequence of LCDR1 of MOG312

[0937] Definition of SEQ ID NO: 199-artificial sequence: amino acid sequence of LCDR2 of MOG312

[0938] Definition of SEQ ID NO: 200-artificial sequence: amino acid sequence of LCDR3 of MOG312

[0939] Definition of SEQ ID NO: 201-artificial sequence: nucleotide sequence encoding VH (excluding signal sequence) of MOG326

[0940] Definition of SEQ ID NO: 202-artificial sequence: amino acid sequence of VH (excluding signal sequence) of MOG326

[0941] Definition of SEQ ID NO: 203-artificial sequence: amino acid sequence of HCDR1 of MOG326

[0942] Definition of SEQ ID NO: 204-artificial sequence: amino acid sequence of HCDR2 of MOG326

[0943] Definition of SEQ ID NO: 205-artificial sequence: amino acid sequence of HCDR3 of MOG326

[0944] Definition of SEQ ID NO: 206-artificial sequence: nucleotide sequence encoding VL (excluding signal sequence) of MOG326

[0945] Definition of SEQ ID NO: 207-artificial sequence: amino acid sequence of VL (excluding signal sequence) of MOG326

[0946] Definition of SEQ ID NO: 208-artificial sequence: amino acid sequence of LCDR1 of MOG326

[0947] Definition of SEQ ID NO: 209-artificial sequence: amino acid sequence of LCDR2 of MOG326

[0948] Definition of SEQ ID NO: 210-artificial sequence: amino acid sequence of LCDR3 of MOG326

[0949] Definition of SEQ ID NO: 211-artificial sequence: nucleotide sequence encoding VH (excluding signal sequence) of MOG329

[0950] Definition of SEQ ID NO: 212-artificial sequence: amino acid sequence of VH (excluding signal sequence) of MOG329

[0951] Definition of SEQ ID NO: 213-artificial sequence: amino acid sequence of HCDR1 of MOG329

[0952] Definition of SEQ ID NO: 214-artificial sequence: amino acid sequence of HCDR2 of MOG329

[0953] Definition of SEQ ID NO: 215-artificial sequence: amino acid sequence of HCDR3 of MOG329

[0954] Definition of SEQ ID NO: 216-artificial sequence: nucleotide sequence encoding VL (excluding signal sequence) of MOG329

[0955] Definition of SEQ ID NO: 217-artificial sequence: amino acid sequence of VL (excluding signal sequence) of MOG329

[0956] Definition of SEQ ID NO: 218-artificial sequence: amino acid sequence of LCDR1 of MOG329

[0957] Definition of SEQ ID NO: 219-artificial sequence: amino acid sequence of LCDR2 of MOG329

[0958] Definition of SEQ ID NO: 220-artificial sequence: amino acid sequence of LCDR3 of MOG329

[0959] Definition of SEQ ID NO: 221-artificial sequence: nucleotide sequence encoding VH (excluding signal sequence) of MOG446

[0960] Definition of SEQ ID NO: 222-artificial sequence: amino acid sequence of VH (excluding signal sequence) of MOG446

[0961] Definition of SEQ ID NO: 223-artificial sequence: amino acid sequence of HCDR1 of MOG446

[0962] Definition of SEQ ID NO: 224-artificial sequence: amino acid sequence of HCDR2 of MOG446

[0963] Definition of SEQ ID NO: 225-artificial sequence: amino acid sequence of HCDR3 of MOG446

[0964] Definition of SEQ ID NO: 226-artificial sequence: nucleotide sequence encoding VL (excluding signal sequence) of MOG446

[0965] Definition of SEQ ID NO: 227-artificial sequence: amino acid sequence of VL (excluding signal sequence) of MOG446

[0966] Definition of SEQ ID NO: 228-artificial sequence: amino acid sequence of LCDR1 of MOG446

[0967] Definition of SEQ ID NO: 229-artificial sequence: amino acid sequence of LCDR2 of MOG446

[0968] Definition of SEQ ID NO: 230-artificial sequence: amino acid sequence of LCDR3 of MOG446

[0969] Definition of SEQ ID NO: 231-artificial sequence: nucleotide sequence encoding VH (excluding signal sequence) of MOG456

[0970] Definition of SEQ ID NO: 232-artificial sequence: amino acid sequence of VH (excluding signal sequence) of MOG456

[0971] Definition of SEQ ID NO: 233-artificial sequence: amino acid sequence of HCDR1 of MOG456

[0972] Definition of SEQ ID NO: 234-artificial sequence: amino acid sequence of HCDR2 of MOG456

[0973] Definition of SEQ ID NO: 235-artificial sequence: amino acid sequence of HCDR3 of MOG456

[0974] Definition of SEQ ID NO: 236-artificial sequence: nucleotide sequence encoding VL (excluding signal sequence) of MOG456

[0975] Definition of SEQ ID NO: 237-artificial sequence: amino acid sequence of VL (excluding signal sequence) of MOG456

[0976] Definition of SEQ ID NO: 238-artificial sequence: amino acid sequence of LCDR1 of MOG456

[0977] Definition of SEQ ID NO: 239-artificial sequence: amino acid sequence of LCDR2 of MOG456

[0978] Definition of SEQ ID NO: 240-artificial sequence: amino acid sequence of LCDR3 of MOG456

[0979] Definition of SEQ ID NO: 241-artificial sequence: nucleotide sequence encoding VH (excluding signal sequence) of MOG473

[0980] Definition of SEQ ID NO: 242-artificial sequence: amino acid sequence of VH (excluding signal sequence) of MOG473

[0981] Definition of SEQ ID NO: 243-artificial sequence: amino acid sequence of HCDR1 of MOG473

[0982] Definition of SEQ ID NO: 244-artificial sequence: amino acid sequence of HCDR2 of MOG473

[0983] Definition of SEQ ID NO: 245-artificial sequence: amino acid sequence of HCDR3 of MOG473

[0984] Definition of SEQ ID NO: 246-artificial sequence: nucleotide sequence encoding VL (excluding signal sequence) of MOG473

[0985] Definition of SEQ ID NO: 247-artificial sequence: amino acid sequence of VL (excluding signal sequence) of MOG473

[0986] Definition of SEQ ID NO: 248-artificial sequence: amino acid sequence of LCDR1 of MOG473

[0987] Definition of SEQ ID NO: 249-artificial sequence: amino acid sequence of LCDR2 of MOG473

[0988] Definition of SEQ ID NO: 250-artificial sequence: amino acid sequence of LCDR3 of MOG473

[0989] Definition of SEQ ID NO: 251-artificial sequence: nucleotide sequence encoding VH (excluding signal sequence) of MOG426

[0990] Definition of SEQ ID NO: 252-artificial sequence: amino acid sequence of VH (excluding signal sequence) of MOG426

[0991] Definition of SEQ ID NO: 253-artificial sequence: nucleotide sequence encoding VL (excluding signal sequence) of MOG426

[0992] Definition of SEQ ID NO: 254-artificial sequence: amino acid sequence of VL (excluding signal sequence) of MOG426

[0993] Definition of SEQ ID NO: 255-artificial sequence: nucleotide sequence encoding VH (excluding signal sequence) of MOG428

[0994] Definition of SEQ ID NO: 256-artificial sequence: amino acid sequence of VH (excluding signal sequence) of MOG428

[0995] Definition of SEQ ID NO: 257-artificial sequence: nucleotide sequence encoding VL (excluding signal sequence) of MOG428

[0996] Definition of SEQ ID NO: 258-artificial sequence: amino acid sequence of VL (excluding signal sequence) of MOG428

[0997] Definition of SEQ ID NO: 259-artificial sequence: nucleotide sequence encoding VH (excluding signal sequence) of MOG313

[0998] Definition of SEQ ID NO: 260-artificial sequence: amino acid sequence of VH (excluding signal sequence) of MOG313

[0999] Definition of SEQ ID NO: 261-artificial sequence: nucleotide sequence encoding VL (excluding signal sequence) of MOG313

[1000] Definition of SEQ ID NO: 262-artificial sequence: amino acid sequence of VL (excluding signal sequence) of MOG313

[1001] Definition of SEQ ID NO: 263-artificial sequence: nucleotide sequence encoding VH (excluding signal sequence) of MOG314

[1002] Definition of SEQ ID NO: 264-artificial sequence: amino acid sequence of VH (excluding signal sequence) of MOG314

[1003] Definition of SEQ ID NO: 265-artificial sequence: nucleotide sequence encoding VL (excluding signal sequence) of MOG314

[1004] Definition of SEQ ID NO: 266-artificial sequence: amino acid sequence of VL (excluding signal sequence) of MOG314

[1005] Definition of SEQ ID NO: 267-artificial sequence: nucleotide sequence encoding VH (excluding signal sequence) of MOG315

[1006] Definition of SEQ ID NO: 268-artificial sequence: amino acid sequence of VH (excluding signal sequence) of MOG315

[1007] Definition of SEQ ID NO: 269-artificial sequence: nucleotide sequence encoding VL (excluding signal sequence) of MOG315

[1008] Definition of SEQ ID NO: 270-artificial sequence: amino acid sequence of VL (excluding signal sequence) of MOG315

[1009] Definition of SEQ ID NO: 271-artificial sequence: nucleotide sequence encoding VH (excluding signal sequence) of MOG331

[1010] Definition of SEQ ID NO: 272-artificial sequence: amino acid sequence of VH (excluding signal sequence) of MOG331

[1011] Definition of SEQ ID NO: 273-artificial sequence: nucleotide sequence encoding VL (excluding signal sequence) of MOG331

[1012] Definition of SEQ ID NO: 274-artificial sequence: amino acid sequence of VL (excluding signal sequence) of MOG331

[1013] Definition of SEQ ID NO: 275-artificial sequence: nucleotide sequence encoding VH (excluding signal sequence) of MOG357

[1014] Definition of SEQ ID NO: 276-artificial sequence: amino acid sequence of VH (excluding signal sequence) of MOG357

[1015] Definition of SEQ ID NO: 277-artificial sequence: nucleotide sequence encoding VL (excluding signal sequence) of MOG357

[1016] Definition of SEQ ID NO: 278-artificial sequence: amino acid sequence of VL (excluding signal sequence) of MOG357

[1017] Definition of SEQ ID NO: 279-artificial sequence: nucleotide sequence encoding VH (excluding signal sequence) of MOG476

[1018] Definition of SEQ ID NO: 280-artificial sequence: amino acid sequence of VH (excluding signal sequence) of MOG476

[1019] Definition of SEQ ID NO: 281-artificial sequence: nucleotide sequence encoding VL (excluding signal sequence) of MOG476

[1020] Definition of SEQ ID NO: 282-artificial sequence: amino acid sequence of VL (excluding signal sequence) of MOG476

[1021] Definition of SEQ ID NO: 283-artificial sequence: nucleotide sequence encoding VH (excluding signal sequence) of MOG323

[1022] Definition of SEQ ID NO: 284-artificial sequence: amino acid sequence of VH (excluding signal sequence) of MOG323

[1023] Definition of SEQ ID NO: 285-artificial sequence: nucleotide sequence encoding VL (excluding signal sequence) of MOG323

[1024] Definition of SEQ ID NO: 286-artificial sequence: amino acid sequence of VL (excluding signal sequence) of MOG323

[1025] Definition of SEQ ID NO: 287-artificial sequence: nucleotide sequence encoding VH (excluding signal sequence) of MOG341

[1026] Definition of SEQ ID NO: 288-artificial sequence: amino acid sequence of VH (excluding signal sequence) of MOG341

[1027] Definition of SEQ ID NO: 289-artificial sequence: nucleotide sequence encoding VL (excluding signal sequence) of MOG341

[1028] Definition of SEQ ID NO: 290-artificial sequence: amino acid sequence of VL (excluding signal sequence) of MOG341

[1029] Definition of SEQ ID NO: 291-artificial sequence: nucleotide sequence encoding VH (excluding signal sequence) of MOG354

[1030] Definition of SEQ ID NO: 292-artificial sequence: amino acid sequence of VH (excluding signal sequence) of MOG354

[1031] Definition of SEQ ID NO: 293-artificial sequence: nucleotide sequence encoding VL (excluding signal sequence) of MOG354

[1032] Definition of SEQ ID NO: 294-artificial sequence: amino acid sequence of VL (excluding signal sequence) of MOG354

[1033] Definition of SEQ ID NO: 295-artificial sequence: nucleotide sequence encoding VH (excluding signal sequence) of MOG355

[1034] Definition of SEQ ID NO: 296-artificial sequence: amino acid sequence of VH (excluding signal sequence) of MOG355

[1035] Definition of SEQ ID NO: 297-artificial sequence: nucleotide sequence encoding VL (excluding signal sequence) of MOG355

[1036] Definition of SEQ ID NO: 298-artificial sequence: amino acid sequence of VL (excluding signal sequence) of MOG355

[1037] Definition of SEQ ID NO: 299-artificial sequence: nucleotide sequence encoding VH (excluding signal sequence) of MOG308

[1038] Definition of SEQ ID NO: 300-artificial sequence: amino acid sequence of VH (excluding signal sequence) of MOG308

[1039] Definition of SEQ ID NO: 301-artificial sequence: nucleotide sequence encoding VL (excluding signal sequence) of MOG308

[1040] Definition of SEQ ID NO: 302-artificial sequence: amino acid sequence of VL (excluding signal sequence) of MOG308

[1041] Definition of SEQ ID NO: 303-artificial sequence: nucleotide sequence encoding VH (excluding signal sequence) of MOG316

[1042] Definition of SEQ ID NO: 304-artificial sequence: amino acid sequence of VH (excluding signal sequence) of MOG316

[1043] Definition of SEQ ID NO: 305-artificial sequence: nucleotide sequence encoding VL (excluding signal sequence) of MOG316

[1044] Definition of SEQ ID NO: 306-artificial sequence: amino acid sequence of VL (excluding signal sequence) of MOG316

[1045] Definition of SEQ ID NO: 307-artificial sequence: nucleotide sequence encoding VH (excluding signal sequence) of MOG319

[1046] Definition of SEQ ID NO: 308-artificial sequence: amino acid sequence of VH (excluding signal sequence) of MOG319

[1047] Definition of SEQ ID NO: 309-artificial sequence: nucleotide sequence encoding VL (excluding signal sequence) of MOG319

[1048] Definition of SEQ ID NO: 310-artificial sequence: amino acid sequence of VL (excluding signal sequence) of MOG319

[1049] Definition of SEQ ID NO: 311-artificial sequence: nucleotide sequence encoding VH (excluding signal sequence) of MOG320

[1050] Definition of SEQ ID NO: 312-artificial sequence: amino acid sequence of VH (excluding signal sequence) of MOG320

[1051] Definition of SEQ ID NO: 313-artificial sequence: nucleotide sequence encoding VL (excluding signal sequence) of MOG320

[1052] Definition of SEQ ID NO: 314-artificial sequence: amino acid sequence of VL (excluding signal sequence) of MOG320

[1053] Definition of SEQ ID NO: 315-artificial sequence: nucleotide sequence encoding VH (excluding signal sequence) of MOG338

[1054] Definition of SEQ ID NO: 316-artificial sequence: amino acid sequence of VH (excluding signal sequence) of MOG338

[1055] Definition of SEQ ID NO: 317-artificial sequence: nucleotide sequence encoding VL (excluding signal sequence) of MOG338

[1056] Definition of SEQ ID NO: 318-artificial sequence: amino acid sequence of VL (excluding signal sequence) of MOG338

[1057] Definition of SEQ ID NO: 319-artificial sequence: nucleotide sequence encoding VH (excluding signal sequence) of MOG352

[1058] Definition of SEQ ID NO: 320-artificial sequence: amino acid sequence of VH (excluding signal sequence) of MOG352

[1059] Definition of SEQ ID NO: 321-artificial sequence: nucleotide sequence encoding VL (excluding signal sequence) of MOG352

[1060] Definition of SEQ ID NO: 322-artificial sequence: amino acid sequence of VL (excluding signal sequence) of MOG352

[1061] Definition of SEQ ID NO: 323-artificial sequence: nucleotide sequence encoding VH (excluding signal sequence) of MOG359

[1062] Definition of SEQ ID NO: 324-artificial sequence: amino acid sequence of VH (excluding signal sequence) of MOG359

[1063] Definition of SEQ ID NO: 325-artificial sequence: nucleotide sequence encoding VL (excluding signal sequence) of MOG359

[1064] Definition of SEQ ID NO: 326-artificial sequence: amino acid sequence of VL (excluding signal sequence) of MOG359

[1065] Definition of SEQ ID NO: 327-artificial sequence: nucleotide sequence encoding VH (excluding signal sequence) of MOG478

[1066] Definition of SEQ ID NO: 328-artificial sequence: amino acid sequence of VH (excluding signal sequence) of MOG478

[1067] Definition of SEQ ID NO: 329-artificial sequence: nucleotide sequence encoding VL (excluding signal sequence) of MOG478

[1068] Definition of SEQ ID NO: 330-artificial sequence: amino acid sequence of VL (excluding signal sequence) of MOG478

[1069] Definition of SEQ ID NO: 331-artificial sequence: nucleotide sequence encoding VH (excluding signal sequence) of MOG470

[1070] Definition of SEQ ID NO: 332-artificial sequence: amino acid sequence of VH (excluding signal sequence) of MOG470

[1071] Definition of SEQ ID NO: 333-artificial sequence: nucleotide sequence encoding VL (excluding signal sequence) of MOG470

[1072] Definition of SEQ ID NO: 334-artificial sequence: amino acid sequence of VL (excluding signal sequence) of MOG470

[1073] Definition of SEQ ID NO: 335-artificial sequence: nucleotide sequence encoding VH (excluding signal sequence) of MOG418

[1074] Definition of SEQ ID NO: 336-artificial sequence: amino acid sequence of VH (excluding signal sequence) of MOG418

[1075] Definition of SEQ ID NO: 337-artificial sequence: nucleotide sequence encoding VL (excluding signal sequence) of MOG418

[1076] Definition of SEQ ID NO: 338-artificial sequence: amino acid sequence of VL (excluding signal sequence) of MOG418

Sequence CWU 1

1

3381438DNAHomo sapiensCDS(1)..(438) 1atg aac ctc ggg ctc agt ttg att ttc ctt gcc ctc att tta aaa ggt 48Met Asn Leu Gly Leu Ser Leu Ile Phe Leu Ala Leu Ile Leu Lys Gly1 5 10 15gtc cag tgt cag gta cag ctg cag cag tca ggc gca gga tta ttg aag 96Val Gln Cys Gln Val Gln Leu Gln Gln Ser Gly Ala Gly Leu Leu Lys 20 25 30cct tcg gag acc ctt tcc ctc acc tgc gct gtg tct ggt ggg tcc ttc 144Pro Ser Glu Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Phe 35 40 45agt ggt tac tac tgg acc tgg atc cgc cag cgc cca ggg aag ggg ctg 192Ser Gly Tyr Tyr Trp Thr Trp Ile Arg Gln Arg Pro Gly Lys Gly Leu 50 55 60gag tgg att gga gaa atc aat cat cgt gga agc acc gat tac aac ccg 240Glu Trp Ile Gly Glu Ile Asn His Arg Gly Ser Thr Asp Tyr Asn Pro65 70 75 80tcc ctc aag agt cga gtc acc atg tca ata gac acg tcc aag agc cag 288Ser Leu Lys Ser Arg Val Thr Met Ser Ile Asp Thr Ser Lys Ser Gln 85 90 95ttc tcc ctg aat ttg aaa tct gtg acc gcc gcg gac acg gct gtg tat 336Phe Ser Leu Asn Leu Lys Ser Val Thr Ala Ala Asp Thr Ala Val Tyr 100 105 110tac tgt gcg aga gcc gcc tgg ggg tct tgt tat gat ggg acc tgc tac 384Tyr Cys Ala Arg Ala Ala Trp Gly Ser Cys Tyr Asp Gly Thr Cys Tyr 115 120 125ccc gct gaa tac ttc caa tac tgg ggc cag gga acc ctg gtc acc gtc 432Pro Ala Glu Tyr Phe Gln Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 130 135 140tcc tca 438Ser Ser1452146PRTHomo sapiens 2Met Asn Leu Gly Leu Ser Leu Ile Phe Leu Ala Leu Ile Leu Lys Gly1 5 10 15Val Gln Cys Gln Val Gln Leu Gln Gln Ser Gly Ala Gly Leu Leu Lys 20 25 30Pro Ser Glu Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Phe 35 40 45Ser Gly Tyr Tyr Trp Thr Trp Ile Arg Gln Arg Pro Gly Lys Gly Leu 50 55 60Glu Trp Ile Gly Glu Ile Asn His Arg Gly Ser Thr Asp Tyr Asn Pro65 70 75 80Ser Leu Lys Ser Arg Val Thr Met Ser Ile Asp Thr Ser Lys Ser Gln 85 90 95Phe Ser Leu Asn Leu Lys Ser Val Thr Ala Ala Asp Thr Ala Val Tyr 100 105 110Tyr Cys Ala Arg Ala Ala Trp Gly Ser Cys Tyr Asp Gly Thr Cys Tyr 115 120 125Pro Ala Glu Tyr Phe Gln Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 130 135 140Ser Ser1453127PRTArtificialDescription of the artificial sequence amino acid sequence of VH of MOG01 excluding signal sequence 3Gln Val Gln Leu Gln Gln Ser Gly Ala Gly Leu Leu Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Phe Ser Gly Tyr 20 25 30Tyr Trp Thr Trp Ile Arg Gln Arg Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Glu Ile Asn His Arg Gly Ser Thr Asp Tyr Asn Pro Ser Leu Lys 50 55 60Ser Arg Val Thr Met Ser Ile Asp Thr Ser Lys Ser Gln Phe Ser Leu65 70 75 80Asn Leu Lys Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Ala Ala Trp Gly Ser Cys Tyr Asp Gly Thr Cys Tyr Pro Ala Glu 100 105 110Tyr Phe Gln Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 12545PRTArtificialDescription of the artificial sequence amino acid sequence of HCDR1 of MOG01 4Gly Tyr Tyr Trp Thr1 5516PRTArtificialDescription of the artificial sequence amino acid sequence of HCDR2 of MOG01 5Glu Ile Asn His Arg Gly Ser Thr Asp Tyr Asn Pro Ser Leu Lys Ser1 5 10 15619PRTArtificialDescription of the artificial sequence amino acid sequence of HCDR3 of MOG01 6Ala Ala Trp Gly Ser Cys Tyr Asp Gly Thr Cys Tyr Pro Ala Glu Tyr1 5 10 15Phe Gln Tyr7390DNAHomo sapiensCDS(1)..(390) 7atg aag ttg cct gtt agg ctg ttg gtg ctg atg ttc tgg att cct gct 48Met Lys Leu Pro Val Arg Leu Leu Val Leu Met Phe Trp Ile Pro Ala1 5 10 15tcc agc agt cag tct gcc ctg act cag cct gcc tcc gtg tct ggg tct 96Ser Ser Ser Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser 20 25 30cct gga cag tcg atc acc atc tcc tgc act gga acc agc cgt gac gtt 144Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Arg Asp Val 35 40 45ggt ggt tat aac tat gtc tcc tgg tac caa caa cac cca ggc aaa gcc 192Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala 50 55 60ccc aaa ctc atg att tat gat gtc aat aat cgg ccc tca ggg gtt tct 240Pro Lys Leu Met Ile Tyr Asp Val Asn Asn Arg Pro Ser Gly Val Ser65 70 75 80aat cgg ttc tct ggc tcc aag tct ggc aac acg gcc tcc ctg acc atc 288Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile 85 90 95tct ggg ctc cag gct gag gac gag gct gat tat ttc tgc agc tca tat 336Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Phe Cys Ser Ser Tyr 100 105 110aca agc agt agc acc cct gtg gta ttc ggc ggt ggg acc aag ctg acc 384Thr Ser Ser Ser Thr Pro Val Val Phe Gly Gly Gly Thr Lys Leu Thr 115 120 125gtc cta 390Val Leu 1308130PRTHomo sapiens 8Met Lys Leu Pro Val Arg Leu Leu Val Leu Met Phe Trp Ile Pro Ala1 5 10 15Ser Ser Ser Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser 20 25 30Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Arg Asp Val 35 40 45Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala 50 55 60Pro Lys Leu Met Ile Tyr Asp Val Asn Asn Arg Pro Ser Gly Val Ser65 70 75 80Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile 85 90 95Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Phe Cys Ser Ser Tyr 100 105 110Thr Ser Ser Ser Thr Pro Val Val Phe Gly Gly Gly Thr Lys Leu Thr 115 120 125Val Leu 1309111PRTArtificialDescription of the artificial sequence amino acid sequence of VL of MOG01 excluding signal sequence 9Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Arg Asp Val Gly Gly Tyr 20 25 30Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Asp Val Asn Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp Glu Ala Asp Tyr Phe Cys Ser Ser Tyr Thr Ser Ser 85 90 95Ser Thr Pro Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 1101014PRTArtificialDescription of the artificial sequence amino acid sequence of LCDR1 of MOG01 10Thr Gly Thr Ser Arg Asp Val Gly Gly Tyr Asn Tyr Val Ser1 5 10117PRTArtificialDescription of the artificial sequence amino acid sequence of LCDR2 of MOG01 11Asp Val Asn Asn Arg Pro Ser1 51211PRTArtificialDescription of the artificial sequence amino acid sequence of LCDR3 of MOG01 12Ser Ser Tyr Thr Ser Ser Ser Thr Pro Val Val1 5 1013423DNAHomo sapiensCDS(1)..(423) 13atg aac ctc ggg ctc agt ttg att ttc ctt gcc ctc att tta aaa ggt 48Met Asn Leu Gly Leu Ser Leu Ile Phe Leu Ala Leu Ile Leu Lys Gly1 5 10 15gtc cag tgt cag gtg cag ctg cag gag tcg ggc cca gga ctg gtg aag 96Val Gln Cys Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys 20 25 30tct tcg gag acc ctg tcc ctc acc tgc gct gtc tct ggt cac tcc atc 144Ser Ser Glu Thr Leu Ser Leu Thr Cys Ala Val Ser Gly His Ser Ile 35 40 45agc agt gct tac tac tgg ggc tgg atc cgg cag ccc cca ggg aag ggg 192Ser Ser Ala Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly 50 55 60ctg gag tgg ctt ggg agt att tat cat agt ggg aac acc tac tac aac 240Leu Glu Trp Leu Gly Ser Ile Tyr His Ser Gly Asn Thr Tyr Tyr Asn65 70 75 80ccg tcc ctc aag agt cga gtc acc ata tca gta gac acg tcc aag aac 288Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn 85 90 95cag ttc tcc ctg agg ctg acc tct gtg acc gcc gca gac acg gcc gtg 336Gln Phe Ser Leu Arg Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val 100 105 110tat tac tgt gcg aga ggg cgt gga tat agt ggc tac gat agc ggt atg 384Tyr Tyr Cys Ala Arg Gly Arg Gly Tyr Ser Gly Tyr Asp Ser Gly Met 115 120 125gac gtc tgg ggc caa ggg acc acg gtc acc gtc tcc tca 423Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 130 135 14014141PRTHomo sapiens 14Met Asn Leu Gly Leu Ser Leu Ile Phe Leu Ala Leu Ile Leu Lys Gly1 5 10 15Val Gln Cys Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys 20 25 30Ser Ser Glu Thr Leu Ser Leu Thr Cys Ala Val Ser Gly His Ser Ile 35 40 45Ser Ser Ala Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly 50 55 60Leu Glu Trp Leu Gly Ser Ile Tyr His Ser Gly Asn Thr Tyr Tyr Asn65 70 75 80Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn 85 90 95Gln Phe Ser Leu Arg Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val 100 105 110Tyr Tyr Cys Ala Arg Gly Arg Gly Tyr Ser Gly Tyr Asp Ser Gly Met 115 120 125Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 130 135 14015122PRTArtificialDescription of the artificial sequence amino acid sequence of VH of MOG09 excluding signal sequence 15Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Ser Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Ala Val Ser Gly His Ser Ile Ser Ser Ala 20 25 30Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp 35 40 45Leu Gly Ser Ile Tyr His Ser Gly Asn Thr Tyr Tyr Asn Pro Ser Leu 50 55 60Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser65 70 75 80Leu Arg Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Arg Gly Tyr Ser Gly Tyr Asp Ser Gly Met Asp Val Trp 100 105 110Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120166PRTArtificialDescription of the artificial sequence amino acid sequence of HCDR1 of MOG09 16Ser Ala Tyr Tyr Trp Gly1 51716PRTArtificialDescription of the artificial sequence amino acid sequence of HCDR2 of MOG09 17Ser Ile Tyr His Ser Gly Asn Thr Tyr Tyr Asn Pro Ser Leu Lys Ser1 5 10 151813PRTArtificialDescription of the artificial sequence amino acid sequence of HCDR3 of MOG09 18Gly Arg Gly Tyr Ser Gly Tyr Asp Ser Gly Met Asp Val1 5 1019387DNAHomo sapiensCDS(1)..(387) 19atg aag ttg cct gtt agg ctg ttg gtg ctg atg ttc tgg att cct gct 48Met Lys Leu Pro Val Arg Leu Leu Val Leu Met Phe Trp Ile Pro Ala1 5 10 15tcc agc agt tcc tat gtg ctg act cag cca ccc tca gcg tct ggg acc 96Ser Ser Ser Ser Tyr Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr 20 25 30ccc ggg cag agg gtc acc atc tct tgt tct gga acc agc tcc aac atc 144Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Thr Ser Ser Asn Ile 35 40 45gga atc aat agt gta aac tgg tat caa cag ctc cca gga atg gcc ccc 192Gly Ile Asn Ser Val Asn Trp Tyr Gln Gln Leu Pro Gly Met Ala Pro 50 55 60aaa ctc gtc atc tac agt agg gat cag cgg ccc tca ggg gtc cct gac 240Lys Leu Val Ile Tyr Ser Arg Asp Gln Arg Pro Ser Gly Val Pro Asp65 70 75 80cga ttc tct ggc tcc cag tct ggc acc tca gcc tcc ctg gcc atc aat 288Arg Phe Ser Gly Ser Gln Ser Gly Thr Ser Ala Ser Leu Ala Ile Asn 85 90 95ggc ctc cag tct gag gat gag gct gat tat tgg tgt tca aca tgg gat 336Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr Trp Cys Ser Thr Trp Asp 100 105 110gac agc ctg aat ggt tgg gtg ttc ggc gga ggg acc aag ctg acc gtc 384Asp Ser Leu Asn Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val 115 120 125cta 387Leu20129PRTHomo sapiens 20Met Lys Leu Pro Val Arg Leu Leu Val Leu Met Phe Trp Ile Pro Ala1 5 10 15Ser Ser Ser Ser Tyr Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr 20 25 30Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Thr Ser Ser Asn Ile 35 40 45Gly Ile Asn Ser Val Asn Trp Tyr Gln Gln Leu Pro Gly Met Ala Pro 50 55 60Lys Leu Val Ile Tyr Ser Arg Asp Gln Arg Pro Ser Gly Val Pro Asp65 70 75 80Arg Phe Ser Gly Ser Gln Ser Gly Thr Ser Ala Ser Leu Ala Ile Asn 85 90 95Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr Trp Cys Ser Thr Trp Asp 100 105 110Asp Ser Leu Asn Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val 115 120 125Leu21110PRTArtificialDescription of the artificial sequence amino acid sequence of VL of MOG09 excluding signal sequence 21Ser Tyr Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln1 5 10 15Arg Val Thr Ile Ser Cys Ser Gly Thr Ser Ser Asn Ile Gly Ile Asn 20 25 30Ser Val Asn Trp Tyr Gln Gln Leu Pro Gly Met Ala Pro Lys Leu Val 35 40 45Ile Tyr Ser Arg Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60Gly Ser Gln Ser Gly Thr Ser Ala Ser Leu Ala Ile Asn Gly Leu Gln65 70 75 80Ser Glu Asp Glu Ala Asp Tyr Trp Cys Ser Thr Trp Asp Asp Ser Leu 85 90 95Asn Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 1102213PRTArtificialDescription of the artificial sequence amino acid sequence of LCDR1 of MOG09 22Ser Gly Thr Ser Ser Asn Ile Gly Ile Asn Ser Val Asn1 5 10237PRTArtificialDescription of the artificial sequence amino acid sequence of LCDR2 of MOG09 23Ser Arg Asp Gln Arg Pro Ser1 52411PRTArtificialDescription of the artificial sequence amino acid sequence of LCDR3 of MOG09 24Ser Thr Trp Asp Asp Ser Leu Asn Gly Trp Val1 5 1025414DNAHomo sapiensCDS(1)..(414) 25atg aac ctc ggg ctc agt ttg att ttc ctt gcc ctc att tta aaa ggt 48Met Asn Leu Gly Leu Ser Leu Ile Phe Leu Ala Leu Ile Leu Lys Gly1 5 10 15gtc cag tgt cag gtg cag ctg gtg caa tct ggg gct gag gtg aag aag 96Val Gln Cys Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys 20 25 30cct ggg gcc tca gtg aag gtc tcc tgc cag gct tct gga tac acg ttc 144Pro Gly Ala Ser Val Lys Val Ser Cys Gln Ala Ser Gly Tyr Thr Phe 35 40 45acc ggc gac tat att cac tgg gtg cga cag gcc cct gga caa ggg ctg 192Thr Gly Asp Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu 50 55 60gaa tac ttg gga tgg atc aac cct gac agg ggt ttc aca tac tat aca 240Glu Tyr Leu Gly Trp Ile Asn Pro Asp Arg Gly Phe Thr Tyr Tyr Thr65 70 75 80cag aag ttt cag ggc agg gtc acc atg acc cgg gac acg tcc agc aac 288Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ser Asn 85 90

95aca gcc tac atg gag ctg agc agc ctg aga tct gac gac acg gcc atg 336Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Met 100 105 110tat tac tgt acg aga gag aac cct cgc gcg tac ttc ttt gac ctc tgg 384Tyr Tyr Cys Thr Arg Glu Asn Pro Arg Ala Tyr Phe Phe Asp Leu Trp 115 120 125ggc cag gga acc ctg gtc acc gtc tcc tca 414Gly Gln Gly Thr Leu Val Thr Val Ser Ser 130 13526138PRTHomo sapiens 26Met Asn Leu Gly Leu Ser Leu Ile Phe Leu Ala Leu Ile Leu Lys Gly1 5 10 15Val Gln Cys Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys 20 25 30Pro Gly Ala Ser Val Lys Val Ser Cys Gln Ala Ser Gly Tyr Thr Phe 35 40 45Thr Gly Asp Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu 50 55 60Glu Tyr Leu Gly Trp Ile Asn Pro Asp Arg Gly Phe Thr Tyr Tyr Thr65 70 75 80Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ser Asn 85 90 95Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Met 100 105 110Tyr Tyr Cys Thr Arg Glu Asn Pro Arg Ala Tyr Phe Phe Asp Leu Trp 115 120 125Gly Gln Gly Thr Leu Val Thr Val Ser Ser 130 13527119PRTArtificialDescription of the artificial sequence amino acid sequence of VH of MOG14 excluding signal sequence 27Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Gln Ala Ser Gly Tyr Thr Phe Thr Gly Asp 20 25 30Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Tyr Leu 35 40 45Gly Trp Ile Asn Pro Asp Arg Gly Phe Thr Tyr Tyr Thr Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ser Asn Thr Ala Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Met Tyr Tyr Cys 85 90 95Thr Arg Glu Asn Pro Arg Ala Tyr Phe Phe Asp Leu Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser 115285PRTArtificialDescription of the artificial sequence amino acid sequence of HCDR1 of MOG14 28Gly Asp Tyr Ile His1 52917PRTArtificialDescription of the artificial sequence amino acid sequence of HCDR2 of MOG14 29Trp Ile Asn Pro Asp Arg Gly Phe Thr Tyr Tyr Thr Gln Lys Phe Gln1 5 10 15Gly3010PRTArtificialDescription of the artificial sequence amino acid sequence of HCDR3 of MOG14 30Glu Asn Pro Arg Ala Tyr Phe Phe Asp Leu1 5 1031381DNAHomo sapiensCDS(1)..(381) 31atg aag ttg cct gtt agg ctg ttg gtg ctg atg ttc tgg att cct gct 48Met Lys Leu Pro Val Arg Leu Leu Val Leu Met Phe Trp Ile Pro Ala1 5 10 15tcc agc agt gaa ata gtg ttg acg cag tct cca ggc acc ctg tct ttg 96Ser Ser Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu 20 25 30tct cca ggg gaa aga gcc act ctc tcc tgc agg gcc agt cag agt att 144Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile 35 40 45agc ggc agc tac gtg acc tgg tac cag cag aag cct ggc cag gct ccc 192Ser Gly Ser Tyr Val Thr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro 50 55 60agg ctc ctc atc tat gct aca tcc aat agg gcc att ggc atc cca gac 240Arg Leu Leu Ile Tyr Ala Thr Ser Asn Arg Ala Ile Gly Ile Pro Asp65 70 75 80aag ttc agt ggc ggt ggg tct ggg aga gac ttc act ctc acc atc aac 288Lys Phe Ser Gly Gly Gly Ser Gly Arg Asp Phe Thr Leu Thr Ile Asn 85 90 95aga ctg gag cct gaa gat ttt gca gtg tat tac tgt cag cag agt gtt 336Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Val 100 105 110agt tct ccg tac act ttt ggc cag ggg acc aag gtg gaa atc aaa 381Ser Ser Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 115 120 12532127PRTHomo sapiens 32Met Lys Leu Pro Val Arg Leu Leu Val Leu Met Phe Trp Ile Pro Ala1 5 10 15Ser Ser Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu 20 25 30Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile 35 40 45Ser Gly Ser Tyr Val Thr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro 50 55 60Arg Leu Leu Ile Tyr Ala Thr Ser Asn Arg Ala Ile Gly Ile Pro Asp65 70 75 80Lys Phe Ser Gly Gly Gly Ser Gly Arg Asp Phe Thr Leu Thr Ile Asn 85 90 95Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Val 100 105 110Ser Ser Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 115 120 12533108PRTArtificialDescription of the artificial sequence amino acid sequence of VL of MOG14 excluding signal sequence 33Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Gly Ser 20 25 30Tyr Val Thr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45Ile Tyr Ala Thr Ser Asn Arg Ala Ile Gly Ile Pro Asp Lys Phe Ser 50 55 60Gly Gly Gly Ser Gly Arg Asp Phe Thr Leu Thr Ile Asn Arg Leu Glu65 70 75 80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Val Ser Ser Pro 85 90 95Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 1053412PRTArtificialDescription of the artificial sequence amino acid sequence of LCDR1 of MOG14 34Arg Ala Ser Gln Ser Ile Ser Gly Ser Tyr Val Thr1 5 10357PRTArtificialDescription of the artificial sequence amino acid sequence of LCDR2 of MOG14 35Ala Thr Ser Asn Arg Ala Ile1 5369PRTArtificialDescription of the artificial sequence amino acid sequence of LCDR3 of MOG14 36Gln Gln Ser Val Ser Ser Pro Tyr Thr1 537411DNAArtificialDescription of the artificial sequence sequence of VHH of iMOG_3Rim1_S32 including signal sequenceCDS(1)..(411) 37atg tac agg atg caa ctc ctg tct tgc att gca cta agt ctt gca ctt 48Met Tyr Arg Met Gln Leu Leu Ser Cys Ile Ala Leu Ser Leu Ala Leu1 5 10 15gtc acg aat tcg cag gtg cag ctc gtg gag tct ggg gga ggc ttg gtg 96Val Thr Asn Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val 20 25 30cag act ggg ggg tct ctg aga ctc tcc tgt gca gcc tct gga agc atg 144Gln Thr Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Met 35 40 45ttc agt acc atg ggc tgg ttc cgc cag gct cca ggg aac cag cgc gag 192Phe Ser Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Asn Gln Arg Glu 50 55 60ttg gtc gcc att atg tca tcc ggt ggt acc gca aac tat gca gac tct 240Leu Val Ala Ile Met Ser Ser Gly Gly Thr Ala Asn Tyr Ala Asp Ser65 70 75 80gtg aag ggc cga ttc acc atc tcc gga gac aac gtc aag aac acg gtg 288Val Lys Gly Arg Phe Thr Ile Ser Gly Asp Asn Val Lys Asn Thr Val 85 90 95act ctc caa atg aac agc ctg aat cca gag gac aca gcc gtc tat tat 336Thr Leu Gln Met Asn Ser Leu Asn Pro Glu Asp Thr Ala Val Tyr Tyr 100 105 110tgt agg ttt acc ggt tgg gtc aag agt tcg ttc tct acg tac tgg ggc 384Cys Arg Phe Thr Gly Trp Val Lys Ser Ser Phe Ser Thr Tyr Trp Gly 115 120 125cag ggg acc cag gtc acc gtc tcc tca 411Gln Gly Thr Gln Val Thr Val Ser Ser 130 13538137PRTArtificialSynthetic Construct 38Met Tyr Arg Met Gln Leu Leu Ser Cys Ile Ala Leu Ser Leu Ala Leu1 5 10 15Val Thr Asn Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val 20 25 30Gln Thr Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Met 35 40 45Phe Ser Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Asn Gln Arg Glu 50 55 60Leu Val Ala Ile Met Ser Ser Gly Gly Thr Ala Asn Tyr Ala Asp Ser65 70 75 80Val Lys Gly Arg Phe Thr Ile Ser Gly Asp Asn Val Lys Asn Thr Val 85 90 95Thr Leu Gln Met Asn Ser Leu Asn Pro Glu Asp Thr Ala Val Tyr Tyr 100 105 110Cys Arg Phe Thr Gly Trp Val Lys Ser Ser Phe Ser Thr Tyr Trp Gly 115 120 125Gln Gly Thr Gln Val Thr Val Ser Ser 130 13539117PRTArtificialDescription of the artificial sequence amino acid sequence of VHH of iMOG_3Rim1_S32 excluding signal sequence 39Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Thr Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Met Phe Ser Thr Met 20 25 30Gly Trp Phe Arg Gln Ala Pro Gly Asn Gln Arg Glu Leu Val Ala Ile 35 40 45Met Ser Ser Gly Gly Thr Ala Asn Tyr Ala Asp Ser Val Lys Gly Arg 50 55 60Phe Thr Ile Ser Gly Asp Asn Val Lys Asn Thr Val Thr Leu Gln Met65 70 75 80Asn Ser Leu Asn Pro Glu Asp Thr Ala Val Tyr Tyr Cys Arg Phe Thr 85 90 95Gly Trp Val Lys Ser Ser Phe Ser Thr Tyr Trp Gly Gln Gly Thr Gln 100 105 110Val Thr Val Ser Ser 115403PRTArtificialDescription of the artificial sequence amino acid sequence of CDR1 of iMOG_3Rim1_S32 40Thr Met Gly14116PRTArtificialDescription of the artificial sequence amino acid sequence of CDR2 of iMOG_3Rim1_S32 41Ile Met Ser Ser Gly Gly Thr Ala Asn Tyr Ala Asp Ser Val Lys Gly1 5 10 154211PRTArtificialDescription of the artificial sequence amino acid sequence of CDR3 of iMOG_3Rim1_S32 42Thr Gly Trp Val Lys Ser Ser Phe Ser Thr Tyr1 5 104336DNAArtificialDescription of the artificial sequence primer1 43ggattcctgc ttccagcagt cagtctgccc tgactc 364436DNAArtificialDescription of the artificial sequence primer2 44ggcggccttg ggctgaccta ggacggtcag cttggt 364580DNAArtificialDescription of the artificial sequence primer3 45acgccatcac agatctgcct cttcaaaatg aagttgcctg ttaggctgtt ggtgctgatg 60ttctggattc ctgcttccag 804636DNAArtificialDescription of the artificial sequence primer4 46aaaaggtgtc cagtgtcagg tacagctgca gcagtc 364732DNAArtificialprimer5 47gccccttggt gctagctgag gagacggtga cc 324880DNAArtificialDescription of the artificial sequence primer6 48acacagaccc gtcgacccct caccatgaac ctcgggctca gtttgatttt ccttgccctc 60attttaaaag gtgtccagtg 804936DNAArtificialDescription of the artificial sequence primer7 49ggattcctgc ttccagcagt tcctatgtgc tgactc 365036DNAArtificialDescription of the artificial sequence primer8 50ggcggccttg ggctgaccta ggacggtcag cttggt 365136DNAArtificialDescription of the artificial sequence primer9 51aaaaggtgtc cagtgtcagg tgcagctgca ggagtc 365232DNAArtificialDescription of the artificial sequence primer10 52gccccttggt gctagctgag gagacggtga cc 325340DNAArtificialDescription of the artificial sequence primer11 53ggattcctgc ttccagcagt gaaatagtgt tgacgcagtc 405436DNAArtificialDescription of the artificial sequence primer12 54gtgcagccac cgtacgtttg atttccacct tggtcc 365536DNAArtificialDescription of the artificial sequence primer13 55aaaaggtgtc cagtgtcagg tgcagctggt gcaatc 365632DNAArtificialDescription of the artificial sequence primer14 56gccccttggt gctagctgag gagacggtga cc 325740DNAArtificialDescription of the artificial sequence primer15 57tgcacttgtc acgaattcgc aggtgcagct cgtggagtct 405845DNAArtificialDescription of the artificial sequence primer16 58accatatttg gactcagatc tggccgctga ggagacggtg acctg 455930DNAArtificialDescription of the artificial sequence primer17 59acagtctcct cagctagcac caaggggcca 306036DNAArtificialDescription of the artificial sequence primer18 60ctgctgcagc tgtacctggg accctcctcc tccgga 366133DNAArtificialDescription of the artificial sequence primer19 61ggaggaggag ggtcccaggt acagctgcag cag 336233DNAArtificialDescription of the artificial sequence primer20 62aagcggccgc ctggatcctc ataggacggt cag 336339DNAArtificialDescription of the artificial sequence primer21 63tcagtcataa tgtctagagg agacatccag atgacccag 396437DNAArtificialDescription of the artificial sequence primer22 64gggcggcctt gggctgacct ttgatctcca ccttggt 376541DNAArtificialDescription of the artificial sequence primer23 65cagcctttcc tggtatactt agtgaggtgc agttggtgga g 416636DNAArtificialDescription of the artificial sequence primer24 66tggccccttg gtgctagccg aggagacggt gaccag 3667738DNARattus norvegicusCDS(1)..(738) 67atg gcc ggt gtg tgg agc ctt tct ctg ccc agc tgc ctc ctg tcc ctg 48Met Ala Gly Val Trp Ser Leu Ser Leu Pro Ser Cys Leu Leu Ser Leu1 5 10 15ctc ctc ctc ctc cag ttg tca cgc agc tac gca gga cag ttc aga gtg 96Leu Leu Leu Leu Gln Leu Ser Arg Ser Tyr Ala Gly Gln Phe Arg Val 20 25 30ata ggg cca ggg cat ccc atc cgg gct tta gtt ggg gat gaa gca gaa 144Ile Gly Pro Gly His Pro Ile Arg Ala Leu Val Gly Asp Glu Ala Glu 35 40 45ctg ccg tgc cgt ata tct cct ggg aag aat gcc acg ggc atg gag gtg 192Leu Pro Cys Arg Ile Ser Pro Gly Lys Asn Ala Thr Gly Met Glu Val 50 55 60ggg tgg tac cgt tct ccc ttt tca aga gtg gtt cat ctg tac cga aat 240Gly Trp Tyr Arg Ser Pro Phe Ser Arg Val Val His Leu Tyr Arg Asn65 70 75 80ggc aag gac caa gac gca gag caa gcg cct gaa tac cgg gga cgc aca 288Gly Lys Asp Gln Asp Ala Glu Gln Ala Pro Glu Tyr Arg Gly Arg Thr 85 90 95gag ctt ctg aaa gag tct atc ggc gag gga aag gtt gcc ctc agg atc 336Glu Leu Leu Lys Glu Ser Ile Gly Glu Gly Lys Val Ala Leu Arg Ile 100 105 110cag aac gtg agg ttc tcg gat gaa gga ggc tac aca tgc ttc ttc aga 384Gln Asn Val Arg Phe Ser Asp Glu Gly Gly Tyr Thr Cys Phe Phe Arg 115 120 125gac cac tcc tac caa gaa gaa gcc gcc gtg gag ttg aaa gta gaa gat 432Asp His Ser Tyr Gln Glu Glu Ala Ala Val Glu Leu Lys Val Glu Asp 130 135 140ccc ttc tac tgg atc aac cct ggc gtg ctg gct ctc att gcc ctt gtg 480Pro Phe Tyr Trp Ile Asn Pro Gly Val Leu Ala Leu Ile Ala Leu Val145 150 155 160cct atg ctg ctc ctg cag gtc tct gta ggc ctt gta ttc ctc ttc ctg 528Pro Met Leu Leu Leu Gln Val Ser Val Gly Leu Val Phe Leu Phe Leu 165 170 175cag cac aga ctg aga gga aaa ctc cgt gca gaa gtc gag aat ctc cat 576Gln His Arg Leu Arg Gly Lys Leu Arg Ala Glu Val Glu Asn Leu His 180 185 190cgg act ttt gat cct cac ttc ctg aga gtg ccc tgc tgg aag ata aca 624Arg Thr Phe Asp Pro His Phe Leu Arg Val Pro Cys Trp Lys Ile Thr 195 200 205ctg ttt gtt att gtc cct gtt ctt gga ccc ctg gtt gct ttg atc atc 672Leu Phe Val Ile Val Pro Val Leu Gly Pro Leu Val Ala Leu Ile Ile 210 215 220tgc tac aac tgg ctg cac cga aga ctg gca gga cag ttt ctt gaa gag 720Cys Tyr Asn Trp Leu His Arg Arg Leu Ala Gly Gln Phe Leu Glu Glu225 230 235 240cta aga aac ccc ttt tga 738Leu Arg Asn Pro Phe 24568245PRTRattus norvegicus 68Met Ala Gly Val Trp Ser Leu Ser Leu Pro Ser Cys Leu Leu Ser Leu1 5 10 15Leu Leu Leu Leu Gln Leu Ser Arg Ser Tyr Ala Gly Gln Phe Arg Val 20 25 30Ile

Gly Pro Gly His Pro Ile Arg Ala Leu Val Gly Asp Glu Ala Glu 35 40 45Leu Pro Cys Arg Ile Ser Pro Gly Lys Asn Ala Thr Gly Met Glu Val 50 55 60Gly Trp Tyr Arg Ser Pro Phe Ser Arg Val Val His Leu Tyr Arg Asn65 70 75 80Gly Lys Asp Gln Asp Ala Glu Gln Ala Pro Glu Tyr Arg Gly Arg Thr 85 90 95Glu Leu Leu Lys Glu Ser Ile Gly Glu Gly Lys Val Ala Leu Arg Ile 100 105 110Gln Asn Val Arg Phe Ser Asp Glu Gly Gly Tyr Thr Cys Phe Phe Arg 115 120 125Asp His Ser Tyr Gln Glu Glu Ala Ala Val Glu Leu Lys Val Glu Asp 130 135 140Pro Phe Tyr Trp Ile Asn Pro Gly Val Leu Ala Leu Ile Ala Leu Val145 150 155 160Pro Met Leu Leu Leu Gln Val Ser Val Gly Leu Val Phe Leu Phe Leu 165 170 175Gln His Arg Leu Arg Gly Lys Leu Arg Ala Glu Val Glu Asn Leu His 180 185 190Arg Thr Phe Asp Pro His Phe Leu Arg Val Pro Cys Trp Lys Ile Thr 195 200 205Leu Phe Val Ile Val Pro Val Leu Gly Pro Leu Val Ala Leu Ile Ile 210 215 220Cys Tyr Asn Trp Leu His Arg Arg Leu Ala Gly Gln Phe Leu Glu Glu225 230 235 240Leu Arg Asn Pro Phe 245691167DNAArtificialDescription of the artificial sequence sequence of rMOG-FLAG-FcCDS(1)..(1167) 69atg gcc ggt gtg tgg agc ctt tct ctg ccc agc tgc ctc ctg tcc ctg 48Met Ala Gly Val Trp Ser Leu Ser Leu Pro Ser Cys Leu Leu Ser Leu1 5 10 15ctc ctc ctc ctc cag ttg tca cgc agc tac gca gga cag ttc aga gtg 96Leu Leu Leu Leu Gln Leu Ser Arg Ser Tyr Ala Gly Gln Phe Arg Val 20 25 30ata ggg cca ggg cat ccc atc cgg gct tta gtt ggg gat gaa gca gaa 144Ile Gly Pro Gly His Pro Ile Arg Ala Leu Val Gly Asp Glu Ala Glu 35 40 45ctg ccg tgc cgt ata tct cct ggg aag aat gcc acg ggc atg gag gtg 192Leu Pro Cys Arg Ile Ser Pro Gly Lys Asn Ala Thr Gly Met Glu Val 50 55 60ggg tgg tac cgt tct ccc ttt tca aga gtg gtt cat ctg tac cga aat 240Gly Trp Tyr Arg Ser Pro Phe Ser Arg Val Val His Leu Tyr Arg Asn65 70 75 80ggc aag gac caa gac gca gag caa gcg cct gaa tac cgg gga cgc aca 288Gly Lys Asp Gln Asp Ala Glu Gln Ala Pro Glu Tyr Arg Gly Arg Thr 85 90 95gag ctt ctg aaa gag tct atc ggc gag gga aag gtt gcc ctc agg atc 336Glu Leu Leu Lys Glu Ser Ile Gly Glu Gly Lys Val Ala Leu Arg Ile 100 105 110cag aac gtg agg ttc tcg gat gaa gga ggc tac aca tgc ttc ttc aga 384Gln Asn Val Arg Phe Ser Asp Glu Gly Gly Tyr Thr Cys Phe Phe Arg 115 120 125gac cac tcc tac caa gaa gaa gcc gcc gtg gag ttg aaa gta gaa gat 432Asp His Ser Tyr Gln Glu Glu Ala Ala Val Glu Leu Lys Val Glu Asp 130 135 140ccc ttc tac tgg tct aga gca gac tac aag gac gac gat gac aag act 480Pro Phe Tyr Trp Ser Arg Ala Asp Tyr Lys Asp Asp Asp Asp Lys Thr145 150 155 160agt gac aaa act cac aca tgc cca ccg tgc cca gca cct gaa ctc ctg 528Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 165 170 175ggg gga ccg tca gtc ttc ctc ttc ccc cca aaa ccc aag gac acc ctc 576Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 180 185 190atg atc tcc cgg acc cct gag gtc aca tgc gtg gtg gtg gac gtg agc 624Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 195 200 205cac gaa gac cct gag gtc aag ttc aac tgg tac gtg gac ggc gtg gag 672His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 210 215 220gtg cat aat gcc aag aca aag ccg cgg gag gag cag tac aac agc acg 720Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr225 230 235 240tac cgt gtg gtc agc gtc ctc acc gtc ctg cac cag gac tgg ctg aat 768Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 245 250 255ggc aag gag tac aag tgc aag gtc tcc aac aaa gcc ctc cca gcc ccc 816Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 260 265 270atc gag aaa acc atc tcc aaa gcc aaa ggg cag ccc cga gaa cca cag 864Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 275 280 285gtg tac acc ctg ccc cca tcc cgg gat gag ctg acc aag aac cag gtc 912Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val 290 295 300agc ctg acc tgc ctg gtc aaa ggc ttc tat ccc agc gac atc gcc gtg 960Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val305 310 315 320gag tgg gag agc aat ggg cag ccg gag aac aac tac aag acc acg cct 1008Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 325 330 335ccc gtg ctg gac tcc gac ggc tcc ttc ttc ctc tac agc aag ctc acc 1056Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 340 345 350gtg gac aag agc agg tgg cag cag ggg aac gtc ttc tca tgc tcc gtg 1104Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 355 360 365atg cat gag gct ctg cac aac cac tac acg cag aag agc ctc tcc ctg 1152Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 370 375 380tct ccg ggt aaa tga 1167Ser Pro Gly Lys38570388PRTArtificialSynthetic Construct 70Met Ala Gly Val Trp Ser Leu Ser Leu Pro Ser Cys Leu Leu Ser Leu1 5 10 15Leu Leu Leu Leu Gln Leu Ser Arg Ser Tyr Ala Gly Gln Phe Arg Val 20 25 30Ile Gly Pro Gly His Pro Ile Arg Ala Leu Val Gly Asp Glu Ala Glu 35 40 45Leu Pro Cys Arg Ile Ser Pro Gly Lys Asn Ala Thr Gly Met Glu Val 50 55 60Gly Trp Tyr Arg Ser Pro Phe Ser Arg Val Val His Leu Tyr Arg Asn65 70 75 80Gly Lys Asp Gln Asp Ala Glu Gln Ala Pro Glu Tyr Arg Gly Arg Thr 85 90 95Glu Leu Leu Lys Glu Ser Ile Gly Glu Gly Lys Val Ala Leu Arg Ile 100 105 110Gln Asn Val Arg Phe Ser Asp Glu Gly Gly Tyr Thr Cys Phe Phe Arg 115 120 125Asp His Ser Tyr Gln Glu Glu Ala Ala Val Glu Leu Lys Val Glu Asp 130 135 140Pro Phe Tyr Trp Ser Arg Ala Asp Tyr Lys Asp Asp Asp Asp Lys Thr145 150 155 160Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 165 170 175Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 180 185 190Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 195 200 205His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 210 215 220Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr225 230 235 240Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 245 250 255Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 260 265 270Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 275 280 285Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val 290 295 300Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val305 310 315 320Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 325 330 335Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 340 345 350Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 355 360 365Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 370 375 380Ser Pro Gly Lys385711137DNAArtificialDescription of the artificial sequence sequence of rMOG-GSTCDS(1)..(1137) 71atg gcc ggt gtg tgg agc ctt tct ctg ccc agc tgc ctc ctg tcc ctg 48Met Ala Gly Val Trp Ser Leu Ser Leu Pro Ser Cys Leu Leu Ser Leu1 5 10 15ctc ctc ctc ctc cag ttg tca cgc agc tac gca gga cag ttc aga gtg 96Leu Leu Leu Leu Gln Leu Ser Arg Ser Tyr Ala Gly Gln Phe Arg Val 20 25 30ata ggg cca ggg cat ccc atc cgg gct tta gtt ggg gat gaa gca gaa 144Ile Gly Pro Gly His Pro Ile Arg Ala Leu Val Gly Asp Glu Ala Glu 35 40 45ctg ccg tgc cgt ata tct cct ggg aag aat gcc acg ggc atg gag gtg 192Leu Pro Cys Arg Ile Ser Pro Gly Lys Asn Ala Thr Gly Met Glu Val 50 55 60ggg tgg tac cgt tct ccc ttt tca aga gtg gtt cat ctg tac cga aat 240Gly Trp Tyr Arg Ser Pro Phe Ser Arg Val Val His Leu Tyr Arg Asn65 70 75 80ggc aag gac caa gac gca gag caa gcg cct gaa tac cgg gga cgc aca 288Gly Lys Asp Gln Asp Ala Glu Gln Ala Pro Glu Tyr Arg Gly Arg Thr 85 90 95gag ctt ctg aaa gag tct atc ggc gag gga aag gtt gcc ctc agg atc 336Glu Leu Leu Lys Glu Ser Ile Gly Glu Gly Lys Val Ala Leu Arg Ile 100 105 110cag aac gtg agg ttc tcg gat gaa gga ggc tac aca tgc ttc ttc aga 384Gln Asn Val Arg Phe Ser Asp Glu Gly Gly Tyr Thr Cys Phe Phe Arg 115 120 125gac cac tcc tac caa gaa gaa gcc gcc gtg gag ttg aaa gta gaa gat 432Asp His Ser Tyr Gln Glu Glu Ala Ala Val Glu Leu Lys Val Glu Asp 130 135 140ccc ttc tac tgg ggt acc ctg gaa gtt ctg ttc cag ggg ccc atg tcc 480Pro Phe Tyr Trp Gly Thr Leu Glu Val Leu Phe Gln Gly Pro Met Ser145 150 155 160cct ata cta ggt tat tgg aaa att aag ggc ctt gtg caa ccc act cga 528Pro Ile Leu Gly Tyr Trp Lys Ile Lys Gly Leu Val Gln Pro Thr Arg 165 170 175ctt ctt ttg gaa tat ctt gaa gaa aaa tat gaa gag cat ttg tat gag 576Leu Leu Leu Glu Tyr Leu Glu Glu Lys Tyr Glu Glu His Leu Tyr Glu 180 185 190cgc gat gaa ggt gat aaa tgg cga aac aaa aag ttt gaa ttg ggt ttg 624Arg Asp Glu Gly Asp Lys Trp Arg Asn Lys Lys Phe Glu Leu Gly Leu 195 200 205gag ttt ccc aat ctt cct tat tat att gat ggt gat gtt aaa tta aca 672Glu Phe Pro Asn Leu Pro Tyr Tyr Ile Asp Gly Asp Val Lys Leu Thr 210 215 220cag tct atg gcc atc ata cgt tat ata gct gac aag cac aac atg ttg 720Gln Ser Met Ala Ile Ile Arg Tyr Ile Ala Asp Lys His Asn Met Leu225 230 235 240ggt ggt tgt cca aaa gag cgt gca gag att tca atg ctt gaa gga gcg 768Gly Gly Cys Pro Lys Glu Arg Ala Glu Ile Ser Met Leu Glu Gly Ala 245 250 255gtt ttg gat att aga tac ggt gtt tcg aga att gca tat agt aaa gac 816Val Leu Asp Ile Arg Tyr Gly Val Ser Arg Ile Ala Tyr Ser Lys Asp 260 265 270ttt gaa act ctc aaa gtt gat ttt ctt agc aag cta cct gaa atg ctg 864Phe Glu Thr Leu Lys Val Asp Phe Leu Ser Lys Leu Pro Glu Met Leu 275 280 285aaa atg ttc gaa gat cgt tta tgt cat aaa aca tat tta aat ggt gat 912Lys Met Phe Glu Asp Arg Leu Cys His Lys Thr Tyr Leu Asn Gly Asp 290 295 300cat gta acc cat cct gac ttc atg ttg tat gac gct ctt gat gtt gtt 960His Val Thr His Pro Asp Phe Met Leu Tyr Asp Ala Leu Asp Val Val305 310 315 320tta tac atg gac cca atg tgc ctg gat gcg ttc cca aaa tta gtt tgt 1008Leu Tyr Met Asp Pro Met Cys Leu Asp Ala Phe Pro Lys Leu Val Cys 325 330 335ttt aaa aaa cgt att gaa gct atc cca caa att gat aag tac ttg aaa 1056Phe Lys Lys Arg Ile Glu Ala Ile Pro Gln Ile Asp Lys Tyr Leu Lys 340 345 350tcc agc aag tat ata gca tgg cct ttg cag ggc tgg caa gcc acg ttt 1104Ser Ser Lys Tyr Ile Ala Trp Pro Leu Gln Gly Trp Gln Ala Thr Phe 355 360 365ggt ggt ggc gac cat cct cca aaa tcg gat tga 1137Gly Gly Gly Asp His Pro Pro Lys Ser Asp 370 37572378PRTArtificialSynthetic Construct 72Met Ala Gly Val Trp Ser Leu Ser Leu Pro Ser Cys Leu Leu Ser Leu1 5 10 15Leu Leu Leu Leu Gln Leu Ser Arg Ser Tyr Ala Gly Gln Phe Arg Val 20 25 30Ile Gly Pro Gly His Pro Ile Arg Ala Leu Val Gly Asp Glu Ala Glu 35 40 45Leu Pro Cys Arg Ile Ser Pro Gly Lys Asn Ala Thr Gly Met Glu Val 50 55 60Gly Trp Tyr Arg Ser Pro Phe Ser Arg Val Val His Leu Tyr Arg Asn65 70 75 80Gly Lys Asp Gln Asp Ala Glu Gln Ala Pro Glu Tyr Arg Gly Arg Thr 85 90 95Glu Leu Leu Lys Glu Ser Ile Gly Glu Gly Lys Val Ala Leu Arg Ile 100 105 110Gln Asn Val Arg Phe Ser Asp Glu Gly Gly Tyr Thr Cys Phe Phe Arg 115 120 125Asp His Ser Tyr Gln Glu Glu Ala Ala Val Glu Leu Lys Val Glu Asp 130 135 140Pro Phe Tyr Trp Gly Thr Leu Glu Val Leu Phe Gln Gly Pro Met Ser145 150 155 160Pro Ile Leu Gly Tyr Trp Lys Ile Lys Gly Leu Val Gln Pro Thr Arg 165 170 175Leu Leu Leu Glu Tyr Leu Glu Glu Lys Tyr Glu Glu His Leu Tyr Glu 180 185 190Arg Asp Glu Gly Asp Lys Trp Arg Asn Lys Lys Phe Glu Leu Gly Leu 195 200 205Glu Phe Pro Asn Leu Pro Tyr Tyr Ile Asp Gly Asp Val Lys Leu Thr 210 215 220Gln Ser Met Ala Ile Ile Arg Tyr Ile Ala Asp Lys His Asn Met Leu225 230 235 240Gly Gly Cys Pro Lys Glu Arg Ala Glu Ile Ser Met Leu Glu Gly Ala 245 250 255Val Leu Asp Ile Arg Tyr Gly Val Ser Arg Ile Ala Tyr Ser Lys Asp 260 265 270Phe Glu Thr Leu Lys Val Asp Phe Leu Ser Lys Leu Pro Glu Met Leu 275 280 285Lys Met Phe Glu Asp Arg Leu Cys His Lys Thr Tyr Leu Asn Gly Asp 290 295 300His Val Thr His Pro Asp Phe Met Leu Tyr Asp Ala Leu Asp Val Val305 310 315 320Leu Tyr Met Asp Pro Met Cys Leu Asp Ala Phe Pro Lys Leu Val Cys 325 330 335Phe Lys Lys Arg Ile Glu Ala Ile Pro Gln Ile Asp Lys Tyr Leu Lys 340 345 350Ser Ser Lys Tyr Ile Ala Trp Pro Leu Gln Gly Trp Gln Ala Thr Phe 355 360 365Gly Gly Gly Asp His Pro Pro Lys Ser Asp 370 37573744DNAMus musculusCDS(1)..(744) 73atg gcc tgt ttg tgg agc ttc tct tgg ccc agc tgc ttc ctc tcc ctt 48Met Ala Cys Leu Trp Ser Phe Ser Trp Pro Ser Cys Phe Leu Ser Leu1 5 10 15ctc ctc ctc ctt ctc ctc cag ttg tca tgc agc tat gca gga caa ttc 96Leu Leu Leu Leu Leu Leu Gln Leu Ser Cys Ser Tyr Ala Gly Gln Phe 20 25 30aga gtg ata gga cca ggg tat ccc atc cgg gct tta gtt ggg gat gaa 144Arg Val Ile Gly Pro Gly Tyr Pro Ile Arg Ala Leu Val Gly Asp Glu 35 40 45gca gag ctg ccg tgc cgc atc tct cct ggg aaa aat gcc acg ggc atg 192Ala Glu Leu Pro Cys Arg Ile Ser Pro Gly Lys Asn Ala Thr Gly Met 50 55 60gag gtg ggt tgg tac cgt tct ccc ttc tca aga gtg gtt cac ctc tac 240Glu Val Gly Trp Tyr Arg Ser Pro Phe Ser Arg Val Val His Leu Tyr65 70 75 80cga aat ggc aag gac caa gat gca gag caa gca cct gaa tac cgg gga 288Arg Asn Gly Lys Asp Gln Asp Ala Glu Gln Ala Pro Glu Tyr Arg Gly 85 90 95cgc aca gag ctt ctg aaa gag act atc agt gag gga aag gtt acc ctt 336Arg Thr Glu Leu Leu Lys Glu Thr Ile Ser Glu Gly Lys Val Thr Leu 100 105 110agg att cag aac gtg aga ttc tca gat gaa gga ggc tac acc tgc ttc 384Arg Ile Gln Asn Val Arg Phe Ser Asp Glu Gly Gly Tyr Thr Cys Phe 115 120 125ttc aga gac cac tct tac caa gaa gag gca gca atg gag ttg aaa gtg 432Phe Arg Asp His

Ser Tyr Gln Glu Glu Ala Ala Met Glu Leu Lys Val 130 135 140gaa gat ccc ttc tat tgg gtc aac ccc ggt gtg ctg act ctc atc gca 480Glu Asp Pro Phe Tyr Trp Val Asn Pro Gly Val Leu Thr Leu Ile Ala145 150 155 160ctt gtg cct acg atc ctc ctg cag gtc tct gta ggc ctt gta ttc ctc 528Leu Val Pro Thr Ile Leu Leu Gln Val Ser Val Gly Leu Val Phe Leu 165 170 175ttc ctg cag cac aga ctg aga gga aaa ctt cgt gca gaa gta gag aat 576Phe Leu Gln His Arg Leu Arg Gly Lys Leu Arg Ala Glu Val Glu Asn 180 185 190ctc cat cgg act ttt gat cct cac ttc ctg agg gtg ccc tgc tgg aag 624Leu His Arg Thr Phe Asp Pro His Phe Leu Arg Val Pro Cys Trp Lys 195 200 205ata aca ctg ttt gtt att gtg cct gtt ctt gga ccc ctg gtt gcc ttg 672Ile Thr Leu Phe Val Ile Val Pro Val Leu Gly Pro Leu Val Ala Leu 210 215 220atc atc tgc tac aac tgg ctg cac cga aga ctg gca gga cag ttt ctt 720Ile Ile Cys Tyr Asn Trp Leu His Arg Arg Leu Ala Gly Gln Phe Leu225 230 235 240gaa gag cta aga aac ccc ttt tga 744Glu Glu Leu Arg Asn Pro Phe 24574247PRTMus musculus 74Met Ala Cys Leu Trp Ser Phe Ser Trp Pro Ser Cys Phe Leu Ser Leu1 5 10 15Leu Leu Leu Leu Leu Leu Gln Leu Ser Cys Ser Tyr Ala Gly Gln Phe 20 25 30Arg Val Ile Gly Pro Gly Tyr Pro Ile Arg Ala Leu Val Gly Asp Glu 35 40 45Ala Glu Leu Pro Cys Arg Ile Ser Pro Gly Lys Asn Ala Thr Gly Met 50 55 60Glu Val Gly Trp Tyr Arg Ser Pro Phe Ser Arg Val Val His Leu Tyr65 70 75 80Arg Asn Gly Lys Asp Gln Asp Ala Glu Gln Ala Pro Glu Tyr Arg Gly 85 90 95Arg Thr Glu Leu Leu Lys Glu Thr Ile Ser Glu Gly Lys Val Thr Leu 100 105 110Arg Ile Gln Asn Val Arg Phe Ser Asp Glu Gly Gly Tyr Thr Cys Phe 115 120 125Phe Arg Asp His Ser Tyr Gln Glu Glu Ala Ala Met Glu Leu Lys Val 130 135 140Glu Asp Pro Phe Tyr Trp Val Asn Pro Gly Val Leu Thr Leu Ile Ala145 150 155 160Leu Val Pro Thr Ile Leu Leu Gln Val Ser Val Gly Leu Val Phe Leu 165 170 175Phe Leu Gln His Arg Leu Arg Gly Lys Leu Arg Ala Glu Val Glu Asn 180 185 190Leu His Arg Thr Phe Asp Pro His Phe Leu Arg Val Pro Cys Trp Lys 195 200 205Ile Thr Leu Phe Val Ile Val Pro Val Leu Gly Pro Leu Val Ala Leu 210 215 220Ile Ile Cys Tyr Asn Trp Leu His Arg Arg Leu Ala Gly Gln Phe Leu225 230 235 240Glu Glu Leu Arg Asn Pro Phe 24575744DNAMacaca fascicularisCDS(1)..(744) 75atg gca agc tta tca aga ccc tct ctg ccc agc tgc ctc tgc tcc ttc 48Met Ala Ser Leu Ser Arg Pro Ser Leu Pro Ser Cys Leu Cys Ser Phe1 5 10 15ctc ctc ctc ctg ctc ctc caa gtg tct tcc agc tac gca gga cag ttc 96Leu Leu Leu Leu Leu Leu Gln Val Ser Ser Ser Tyr Ala Gly Gln Phe 20 25 30aga gtg ata gga cca aga caa cct atc cgg gct ctg gtc ggt gat gaa 144Arg Val Ile Gly Pro Arg Gln Pro Ile Arg Ala Leu Val Gly Asp Glu 35 40 45gtg gaa ttg cca tgt cgc ata tct cct ggg aag aac gct aca ggc atg 192Val Glu Leu Pro Cys Arg Ile Ser Pro Gly Lys Asn Ala Thr Gly Met 50 55 60gaa gtg gga tgg tac cgg ccc ccc ttc tct agg gtg gtt cat ctc tac 240Glu Val Gly Trp Tyr Arg Pro Pro Phe Ser Arg Val Val His Leu Tyr65 70 75 80aga aat ggc agg gac caa gat gga gag caa gca cct gaa tat cgg ggc 288Arg Asn Gly Arg Asp Gln Asp Gly Glu Gln Ala Pro Glu Tyr Arg Gly 85 90 95cgg aca gag ctg ctg aaa gac gct att ggt gag gga aag gtg act ctc 336Arg Thr Glu Leu Leu Lys Asp Ala Ile Gly Glu Gly Lys Val Thr Leu 100 105 110agg atc cgg aat gta agg ttc tca gat gaa gga ggt ttc acc tgc ttc 384Arg Ile Arg Asn Val Arg Phe Ser Asp Glu Gly Gly Phe Thr Cys Phe 115 120 125ttc cga gat cat tct tac caa gag gag gca gca ata gaa ttg aaa gtg 432Phe Arg Asp His Ser Tyr Gln Glu Glu Ala Ala Ile Glu Leu Lys Val 130 135 140gaa gat ccc ttc tac tgg gtc agc cct gca gtg ctg gtt ctc ctc gcg 480Glu Asp Pro Phe Tyr Trp Val Ser Pro Ala Val Leu Val Leu Leu Ala145 150 155 160gtg ctg cct gtg ctc ctt ctg cag atc act gtc ggc ctc gtc ttc ctc 528Val Leu Pro Val Leu Leu Leu Gln Ile Thr Val Gly Leu Val Phe Leu 165 170 175tgc ctg cag tat aga ctg aga gga aaa ctt cga gca gag ata gag aat 576Cys Leu Gln Tyr Arg Leu Arg Gly Lys Leu Arg Ala Glu Ile Glu Asn 180 185 190ctc cac cgg act ttt gat ccc cac ttt ctg agg gtg ccc tgc tgg aag 624Leu His Arg Thr Phe Asp Pro His Phe Leu Arg Val Pro Cys Trp Lys 195 200 205ata acc ctg ttt gta att gtg ccg gtt ctt gga ccc ctg gtt gcc ttg 672Ile Thr Leu Phe Val Ile Val Pro Val Leu Gly Pro Leu Val Ala Leu 210 215 220atc atc tgc tac aac tgg cta cat cga aga cta gca ggg caa ttc ctt 720Ile Ile Cys Tyr Asn Trp Leu His Arg Arg Leu Ala Gly Gln Phe Leu225 230 235 240gaa gag cta aga aac cct ttc tga 744Glu Glu Leu Arg Asn Pro Phe 24576247PRTMacaca fascicularis 76Met Ala Ser Leu Ser Arg Pro Ser Leu Pro Ser Cys Leu Cys Ser Phe1 5 10 15Leu Leu Leu Leu Leu Leu Gln Val Ser Ser Ser Tyr Ala Gly Gln Phe 20 25 30Arg Val Ile Gly Pro Arg Gln Pro Ile Arg Ala Leu Val Gly Asp Glu 35 40 45Val Glu Leu Pro Cys Arg Ile Ser Pro Gly Lys Asn Ala Thr Gly Met 50 55 60Glu Val Gly Trp Tyr Arg Pro Pro Phe Ser Arg Val Val His Leu Tyr65 70 75 80Arg Asn Gly Arg Asp Gln Asp Gly Glu Gln Ala Pro Glu Tyr Arg Gly 85 90 95Arg Thr Glu Leu Leu Lys Asp Ala Ile Gly Glu Gly Lys Val Thr Leu 100 105 110Arg Ile Arg Asn Val Arg Phe Ser Asp Glu Gly Gly Phe Thr Cys Phe 115 120 125Phe Arg Asp His Ser Tyr Gln Glu Glu Ala Ala Ile Glu Leu Lys Val 130 135 140Glu Asp Pro Phe Tyr Trp Val Ser Pro Ala Val Leu Val Leu Leu Ala145 150 155 160Val Leu Pro Val Leu Leu Leu Gln Ile Thr Val Gly Leu Val Phe Leu 165 170 175Cys Leu Gln Tyr Arg Leu Arg Gly Lys Leu Arg Ala Glu Ile Glu Asn 180 185 190Leu His Arg Thr Phe Asp Pro His Phe Leu Arg Val Pro Cys Trp Lys 195 200 205Ile Thr Leu Phe Val Ile Val Pro Val Leu Gly Pro Leu Val Ala Leu 210 215 220Ile Ile Cys Tyr Asn Trp Leu His Arg Arg Leu Ala Gly Gln Phe Leu225 230 235 240Glu Glu Leu Arg Asn Pro Phe 24577744DNAHomo sapiensCDS(1)..(744) 77atg gca agc tta tca aga ccc tct ctg ccc agc tgc ctc tgc tcc ttc 48Met Ala Ser Leu Ser Arg Pro Ser Leu Pro Ser Cys Leu Cys Ser Phe1 5 10 15ctc ctc ctc ctc ctc ctc caa gtg tct tcc agc tat gca ggg cag ttc 96Leu Leu Leu Leu Leu Leu Gln Val Ser Ser Ser Tyr Ala Gly Gln Phe 20 25 30aga gtg ata gga cca aga cac cct atc cgg gct ctg gtc ggg gat gaa 144Arg Val Ile Gly Pro Arg His Pro Ile Arg Ala Leu Val Gly Asp Glu 35 40 45gtg gaa ttg cca tgt cgc ata tct cct ggg aag aac gct aca ggc atg 192Val Glu Leu Pro Cys Arg Ile Ser Pro Gly Lys Asn Ala Thr Gly Met 50 55 60gag gtg ggg tgg tac cgc ccc ccc ttc tct agg gtg gtt cat ctc tac 240Glu Val Gly Trp Tyr Arg Pro Pro Phe Ser Arg Val Val His Leu Tyr65 70 75 80aga aat ggc aag gac caa gat gga gac cag gca cct gaa tat cgg ggc 288Arg Asn Gly Lys Asp Gln Asp Gly Asp Gln Ala Pro Glu Tyr Arg Gly 85 90 95cgg aca gag ctg ctg aaa gat gct att ggt gag gga aag gtg act ctc 336Arg Thr Glu Leu Leu Lys Asp Ala Ile Gly Glu Gly Lys Val Thr Leu 100 105 110agg atc cgg aat gta agg ttc tca gat gaa gga ggt ttc acc tgc ttc 384Arg Ile Arg Asn Val Arg Phe Ser Asp Glu Gly Gly Phe Thr Cys Phe 115 120 125ttc cga gat cat tct tac caa gag gag gca gca atg gaa ttg aaa gta 432Phe Arg Asp His Ser Tyr Gln Glu Glu Ala Ala Met Glu Leu Lys Val 130 135 140gaa gat cct ttc tac tgg gtg agc cct gga gtg ctg gtt ctc ctc gcg 480Glu Asp Pro Phe Tyr Trp Val Ser Pro Gly Val Leu Val Leu Leu Ala145 150 155 160gtg ctg cct gtg ctc ctc ctg cag atc act gtt ggc ctc gtc ttc ctc 528Val Leu Pro Val Leu Leu Leu Gln Ile Thr Val Gly Leu Val Phe Leu 165 170 175tgc ctg cag tac aga ctg aga gga aaa ctt cga gca gag ata gag aat 576Cys Leu Gln Tyr Arg Leu Arg Gly Lys Leu Arg Ala Glu Ile Glu Asn 180 185 190ctc cac cgg act ttt gat ccc cac ttt ctg agg gtg ccc tgc tgg aag 624Leu His Arg Thr Phe Asp Pro His Phe Leu Arg Val Pro Cys Trp Lys 195 200 205ata acc ctg ttt gta att gtg ccg gtt ctt gga ccc ttg gtt gcc ttg 672Ile Thr Leu Phe Val Ile Val Pro Val Leu Gly Pro Leu Val Ala Leu 210 215 220atc atc tgc tac aac tgg cta cat cga aga cta gca ggg caa ttc ctt 720Ile Ile Cys Tyr Asn Trp Leu His Arg Arg Leu Ala Gly Gln Phe Leu225 230 235 240gaa gag cta cga aat ccc ttc tga 744Glu Glu Leu Arg Asn Pro Phe 24578247PRTHomo sapiens 78Met Ala Ser Leu Ser Arg Pro Ser Leu Pro Ser Cys Leu Cys Ser Phe1 5 10 15Leu Leu Leu Leu Leu Leu Gln Val Ser Ser Ser Tyr Ala Gly Gln Phe 20 25 30Arg Val Ile Gly Pro Arg His Pro Ile Arg Ala Leu Val Gly Asp Glu 35 40 45Val Glu Leu Pro Cys Arg Ile Ser Pro Gly Lys Asn Ala Thr Gly Met 50 55 60Glu Val Gly Trp Tyr Arg Pro Pro Phe Ser Arg Val Val His Leu Tyr65 70 75 80Arg Asn Gly Lys Asp Gln Asp Gly Asp Gln Ala Pro Glu Tyr Arg Gly 85 90 95Arg Thr Glu Leu Leu Lys Asp Ala Ile Gly Glu Gly Lys Val Thr Leu 100 105 110Arg Ile Arg Asn Val Arg Phe Ser Asp Glu Gly Gly Phe Thr Cys Phe 115 120 125Phe Arg Asp His Ser Tyr Gln Glu Glu Ala Ala Met Glu Leu Lys Val 130 135 140Glu Asp Pro Phe Tyr Trp Val Ser Pro Gly Val Leu Val Leu Leu Ala145 150 155 160Val Leu Pro Val Leu Leu Leu Gln Ile Thr Val Gly Leu Val Phe Leu 165 170 175Cys Leu Gln Tyr Arg Leu Arg Gly Lys Leu Arg Ala Glu Ile Glu Asn 180 185 190Leu His Arg Thr Phe Asp Pro His Phe Leu Arg Val Pro Cys Trp Lys 195 200 205Ile Thr Leu Phe Val Ile Val Pro Val Leu Gly Pro Leu Val Ala Leu 210 215 220Ile Ile Cys Tyr Asn Trp Leu His Arg Arg Leu Ala Gly Gln Phe Leu225 230 235 240Glu Glu Leu Arg Asn Pro Phe 2457933DNAArtificialDescription of the artificial sequence primer25 79gagacgccat cacagatcat cccaccatgt aca 338033DNAArtificialDescription of the artificial sequence primer26 80gtaaccgtta acggatcctc atttacccag aga 338136DNAArtificialDescription of the artificial sequence primer27 81accaaggtgg agatcaaacg tacggtggct gcacca 368236DNAArtificialDescription of the artificial sequence primer28 82cggccacacg ttgaattctc aacactctcc cctgtt 368336DNAArtificialDescription of the artificial sequence primer29 83gattcctgct tccagcagtc agtttgtgct ttctca 368436DNAArtificialDescription of the artificial sequence primer30 84ggcggccttg ggctgaccta ggacagtgag cttggt 368536DNAArtificialDescription of the artificial sequence primer31 85ttaaaaggtg tccagtgtga ggtgcagctg gtggaa 368636DNAArtificialDescription of the artificial sequence primer32 86tggccccttg gtgctagctg aggagactgt gaccat 368738DNAArtificialDescription of the artificial sequence primer33 87tcagtcataa tgtctagagg acagtttgtg ctttctca 388836DNAArtificialDescription of the artificial sequence primer34 88cggccacacg ttgaattctc atgaacattc tgtagg 368941DNAArtificialDescription of the artificial sequence primer35 89cagcctttcc tggtatactt agtgaggtgc agctggtgga a 419030DNAArtificialDescription of the artificial sequence primer36 90acagtctcct cagctagcac caaggggcca 309135DNAArtificialDescription of the artificial sequence primer37 91tccaccagct gcacctcgga ccctcctcct ccgga 359233DNAArtificialDescription of the artificial sequence primer38 92ggaggaggag ggtccgaggt gcagctggtg gaa 339336DNAArtificialDescription of the artificial sequence primer39 93aagcggccgc ctggatcctc ataggacagt gagctt 369433DNAArtificialDescription of the artificial sequence primer40 94agacgccatc acagatctgc ctcttcaaaa tga 339536DNAArtificialDescription of the artificial sequence primer41 95tggtgcagcc accgtacgtt tgatttccag cttggt 369633DNAArtificialDescription of the artificial sequence primer42 96gaacacagac ccgtcgaccc ctcaccatga acc 339736DNAArtificialDescription of the artificial sequence primer43 97tggccccttg gtgctagcgg aggagactgt gagagt 36982640DNAArtificialDescription of the artificial sequence sequence of hHER2-GSTCDS(1)..(2640) 98atg gag ctg gcg gcc ttg tgc cgc tgg ggg ctc ctc ctc gcc ctc ttg 48Met Glu Leu Ala Ala Leu Cys Arg Trp Gly Leu Leu Leu Ala Leu Leu1 5 10 15ccc ccc gga gcc gcg agc acc caa gtg tgc acc ggc aca gac atg aag 96Pro Pro Gly Ala Ala Ser Thr Gln Val Cys Thr Gly Thr Asp Met Lys 20 25 30ctg cgg ctc cct gcc agt ccc gag acc cac ctg gac atg ctc cgc cac 144Leu Arg Leu Pro Ala Ser Pro Glu Thr His Leu Asp Met Leu Arg His 35 40 45ctc tac cag ggc tgc cag gtg gtg cag gga aac ctg gaa ctc acc tac 192Leu Tyr Gln Gly Cys Gln Val Val Gln Gly Asn Leu Glu Leu Thr Tyr 50 55 60ctg ccc acc aat gcc agc ctg tcc ttc ctg cag gat atc cag gag gtg 240Leu Pro Thr Asn Ala Ser Leu Ser Phe Leu Gln Asp Ile Gln Glu Val65 70 75 80cag ggc tac gtg ctc atc gct cac aac caa gtg agg cag gtc cca ctg 288Gln Gly Tyr Val Leu Ile Ala His Asn Gln Val Arg Gln Val Pro Leu 85 90 95cag agg ctg cgg att gtg cga ggc acc cag ctc ttt gag gac aac tat 336Gln Arg Leu Arg Ile Val Arg Gly Thr Gln Leu Phe Glu Asp Asn Tyr 100 105 110gcc ctg gcc gtg cta gac aat gga gac ccg ctg aac aat acc acc cct 384Ala Leu Ala Val Leu Asp Asn Gly Asp Pro Leu Asn Asn Thr Thr Pro 115 120 125gtc aca ggg gcc tcc cca gga ggc ctg cgg gag ctg cag ctt cga agc 432Val Thr Gly Ala Ser Pro Gly Gly Leu Arg Glu Leu Gln Leu Arg Ser 130 135 140ctc aca gag atc ttg aaa gga ggg gtc ttg atc cag cgg aac ccc cag 480Leu Thr Glu Ile Leu Lys Gly Gly Val Leu Ile Gln Arg Asn Pro Gln145 150 155 160ctc tgc tac cag gac acg att ttg tgg aag gac atc ttc cac aag aac 528Leu Cys Tyr Gln Asp Thr Ile Leu Trp Lys Asp Ile Phe His Lys Asn 165 170 175aac cag ctg gct ctc aca ctg ata gac acc aac cgc tct cgg gcc tgc 576Asn Gln Leu Ala Leu Thr Leu Ile Asp Thr Asn Arg Ser Arg Ala Cys 180 185 190cac ccc tgt tct ccg atg tgt aag ggc tcc cgc tgc tgg gga gag agt 624His Pro Cys Ser Pro Met Cys Lys Gly Ser Arg Cys Trp Gly Glu Ser 195 200 205tct gag gat tgt cag agc ctg acg cgc act gtc tgt gcc ggt

ggc tgt 672Ser Glu Asp Cys Gln Ser Leu Thr Arg Thr Val Cys Ala Gly Gly Cys 210 215 220gcc cgc tgc aag ggg cca ctg ccc act gac tgc tgc cat gag cag tgt 720Ala Arg Cys Lys Gly Pro Leu Pro Thr Asp Cys Cys His Glu Gln Cys225 230 235 240gct gcc ggc tgc acg ggc ccc aag cac tct gac tgc ctg gcc tgc ctc 768Ala Ala Gly Cys Thr Gly Pro Lys His Ser Asp Cys Leu Ala Cys Leu 245 250 255cac ttc aac cac agt ggc atc tgt gag ctg cac tgc cca gcc ctg gtc 816His Phe Asn His Ser Gly Ile Cys Glu Leu His Cys Pro Ala Leu Val 260 265 270acc tac aac aca gac acg ttt gag tcc atg ccc aat ccc gag ggc cgg 864Thr Tyr Asn Thr Asp Thr Phe Glu Ser Met Pro Asn Pro Glu Gly Arg 275 280 285tat aca ttc ggc gcc agc tgt gtg act gcc tgt ccc tac aac tac ctt 912Tyr Thr Phe Gly Ala Ser Cys Val Thr Ala Cys Pro Tyr Asn Tyr Leu 290 295 300tct acg gac gtg gga tcc tgc acc ctc gtc tgc ccc ctg cac aac caa 960Ser Thr Asp Val Gly Ser Cys Thr Leu Val Cys Pro Leu His Asn Gln305 310 315 320gag gtg aca gca gag gat gga aca cag cgg tgt gag aag tgc agc aag 1008Glu Val Thr Ala Glu Asp Gly Thr Gln Arg Cys Glu Lys Cys Ser Lys 325 330 335ccc tgt gcc cga gtg tgc tat ggt ctg ggc atg gag cac ttg cga gag 1056Pro Cys Ala Arg Val Cys Tyr Gly Leu Gly Met Glu His Leu Arg Glu 340 345 350gtg agg gca gtt acc agt gcc aat atc cag gag ttt gct ggc tgc aag 1104Val Arg Ala Val Thr Ser Ala Asn Ile Gln Glu Phe Ala Gly Cys Lys 355 360 365aag atc ttt ggg agc ctg gca ttt ctg ccg gag agc ttt gat ggg gac 1152Lys Ile Phe Gly Ser Leu Ala Phe Leu Pro Glu Ser Phe Asp Gly Asp 370 375 380cca gcc tcc aac act gcc ccg ctc cag cca gag cag ctc caa gtg ttt 1200Pro Ala Ser Asn Thr Ala Pro Leu Gln Pro Glu Gln Leu Gln Val Phe385 390 395 400gag act ctg gaa gag atc aca ggt tac cta tac atc tca gca tgg ccg 1248Glu Thr Leu Glu Glu Ile Thr Gly Tyr Leu Tyr Ile Ser Ala Trp Pro 405 410 415gac agc ctg cct gac ctc agc gtc ttc cag aac ctg caa gta atc cgg 1296Asp Ser Leu Pro Asp Leu Ser Val Phe Gln Asn Leu Gln Val Ile Arg 420 425 430gga cga att ctg cac aat ggc gcc tac tcg ctg acc ctg caa ggg ctg 1344Gly Arg Ile Leu His Asn Gly Ala Tyr Ser Leu Thr Leu Gln Gly Leu 435 440 445ggc atc agc tgg ctg ggg ctg cgc tca ctg agg gaa ctg ggc agt gga 1392Gly Ile Ser Trp Leu Gly Leu Arg Ser Leu Arg Glu Leu Gly Ser Gly 450 455 460ctg gcc ctc atc cac cat aac acc cac ctc tgc ttc gtg cac acg gtg 1440Leu Ala Leu Ile His His Asn Thr His Leu Cys Phe Val His Thr Val465 470 475 480ccc tgg gac cag ctc ttt cgg aac ccg cac caa gct ctg ctc cac act 1488Pro Trp Asp Gln Leu Phe Arg Asn Pro His Gln Ala Leu Leu His Thr 485 490 495gcc aac cgg cca gag gac gag tgt gtg ggc gag ggc ctg gcc tgc cac 1536Ala Asn Arg Pro Glu Asp Glu Cys Val Gly Glu Gly Leu Ala Cys His 500 505 510cag ctg tgc gcc cga ggg cac tgc tgg ggt cca ggg ccc acc cag tgt 1584Gln Leu Cys Ala Arg Gly His Cys Trp Gly Pro Gly Pro Thr Gln Cys 515 520 525gtc aac tgc agc cag ttc ctt cgg ggc cag gag tgc gtg gag gaa tgc 1632Val Asn Cys Ser Gln Phe Leu Arg Gly Gln Glu Cys Val Glu Glu Cys 530 535 540cga gta ctg cag ggg ctc ccc agg gag tat gtg aat gcc agg cac tgt 1680Arg Val Leu Gln Gly Leu Pro Arg Glu Tyr Val Asn Ala Arg His Cys545 550 555 560ttg ccg tgc cac cct gag tgt cag ccc cag aat ggc tca gtg acc tgt 1728Leu Pro Cys His Pro Glu Cys Gln Pro Gln Asn Gly Ser Val Thr Cys 565 570 575ttt gga ccg gag gct gac cag tgt gtg gcc tgt gcc cac tat aag gac 1776Phe Gly Pro Glu Ala Asp Gln Cys Val Ala Cys Ala His Tyr Lys Asp 580 585 590cct ccc ttc tgc gtg gcc cgc tgc ccc agc ggt gtg aaa cct gac ctc 1824Pro Pro Phe Cys Val Ala Arg Cys Pro Ser Gly Val Lys Pro Asp Leu 595 600 605tcc tac atg ccc atc tgg aag ttt cca gat gag gag ggc gca tgc cag 1872Ser Tyr Met Pro Ile Trp Lys Phe Pro Asp Glu Glu Gly Ala Cys Gln 610 615 620cct tgc ccc atc aac tgc acc cac tcc tgt gtg gac ctg gat gac aag 1920Pro Cys Pro Ile Asn Cys Thr His Ser Cys Val Asp Leu Asp Asp Lys625 630 635 640ggc tgc ccc gcc gag cag aga gcc agc ggt acc ctg gaa gtt ctg ttc 1968Gly Cys Pro Ala Glu Gln Arg Ala Ser Gly Thr Leu Glu Val Leu Phe 645 650 655cag ggg ccc atg tcc cct ata cta ggt tat tgg aaa att aag ggc ctt 2016Gln Gly Pro Met Ser Pro Ile Leu Gly Tyr Trp Lys Ile Lys Gly Leu 660 665 670gtg caa ccc act cga ctt ctt ttg gaa tat ctt gaa gaa aaa tat gaa 2064Val Gln Pro Thr Arg Leu Leu Leu Glu Tyr Leu Glu Glu Lys Tyr Glu 675 680 685gag cat ttg tat gag cgc gat gaa ggt gat aaa tgg cga aac aaa aag 2112Glu His Leu Tyr Glu Arg Asp Glu Gly Asp Lys Trp Arg Asn Lys Lys 690 695 700ttt gaa ttg ggt ttg gag ttt ccc aat ctt cct tat tat att gat ggt 2160Phe Glu Leu Gly Leu Glu Phe Pro Asn Leu Pro Tyr Tyr Ile Asp Gly705 710 715 720gat gtt aaa tta aca cag tct atg gcc atc ata cgt tat ata gct gac 2208Asp Val Lys Leu Thr Gln Ser Met Ala Ile Ile Arg Tyr Ile Ala Asp 725 730 735aag cac aac atg ttg ggt ggt tgt cca aaa gag cgt gca gag att tca 2256Lys His Asn Met Leu Gly Gly Cys Pro Lys Glu Arg Ala Glu Ile Ser 740 745 750atg ctt gaa gga gcg gtt ttg gat att aga tac ggt gtt tcg aga att 2304Met Leu Glu Gly Ala Val Leu Asp Ile Arg Tyr Gly Val Ser Arg Ile 755 760 765gca tat agt aaa gac ttt gaa act ctc aaa gtt gat ttt ctt agc aag 2352Ala Tyr Ser Lys Asp Phe Glu Thr Leu Lys Val Asp Phe Leu Ser Lys 770 775 780cta cct gaa atg ctg aaa atg ttc gaa gat cgt tta tgt cat aaa aca 2400Leu Pro Glu Met Leu Lys Met Phe Glu Asp Arg Leu Cys His Lys Thr785 790 795 800tat tta aat ggt gat cat gta acc cat cct gac ttc atg ttg tat gac 2448Tyr Leu Asn Gly Asp His Val Thr His Pro Asp Phe Met Leu Tyr Asp 805 810 815gct ctt gat gtt gtt tta tac atg gac cca atg tgc ctg gat gcg ttc 2496Ala Leu Asp Val Val Leu Tyr Met Asp Pro Met Cys Leu Asp Ala Phe 820 825 830cca aaa tta gtt tgt ttt aaa aaa cgt att gaa gct atc cca caa att 2544Pro Lys Leu Val Cys Phe Lys Lys Arg Ile Glu Ala Ile Pro Gln Ile 835 840 845gat aag tac ttg aaa tcc agc aag tat ata gca tgg cct ttg cag ggc 2592Asp Lys Tyr Leu Lys Ser Ser Lys Tyr Ile Ala Trp Pro Leu Gln Gly 850 855 860tgg caa gcc acg ttt ggt ggt ggc gac cat cct cca aaa tcg gat tga 2640Trp Gln Ala Thr Phe Gly Gly Gly Asp His Pro Pro Lys Ser Asp865 870 87599879PRTArtificialSynthetic Construct 99Met Glu Leu Ala Ala Leu Cys Arg Trp Gly Leu Leu Leu Ala Leu Leu1 5 10 15Pro Pro Gly Ala Ala Ser Thr Gln Val Cys Thr Gly Thr Asp Met Lys 20 25 30Leu Arg Leu Pro Ala Ser Pro Glu Thr His Leu Asp Met Leu Arg His 35 40 45Leu Tyr Gln Gly Cys Gln Val Val Gln Gly Asn Leu Glu Leu Thr Tyr 50 55 60Leu Pro Thr Asn Ala Ser Leu Ser Phe Leu Gln Asp Ile Gln Glu Val65 70 75 80Gln Gly Tyr Val Leu Ile Ala His Asn Gln Val Arg Gln Val Pro Leu 85 90 95Gln Arg Leu Arg Ile Val Arg Gly Thr Gln Leu Phe Glu Asp Asn Tyr 100 105 110Ala Leu Ala Val Leu Asp Asn Gly Asp Pro Leu Asn Asn Thr Thr Pro 115 120 125Val Thr Gly Ala Ser Pro Gly Gly Leu Arg Glu Leu Gln Leu Arg Ser 130 135 140Leu Thr Glu Ile Leu Lys Gly Gly Val Leu Ile Gln Arg Asn Pro Gln145 150 155 160Leu Cys Tyr Gln Asp Thr Ile Leu Trp Lys Asp Ile Phe His Lys Asn 165 170 175Asn Gln Leu Ala Leu Thr Leu Ile Asp Thr Asn Arg Ser Arg Ala Cys 180 185 190His Pro Cys Ser Pro Met Cys Lys Gly Ser Arg Cys Trp Gly Glu Ser 195 200 205Ser Glu Asp Cys Gln Ser Leu Thr Arg Thr Val Cys Ala Gly Gly Cys 210 215 220Ala Arg Cys Lys Gly Pro Leu Pro Thr Asp Cys Cys His Glu Gln Cys225 230 235 240Ala Ala Gly Cys Thr Gly Pro Lys His Ser Asp Cys Leu Ala Cys Leu 245 250 255His Phe Asn His Ser Gly Ile Cys Glu Leu His Cys Pro Ala Leu Val 260 265 270Thr Tyr Asn Thr Asp Thr Phe Glu Ser Met Pro Asn Pro Glu Gly Arg 275 280 285Tyr Thr Phe Gly Ala Ser Cys Val Thr Ala Cys Pro Tyr Asn Tyr Leu 290 295 300Ser Thr Asp Val Gly Ser Cys Thr Leu Val Cys Pro Leu His Asn Gln305 310 315 320Glu Val Thr Ala Glu Asp Gly Thr Gln Arg Cys Glu Lys Cys Ser Lys 325 330 335Pro Cys Ala Arg Val Cys Tyr Gly Leu Gly Met Glu His Leu Arg Glu 340 345 350Val Arg Ala Val Thr Ser Ala Asn Ile Gln Glu Phe Ala Gly Cys Lys 355 360 365Lys Ile Phe Gly Ser Leu Ala Phe Leu Pro Glu Ser Phe Asp Gly Asp 370 375 380Pro Ala Ser Asn Thr Ala Pro Leu Gln Pro Glu Gln Leu Gln Val Phe385 390 395 400Glu Thr Leu Glu Glu Ile Thr Gly Tyr Leu Tyr Ile Ser Ala Trp Pro 405 410 415Asp Ser Leu Pro Asp Leu Ser Val Phe Gln Asn Leu Gln Val Ile Arg 420 425 430Gly Arg Ile Leu His Asn Gly Ala Tyr Ser Leu Thr Leu Gln Gly Leu 435 440 445Gly Ile Ser Trp Leu Gly Leu Arg Ser Leu Arg Glu Leu Gly Ser Gly 450 455 460Leu Ala Leu Ile His His Asn Thr His Leu Cys Phe Val His Thr Val465 470 475 480Pro Trp Asp Gln Leu Phe Arg Asn Pro His Gln Ala Leu Leu His Thr 485 490 495Ala Asn Arg Pro Glu Asp Glu Cys Val Gly Glu Gly Leu Ala Cys His 500 505 510Gln Leu Cys Ala Arg Gly His Cys Trp Gly Pro Gly Pro Thr Gln Cys 515 520 525Val Asn Cys Ser Gln Phe Leu Arg Gly Gln Glu Cys Val Glu Glu Cys 530 535 540Arg Val Leu Gln Gly Leu Pro Arg Glu Tyr Val Asn Ala Arg His Cys545 550 555 560Leu Pro Cys His Pro Glu Cys Gln Pro Gln Asn Gly Ser Val Thr Cys 565 570 575Phe Gly Pro Glu Ala Asp Gln Cys Val Ala Cys Ala His Tyr Lys Asp 580 585 590Pro Pro Phe Cys Val Ala Arg Cys Pro Ser Gly Val Lys Pro Asp Leu 595 600 605Ser Tyr Met Pro Ile Trp Lys Phe Pro Asp Glu Glu Gly Ala Cys Gln 610 615 620Pro Cys Pro Ile Asn Cys Thr His Ser Cys Val Asp Leu Asp Asp Lys625 630 635 640Gly Cys Pro Ala Glu Gln Arg Ala Ser Gly Thr Leu Glu Val Leu Phe 645 650 655Gln Gly Pro Met Ser Pro Ile Leu Gly Tyr Trp Lys Ile Lys Gly Leu 660 665 670Val Gln Pro Thr Arg Leu Leu Leu Glu Tyr Leu Glu Glu Lys Tyr Glu 675 680 685Glu His Leu Tyr Glu Arg Asp Glu Gly Asp Lys Trp Arg Asn Lys Lys 690 695 700Phe Glu Leu Gly Leu Glu Phe Pro Asn Leu Pro Tyr Tyr Ile Asp Gly705 710 715 720Asp Val Lys Leu Thr Gln Ser Met Ala Ile Ile Arg Tyr Ile Ala Asp 725 730 735Lys His Asn Met Leu Gly Gly Cys Pro Lys Glu Arg Ala Glu Ile Ser 740 745 750Met Leu Glu Gly Ala Val Leu Asp Ile Arg Tyr Gly Val Ser Arg Ile 755 760 765Ala Tyr Ser Lys Asp Phe Glu Thr Leu Lys Val Asp Phe Leu Ser Lys 770 775 780Leu Pro Glu Met Leu Lys Met Phe Glu Asp Arg Leu Cys His Lys Thr785 790 795 800Tyr Leu Asn Gly Asp His Val Thr His Pro Asp Phe Met Leu Tyr Asp 805 810 815Ala Leu Asp Val Val Leu Tyr Met Asp Pro Met Cys Leu Asp Ala Phe 820 825 830Pro Lys Leu Val Cys Phe Lys Lys Arg Ile Glu Ala Ile Pro Gln Ile 835 840 845Asp Lys Tyr Leu Lys Ser Ser Lys Tyr Ile Ala Trp Pro Leu Gln Gly 850 855 860Trp Gln Ala Thr Phe Gly Gly Gly Asp His Pro Pro Lys Ser Asp865 870 8751001182DNAArtificial SequenceDescription of the artificial sequence base sequence of hMOG-FLAG-Fc including signal sequence 100atggcaagct tatcaagacc ctctctgccc agctgcctct gctccttcct cctcctcctc 60ctcctccaag tgtcttccag ctatgcaggg cagttcagag tgataggacc aagacaccct 120atccgggctc tggtcgggga tgaagtggaa ttgccatgtc gcatatctcc tgggaagaac 180gctacaggca tggaggtggg gtggtaccgc ccccccttct ctagggtggt tcatctctac 240agaaatggca aggaccaaga tggagaccag gcacctgaat atcggggccg gacagagctg 300ctgaaagatg ctattggtga gggaaaggtg actctcagga tccggaatgt aaggttctca 360gatgaaggag gtttcacctg cttcttccga gatcattctt accaagagga ggcagcaatg 420gaattgaaag tagaagatcc tttctactgg gtgagccctg gatctagagc agactacaag 480gacgacgatg acaagactag tgacaaaact cacacatgcc caccgtgccc agcacctgaa 540ctcctggggg gaccgtcagt cttcctcttc cccccaaaac ccaaggacac cctcatgatc 600tcccggaccc ctgaggtcac atgcgtggtg gtggacgtga gccacgaaga ccctgaggtc 660aagttcaact ggtacgtgga cggcgtggag gtgcataatg ccaagacaaa gccgcgggag 720gagcagtaca acagcacgta ccgtgtggtc agcgtcctca ccgtcctgca ccaggactgg 780ctgaatggca aggagtacaa gtgcaaggtc tccaacaaag ccctcccagc ccccatcgag 840aaaaccatct ccaaagccaa agggcagccc cgagaaccac aggtgtacac cctgccccca 900tcccgggatg agctgaccaa gaaccaggtc agcctgacct gcctggtcaa aggcttctat 960cccagcgaca tcgccgtgga gtgggagagc aatgggcagc cggagaacaa ctacaagacc 1020acgcctcccg tgctggactc cgacggctcc ttcttcctct acagcaagct caccgtggac 1080aagagcaggt ggcagcaggg gaacgtcttc tcatgctccg tgatgcatga ggctctgcac 1140aaccactaca cgcagaagag cctctccctg tctccgggta aa 1182101394PRTArtificial SequenceDescription of the artificial sequence amino acid sequence of hMOG-FLAG-Fc including signal sequence 101Met Ala Ser Leu Ser Arg Pro Ser Leu Pro Ser Cys Leu Cys Ser Phe1 5 10 15Leu Leu Leu Leu Leu Leu Gln Val Ser Ser Ser Tyr Ala Gly Gln Phe 20 25 30Arg Val Ile Gly Pro Arg His Pro Ile Arg Ala Leu Val Gly Asp Glu 35 40 45Val Glu Leu Pro Cys Arg Ile Ser Pro Gly Lys Asn Ala Thr Gly Met 50 55 60Glu Val Gly Trp Tyr Arg Pro Pro Phe Ser Arg Val Val His Leu Tyr65 70 75 80Arg Asn Gly Lys Asp Gln Asp Gly Asp Gln Ala Pro Glu Tyr Arg Gly 85 90 95Arg Thr Glu Leu Leu Lys Asp Ala Ile Gly Glu Gly Lys Val Thr Leu 100 105 110Arg Ile Arg Asn Val Arg Phe Ser Asp Glu Gly Gly Phe Thr Cys Phe 115 120 125Phe Arg Asp His Ser Tyr Gln Glu Glu Ala Ala Met Glu Leu Lys Val 130 135 140Glu Asp Pro Phe Tyr Trp Val Ser Pro Gly Ser Arg Ala Asp Tyr Lys145 150 155 160Asp Asp Asp Asp Lys Thr Ser Asp Lys Thr His Thr Cys Pro Pro Cys 165 170 175Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 180 185 190Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 195 200 205Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 210 215 220Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu225 230 235 240Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 245 250 255His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 260 265 270Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 275 280

285Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu 290 295 300Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr305 310 315 320Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 325 330 335Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 340 345 350Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 355 360 365Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 370 375 380Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys385 3901021182DNAArtificial SequenceThe Description of the artificial sequence base sequence of mMOG-FLAG-Fc including signal sequence 102atggcctgtt tgtggagctt ctcttggccc agctgcttcc tctcccttct cctcctcctt 60ctcctccagt tgtcatgcag ctatgcagga caattcagag tgataggacc agggtatccc 120atccgggctt tagttgggga tgaagcagag ctgccgtgcc gcatctctcc tgggaaaaat 180gccacgggca tggaggtggg ttggtaccgt tctcccttct caagagtggt tcacctctac 240cgaaatggca aggaccaaga tgcagagcaa gcacctgaat accggggacg cacagagctt 300ctgaaagaga ctatcagtga gggaaaggtt acccttagga ttcagaacgt gagattctca 360gatgaaggag gctacacctg cttcttcaga gaccactctt accaagaaga ggcagcaatg 420gagttgaaag tggaagatcc cttctattgg gtcaaccccg gttctagagc agactacaag 480gacgacgatg acaagactag tgacaaaact cacacatgcc caccgtgccc agcacctgaa 540ctcctggggg gaccgtcagt cttcctcttc cccccaaaac ccaaggacac cctcatgatc 600tcccggaccc ctgaggtcac atgcgtggtg gtggacgtga gccacgaaga ccctgaggtc 660aagttcaact ggtacgtgga cggcgtggag gtgcataatg ccaagacaaa gccgcgggag 720gagcagtaca acagcacgta ccgtgtggtc agcgtcctca ccgtcctgca ccaggactgg 780ctgaatggca aggagtacaa gtgcaaggtc tccaacaaag ccctcccagc ccccatcgag 840aaaaccatct ccaaagccaa agggcagccc cgagaaccac aggtgtacac cctgccccca 900tcccgggatg agctgaccaa gaaccaggtc agcctgacct gcctggtcaa aggcttctat 960cccagcgaca tcgccgtgga gtgggagagc aatgggcagc cggagaacaa ctacaagacc 1020acgcctcccg tgctggactc cgacggctcc ttcttcctct acagcaagct caccgtggac 1080aagagcaggt ggcagcaggg gaacgtcttc tcatgctccg tgatgcatga ggctctgcac 1140aaccactaca cgcagaagag cctctccctg tctccgggta aa 1182103394PRTArtificial SequenceDescription of the artificial sequence amino acid sequence of mMOG-FLAG-Fc including signal sequence 103Met Ala Cys Leu Trp Ser Phe Ser Trp Pro Ser Cys Phe Leu Ser Leu1 5 10 15Leu Leu Leu Leu Leu Leu Gln Leu Ser Cys Ser Tyr Ala Gly Gln Phe 20 25 30Arg Val Ile Gly Pro Gly Tyr Pro Ile Arg Ala Leu Val Gly Asp Glu 35 40 45Ala Glu Leu Pro Cys Arg Ile Ser Pro Gly Lys Asn Ala Thr Gly Met 50 55 60Glu Val Gly Trp Tyr Arg Ser Pro Phe Ser Arg Val Val His Leu Tyr65 70 75 80Arg Asn Gly Lys Asp Gln Asp Ala Glu Gln Ala Pro Glu Tyr Arg Gly 85 90 95Arg Thr Glu Leu Leu Lys Glu Thr Ile Ser Glu Gly Lys Val Thr Leu 100 105 110Arg Ile Gln Asn Val Arg Phe Ser Asp Glu Gly Gly Tyr Thr Cys Phe 115 120 125Phe Arg Asp His Ser Tyr Gln Glu Glu Ala Ala Met Glu Leu Lys Val 130 135 140Glu Asp Pro Phe Tyr Trp Val Asn Pro Gly Ser Arg Ala Asp Tyr Lys145 150 155 160Asp Asp Asp Asp Lys Thr Ser Asp Lys Thr His Thr Cys Pro Pro Cys 165 170 175Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 180 185 190Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 195 200 205Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 210 215 220Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu225 230 235 240Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 245 250 255His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 260 265 270Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 275 280 285Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu 290 295 300Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr305 310 315 320Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 325 330 335Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 340 345 350Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 355 360 365Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 370 375 380Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys385 3901041152DNAArtificial SequenceDescription of the artificial sequence base sequence of hMOG-GST including signal sequence 104atggcaagct tatcaagacc ctctctgccc agctgcctct gctccttcct cctcctcctc 60ctcctccaag tgtcttccag ctatgcaggg cagttcagag tgataggacc aagacaccct 120atccgggctc tggtcgggga tgaagtggaa ttgccatgtc gcatatctcc tgggaagaac 180gctacaggca tggaggtggg gtggtaccgc ccccccttct ctagggtggt tcatctctac 240agaaatggca aggaccaaga tggagaccag gcacctgaat atcggggccg gacagagctg 300ctgaaagatg ctattggtga gggaaaggtg actctcagga tccggaatgt aaggttctca 360gatgaaggag gtttcacctg cttcttccga gatcattctt accaagagga ggcagcaatg 420gaattgaaag tagaagatcc tttctactgg gtgagccctg gaggtaccct ggaagttctg 480ttccaggggc ccatgtcccc tatactaggt tattggaaaa ttaagggcct tgtgcaaccc 540actcgacttc ttttggaata tcttgaagaa aaatatgaag agcatttgta tgagcgcgat 600gaaggtgata aatggcgaaa caaaaagttt gaattgggtt tggagtttcc caatcttcct 660tattatattg atggtgatgt taaattaaca cagtctatgg ccatcatacg ttatatagct 720gacaagcaca acatgttggg tggttgtcca aaagagcgtg cagagatttc aatgcttgaa 780ggagcggttt tggatattag atacggtgtt tcgagaattg catatagtaa agactttgaa 840actctcaaag ttgattttct tagcaagcta cctgaaatgc tgaaaatgtt cgaagatcgt 900ttatgtcata aaacatattt aaatggtgat catgtaaccc atcctgactt catgttgtat 960gacgctcttg atgttgtttt atacatggac ccaatgtgcc tggatgcgtt cccaaaatta 1020gtttgtttta aaaaacgtat tgaagctatc ccacaaattg ataagtactt gaaatccagc 1080aagtatatag catggccttt gcagggctgg caagccacgt ttggtggtgg cgaccatcct 1140ccaaaatcgg at 1152105384PRTArtificial SequenceDescription of the artificial sequence amino acid sequence of hMOG-GST including signal sequence 105Met Ala Ser Leu Ser Arg Pro Ser Leu Pro Ser Cys Leu Cys Ser Phe1 5 10 15Leu Leu Leu Leu Leu Leu Gln Val Ser Ser Ser Tyr Ala Gly Gln Phe 20 25 30Arg Val Ile Gly Pro Arg His Pro Ile Arg Ala Leu Val Gly Asp Glu 35 40 45Val Glu Leu Pro Cys Arg Ile Ser Pro Gly Lys Asn Ala Thr Gly Met 50 55 60Glu Val Gly Trp Tyr Arg Pro Pro Phe Ser Arg Val Val His Leu Tyr65 70 75 80Arg Asn Gly Lys Asp Gln Asp Gly Asp Gln Ala Pro Glu Tyr Arg Gly 85 90 95Arg Thr Glu Leu Leu Lys Asp Ala Ile Gly Glu Gly Lys Val Thr Leu 100 105 110Arg Ile Arg Asn Val Arg Phe Ser Asp Glu Gly Gly Phe Thr Cys Phe 115 120 125Phe Arg Asp His Ser Tyr Gln Glu Glu Ala Ala Met Glu Leu Lys Val 130 135 140Glu Asp Pro Phe Tyr Trp Val Ser Pro Gly Gly Thr Leu Glu Val Leu145 150 155 160Phe Gln Gly Pro Met Ser Pro Ile Leu Gly Tyr Trp Lys Ile Lys Gly 165 170 175Leu Val Gln Pro Thr Arg Leu Leu Leu Glu Tyr Leu Glu Glu Lys Tyr 180 185 190Glu Glu His Leu Tyr Glu Arg Asp Glu Gly Asp Lys Trp Arg Asn Lys 195 200 205Lys Phe Glu Leu Gly Leu Glu Phe Pro Asn Leu Pro Tyr Tyr Ile Asp 210 215 220Gly Asp Val Lys Leu Thr Gln Ser Met Ala Ile Ile Arg Tyr Ile Ala225 230 235 240Asp Lys His Asn Met Leu Gly Gly Cys Pro Lys Glu Arg Ala Glu Ile 245 250 255Ser Met Leu Glu Gly Ala Val Leu Asp Ile Arg Tyr Gly Val Ser Arg 260 265 270Ile Ala Tyr Ser Lys Asp Phe Glu Thr Leu Lys Val Asp Phe Leu Ser 275 280 285Lys Leu Pro Glu Met Leu Lys Met Phe Glu Asp Arg Leu Cys His Lys 290 295 300Thr Tyr Leu Asn Gly Asp His Val Thr His Pro Asp Phe Met Leu Tyr305 310 315 320Asp Ala Leu Asp Val Val Leu Tyr Met Asp Pro Met Cys Leu Asp Ala 325 330 335Phe Pro Lys Leu Val Cys Phe Lys Lys Arg Ile Glu Ala Ile Pro Gln 340 345 350Ile Asp Lys Tyr Leu Lys Ser Ser Lys Tyr Ile Ala Trp Pro Leu Gln 355 360 365Gly Trp Gln Ala Thr Phe Gly Gly Gly Asp His Pro Pro Lys Ser Asp 370 375 3801061152DNAArtificial SequenceDescription of the artificial sequence base sequence of mMOG-GST including signal sequence 106atggcctgtt tgtggagctt ctcttggccc agctgcttcc tctcccttct cctcctcctt 60ctcctccagt tgtcatgcag ctatgcagga caattcagag tgataggacc agggtatccc 120atccgggctt tagttgggga tgaagcagag ctgccgtgcc gcatctctcc tgggaaaaat 180gccacgggca tggaggtggg ttggtaccgt tctcccttct caagagtggt tcacctctac 240cgaaatggca aggaccaaga tgcagagcaa gcacctgaat accggggacg cacagagctt 300ctgaaagaga ctatcagtga gggaaaggtt acccttagga ttcagaacgt gagattctca 360gatgaaggag gctacacctg cttcttcaga gaccactctt accaagaaga ggcagcaatg 420gagttgaaag tggaagatcc cttctattgg gtcaaccccg gtggtaccct ggaagttctg 480ttccaggggc ccatgtcccc tatactaggt tattggaaaa ttaagggcct tgtgcaaccc 540actcgacttc ttttggaata tcttgaagaa aaatatgaag agcatttgta tgagcgcgat 600gaaggtgata aatggcgaaa caaaaagttt gaattgggtt tggagtttcc caatcttcct 660tattatattg atggtgatgt taaattaaca cagtctatgg ccatcatacg ttatatagct 720gacaagcaca acatgttggg tggttgtcca aaagagcgtg cagagatttc aatgcttgaa 780ggagcggttt tggatattag atacggtgtt tcgagaattg catatagtaa agactttgaa 840actctcaaag ttgattttct tagcaagcta cctgaaatgc tgaaaatgtt cgaagatcgt 900ttatgtcata aaacatattt aaatggtgat catgtaaccc atcctgactt catgttgtat 960gacgctcttg atgttgtttt atacatggac ccaatgtgcc tggatgcgtt cccaaaatta 1020gtttgtttta aaaaacgtat tgaagctatc ccacaaattg ataagtactt gaaatccagc 1080aagtatatag catggccttt gcagggctgg caagccacgt ttggtggtgg cgaccatcct 1140ccaaaatcgg at 1152107384PRTArtificial SequenceDescription of the artificial sequence amino acid sequence of mMOG-GST including signal sequence 107Met Ala Cys Leu Trp Ser Phe Ser Trp Pro Ser Cys Phe Leu Ser Leu1 5 10 15Leu Leu Leu Leu Leu Leu Gln Leu Ser Cys Ser Tyr Ala Gly Gln Phe 20 25 30Arg Val Ile Gly Pro Gly Tyr Pro Ile Arg Ala Leu Val Gly Asp Glu 35 40 45Ala Glu Leu Pro Cys Arg Ile Ser Pro Gly Lys Asn Ala Thr Gly Met 50 55 60Glu Val Gly Trp Tyr Arg Ser Pro Phe Ser Arg Val Val His Leu Tyr65 70 75 80Arg Asn Gly Lys Asp Gln Asp Ala Glu Gln Ala Pro Glu Tyr Arg Gly 85 90 95Arg Thr Glu Leu Leu Lys Glu Thr Ile Ser Glu Gly Lys Val Thr Leu 100 105 110Arg Ile Gln Asn Val Arg Phe Ser Asp Glu Gly Gly Tyr Thr Cys Phe 115 120 125Phe Arg Asp His Ser Tyr Gln Glu Glu Ala Ala Met Glu Leu Lys Val 130 135 140Glu Asp Pro Phe Tyr Trp Val Asn Pro Gly Gly Thr Leu Glu Val Leu145 150 155 160Phe Gln Gly Pro Met Ser Pro Ile Leu Gly Tyr Trp Lys Ile Lys Gly 165 170 175Leu Val Gln Pro Thr Arg Leu Leu Leu Glu Tyr Leu Glu Glu Lys Tyr 180 185 190Glu Glu His Leu Tyr Glu Arg Asp Glu Gly Asp Lys Trp Arg Asn Lys 195 200 205Lys Phe Glu Leu Gly Leu Glu Phe Pro Asn Leu Pro Tyr Tyr Ile Asp 210 215 220Gly Asp Val Lys Leu Thr Gln Ser Met Ala Ile Ile Arg Tyr Ile Ala225 230 235 240Asp Lys His Asn Met Leu Gly Gly Cys Pro Lys Glu Arg Ala Glu Ile 245 250 255Ser Met Leu Glu Gly Ala Val Leu Asp Ile Arg Tyr Gly Val Ser Arg 260 265 270Ile Ala Tyr Ser Lys Asp Phe Glu Thr Leu Lys Val Asp Phe Leu Ser 275 280 285Lys Leu Pro Glu Met Leu Lys Met Phe Glu Asp Arg Leu Cys His Lys 290 295 300Thr Tyr Leu Asn Gly Asp His Val Thr His Pro Asp Phe Met Leu Tyr305 310 315 320Asp Ala Leu Asp Val Val Leu Tyr Met Asp Pro Met Cys Leu Asp Ala 325 330 335Phe Pro Lys Leu Val Cys Phe Lys Lys Arg Ile Glu Ala Ile Pro Gln 340 345 350Ile Asp Lys Tyr Leu Lys Ser Ser Lys Tyr Ile Ala Trp Pro Leu Gln 355 360 365Gly Trp Gln Ala Thr Phe Gly Gly Gly Asp His Pro Pro Lys Ser Asp 370 375 3801081371DNAArtificial SequenceDescription of the artificial sequence base sequence of the antibody sequence of pCI-AVM-hLG4PE (R409K / S354C / T366W) -FLAG tag excluding signal sequence 108gaggtgcagc tggtggaatc tgggggaggc ttagtgcagc ctggaagatc cctgaaactc 60tcctgtgcag cctcaggatt cactttcagt aactatgcca tggcttgggt ccgccgggct 120ccaacgaagg gtctggagtg ggtcgcatcc attagtaatg gtggtggtaa cacttactat 180cgcgactccg tgaagggccg attcactatc tccagagatg atgcaaaaaa caccctatac 240ctgcaaatgg acagtctgag gtctgaggac acggccactt attactgtgc aagacacggg 300aattatatat attatgggtc cttctttgat tactggggcc aaggagtcat ggtcacagtc 360tcctcagcta gcaccaaggg gccatccgtc ttccccctgg cgccctgctc caggagcacc 420tccgagagca cagccgccct gggctgcctg gtcaaggact acttccccga accggtgacg 480gtgtcgtgga actcaggcgc cctgaccagc ggcgtgcaca ccttcccggc tgtcctacag 540tcctcaggac tctactccct cagcagcgtg gtgaccgtgc cctccagcag cttgggcacg 600aagacctaca cctgcaacgt agatcacaag cccagcaaca ccaaggtgga caagagagtt 660gagtccaaat atggtccccc atgcccacca tgcccagcac ctgagttcga ggggggacca 720tcagtcttcc tgttcccccc aaaacccaag gacactctca tgatctcccg gacccctgag 780gtcacgtgcg tggtggtgga cgtgagccag gaagaccccg aggtccagtt caactggtac 840gtggatggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gttcaacagc 900acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa cggcaaggag 960tacaagtgca aggtctccaa caaaggcctc ccgtcctcca tcgagaaaac catctccaaa 1020gccaaagggc agccccgaga gccacaggtg tacaccctgc ccccatgcca ggaggagatg 1080accaagaacc aggtcagcct gtggtgcctg gtcaaaggct tctaccccag cgacatcgcc 1140gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200gactccgacg gctccttctt cctctacagc aagctaaccg tggacaagag caggtggcag 1260gaggggaatg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacacag 1320aagagcctct ccctgtctct gggtaaagac tacaaggacg acgatgacaa g 1371109457PRTArtificial SequenceDescription of the artificial sequence amino acid sequence of the antibody sequence of pCI-AVM-hLG4PE (R409K / S354C / T366W) -FLAG tag excluding signal sequence 109Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Ala Met Ala Trp Val Arg Arg Ala Pro Thr Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Ser Asn Gly Gly Gly Asn Thr Tyr Tyr Arg Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asp Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Arg His Gly Asn Tyr Ile Tyr Tyr Gly Ser Phe Phe Asp Tyr Trp 100 105 110Gly Gln Gly Val Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr145 150 155 160Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215

220Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro225 230 235 240Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 260 265 270Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val 290 295 300Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu305 310 315 320Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350Leu Pro Pro Cys Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp 355 360 365Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445Lys Asp Tyr Lys Asp Asp Asp Asp Lys 450 4551101380DNAArtificial SequenceDescription of the artificial sequence base sequence of the antibody sequence of pCI-MOG01-hLG4PE (R409K / Y349C / T366S / L368A / Y407V) -His tag excluding signal sequence 110caggtacagc tgcagcagtc aggcgcagga ttattgaagc cttcggagac cctttccctc 60acctgcgctg tgtctggtgg gtccttcagt ggttactact ggacctggat ccgccagcgc 120ccagggaagg ggctggagtg gattggagaa atcaatcatc gtggaagcac cgattacaac 180ccgtccctca agagtcgagt caccatgtca atagacacgt ccaagagcca gttctccctg 240aatttgaaat ctgtgaccgc cgcggacacg gctgtgtatt actgtgcgag agccgcctgg 300gggtcttgtt atgatgggac ctgctacccc gctgaatact tccaatactg gggccaggga 360accctggtca ccgtctcctc agctagcacc aaggggccat ccgtcttccc cctggcgccc 420tgctccagga gcacctccga gagcacagcc gccctgggct gcctggtcaa ggactacttc 480cccgaaccgg tgacggtgtc gtggaactca ggcgccctga ccagcggcgt gcacaccttc 540ccggctgtcc tacagtcctc aggactctac tccctcagca gcgtggtgac cgtgccctcc 600agcagcttgg gcacgaagac ctacacctgc aacgtagatc acaagcccag caacaccaag 660gtggacaaga gagttgagtc caaatatggt cccccatgcc caccatgccc agcacctgag 720ttcgaggggg gaccatcagt cttcctgttc cccccaaaac ccaaggacac tctcatgatc 780tcccggaccc ctgaggtcac gtgcgtggtg gtggacgtga gccaggaaga ccccgaggtc 840cagttcaact ggtacgtgga tggcgtggag gtgcataatg ccaagacaaa gccgcgggag 900gagcagttca acagcacgta ccgtgtggtc agcgtcctca ccgtcctgca ccaggactgg 960ctgaacggca aggagtacaa gtgcaaggtc tccaacaaag gcctcccgtc ctccatcgag 1020aaaaccatct ccaaagccaa agggcagccc cgagagccac aggtgtgcac cctgccccca 1080tcccaggagg agatgaccaa gaaccaggtc agcctgtcct gcgcggtcaa aggcttctac 1140cccagcgaca tcgccgtgga gtgggagagc aatgggcagc cggagaacaa ctacaagacc 1200acgcctcccg tgctggactc cgacggctcc ttcttcctcg tcagcaagct aaccgtggac 1260aagagcaggt ggcaggaggg gaatgtcttc tcatgctccg tgatgcatga ggctctgcac 1320aaccactaca cacagaagag cctctccctg tctctgggta aacaccacca ccaccaccac 1380111460PRTArtificial SequenceDescription of the artificial sequence amino acid sequence of the antibody sequence of pCI-MOG01-hLG4PE (R409K / Y349C / T366S / L368A / Y407V) -His tag excluding signal sequence 111Gln Val Gln Leu Gln Gln Ser Gly Ala Gly Leu Leu Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Phe Ser Gly Tyr 20 25 30Tyr Trp Thr Trp Ile Arg Gln Arg Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Glu Ile Asn His Arg Gly Ser Thr Asp Tyr Asn Pro Ser Leu Lys 50 55 60Ser Arg Val Thr Met Ser Ile Asp Thr Ser Lys Ser Gln Phe Ser Leu65 70 75 80Asn Leu Lys Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Ala Ala Trp Gly Ser Cys Tyr Asp Gly Thr Cys Tyr Pro Ala Glu 100 105 110Tyr Phe Gln Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 115 120 125Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser 130 135 140Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe145 150 155 160Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly 165 170 175Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu 180 185 190Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr 195 200 205Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg 210 215 220Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu225 230 235 240Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 245 250 255Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 260 265 270Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly 275 280 285Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn 290 295 300Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp305 310 315 320Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro 325 330 335Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 340 345 350Pro Gln Val Cys Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn 355 360 365Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile 370 375 380Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr385 390 395 400Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys 405 410 415Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys 420 425 430Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 435 440 445Ser Leu Ser Leu Gly Lys His His His His His His 450 455 4601122043DNAArtificial SequenceDescription of the artificial sequence base sequence of the antibody sequence of pCI-AVM-hLG4PE (R409K) - linker-MOG01 VL-CL excluding signal sequence 112gaggtgcagc tggtggaatc tgggggaggc ttagtgcagc ctggaagatc cctgaaactc 60tcctgtgcag cctcaggatt cactttcagt aactatgcca tggcttgggt ccgccgggct 120ccaacgaagg gtctggagtg ggtcgcatcc attagtaatg gtggtggtaa cacttactat 180cgcgactccg tgaagggccg attcactatc tccagagatg atgcaaaaaa caccctatac 240ctgcaaatgg acagtctgag gtctgaggac acggccactt attactgtgc aagacacggg 300aattatatat attatgggtc cttctttgat tactggggcc aaggagtcat ggtcacagtc 360tcctcagcta gcaccaaggg gccatccgtc ttccccctgg cgccctgctc caggagcacc 420tccgagagca cagccgccct gggctgcctg gtcaaggact acttccccga accggtgacg 480gtgtcgtgga actcaggcgc cctgaccagc ggcgtgcaca ccttcccggc tgtcctacag 540tcctcaggac tctactccct cagcagcgtg gtgaccgtgc cctccagcag cttgggcacg 600aagacctaca cctgcaacgt agatcacaag cccagcaaca ccaaggtgga caagagagtt 660gagtccaaat atggtccccc atgcccacca tgcccagcac ctgagttcga ggggggacca 720tcagtcttcc tgttcccccc aaaacccaag gacactctca tgatctcccg gacccctgag 780gtcacgtgcg tggtggtgga cgtgagccag gaagaccccg aggtccagtt caactggtac 840gtggatggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gttcaacagc 900acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa cggcaaggag 960tacaagtgca aggtctccaa caaaggcctc ccgtcctcca tcgagaaaac catctccaaa 1020gccaaagggc agccccgaga gccacaggtg tacaccctgc ccccatccca ggaggagatg 1080accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctaccccag cgacatcgcc 1140gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200gactccgacg gctccttctt cctctacagc aagctaaccg tggacaagag caggtggcag 1260gaggggaatg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacacag 1320aagagcctct ccctgtctct gggtaaagga ggaggagggt ccggaggagg agggtccgga 1380ggaggagggt cccagtctgc cctgactcag cctgcctccg tgtctgggtc tcctggacag 1440tcgatcacca tctcctgcac tggaaccagc cgtgacgttg gtggttataa ctatgtctcc 1500tggtaccaac aacacccagg caaagccccc aaactcatga tttatgatgt caataatcgg 1560ccctcagggg tttctaatcg gttctctggc tccaagtctg gcaacacggc ctccctgacc 1620atctctgggc tccaggctga ggacgaggct gattatttct gcagctcata tacaagcagt 1680agcacccctg tggtattcgg cggtgggacc aagctgaccg tcctaggtca gcccaaggcc 1740gccccctcgg tcactctgtt cccgccctcc tctgaggagc ttcaagccaa caaggccaca 1800ctggtgtgtc tcataagtga cttctacccg ggagccgtga cagtggcctg gaaggcagat 1860agcagccccg tcaaggcggg agtggagacc accacaccct ccaaacaaag caacaacaag 1920tacgcggcca gcagctacct gagcctgacg cctgagcagt ggaagtccca cagaagctac 1980agctgccagg tcacgcatga agggagcacc gtggagaaga cagtggcccc tacagaatgt 2040tca 2043113681PRTArtificial SequenceDescription of the artificial sequence amino acid sequence of the antibody sequence of pCI-AVM-hLG4PE (R409K)- linker-MOG01 VL-CL excluding signal sequence 113Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Ala Met Ala Trp Val Arg Arg Ala Pro Thr Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Ser Asn Gly Gly Gly Asn Thr Tyr Tyr Arg Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asp Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Arg His Gly Asn Tyr Ile Tyr Tyr Gly Ser Phe Phe Asp Tyr Trp 100 105 110Gly Gln Gly Val Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr145 150 155 160Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro225 230 235 240Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 260 265 270Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val 290 295 300Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu305 310 315 320Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 450 455 460Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln465 470 475 480Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Arg Asp Val Gly Gly Tyr 485 490 495Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 500 505 510Met Ile Tyr Asp Val Asn Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 515 520 525Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 530 535 540Gln Ala Glu Asp Glu Ala Asp Tyr Phe Cys Ser Ser Tyr Thr Ser Ser545 550 555 560Ser Thr Pro Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 565 570 575Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu 580 585 590Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe 595 600 605Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val 610 615 620Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys625 630 635 640Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser 645 650 655His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu 660 665 670Lys Thr Val Ala Pro Thr Glu Cys Ser 675 680114675DNAArtificial SequenceDescription of the artificial sequence base sequence of antibody sequence of pCI-MOG01 VH-CH excluding signal sequence 114caggtacagc tgcagcagtc aggcgcagga ttattgaagc cttcggagac cctttccctc 60acctgcgctg tgtctggtgg gtccttcagt ggttactact ggacctggat ccgccagcgc 120ccagggaagg ggctggagtg gattggagaa atcaatcatc gtggaagcac cgattacaac 180ccgtccctca agagtcgagt caccatgtca atagacacgt ccaagagcca gttctccctg 240aatttgaaat ctgtgaccgc cgcggacacg gctgtgtatt actgtgcgag agccgcctgg 300gggtcttgtt atgatgggac ctgctacccc gctgaatact tccaatactg gggccaggga 360accctggtca ccgtctcctc agctagcacc aaggggccat ccgtcttccc cctggcgccc 420tgctccagga gcacctccga gagcacagcc gccctgggct gcctggtcaa ggactacttc 480cccgaaccgg tgacggtgtc gtggaactca ggcgccctga ccagcggcgt gcacaccttc 540ccggctgtcc tacagtcctc aggactctac tccctcagca gcgtggtgac cgtgccctcc 600agcagcttgg gcacgaagac ctacacctgc aacgtagatc acaagcccag caacaccaag 660gtggacaaga gagtt 675115225PRTArtificial SequenceDescription of the artificial sequence amino acid sequence of antibody sequence of pCI-MOG01 VH-CH excluding signal sequence 115Gln Val Gln Leu Gln Gln Ser Gly Ala Gly Leu Leu Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Phe Ser Gly Tyr 20 25 30Tyr Trp Thr Trp Ile Arg Gln Arg Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Glu Ile Asn His Arg Gly Ser Thr Asp Tyr Asn Pro Ser Leu Lys 50 55 60Ser Arg Val Thr Met Ser Ile Asp Thr Ser Lys Ser Gln Phe Ser Leu65 70 75 80Asn Leu Lys Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Ala Ala Trp Gly Ser Cys Tyr Asp Gly Thr Cys Tyr Pro Ala Glu 100 105 110Tyr Phe Gln Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 115 120 125Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser 130 135 140Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe145 150 155 160Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly 165 170 175Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu 180 185 190Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr 195 200 205Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg 210 215 220Val2251162181DNAArtificial SequenceDescription of the artificial sequence base sequence of antibody sequence of pCI-AVM-hLG4PE (R409K

/ S354C / T366W) -linker-MOG01 scFv-FLAG tag excluding signal sequence 116gaggtgcagc tggtggaatc tgggggaggc ttagtgcagc ctggaagatc cctgaaactc 60tcctgtgcag cctcaggatt cactttcagt aactatgcca tggcttgggt ccgccgggct 120ccaacgaagg gtctggagtg ggtcgcatcc attagtaatg gtggtggtaa cacttactat 180cgcgactccg tgaagggccg attcactatc tccagagatg atgcaaaaaa caccctatac 240ctgcaaatgg acagtctgag gtctgaggac acggccactt attactgtgc aagacacggg 300aattatatat attatgggtc cttctttgat tactggggcc aaggagtcat ggtcacagtc 360tcctcagcta gcaccaaggg gccatccgtc ttccccctgg cgccctgctc caggagcacc 420tccgagagca cagccgccct gggctgcctg gtcaaggact acttccccga accggtgacg 480gtgtcgtgga actcaggcgc cctgaccagc ggcgtgcaca ccttcccggc tgtcctacag 540tcctcaggac tctactccct cagcagcgtg gtgaccgtgc cctccagcag cttgggcacg 600aagacctaca cctgcaacgt agatcacaag cccagcaaca ccaaggtgga caagagagtt 660gagtccaaat atggtccccc atgcccacca tgcccagcac ctgagttcga ggggggacca 720tcagtcttcc tgttcccccc aaaacccaag gacactctca tgatctcccg gacccctgag 780gtcacgtgcg tggtggtgga cgtgagccag gaagaccccg aggtccagtt caactggtac 840gtggatggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gttcaacagc 900acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa cggcaaggag 960tacaagtgca aggtctccaa caaaggcctc ccgtcctcca tcgagaaaac catctccaaa 1020gccaaagggc agccccgaga gccacaggtg tacaccctgc ccccatgcca ggaggagatg 1080accaagaacc aggtcagcct gtggtgcctg gtcaaaggct tctaccccag cgacatcgcc 1140gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200gactccgacg gctccttctt cctctacagc aagctaaccg tggacaagag caggtggcag 1260gaggggaatg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacacag 1320aagagcctct ccctgtctct gggtggagga agcggaggag gagggtccgg aggaggaggg 1380tccggaggag gagggtccca ggtacagctg cagcagtcag gcgcaggatt attgaagcct 1440tcggagaccc tttccctcac ctgcgctgtg tctggtgggt ccttcagtgg ttactactgg 1500acctggatcc gccagcgccc agggaagggg ctggagtgga ttggagaaat caatcatcgt 1560ggaagcaccg attacaaccc gtccctcaag agtcgagtca ccatgtcaat agacacgtcc 1620aagagccagt tctccctgaa tttgaaatct gtgaccgccg cggacacggc tgtgtattac 1680tgtgcgagag ccgcctgggg gtcttgttat gatgggacct gctaccccgc tgaatacttc 1740caatactggg gccagggaac cctggtcacc gtctcctcag gaggcggtgg cagcggtggg 1800cgcgcctcgg gcggaggtgg ttcacagtct gccctgactc agcctgcctc cgtgtctggg 1860tctcctggac agtcgatcac catctcctgc actggaacca gccgtgacgt tggtggttat 1920aactatgtct cctggtacca acaacaccca ggcaaagccc ccaaactcat gatttatgat 1980gtcaataatc ggccctcagg ggtttctaat cggttctctg gctccaagtc tggcaacacg 2040gcctccctga ccatctctgg gctccaggct gaggacgagg ctgattattt ctgcagctca 2100tatacaagca gtagcacccc tgtggtattc ggcggtggga ccaagctgac cgtcctagac 2160tacaaggacg acgatgacaa g 2181117727PRTArtificial SequenceDescription of the artificial sequence amino acid sequence of the antibody sequence of pCI-AVM-hLG4PE (R409K / S354C / T366W) -linker-MOG01 scFv-FLAG tag excluding signal sequence 117Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Ala Met Ala Trp Val Arg Arg Ala Pro Thr Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Ser Asn Gly Gly Gly Asn Thr Tyr Tyr Arg Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asp Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Arg His Gly Asn Tyr Ile Tyr Tyr Gly Ser Phe Phe Asp Tyr Trp 100 105 110Gly Gln Gly Val Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr145 150 155 160Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro225 230 235 240Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 260 265 270Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val 290 295 300Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu305 310 315 320Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350Leu Pro Pro Cys Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp 355 360 365Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 450 455 460Gly Ser Gln Val Gln Leu Gln Gln Ser Gly Ala Gly Leu Leu Lys Pro465 470 475 480Ser Glu Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Phe Ser 485 490 495Gly Tyr Tyr Trp Thr Trp Ile Arg Gln Arg Pro Gly Lys Gly Leu Glu 500 505 510Trp Ile Gly Glu Ile Asn His Arg Gly Ser Thr Asp Tyr Asn Pro Ser 515 520 525Leu Lys Ser Arg Val Thr Met Ser Ile Asp Thr Ser Lys Ser Gln Phe 530 535 540Ser Leu Asn Leu Lys Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr545 550 555 560Cys Ala Arg Ala Ala Trp Gly Ser Cys Tyr Asp Gly Thr Cys Tyr Pro 565 570 575Ala Glu Tyr Phe Gln Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 580 585 590Ser Gly Gly Gly Gly Ser Gly Gly Arg Ala Ser Gly Gly Gly Gly Ser 595 600 605Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 610 615 620Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Arg Asp Val Gly Gly Tyr625 630 635 640Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 645 650 655Met Ile Tyr Asp Val Asn Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 660 665 670Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 675 680 685Gln Ala Glu Asp Glu Ala Asp Tyr Phe Cys Ser Ser Tyr Thr Ser Ser 690 695 700Ser Thr Pro Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Asp705 710 715 720Tyr Lys Asp Asp Asp Asp Lys 7251181365DNAArtificial SequenceDescription of the artificial sequence base sequence of the antibody sequence of pCI-AVM-hLG4PE (R409K / Y349C / T366S / L368A / Y407V) -His tag excluding signal sequence 118gaggtgcagc tggtggaatc tgggggaggc ttagtgcagc ctggaagatc cctgaaactc 60tcctgtgcag cctcaggatt cactttcagt aactatgcca tggcttgggt ccgccgggct 120ccaacgaagg gtctggagtg ggtcgcatcc attagtaatg gtggtggtaa cacttactat 180cgcgactccg tgaagggccg attcactatc tccagagatg atgcaaaaaa caccctatac 240ctgcaaatgg acagtctgag gtctgaggac acggccactt attactgtgc aagacacggg 300aattatatat attatgggtc cttctttgat tactggggcc aaggagtcat ggtcacagtc 360tcctcagcta gcaccaaggg gccatccgtc ttccccctgg cgccctgctc caggagcacc 420tccgagagca cagccgccct gggctgcctg gtcaaggact acttccccga accggtgacg 480gtgtcgtgga actcaggcgc cctgaccagc ggcgtgcaca ccttcccggc tgtcctacag 540tcctcaggac tctactccct cagcagcgtg gtgaccgtgc cctccagcag cttgggcacg 600aagacctaca cctgcaacgt agatcacaag cccagcaaca ccaaggtgga caagagagtt 660gagtccaaat atggtccccc atgcccacca tgcccagcac ctgagttcga ggggggacca 720tcagtcttcc tgttcccccc aaaacccaag gacactctca tgatctcccg gacccctgag 780gtcacgtgcg tggtggtgga cgtgagccag gaagaccccg aggtccagtt caactggtac 840gtggatggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gttcaacagc 900acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa cggcaaggag 960tacaagtgca aggtctccaa caaaggcctc ccgtcctcca tcgagaaaac catctccaaa 1020gccaaagggc agccccgaga gccacaggtg tgcaccctgc ccccatccca ggaggagatg 1080accaagaacc aggtcagcct gtcctgcgcg gtcaaaggct tctaccccag cgacatcgcc 1140gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200gactccgacg gctccttctt cctcgtcagc aagctaaccg tggacaagag caggtggcag 1260gaggggaatg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacacag 1320aagagcctct ccctgtctct gggtaaacac caccaccacc accac 1365119455PRTArtificial SequenceDescription of the artificial sequence amino acid sequence of the antibody sequence of pCI-AVM-hLG4PE (R409K / Y349C / T366S / L368A / Y407V) -His tag excluding signal sequence 119Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Ala Met Ala Trp Val Arg Arg Ala Pro Thr Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Ser Asn Gly Gly Gly Asn Thr Tyr Tyr Arg Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asp Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Arg His Gly Asn Tyr Ile Tyr Tyr Gly Ser Phe Phe Asp Tyr Trp 100 105 110Gly Gln Gly Val Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr145 150 155 160Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro225 230 235 240Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 260 265 270Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val 290 295 300Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu305 310 315 320Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr 340 345 350Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Ser 355 360 365Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys 405 410 415Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445Lys His His His His His His 450 4551202151DNAArtificial SequenceDescription of the artificial sequence base sequence of the antibody sequence of pCI-AVM-hLG4PE (R409K) _MOG01 scFv2 excluding signal sequence 120gaggtgcagc tggtggaatc tgggggaggc ttagtgcagc ctggaagatc cctgaaactc 60tcctgtgcag cctcaggatt cactttcagt aactatgcca tggcttgggt ccgccgggct 120ccaacgaagg gtctggagtg ggtcgcatcc attagtaatg gtggtggtaa cacttactat 180cgcgactccg tgaagggccg attcactatc tccagagatg atgcaaaaaa caccctatac 240ctgcaaatgg acagtctgag gtctgaggac acggccactt attactgtgc aagacacggg 300aattatatat attatgggtc cttctttgat tactggggcc aaggagtcat ggtcacagtc 360tcctcagcta gcaccaaggg gccatccgtc ttccccctgg cgccctgctc caggagcacc 420tccgagagca cagccgccct gggctgcctg gtcaaggact acttccccga accggtgacg 480gtgtcgtgga actcaggcgc cctgaccagc ggcgtgcaca ccttcccggc tgtcctacag 540tcctcaggac tctactccct cagcagcgtg gtgaccgtgc cctccagcag cttgggcacg 600aagacctaca cctgcaacgt agatcacaag cccagcaaca ccaaggtgga caagagagtt 660gagtccaaat atggtccccc atgcccacca tgcccagcac ctgagttcga ggggggacca 720tcagtcttcc tgttcccccc aaaacccaag gacactctca tgatctcccg gacccctgag 780gtcacgtgcg tggtggtgga cgtgagccag gaagaccccg aggtccagtt caactggtac 840gtggatggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gttcaacagc 900acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa cggcaaggag 960tacaagtgca aggtctccaa caaaggcctc ccgtcctcca tcgagaaaac catctccaaa 1020gccaaagggc agccccgaga gccacaggtg tacaccctgc ccccatccca ggaggagatg 1080accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctaccccag cgacatcgcc 1140gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200gactccgacg gctccttctt cctctacagc aagctaaccg tggacaagag caggtggcag 1260gaggggaatg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacacag 1320aagagcctct ccctgtctct gggtaaagga ggaggagggt ccggaggagg agggtccgga 1380ggaggagggt cccaggtaca gctgcagcag tcaggcgcag gattattgaa gccttcggag 1440accctttccc tcacctgcgc tgtgtctggt gggtccttca gtggttacta ctggacctgg 1500atccgccagc gcccagggaa ggggctggag tggattggag aaatcaatca tcgtggaagc 1560accgattaca acccgtccct caagagtcga gtcaccatgt caatagacac gtccaagagc 1620cagttctccc tgaatttgaa atctgtgacc gccgcggaca cggctgtgta ttactgtgcg 1680agagccgcct gggggtcttg ttatgatggg acctgctacc ccgctgaata cttccaatac 1740tggggccagg gaaccctggt caccgtctcc tcaggaggcg gtggcagcgg tgggcgcgcc 1800tcgggcggag gtggttcaca gtctgccctg actcagcctg cctccgtgtc tgggtctcct 1860ggacagtcga tcaccatctc ctgcactgga accagccgtg acgttggtgg ttataactat 1920gtctcctggt accaacaaca cccaggcaaa gcccccaaac tcatgattta tgatgtcaat 1980aatcggccct caggggtttc taatcggttc tctggctcca agtctggcaa cacggcctcc 2040ctgaccatct ctgggctcca ggctgaggac gaggctgatt atttctgcag ctcatataca 2100agcagtagca cccctgtggt attcggcggt gggaccaagc tgaccgtcct a 2151121717PRTArtificial SequenceDescription of the artificial sequence amino acid sequence of antibody sequence of pCI-AVM-hLG4PE (R409K) _MOG 01 scFv 2 excluding signal sequence 121Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Ala Met Ala Trp Val Arg Arg Ala Pro Thr Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Ser Asn Gly Gly Gly Asn Thr Tyr Tyr Arg Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asp Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Arg His Gly Asn Tyr Ile Tyr Tyr Gly Ser Phe Phe Asp Tyr Trp 100 105 110Gly Gln Gly Val Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr145 150 155 160Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185

190Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro225 230 235 240Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 260 265 270Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val 290 295 300Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu305 310 315 320Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 450 455 460Gln Val Gln Leu Gln Gln Ser Gly Ala Gly Leu Leu Lys Pro Ser Glu465 470 475 480Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Phe Ser Gly Tyr 485 490 495Tyr Trp Thr Trp Ile Arg Gln Arg Pro Gly Lys Gly Leu Glu Trp Ile 500 505 510Gly Glu Ile Asn His Arg Gly Ser Thr Asp Tyr Asn Pro Ser Leu Lys 515 520 525Ser Arg Val Thr Met Ser Ile Asp Thr Ser Lys Ser Gln Phe Ser Leu 530 535 540Asn Leu Lys Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala545 550 555 560Arg Ala Ala Trp Gly Ser Cys Tyr Asp Gly Thr Cys Tyr Pro Ala Glu 565 570 575Tyr Phe Gln Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly 580 585 590Gly Gly Gly Ser Gly Gly Arg Ala Ser Gly Gly Gly Gly Ser Gln Ser 595 600 605Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln Ser Ile 610 615 620Thr Ile Ser Cys Thr Gly Thr Ser Arg Asp Val Gly Gly Tyr Asn Tyr625 630 635 640Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Met Ile 645 650 655Tyr Asp Val Asn Asn Arg Pro Ser Gly Val Ser Asn Arg Phe Ser Gly 660 665 670Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala 675 680 685Glu Asp Glu Ala Asp Tyr Phe Cys Ser Ser Tyr Thr Ser Ser Ser Thr 690 695 700Pro Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu705 710 7151222157DNAArtificial SequenceDescription of the artificial sequence base sequence of antibody sequence of pCI-AVM-hLG4PE (R409K) _MOG01 scFv3 excluding signal sequence 122gaggtgcagc tggtggaatc tgggggaggc ttagtgcagc ctggaagatc cctgaaactc 60tcctgtgcag cctcaggatt cactttcagt aactatgcca tggcttgggt ccgccgggct 120ccaacgaagg gtctggagtg ggtcgcatcc attagtaatg gtggtggtaa cacttactat 180cgcgactccg tgaagggccg attcactatc tccagagatg atgcaaaaaa caccctatac 240ctgcaaatgg acagtctgag gtctgaggac acggccactt attactgtgc aagacacggg 300aattatatat attatgggtc cttctttgat tactggggcc aaggagtcat ggtcacagtc 360tcctcagcta gcaccaaggg gccatccgtc ttccccctgg cgccctgctc caggagcacc 420tccgagagca cagccgccct gggctgcctg gtcaaggact acttccccga accggtgacg 480gtgtcgtgga actcaggcgc cctgaccagc ggcgtgcaca ccttcccggc tgtcctacag 540tcctcaggac tctactccct cagcagcgtg gtgaccgtgc cctccagcag cttgggcacg 600aagacctaca cctgcaacgt agatcacaag cccagcaaca ccaaggtgga caagagagtt 660gagtccaaat atggtccccc atgcccacca tgcccagcac ctgagttcga ggggggacca 720tcagtcttcc tgttcccccc aaaacccaag gacactctca tgatctcccg gacccctgag 780gtcacgtgcg tggtggtgga cgtgagccag gaagaccccg aggtccagtt caactggtac 840gtggatggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gttcaacagc 900acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa cggcaaggag 960tacaagtgca aggtctccaa caaaggcctc ccgtcctcca tcgagaaaac catctccaaa 1020gccaaagggc agccccgaga gccacaggtg tacaccctgc ccccatccca ggaggagatg 1080accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctaccccag cgacatcgcc 1140gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200gactccgacg gctccttctt cctctacagc aagctaaccg tggacaagag caggtggcag 1260gaggggaatg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacacag 1320aagagcctct ccctgtctct gggtggagga agcggaggag gagggtccgg aggaggaggg 1380tccggaggag gagggtccca gtctgccctg actcagcctg cctccgtgtc tgggtctcct 1440ggacagtcga tcaccatctc ctgcactgga accagccgtg acgttggtgg ttataactat 1500gtctcctggt accaacaaca cccaggcaaa gcccccaaac tcatgattta tgatgtcaat 1560aatcggccct caggggtttc taatcggttc tctggctcca agtctggcaa cacggcctcc 1620ctgaccatct ctgggctcca ggctgaggac gaggctgatt atttctgcag ctcatataca 1680agcagtagca cccctgtggt attcggcggt gggaccaagc tgaccgtcct aggaggcggt 1740ggcagcggtg ggcgcgcctc gggcggaggt ggttcacagg tacagctgca gcagtcaggc 1800gcaggattat tgaagccttc ggagaccctt tccctcacct gcgctgtgtc tggtgggtcc 1860ttcagtggtt actactggac ctggatccgc cagcgcccag ggaaggggct ggagtggatt 1920ggagaaatca atcatcgtgg aagcaccgat tacaacccgt ccctcaagag tcgagtcacc 1980atgtcaatag acacgtccaa gagccagttc tccctgaatt tgaaatctgt gaccgccgcg 2040gacacggctg tgtattactg tgcgagagcc gcctgggggt cttgttatga tgggacctgc 2100taccccgctg aatacttcca atactggggc cagggaaccc tggtcaccgt ctcctca 2157123719PRTArtificial SequenceDescription of the artificial sequence amino acid sequence of the antibody sequence of pCI-AVM-hLG4PE (R409K) _MOG 01 scFv 3 excluding signal sequence 123Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Ala Met Ala Trp Val Arg Arg Ala Pro Thr Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Ser Asn Gly Gly Gly Asn Thr Tyr Tyr Arg Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asp Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Arg His Gly Asn Tyr Ile Tyr Tyr Gly Ser Phe Phe Asp Tyr Trp 100 105 110Gly Gln Gly Val Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr145 150 155 160Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro225 230 235 240Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 260 265 270Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val 290 295 300Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu305 310 315 320Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 450 455 460Gly Ser Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro465 470 475 480Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Arg Asp Val Gly 485 490 495Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro 500 505 510Lys Leu Met Ile Tyr Asp Val Asn Asn Arg Pro Ser Gly Val Ser Asn 515 520 525Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser 530 535 540Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Phe Cys Ser Ser Tyr Thr545 550 555 560Ser Ser Ser Thr Pro Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val 565 570 575Leu Gly Gly Gly Gly Ser Gly Gly Arg Ala Ser Gly Gly Gly Gly Ser 580 585 590Gln Val Gln Leu Gln Gln Ser Gly Ala Gly Leu Leu Lys Pro Ser Glu 595 600 605Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Phe Ser Gly Tyr 610 615 620Tyr Trp Thr Trp Ile Arg Gln Arg Pro Gly Lys Gly Leu Glu Trp Ile625 630 635 640Gly Glu Ile Asn His Arg Gly Ser Thr Asp Tyr Asn Pro Ser Leu Lys 645 650 655Ser Arg Val Thr Met Ser Ile Asp Thr Ser Lys Ser Gln Phe Ser Leu 660 665 670Asn Leu Lys Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 675 680 685Arg Ala Ala Trp Gly Ser Cys Tyr Asp Gly Thr Cys Tyr Pro Ala Glu 690 695 700Tyr Phe Gln Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser705 710 7151242175DNAArtificial SequenceDescription of the artificial sequence base sequence of the antibody sequence of pCI-AVM-hLG4PE (R409K) _MOG 01 scFv 4 excluding signal sequence 124gaggtgcagc tggtggaatc tgggggaggc ttagtgcagc ctggaagatc cctgaaactc 60tcctgtgcag cctcaggatt cactttcagt aactatgcca tggcttgggt ccgccgggct 120ccaacgaagg gtctggagtg ggtcgcatcc attagtaatg gtggtggtaa cacttactat 180cgcgactccg tgaagggccg attcactatc tccagagatg atgcaaaaaa caccctatac 240ctgcaaatgg acagtctgag gtctgaggac acggccactt attactgtgc aagacacggg 300aattatatat attatgggtc cttctttgat tactggggcc aaggagtcat ggtcacagtc 360tcctcagcta gcaccaaggg gccatccgtc ttccccctgg cgccctgctc caggagcacc 420tccgagagca cagccgccct gggctgcctg gtcaaggact acttccccga accggtgacg 480gtgtcgtgga actcaggcgc cctgaccagc ggcgtgcaca ccttcccggc tgtcctacag 540tcctcaggac tctactccct cagcagcgtg gtgaccgtgc cctccagcag cttgggcacg 600aagacctaca cctgcaacgt agatcacaag cccagcaaca ccaaggtgga caagagagtt 660gagtccaaat atggtccccc atgcccacca tgcccagcac ctgagttcga ggggggacca 720tcagtcttcc tgttcccccc aaaacccaag gacactctca tgatctcccg gacccctgag 780gtcacgtgcg tggtggtgga cgtgagccag gaagaccccg aggtccagtt caactggtac 840gtggatggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gttcaacagc 900acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa cggcaaggag 960tacaagtgca aggtctccaa caaaggcctc ccgtcctcca tcgagaaaac catctccaaa 1020gccaaagggc agccccgaga gccacaggtg tacaccctgc ccccatccca ggaggagatg 1080accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctaccccag cgacatcgcc 1140gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200gactccgacg gctccttctt cctctacagc aagctaaccg tggacaagag caggtggcag 1260gaggggaatg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacacag 1320aagagcctct ccctgtctct gggtggagga ggagggtccg gaggaggagg gtccggtgga 1380ggtgggtccc aggtacagct gcagcagtca ggcgcaggat tattgaagcc ttcggagacc 1440ctttccctca cctgcgctgt gtctggtggg tccttcagtg gttactactg gacctggatc 1500cgccagcgcc cagggaaggg gctggagtgg attggagaaa tcaatcatcg tggaagcacc 1560gattacaacc cgtccctcaa gagtcgagtc accatgtcaa tagacacgtc caagagccag 1620ttctccctga atttgaaatc tgtgaccgcc gcggacacgg ctgtgtatta ctgtgcgaga 1680gccgcctggg ggtcttgtta tgatgggacc tgctaccccg ctgaatactt ccaatactgg 1740ggccagggaa ccctggtcac cgtctcctca gctagcaccg gaggcggtgg cagcggagga 1800ggagggtccg gtgggggcgg ctcgggcgga ggtggttcac agtctgccct gactcagcct 1860gcctccgtgt ctgggtctcc tggacagtcg atcaccatct cctgcactgg aaccagccgt 1920gacgttggtg gttataacta tgtctcctgg taccaacaac acccaggcaa agcccccaaa 1980ctcatgattt atgatgtcaa taatcggccc tcaggggttt ctaatcggtt ctctggctcc 2040aagtctggca acacggcctc cctgaccatc tctgggctcc aggctgagga cgaggctgat 2100tatttctgca gctcatatac aagcagtagc acccctgtgg tattcggcgg tgggaccaag 2160ctgaccgtcc taggt 2175125725PRTArtificial SequenceDescription of the artificial sequence amino acid sequence of the antibody sequence of pCI-AVM-hLG4PE (R409K) _MOG 01 scFv 4 excluding signal sequence 125Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Ala Met Ala Trp Val Arg Arg Ala Pro Thr Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Ser Asn Gly Gly Gly Asn Thr Tyr Tyr Arg Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asp Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Arg His Gly Asn Tyr Ile Tyr Tyr Gly Ser Phe Phe Asp Tyr Trp 100 105 110Gly Gln Gly Val Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr145 150 155 160Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro225 230 235 240Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 260 265 270Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val 290 295 300Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu305 310 315 320Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp

Lys 405 410 415Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln 450 455 460Val Gln Leu Gln Gln Ser Gly Ala Gly Leu Leu Lys Pro Ser Glu Thr465 470 475 480Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Phe Ser Gly Tyr Tyr 485 490 495Trp Thr Trp Ile Arg Gln Arg Pro Gly Lys Gly Leu Glu Trp Ile Gly 500 505 510Glu Ile Asn His Arg Gly Ser Thr Asp Tyr Asn Pro Ser Leu Lys Ser 515 520 525Arg Val Thr Met Ser Ile Asp Thr Ser Lys Ser Gln Phe Ser Leu Asn 530 535 540Leu Lys Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg545 550 555 560Ala Ala Trp Gly Ser Cys Tyr Asp Gly Thr Cys Tyr Pro Ala Glu Tyr 565 570 575Phe Gln Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser 580 585 590Thr Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 595 600 605Gly Gly Gly Gly Ser Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser 610 615 620Gly Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Arg625 630 635 640Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly 645 650 655Lys Ala Pro Lys Leu Met Ile Tyr Asp Val Asn Asn Arg Pro Ser Gly 660 665 670Val Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu 675 680 685Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Phe Cys Ser 690 695 700Ser Tyr Thr Ser Ser Ser Thr Pro Val Val Phe Gly Gly Gly Thr Lys705 710 715 720Leu Thr Val Leu Gly 7251262175DNAArtificial SequenceDescription of the artificial sequence base sequence of antibody sequence of pCI-AVM-hLG4PE (R409K) _MOG 01 scFv 5 excluding signal sequence 126gaggtgcagc tggtggaatc tgggggaggc ttagtgcagc ctggaagatc cctgaaactc 60tcctgtgcag cctcaggatt cactttcagt aactatgcca tggcttgggt ccgccgggct 120ccaacgaagg gtctggagtg ggtcgcatcc attagtaatg gtggtggtaa cacttactat 180cgcgactccg tgaagggccg attcactatc tccagagatg atgcaaaaaa caccctatac 240ctgcaaatgg acagtctgag gtctgaggac acggccactt attactgtgc aagacacggg 300aattatatat attatgggtc cttctttgat tactggggcc aaggagtcat ggtcacagtc 360tcctcagcta gcaccaaggg gccatccgtc ttccccctgg cgccctgctc caggagcacc 420tccgagagca cagccgccct gggctgcctg gtcaaggact acttccccga accggtgacg 480gtgtcgtgga actcaggcgc cctgaccagc ggcgtgcaca ccttcccggc tgtcctacag 540tcctcaggac tctactccct cagcagcgtg gtgaccgtgc cctccagcag cttgggcacg 600aagacctaca cctgcaacgt agatcacaag cccagcaaca ccaaggtgga caagagagtt 660gagtccaaat atggtccccc atgcccacca tgcccagcac ctgagttcga ggggggacca 720tcagtcttcc tgttcccccc aaaacccaag gacactctca tgatctcccg gacccctgag 780gtcacgtgcg tggtggtgga cgtgagccag gaagaccccg aggtccagtt caactggtac 840gtggatggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gttcaacagc 900acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa cggcaaggag 960tacaagtgca aggtctccaa caaaggcctc ccgtcctcca tcgagaaaac catctccaaa 1020gccaaagggc agccccgaga gccacaggtg tacaccctgc ccccatccca ggaggagatg 1080accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctaccccag cgacatcgcc 1140gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200gactccgacg gctccttctt cctctacagc aagctaaccg tggacaagag caggtggcag 1260gaggggaatg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacacag 1320aagagcctct ccctgtctct gggtggagga ggagggtccg gaggaggagg gtccggtgga 1380ggtgggtccc agtctgccct gactcagcct gcctccgtgt ctgggtctcc tggacagtcg 1440atcaccatct cctgcactgg aaccagccgt gacgttggtg gttataacta tgtctcctgg 1500taccaacaac acccaggcaa agcccccaaa ctcatgattt atgatgtcaa taatcggccc 1560tcaggggttt ctaatcggtt ctctggctcc aagtctggca acacggcctc cctgaccatc 1620tctgggctcc aggctgagga cgaggctgat tatttctgca gctcatatac aagcagtagc 1680acccctgtgg tattcggcgg tgggaccaag ctgaccgtcc taggtggagg cggtggcagc 1740ggaggaggag ggtccggtgg gggcggctcg ggcggaggtg gttcacaggt acagctgcag 1800cagtcaggcg caggattatt gaagccttcg gagacccttt ccctcacctg cgctgtgtct 1860ggtgggtcct tcagtggtta ctactggacc tggatccgcc agcgcccagg gaaggggctg 1920gagtggattg gagaaatcaa tcatcgtgga agcaccgatt acaacccgtc cctcaagagt 1980cgagtcacca tgtcaataga cacgtccaag agccagttct ccctgaattt gaaatctgtg 2040accgccgcgg acacggctgt gtattactgt gcgagagccg cctgggggtc ttgttatgat 2100gggacctgct accccgctga atacttccaa tactggggcc agggaaccct ggtcaccgtc 2160tcctcagcta gcacc 2175127725PRTArtificial SequenceDescription of the artificial sequence amino acid sequence of the antibody sequence of pCI-AVM-hLG4PE (R409K) _MOG01 scFv5 excluding signal sequence 127Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Ala Met Ala Trp Val Arg Arg Ala Pro Thr Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Ser Asn Gly Gly Gly Asn Thr Tyr Tyr Arg Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asp Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Arg His Gly Asn Tyr Ile Tyr Tyr Gly Ser Phe Phe Asp Tyr Trp 100 105 110Gly Gln Gly Val Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr145 150 155 160Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro225 230 235 240Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 260 265 270Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val 290 295 300Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu305 310 315 320Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln 450 455 460Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln Ser465 470 475 480Ile Thr Ile Ser Cys Thr Gly Thr Ser Arg Asp Val Gly Gly Tyr Asn 485 490 495Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Met 500 505 510Ile Tyr Asp Val Asn Asn Arg Pro Ser Gly Val Ser Asn Arg Phe Ser 515 520 525Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln 530 535 540Ala Glu Asp Glu Ala Asp Tyr Phe Cys Ser Ser Tyr Thr Ser Ser Ser545 550 555 560Thr Pro Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly 565 570 575Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 580 585 590Gly Gly Ser Gln Val Gln Leu Gln Gln Ser Gly Ala Gly Leu Leu Lys 595 600 605Pro Ser Glu Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Phe 610 615 620Ser Gly Tyr Tyr Trp Thr Trp Ile Arg Gln Arg Pro Gly Lys Gly Leu625 630 635 640Glu Trp Ile Gly Glu Ile Asn His Arg Gly Ser Thr Asp Tyr Asn Pro 645 650 655Ser Leu Lys Ser Arg Val Thr Met Ser Ile Asp Thr Ser Lys Ser Gln 660 665 670Phe Ser Leu Asn Leu Lys Ser Val Thr Ala Ala Asp Thr Ala Val Tyr 675 680 685Tyr Cys Ala Arg Ala Ala Trp Gly Ser Cys Tyr Asp Gly Thr Cys Tyr 690 695 700Pro Ala Glu Tyr Phe Gln Tyr Trp Gly Gln Gly Thr Leu Val Thr Val705 710 715 720Ser Ser Ala Ser Thr 7251282148DNAArtificial SequenceDescription of the artificial sequence base sequence of the antibody sequence of pCI-AVM-hLG4PE (R409K) _MOG01 scFv6 excluding signal sequence 128gaggtgcagc tggtggaatc tgggggaggc ttagtgcagc ctggaagatc cctgaaactc 60tcctgtgcag cctcaggatt cactttcagt aactatgcca tggcttgggt ccgccgggct 120ccaacgaagg gtctggagtg ggtcgcatcc attagtaatg gtggtggtaa cacttactat 180cgcgactccg tgaagggccg attcactatc tccagagatg atgcaaaaaa caccctatac 240ctgcaaatgg acagtctgag gtctgaggac acggccactt attactgtgc aagacacggg 300aattatatat attatgggtc cttctttgat tactggggcc aaggagtcat ggtcacagtc 360tcctcagcta gcaccaaggg gccatccgtc ttccccctgg cgccctgctc caggagcacc 420tccgagagca cagccgccct gggctgcctg gtcaaggact acttccccga accggtgacg 480gtgtcgtgga actcaggcgc cctgaccagc ggcgtgcaca ccttcccggc tgtcctacag 540tcctcaggac tctactccct cagcagcgtg gtgaccgtgc cctccagcag cttgggcacg 600aagacctaca cctgcaacgt agatcacaag cccagcaaca ccaaggtgga caagagagtt 660gagtccaaat atggtccccc atgcccacca tgcccagcac ctgagttcga ggggggacca 720tcagtcttcc tgttcccccc aaaacccaag gacactctca tgatctcccg gacccctgag 780gtcacgtgcg tggtggtgga cgtgagccag gaagaccccg aggtccagtt caactggtac 840gtggatggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gttcaacagc 900acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa cggcaaggag 960tacaagtgca aggtctccaa caaaggcctc ccgtcctcca tcgagaaaac catctccaaa 1020gccaaagggc agccccgaga gccacaggtg tacaccctgc ccccatccca ggaggagatg 1080accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctaccccag cgacatcgcc 1140gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200gactccgacg gctccttctt cctctacagc aagctaaccg tggacaagag caggtggcag 1260gaggggaatg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacacag 1320aagagcctct ccctgtctct gggtggagga ggagggtccg gaggaggagg gtccggtgga 1380ggtgggtccc agtctgccct gactcagcct gcctccgtgt ctgggtctcc tggacagtcg 1440atcaccatct cctgcactgg aaccagccgt gacgttggtg gttataacta tgtctcctgg 1500taccaacaac acccaggcaa agcccccaaa ctcatgattt atgatgtcaa taatcggccc 1560tcaggggttt ctaatcggtt ctctggctcc aagtctggca acacggcctc cctgaccatc 1620tctgggctcc aggctgagga cgaggctgat tatttctgca gctcatatac aagcagtagc 1680acccctgtgg tattcggcgg tgggaccaag ctgaccgtcc taggaggcgg tggcagcggt 1740gggcgcgcct cgggcggagg tggttcacag gtacagctgc agcagtcagg cgcaggatta 1800ttgaagcctt cggagaccct ttccctcacc tgcgctgtgt ctggtgggtc cttcagtggt 1860tactactgga cctggatccg ccagcgccca gggaaggggc tggagtggat tggagaaatc 1920aatcatcgtg gaagcaccga ttacaacccg tccctcaaga gtcgagtcac catgtcaata 1980gacacgtcca agagccagtt ctccctgaat ttgaaatctg tgaccgccgc ggacacggct 2040gtgtattact gtgcgagagc cgcctggggg tcttgttatg atgggacctg ctaccccgct 2100gaatacttcc aatactgggg ccagggaacc ctggtcaccg tctcctca 2148129716PRTArtificial SequenceDescription of the artificial sequence amino acid sequence of the antibody sequence of pCI-AVM-hLG4PE (R409K) _MOG 01 scFv 6 excluding signal sequence 129Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Ala Met Ala Trp Val Arg Arg Ala Pro Thr Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Ser Asn Gly Gly Gly Asn Thr Tyr Tyr Arg Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asp Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Arg His Gly Asn Tyr Ile Tyr Tyr Gly Ser Phe Phe Asp Tyr Trp 100 105 110Gly Gln Gly Val Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr145 150 155 160Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro225 230 235 240Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 260 265 270Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val 290 295 300Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu305 310 315 320Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln 450 455 460Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln Ser465 470 475 480Ile Thr Ile Ser Cys Thr Gly Thr Ser Arg Asp Val Gly Gly Tyr Asn 485 490 495Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Met 500 505 510Ile Tyr Asp Val Asn Asn Arg Pro Ser Gly Val Ser Asn Arg Phe Ser 515 520 525Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln 530 535 540Ala Glu Asp Glu Ala Asp Tyr Phe Cys Ser Ser Tyr Thr Ser Ser Ser545 550 555 560Thr Pro Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly 565 570 575Gly Gly Ser Gly Gly Arg Ala Ser Gly Gly Gly Gly Ser Gln Val Gln 580 585 590Leu Gln Gln Ser Gly Ala Gly Leu Leu Lys Pro Ser Glu Thr Leu Ser 595

600 605Leu Thr Cys Ala Val Ser Gly Gly Ser Phe Ser Gly Tyr Tyr Trp Thr 610 615 620Trp Ile Arg Gln Arg Pro Gly Lys Gly Leu Glu Trp Ile Gly Glu Ile625 630 635 640Asn His Arg Gly Ser Thr Asp Tyr Asn Pro Ser Leu Lys Ser Arg Val 645 650 655Thr Met Ser Ile Asp Thr Ser Lys Ser Gln Phe Ser Leu Asn Leu Lys 660 665 670Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ala Ala 675 680 685Trp Gly Ser Cys Tyr Asp Gly Thr Cys Tyr Pro Ala Glu Tyr Phe Gln 690 695 700Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser705 710 7151302172DNAArtificial SequenceDescription of the artificial sequence base sequence of the antibody sequence of pCI-AVM-hLG4PE (R409K) _MOG01 scFv7 excluding signal sequence 130gaggtgcagc tggtggaatc tgggggaggc ttagtgcagc ctggaagatc cctgaaactc 60tcctgtgcag cctcaggatt cactttcagt aactatgcca tggcttgggt ccgccgggct 120ccaacgaagg gtctggagtg ggtcgcatcc attagtaatg gtggtggtaa cacttactat 180cgcgactccg tgaagggccg attcactatc tccagagatg atgcaaaaaa caccctatac 240ctgcaaatgg acagtctgag gtctgaggac acggccactt attactgtgc aagacacggg 300aattatatat attatgggtc cttctttgat tactggggcc aaggagtcat ggtcacagtc 360tcctcagcta gcaccaaggg gccatccgtc ttccccctgg cgccctgctc caggagcacc 420tccgagagca cagccgccct gggctgcctg gtcaaggact acttccccga accggtgacg 480gtgtcgtgga actcaggcgc cctgaccagc ggcgtgcaca ccttcccggc tgtcctacag 540tcctcaggac tctactccct cagcagcgtg gtgaccgtgc cctccagcag cttgggcacg 600aagacctaca cctgcaacgt agatcacaag cccagcaaca ccaaggtgga caagagagtt 660gagtccaaat atggtccccc atgcccacca tgcccagcac ctgagttcga ggggggacca 720tcagtcttcc tgttcccccc aaaacccaag gacactctca tgatctcccg gacccctgag 780gtcacgtgcg tggtggtgga cgtgagccag gaagaccccg aggtccagtt caactggtac 840gtggatggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gttcaacagc 900acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa cggcaaggag 960tacaagtgca aggtctccaa caaaggcctc ccgtcctcca tcgagaaaac catctccaaa 1020gccaaagggc agccccgaga gccacaggtg tacaccctgc ccccatccca ggaggagatg 1080accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctaccccag cgacatcgcc 1140gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200gactccgacg gctccttctt cctctacagc aagctaaccg tggacaagag caggtggcag 1260gaggggaatg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacacag 1320aagagcctct ccctgtctct gggtggagga agcggaggag gagggtccgg aggaggaggg 1380tccggaggag gagggtccca gtctgccctg actcagcctg cctccgtgtc tgggtctcct 1440ggacagtcga tcaccatctc ctgcactgga accagccgtg acgttggtgg ttataactat 1500gtctcctggt accaacaaca cccaggcaaa gcccccaaac tcatgattta tgatgtcaat 1560aatcggccct caggggtttc taatcggttc tctggctcca agtctggcaa cacggcctcc 1620ctgaccatct ctgggctcca ggctgaggac gaggctgatt atttctgcag ctcatataca 1680agcagtagca cccctgtggt attcggcggt gggaccaagc tgaccgtcct aggaggcggt 1740ggcagcggag gaggagggtc cggtgggggc ggctcgggcg gaggtggttc acaggtacag 1800ctgcagcagt caggcgcagg attattgaag ccttcggaga ccctttccct cacctgcgct 1860gtgtctggtg ggtccttcag tggttactac tggacctgga tccgccagcg cccagggaag 1920gggctggagt ggattggaga aatcaatcat cgtggaagca ccgattacaa cccgtccctc 1980aagagtcgag tcaccatgtc aatagacacg tccaagagcc agttctccct gaatttgaaa 2040tctgtgaccg ccgcggacac ggctgtgtat tactgtgcga gagccgcctg ggggtcttgt 2100tatgatggga cctgctaccc cgctgaatac ttccaatact ggggccaggg aaccctggtc 2160accgtctcct ca 2172131724PRTArtificial SequenceDescription of the artificial sequence amino acid sequence of the antibody sequence of pCI-AVM-hLG4PE (R409K) _MOG01 scFv7 excluding signal sequence 131Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Ala Met Ala Trp Val Arg Arg Ala Pro Thr Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Ser Asn Gly Gly Gly Asn Thr Tyr Tyr Arg Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asp Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Arg His Gly Asn Tyr Ile Tyr Tyr Gly Ser Phe Phe Asp Tyr Trp 100 105 110Gly Gln Gly Val Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr145 150 155 160Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro225 230 235 240Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 260 265 270Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val 290 295 300Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu305 310 315 320Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 450 455 460Gly Ser Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro465 470 475 480Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Arg Asp Val Gly 485 490 495Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro 500 505 510Lys Leu Met Ile Tyr Asp Val Asn Asn Arg Pro Ser Gly Val Ser Asn 515 520 525Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser 530 535 540Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Phe Cys Ser Ser Tyr Thr545 550 555 560Ser Ser Ser Thr Pro Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val 565 570 575Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 580 585 590Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Gln Ser Gly Ala Gly Leu 595 600 605Leu Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly 610 615 620Ser Phe Ser Gly Tyr Tyr Trp Thr Trp Ile Arg Gln Arg Pro Gly Lys625 630 635 640Gly Leu Glu Trp Ile Gly Glu Ile Asn His Arg Gly Ser Thr Asp Tyr 645 650 655Asn Pro Ser Leu Lys Ser Arg Val Thr Met Ser Ile Asp Thr Ser Lys 660 665 670Ser Gln Phe Ser Leu Asn Leu Lys Ser Val Thr Ala Ala Asp Thr Ala 675 680 685Val Tyr Tyr Cys Ala Arg Ala Ala Trp Gly Ser Cys Tyr Asp Gly Thr 690 695 700Cys Tyr Pro Ala Glu Tyr Phe Gln Tyr Trp Gly Gln Gly Thr Leu Val705 710 715 720Thr Val Ser Ser1322169DNAArtificial SequenceDescription of the artificial sequence base sequence of the antibody sequence of pCI-AVM-hLG4PE (R409K) _MOG 01 scFv 8 excluding signal sequence 132gaggtgcagc tggtggaatc tgggggaggc ttagtgcagc ctggaagatc cctgaaactc 60tcctgtgcag cctcaggatt cactttcagt aactatgcca tggcttgggt ccgccgggct 120ccaacgaagg gtctggagtg ggtcgcatcc attagtaatg gtggtggtaa cacttactat 180cgcgactccg tgaagggccg attcactatc tccagagatg atgcaaaaaa caccctatac 240ctgcaaatgg acagtctgag gtctgaggac acggccactt attactgtgc aagacacggg 300aattatatat attatgggtc cttctttgat tactggggcc aaggagtcat ggtcacagtc 360tcctcagcta gcaccaaggg gccatccgtc ttccccctgg cgccctgctc caggagcacc 420tccgagagca cagccgccct gggctgcctg gtcaaggact acttccccga accggtgacg 480gtgtcgtgga actcaggcgc cctgaccagc ggcgtgcaca ccttcccggc tgtcctacag 540tcctcaggac tctactccct cagcagcgtg gtgaccgtgc cctccagcag cttgggcacg 600aagacctaca cctgcaacgt agatcacaag cccagcaaca ccaaggtgga caagagagtt 660gagtccaaat atggtccccc atgcccacca tgcccagcac ctgagttcga ggggggacca 720tcagtcttcc tgttcccccc aaaacccaag gacactctca tgatctcccg gacccctgag 780gtcacgtgcg tggtggtgga cgtgagccag gaagaccccg aggtccagtt caactggtac 840gtggatggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gttcaacagc 900acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa cggcaaggag 960tacaagtgca aggtctccaa caaaggcctc ccgtcctcca tcgagaaaac catctccaaa 1020gccaaagggc agccccgaga gccacaggtg tacaccctgc ccccatccca ggaggagatg 1080accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctaccccag cgacatcgcc 1140gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200gactccgacg gctccttctt cctctacagc aagctaaccg tggacaagag caggtggcag 1260gaggggaatg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacacag 1320aagagcctct ccctgtctct gggtggagga agcggaggag gagggtccgg aggaggaggg 1380tccggaggag gagggtccca gtctgccctg actcagcctg cctccgtgtc tgggtctcct 1440ggacagtcga tcaccatctc ctgcactgga accagccgtg acgttggtgg ttataactat 1500gtctcctggt accaacaaca cccaggcaaa gcccccaaac tcatgattta tgatgtcaat 1560aatcggccct caggggtttc taatcggttc tctggctcca agtctggcaa cacggcctcc 1620ctgaccatct ctgggctcca ggctgaggac gaggctgatt atttctgcag ctcatataca 1680agcagtagca cccctgtggt attcggcggt gggaccaagc tgaccgtcct aggtggaggc 1740ggtggcagcg gtgggcgcgc ctcgggcgga ggtggttcac aggtacagct gcagcagtca 1800ggcgcaggat tattgaagcc ttcggagacc ctttccctca cctgcgctgt gtctggtggg 1860tccttcagtg gttactactg gacctggatc cgccagcgcc cagggaaggg gctggagtgg 1920attggagaaa tcaatcatcg tggaagcacc gattacaacc cgtccctcaa gagtcgagtc 1980accatgtcaa tagacacgtc caagagccag ttctccctga atttgaaatc tgtgaccgcc 2040gcggacacgg ctgtgtatta ctgtgcgaga gccgcctggg ggtcttgtta tgatgggacc 2100tgctaccccg ctgaatactt ccaatactgg ggccagggaa ccctggtcac cgtctcctca 2160gctagcacc 2169133723PRTArtificial SequenceDescription of the artificial sequence amino acid sequence of the antibody sequence of pCI-AVM-hLG4PE (R409K) _MOG 01 scFv 8 excluding signal sequence 133Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Ala Met Ala Trp Val Arg Arg Ala Pro Thr Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Ser Asn Gly Gly Gly Asn Thr Tyr Tyr Arg Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asp Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Arg His Gly Asn Tyr Ile Tyr Tyr Gly Ser Phe Phe Asp Tyr Trp 100 105 110Gly Gln Gly Val Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr145 150 155 160Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro225 230 235 240Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 260 265 270Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val 290 295 300Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu305 310 315 320Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 450 455 460Gly Ser Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro465 470 475 480Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Arg Asp Val Gly 485 490 495Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro 500 505 510Lys Leu Met Ile Tyr Asp Val Asn Asn Arg Pro Ser Gly Val Ser Asn 515 520 525Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser 530 535 540Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Phe Cys Ser Ser Tyr Thr545 550 555 560Ser Ser Ser Thr Pro Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val 565 570 575Leu Gly Gly Gly Gly Gly Ser Gly Gly Arg Ala Ser Gly Gly Gly Gly 580 585 590Ser Gln Val Gln Leu Gln Gln Ser Gly Ala Gly Leu Leu Lys Pro Ser 595 600 605Glu Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Phe Ser Gly 610 615 620Tyr Tyr Trp Thr Trp Ile Arg Gln Arg Pro Gly Lys Gly Leu Glu Trp625 630 635 640Ile Gly Glu Ile Asn His Arg Gly Ser Thr Asp Tyr Asn Pro Ser Leu 645 650 655Lys Ser Arg Val Thr Met Ser Ile Asp Thr Ser Lys Ser Gln Phe Ser 660 665 670Leu Asn Leu Lys Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 675 680 685Ala Arg Ala Ala Trp Gly Ser Cys Tyr Asp Gly Thr Cys Tyr Pro Ala 690 695 700Glu Tyr Phe Gln Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser705 710 715 720Ala Ser Thr1342163DNAArtificial SequenceDescription of the artificial sequence base sequence of antibody sequence of pCI-AVM-hLG4PE (R409K) _MOG01 scFv9 excluding signal sequence 134gaggtgcagc tggtggaatc tgggggaggc ttagtgcagc ctggaagatc cctgaaactc 60tcctgtgcag cctcaggatt cactttcagt aactatgcca tggcttgggt ccgccgggct 120ccaacgaagg gtctggagtg ggtcgcatcc attagtaatg gtggtggtaa cacttactat 180cgcgactccg tgaagggccg attcactatc tccagagatg atgcaaaaaa caccctatac 240ctgcaaatgg acagtctgag gtctgaggac acggccactt attactgtgc aagacacggg 300aattatatat attatgggtc cttctttgat tactggggcc aaggagtcat

ggtcacagtc 360tcctcagcta gcaccaaggg gccatccgtc ttccccctgg cgccctgctc caggagcacc 420tccgagagca cagccgccct gggctgcctg gtcaaggact acttccccga accggtgacg 480gtgtcgtgga actcaggcgc cctgaccagc ggcgtgcaca ccttcccggc tgtcctacag 540tcctcaggac tctactccct cagcagcgtg gtgaccgtgc cctccagcag cttgggcacg 600aagacctaca cctgcaacgt agatcacaag cccagcaaca ccaaggtgga caagagagtt 660gagtccaaat atggtccccc atgcccacca tgcccagcac ctgagttcga ggggggacca 720tcagtcttcc tgttcccccc aaaacccaag gacactctca tgatctcccg gacccctgag 780gtcacgtgcg tggtggtgga cgtgagccag gaagaccccg aggtccagtt caactggtac 840gtggatggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gttcaacagc 900acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa cggcaaggag 960tacaagtgca aggtctccaa caaaggcctc ccgtcctcca tcgagaaaac catctccaaa 1020gccaaagggc agccccgaga gccacaggtg tacaccctgc ccccatccca ggaggagatg 1080accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctaccccag cgacatcgcc 1140gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200gactccgacg gctccttctt cctctacagc aagctaaccg tggacaagag caggtggcag 1260gaggggaatg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacacag 1320aagagcctct ccctgtctct gggtggagga ggagggtccg gaggaggagg gtccggtgga 1380ggtgggtccc agtctgccct gactcagcct gcctccgtgt ctgggtctcc tggacagtcg 1440atcaccatct cctgcactgg aaccagccgt gacgttggtg gttataacta tgtctcctgg 1500taccaacaac acccaggcaa agcccccaaa ctcatgattt atgatgtcaa taatcggccc 1560tcaggggttt ctaatcggtt ctctggctcc aagtctggca acacggcctc cctgaccatc 1620tctgggctcc aggctgagga cgaggctgat tatttctgca gctcatatac aagcagtagc 1680acccctgtgg tattcggcgg tgggaccaag ctgaccgtcc taggaggcgg tggcagcgga 1740ggaggagggt ccggtggggg cggctcgggc ggaggtggtt cacaggtaca gctgcagcag 1800tcaggcgcag gattattgaa gccttcggag accctttccc tcacctgcgc tgtgtctggt 1860gggtccttca gtggttacta ctggacctgg atccgccagc gcccagggaa ggggctggag 1920tggattggag aaatcaatca tcgtggaagc accgattaca acccgtccct caagagtcga 1980gtcaccatgt caatagacac gtccaagagc cagttctccc tgaatttgaa atctgtgacc 2040gccgcggaca cggctgtgta ttactgtgcg agagccgcct gggggtcttg ttatgatggg 2100acctgctacc ccgctgaata cttccaatac tggggccagg gaaccctggt caccgtctcc 2160tca 2163135721PRTArtificial SequenceDescription of the artificial sequence amino acid sequence of the antibody sequence of pCI-AVM-hLG4PE (R409K) _MOG01 scFv9 excluding signal sequence 135Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Ala Met Ala Trp Val Arg Arg Ala Pro Thr Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Ser Asn Gly Gly Gly Asn Thr Tyr Tyr Arg Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asp Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Arg His Gly Asn Tyr Ile Tyr Tyr Gly Ser Phe Phe Asp Tyr Trp 100 105 110Gly Gln Gly Val Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr145 150 155 160Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro225 230 235 240Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 260 265 270Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val 290 295 300Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu305 310 315 320Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln 450 455 460Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln Ser465 470 475 480Ile Thr Ile Ser Cys Thr Gly Thr Ser Arg Asp Val Gly Gly Tyr Asn 485 490 495Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Met 500 505 510Ile Tyr Asp Val Asn Asn Arg Pro Ser Gly Val Ser Asn Arg Phe Ser 515 520 525Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln 530 535 540Ala Glu Asp Glu Ala Asp Tyr Phe Cys Ser Ser Tyr Thr Ser Ser Ser545 550 555 560Thr Pro Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly 565 570 575Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 580 585 590Gly Ser Gln Val Gln Leu Gln Gln Ser Gly Ala Gly Leu Leu Lys Pro 595 600 605Ser Glu Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Phe Ser 610 615 620Gly Tyr Tyr Trp Thr Trp Ile Arg Gln Arg Pro Gly Lys Gly Leu Glu625 630 635 640Trp Ile Gly Glu Ile Asn His Arg Gly Ser Thr Asp Tyr Asn Pro Ser 645 650 655Leu Lys Ser Arg Val Thr Met Ser Ile Asp Thr Ser Lys Ser Gln Phe 660 665 670Ser Leu Asn Leu Lys Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 675 680 685Cys Ala Arg Ala Ala Trp Gly Ser Cys Tyr Asp Gly Thr Cys Tyr Pro 690 695 700Ala Glu Tyr Phe Gln Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser705 710 715 720Ser1362160DNAArtificial SequenceDescription of the artificial sequence base sequence of antibody sequence of pCI-AVM-hLG4PE (R409K) _MOG 01 scFv 10 excluding signal sequence 136gaggtgcagc tggtggaatc tgggggaggc ttagtgcagc ctggaagatc cctgaaactc 60tcctgtgcag cctcaggatt cactttcagt aactatgcca tggcttgggt ccgccgggct 120ccaacgaagg gtctggagtg ggtcgcatcc attagtaatg gtggtggtaa cacttactat 180cgcgactccg tgaagggccg attcactatc tccagagatg atgcaaaaaa caccctatac 240ctgcaaatgg acagtctgag gtctgaggac acggccactt attactgtgc aagacacggg 300aattatatat attatgggtc cttctttgat tactggggcc aaggagtcat ggtcacagtc 360tcctcagcta gcaccaaggg gccatccgtc ttccccctgg cgccctgctc caggagcacc 420tccgagagca cagccgccct gggctgcctg gtcaaggact acttccccga accggtgacg 480gtgtcgtgga actcaggcgc cctgaccagc ggcgtgcaca ccttcccggc tgtcctacag 540tcctcaggac tctactccct cagcagcgtg gtgaccgtgc cctccagcag cttgggcacg 600aagacctaca cctgcaacgt agatcacaag cccagcaaca ccaaggtgga caagagagtt 660gagtccaaat atggtccccc atgcccacca tgcccagcac ctgagttcga ggggggacca 720tcagtcttcc tgttcccccc aaaacccaag gacactctca tgatctcccg gacccctgag 780gtcacgtgcg tggtggtgga cgtgagccag gaagaccccg aggtccagtt caactggtac 840gtggatggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gttcaacagc 900acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa cggcaaggag 960tacaagtgca aggtctccaa caaaggcctc ccgtcctcca tcgagaaaac catctccaaa 1020gccaaagggc agccccgaga gccacaggtg tacaccctgc ccccatccca ggaggagatg 1080accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctaccccag cgacatcgcc 1140gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200gactccgacg gctccttctt cctctacagc aagctaaccg tggacaagag caggtggcag 1260gaggggaatg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacacag 1320aagagcctct ccctgtctct gggtggagga ggagggtccg gaggaggagg gtccggtgga 1380ggtgggtccc agtctgccct gactcagcct gcctccgtgt ctgggtctcc tggacagtcg 1440atcaccatct cctgcactgg aaccagccgt gacgttggtg gttataacta tgtctcctgg 1500taccaacaac acccaggcaa agcccccaaa ctcatgattt atgatgtcaa taatcggccc 1560tcaggggttt ctaatcggtt ctctggctcc aagtctggca acacggcctc cctgaccatc 1620tctgggctcc aggctgagga cgaggctgat tatttctgca gctcatatac aagcagtagc 1680acccctgtgg tattcggcgg tgggaccaag ctgaccgtcc taggtggagg cggtggcagc 1740ggtgggcgcg cctcgggcgg aggtggttca caggtacagc tgcagcagtc aggcgcagga 1800ttattgaagc cttcggagac cctttccctc acctgcgctg tgtctggtgg gtccttcagt 1860ggttactact ggacctggat ccgccagcgc ccagggaagg ggctggagtg gattggagaa 1920atcaatcatc gtggaagcac cgattacaac ccgtccctca agagtcgagt caccatgtca 1980atagacacgt ccaagagcca gttctccctg aatttgaaat ctgtgaccgc cgcggacacg 2040gctgtgtatt actgtgcgag agccgcctgg gggtcttgtt atgatgggac ctgctacccc 2100gctgaatact tccaatactg gggccaggga accctggtca ccgtctcctc agctagcacc 2160137720PRTArtificial SequenceDescription of the artificial sequence amino acid sequence of the antibody sequence of pCI-AVM-hLG4PE (R409K) _MOG 01 scFv 10 excluding signal sequence 137Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Ala Met Ala Trp Val Arg Arg Ala Pro Thr Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Ser Asn Gly Gly Gly Asn Thr Tyr Tyr Arg Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asp Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Arg His Gly Asn Tyr Ile Tyr Tyr Gly Ser Phe Phe Asp Tyr Trp 100 105 110Gly Gln Gly Val Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr145 150 155 160Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro225 230 235 240Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 260 265 270Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val 290 295 300Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu305 310 315 320Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln 450 455 460Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln Ser465 470 475 480Ile Thr Ile Ser Cys Thr Gly Thr Ser Arg Asp Val Gly Gly Tyr Asn 485 490 495Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Met 500 505 510Ile Tyr Asp Val Asn Asn Arg Pro Ser Gly Val Ser Asn Arg Phe Ser 515 520 525Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln 530 535 540Ala Glu Asp Glu Ala Asp Tyr Phe Cys Ser Ser Tyr Thr Ser Ser Ser545 550 555 560Thr Pro Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly 565 570 575Gly Gly Gly Ser Gly Gly Arg Ala Ser Gly Gly Gly Gly Ser Gln Val 580 585 590Gln Leu Gln Gln Ser Gly Ala Gly Leu Leu Lys Pro Ser Glu Thr Leu 595 600 605Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Phe Ser Gly Tyr Tyr Trp 610 615 620Thr Trp Ile Arg Gln Arg Pro Gly Lys Gly Leu Glu Trp Ile Gly Glu625 630 635 640Ile Asn His Arg Gly Ser Thr Asp Tyr Asn Pro Ser Leu Lys Ser Arg 645 650 655Val Thr Met Ser Ile Asp Thr Ser Lys Ser Gln Phe Ser Leu Asn Leu 660 665 670Lys Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ala 675 680 685Ala Trp Gly Ser Cys Tyr Asp Gly Thr Cys Tyr Pro Ala Glu Tyr Phe 690 695 700Gln Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr705 710 715 7201382184DNAArtificial SequenceDescription of the artificial sequence base sequence of the antibody sequence of pCI-AVM-hLG4PE (R409K) _MOG01 scFv11 excluding signal sequence 138gaggtgcagc tggtggaatc tgggggaggc ttagtgcagc ctggaagatc cctgaaactc 60tcctgtgcag cctcaggatt cactttcagt aactatgcca tggcttgggt ccgccgggct 120ccaacgaagg gtctggagtg ggtcgcatcc attagtaatg gtggtggtaa cacttactat 180cgcgactccg tgaagggccg attcactatc tccagagatg atgcaaaaaa caccctatac 240ctgcaaatgg acagtctgag gtctgaggac acggccactt attactgtgc aagacacggg 300aattatatat attatgggtc cttctttgat tactggggcc aaggagtcat ggtcacagtc 360tcctcagcta gcaccaaggg gccatccgtc ttccccctgg cgccctgctc caggagcacc 420tccgagagca cagccgccct gggctgcctg gtcaaggact acttccccga accggtgacg 480gtgtcgtgga actcaggcgc cctgaccagc ggcgtgcaca ccttcccggc tgtcctacag 540tcctcaggac tctactccct cagcagcgtg gtgaccgtgc cctccagcag cttgggcacg 600aagacctaca cctgcaacgt agatcacaag cccagcaaca ccaaggtgga caagagagtt 660gagtccaaat atggtccccc atgcccacca tgcccagcac ctgagttcga ggggggacca 720tcagtcttcc tgttcccccc aaaacccaag gacactctca tgatctcccg gacccctgag 780gtcacgtgcg tggtggtgga cgtgagccag gaagaccccg aggtccagtt caactggtac 840gtggatggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gttcaacagc 900acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa cggcaaggag 960tacaagtgca aggtctccaa caaaggcctc ccgtcctcca tcgagaaaac catctccaaa 1020gccaaagggc agccccgaga gccacaggtg tacaccctgc ccccatccca ggaggagatg 1080accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctaccccag cgacatcgcc 1140gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200gactccgacg gctccttctt cctctacagc aagctaaccg tggacaagag caggtggcag 1260gaggggaatg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacacag 1320aagagcctct ccctgtctct gggtggagga agcggaggag gagggtccgg aggaggaggg 1380tccggaggag gagggtccca gtctgccctg actcagcctg cctccgtgtc tgggtctcct 1440ggacagtcga tcaccatctc ctgcactgga accagccgtg acgttggtgg ttataactat 1500gtctcctggt accaacaaca cccaggcaaa gcccccaaac tcatgattta tgatgtcaat 1560aatcggccct caggggtttc

taatcggttc tctggctcca agtctggcaa cacggcctcc 1620ctgaccatct ctgggctcca ggctgaggac gaggctgatt atttctgcag ctcatataca 1680agcagtagca cccctgtggt attcggcggt gggaccaagc tgaccgtcct aggtggaggc 1740ggtggcagcg gaggaggagg gtccggtggg ggcggctcgg gcggaggtgg ttcacaggta 1800cagctgcagc agtcaggcgc aggattattg aagccttcgg agaccctttc cctcacctgc 1860gctgtgtctg gtgggtcctt cagtggttac tactggacct ggatccgcca gcgcccaggg 1920aaggggctgg agtggattgg agaaatcaat catcgtggaa gcaccgatta caacccgtcc 1980ctcaagagtc gagtcaccat gtcaatagac acgtccaaga gccagttctc cctgaatttg 2040aaatctgtga ccgccgcgga cacggctgtg tattactgtg cgagagccgc ctgggggtct 2100tgttatgatg ggacctgcta ccccgctgaa tacttccaat actggggcca gggaaccctg 2160gtcaccgtct cctcagctag cacc 2184139728PRTArtificial SequenceDescription of the artificial sequence amino acid sequence of the antibody sequence of pCI-AVM-hLG4PE (R409K) _MOG 01 scFv 11 excluding signal sequence 139Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Ala Met Ala Trp Val Arg Arg Ala Pro Thr Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Ser Asn Gly Gly Gly Asn Thr Tyr Tyr Arg Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asp Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Arg His Gly Asn Tyr Ile Tyr Tyr Gly Ser Phe Phe Asp Tyr Trp 100 105 110Gly Gln Gly Val Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr145 150 155 160Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro225 230 235 240Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 260 265 270Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val 290 295 300Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu305 310 315 320Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 450 455 460Gly Ser Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro465 470 475 480Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Arg Asp Val Gly 485 490 495Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro 500 505 510Lys Leu Met Ile Tyr Asp Val Asn Asn Arg Pro Ser Gly Val Ser Asn 515 520 525Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser 530 535 540Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Phe Cys Ser Ser Tyr Thr545 550 555 560Ser Ser Ser Thr Pro Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val 565 570 575Leu Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 580 585 590Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Gln Ser Gly Ala Gly 595 600 605Leu Leu Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Ala Val Ser Gly 610 615 620Gly Ser Phe Ser Gly Tyr Tyr Trp Thr Trp Ile Arg Gln Arg Pro Gly625 630 635 640Lys Gly Leu Glu Trp Ile Gly Glu Ile Asn His Arg Gly Ser Thr Asp 645 650 655Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Met Ser Ile Asp Thr Ser 660 665 670Lys Ser Gln Phe Ser Leu Asn Leu Lys Ser Val Thr Ala Ala Asp Thr 675 680 685Ala Val Tyr Tyr Cys Ala Arg Ala Ala Trp Gly Ser Cys Tyr Asp Gly 690 695 700Thr Cys Tyr Pro Ala Glu Tyr Phe Gln Tyr Trp Gly Gln Gly Thr Leu705 710 715 720Val Thr Val Ser Ser Ala Ser Thr 7251402040DNAArtificial SequenceDescription of the artificial sequence base sequence of the antibody sequence of pCI-AVM-hLG4PE (R409K) -linker-AVMVL-CL excluding signal sequence 140gaggtgcagc tggtggaatc tgggggaggc ttagtgcagc ctggaagatc cctgaaactc 60tcctgtgcag cctcaggatt cactttcagt aactatgcca tggcttgggt ccgccgggct 120ccaacgaagg gtctggagtg ggtcgcatcc attagtaatg gtggtggtaa cacttactat 180cgcgactccg tgaagggccg attcactatc tccagagatg atgcaaaaaa caccctatac 240ctgcaaatgg acagtctgag gtctgaggac acggccactt attactgtgc aagacacggg 300aattatatat attatgggtc cttctttgat tactggggcc aaggagtcat ggtcacagtc 360tcctcagcta gcaccaaggg gccatccgtc ttccccctgg cgccctgctc caggagcacc 420tccgagagca cagccgccct gggctgcctg gtcaaggact acttccccga accggtgacg 480gtgtcgtgga actcaggcgc cctgaccagc ggcgtgcaca ccttcccggc tgtcctacag 540tcctcaggac tctactccct cagcagcgtg gtgaccgtgc cctccagcag cttgggcacg 600aagacctaca cctgcaacgt agatcacaag cccagcaaca ccaaggtgga caagagagtt 660gagtccaaat atggtccccc atgcccacca tgcccagcac ctgagttcga ggggggacca 720tcagtcttcc tgttcccccc aaaacccaag gacactctca tgatctcccg gacccctgag 780gtcacgtgcg tggtggtgga cgtgagccag gaagaccccg aggtccagtt caactggtac 840gtggatggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gttcaacagc 900acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa cggcaaggag 960tacaagtgca aggtctccaa caaaggcctc ccgtcctcca tcgagaaaac catctccaaa 1020gccaaagggc agccccgaga gccacaggtg tacaccctgc ccccatccca ggaggagatg 1080accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctaccccag cgacatcgcc 1140gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200gactccgacg gctccttctt cctctacagc aagctaaccg tggacaagag caggtggcag 1260gaggggaatg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacacag 1320aagagcctct ccctgtctct gggtaaagga ggaggagggt ccggaggagg agggtccgga 1380ggaggagggt cccagtttgt gctttctcag ccaaactctg tgtctacgaa tctcggaagc 1440acagtcaaac tgtcttgcaa gcgcagcact ggtaacattg gaagcaatta tgtgagctgg 1500taccagcagc atgagggaag atctcccacc actatgattt atagggatga taagagacca 1560gatggagttc ctgacaggtt ctctggctcc attgacagat cttccgactc agccctcctg 1620acaatcaata atgtgcagac tgaagatgaa gctgactact tctgtcagtc ttacagtagt 1680ggtattaata ttttcggcgg tggaaccaag ctcactgtcc taggtcagcc caaggccgcc 1740ccctcggtca ctctgttccc gccctcctct gaggagcttc aagccaacaa ggccacactg 1800gtgtgtctca taagtgactt ctacccggga gccgtgacag tggcctggaa ggcagatagc 1860agccccgtca aggcgggagt ggagaccacc acaccctcca aacaaagcaa caacaagtac 1920gcggccagca gctacctgag cctgacgcct gagcagtgga agtcccacag aagctacagc 1980tgccaggtca cgcatgaagg gagcaccgtg gagaagacag tggcccctac agaatgttca 2040141680PRTArtificial SequenceDescription of the artificial sequence amino acid sequence of the antibody sequence of pCI-AVM-hLG4PE (R409K) -linker-AVMVL-CL excluding signal sequence 141Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Ala Met Ala Trp Val Arg Arg Ala Pro Thr Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Ser Asn Gly Gly Gly Asn Thr Tyr Tyr Arg Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asp Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Arg His Gly Asn Tyr Ile Tyr Tyr Gly Ser Phe Phe Asp Tyr Trp 100 105 110Gly Gln Gly Val Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr145 150 155 160Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro225 230 235 240Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 260 265 270Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val 290 295 300Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu305 310 315 320Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 450 455 460Gln Phe Val Leu Ser Gln Pro Asn Ser Val Ser Thr Asn Leu Gly Ser465 470 475 480Thr Val Lys Leu Ser Cys Lys Arg Ser Thr Gly Asn Ile Gly Ser Asn 485 490 495Tyr Val Ser Trp Tyr Gln Gln His Glu Gly Arg Ser Pro Thr Thr Met 500 505 510Ile Tyr Arg Asp Asp Lys Arg Pro Asp Gly Val Pro Asp Arg Phe Ser 515 520 525Gly Ser Ile Asp Arg Ser Ser Asp Ser Ala Leu Leu Thr Ile Asn Asn 530 535 540Val Gln Thr Glu Asp Glu Ala Asp Tyr Phe Cys Gln Ser Tyr Ser Ser545 550 555 560Gly Ile Asn Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln 565 570 575Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu 580 585 590Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr 595 600 605Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys 610 615 620Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr625 630 635 640Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His 645 650 655Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys 660 665 670Thr Val Ala Pro Thr Glu Cys Ser 675 680142660DNAArtificial SequenceDescription of the artificial sequence base sequence of antibody sequence of pCI-AVMVH-CH excluding signal sequence 142gaggtgcagc tggtggaatc tgggggaggc ttagtgcagc ctggaagatc cctgaaactc 60tcctgtgcag cctcaggatt cactttcagt aactatgcca tggcttgggt ccgccgggct 120ccaacgaagg gtctggagtg ggtcgcatcc attagtaatg gtggtggtaa cacttactat 180cgcgactccg tgaagggccg attcactatc tccagagatg atgcaaaaaa caccctatac 240ctgcaaatgg acagtctgag gtctgaggac acggccactt attactgtgc aagacacggg 300aattatatat attatgggtc cttctttgat tactggggcc aaggagtcat ggtcacagtc 360tcctcagcta gcaccaaggg gccatccgtc ttccccctgg cgccctgctc caggagcacc 420tccgagagca cagccgccct gggctgcctg gtcaaggact acttccccga accggtgacg 480gtgtcgtgga actcaggcgc cctgaccagc ggcgtgcaca ccttcccggc tgtcctacag 540tcctcaggac tctactccct cagcagcgtg gtgaccgtgc cctccagcag cttgggcacg 600aagacctaca cctgcaacgt agatcacaag cccagcaaca ccaaggtgga caagagagtt 660143220PRTArtificial SequenceDescription of the artificial sequence amino acid sequence of antibody sequence of pCI-AVMVH-CH excluding signal sequence 143Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Ala Met Ala Trp Val Arg Arg Ala Pro Thr Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Ser Asn Gly Gly Gly Asn Thr Tyr Tyr Arg Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asp Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Arg His Gly Asn Tyr Ile Tyr Tyr Gly Ser Phe Phe Asp Tyr Trp 100 105 110Gly Gln Gly Val Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr145 150 155 160Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val 210 215 2201442163DNAArtificial SequenceDescription of the artificial sequence base sequence of the antibody sequence of pCI-AVM-hLG4PE (R409K / S354C / T366W) -linker-AVMscFv-FLAG tag excluding signal sequence 144gaggtgcagc tggtggaatc tgggggaggc ttagtgcagc ctggaagatc cctgaaactc 60tcctgtgcag cctcaggatt cactttcagt aactatgcca tggcttgggt ccgccgggct 120ccaacgaagg gtctggagtg ggtcgcatcc attagtaatg gtggtggtaa cacttactat 180cgcgactccg tgaagggccg attcactatc tccagagatg atgcaaaaaa caccctatac 240ctgcaaatgg acagtctgag gtctgaggac acggccactt attactgtgc aagacacggg 300aattatatat attatgggtc cttctttgat tactggggcc aaggagtcat ggtcacagtc 360tcctcagcta gcaccaaggg gccatccgtc ttccccctgg cgccctgctc caggagcacc 420tccgagagca cagccgccct gggctgcctg gtcaaggact acttccccga accggtgacg 480gtgtcgtgga actcaggcgc cctgaccagc ggcgtgcaca ccttcccggc tgtcctacag 540tcctcaggac tctactccct cagcagcgtg gtgaccgtgc cctccagcag cttgggcacg 600aagacctaca cctgcaacgt agatcacaag cccagcaaca ccaaggtgga caagagagtt 660gagtccaaat atggtccccc atgcccacca tgcccagcac ctgagttcga ggggggacca 720tcagtcttcc tgttcccccc aaaacccaag gacactctca tgatctcccg gacccctgag 780gtcacgtgcg tggtggtgga cgtgagccag gaagaccccg aggtccagtt caactggtac 840gtggatggcg tggaggtgca taatgccaag acaaagccgc

gggaggagca gttcaacagc 900acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa cggcaaggag 960tacaagtgca aggtctccaa caaaggcctc ccgtcctcca tcgagaaaac catctccaaa 1020gccaaagggc agccccgaga gccacaggtg tacaccctgc ccccatgcca ggaggagatg 1080accaagaacc aggtcagcct gtggtgcctg gtcaaaggct tctaccccag cgacatcgcc 1140gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200gactccgacg gctccttctt cctctacagc aagctaaccg tggacaagag caggtggcag 1260gaggggaatg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacacag 1320aagagcctct ccctgtctct gggtggagga agcggaggag gagggtccgg aggaggaggg 1380tccggaggag gagggtccga ggtgcagctg gtggaatctg ggggaggctt agtgcagcct 1440ggaagatccc tgaaactctc ctgtgcagcc tcaggattca ctttcagtaa ctatgccatg 1500gcttgggtcc gccgggctcc aacgaagggt ctggagtggg tcgcatccat tagtaatggt 1560ggtggtaaca cttactatcg cgactccgtg aagggccgat tcactatctc cagagatgat 1620gcaaaaaaca ccctatacct gcaaatggac agtctgaggt ctgaggacac ggccacttat 1680tactgtgcaa gacacgggaa ttatatatat tatgggtcct tctttgatta ctggggccaa 1740ggagtcatgg tcacagtctc ctcaggaggc ggtggcagcg gtgggcgcgc ctcgggcgga 1800ggtggttcac agtttgtgct ttctcagcca aactctgtgt ctacgaatct cggaagcaca 1860gtcaaactgt cttgcaagcg cagcactggt aacattggaa gcaattatgt gagctggtac 1920cagcagcatg agggaagatc tcccaccact atgatttata gggatgataa gagaccagat 1980ggagttcctg acaggttctc tggctccatt gacagatctt ccgactcagc cctcctgaca 2040atcaataatg tgcagactga agatgaagct gactacttct gtcagtctta cagtagtggt 2100attaatattt tcggcggtgg aaccaagctc actgtcctag actacaagga cgacgatgac 2160aag 2163145721PRTArtificial SequenceDescription of the artificial sequence amino acid sequence of the antibody sequence of pCI-AVM-hLG4PE (R409K / S354C / T366W) -linker-AVMscFv-FLAG tag excluding signal sequence 145Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Ala Met Ala Trp Val Arg Arg Ala Pro Thr Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Ser Asn Gly Gly Gly Asn Thr Tyr Tyr Arg Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asp Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Arg His Gly Asn Tyr Ile Tyr Tyr Gly Ser Phe Phe Asp Tyr Trp 100 105 110Gly Gln Gly Val Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr145 150 155 160Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro225 230 235 240Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 260 265 270Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val 290 295 300Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu305 310 315 320Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350Leu Pro Pro Cys Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp 355 360 365Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 450 455 460Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro465 470 475 480Gly Arg Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser 485 490 495Asn Tyr Ala Met Ala Trp Val Arg Arg Ala Pro Thr Lys Gly Leu Glu 500 505 510Trp Val Ala Ser Ile Ser Asn Gly Gly Gly Asn Thr Tyr Tyr Arg Asp 515 520 525Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Thr 530 535 540Leu Tyr Leu Gln Met Asp Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr545 550 555 560Tyr Cys Ala Arg His Gly Asn Tyr Ile Tyr Tyr Gly Ser Phe Phe Asp 565 570 575Tyr Trp Gly Gln Gly Val Met Val Thr Val Ser Ser Gly Gly Gly Gly 580 585 590Ser Gly Gly Arg Ala Ser Gly Gly Gly Gly Ser Gln Phe Val Leu Ser 595 600 605Gln Pro Asn Ser Val Ser Thr Asn Leu Gly Ser Thr Val Lys Leu Ser 610 615 620Cys Lys Arg Ser Thr Gly Asn Ile Gly Ser Asn Tyr Val Ser Trp Tyr625 630 635 640Gln Gln His Glu Gly Arg Ser Pro Thr Thr Met Ile Tyr Arg Asp Asp 645 650 655Lys Arg Pro Asp Gly Val Pro Asp Arg Phe Ser Gly Ser Ile Asp Arg 660 665 670Ser Ser Asp Ser Ala Leu Leu Thr Ile Asn Asn Val Gln Thr Glu Asp 675 680 685Glu Ala Asp Tyr Phe Cys Gln Ser Tyr Ser Ser Gly Ile Asn Ile Phe 690 695 700Gly Gly Gly Thr Lys Leu Thr Val Leu Asp Tyr Lys Asp Asp Asp Asp705 710 715 720Lys1462139DNAArtificial SequenceDescription of the artificial sequence base sequence of the antibody sequence of pCI-AVM-hLG4PE (R409K) _AVMscFv3 excluding signal sequence 146gaggtgcagc tggtggaatc tgggggaggc ttagtgcagc ctggaagatc cctgaaactc 60tcctgtgcag cctcaggatt cactttcagt aactatgcca tggcttgggt ccgccgggct 120ccaacgaagg gtctggagtg ggtcgcatcc attagtaatg gtggtggtaa cacttactat 180cgcgactccg tgaagggccg attcactatc tccagagatg atgcaaaaaa caccctatac 240ctgcaaatgg acagtctgag gtctgaggac acggccactt attactgtgc aagacacggg 300aattatatat attatgggtc cttctttgat tactggggcc aaggagtcat ggtcacagtc 360tcctcagcta gcaccaaggg gccatccgtc ttccccctgg cgccctgctc caggagcacc 420tccgagagca cagccgccct gggctgcctg gtcaaggact acttccccga accggtgacg 480gtgtcgtgga actcaggcgc cctgaccagc ggcgtgcaca ccttcccggc tgtcctacag 540tcctcaggac tctactccct cagcagcgtg gtgaccgtgc cctccagcag cttgggcacg 600aagacctaca cctgcaacgt agatcacaag cccagcaaca ccaaggtgga caagagagtt 660gagtccaaat atggtccccc atgcccacca tgcccagcac ctgagttcga ggggggacca 720tcagtcttcc tgttcccccc aaaacccaag gacactctca tgatctcccg gacccctgag 780gtcacgtgcg tggtggtgga cgtgagccag gaagaccccg aggtccagtt caactggtac 840gtggatggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gttcaacagc 900acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa cggcaaggag 960tacaagtgca aggtctccaa caaaggcctc ccgtcctcca tcgagaaaac catctccaaa 1020gccaaagggc agccccgaga gccacaggtg tacaccctgc ccccatccca ggaggagatg 1080accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctaccccag cgacatcgcc 1140gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200gactccgacg gctccttctt cctctacagc aagctaaccg tggacaagag caggtggcag 1260gaggggaatg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacacag 1320aagagcctct ccctgtctct gggtggagga agcggaggag gagggtccgg aggaggaggg 1380tccggaggag gagggtccca gtttgtgctt tctcagccaa actctgtgtc tacgaatctc 1440ggaagcacag tcaaactgtc ttgcaagcgc agcactggta acattggaag caattatgtg 1500agctggtacc agcagcatga gggaagatct cccaccacta tgatttatag ggatgataag 1560agaccagatg gagttcctga caggttctct ggctccattg acagatcttc cgactcagcc 1620ctcctgacaa tcaataatgt gcagactgaa gatgaagctg actacttctg tcagtcttac 1680agtagtggta ttaatatttt cggcggtgga accaagctca ctgtcctagg aggcggtggc 1740agcggtgggc gcgcctcggg cggaggtggt tcagaggtgc agctggtgga atctggggga 1800ggcttagtgc agcctggaag atccctgaaa ctctcctgtg cagcctcagg attcactttc 1860agtaactatg ccatggcttg ggtccgccgg gctccaacga agggtctgga gtgggtcgca 1920tccattagta atggtggtgg taacacttac tatcgcgact ccgtgaaggg ccgattcact 1980atctccagag atgatgcaaa aaacacccta tacctgcaaa tggacagtct gaggtctgag 2040gacacggcca cttattactg tgcaagacac gggaattata tatattatgg gtccttcttt 2100gattactggg gccaaggagt catggtcaca gtctcctca 2139147713PRTArtificial SequenceDescription of the artificial sequence amino acid sequence of the antibody sequence of pCI-AVM-hLG4PE (R409K) _AVMscFv3 excluding signal sequence 147Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Ala Met Ala Trp Val Arg Arg Ala Pro Thr Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Ser Asn Gly Gly Gly Asn Thr Tyr Tyr Arg Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asp Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Arg His Gly Asn Tyr Ile Tyr Tyr Gly Ser Phe Phe Asp Tyr Trp 100 105 110Gly Gln Gly Val Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr145 150 155 160Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro225 230 235 240Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 260 265 270Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val 290 295 300Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu305 310 315 320Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 450 455 460Gly Ser Gln Phe Val Leu Ser Gln Pro Asn Ser Val Ser Thr Asn Leu465 470 475 480Gly Ser Thr Val Lys Leu Ser Cys Lys Arg Ser Thr Gly Asn Ile Gly 485 490 495Ser Asn Tyr Val Ser Trp Tyr Gln Gln His Glu Gly Arg Ser Pro Thr 500 505 510Thr Met Ile Tyr Arg Asp Asp Lys Arg Pro Asp Gly Val Pro Asp Arg 515 520 525Phe Ser Gly Ser Ile Asp Arg Ser Ser Asp Ser Ala Leu Leu Thr Ile 530 535 540Asn Asn Val Gln Thr Glu Asp Glu Ala Asp Tyr Phe Cys Gln Ser Tyr545 550 555 560Ser Ser Gly Ile Asn Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 565 570 575Gly Gly Gly Gly Ser Gly Gly Arg Ala Ser Gly Gly Gly Gly Ser Glu 580 585 590Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg Ser 595 600 605Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr Ala 610 615 620Met Ala Trp Val Arg Arg Ala Pro Thr Lys Gly Leu Glu Trp Val Ala625 630 635 640Ser Ile Ser Asn Gly Gly Gly Asn Thr Tyr Tyr Arg Asp Ser Val Lys 645 650 655Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Thr Leu Tyr Leu 660 665 670Gln Met Asp Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys Ala 675 680 685Arg His Gly Asn Tyr Ile Tyr Tyr Gly Ser Phe Phe Asp Tyr Trp Gly 690 695 700Gln Gly Val Met Val Thr Val Ser Ser705 7101482157DNAArtificial SequenceDescription of the artificial sequence base sequence of the antibody sequence of pCI-AVM-hLG4PE (R409K) _AVMscFv5 excluding signal sequence 148gaggtgcagc tggtggaatc tgggggaggc ttagtgcagc ctggaagatc cctgaaactc 60tcctgtgcag cctcaggatt cactttcagt aactatgcca tggcttgggt ccgccgggct 120ccaacgaagg gtctggagtg ggtcgcatcc attagtaatg gtggtggtaa cacttactat 180cgcgactccg tgaagggccg attcactatc tccagagatg atgcaaaaaa caccctatac 240ctgcaaatgg acagtctgag gtctgaggac acggccactt attactgtgc aagacacggg 300aattatatat attatgggtc cttctttgat tactggggcc aaggagtcat ggtcacagtc 360tcctcagcta gcaccaaggg gccatccgtc ttccccctgg cgccctgctc caggagcacc 420tccgagagca cagccgccct gggctgcctg gtcaaggact acttccccga accggtgacg 480gtgtcgtgga actcaggcgc cctgaccagc ggcgtgcaca ccttcccggc tgtcctacag 540tcctcaggac tctactccct cagcagcgtg gtgaccgtgc cctccagcag cttgggcacg 600aagacctaca cctgcaacgt agatcacaag cccagcaaca ccaaggtgga caagagagtt 660gagtccaaat atggtccccc atgcccacca tgcccagcac ctgagttcga ggggggacca 720tcagtcttcc tgttcccccc aaaacccaag gacactctca tgatctcccg gacccctgag 780gtcacgtgcg tggtggtgga cgtgagccag gaagaccccg aggtccagtt caactggtac 840gtggatggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gttcaacagc 900acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa cggcaaggag 960tacaagtgca aggtctccaa caaaggcctc ccgtcctcca tcgagaaaac catctccaaa 1020gccaaagggc agccccgaga gccacaggtg tacaccctgc ccccatccca ggaggagatg 1080accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctaccccag cgacatcgcc 1140gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200gactccgacg gctccttctt cctctacagc aagctaaccg tggacaagag caggtggcag 1260gaggggaatg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacacag 1320aagagcctct ccctgtctct gggtggagga ggagggtccg gaggaggagg gtccggtgga 1380ggtgggtccc agtttgtgct ttctcagcca aactctgtgt ctacgaatct cggaagcaca 1440gtcaaactgt cttgcaagcg cagcactggt aacattggaa gcaattatgt gagctggtac 1500cagcagcatg agggaagatc tcccaccact atgatttata gggatgataa gagaccagat 1560ggagttcctg acaggttctc tggctccatt gacagatctt ccgactcagc cctcctgaca 1620atcaataatg tgcagactga agatgaagct gactacttct gtcagtctta cagtagtggt 1680attaatattt tcggcggtgg aaccaagctc actgtcctag gtggaggcgg tggcagcgga 1740ggaggagggt ccggtggggg cggctcgggc ggaggtggtt cagaggtgca gctggtggaa 1800tctgggggag gcttagtgca gcctggaaga tccctgaaac tctcctgtgc agcctcagga 1860ttcactttca gtaactatgc catggcttgg gtccgccggg ctccaacgaa gggtctggag 1920tgggtcgcat ccattagtaa tggtggtggt aacacttact atcgcgactc cgtgaagggc 1980cgattcacta tctccagaga tgatgcaaaa aacaccctat acctgcaaat ggacagtctg 2040aggtctgagg acacggccac ttattactgt gcaagacacg ggaattatat atattatggg 2100tccttctttg attactgggg ccaaggagtc atggtcacag tctcctcagc tagcacc 2157149719PRTArtificial

SequenceDescription of the artificial sequence amino acid sequence of the antibody sequence of pCI-AVM-hLG4PE (R409K) _AVMscFv5 excluding signal sequence 149Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Ala Met Ala Trp Val Arg Arg Ala Pro Thr Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Ser Asn Gly Gly Gly Asn Thr Tyr Tyr Arg Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asp Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Arg His Gly Asn Tyr Ile Tyr Tyr Gly Ser Phe Phe Asp Tyr Trp 100 105 110Gly Gln Gly Val Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr145 150 155 160Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro225 230 235 240Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 260 265 270Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val 290 295 300Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu305 310 315 320Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln 450 455 460Phe Val Leu Ser Gln Pro Asn Ser Val Ser Thr Asn Leu Gly Ser Thr465 470 475 480Val Lys Leu Ser Cys Lys Arg Ser Thr Gly Asn Ile Gly Ser Asn Tyr 485 490 495Val Ser Trp Tyr Gln Gln His Glu Gly Arg Ser Pro Thr Thr Met Ile 500 505 510Tyr Arg Asp Asp Lys Arg Pro Asp Gly Val Pro Asp Arg Phe Ser Gly 515 520 525Ser Ile Asp Arg Ser Ser Asp Ser Ala Leu Leu Thr Ile Asn Asn Val 530 535 540Gln Thr Glu Asp Glu Ala Asp Tyr Phe Cys Gln Ser Tyr Ser Ser Gly545 550 555 560Ile Asn Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Gly 565 570 575Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 580 585 590Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro 595 600 605Gly Arg Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser 610 615 620Asn Tyr Ala Met Ala Trp Val Arg Arg Ala Pro Thr Lys Gly Leu Glu625 630 635 640Trp Val Ala Ser Ile Ser Asn Gly Gly Gly Asn Thr Tyr Tyr Arg Asp 645 650 655Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Thr 660 665 670Leu Tyr Leu Gln Met Asp Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr 675 680 685Tyr Cys Ala Arg His Gly Asn Tyr Ile Tyr Tyr Gly Ser Phe Phe Asp 690 695 700Tyr Trp Gly Gln Gly Val Met Val Thr Val Ser Ser Ala Ser Thr705 710 7151501887DNAArtificial SequenceDescription of the artificial sequence base sequence of Acid Sphingomyelinase (ASM) 150atgccccgct acggagcgtc actccgccag agctgcccca ggtccggccg ggagcaggga 60caagacggga ccgccggagc ccccggactc ctttggatgg gcctggtgct ggcgctggcg 120ctggcgctgg cgctggctct gtctgactct cgggttctct gggctccggc agaggctcac 180cctctttctc cccaaggcca tcctgccagg ttacatcgca tagtgccccg gctccgagat 240gtctttgggt gggggaacct cacctgccca atctgcaaag gtctattcac cgccatcaac 300ctcgggctga agaaggaacc caatgtggct cgcgtgggct ccgtggccat caagctgtgc 360aatctgctga agatagcacc acctgccgtg tgccaatcca ttgtccacct ctttgaggat 420gacatggtgg aggtgtggag acgctcagtg ctgagcccat ctgaggcctg tggcctgctc 480ctgggctcca cctgtgggca ctgggacatt ttctcatctt ggaacatctc tttgcctact 540gtgccgaagc cgccccccaa accccctagc cccccagccc caggtgcccc tgtcagccgc 600atcctcttcc tcactgacct gcactgggat catgactacc tggagggcac ggaccctgac 660tgtgcagacc cactgtgctg ccgccggggt tctggcctgc cgcccgcatc ccggccaggt 720gccggatact ggggcgaata cagcaagtgt gacctgcccc tgaggaccct ggagagcctg 780ttgagtgggc tgggcccagc cggccctttt gatatggtgt actggacagg agacatcccc 840gcacatgatg tctggcacca gactcgtcag gaccaactgc gggccctgac caccgtcaca 900gcacttgtga ggaagttcct ggggccagtg ccagtgtacc ctgctgtggg taaccatgaa 960agcatacctg tcaatagctt ccctcccccc ttcattgagg gcaaccactc ctcccgctgg 1020ctctatgaag cgatggccaa ggcttgggag ccctggctgc ctgccgaagc cctgcgcacc 1080ctcagaattg gggggttcta tgctctttcc ccataccccg gtctccgcct catctctctc 1140aatatgaatt tttgttcccg tgagaacttc tggctcttga tcaactccac ggatcccgca 1200ggacagctcc agtggctggt gggggagctt caggctgctg aggatcgagg agacaaagtg 1260catataattg gccacattcc cccagggcac tgtctgaaga gctggagctg gaattattac 1320cgaattgtag ccaggtatga gaacaccctg gctgctcagt tctttggcca cactcatgtg 1380gatgaatttg aggtcttcta tgatgaagag actctgagcc ggccgctggc tgtagccttc 1440ctggcaccca gtgcaactac ctacatcggc cttaatcctg gttaccgtgt gtaccaaata 1500gatggaaact actccaggag ctctcacgtg gtcctggacc atgagaccta catcctgaat 1560ctgacccagg caaacatacc gggagccata ccgcactggc agcttctcta cagggctcga 1620gaaacctatg ggctgcccaa cacactgcct accgcctggc acaacctggt atatcgcatg 1680cggggcgaca tgcaactttt ccagaccttc tggtttctct accataaggg ccacccaccc 1740tcggagccct gtggcacgcc ctgccgtctg gctactcttt gtgcccagct ctctgcccgt 1800gctgacagcc ctgctctgtg ccgccacctg atgccagatg ggagcctccc agaggcccag 1860agcctgtggc caaggccact gttttgc 1887151369DNAArtificial SequenceDescription of the artificial sequence base sequence encoding VH excluding signal sequence of MOG 301 151caggtgcagc tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60tcctgcaagg cttctggtta cagctttacc agctatggta tcaactgggt gcgacaggcc 120ccaggacaag ggcttgagtg gatgggatgg atcagcgctt acaatggtta cacaaactat 180gcacagaagc tccagggcag agtcaccatg accagagaca catccacgcg cacagcctac 240atggagctga ggagcctgag atctgacgac acggccgtgt attactgtgc gagagagtac 300gatattttga ctggttattc cgatgctttt gatatctggg gccaagggac cctggtcact 360gtctcctca 369152123PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VH excluding signal sequence of MOG 301 152Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30Gly Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Ser Ala Tyr Asn Gly Tyr Thr Asn Tyr Ala Gln Lys Leu 50 55 60Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Arg Thr Ala Tyr65 70 75 80Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Tyr Asp Ile Leu Thr Gly Tyr Ser Asp Ala Phe Asp Ile 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 1201535PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of HCDR1 of MOG 301 153Ser Tyr Gly Ile Asn1 515417PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of HCDR2 of MOG 301 154Trp Ile Ser Ala Tyr Asn Gly Tyr Thr Asn Tyr Ala Gln Lys Leu Gln1 5 10 15Gly15514PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of HCDR3 of MOG 301 155Glu Tyr Asp Ile Leu Thr Gly Tyr Ser Asp Ala Phe Asp Ile1 5 10156324DNAArtificial SequenceDescription of the artificial sequence base sequence encoding VL excluding signal sequence of MOG 301 156gaaatagtga tgacacagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcaccgct cactttcggc 300ggagggacca aggtggaaat caaa 324157108PRTArtificial SequenceDescription of the artificial sequence amino acid sequence of VL excluding signal sequence of MOG 301 157Glu Ile Val Met Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro 85 90 95Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 10515812PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of LCDR 1 of MOG 301 158Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala1 5 101597PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of LCDR 2 of MOG 301 159Gly Ala Ser Ser Arg Ala Thr1 51609PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of LCDR 3 of MOG 301 160Gln Gln Tyr Gly Ser Ser Pro Leu Thr1 5161366DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VH excluding signal sequence of MOG 303 161gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt cacctttagc agctatgcca tgggctgggt ccgccaggct 120ccagggaagg ggctggaatg ggtctcagct gttagtggta gtggtggtag cacatactac 180gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaaaggagga 300tacgatattt tgactggtta cttctttgac tactggggcc agggaaccac ggtcactgtc 360tcctca 366162122PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VH excluding signal sequence of MOG303 162Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala Val Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Gly Gly Tyr Asp Ile Leu Thr Gly Tyr Phe Phe Asp Tyr Trp 100 105 110Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 1201635PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of HCDR1 of MOG303 163Ser Tyr Ala Met Gly1 516417PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of HCDR2 of MOG303 164Ala Val Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys1 5 10 15Gly16513PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of HCDR3 of MOG303 165Gly Gly Tyr Asp Ile Leu Thr Gly Tyr Phe Phe Asp Tyr1 5 10166321DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VL excluding signal sequence of MOG 303 166gccatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gggcattagc agtgctttag cctggtatca gcagaaacca 120gggaaagctc ctaagctcct gatctatgat gcctccagtt tggaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacttatta ctgtcaacag tttaatagtt acccattcac tttcggccct 300gggacacgac tggagattaa a 321167107PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VL excluding signal sequence of MOG 303 167Ala Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ala 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Phe 85 90 95Thr Phe Gly Pro Gly Thr Arg Leu Glu Ile Lys 100 10516811PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of LCDR 1 of MOG 303 168Arg Ala Ser Gln Gly Ile Ser Ser Ala Leu Ala1 5 101697PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of LCDR 2 of MOG 303 169Asp Ala Ser Ser Leu Glu Ser1 51709PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of LCDR 3 of MOG 303 170Gln Gln Phe Asn Ser Tyr Pro Phe Thr1 5171381DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VH (excluding signal sequence) of MOG 307 171cgggtcacct tgagggagtc tggtcctacg ctggtgaaac ccacacagac cctcacgctg 60acctgcacct tctctgggtt ctcactcagc actagtggag tgggtgtggg ctggatccgt 120cagcccccag gaaaggccct ggagtggctt gcactcattt tttgggatga tgatagtcac 180tacagcccat ctctgaagag caggctcacc atcaccaagg acacctccaa aaaccaggtg 240gtccttacaa tgaccaacat ggaccctgtg gacacagcca catattactg tgcacggtat 300tactttggtt cggggagtta tttccctagc tactggtact tcgatctctg gggccgtggc 360accctggtca ctgtctcctc a 381172127PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VH excluding signal sequence of MOG 307 172Arg Val Thr Leu Arg Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln1 5 10 15Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser 20 25 30Gly Val Gly Val Gly Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu 35 40 45Trp Leu Ala Leu Ile Phe Trp Asp Asp Asp Ser His Tyr Ser Pro Ser 50 55 60Leu Lys Ser Arg Leu Thr Ile Thr Lys Asp Thr Ser Lys Asn Gln Val65 70 75 80Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95Cys Ala Arg Tyr Tyr Phe

Gly Ser Gly Ser Tyr Phe Pro Ser Tyr Trp 100 105 110Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 1251737PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of HCDR1 of MOG 307 173Thr Ser Gly Val Gly Val Gly1 517416PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of HCDR2 of MOG 307 174Leu Ile Phe Trp Asp Asp Asp Ser His Tyr Ser Pro Ser Leu Lys Ser1 5 10 1517517PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of HCDR3 of MOG 307 175Tyr Tyr Phe Gly Ser Gly Ser Tyr Phe Pro Ser Tyr Trp Tyr Phe Asp1 5 10 15Leu176321DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VL excluding signal sequence of MOG 307 176gaaatagtga tgacacagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agctacttag cctggtacca acagaaacct 120ggccaggctc ccaggctcct catctatgat gcatccaaca gggccactgg catcccagcc 180aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240gaagattttg cagtttatta ctgtcagcag cgtagcaact ggcctccgac gttcggccaa 300gggaccaagg tggagatcaa a 321177107PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VL excluding signal sequence of MOG 307 177Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 10517811PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of LCDR 1 of MOG 307 178Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala1 5 101797PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of LCDR 2 of MOG 307 179Asp Ala Ser Asn Arg Ala Thr1 51809PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of LCDR 3 of MOG 307 180Gln Gln Arg Ser Asn Trp Pro Pro Thr1 5181360DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VH excluding signal sequence of MOG 310 181caggtgcagc tggtgcaatc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60tcctgcaagg cttctggagg caccttcagc agatatgcta tcagctgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggaggg atcatcccta tgtttagtac agcaaactac 180gcacagaagt tccagggcag agtcacgatt accgcggacg aatccacgag cacagcctac 240atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagagattgg 300gcagtggctg gtatgggctt taactactgg ggccagggaa ccctggtcac tgtctcctca 360182120PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VH excluding signal sequence of MOG 310 182Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Arg Tyr 20 25 30Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Gly Ile Ile Pro Met Phe Ser Thr Ala Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Trp Ala Val Ala Gly Met Gly Phe Asn Tyr Trp Gly Gln 100 105 110Gly Thr Leu Val Thr Val Ser Ser 115 1201835PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of HCDR1 of MOG 310 183Arg Tyr Ala Ile Ser1 518417PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of HCDR2 of MOG 310 184Gly Ile Ile Pro Met Phe Ser Thr Ala Asn Tyr Ala Gln Lys Phe Gln1 5 10 15Gly18511PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of HCDR3 of MOG 310 185Asp Trp Ala Val Ala Gly Met Gly Phe Asn Tyr1 5 10186324DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VL excluding signal sequence of MOG 310 186gaaattgtgt tgacacagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcaccgta cacttttggc 300caggggacca aagtggatat caaa 324187108PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VL excluding signal sequence of MOG 310 187Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro 85 90 95Tyr Thr Phe Gly Gln Gly Thr Lys Val Asp Ile Lys 100 10518812PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of LCDR1 of MOG 310 188Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala1 5 101897PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of LCDR 2 of MOG 310 189Gly Ala Ser Ser Arg Ala Thr1 51909PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of LCDR3 of MOG 310 190Gln Gln Tyr Gly Ser Ser Pro Tyr Thr1 5191354DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VH excluding signal sequence of MOG 312 191caggtgcagc tacagcagtg gggcgcagga ctgttgaagc cttcggagac cctgtccctc 60acctgcgctg tctatggtgg gtccttaagt ggttactact ggagctggat ccgccagccc 120ccagggaagg ggctggagtg gattggggat atcactcata gtggaagcac caactacaac 180ccgtccctca agagtcgagt caccatgtca gttgacacgt ccaaaaacca gttctccctg 240aacctgaact ctgtgaccgc cgcggacacg gctgtgtatt actgtgcgag aagggggata 300ggagctgctg tctttgacct ctggggccag ggaaccctgg tcactgtctc ctca 354192118PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VH excluding signal sequence of MOG 312 192Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Leu Ser Gly Tyr 20 25 30Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Asp Ile Thr His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60Ser Arg Val Thr Met Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu65 70 75 80Asn Leu Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Arg Gly Ile Gly Ala Ala Val Phe Asp Leu Trp Gly Gln Gly Thr 100 105 110Leu Val Thr Val Ser Ser 1151935PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of HCDR1 of MOG 312 193Gly Tyr Tyr Trp Ser1 519416PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of HCDR2 of MOG 312 194Asp Ile Thr His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys Ser1 5 10 1519510PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of HCDR3 of MOG 312 195Arg Gly Ile Gly Ala Ala Val Phe Asp Leu1 5 10196324DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VL excluding signal sequence of MOG 312 196gaaatagtgt tgacgcagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt ttgcagtgta ttactgtcag cagcgtagca actggcctct cactttcggc 300ggagggacca aggtggagat caaa 324197108PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VL excluding signal sequence of MOG 312 197Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro 85 90 95Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 10519812PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of LCDR 1 of MOG 312 198Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala1 5 101997PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of LCDR 2 of MOG 312 199Gly Ala Ser Ser Arg Ala Thr1 52009PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of LCDR 3 of MOG 312 200Gln Gln Arg Ser Asn Trp Pro Leu Thr1 5201366DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VH excluding signal sequence of MOG 326 201gaggtccagc tggtacagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtt 60tcctgcaagg catctggata caccttcacc agctactata tgcactgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggaata atcaacccta gtggtggtag cacaagctac 180gcacagaagt tccagggcag agtcaccatg accagggaca cgtccacgag cacagtctac 240atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagagggtat 300tacgatattt tgactggttc cttctttgac tactggggcc agggaaccct ggtcactgtc 360tcctca 366202122PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VH excluding signal sequence of MOG 326 202Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Tyr Tyr Asp Ile Leu Thr Gly Ser Phe Phe Asp Tyr Trp 100 105 110Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 1202035PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of HCDR1 of MOG 326 203Ser Tyr Tyr Met His1 520417PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of HCDR2 of MOG 326 204Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe Gln1 5 10 15Gly20513PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of HCDR3 of MOG 326 205Gly Tyr Tyr Asp Ile Leu Thr Gly Ser Phe Phe Asp Tyr1 5 10206321DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VL excluding signal sequence of MOG 326 206gacatcgtga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gggcattagc agtgctttag tctggtatca gcagaaacca 120gggaaagctc ctaagctcct gatctatgat gcctccagtt tggaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacttatta ctgtcaacag tttaatagtt accctctcac tttcggcgga 300gggaccaaag tggatatcaa a 321207107PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VL excluding signal sequence of MOG 326 207Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ala 20 25 30Leu Val Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Asp Ile Lys 100 10520811PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of LCDR 1 of MOG 326 208Arg Ala Ser Gln Gly Ile Ser Ser Ala Leu Val1 5 102097PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of LCDR 2 of MOG 326 209Asp Ala Ser Ser Leu Glu Ser1 52109PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of LCDR 3 of MOG 326 210Gln Gln Phe Asn Ser Tyr Pro Leu Thr1 5211357DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VH excluding signal sequence of MOG 329 211caggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt cgcctttcgc aactatgcca tgaactgggt ccgccaggct 120ccagggaagg ggctggagtg ggtctcagct attagtggta gtggtggtag cacatactac 180gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggccgttt attactgtgc gagagactac 300ggtggtatct ccccctttga ctactggggc cagggaaccc tggtcactgt ctcctca 357212119PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VH excluding signal sequence of MOG 329 212Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Arg Asn Tyr 20 25 30Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Tyr Gly Gly Ile Ser Pro Phe Asp Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser 1152135PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of HCDR1 of MOG 329 213Asn Tyr Ala Met Asn1 521417PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of HCDR2 of MOG 329 214Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys1 5 10 15Gly21510PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of HCDR3 of MOG 329 215Asp Tyr Gly Gly Ile Ser Pro Phe Asp Tyr1 5 10216321DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VL excluding signal sequence of MOG 329

216gacatccagt tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gggcattagc agtgctttag cctggtatca gcagaaacca 120gggaaagctc ctaagctcct gatctatgat gcctccagtt tggaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacttatta ctgtcaacag tttaatagtt accctcacac ttttggccag 300gggaccaaag tggatatcaa a 321217107PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VL excluding signal sequence of MOG 329 217Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ala 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro His 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Asp Ile Lys 100 10521811PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of LCDR 1 of MOG 329 218Arg Ala Ser Gln Gly Ile Ser Ser Ala Leu Ala1 5 102197PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of LCDR 2 of MOG 329 219Asp Ala Ser Ser Leu Glu Ser1 52209PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of LCDR 3 of MOG 329 220Gln Gln Phe Asn Ser Tyr Pro His Thr1 5221372DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VH excluding signal sequence of MOG446 221caggtgcagc tggtggagtc tgggggaggt gtggtacggc cgggggggtc cctgagactc 60tcctgtgcag cctctggatt cacctttgat gattatggca tgagctgggt ccgccaagct 120ccagggaagg ggctggagtg ggtctctaat attaattgga atggtgatag cacaggttat 180gtagactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240ctgcaaatga acagtctgag agccgaggac acggccttgt attactgtgc gagagcgagg 300acctattact atgtttcggg gaggtactac tttgactact ggggccaggg aaccctggtc 360actgtctcct ca 372222124PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VH excluding signal sequence of MOG446 222Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Arg Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Asn Ile Asn Trp Asn Gly Asp Ser Thr Gly Tyr Val Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95Ala Arg Ala Arg Thr Tyr Tyr Tyr Val Ser Gly Arg Tyr Tyr Phe Asp 100 105 110Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 1202235PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of HCDR1 of MOG446 223Asp Tyr Gly Met Ser1 522417PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of HCDR2 of MOG446 224Asn Ile Asn Trp Asn Gly Asp Ser Thr Gly Tyr Val Asp Ser Val Lys1 5 10 15Gly22515PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of HCDR3 of MOG446 225Ala Arg Thr Tyr Tyr Tyr Val Ser Gly Arg Tyr Tyr Phe Asp Tyr1 5 10 15226321DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VL excluding signal sequence of MOG446 226gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gggcattagc agtgctttag cctggtatca gcagaaacca 120gggaaagctc ctaagctcct gatctatgat gcctccagtt tggaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacttatta ctgtcaacag tttaatagtt acccgctcac tttcggcgga 300gggaccaagg tggaaatcaa a 321227107PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VL excluding signal sequence of MOG446 227Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ala 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 10522811PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of LCDR1 of MOG446 228Arg Ala Ser Gln Gly Ile Ser Ser Ala Leu Ala1 5 102297PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of LCDR2 of MOG446 229Asp Ala Ser Ser Leu Glu Ser1 52309PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of LCDR3 of MOG446 230Gln Gln Phe Asn Ser Tyr Pro Leu Thr1 5231366DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VH excluding signal sequence of MOG456 231gaggtgcagc tggtggagtc tgggggaggc ctggtcaagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatagca tgcactgggt ccgccaggct 120ccagggaagg ggctggagtg ggtctcatcc attggtagta ggagtcgtta catatactac 180gcagactcag tgaagggccg attcaccatc tccagagaca acgccaagaa ctcactgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gaaagggtat 300tacgatattt tgactggttc tctctttgac tactggggcc agggaaccct ggtcactgtc 360tcctca 366232122PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VH excluding signal sequence of MOG 456 232Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ser Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Gly Ser Arg Ser Arg Tyr Ile Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Gly Tyr Tyr Asp Ile Leu Thr Gly Ser Leu Phe Asp Tyr Trp 100 105 110Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 1202335PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of HCDR1 of MOG456 233Ser Tyr Ser Met His1 523417PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of HCDR2 of MOG456 234Ser Ile Gly Ser Arg Ser Arg Tyr Ile Tyr Tyr Ala Asp Ser Val Lys1 5 10 15Gly23513PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of HCDR3 of MOG 456 235Gly Tyr Tyr Asp Ile Leu Thr Gly Ser Leu Phe Asp Tyr1 5 10236321DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VL excluding signal sequence of MOG456 236gacatcgtga tgacccagtc tccatcctca ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgtc gggcgagtca gggtattagc agtgctttag cctggtatca gcagaaacca 120gggaaagctc ctaagctcct gatctatgat gcctccagtt tggaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacttatta ctgtcaacag tttaatagtt acccgtggac gttcggccaa 300gggaccaagg tggagatcaa a 321237107PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VL excluding signal sequence of MOG456 237Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ala 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Trp 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 10523811PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of LCDR 1 of MOG 456 238Arg Ala Ser Gln Gly Ile Ser Ser Ala Leu Ala1 5 102397PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of LCDR 2 of MOG 456 239Asp Ala Ser Ser Leu Glu Ser1 52409PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of LCDR 3 of MOG 456 240Gln Gln Phe Asn Ser Tyr Pro Trp Thr1 5241357DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VH excluding signal sequence of MOG 473 241caggtgcagc tggtggagtc tgggggaggc ctggtcaagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatagca tgcactgggt ccgccaggct 120ccagggaagg ggctggagtg ggtttcggac attagtacta atagtagaac cagaaactat 180gcagactctg tgaagggccg attcaccatc tccagagaca atgccaagaa ctcagtgtat 240ctgcaaatgc acagcctgag ggacgaggac acggctgtgt actactgtgc gagagactac 300ggtggtatct attactttga ctattggggc cagggaaccc tggtcactgt ctcctca 357242119PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VH excluding signal sequence of MOG 473 242Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ser Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Asp Ile Ser Thr Asn Ser Arg Thr Arg Asn Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Val Tyr65 70 75 80Leu Gln Met His Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Tyr Gly Gly Ile Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser 1152435PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of HCDR1 of MOG 473 243Ser Tyr Ser Met His1 524417PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of HCDR2 of MOG 473 244Asp Ile Ser Thr Asn Ser Arg Thr Arg Asn Tyr Ala Asp Ser Val Lys1 5 10 15Gly24510PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of HCDR3 of MOG 473 245Asp Tyr Gly Gly Ile Tyr Tyr Phe Asp Tyr1 5 10246324DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VL excluding signal sequence of MOG 473 246gaaatagtga tgacacagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agctacttag cctggtacca acagaaacct 120ggccaggctc ccaggctcct catctatgat gcatccaaca gggccactgg catcccagcc 180aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240gaagattttg cagtttatta ctgtcagcag cgtagcaact ggcctccgta cacttttggc 300caggggacca agctggagat caaa 324247108PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VL excluding signal sequence of MOG 473 247Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro 85 90 95Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 10524811PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of LCDR1 of MOG 473 248Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala1 5 102497PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of LCDR 2 of MOG 473 249Asp Ala Ser Asn Arg Ala Thr1 525010PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of LCDR 3 of MOG 473 250Gln Gln Arg Ser Asn Trp Pro Pro Tyr Thr1 5 10251369DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VH excluding signal sequence of MOG426 251caggtccagc tggtacagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60tcctgcaagg cttctggtta cagctttaac agctatggta tcaactgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggatgg atcagcgctt acactggtaa aacaagttat 180gcacagaagg tccagggcag agtcaccatg accacagaca gatccacgag cacagcctac 240atggagctga ggagcctgag atctgacgac acggccatgt attactgtgc gagagagtac 300gatattttga ctggttattc cgatgctttt gatacctggg gccaagggac aatggtcacc 360gtctcttca 369252123PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VH excluding signal sequence of MOG426 252Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Asn Ser Tyr 20 25 30Gly Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Ser Ala Tyr Thr Gly Lys Thr Ser Tyr Ala Gln Lys Val 50 55 60Gln Gly Arg Val Thr Met Thr Thr Asp Arg Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Met Tyr Tyr Cys 85 90 95Ala Arg Glu Tyr Asp Ile Leu Thr Gly Tyr Ser Asp Ala Phe Asp Thr 100 105 110Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 115 120253321DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VL excluding signal sequence of MOG426 253gaaattgtgt tgacgcagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agctacttag cctggtacca acagaaacct 120ggccaggctc ccaggctcct catctatgat gcatccaaca gggccactgg catcccagcc 180aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240gaagattttg cagtttatta ctgtcagcag cgtggcaact ggccgctcac tttcggcgga 300gggaccaagc tggagatcaa a 321254107PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VL excluding signal sequence of MOG426 254Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Gly Asn Trp Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105255369DNAArtificial SequenceThe Description of the artificial sequence

base sequence encoding VH excluding signal sequence of MOG428 255gaggtccagc tggtacagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60tcctgcaagg cttctggtta cagctttaac agctatggta tcaactgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggatgg atcagcgctt acactggtaa aacaagttat 180gcacagaagg tccagggcag agtcaccatg accacagaca gatccacgag cacagcctac 240atggagctga ggagcctgag atctgacgac acggccatgt attactgtgc gagagagtac 300gatattttga ctggttattc cgatgctttt gatacctggg gccaagggac aatggtcacc 360gtctcttca 369256123PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VH excluding signal sequence of MOG428 256Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Asn Ser Tyr 20 25 30Gly Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Ser Ala Tyr Thr Gly Lys Thr Ser Tyr Ala Gln Lys Val 50 55 60Gln Gly Arg Val Thr Met Thr Thr Asp Arg Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Met Tyr Tyr Cys 85 90 95Ala Arg Glu Tyr Asp Ile Leu Thr Gly Tyr Ser Asp Ala Phe Asp Thr 100 105 110Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 115 120257324DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VL excluding signal sequence of MOG428 257gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcacctcg gacgttcggc 300caagggacca agctggagat caaa 324258108PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VL excluding signal sequence of MOG428 258Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro 85 90 95Arg Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105259366DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VH excluding signal sequence of MOG 313 259caggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt cacctttagc agctatgcca tgagctgggt ccgccaggct 120ccagggaagg ggctggagtg ggtctcagtt attagtggta gtggtggtag cacatactac 180gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaaagcatat 300tacgatattt tgactggttc cctctttgac tcctggggcc agggaaccct ggtcactgtc 360tcctca 366260122PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VH excluding signal sequence of MOG 313 260Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Val Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Ala Tyr Tyr Asp Ile Leu Thr Gly Ser Leu Phe Asp Ser Trp 100 105 110Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120261321DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VL excluding signal sequence of MOG 313 261gacatcgtga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gggcattagc agtgctttag cctggtatca gcagaaacca 120gggaaagctc ctaagctcct gatctatgat gcctccagtt tggaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacttatta ctgtcaacag tttaatagtt accctctcac tttcggcgga 300gggaccaagg tggaaatcaa a 321262107PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VL excluding signal sequence of MOG 262Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ala 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105263366DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VH excluding signal sequence of MOG 314 263caggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt cacctttagc agctatgcca tgagctgggt ccgccaggct 120ccagggaagg ggctggagtg ggtctcagct attagtggta gaggtagtag cacatactac 180gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaaaggctat 300tacgatattt tgactggttc cttctttgac tactggggcc agggaaccct ggtcaccgtc 360tcctca 366264122PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VH excluding signal sequence of MOG 314 264Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala Ile Ser Gly Arg Gly Ser Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Gly Tyr Tyr Asp Ile Leu Thr Gly Ser Phe Phe Asp Tyr Trp 100 105 110Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120265321DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VL excluding signal sequence of MOG 314 265gacatccagt tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gggcattagc agtgctttag cctggtatca gcagaaacca 120gggaaagctc ctaagctcct gatctatgat gcctccagtt tggaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacttatta ctgtcaacag tttaatagtt acccgtacac ttttggccag 300gggaccaagc tggagatcaa a 321266107PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VL excluding signal sequence of MOG 314 266Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ala 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Tyr 85 90 95Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105267366DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VH excluding signal sequence of MOG 315 267gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt cacctttagc acctatgcca tgagctgggt ccgccaggct 120ccagggaagg ggctggagtg ggtctcagct attagtggta gtggtgttag cacatactac 180gcagactccg tgaagggccg gttcaccctc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaaagcgtat 300tacgatattt tgactggtaa tttccttgac tactggggcc agggaaccct ggtcactgtc 360tcctca 366268122PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VH excluding signal sequence of MOG 315 268Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr 20 25 30Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala Ile Ser Gly Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Leu Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Ala Tyr Tyr Asp Ile Leu Thr Gly Asn Phe Leu Asp Tyr Trp 100 105 110Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120269321DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VL excluding signal sequence of MOG 315 269gccatccagt tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gggcattagc agtgctttag cctggtatca gcagaaacca 120gggaaagctc ctaagctcct gatctatgat gcctccagtt tggaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacttatta ctgtcaacag tttaatagtt acccgctcac tttcggcgga 300gggaccaagg tggaaatcaa a 321270107PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VL excluding signal sequence of MOG 315 270Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ala 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105271366DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VH excluding signal sequence of MOG331 271gaggtgcagc tggtggagtc cgggggaggc ttggtatagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt cacctttagc agctatgcca tgagctgggt ccgccaggct 120ccagggaagg ggctggagtg ggtctcagct attagtggta gtggtggtag cacatactac 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacactgtat 240ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaaagcgtat 300tacgatattt tgactggttc cttctttgac tactggggcc agggaaccct ggtcactgtc 360tcctca 366272122PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VH excluding signal sequence of MOG331 272Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Tyr Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Ala Tyr Tyr Asp Ile Leu Thr Gly Ser Phe Phe Asp Tyr Trp 100 105 110Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120273321DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VL excluding signal sequence of MOG331 273gaaatagtga tgacacagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agctacttag cctggtacca acagaaacct 120ggccaggctc ccaggctcct catctatgat gcatccaaca gggccactgg catcccagcc 180aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag actggagcct 240gaagattttg cagtgtatta ctgtcagcag tatggtagct caccgctcac tttcggcgga 300gggaccaagc tggagatcaa a 321274107PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VL excluding signal sequence of MOG331 274Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105275366DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VH excluding signal sequence of MOG357 275gaggtgcagc tggtggagac tgggggaggc ttggtacagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt cacctttagc agctatgcca tgagctgggt ccgccaggct 120ccagggaagg ggctggagtg ggtctcagat attaatcata gtggtggtag cacatactac 180gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagca cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaaagactat 300tacgatattt tgactggttc cttctttgac tactggggcc agggaaccct ggtcactgtc 360tcctca 366276122PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VH excluding signal sequence of MOG 357 276Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Asp Ile Asn His Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys His Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Asp Tyr Tyr Asp Ile Leu Thr Gly Ser Phe Phe Asp Tyr Trp 100 105 110Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120277321DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VL excluding signal sequence of MOG 357 277gacatcgtga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gggcattagc agtgctttag cctggtatca gcagaaacca 120gggaaagctc ctaagctcct gatctatgat gcctccagtt tggaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacttatta ctgtcaacag tttaatagtt acccgtggac gttcggccaa 300gggaccaagg tggagatcaa a 321278107PRTArtificial

SequenceThe Description of the artificial sequence amino acid sequence of VL excluding signal sequence of MOG 357 278Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ala 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Trp 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105279366DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VH excluding signal sequence of MOG 476 279gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt cacttttagc agctatgcca tgaactgggt ccgccaggct 120ccagggaagg ggctggagtg ggtctcagct attagttata gtggtcgtag cacatactac 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaagggcctt 300tacgatattt tgactggtgg cggatttgac tactggggcc agggaaccct ggtcaccgtc 360tcttca 366280122PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VH excluding signal sequence of MOG 476 280Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala Ile Ser Tyr Ser Gly Arg Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Gly Leu Tyr Asp Ile Leu Thr Gly Gly Gly Phe Asp Tyr Trp 100 105 110Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120281321DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VL excluding signal sequence of MOG 476 281gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gggcattagc agtgctttag cctggtatca gcagaaacca 120gggaaagctc ctaagctcct gatctatgat gcctccagtt tggaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacttatta ctgtcaacag tttaatagtt acccgtccac ttttggccag 300gggacacgac tggagattaa a 321282107PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VL excluding signal sequence of MOG 476 282Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ala 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Ser 85 90 95Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105283381DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VH excluding signal sequence of MOG 323 283cggatcacct tgagggagtc tggtcctacg ctggtgaaac ccacacagac cctcacgctg 60acctgcacct tctctgggtt ctcactcagc actagtggag tgggtgtggg ctggatccgt 120cagcccccag gaaaggccct ggagtggctt gcactcattt tttgggatga tgatagtcac 180tacagcccat ctctgaagag caggctcacc atcaccaagg acacctccaa aaaccaggtg 240gtccttacaa tgaccaacat ggaccctgtg gacacagcca catattactg tgcacggtat 300tactttggtt cggggagtta tttccctagc tactggtact tcgatctctg gggccgtggc 360accctggtca ccgtctcctc a 381284127PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VH excluding signal sequence of MOG 323 284Arg Ile Thr Leu Arg Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln1 5 10 15Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser 20 25 30Gly Val Gly Val Gly Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu 35 40 45Trp Leu Ala Leu Ile Phe Trp Asp Asp Asp Ser His Tyr Ser Pro Ser 50 55 60Leu Lys Ser Arg Leu Thr Ile Thr Lys Asp Thr Ser Lys Asn Gln Val65 70 75 80Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95Cys Ala Arg Tyr Tyr Phe Gly Ser Gly Ser Tyr Phe Pro Ser Tyr Trp 100 105 110Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 125285321DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VL excluding signal sequence of MOG 323 285gaaatagtga tgacgcagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agctacttag cctggtacca acagaaacct 120ggccaggctc ccaggctcct catctatgat gcatccaaca gggccactgg catcccagcc 180aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240gaagattttg cagtttatta ctgtcagcag cgtagcaact ggcctcccac tttcggcgga 300gggaccaagc tggagatcaa a 321286107PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VL excluding signal sequence of MOG 323 286Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro 85 90 95Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105287381DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VH excluding signal sequence of MOG 341 287cggatcacct tgaaggagtc tggtcctacg ctggtgaaac ccacacagac cctcacgctg 60acctgcacct tctctgggtt ctcactcagc actagtggag tgggtgtggg ctggatccgt 120cagcccccag gaaaggccct ggagtggctt gcactcattt attgggatga tgataaacac 180tacagcccat ctctgaagag caggctcacc atcaccaagg acacctccaa aaaccaggtg 240gtccttacaa tgaccaacat ggaccctgtg gacacagcca catattactg tgcacggtat 300tactttggtt cggggagtta ttcccctagc tactggtact tcgatctctg gggccgtggc 360accctggtca ctgtctcctc a 381288127PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VH excluding signal sequence of MOG 341 288Arg Ile Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln1 5 10 15Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser 20 25 30Gly Val Gly Val Gly Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu 35 40 45Trp Leu Ala Leu Ile Tyr Trp Asp Asp Asp Lys His Tyr Ser Pro Ser 50 55 60Leu Lys Ser Arg Leu Thr Ile Thr Lys Asp Thr Ser Lys Asn Gln Val65 70 75 80Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95Cys Ala Arg Tyr Tyr Phe Gly Ser Gly Ser Tyr Ser Pro Ser Tyr Trp 100 105 110Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 125289321DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VL excluding signal sequence of MOG 341 289gaaattgtgt tgacgcagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agctacttag cctggtacca acagaaacct 120ggccaggctc ccaggctcct catctatgat gcatccaaca gggccactgg catcccagcc 180aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240gaagattttg cagtttatta ctgtcagcag cgtagcaact ggcctcccac tttcggcgga 300gggaccaagg tggagatcaa a 321290107PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VL excluding signal sequence of MOG 341 290Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105291381DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VH excluding signal sequence of MOG 354 291cggatcacct tgagggagtc tggtcctacg ctggtgaaac ccacacagac cctcacgctg 60acctgcacct cctctgggct ctcactcagc actagtggag tgggtgtggg ctggatccgt 120cagcccccag gaaaggccct ggagtggctt gcactcattt tttgggatga tgatacacac 180tacagcccat ctctgaagag caggctcacc atcaccaagg acacctccaa aaaccaggtg 240gtccttacaa tgaccaacat ggaccctgtg gacacagcca catattactg tgcacggtat 300tactttggtt cggggagtta tttccctagc tactggtact tcgatctctg gggccgtggc 360accatggtca ccgtctcttc a 381292127PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VH excluding signal sequence of MOG 354 292Arg Ile Thr Leu Arg Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln1 5 10 15Thr Leu Thr Leu Thr Cys Thr Ser Ser Gly Leu Ser Leu Ser Thr Ser 20 25 30Gly Val Gly Val Gly Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu 35 40 45Trp Leu Ala Leu Ile Phe Trp Asp Asp Asp Thr His Tyr Ser Pro Ser 50 55 60Leu Lys Ser Arg Leu Thr Ile Thr Lys Asp Thr Ser Lys Asn Gln Val65 70 75 80Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95Cys Ala Arg Tyr Tyr Phe Gly Ser Gly Ser Tyr Phe Pro Ser Tyr Trp 100 105 110Tyr Phe Asp Leu Trp Gly Arg Gly Thr Met Val Thr Val Ser Ser 115 120 125293321DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VL excluding signal sequence of MOG 354 293gaaatagtga tgacgcagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agctacttag cctggtacca acagaaacct 120ggccaggctc ccaggctcct catctatgat gcatccaaca gggccactgg catcccagcc 180aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240gaagattttg cagtttatta ctgtcagcag cgtagcaact ggccgctcac tttcggcgga 300gggaccaagg tggaaatcaa a 321294107PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VL excluding signal sequence of MOG 354 294Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105295381DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VH excluding signal sequence of MOG 355 295cggatcacct tgagggagtc tggtcctacg ctggtgaaac ccacacagac cctcacgctg 60acctgcacct cctctgggct ctcactcagc actagtggag tgggtgtggg ctggatccgt 120cagcccccag gaaaggccct ggagtggctt gcactcattt tttgggatga tgatacacac 180tacagcccat ctctgaagag caggctcacc atcaccaagg acacctccaa aaaccaggtg 240gtccttacaa tgaccaacat ggaccctgtg gacacagcca catattactg tgcacggtat 300tactttggtt cggggagtta tttccctagc tactggtact tcgatctctg gggccgtggc 360accctggtca ctgtctcctc a 381296127PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VH excluding signal sequence of MOG 355 296Arg Ile Thr Leu Arg Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln1 5 10 15Thr Leu Thr Leu Thr Cys Thr Ser Ser Gly Leu Ser Leu Ser Thr Ser 20 25 30Gly Val Gly Val Gly Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu 35 40 45Trp Leu Ala Leu Ile Phe Trp Asp Asp Asp Thr His Tyr Ser Pro Ser 50 55 60Leu Lys Ser Arg Leu Thr Ile Thr Lys Asp Thr Ser Lys Asn Gln Val65 70 75 80Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95Cys Ala Arg Tyr Tyr Phe Gly Ser Gly Ser Tyr Phe Pro Ser Tyr Trp 100 105 110Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 125297321DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VL excluding signal sequence of MOG 355 297gaaatagtgt tgacacagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agctacttag cctggtacca acagaaacct 120ggccaggctc ccaggctcct catctatgat gcatccaaca gggccactgg catcccagcc 180aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240gaagattttg cagtttatta ctgtcagcag cgtagcaact ggccgctcac tttcggcgga 300gggaccaagc tggagatcaa a 321298107PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VL excluding signal sequence of MOG 355 298Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105299360DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VH excluding signal sequence of MOG 308 299gaggtgcagc tggtgcagtc cggggctgag gtgaggaagt ctgggtcctc ggtgaaggtc 60tcctgcaagg cttctggagg caccttcagc agatatgcta tcagctgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggaggg atcatcccta tgtttagtac gacaaactac 180gcacagaagt tccagggcag agtcacgatt accgcggacg aatccacgag cacagcctac 240atggaactga gcagcctgag atctgaggac acggccgtgt attactgtgc gagagattgg 300gcagtggctg gtatggggtt tgcctactgg ggccagggaa ccctggtcac cgtctcctca 360300120PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VH excluding signal sequence of MOG 308 300Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Arg Lys Ser Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Arg Tyr 20 25 30Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Gly Ile Ile Pro Met Phe Ser Thr Thr Asn Tyr Ala Gln Lys Phe 50 55

60Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Trp Ala Val Ala Gly Met Gly Phe Ala Tyr Trp Gly Gln 100 105 110Gly Thr Leu Val Thr Val Ser Ser 115 120301321DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VL excluding signal sequence of MOG 308 301gaaatagtga tgacacagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agctacttag cctggtacca acagaaacct 120ggccaggctc ccaggctcct catctatgat gcatccaaca gggccactgg catcccagcc 180aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240gaagattttg cagtttatta ctgtcagcag cgtagcaact ggcctccgac gttcggccaa 300gggaccaaag tggatatcaa a 321302107PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VL excluding signal sequence of MOG 308 302Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Asp Ile Lys 100 105303360DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VH excluding signal sequence of MOG 316 303gaagtgcagc tggtgcagtc cggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60tcctgcaagg cttctggagg caccttcagc agatatgcta tcagctgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggaggg atcatcccta tgtttaatac agcaaactac 180gcacagaagt tccagggcag agtcacgatt accgcggacg aatccacgag cacagcctac 240atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagagattgg 300gcagtggctg gtatggggtt taactactgg ggccagggaa ccctggtcac cgtctcctca 360304120PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VH excluding signal sequence of MOG 316 304Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Arg Tyr 20 25 30Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Gly Ile Ile Pro Met Phe Asn Thr Ala Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Trp Ala Val Ala Gly Met Gly Phe Asn Tyr Trp Gly Gln 100 105 110Gly Thr Leu Val Thr Val Ser Ser 115 120305321DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VL excluding signal sequence of MOG 316 305gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gggcattaac agtgctttag cctggtatca gcagaaacca 120gggaaagctc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacttatta ctgccaacag tataatagtt acccgatcac cttcggccaa 300gggacacgac tggagattaa a 321306107PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VL excluding signal sequence of MOG 316 306Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Asn Ser Ala 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Ile 85 90 95Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105307360DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VH excluding signal sequence of MOG 319 307caggtgcagc tggtgcaatc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60tcctgcaagg cttctggagg caccttcagc agatatgcta tcagctgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggaggg atcatcccta tgtttagtac agcaaactac 180gcacagaagt tccagggcag agtcacgatt accgcggacg aatccacgag cacagcctac 240atggagctga gcagcctgag atctgacgac acggccgtgt attactgtgc gagagattgg 300gcagtggctg gtatgggctt taactactgg ggccagggaa ccctggtcac tgtctcctca 360308120PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VH excluding signal sequence of MOG 319 308Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Arg Tyr 20 25 30Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Gly Ile Ile Pro Met Phe Ser Thr Ala Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Trp Ala Val Ala Gly Met Gly Phe Asn Tyr Trp Gly Gln 100 105 110Gly Thr Leu Val Thr Val Ser Ser 115 120309324DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VL excluding signal sequence of MOG 319 309gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcaccatt cactttcggc 300cctgggacca aggtggaaat caaa 324310108PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VL excluding signal sequence of MOG 319 310Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro 85 90 95Phe Thr Phe Gly Pro Gly Thr Lys Val Glu Ile Lys 100 105311360DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VH excluding signal sequence of MOG 320 311caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60tcctgcaagg cttctggagg caccttcagc agatatgcta tcaactgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggaggg atcatcccta tgtttagtac agtaaattac 180gcacagaagt tccagggcag agtcacgatt accgcggacg aatccacgag cacagcctac 240atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagagattgg 300gcagtggctg gtatggggtt tgactactgg ggccagggaa ccctggtcac cgtctcctca 360312120PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VH excluding signal sequence of MOG 320 312Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Arg Tyr 20 25 30Ala Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Gly Ile Ile Pro Met Phe Ser Thr Val Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Trp Ala Val Ala Gly Met Gly Phe Asp Tyr Trp Gly Gln 100 105 110Gly Thr Leu Val Thr Val Ser Ser 115 120313324DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VL excluding signal sequence of MOG 320 313gaaatagtgt tgacacagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcaccatt cactttcggc 300cctgggacca aagtggatat caaa 324314108PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VL excluding signal sequence of MOG 320 314Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro 85 90 95Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys 100 105315360DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VH excluding signal sequence of MOG 338 315caggtccagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60tcctgcaagg cttctggagg caccttcagc agatatgcta tcagctgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggaggg atcatcccta tgtttaatac agcaaactac 180gcacagaagt tccagggcag agtcacgatt accgcggacg aatccacgag cacagcctac 240atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagagattgg 300gcagtggctg gtatggggtt tgacccctgg ggccagggaa ccctggtcac tgtctcctca 360316120PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VH excluding signal sequence of MOG 338 316Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Arg Tyr 20 25 30Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Gly Ile Ile Pro Met Phe Asn Thr Ala Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Trp Ala Val Ala Gly Met Gly Phe Asp Pro Trp Gly Gln 100 105 110Gly Thr Leu Val Thr Val Ser Ser 115 120317321DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VL excluding signal sequence of MOG 338 317gaaattgtgt tgacgcagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agctacttag cctggtacca acagaaacct 120ggccaggctc ccaggctcct catctatgat gcatccaaca gggccactgg catcccagcc 180aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240gaagattttg cagtttatta ctgtcagcag cgtaacaact ggcctctcac tttcggcgga 300gggaccaagc tggagatcaa a 321318107PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VL excluding signal sequence of MOG 338 318Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Asn Asn Trp Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105319360DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VH excluding signal sequence of MOG352 319gaggtgcagc tggtgcagtc cggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60tcctgcaagg cttctggagg caccttcagc agatatgcta tcaactgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggaggg atcatcccta tgtttagtac agtaaactac 180gcacagaagt tccagggcag agtcacgatt accgcggacg aatccacgag cacagcctac 240atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagagattgg 300gcagtggctg gtatggggtt tgactactgg ggccagggaa ccctggtcac tgtctcctca 360320120PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VH excluding signal sequence of MOG352 320Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Arg Tyr 20 25 30Ala Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Gly Ile Ile Pro Met Phe Ser Thr Val Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Trp Ala Val Ala Gly Met Gly Phe Asp Tyr Trp Gly Gln 100 105 110Gly Thr Leu Val Thr Val Ser Ser 115 120321321DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VL excluding signal sequence of MOG352 321gccatccaga tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60atcacttgtc gggcgagtca gggtattagc agctggttag cctggtatca gcataaacca 120gggaaagccc ctaagtccct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacttatta ctgccaacag tataatagtt acccgctcac tttcggcgga 300gggaccaaag tggatatcaa a 321322107PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VL excluding signal sequence of MOG 352 322Ala Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp 20 25 30Leu Ala Trp Tyr Gln His Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Asp Ile Lys 100 105323360DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VH excluding signal sequence of MOG 359 323gaggtccagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60tcctgcaagg cttctggagg caccttcagc agatatgcta tcagctgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggaggg atcatcccta tgtttaatac agcaaactac 180gcacagaagt tccagggcag agtcacgatt accgcggacg aatccacgag cacagcctac 240atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagagattgg 300gcagtggctg gtatggggtt taactactgg ggccagggaa ccctggtcac tgtctcctca 360324120PRTArtificial SequenceThe Description of the artificial sequence amino acid

sequence of VH excluding signal sequence of MOG 359 324Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Arg Tyr 20 25 30Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Gly Ile Ile Pro Met Phe Asn Thr Ala Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Trp Ala Val Ala Gly Met Gly Phe Asn Tyr Trp Gly Gln 100 105 110Gly Thr Leu Val Thr Val Ser Ser 115 120325324DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VL excluding signal sequence of MOG 359 325gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcaccgct cactttcggc 300ggagggacca agctggagat caaa 324326108PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VL excluding signal sequence of MOG 359 326Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro 85 90 95Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105327360DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VH excluding signal sequence of MOG 478 327gaggtccagc tggtacagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60tcctgcaagg cttctggagg caccttcagc agatatgcta tcagctgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggaggg atcatcccta tgtttgctac agcaaactac 180gcacagaagt tccaggccag agtcacgatt accgcggacg aaaccacgag cacagcctac 240atggagctga gcagcctgag atctgaggac acgggcgtgt attactgtgc gagagattgg 300gcagtggctg ctatggggtt tgcccactgg ggccagggaa ccctggtcac tgtctcctca 360328120PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VH excluding signal sequence of MOG 478 328Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Arg Tyr 20 25 30Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Gly Ile Ile Pro Met Phe Ala Thr Ala Asn Tyr Ala Gln Lys Phe 50 55 60Gln Ala Arg Val Thr Ile Thr Ala Asp Glu Thr Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Gly Val Tyr Tyr Cys 85 90 95Ala Arg Asp Trp Ala Val Ala Ala Met Gly Phe Ala His Trp Gly Gln 100 105 110Gly Thr Leu Val Thr Val Ser Ser 115 120329324DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VL excluding signal sequence of MOG 478 329gaaatagtga tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcaccgat caccttcggc 300caagggacac gactggagat taaa 324330108PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VL excluding signal sequence of MOG 478 330Glu Ile Val Met Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro 85 90 95Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105331357DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VH excluding signal sequence of MOG 470 331caggtgcagc tggtggagtc tgggggaggc ttggtacagc cgggggggtc cctgagactc 60tcctgtgcag cctctggatt cacctttagc agctatgcca tgaactgggt ccgccaggct 120ccagggaagg ggctggagtg ggtctcagct attagtggta gtggtggtag cacatactac 180gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaagtga acagcctgag agccgaggac acggccgttt attactgtgc gagagactac 300ggtggtatct ccccctttga ctactggggc cagggaaccc tggtcaccgt ctcctca 357332119PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VH excluding signal sequence of MOG 470 332Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Val Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Tyr Gly Gly Ile Ser Pro Phe Asp Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser 115333321DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VL excluding signal sequence of MOG 470 333gaaatagtga tgacacagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agctacttag cctggtacca acagaaacct 120ggccaggctc ccaggctcct catctatgat gcatccaaca gggccactgg catcccagcc 180aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag actggagcct 240gaagattttg cagtgtatta ctgtcagcag tatggtagct caccgtacac ttttggccag 300gggacacgac tggagattaa a 321334107PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VL excluding signal sequence of MOG 470 334Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro Tyr 85 90 95Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105335366DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VH excluding signal sequence of MOG 418 335caggtgtagc tggtgcagtc tgggggaggc ctggtcaagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatagca tgcactgggt ccgccaggct 120ccagggaagg ggctggagtg ggtctcatcc attagtcata gtagtagtta catatcctac 180gcagactcag tgaagggccg attcaccatc tccagagaca acgccaagaa ttcactgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gaaagggtat 300tacgatattt tgactggttc tctctttgac tactggggcc agggaaccct ggtcaccgtc 360tcctca 366336122PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VH excluding signal sequence of MOG 418 336Gln Val Tyr Leu Val Gln Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ser Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Ser His Ser Ser Ser Tyr Ile Ser Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Gly Tyr Tyr Asp Ile Leu Thr Gly Ser Leu Phe Asp Tyr Trp 100 105 110Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120337321DNAArtificial SequenceThe Description of the artificial sequence base sequence encoding VL excluding signal sequence of MOG 418 337gaaattgtgt tgacgcagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agctacttag cctggtacca acagaaacct 120ggccaggctc ccaggctcct catctatgat gcatccaaca gggccactgg catcccagcc 180aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag actggagcct 240gaagattttg cagtgtatta ctgtcagcag tatggtagct caccattcac tttcggccct 300gggaccaaag tggatatcaa a 321338107PRTArtificial SequenceThe Description of the artificial sequence amino acid sequence of VL excluding signal sequence of MOG 418 338Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro Phe 85 90 95Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys 100 105

Claims

1. An antibody which binds to myelin oligodendrocyte glycoprotein (MOG) or an antibody fragment thereof, wherein the antibody comprises any of the (a) to (q): (a) an antibody in which the amino acid sequences of complementarily determining regions (CDRs) 1 to 3 of the heavy chain variable region (VH) of the antibody comprise the amino acid sequences of SEQ ID NOs: 16, 17 and 18, respectively, and in which the amino acid sequences of CDRs 1 to 3 of the light chain variable region (VL) of the antibody comprise the amino acid sequences of SEQ ID NOs: 22, 23 and 24, respectively, (b) an antibody in which the amino acid sequences of CDRs 1 to 3 of VH of the antibody comprise the amino acid sequences of SEQ ID NOs: 28, 29 and 30, respectively, and in which the amino acid sequences of CDRs 1 to 3 of VL of the antibody comprise the amino acid sequences of SEQ ID NOs: 34, 35 and 36, respectively, (c) an antibody fragment in which the amino acid sequences of CDRs 1 to 3 of a heavy chain variable region of a heavy chain antibody (VHH) comprise the amino acid sequences of SEQ ID NOs: 40, 41 and 42, respectively, (d) an antibody in which the amino acid sequences of CDRs 1 to 3 of VH of the antibody comprise the amino acid sequences of SEQ ID NOs: 153, 154 and 155, respectively, and in which the amino acid sequences of CDRs 1 to 3 of VL of the antibody comprise the amino acid sequences of SEQ ID NOs: 158, 159 and 160, respectively, (e) an antibody in which the amino acid sequences of CDRs 1 to 3 of VH of the antibody comprise the amino acid sequences of SEQ ID NOs: 163, 164 and 165, respectively, and in which the amino acid sequences of CDRs 1 to 3 of VL of the antibody comprise the amino acid sequences of SEQ ID NOs: 168, 169 and 170, respectively, (f) an antibody in which the amino acid sequences of CDRs 1 to 3 of VH of the antibody comprise the amino acid sequences of SEQ ID NOs: 173, 174 and 175, respectively, and in which the amino acid sequences of CDRs 1 to 3 of VL of the antibody comprise the amino acid sequences of SEQ ID NOs: 178, 179 and 180, respectively, (g) an antibody in which the amino acid sequences of CDRs 1 to 3 of VH of the antibody comprise the amino acid sequences of SEQ ID NOs: 183, 184 and 185, respectively, and in which the amino acid sequences of CDRs 1 to 3 of VL of the antibody comprise the amino acid sequences of SEQ ID NOs: 188, 189 and 190, respectively, (h) an antibody in which the amino acid sequences of CDRs 1 to 3 of VH of the antibody comprise the amino acid sequences of SEQ ID NOs: 193, 194 and 195, respectively, and in which the amino acid sequences of CDRs 1 to 3 of VL of the antibody comprise the amino acid sequences of SEQ ID NOs: 198, 199 and 200, respectively, (i) an antibody in which the amino acid sequences of CDRs 1 to 3 of VH of the antibody comprise the amino acid sequences of SEQ ID NOs: 203, 204 and 205, respectively, and in which the amino acid sequences of CDRs 1 to 3 of VL of the antibody comprise the amino acid sequences of SEQ ID NOs: 208, 209 and 210, respectively, (j) an antibody in which the amino acid sequences of CDRs 1 to 3 of VH of the antibody comprise the amino acid sequences of SEQ ID NOs: 213, 214 and 215, respectively, and in which the amino acid sequences of CDRs 1 to 3 of VL of the antibody comprise the amino acid sequences of SEQ ID NOs: 218, 219 and 220, respectively, (k) an antibody in which the amino acid sequences of CDRs 1 to 3 of VH of the antibody comprise the amino acid sequences of SEQ ID NOs: 223, 224 and 225, respectively, and in which the amino acid sequences of CDRs 1 to 3 of VL of the antibody comprise the amino acid sequences of SEQ ID NOs: 228, 229 and 230, respectively, (l) an antibody in which the amino acid sequences of CDRs 1 to 3 of VH of the antibody comprise the amino acid sequences of SEQ ID NOs: 233, 234 and 235, respectively, and in which the amino acid sequences of CDRs 1 to 3 of VL of the antibody comprise the amino acid sequences of SEQ ID NOs: 238, 239 and 240, respectively, (m) an antibody in which the amino acid sequences of CDRs 1 to 3 of VH of the antibody comprise the amino acid sequences of SEQ ID NOs: 243, 244 and 245, respectively, and in which the amino acid sequences of CDRs 1 to 3 of VL of the antibody comprise the amino acid sequences of SEQ ID NOs: 248, 249 and 250, respectively, (n) an antibody which competes in binding to MOG with at least one of the antibodies described in (a) to (m), (o) an antibody which binds to an epitope comprising an epitope to which any one of the antibodies described in (a) to (m) binds, (p) an antibody which binds to the same epitope as an epitope to which any one of the antibodies described in (a) to (m) binds, and (q) an antibody which comprises an amino acid sequence having homology of 85% or higher to the amino acid sequence of any one of the antibodies described in (a) to (m).

2. The antibody or the antibody fragment according to claim 1, wherein the antibody is selected from the group consisting of (a) to (m), (n1) to (n22) and (o): (a) an antibody in which the amino acid sequence of VH comprises the amino acid sequence of SEQ ID NO: 15 and in which the amino acid sequence of VL comprises the amino acid sequence of SEQ ID NO: 21, (b) an antibody in which the amino acid sequence of VH comprises the amino acid sequence of SEQ ID NO: 27 and in which the amino acid sequence of VL comprises the amino acid sequence of SEQ ID NO: 33, (c) an antibody fragment in which the amino acid sequence of VHH comprises the amino acid sequence of SEQ ID NO: 39, (d) an antibody in which the amino acid sequence of VH comprises the amino acid sequence of SEQ ID NO: 152 and in which the amino acid sequence of VL comprises the amino acid sequence of SEQ ID NO: 157, (e) an antibody in which the amino acid sequence of VH comprises the amino acid sequence of SEQ ID NO: 162 and in which the amino acid sequence of VL comprises the amino acid sequence of SEQ ID NO: 167, (f) an antibody in which the amino acid sequence of VH comprises the amino acid sequence of SEQ ID NO: 172 and in which the amino acid sequence of VL comprises the amino acid sequence of SEQ ID NO: 177, (g) an antibody in which the amino acid sequence of VH comprises the amino acid sequence of SEQ ID NO: 182 and in which the amino acid sequence of VL comprises the amino acid sequence of SEQ ID NO: 187, (h) an antibody in which the amino acid sequence of VH comprises the amino acid sequence of SEQ ID NO: 192 and in which the amino acid sequence of VL comprises the amino acid sequence of SEQ ID NO: 197, (i) an antibody in which the amino acid sequence of VH comprises the amino acid sequence of SEQ ID NO: 202 and in which the amino acid sequence of VL comprises the amino acid sequence of SEQ ID NO: 207, (j) an antibody in which the amino acid sequence of VH comprises the amino acid sequence of SEQ ID NO: 212 and in which the amino acid sequence of VL comprises the amino acid sequence of SEQ ID NO: 217, (k) an antibody in which the amino acid sequence of VH comprises the amino acid sequence of SEQ ID NO: 222 and in which the amino acid sequence of VL comprises the amino acid sequence of SEQ ID NO: 227, (l) an antibody in which the amino acid sequence of VH comprises the amino acid sequence of SEQ ID NO: 232 and in which the amino acid sequence of VL comprises the amino acid sequence of SEQ ID NO: 237, (m) an antibody in which the amino acid sequence of VH comprises the amino acid sequence of SEQ ID NO: 242 and in which the amino acid sequence of VL comprises the amino acid sequence of SEQ ID NO: 247, (n1) an antibody in which the amino acid sequence of VH comprises the amino acid sequence of SEQ ID NO: 252 and in which the amino acid sequence of VL comprises the amino acid sequence of SEQ ID NO: 254, (n2) an antibody in which the amino acid sequence of VH comprises the amino acid sequence of SEQ ID NO: 256 and in which the amino acid sequence of VL comprises the amino acid sequence of SEQ ID NO: 258, (n3) an antibody in which the amino acid sequence of VH comprises the amino acid sequence of SEQ ID NO: 260 and in which the amino acid sequence of VL comprises the amino acid sequence of SEQ ID NO: 262, (n4) an antibody in which the amino acid sequence of VH comprises the amino acid sequence of SEQ ID NO: 264 and in which the amino acid sequence of VL comprises the amino acid sequence of SEQ ID NO: 266, (n5) an antibody in which the amino acid sequence of VH comprises the amino acid sequence of SEQ ID NO: 268 and in which the amino acid sequence of VL comprises the amino acid sequence of SEQ ID NO: 270, (n6) an antibody in which the amino acid sequence of VH comprises the amino acid sequence of SEQ ID NO: 272 and in which the amino acid sequence of VL comprises the amino acid sequence of SEQ ID NO: 274, (n7) an antibody in which the amino acid sequence of VH comprises the amino acid sequence of SEQ ID NO: 276 and in which the amino acid sequence of VL comprises the amino acid sequence of SEQ ID NO: 278, (n8) an antibody in which the amino acid sequence of VH comprises the amino acid sequence of SEQ ID NO: 280 and in which the amino acid sequence of VL comprises the amino acid sequence of SEQ ID NO: 282, (n9) an antibody in which the amino acid sequence of VH comprises the amino acid sequence of SEQ ID NO: 284 and in which the amino acid sequence of VL comprises the amino acid sequence of SEQ ID NO: 286, (n10) an antibody in which the amino acid sequence of VH comprises the amino acid sequence of SEQ ID NO: 288 and in which the amino acid sequence of VL comprises the amino acid sequence of SEQ ID NO: 290, (n11) an antibody in which the amino acid sequence of VH comprises the amino acid sequence of SEQ ID NO: 292 and in which the amino acid sequence of VL comprises the amino acid sequence of SEQ ID NO: 294, (n12) an antibody in which the amino acid sequence of VH comprises the amino acid sequence of SEQ ID NO: 296 and in which the amino acid sequence of VL comprises the amino acid sequence of SEQ ID NO: 298, (n13) an antibody in which the amino acid sequence of VH comprises the amino acid sequence of SEQ ID NO: 300 and in which the amino acid sequence of VL comprises the amino acid sequence of SEQ ID NO: 302, (n14) an antibody in which the amino acid sequence of VH comprises the amino acid sequence of SEQ ID NO: 304 and in which the amino acid sequence of VL comprises the amino acid sequence of SEQ ID NO: 306, (n15) an antibody in which the amino acid sequence of VH comprises the amino acid sequence of SEQ ID NO: 308 and in which the amino acid sequence of VL comprises the amino acid sequence of SEQ ID NO: 310, (n16) an antibody in which the amino acid sequence of VH comprises the amino acid sequence of SEQ ID NO: 312 and in which the amino acid sequence of VL comprises the amino acid sequence of SEQ ID NO: 314, (n17) an antibody in which the amino acid sequence of VH comprises the amino acid sequence of SEQ ID NO: 316 and in which the amino acid sequence of VL comprises the amino acid sequence of SEQ ID NO: 318, (n18) an antibody in which the amino acid sequence of VH comprises the amino acid sequence of SEQ ID NO: 320 and in which the amino acid sequence of VL comprises the amino acid sequence of SEQ ID NO: 322, (n19) an antibody in which the amino acid sequence of VH comprises the amino acid sequence of SEQ ID NO: 324 and in which the amino acid sequence of VL comprises the amino acid sequence of SEQ ID NO: 326, (n20) an antibody in which the amino acid sequence of VH comprises the amino acid sequence of SEQ ID NO: 328 and in which the amino acid sequence of VL comprises the amino acid sequence of SEQ ID NO: 330, (n21) an antibody in which the amino acid sequence of VH comprises the amino acid sequence of SEQ ID NO: 332 and in which the amino acid sequence of VL comprises the amino acid sequence of SEQ ID NO: 334, (n22) an antibody in which the amino acid sequence of VH comprises the amino acid sequence of SEQ ID NO: 336 and in which the amino acid sequence of VL comprises the amino acid sequence of SEQ ID NO: 338, and (o) an antibody which comprises an amino acid sequence having homology of 85% or higher to the amino acid sequence of any one of the antibodies described in (a) to (m) and (n1) to (n22).

3. The antibody or the antibody fragment according to claim 1, wherein the antibody or the antibody fragment is a bispecific antibody.

4. The antibody or the antibody fragment according to claim 3, wherein the bispecific antibody binds to MOG and an antigen that is present in a brain.

5. The antibody or the antibody fragment according to claim 3, wherein the bispecific antibody comprises an antigen binding site which binds to MOG and an antigen binding site which binds to an antigen that is present in a brain.

6. The antibody fragment according to claim 1 which is selected from the group consisting of Fab, Fab', F(ab').sub.2, a single chain antibody (scFv), a dimerized V region (diabody), a disulfide-stabilized V region (dsFv), VHH, and a peptide comprising CDR.

7. The antibody or the antibody fragment according to claim 1, wherein the antibody is a genetically recombinant antibody.

8. The antibody or the antibody fragment according to claim 1, wherein the antibody is selected from the group consisting of a chimeric antibody, a humanized antibody, and a human antibody.

9. A composition which comprises the antibody or the antibody fragment according to claim 1.

10. The composition according to claim 9, wherein the composition further comprises a carrier or a stabilizing agent.

11. The composition according to claim 9, wherein the composition further comprises one or more pharmacologically acceptable carriers.