CN113402602B - Novel coronavirus SARS-CoV-2 neutralizing antibody and application thereof - Google Patents

Novel coronavirus SARS-CoV-2 neutralizing antibody and application thereof Download PDF

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CN113402602B
CN113402602B CN202010484383.XA CN202010484383A CN113402602B CN 113402602 B CN113402602 B CN 113402602B CN 202010484383 A CN202010484383 A CN 202010484383A CN 113402602 B CN113402602 B CN 113402602B
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CN113402602A (en
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赵文祥
刘明耀
魏海涛
褚敏
晁瑞华
尚玉栓
王平
李亚男
夏永洋
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Zhejiang Xiangyao Biomedical Co ltd
Shanghai Xiangyao Biotechnology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56983—Viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
    • C07K2317/622—Single chain antibody (scFv)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/005—Assays involving biological materials from specific organisms or of a specific nature from viruses
    • G01N2333/08—RNA viruses
    • G01N2333/165—Coronaviridae, e.g. avian infectious bronchitis virus

Abstract

The invention discloses an antibody, which can be combined to an RBD region in a Spike protein S1 subunit of a novel coronavirus SARS-CoV-2 so as to block the combination activity of a host cell membrane surface receptor ACE2 and a Spike protein; the antibody is a neutralizing fully human antibody; wherein the antibody comprises a heavy chain VH and a light chain VL, each having the variable regions CDR1, CDR2 and CDR 3. The invention also relates to relative application of the antibody, in particular to preparation of a complete IgG antibody and an affinity maturation antibody, and application of the corresponding antibody in treatment and/or prevention of novel coronavirus SARS-CoV-2. The fully humanized scFv single-chain antibody and the IgG antibody thereof obtained by screening can recognize and combine the RBD region of Spike protein, can effectively block the binding activity of ACE2 and the Spike protein, have no toxicity to cells, can obviously inhibit the cytopathic effect caused by virus infection, and obviously enhance the affinity of the antibody after the affinity is mature and the blocking effect on the Spike protein and ACE 2.

Description

Novel coronavirus SARS-CoV-2 neutralizing antibody and application thereof
Technical Field
The invention relates to the field of biomedicine, in particular to a novel coronavirus SARS-CoV-2 neutralizing antibody and application thereof.
Background
The mean incubation period of the pneumonia of the novel coronavirus (SARS-CoV-2) is 3-7 days, and the symptoms of the upper respiratory tract infection are not prominent. Part of patients infected by the novel coronavirus only show low fever, slight weakness and the like, and do not have the pulmonary inflammation. And the patients with severe and critical diseases can show moderate-low fever, even no obvious fever. These non-specific clinical manifestations present even greater challenges to epidemic control. Effective vaccines and therapeutic drugs play a critical role in controlling viral transmission and improving patient prognosis. However, up to now, there is no relevant vaccine against coronaviruses. In the aspect of drug therapy, broad-spectrum interferon and lopinavir/ritonavir are mainly adopted for antiviral treatment of novel coronavirus infection, the curative effect is not obvious, and no specific antiviral drug exists, so that a corresponding therapeutic drug is urgently needed to be developed.
The neutralizing antibody can be used for specifically and effectively preventing and treating the virus infection. However, the availability of human plasma and/or immunoglobulins with high affinity against pathogens requires a large donation by convalescent patients and presents other potential infection risks, thereby limiting the widespread use of these human-derived products. With the research on coronaviruses, it is now clear that the Spike protein on the surface of coronaviruses plays a key role in the invasion of viruses into hosts, and there is a Receptor Binding Domain (RBD) in the S1 subunit of the protein, which binds to the cell surface of a host and is responsible for recognizing cell receptors. Thus, an antibody that specifically binds to the RBD region will have good virus neutralization. As can be seen by aligning the sequence of the Spike protein RBD of SARS-CoV-2, SARS-CoV and MERS-CoV, the sequence similarity of SARS-CoV-2 and SARS-CoV in RBD region is 73.5%. SARS-CoV can enter into cells by binding with host cell membrane surface receptor ACE2 through this region, and thus like SARS-CoV, develops antibodies against the SARS-CoV-2RBD region of the novel coronavirus or has a virus-neutralizing effect. It was shown that, unlike SARS-CoV, several critical amino acids in the RBD region of the Spike protein of the novel SARS-CoV-2 coronavirus, which bind to ACE2, are mutated, and that neutralizing antibodies against SARS-CoV, which have been developed in the past, may not have a neutralizing effect on the virus. Thus, there is a need to develop new neutralizing antibodies against SARS-CoV-2 novel coronavirus.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides a novel coronavirus SARS-CoV-2 neutralizing antibody and a preparation method and application thereof.
In order to achieve the purpose, the invention adopts the following technical scheme:
the first aspect of the invention provides an antibody, which can bind to the RBD region in the S1 subunit of Spike protein of the novel coronavirus SARS-CoV-2, thereby blocking the binding activity of the host cell membrane surface receptor ACE2 and Spike protein.
In order to further optimize the technical scheme, the technical measures adopted by the invention also comprise:
further, the antibody is a neutralizing fully human antibody.
Further, the antibody comprises a heavy chain VH and a light chain VL, each comprising the variable regions CDR1, CDR2, and CDR 3; wherein, the first and the second end of the pipe are connected with each other,
the amino acid sequence of CDR1 of VH is selected from one of SEQ ID NO.63-SEQ ID NO.76, SEQ ID NO.303-SEQ ID NO. 305;
and/or the amino acid sequence of CDR2 of VH is selected from one of SEQ ID NO.77-SEQ ID NO.86, SEQ ID NO.306-SEQ ID NO. 308;
and/or the amino acid sequence of CDR3 of VH is selected from one of SEQ ID NO.87-SEQ ID NO.104, SEQ ID NO.309-SEQ ID NO. 312;
and/or the amino acid sequence of the CDR1 of the VL is selected from one of SEQ ID NO.105-SEQ ID NO.119, SEQ ID NO.313-SEQ ID NO. 315;
and/or the amino acid sequence of the CDR2 of the VL is selected from one of SEQ ID NO.120-SEQ ID NO.126 and SEQ ID NO. 316;
and/or the amino acid sequence of the CDR3 of the VL is selected from one of SEQ ID NO.127-SEQ ID NO.152, SEQ ID NO.317-SEQ ID NO. 327.
Further, the amino acid sequence of VH of the antibody is selected from one of SEQ ID NO.1-SEQ ID NO.30, SEQ ID NO.279-SEQ ID NO. 289; and/or the amino acid sequence of the VL of the antibody is selected from one of SEQ ID NO.31-SEQ ID NO.62, SEQ ID NO.290-SEQ ID NO. 302.
Still further, the amino acid sequence of VH of the antibody is selected from one of SEQ ID NO.2-SEQ ID NO.4, SEQ ID NO. 14; and/or the amino acid sequence of the VL of the antibody is selected from one of SEQ ID NO.32-SEQ ID NO.34 and SEQ ID NO. 44.
In a second aspect of the present invention, there is provided an antibody derived from any one of the above antibodies, which is selected from one of the following (1) to (4):
(1) a single-chain antibody obtained by linking the VH and VL of any one of the above-mentioned antibodies;
(2) a fusion antibody comprising the single-chain antibody of (1);
(3) a Fab comprising the VH and VL of any of the above antibodies;
(4) an intact antibody comprising the VH and VL of any one of the above antibodies.
Further, the derivative antibody is an scFv single-chain antibody, and the amino acid sequence of the scFv single-chain antibody is selected from one of SEQ ID NO.215-SEQ ID NO.246, and SEQ ID NO.356-SEQ ID NO. 368.
Further, the amino acid sequence of the scFv single-chain antibody is one of SEQ ID NO.216-SEQ ID NO.218 and SEQ ID NO. 228. More specifically, the scFv single chain antibodies are HTS0422, HTS0433, HTS0446 and HTS0483 in table 1 below, whose heavy chain, light chain and their variable region sequences are also shown in table 1.
It is understood that the scFv single-chain antibody is a fully human antibody and can be directly developed into an antibody drug for human use. Constructing and expressing the gene encoding the human scFv antibody to obtain various small molecular genetic engineering antibodies, such as Fab antibody, F (ab) 2 Single-chain antibody, nano-antibody, antibody fusion protein, IgG whole antibody and the like.
Further, the derivative antibody is an intact IgG antibody; wherein the preparation steps of the complete IgG antibody comprise: the gene segments encoding the VH and VL are subcloned into human IgG1CH vector and light chain CL expression vector respectively, transfected into cells for expression and affinity purified. Furthermore, the human IgG1CH vector was pTT5-hIgG1, the light chain CL expression vector was pTT5-hKappa, and the transfected cells were 293F cells, which were affinity purified using protein G.
The third aspect of the present invention provides a biomaterial related to any one of the above antibodies, which is selected from one of the following (a) to (B):
(A) a nucleic acid molecule encoding any one of the above antibodies or derivative antibodies;
(B) an expression cassette, a recombinant vector, a recombinant microorganism, a recombinant cell line comprising the nucleic acid molecule of (A).
It is understood that expression cassettes, recombinant vectors, recombinant microorganisms, recombinant cell lines can be prepared using methods conventional in the art.
Further, in the above biological material, the nucleic acid encoding said VH has a sequence selected from one of SEQ ID NO.153 to SEQ ID NO.182, SEQ ID NO.328 to SEQ ID NO. 342; and/or, the sequence of the nucleic acid encoding the VL is selected from one of SEQ ID NO.183-SEQ ID NO.214, SEQ ID NO.343-SEQ ID NO. 355; and/or, the sequence of the nucleic acid for coding the scFv single-chain antibody is selected from one of SEQ ID NO.247-SEQ ID NO.278 and SEQ ID NO.369-SEQ ID NO. 381.
Still further, in the above-mentioned biomaterial, the sequence of the nucleic acid encoding said VH is selected from one of SEQ ID No.154 to SEQ ID No.156, SEQ ID No. 166; and/or, the sequence of the nucleic acid encoding the VL is selected from one of SEQ ID NO.184-SEQ ID NO.186, SEQ ID NO. 196; and/or, the sequence of the nucleic acid for coding the scFv single-chain antibody is selected from one of SEQ ID NO.248-SEQ ID NO.250 and SEQ ID NO. 260.
The nucleotide sequence of the above-described antibody or derived antibody can be readily mutated by one skilled in the art using known methods, such as directed evolution and point mutation. The nucleotide which is artificially modified and has 75% or more identity to the nucleotide sequence of the antibody or the derivative antibody of the present invention is a nucleotide sequence derived from the present invention and equivalent to the sequence of the present invention as long as the nucleotide encodes the antibody or the derivative antibody and has the activity of the antibody or the derivative antibody.
Further, the number of the scFv single chain antibody is 45, wherein, an antibody heavy chain is represented by VH, and a heavy chain variable region is represented by VH CDR1, VH CDR2 and VH CDR 3; the antibody light chain is represented by VL, wherein the light chain variable regions are represented by VL CDR1, VL CDR2, and VL CDR3, and the Germline gene sequences of the variable regions of the antibody heavy chain and the antibody light chain were studied, and are represented by VH _ Germline and VL Germline, respectively.
The related sequences of the 45 scFv single chain antibodies are shown in table 1 below:
TABLE 1 related sequences of scFv Single chain antibodies
Figure GDA0002642041300000041
Figure GDA0002642041300000051
Figure GDA0002642041300000061
Figure GDA0002642041300000071
Figure GDA0002642041300000081
Figure GDA0002642041300000091
Figure GDA0002642041300000101
TABLE 1 related sequences of scFv Single chain antibodies
Figure GDA0002642041300000102
Figure GDA0002642041300000111
Figure GDA0002642041300000121
Figure GDA0002642041300000131
Figure GDA0002642041300000141
Figure GDA0002642041300000151
Figure GDA0002642041300000161
TABLE 1 related sequences of scFv Single chain antibodies
Figure GDA0002642041300000162
Figure GDA0002642041300000171
TABLE 1 related sequences of scFv Single chain antibodies
Figure GDA0002642041300000172
Figure GDA0002642041300000181
Figure GDA0002642041300000191
Figure GDA0002642041300000201
Figure GDA0002642041300000211
Figure GDA0002642041300000221
TABLE 1 related sequences of scFv Single chain antibodies
Figure GDA0002642041300000222
Figure GDA0002642041300000231
Figure GDA0002642041300000241
Figure GDA0002642041300000251
Figure GDA0002642041300000261
Figure GDA0002642041300000271
TABLE 1 related sequences of scFv Single chain antibodies
Figure GDA0002642041300000272
Figure GDA0002642041300000281
TABLE 1 related sequences of scFv Single chain antibodies
Figure GDA0002642041300000282
Figure GDA0002642041300000291
Figure GDA0002642041300000301
Figure GDA0002642041300000311
Figure GDA0002642041300000321
Figure GDA0002642041300000331
Figure GDA0002642041300000341
Figure GDA0002642041300000351
Figure GDA0002642041300000361
Figure GDA0002642041300000371
TABLE 1 related sequences of scFv Single chain antibodies
Figure GDA0002642041300000372
Figure GDA0002642041300000381
Figure GDA0002642041300000391
Figure GDA0002642041300000401
Figure GDA0002642041300000411
Figure GDA0002642041300000421
In a fourth aspect of the present invention, there is provided an affinity matured antibody obtained from any one of the antibodies described above after affinity maturation.
Further, the amino acid sequence of VH CDR1 of the affinity matured antibody is SEQ ID NO.64 or SEQ ID NO.69, the amino acid sequence of VH CDR2 is SEQ ID NO.77, SEQ ID NO.382 or SEQ ID NO.383, and the amino acid sequence of VH CDR3 is SEQ ID NO.88 or SEQ ID NO. 95; the amino acid sequence of VL CDR1 of the affinity matured antibody is SEQ ID NO.106 or SEQ ID NO.107, the amino acid sequence of VL CDR2 is SEQ ID NO.120 or SEQ ID NO.123, and the amino acid sequence of VL CDR3 is one of SEQ ID NO.129 or SEQ ID NO.392-SEQ ID NO. 396.
Further, the amino acid sequence of the VH of the affinity matured antibody is selected from one of SEQ ID NO. 384-SEQ ID NO. 387; the amino acid sequence of VL of the affinity matured antibody is selected from one of SEQ ID NO. 397-402.
Further, the sequence of the nucleic acid encoding the affinity matured antibody VH is selected from one of SEQ ID NO.388-SEQ ID NO. 391; the sequence of the nucleic acid for encoding the VL of the affinity matured antibody is selected from one of SEQ ID NO.403-SEQ ID NO. 408.
Further, the preparation step of the affinity matured antibody comprises:
designing a point mutation primer, and designing NNS (N represents any base, and S represents base C or G) aiming at the CDR region of any antibody;
performing PCR reaction according to the mutation primer designed in the step (1) to circularly batch plasmids;
step (3) carrying out plasmid recovery on the PCR reaction product in the step (2), and carrying out transformation and plasmid preparation on the PCR product;
step (4) carrying out scFv blocking activity detection on each site-directed mutated clone induced expression scFv;
and (5) performing single cloning on the mutation with high affinity, and performing identification sequencing to obtain the affinity matured antibody.
Further, the PCR reaction system and the reaction conditions thereof are as follows:
volume (uL)
Fn-primer(2μM) 5
Rn-primer(2μM) 5
Template plasmid (100ng/uL) 1
PrimerSRAR Max Premix 5
Water (W) 34
Total volume 50
Wherein, Fn and Rn are based on the sequences of light chain and heavy chain CDR1, CDR2 and CDR3 regions, only a single site of the CDR region is mutated each time, the base of the site is represented by NNS, the forward primer is sequentially named as F1-primer, F2-primer … … Fn-primer, and the reverse primer is sequentially named as R1-primer and R2-primer … … Rn-primer;
reaction conditions are as follows: denaturation at 95 deg.C for 5 min; 30S at 95 ℃, 30S at 58 ℃ and 4min at 72 ℃; 10min at 72 ℃.
Further, affinity maturation was performed for HTS0422, HTS0433, HTS0446, HTS0483 in table 1 above; HTS0433 and HTS0483 were affinity matured more specifically, and the sequence information of the antibody after affinity maturation is shown in table 2 below:
TABLE 2 affinity matured antibody sequences
Figure GDA0002642041300000441
TABLE 2 affinity matured antibody sequences
Figure GDA0002642041300000442
TABLE 2 affinity matured antibody sequences
Figure GDA0002642041300000443
Figure GDA0002642041300000451
TABLE 2 affinity matured antibody sequences
Figure GDA0002642041300000452
Figure GDA0002642041300000461
TABLE 2 affinity matured antibody sequences
Figure GDA0002642041300000462
TABLE 2 affinity matured antibody sequences
Figure GDA0002642041300000463
TABLE 2 affinity matured antibody sequences
Figure GDA0002642041300000464
Figure GDA0002642041300000471
TABLE 2 affinity matured antibody sequences
Figure GDA0002642041300000472
The fifth aspect of the invention provides a product for treating and/or preventing the novel coronavirus SARS-CoV-2 and diseases caused by the same, wherein the active ingredient of the product is any one of the above-mentioned antibody, derivative antibody, biological material or affinity matured antibody.
The sixth aspect of the invention provides an application of any one of the above antibodies, derivative antibodies, biological materials or affinity matured antibodies in preparing products for treating and/or preventing novel coronavirus SARS-CoV-2 and diseases caused by the coronavirus SARS-CoV-2.
Further, the product may be a diagnostic agent, a therapeutic drug, a vaccine, and the like.
In a seventh aspect of the present invention, there is provided a method for producing any one of the above antibodies, comprising the steps of:
step 1) establishing a fully humanized phage antibody library by using peripheral blood of a patient in a rehabilitation period infected by the novel coronavirus;
step 2) carrying out panning on the fully human phage antibody library constructed in the step 1) by using biotinylated Spike1-RBD protein to obtain potential antibodies with RBD binding activity;
step 3) screening antibodies with potential neutralizing activity by analyzing the potential antibodies obtained in step 2) at the cell and protein level to block the binding activity of ACE2 and Spike protein.
In order to further optimize the preparation method, the technical measures adopted by the invention also comprise the following steps:
further, the preparation method specifically comprises the following steps:
a. panning of the fully human antibody library Using biotinylated Spike1-RBD protein
Blocking phage antibodies at room temperature, adding antigens, incubating at room temperature, adding magnetic beads, incubating at room temperature, washing off unbound phage, eluting phage bound on the magnetic beads, neutralizing eluate, infecting Escherichia coli in logarithmic growth phase with part of phage, and preparing phage for next round of panning; gradually increasing the screening intensity of each round, and stopping the elutriation when the enrichment degree reaches more than 100 times;
b. screening of Single chain antibody Positive clones against Spike1-RBD Using phase Elisa
Selecting an escherichia coli monoclonal infected by the elutriated phage, inoculating a culture medium, transferring to a new culture medium after overnight culture, adding an auxiliary phage after the culture is carried out until the logarithmic growth phase, standing for infection, centrifuging, using the culture medium for overnight culture, centrifuging, and taking a phage supernatant for cloning identification; coating an enzyme label plate with Spike1-RBD antigen, sealing overnight, adding phage supernatant for incubation, washing away unbound phage, adding antibody for incubation, washing, developing, terminating reaction, reading at 450nm with an enzyme label apparatus, selecting clone with OD450>0.3 for sequencing, analyzing sequence, and removing molecules with potential development risk to obtain scFv single-chain antibody.
Further, the above preparation method further comprises a purification step of the scFv single chain antibody, which may be a purification method conventional in the art.
Compared with the prior art, the invention adopts the technical scheme, and has the following technical effects:
the invention establishes a fully human phage antibody library by utilizing peripheral blood of a patient in a convalescent period infected by a novel coronavirus, elutriates RBD region protein of the virus Spike and cells over expressing the region, analyzes the binding activity of an antibody blocking ACE2 and the Spike protein on the levels of the cells and the proteins, screens out an antibody with potential neutralization activity, and prepares a complete IgG antibody and matures the affinity according to the antibody. The examples show that the fully humanized scFv single-chain antibody and the IgG antibody thereof obtained by the invention can recognize and combine the RBD region of the Spike protein, can effectively block the combination activity of ACE2 and the Spike protein, and the antibody with each concentration (30, 15, 7.5, 3.75, 1.875 and 0.938 mug/ml) is nontoxic to cells, safe and reliable, can obviously inhibit cytopathic effect caused by virus infection under a certain concentration, can effectively inhibit new coronavirus, and compared with the original sequence, the antibody sequence after affinity maturation has certain degree of improvement of affinity, the blocking effect on the Spike1-RBD and ACE2 is obviously enhanced, and the antibodies have application value in treating and/or preventing the novel coronavirus SARS-CoV-2.
Drawings
FIG. 1 is a schematic diagram of ELISA detection of binding activity of panning terminated monoclonal scFv to Spike1-RBD protein in one embodiment of the present invention;
FIG. 2 is a schematic representation of the PAGE identification after scFv purification according to an embodiment of the invention;
FIG. 3 is a schematic diagram showing ELISA detection of binding activity of purified scFv to Spike1-RBD protein according to one embodiment of the present invention;
FIG. 4 is a schematic diagram of ELISA detection of purified scFv blocking the binding of Spike1-RBD to ACE2 in one embodiment of the present invention;
FIG. 5 is a diagram showing FACS detection of scFv blockade of the binding of Spike1-RBD to ACE2 in accordance with one embodiment of the present invention; wherein NC (negative control) is an unrelated sequence;
FIGS. 6A to 6G are schematic diagrams showing ELISA detection of the binding activity of an IgG form of antibody to Spike1-RBD protein according to an embodiment of the present invention; wherein NC (negative control) is an unrelated sequence;
FIGS. 7A-7F are schematic diagrams of ELISA detection of IgG antibodies blocking the binding of Spike1-RBD to ACE2 according to an embodiment of the present invention;
FIG. 8 is a graphical representation of the results of the scFv antibody neutralization activity assay in one embodiment of the present invention;
FIG. 9 is a diagram showing ELISA detection of binding activity of affinity matured sequence to Spike1-RBD according to one embodiment of the invention;
FIG. 10 is a schematic diagram of ELISA detection of IgG antibody blocking the binding of Spike1-RBD to ACE2 in one embodiment of the invention.
Detailed Description
The invention relates to an antibody, which can be combined with RBD region in the S1 subunit of Spike protein of novel coronavirus SARS-CoV-2, thereby blocking the combination activity of host cell membrane surface receptor ACE2 and Spike protein; the antibody is a neutralizing fully human antibody; wherein the antibody comprises a heavy chain VH and a light chain VL, each having the variable regions CDR1, CDR2 and CDR 3. The invention also relates to relative application of the antibody, in particular to preparation of a complete IgG antibody and an affinity mature antibody, and application of the corresponding antibody in treatment and/or prevention of novel coronavirus SARS-CoV-2.
The following description of the embodiments of the present invention will be made with reference to the accompanying drawings. The following examples are only for illustrating the technical solutions of the present invention more clearly, and the protection scope of the present invention is not limited thereby. Experimental procedures without specific conditions noted in the following examples were selected according to methods and conditions conventional in the art, or according to the commercial specifications.
Example 1-screening of neutralizing antibodies
This example is the screening of fully humanized scFv single chain antibodies, comprising the steps of:
(1) establishing a fully human phage antibody library;
peripheral blood from patients who had been infected with 2019-nCOV virus and recovered was collected and their serum titers were determined. Selecting high-titer sample, separating lymphocyte, extracting total RNA of cell, synthesizing cDNA, utilizing specific antibody heavy chain primer and light chain primer to amplify variable region gene of antibody, cloning it on phage display carrier and transferring it into host cell. And (3) evaluating the diversity and effectiveness of the antibody library by NGS sequencing and utilizing quality control indexes such as library capacity, clone positive rate, heavy and light chain pairing, CDR3 distribution, phage display rate and the like.
(2) Screening a phage library: panning the fully human antibody repertoire with biotinylated Spike1-RBD protein;
firstly, blocking phage antibody with blocking solution (PBST/5% skimmed milk powder) at room temperature for 2h, wherein the input amount of phage is 10 10～12 pfu, then 10. mu.g of antigen, incubated for 1h at room temperature, after which 50. mu.l of pre-blocked
Figure GDA0002642041300000501
M-280Streptavidin magnetic beads, incubated at room temperature for 30 min. Washing off the unbound phage by PBST, eluting the phage bound to the magnetic beads by 0.1M HCl-Glycine, neutralizing the eluate with Tris-HCl, and taking part of phage to infect Escherichia coli TG1 in logarithmic growth phase to prepare phage for the next round of panning. Gradually increasing the screening intensity of each round, and stopping the elutriation when the enrichment degree reaches more than 100 times.
(3) Screening single-chain antibody positive clones resisting Spike1-RBD by using phase Elisa;
a single clone of TGl infected with phage after four rounds of panning was selected and inoculated into a 96-well plate in a medium of 2 YT/2% glucose/(100. mu.g/ml Ampicilline). After overnight culture at 37 ℃/250rpm, the culture medium is transferred to a new culture medium, after the culture is carried out until logarithmic growth phase, M13K07 helper phage is added, and the culture medium is statically infected for 1h at 37 ℃. Centrifugation was carried out at 4000rpm for 15min, and 2 YT/(100. mu.g/ml Ampicilline)/(70. mu.g/ml Kanamycin) was used for overnight culture at 30 ℃. And centrifuging to take phage supernatant to perform ELISA identification cloning. The Costar-9018 enzyme-labeled plate was coated with 0.5. mu.g/ml of Spike1-RBD antigen, blocked with 3% BSA overnight at 4 ℃ and incubated for 2h at 4 ℃ with phage supernatant. Unbound phage were washed away and Ml3 Bacteriophage antibody (HRP) was added and incubated for 1h at 4 ℃. After washing, adding TMB color development solution for color development, stopping reaction by using 2M HCl, reading at 450nm by using an enzyme-labeling instrument, judging that the clone with OD450> three times of baseline, namely OD450>0.3 is positive clone, and obtaining 470 positive clones in total. The clone with OD450>0.3 is selected for sequencing, the sequence is subjected to Germine analysis and PTMs locus analysis, after molecules with potential development risks are excluded, 45 scFv single-chain antibodies are obtained, and the ELISA detection panning termination monoclonal scFv and the binding activity result of the Spike1-RBD protein are shown in figure 1.
The resulting antibody heavy chains of the 45 anti-Spike 1-RBD single chain antibodies are represented by VH, wherein the heavy chain variable regions are represented by CDR1, CDR2 and CDR 3; the light chain of the antibody is shown as VL, wherein the light chain variable region is shown as CDR1, CDR2 and CDR3, and the numbering and related sequence information of the corresponding anti-Spike 1-RBD single chain antibody is shown in Table 1 of the summary of the invention section.
Example 2 expression purification of scFv
This example expresses and purifies 45 scFv single-chain antibodies selected in example 1, which comprises the following steps:
the Escherichia coli TGl after shaking is inoculated according to the ratio of 1:100 and cultured at 37 ℃ and 220 rpm. When OD is about 0.5, centrifuging at 8000rpm for 5min at room temperature to obtain bacterial liquid precipitate, inducing with IPTG, culturing at 30 deg.C for 12 hr, collecting expression supernatant, and purifying. The purification steps are as follows:
1) turning the bottle slightly upside down for several times to mix the medium evenly;
2) sucking a certain amount of medium, adding the medium into a column, wherein the height of the column is about 3-4 cm, and sealing the column when the medium is settled to the bottom;
3) draining the storage solution, and adding 10mL of balance buffer solution to balance the chromatography medium;
4) centrifuging at 4000rpm at 4 deg.C for 10min in a centrifuge bottle, transferring the supernatant to a new centrifuge bottle, and centrifuging at 12000rpm at 4 deg.C for 30 min;
5) loading the sample, and controlling the flow rate to be 1 mL/min;
6)25mL of 10mM imidazole washing buffer is used for washing the column, and the flow rate is controlled to be 1 mL/min;
7)25mL of 20mM imidazole washing buffer is used for washing the column, and the flow rate is controlled to be 1 mL/min;
8) washing the column with 5mL of 250mM imidazole elution buffer solution, controlling the flow rate to be 1mL/min, and collecting the eluent;
9) concentrating, adding the eluate into an ultrafiltration tube, centrifuging at 1500rpm and 4 deg.C for 10min, and concentrating scFv;
10) PAGE identification and concentration determination.
The scFv of the 45 samples was purified, the detection result after purification is shown in fig. 2, each sample obtained more than 0.5mg, and the subsequent verification of the related activities is exemplified by HTS0422, HTS0433, HTS0446, and HTS 0483.
Example 3 detection of the binding Activity of scFv by ELISA
This example uses antibodies HTS0422, HTS0433, HTS0446 and HTS0483 as examples to detect binding of purified scFv to Spike1-RBD antigen using ELISA. The method comprises the following specific steps:
1)384-well plate coated antigen, each hole adding 25 u L1 u g/mL concentration of Spike1-RBD antigen, sealing, 4 degrees C coating overnight;
2) discarding the supernatant, washing 3 times with 100. mu.L Wash Buffer per well;
3) sealing each hole with 25 mu L of sealing liquid at room temperature for 1 hour, discarding the liquid of the sealed enzyme label plate, and washing each hole with 100 mu L of Wash Buffer for 3 times;
4) diluting the scFv antibody with the highest concentration of 200 mu g/ml, and carrying out four-time gradient dilution for 8 points;
5) diluted antibody 25 μ L/well was added to the appropriate wells and incubated for 2 hours at room temperature;
6) discarding the supernatant, drying the supernatant by using absorbent paper, and washing for 3 times by using 100 mu L of Wash Buffer;
7) adding diluted 25 mu L of Anti-C-myc-HRP into each well, and incubating for 1 hour at room temperature;
8) discarding the supernatant, drying the supernatant by using absorbent paper, and washing for 5 times by using 100 mu L of Wash Buffer;
9) adding 25 μ L of 1X TMB into each well, shaking in dark at room temperature, and developing for 10 min;
10) adding 25 mu L of stop solution into each hole;
11) reading a light absorption value of 450nm by using a microplate reader;
the detection results of the scFv antibody are shown in FIG. 3, and the antibodies HTS0422, HTS0433, HTS0446 and HTS0483 can be specifically combined with Spike1-RBD antigen and show a dose-effect relationship.
Example 4 ELISA detection of scFv blocking the binding of Spike1-RBD to ACE2 receptor
In this example, antibodies HTS0422, HTS0433, HTS0446 and HTS0483 were used as examples to detect purified scFv to block the binding of Spike1-RBD to ACE2 receptor by ELISA. The method comprises the following specific steps:
1)384-well plate coating antigen, each hole adding 25 u L1 u g/mL concentration ACE2 antigen, sealing, 4 degrees C coating overnight;
2) discarding the supernatant, washing 3 times with 100. mu.L Wash Buffer per well;
3) sealing each hole with 25 mu L of sealing liquid for 1 hour at room temperature, discarding the liquid of the sealed enzyme label plate, and washing each hole with 100 mu L of Wash Buffer for 3 times;
4) diluting the scFv antibody with the highest concentration of 200 mu g/ml, diluting by four times of gradient, mixing with Spike-RBD protein uniformly at 8 points, and incubating for 1 hour at room temperature;
5) add 25. mu.l of pre-treated scFv and Spike-RBD mix per well and incubate for 2 hours at room temperature;
6) discarding the supernatant, drying the supernatant by using absorbent paper, and washing for 3 times by using 100 mu L of Wash Buffer;
7) adding diluted 25 mu L of Anti-mFC-HRP into each hole, and incubating for 1 hour at room temperature;
8) discarding the supernatant, drying the supernatant by using absorbent paper, and washing for 5 times by using 100 mu L of Wash Buffer;
9) adding 25 μ L of 1X TMB into each well, shaking in dark at room temperature, and developing for 10 min;
10) adding 25 mu L of stop solution into each hole;
11) the absorbance at 450nm was read using a microplate reader.
The detection result of the scFv antibody is shown in FIG. 4, and the antibodies HTS0422, HTS0433, HTS0446 and HTS0483 can block the combination of Spike1-RBD and AEC2, and show a dose-effect relationship.
Example 5-FACS detection of scFv to Block the binding of Spike1-RBD to the ACE2 receptor
In this example, FACS was used to detect purified scFv to block the binding of Spike1-RBD to ACE2 receptor using antibodies HTS0422, HTS0433, HTS0446 and HTS0483 as examples. The method comprises the following specific steps:
1) diluting the antibody in a gradient with the highest concentration of 100 mu g/ml by four times;
2) mixing 30 μ L of diluted antibody with 30 μ L of Spike1-RBD protein of 0.1 μ g/ml, and incubating on ice for 30 min;
3) digestion of cells, 96-well plate 3X 10 plates per well 5 A cell;
4) centrifuging at 4 deg.C and 1500rpm for 1min, and discarding the supernatant;
5) adding 50 μ L of the pretreated antigen-antibody mixture into each well, and incubating on ice for 30 min;
6) adding 150 μ L DPBS into each well, centrifuging at 4 deg.C and 1500rpm for 1min, and removing supernatant;
7) DPBS 1:800 dilution secondary antibody, 50 μ L heavy suspension, ice incubation for 30-60 min;
8) adding 150 microliter of DPBS into each hole, centrifuging at 4 ℃ and 1500rpm for 1min, and removing supernatant;
9) adding 200 μ L DPBS into each well, centrifuging at 4 deg.C and 1500rpm for 1min, and removing supernatant;
10) add 100. mu.L of DPBS resuspended cells per well and flow assay.
The detection results of the scFv antibody are shown in FIG. 5, and the antibodies HTS0422, HTS0433, HTS0446 and HTS0483 all block the combination of Spike1-RBD and AEC2, and show a dose-effect relationship.
Example 6 expression purification of intact IgG antibodies
This example is to prepare a complete IgG antibody from the VH and VL gene segments of the scFv single chain antibody of example 1, comprising the steps of: VH and VL gene fragments of scFv were subcloned into human IgG1CH vector pTT5-hIgG1 and kappa light chain CL expression vector pTT5-hKappa, respectively, simultaneously transfected into 293F cells for expression and affinity purification by protein G.
Among all 45 positive clones, 37 whole IgG antibodies were selected to be expressed, HTS0390, HTS0414, HTS0422, HTS0433, HTS0446, HTS0448, HTS0460, HTS0461, HTS0471, HTS0472, HTS0476, HTS0477, HTS0478, HTS0483, HTS0777, HTS0778, HTS0829, HTS0842, HTS0888, HTS0889, HTS0895, HTS0896, HTS0910, HTS0916, HTS0917, HTS0921, HTS0922, HTS0936, HTS0943, HTS0944, HTS0948, HTS1021, HTS1049, HTS1072, HTS1099, HTS1125, HTS 1128.
Example 7 ELISA detection of the binding Activity of IgG antibodies
This example shows that the purified whole IgG antibody of example 6 was tested for binding to Spike1-RBD antigen by ELISA. The method comprises the following specific steps:
1)384-well plate coating antigen, each hole add 25 u L1 u g/mL concentration of Spike1-RBD antigen, seal, 4 degrees C coating overnight;
2) discarding the supernatant, washing 3 times with 100. mu.L Wash Buffer per well;
3) sealing each hole with 25 mu L of sealing liquid at room temperature for 1 hour, discarding the liquid of the sealed enzyme label plate, and washing each hole with 100 mu L of Wash Buffer for 3 times;
4) diluting IgG antibody with the highest concentration of 50 mug/ml, and performing three-time gradient dilution for 12 points;
5) add diluted antibody 25 μ L/well to appropriate wells and incubate for 2 hours at room temperature;
6) discarding the supernatant, drying the supernatant by using absorbent paper, and washing for 3 times by using 100 mu L of Wash Buffer;
7) adding diluted 25 mu L of Anti-human-FC-HRP into each hole, and incubating for 1 hour at room temperature;
8) discarding the supernatant, drying the supernatant by using absorbent paper, and washing for 5 times by using 100 mu L of Wash Buffer;
9) adding 25 μ L of 1X TMB into each well, shaking in dark at room temperature, and developing for 10 min;
10) adding 25 mu L of stop solution into each hole;
11) reading a light absorption value of 450nm by using a microplate reader;
the results of the above IgG antibody tests are shown in FIGS. 6A-6G, and the IgG antibodies were able to specifically bind to Spike1-RBD antigen and showed dose-response relationship.
Example 8 ELISA detection of IgG antibodies blocking the binding of Spike1-RBD to ACE2 receptor
This example uses ELISA to detect that the purified whole IgG antibody of example 6 blocks the binding of Spike1-RBD to ACE2 receptor. The method comprises the following specific steps:
1)384-well plate coated antigen, each well is added with 25 μ L ACE2 antigen with the concentration of 1.5 μ g/mL, sealed and coated overnight at 4 ℃;
2) discarding the supernatant, washing 3 times with 100. mu.L Wash Buffer per well;
3) sealing each hole with 25 mu L of sealing liquid at room temperature for 1 hour, discarding the liquid of the sealed enzyme label plate, and washing each hole with 100 mu L of Wash Buffer for 3 times;
4) diluting IgG antibody with the highest concentration of 100 mu g/ml, diluting with three times of gradient, mixing with Spike-RBD protein at 11 points, and incubating for 1 hour at room temperature;
5) add 25. mu.l of the pre-treated IgG antibody and the Spike-RBD mixture per well and incubate for 2 hours at room temperature;
6) discarding the supernatant, drying the supernatant by using absorbent paper, and washing for 3 times by using 100 mu L of Wash Buffer;
7) adding diluted 25 mu L of Anti-mFC-HRP into each well, and incubating for 1 hour at room temperature;
8) discarding the supernatant, drying the supernatant by using absorbent paper, and washing for 5 times by using 100 mu L of Wash Buffer;
9) adding 25 μ L of 1X TMB into each well, shaking in dark at room temperature, and developing for 10 min;
10) adding 25 mu L of stop solution into each hole;
11) the absorbance at 450nm was read using a microplate reader.
The detection results of the IgG antibodies are shown in FIGS. 7A-7F, and the IgG antibodies can block the combination of Spike1-RBD and AEC2 and show a dose-effect relationship, wherein the HTS0422, HTS0433, HTS0483, HTS0446 and HTS0778 have the best effect.
Example 9 antibody toxicity test
In this example, the CCK8 experiment is performed to verify the antibody toxicity effects of antibodies HTS0422, HTS0433, HTS0483, HTS0446 and HTS0390, and the specific steps are as follows:
(1) serum-free medium was used to dilute the anti-neocoronaviruse antibodies HTS0422, HTS0433l, HTS0446, HTS0390, HTS0483 at an initial antibody concentration of 60 μ g/ml, 2-fold gradient dilution, with 6 dilutions co-diluted, i.e. antibody concentrations formulated at 60, 30, 15, 7.5, 3.75, 1.875 μ g/ml.
(2) In 96-well cell culture plates, 100. mu.l of antibody fluid was added at each concentration (60, 30, 15, 7.5, 3.75, 1.875. mu.g/ml) per well. Vero-E6 cells (1X 10) were then added 5 Cell concentration/ml was suspended in 10% FBS in MEM medium) 100 μ l, antibody final concentrations were: 30. 15, 7.5, 3.75, 1.875, 0.938 mug/ml. The cell culture plate is vibrated, mixed evenly and then placed in 5 percent CO 2 In the incubator, 4 multiple wells were set.
(3) After 6 days of incubation, 20. mu.l/well of CCK-8 reagent (MCE, USA) was added to each well, and after 3 hours of incubation, OD at 450nm was measured using a microplate reader to analyze the dose-toxic effect of the antibody on the cells, and the results are shown in the following table:
Figure GDA0002642041300000561
the results of the above CCK-8 assay show that the antibody tested at each concentration (30, 15, 7.5, 3.75, 1.875, 0.938. mu.g/ml) had no toxic effect on Vero-E6 cells compared to the untreated cell control.
Example 10 detection of neutralizing Activity of antibodies
In this example, the neutralizing activity of HTS0422, HTS0433, HTS0446, HTS0483, and HTS0390 antibodies was tested by a euvirus blocking assay, which specifically comprises the following steps:
(1) serum-free medium was used to dilute the anti-neocoronavirus antibodies HTS0422, HTS0433, HTS0446, HTS0483 and HTS0390 at an initial antibody concentration of 60 μ g/ml, 2-fold gradient dilutions, with 12 dilutions co-diluted, i.e. formulated antibody concentrations of 60, 30, 15, 7.5, 3.75, 1.875, 0.938, 0.469, 0.235, 0.118, 0.059, 0.029 μ g/ml.
(2) In a 96-well plate, 50. mu.l of antibody solution was added at each concentration, followed by an equal volume of 50. mu.l of neocoronaviruse containing 100TCID50 at final antibody concentrations of 30, 15, 7.5, 3.75, 1.875, 0.938, 0.469, 0.235, 0.118, 0.059, 0.029, 0.0145. mu.g/ml, mixed and incubated in a 35 ℃ incubator for 60 min. Freshly prepared Vero-E6 cell suspension (2X 10) was added to each well 5 /ml in 10% FBS-MEM) was mixed in 100. mu.l and placed in a cell culture chamber containing 5% CO2 at 35 ℃ for further 6 days. Each antibody concentration tested was plated in 4 replicates.
(3) Cell growth was observed microscopically from day 2 after inoculation, and cytopathic effect (CPE) was observed and recorded at day 4. And finally judging the result on the 6 th day according to the cytopathic effect. The neutralizing efficiency of the antibody, i.e., the lowest concentration of antibody that can protect 50% of the cells from infection with 100TCID50 virus fluid, was calculated.
(4) The effect of the antibody-treated virus on the pathology of Vero E6 cells was observed under a microscope at various concentrations, and the inhibitory effect of the antibody on the novel coronavirus was analyzed, and the results are shown in the following table and fig. 8.
Figure GDA0002642041300000571
According to the results, the cytopathic effect caused by virus infection can be obviously inhibited by the HTS0422 which is more than or equal to 1.875ug/ml, the HTS0433 which is more than or equal to 1.875ug/ml, the HTS0446 which is more than or equal to 7.5ug/ml and the HTS0483 which is more than or equal to 1.875 ug/ml. HTS0390, however, had no significant antiviral effect at all concentrations tested.
Example 11 affinity maturation of antibodies
The above examples prove that the binding effect and blocking effect of HTS0422, HTS0433, HTS0446 and HTS0483 are the best, and the affinity maturation of HTS0433 and HTS0483 is selected, and the specific steps are as follows:
(1) designing point mutation primer, designing NNS (N represents arbitrary base, S represents base C or G) aiming at CDR region of HTS0433 and HTS0483
(2) Plasmids were circularized using either HTS0433 or HTS0483 as templates.
Volume (uL)
Fn-primer(2μM) 5
Rn-primer(2μM) 5
Template plasmid (100ng/uL) 1
PrimerSRAR Max Premix 5
Water (W) 34
Total volume 50
Remarking: fn and Rn are based on sequences of HTS0433 or HTS0483 light chain and heavy chain CDR1, CDR2 and CDR3 regions, only a single site in the CDR region is mutated each time, the base of the site is represented by NNS, the forward primer is sequentially named as F1-primer, F2-primer … … Fn-primer, and the reverse primer is sequentially named as R1-primer and R2-primer … … Rn-primer.
The reaction solution was added to the PCR tube as above and mixed well. Placing the PCR reaction tube in a PCR instrument, and setting reaction conditions as follows: denaturation at 95 deg.C for 5 min; 30S at 95 ℃, 30S at 58 ℃ and 4min at 72 ℃; 10min at 72 ℃; the product can be stored for a short time at 4 ℃ and used for subsequent experiments.
(3) And (3) recovering the plasmid by using the PCR product recovery kit, and carrying out the transformation of the PCR product and the preparation of the plasmid according to a conventional method.
(4) Clones with each site-directed mutation were induced to express scFv and tested for scFv blocking activity, as described in example 2 and example 5.
(5) The high affinity mutations were identified by single cloning, step 4. High affinity clones were sequenced. The sequences after affinity maturation are shown in table 2 of the summary section.
Example 12 ELISA detection of the binding Activity of antibodies after affinity maturation
In this example, the binding force between the affinity matured antibody prepared in example 11 and the Spike1-RBD antigen was measured by ELISA, which was performed in the same manner as in example 7, and the results are shown in FIG. 9. The experimental results show that the affinity of the antibody sequence after affinity maturation is improved compared with the original sequence.
Example 13 ELISA detection of antibody blockade of the binding of Spike1-RBD to ACE2 receptor after affinity maturation
In this example, ELISA was used to detect the binding activity of the affinity matured antibody prepared in example 11 for blocking the binding activity of Spike1-RBD and ACE2, which was performed in the same manner as in example 8, and the results are shown in FIG. 10. The experimental results show that the blocking effect of AGE0003 and AGE0004 is obviously enhanced compared with the original sequence of the antibody sequence after affinity maturation.
The above examples show that the fully humanized scFv single chain antibody and IgG antibody thereof obtained by screening can recognize and bind to RBD region of Spike protein, can effectively block the binding activity of ACE2 and Spike protein, have no toxicity to cells, can obviously inhibit cytopathic effect caused by virus infection, and obviously enhance the affinity of antibody sequence after the affinity maturation and the blocking effect of Spike1-RBD and ACE2, and have application value in treating and/or preventing novel coronavirus SARS-CoV-2.
The embodiments of the present invention have been described in detail, but the embodiments are merely examples, and the present invention is not limited to the embodiments described above. Any equivalent modifications and substitutions to those skilled in the art are also within the scope of the present invention. Accordingly, equivalent changes and modifications made without departing from the spirit and scope of the present invention should be covered by the present invention.
Sequence listing
<110> Shanghai Xiang Yao Biotechnology Limited liability company
Zhejiang Xiangyao biomedical Co.,Ltd.
<120> novel coronavirus SARS-CoV-2 neutralizing antibody and application thereof
<150> 202010188367.6
<151> 2020-03-17
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Gly Arg Phe Thr Ile Ser Arg His Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Leu Val Ser Ser Gly Met Asp Val Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser
115
<210> 10
<211> 128
<212> PRT
<213> VH(Artificial Sequence)
<400> 10
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Ser Ala Tyr His Gly Asn Thr Asn Tyr Ala Gln Lys Leu
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Leu Ala Pro Ser Tyr Cys Gly Gly Asp Cys Tyr Pro Arg
100 105 110
Ala Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 11
<211> 117
<212> PRT
<213> VH(Artificial Sequence)
<400> 11
Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Val Thr Val Ser Ser Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg His Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Leu Val Ser Ser Gly Met Asp Val Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 12
<211> 128
<212> PRT
<213> VH(Artificial Sequence)
<400> 12
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Ser Gly Phe His Gly Asn Thr Asn Tyr Ala Gln Lys Leu
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Leu Ala Pro Ser Tyr Cys Gly Gly Asp Cys Tyr Pro Arg
100 105 110
Ala Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 13
<211> 117
<212> PRT
<213> VH(Artificial Sequence)
<400> 13
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Gly Ser Asn
20 25 30
Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Leu Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Leu Val Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser
115
<210> 14
<211> 118
<212> PRT
<213> VH(Artificial Sequence)
<400> 14
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ile Thr Val Ser Ser Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Ser Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Leu Gln Glu Arg Gly Gly Met Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 15
<211> 118
<212> PRT
<213> VH(Artificial Sequence)
<400> 15
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ile Thr Val Ser Ser Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Ser Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Leu Gln Glu Arg Gly Gly Met Asp Val Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 16
<211> 123
<212> PRT
<213> VH(Artificial Sequence)
<400> 16
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Arg Ser Pro Ser Ile Ala Ala Ala Ala Asn Ala Phe Asp Ile
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 17
<211> 122
<212> PRT
<213> VH(Artificial Sequence)
<400> 17
Gln Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asn Ser Gly Ala Thr Asn Phe Ala Gln Lys Phe
50 55 60
Arg Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Thr Thr Ala Tyr
65 70 75 80
Met Glu Met Ser Arg Leu Ile Ser Asp Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Arg Asp Arg Gly Phe Ser Ile Val Ser Tyr Ala Met Asp Val Trp
100 105 110
Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 18
<211> 116
<212> PRT
<213> VH(Artificial Sequence)
<400> 18
Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Asp Phe Thr Val Ser Ser Asn
20 25 30
Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Leu Ile Tyr Pro Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Leu Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Arg Gly Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 19
<211> 122
<212> PRT
<213> VH(Artificial Sequence)
<400> 19
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Glu Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Val Gly Lys Arg Gly Val Phe Leu Gly Gly Met Asp Val Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 20
<211> 121
<212> PRT
<213> VH(Artificial Sequence)
<400> 20
Gln Val Gln Leu Gln Gln Trp Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ser Val Ser Gly Gly Ser Ile Thr Gln Ile
20 25 30
Ile Tyr Tyr Trp Ala Trp Ile Arg Gln Pro Pro Gly Arg Gly Leu Glu
35 40 45
Trp Ile Gly Ser Ile Tyr Tyr Arg Gly Ser Thr Ser Ser Asn Pro Ser
50 55 60
Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Asn Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Ala Val Arg His Asp Tyr Asn Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 21
<211> 122
<212> PRT
<213> VH(Artificial Sequence)
<400> 21
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Val Gly Lys Arg Gly Val Phe Leu Gly Gly Met Asp Val Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 22
<211> 117
<212> PRT
<213> VH(Artificial Sequence)
<400> 22
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Val Thr Val Ser Ser Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ser Gly Gly Thr Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Leu Gly Pro Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser
115
<210> 23
<211> 117
<212> PRT
<213> VH(Artificial Sequence)
<400> 23
Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Arg Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Leu Val Val Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser
115
<210> 24
<211> 122
<212> PRT
<213> VH(Artificial Sequence)
<400> 24
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Val Gly Lys Arg Gly Val Phe Leu Gly Gly Met Asp Val Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 25
<211> 118
<212> PRT
<213> VH(Artificial Sequence)
<400> 25
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Ser Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Leu Leu Glu Val Gly Gly Met Asp Val Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser
115
<210> 26
<211> 130
<212> PRT
<213> VH(Artificial Sequence)
<400> 26
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Glu Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Thr Thr Asp Gln Pro Glu Gly Tyr Tyr Gly Ser Gly Ser Val
100 105 110
Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val
115 120 125
Ser Ser
130
<210> 27
<211> 116
<212> PRT
<213> VH(Artificial Sequence)
<400> 27
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Val Thr Val Ser Ser Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Thr Leu Tyr Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 28
<211> 130
<212> PRT
<213> VH(Artificial Sequence)
<400> 28
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Thr Thr Asp Gln Pro Glu Gly Tyr Tyr Gly Ser Gly Ser Val
100 105 110
Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val
115 120 125
Ser Ser
130
<210> 29
<211> 117
<212> PRT
<213> VH(Artificial Sequence)
<400> 29
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Ser Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Leu Val Ala Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser
115
<210> 30
<211> 118
<212> PRT
<213> VH(Artificial Sequence)
<400> 30
Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Ser Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Leu Leu Glu Val Gly Gly Met Asp Val Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 31
<211> 107
<212> PRT
<213> VL(Artificial Sequence)
<400> 31
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Pro
85 90 95
Ala Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
100 105
<210> 32
<211> 107
<212> PRT
<213> VL(Artificial Sequence)
<400> 32
Ala Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Phe Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser His Ser Thr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 33
<211> 107
<212> PRT
<213> VL(Artificial Sequence)
<400> 33
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 34
<211> 107
<212> PRT
<213> VL(Artificial Sequence)
<400> 34
Ala Ile Arg Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 35
<211> 107
<212> PRT
<213> VL(Artificial Sequence)
<400> 35
Ala Ile Arg Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 36
<211> 108
<212> PRT
<213> VL(Artificial Sequence)
<400> 36
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Ser
85 90 95
Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 37
<211> 103
<212> PRT
<213> VL(Artificial Sequence)
<400> 37
Ala Ile Arg Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Glu Ala Phe Gly Gly
85 90 95
Gly Thr Lys Val Glu Ile Lys
100
<210> 38
<211> 106
<212> PRT
<213> VL(Artificial Sequence)
<400> 38
Ala Ile Gln Leu Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Asn Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser His Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Ile Tyr Tyr Cys Gln Gln His Asn Ser Tyr Pro Thr
85 90 95
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 39
<211> 107
<212> PRT
<213> VL(Artificial Sequence)
<400> 39
Glu Ile Val Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Glu Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Gln Gly Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Ser Tyr Pro Phe
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 40
<211> 107
<212> PRT
<213> VL(Artificial Sequence)
<400> 40
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 41
<211> 108
<212> PRT
<213> VL(Artificial Sequence)
<400> 41
Ala Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Ala Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Ser Tyr Pro Pro
85 90 95
Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 42
<211> 107
<212> PRT
<213> VL(Artificial Sequence)
<400> 42
Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Leu Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 43
<211> 108
<212> PRT
<213> VL(Artificial Sequence)
<400> 43
Asp Ile Val Met Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Ser Tyr Pro Pro
85 90 95
Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 44
<211> 108
<212> PRT
<213> VL(Artificial Sequence)
<400> 44
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Gly Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Leu Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Asp Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 45
<211> 106
<212> PRT
<213> VL(Artificial Sequence)
<400> 45
Asp Ile Gln Leu Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ala Ile Ser Asn Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Glu Ala Ser Asn Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Gly Asn Tyr Trp Thr
85 90 95
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 46
<211> 107
<212> PRT
<213> VL(Artificial Sequence)
<400> 46
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 47
<211> 107
<212> PRT
<213> VL(Artificial Sequence)
<400> 47
Asp Ile Val Met Thr Gln Ser Ser Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 48
<211> 107
<212> PRT
<213> VL(Artificial Sequence)
<400> 48
Ala Ile Arg Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Thr Ile Thr Asp Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Ser Trp
85 90 95
Ala Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 49
<211> 107
<212> PRT
<213> VL(Artificial Sequence)
<400> 49
Ala Ile Arg Met Thr Gln Phe Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Gly Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Ser His
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 50
<211> 108
<212> PRT
<213> VL(Artificial Sequence)
<400> 50
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asn Leu Pro Leu
85 90 95
Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
100 105
<210> 51
<211> 112
<212> PRT
<213> VL(Artificial Sequence)
<400> 51
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Ser Ala Ser Leu Ser Cys Arg Ser Ser Gln Ser Leu Leu His Arg
20 25 30
Ser Gly His Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Gly Ser Ile Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly
85 90 95
Leu Gln Pro Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 52
<211> 107
<212> PRT
<213> VL(Artificial Sequence)
<400> 52
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 53
<211> 112
<212> PRT
<213> VL(Artificial Sequence)
<400> 53
Asp Ile Val Met Thr Gln Pro Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala
85 90 95
Leu Gln Thr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 54
<211> 108
<212> PRT
<213> VL(Artificial Sequence)
<400> 54
Ala Ile Arg Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ile Ile Ser Asp Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Arg Pro Gly Glu Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Val Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Asp Ser Gly
85 90 95
His Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Arg
100 105
<210> 55
<211> 107
<212> PRT
<213> VL(Artificial Sequence)
<400> 55
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 56
<211> 112
<212> PRT
<213> VL(Artificial Sequence)
<400> 56
Asp Ile Val Met Thr Gln Pro Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Gly Asp Val Gly Val Tyr Tyr Cys Met Gln Ala
85 90 95
Leu Gln Thr Pro Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
100 105 110
<210> 57
<211> 108
<212> PRT
<213> VL(Artificial Sequence)
<400> 57
Glu Ile Val Met Thr Gln Ser Pro Asp Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 58
<211> 113
<212> PRT
<213> VL(Artificial Sequence)
<400> 58
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asp Gly Asn Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn Arg Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly
85 90 95
Thr His Trp Pro Pro Asn Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
100 105 110
Lys
<210> 59
<211> 109
<212> PRT
<213> VL(Artificial Sequence)
<400> 59
Ala Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Ser Asp
85 90 95
Met Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 60
<211> 112
<212> PRT
<213> VL(Artificial Sequence)
<400> 60
Asp Ile Val Met Thr Gln Pro Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asp Gly Asn Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn Arg Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly
85 90 95
Thr His Trp Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 61
<211> 107
<212> PRT
<213> VL(Artificial Sequence)
<400> 61
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Ser Tyr Pro Phe
85 90 95
Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
100 105
<210> 62
<211> 108
<212> PRT
<213> VL(Artificial Sequence)
<400> 62
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Glu Gln Leu Lys Ser Tyr Pro Pro
85 90 95
Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 63
<211> 8
<212> PRT
<213> VH_CDR1(Artificial Sequence)
<400> 63
Gly Val Thr Val Ser Ser Asn Tyr
1 5
<210> 64
<211> 8
<212> PRT
<213> VH_CDR1(Artificial Sequence)
<400> 64
Gly Phe Thr Phe Asp Asp Tyr Ala
1 5
<210> 65
<211> 8
<212> PRT
<213> VH_CDR1(Artificial Sequence)
<400> 65
Gly Phe Thr Val Ser Ser Asn Tyr
1 5
<210> 66
<211> 8
<212> PRT
<213> VH_CDR1(Artificial Sequence)
<400> 66
Gly Tyr Thr Phe Thr Gly Tyr Tyr
1 5
<210> 67
<211> 8
<212> PRT
<213> VH_CDR1(Artificial Sequence)
<400> 67
Gly Tyr Thr Phe Thr Ser Tyr Gly
1 5
<210> 68
<211> 8
<212> PRT
<213> VH_CDR1(Artificial Sequence)
<400> 68
Gly Phe Thr Val Gly Ser Asn Tyr
1 5
<210> 69
<211> 8
<212> PRT
<213> VH_CDR1(Artificial Sequence)
<400> 69
Gly Ile Thr Val Ser Ser Asn Tyr
1 5
<210> 70
<211> 8
<212> PRT
<213> VH_CDR1(Artificial Sequence)
<400> 70
Gly Phe Thr Phe Ser Ser Tyr Ala
1 5
<210> 71
<211> 8
<212> PRT
<213> VH_CDR1(Artificial Sequence)
<400> 71
Asp Phe Thr Val Ser Ser Asn Tyr
1 5
<210> 72
<211> 8
<212> PRT
<213> VH_CDR1(Artificial Sequence)
<400> 72
Gly Phe Thr Phe Ser Thr Tyr Ala
1 5
<210> 73
<211> 10
<212> PRT
<213> VH_CDR1(Artificial Sequence)
<400> 73
Gly Gly Ser Ile Thr Gln Ile Ile Tyr Tyr
1 5 10
<210> 74
<211> 8
<212> PRT
<213> VH_CDR1(Artificial Sequence)
<400> 74
Gly Phe Thr Val Ser Arg Asn Tyr
1 5
<210> 75
<211> 8
<212> PRT
<213> VH_CDR1(Artificial Sequence)
<400> 75
Glu Phe Thr Phe Ser Asn Ala Trp
1 5
<210> 76
<211> 8
<212> PRT
<213> VH_CDR1(Artificial Sequence)
<400> 76
Gly Phe Thr Phe Ser Asn Ala Trp
1 5
<210> 77
<211> 7
<212> PRT
<213> VH_CDR2(Artificial Sequence)
<400> 77
Ile Tyr Ser Gly Gly Ser Thr
1 5
<210> 78
<211> 8
<212> PRT
<213> VH_CDR2(Artificial Sequence)
<400> 78
Ile Ser Trp Asn Ser Gly Ser Ile
1 5
<210> 79
<211> 8
<212> PRT
<213> VH_CDR2(Artificial Sequence)
<400> 79
Ile Asn Pro Asn Ser Gly Ala Thr
1 5
<210> 80
<211> 8
<212> PRT
<213> VH_CDR2(Artificial Sequence)
<400> 80
Ile Ser Ala Tyr His Gly Asn Thr
1 5
<210> 81
<211> 8
<212> PRT
<213> VH_CDR2(Artificial Sequence)
<400> 81
Ile Ser Gly Phe His Gly Asn Thr
1 5
<210> 82
<211> 8
<212> PRT
<213> VH_CDR2(Artificial Sequence)
<400> 82
Ile Ser Tyr Asp Gly Ser Asn Lys
1 5
<210> 83
<211> 7
<212> PRT
<213> VH_CDR2(Artificial Sequence)
<400> 83
Ile Tyr Pro Gly Gly Ser Thr
1 5
<210> 84
<211> 7
<212> PRT
<213> VH_CDR2(Artificial Sequence)
<400> 84
Ile Tyr Tyr Arg Gly Ser Thr
1 5
<210> 85
<211> 7
<212> PRT
<213> VH_CDR2(Artificial Sequence)
<400> 85
Ile Tyr Ser Gly Gly Thr Thr
1 5
<210> 86
<211> 10
<212> PRT
<213> VH_CDR2(Artificial Sequence)
<400> 86
Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr
1 5 10
<210> 87
<211> 11
<212> PRT
<213> VH_CDR3(Artificial Sequence)
<400> 87
Ala Arg Asp Leu Val Ser Ser Gly Met Asp Val
1 5 10
<210> 88
<211> 25
<212> PRT
<213> VH_CDR3(Artificial Sequence)
<400> 88
Ala Lys Glu Asp Ala Gly Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr
1 5 10 15
Pro Lys Ala His Trp Tyr Phe Asp Leu
20 25
<210> 89
<211> 12
<212> PRT
<213> VH_CDR3(Artificial Sequence)
<400> 89
Ala Arg Asp Leu Asp Ile Ala Gly Gly Met Asp Val
1 5 10
<210> 90
<211> 11
<212> PRT
<213> VH_CDR3(Artificial Sequence)
<400> 90
Ala Arg Asp Leu Val Val Tyr Gly Met Asp Val
1 5 10
<210> 91
<211> 11
<212> PRT
<213> VH_CDR3(Artificial Sequence)
<400> 91
Ala Arg Asp Leu Val Val Phe Gly Met Asp Val
1 5 10
<210> 92
<211> 15
<212> PRT
<213> VH_CDR3(Artificial Sequence)
<400> 92
Ala Arg Asp Arg Gly Phe Ser Ile Val Ser Tyr Ala Met Asp Val
1 5 10 15
<210> 93
<211> 21
<212> PRT
<213> VH_CDR3(Artificial Sequence)
<400> 93
Ala Arg Gly Leu Ala Pro Ser Tyr Cys Gly Gly Asp Cys Tyr Pro Arg
1 5 10 15
Ala Pro Phe Asp Tyr
20
<210> 94
<211> 11
<212> PRT
<213> VH_CDR3(Artificial Sequence)
<400> 94
Ala Arg Asp Leu Val Tyr Tyr Gly Met Asp Val
1 5 10
<210> 95
<211> 12
<212> PRT
<213> VH_CDR3(Artificial Sequence)
<400> 95
Ala Arg Asp Leu Gln Glu Arg Gly Gly Met Asp Val
1 5 10
<210> 96
<211> 16
<212> PRT
<213> VH_CDR3(Artificial Sequence)
<400> 96
Ala Ser Arg Ser Pro Ser Ile Ala Ala Ala Ala Asn Ala Phe Asp Ile
1 5 10 15
<210> 97
<211> 10
<212> PRT
<213> VH_CDR3(Artificial Sequence)
<400> 97
Ala Arg Asp Arg Gly Asp Ala Phe Asp Ile
1 5 10
<210> 98
<211> 15
<212> PRT
<213> VH_CDR3(Artificial Sequence)
<400> 98
Ala Arg Val Gly Lys Arg Gly Val Phe Leu Gly Gly Met Asp Val
1 5 10 15
<210> 99
<211> 13
<212> PRT
<213> VH_CDR3(Artificial Sequence)
<400> 99
Ala Arg Ala Val Arg His Asp Tyr Asn Tyr Phe Asp Tyr
1 5 10
<210> 100
<211> 11
<212> PRT
<213> VH_CDR3(Artificial Sequence)
<400> 100
Ala Arg Asp Leu Gly Pro Tyr Gly Met Asp Val
1 5 10
<210> 101
<211> 12
<212> PRT
<213> VH_CDR3(Artificial Sequence)
<400> 101
Ala Arg Asp Leu Leu Glu Val Gly Gly Met Asp Val
1 5 10
<210> 102
<211> 21
<212> PRT
<213> VH_CDR3(Artificial Sequence)
<400> 102
Thr Thr Asp Gln Pro Glu Gly Tyr Tyr Gly Ser Gly Ser Val Tyr Tyr
1 5 10 15
Tyr Gly Met Asp Val
20
<210> 103
<211> 10
<212> PRT
<213> VH_CDR3(Artificial Sequence)
<400> 103
Ala Arg Thr Leu Tyr Asp Ala Phe Asp Ile
1 5 10
<210> 104
<211> 11
<212> PRT
<213> VH_CDR3(Artificial Sequence)
<400> 104
Ala Arg Asp Leu Val Ala Tyr Gly Met Asp Val
1 5 10
<210> 105
<211> 6
<212> PRT
<213> VL_CDR1(Artificial Sequence)
<400> 105
Gln Gly Ile Ser Ser Trp
1 5
<210> 106
<211> 6
<212> PRT
<213> VL_CDR1(Artificial Sequence)
<400> 106
Gln Ser Ile Ser Ser Tyr
1 5
<210> 107
<211> 7
<212> PRT
<213> VL_CDR1(Artificial Sequence)
<400> 107
Gln Ser Val Ser Ser Ser Tyr
1 5
<210> 108
<211> 6
<212> PRT
<213> VL_CDR1(Artificial Sequence)
<400> 108
Gln Ser Ile Asn Ser Trp
1 5
<210> 109
<211> 6
<212> PRT
<213> VL_CDR1(Artificial Sequence)
<400> 109
Gln Gly Ile Ser Ser Tyr
1 5
<210> 110
<211> 6
<212> PRT
<213> VL_CDR1(Artificial Sequence)
<400> 110
Gln Ala Ile Ser Asn Trp
1 5
<210> 111
<211> 6
<212> PRT
<213> VL_CDR1(Artificial Sequence)
<400> 111
Gln Thr Ile Thr Asp Trp
1 5
<210> 112
<211> 6
<212> PRT
<213> VL_CDR1(Artificial Sequence)
<400> 112
Gln Ser Ile Gly Ser Trp
1 5
<210> 113
<211> 6
<212> PRT
<213> VL_CDR1(Artificial Sequence)
<400> 113
Gln Asp Ile Ser Asn Tyr
1 5
<210> 114
<211> 11
<212> PRT
<213> VL_CDR1(Artificial Sequence)
<400> 114
Gln Ser Leu Leu His Arg Ser Gly His Asn Tyr
1 5 10
<210> 115
<211> 11
<212> PRT
<213> VL_CDR1(Artificial Sequence)
<400> 115
Gln Ser Leu Leu His Ser Asn Gly Tyr Asn Tyr
1 5 10
<210> 116
<211> 6
<212> PRT
<213> VL_CDR1(Artificial Sequence)
<400> 116
Gln Ile Ile Ser Asp Trp
1 5
<210> 117
<211> 7
<212> PRT
<213> VL_CDR1(Artificial Sequence)
<400> 117
Glu Ser Val Ser Ser Ser Tyr
1 5
<210> 118
<211> 11
<212> PRT
<213> VL_CDR1(Artificial Sequence)
<400> 118
Gln Ser Leu Val His Ser Asp Gly Asn Thr Tyr
1 5 10
<210> 119
<211> 6
<212> PRT
<213> VL_CDR1(Artificial Sequence)
<400> 119
Gln Ser Ile Ser Ser Trp
1 5
<210> 120
<211> 3
<212> PRT
<213> VL_CDR2(Artificial Sequence)
<400> 120
Ala Ala Ser
1
<210> 121
<211> 3
<212> PRT
<213> VL_CDR2(Artificial Sequence)
<400> 121
Gly Ala Ser
1
<210> 122
<211> 3
<212> PRT
<213> VL_CDR2(Artificial Sequence)
<400> 122
Lys Ala Ser
1
<210> 123
<211> 3
<212> PRT
<213> VL_CDR2(Artificial Sequence)
<400> 123
Asp Ala Ser
1
<210> 124
<211> 3
<212> PRT
<213> VL_CDR2(Artificial Sequence)
<400> 124
Glu Ala Ser
1
<210> 125
<211> 3
<212> PRT
<213> VL_CDR2(Artificial Sequence)
<400> 125
Leu Gly Ser
1
<210> 126
<211> 3
<212> PRT
<213> VL_CDR2(Artificial Sequence)
<400> 126
Lys Val Ser
1
<210> 127
<211> 9
<212> PRT
<213> VL_CDR3(Artificial Sequence)
<400> 127
Gln Gln Ala Asn Ser Phe Pro Pro Ala
1 5
<210> 128
<211> 9
<212> PRT
<213> VL_CDR3(Artificial Sequence)
<400> 128
Gln Gln Ser His Ser Thr Pro Tyr Thr
1 5
<210> 129
<211> 9
<212> PRT
<213> VL_CDR3(Artificial Sequence)
<400> 129
Gln Gln Ser Tyr Ser Thr Pro Arg Thr
1 5
<210> 130
<211> 9
<212> PRT
<213> VL_CDR3(Artificial Sequence)
<400> 130
Gln Gln Ser Tyr Ser Thr Pro Tyr Thr
1 5
<210> 131
<211> 9
<212> PRT
<213> VL_CDR3(Artificial Sequence)
<400> 131
Gln Gln Tyr Gly Ser Ser Ser Tyr Thr
1 5
<210> 132
<211> 5
<212> PRT
<213> VL_CDR3(Artificial Sequence)
<400> 132
Gln Gln Ala Glu Ala
1 5
<210> 133
<211> 8
<212> PRT
<213> VL_CDR3(Artificial Sequence)
<400> 133
Gln Gln His Asn Ser Tyr Pro Thr
1 5
<210> 134
<211> 9
<212> PRT
<213> VL_CDR3(Artificial Sequence)
<400> 134
Gln Gln Leu Asn Ser Tyr Pro Phe Thr
1 5
<210> 135
<211> 10
<212> PRT
<213> VL_CDR3(Artificial Sequence)
<400> 135
Gln Gln Leu Asn Ser Tyr Pro Pro Tyr Thr
1 5 10
<210> 136
<211> 9
<212> PRT
<213> VL_CDR3(Artificial Sequence)
<400> 136
Gln Gln Ser Tyr Ser Thr Leu Leu Thr
1 5
<210> 137
<211> 9
<212> PRT
<213> VL_CDR3(Artificial Sequence)
<400> 137
Gln Gln Tyr Gly Ser Ser Pro Leu Thr
1 5
<210> 138
<211> 8
<212> PRT
<213> VL_CDR3(Artificial Sequence)
<400> 138
Gln Gln Tyr Gly Asn Tyr Trp Thr
1 5
<210> 139
<211> 9
<212> PRT
<213> VL_CDR3(Artificial Sequence)
<400> 139
Gln Gln Ser Tyr Ser Thr Pro Leu Thr
1 5
<210> 140
<211> 9
<212> PRT
<213> VL_CDR3(Artificial Sequence)
<400> 140
Gln Gln Tyr Asn Ser Tyr Ser Trp Ala
1 5
<210> 141
<211> 9
<212> PRT
<213> VL_CDR3(Artificial Sequence)
<400> 141
Gln Gln Tyr Asn Ser Tyr Ser His Thr
1 5
<210> 142
<211> 10
<212> PRT
<213> VL_CDR3(Artificial Sequence)
<400> 142
Gln Gln Tyr Asp Asn Leu Pro Leu Phe Thr
1 5 10
<210> 143
<211> 9
<212> PRT
<213> VL_CDR3(Artificial Sequence)
<400> 143
Met Gln Gly Leu Gln Pro Pro Tyr Thr
1 5
<210> 144
<211> 9
<212> PRT
<213> VL_CDR3(Artificial Sequence)
<400> 144
Met Gln Ala Leu Gln Thr Pro Tyr Thr
1 5
<210> 145
<211> 10
<212> PRT
<213> VL_CDR3(Artificial Sequence)
<400> 145
Gln Gln Tyr Asn Ser Asp Ser Gly His Thr
1 5 10
<210> 146
<211> 9
<212> PRT
<213> VL_CDR3(Artificial Sequence)
<400> 146
Gln Gln Ala Asn Ser Phe Pro Pro Thr
1 5
<210> 147
<211> 9
<212> PRT
<213> VL_CDR3(Artificial Sequence)
<400> 147
Met Gln Ala Leu Gln Thr Pro Phe Thr
1 5
<210> 148
<211> 9
<212> PRT
<213> VL_CDR3(Artificial Sequence)
<400> 148
Gln Gln Tyr Gly Ser Ser Pro Tyr Thr
1 5
<210> 149
<211> 10
<212> PRT
<213> VL_CDR3(Artificial Sequence)
<400> 149
Met Gln Gly Thr His Trp Pro Pro Asn Thr
1 5 10
<210> 150
<211> 11
<212> PRT
<213> VL_CDR3(Artificial Sequence)
<400> 150
Gln Gln Tyr Asn Ser Tyr Ser Asp Met Tyr Thr
1 5 10
<210> 151
<211> 9
<212> PRT
<213> VL_CDR3(Artificial Sequence)
<400> 151
Met Gln Gly Thr His Trp Pro Tyr Thr
1 5
<210> 152
<211> 10
<212> PRT
<213> VL_CDR3(Artificial Sequence)
<400> 152
Glu Gln Leu Lys Ser Tyr Pro Pro Tyr Thr
1 5 10
<210> 153
<211> 351
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 153
caggttcagc tggtgcagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggggt caccgtcagt agcaactaca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggccgatt caccatctcc agacacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc tgaggacacg gccgtgtatt actgtgcgag agatctggtg 300
tcgtccggta tggacgtctg gggccaaggg accacggtca ccgtctcgag t 351
<210> 154
<211> 396
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 154
gaggtgcagc tggtggagtc cgggggaggc ttggtacagc ctggcaggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaagct 120
ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggtag cataggctat 180
gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240
ctgcaaatga acagtctgag agctgaggac acggccttgt attactgtgc aaaagaggat 300
gcggggtatt actatgatag tagtggttat tactacccta aagcccactg gtacttcgat 360
ctctggggcc gtggcacaat ggtcaccgtc tcgagt 396
<210> 155
<211> 396
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 155
gaggtgcagc tggtggagtc cgggggaggc ttggtacagc ctggcaggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaagct 120
ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggtag cataggctat 180
gcggactctg tgaagggccg attcaccatt tccagagaca acgccaagaa ctccctgtat 240
ctgcaaatgg acagtctgag agctgaggac acggccttgt attactgtgc aaaagaggat 300
gcggggtatt actatgatag tagtggttat tactacccta aagcccactg gtacttcgat 360
ctctggggcc gtggcaccct ggtcactgtc tcgagt 396
<210> 156
<211> 396
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 156
caggttcagc tggtgcagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaagct 120
ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggtag cataggctat 180
gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240
ctgcaaatga acagtctgag agctgaggac acggccttgt attactgtgc aaaagaggat 300
gcggggtatt actatgatag tagtggttat tactacccta aagcccactg gtacttcgat 360
ctctggggcc gtggcaccct ggtcaccgtc tcgagt 396
<210> 157
<211> 354
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 157
gaggtgcaac tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt caccgtcagt agcaactaca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc tgaggacacg gctgtgtatt actgtgcgag agatctggat 300
atagccgggg gtatggacgt ctggggccaa gggaccctgg tcaccgtctc gagt 354
<210> 158
<211> 351
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 158
gaggtgcagc tggtgcagtc tggaggaggc ttgatccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctgggtt caccgtcagt agcaactaca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gccgtgtatt actgtgcgag agacctagta 300
gtctacggta tggacgtctg gggccaaggg accacggtca ccgtctcgag t 351
<210> 159
<211> 351
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 159
gaggtgcagc tggtggagtc tggaggaggc ttgatccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctgggtt caccgtcagt agcaactaca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gccgtgtatt actgtgcgag agatctggtg 300
gtattcggta tggacgtctg gggccaaggg accacggtca ccgtctcgag t 351
<210> 160
<211> 366
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 160
gaggtgcagc tggtggagtc tggggctgag gtgaagaagc ctggggcctc agtgaaagtc 60
tcctgcaagg cttctggata caccttcacc ggttactata tccactgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggatgg atcaacccta acagtggtgc cacaaacttt 180
gcacagaagt ttcggggcag ggtcaccatg accagggaca cctccatcac cacagcctac 240
atggagatga gcaggctgat atctgacgac acggccgtgt atttctgtgc gagagatcga 300
ggcttcagta tcgtatccta cgctatggac gtctggggcc aagggaccac ggtcaccgtc 360
tcgagt 366
<210> 161
<211> 351
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 161
gaggtgcagc tggtggagac tggaggaggc ttggtccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggggt caccgtcagt agcaactaca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggccgatt caccatctcc agacacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc tgaggacacg gccgtgtatt actgtgcgag agatctggtg 300
tcgtccggta tggacgtctg gggccaaggg accacggtca ccgtctcgag t 351
<210> 162
<211> 384
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 162
gaggtgcagc tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg cttctggtta cacctttacc agctatggta tcagctgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggatgg atcagcgctt accatggtaa cacaaactat 180
gcacagaagc tccagggcag agtcaccatg accacagaca catccacgag cacagcctac 240
atggagctga ggagcctgag atctgacgac acggccgtgt attactgtgc gagaggcctg 300
gccccatcat attgtggtgg tgactgctat cctcgggccc catttgacta ctggggccag 360
ggaaccctgg tcaccgtctc gagt 384
<210> 163
<211> 351
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 163
gaggtgcagc tggtgcagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggggt caccgtcagt agcaactaca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggccgatt caccatctcc agacacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc tgaggacacg gccgtgtatt actgtgcgag agatctggtg 300
tcgtccggta tggacgtctg gggccaaggg accctggtca ccgtctcgag t 351
<210> 164
<211> 384
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 164
gaggtgcagc tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg cttctggtta cacctttacc agctatggta tcagctgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggatgg atcagcggtt tccacggtaa cacaaactat 180
gcacagaagc tccagggcag agtcaccatg accacagaca catccacgag cacagcctac 240
atggagctga ggagcctgag atctgacgac acggccgtgt attactgtgc gagaggcctg 300
gccccatcat attgtggtgg tgactgctat cctcgggccc catttgacta ctggggccag 360
ggaaccctgg tcaccgtctc gagt 384
<210> 165
<211> 351
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 165
gaggtgcagc tggtggagac tggaggaggc ttgatccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctgggtt caccgtcggt agcaactaca tgaactgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcactt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gccgtgtatt actgtgcgag agacttagtc 300
tactacggta tggacgtctg gggccaaggg accacggtca ccgtctcgag t 351
<210> 166
<211> 354
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 166
caggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggaat caccgtcagt agcaactaca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggcagatt cagcatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gctgtgtatt actgtgcgag agatcttcag 300
gagcgaggcg gtatggacgt ctggggccaa gggaccacgg tcaccgtctc gagt 354
<210> 167
<211> 354
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 167
caggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggaat caccgtcagt agcaactaca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggcagatt cagcatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gctgtgtatt actgtgcgag agatcttcag 300
gagcgaggcg gtatggacgt ctggggccaa gggaccctgg tcaccgtctc gagt 354
<210> 168
<211> 369
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 168
gaggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60
tcctgtgcag cctctggatt caccttcagt agctatgcta tgcactgggt ccgccaggct 120
ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactac 180
gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagccgatcc 300
cccagtatag cagcagccgc taatgctttt gatatctggg gccaagggac cacggtcacc 360
gtctcgagt 369
<210> 169
<211> 366
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 169
caggtgcagc tggtggagtc tggggctgag gtgaagaagc ctggggcctc agtgaaagtc 60
tcctgcaagg cttctggata caccttcacc ggttactata tccactgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggatgg atcaacccta acagtggtgc cacaaacttt 180
gcacagaagt ttcggggcag ggtcaccatg accagggaca cctccatcac cacagcctac 240
atggagatga gcaggctgat atctgacgac acggccgtgt atttctgtgc gagagatcga 300
ggcttcagta tcgtatccta cgctatggac gtctggggcc aagggaccac ggtcaccgtc 360
tcgagt 366
<210> 170
<211> 348
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 170
caggtccagc tggtgcagtc tgggggaggc ttgatccagc ctggggggtc cctgagactc 60
tcctgtacag cctctgactt caccgtcagt agcaactaca tgacctgggt ccgccaggct 120
ccagggaagg gactggagtg ggtctcactt atttatcccg gtggtagcac atactacgca 180
gactccctga agggccgatt caccatctcc agagacaatt ccaagaacac gctatacctt 240
caaatgaaca gcctgagagt tgaggacacg gctgtgtatt actgtgcgag agaccggggc 300
gatgcatttg atatctgggg ccaagggacc acggtcaccg tctcgagt 348
<210> 171
<211> 366
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 171
gaggtgcagc tggtggagtc cgggggaggc gtggtccagc ctgggaggtc cctgagactc 60
tcctgtgcag cgtctggatt caccttcagt acctatgcta tgcactgggt ccgccaggct 120
ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactac 180
gcagactccg tgaagggccg attcaccatc tccagagaca attccgagaa cacgctgtat 240
ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagagtagga 300
aaaagggggg ttttcctggg gggtatggac gtctggggcc aaggcaccct ggtcaccgtc 360
tcgagt 366
<210> 172
<211> 363
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 172
caggtgcagc tacaacagtg gggcccagga ctggtgaagc cttcggagac cctgtccctc 60
acctgtagcg tctctggtgg ctccatcacg cagattattt actactgggc ctggatccgc 120
cagcccccag ggagggggct ggagtggatt gggagtatct actatagggg gagcacctcc 180
tccaacccgt ccctcaagag tcgagtcacc atatccgtag acacgtccaa gaaccagttc 240
tccctgaacc taacctctgt gaccgccgca gacacggctg tgtattactg tgcgagggcg 300
gttagacatg actacaacta ttttgactac tggggccagg gaaccctggt caccgtctcg 360
agt 363
<210> 173
<211> 366
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 173
gaggtgcagc tgttggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60
tcctgtgcag cgtctggatt caccttcagt acctatgcta tgcactgggt ccgccaggct 120
ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactac 180
gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagagtagga 300
aaaagggggg ttttcctggg gggtatggac gtctggggcc aagggaccct ggtcaccgtc 360
tcgagt 366
<210> 174
<211> 351
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 174
gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggagt caccgtcagt agcaactaca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatagcg gcggtaccac atactacgca 180
gactccgtga agggcagatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gctgtgtatt actgtgcgag agatctgggg 300
ccatacggta tggacgtctg gggccaaggg accacggtca ccgtctcgag t 351
<210> 175
<211> 351
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 175
gaggtgcagc tggtgcagtc tggaggaggc ttgatccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctgggtt caccgtcagt aggaactaca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gccgtgtatt actgtgcgag agatctggtg 300
gtttacggta tggacgtctg gggccaaggg accacggtca ccgtctcgag t 351
<210> 176
<211> 366
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 176
gaagtgcagc tggtggagtc tgggggaggc gtggtccagc ctggggggtc cctgagactc 60
tcctgtgcag cgtctggatt caccttcagt acctatgcta tgcactgggt ccgccaggct 120
ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactac 180
gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagagtagga 300
aaaagggggg ttttcctggg gggtatggac gtctggggcc aagggaccct ggtcaccgtc 360
tcgagt 366
<210> 177
<211> 354
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 177
gaggtgcagc tggtggagac tggaggaggc ttgatccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctgggtt caccgtcagt agcaactaca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gccgtgtatt actgtgcgag agatctctta 300
gaagtagggg gtatggacgt ctggggccaa gggacaatgg tcaccgtctc gagt 354
<210> 178
<211> 390
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 178
gaggtgcaac tggtggagtc tgggggaggc ttggtaaagc ctggggggtc ccttagactc 60
tcctgtgcag cctctgagtt cactttcagt aacgcctgga tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggttggccgt attaaaagca aaactgatgg tgggacaaca 180
gactacgctg cacccgtgaa aggcagattc accatctcaa gagatgattc aaaaaacacg 240
ctgtatctgc aaatgaacag cctgaaaacc gaggacacag ccgtgtatta ctgtaccaca 300
gatcaaccgg agggatacta tggttcgggg agtgtctact actacggtat ggacgtctgg 360
ggccaaggga ccacggtcac cgtctcgagt 390
<210> 179
<211> 348
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 179
gaggtgcagc tggtggagac tggaggaggc ttgatccagc ctggggggtc cctgagactc 60
tcttgtgcag cctctggggt caccgtcagt agcaactaca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggccgatt caccatctcc agagacaatt ccaagaatac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gccgtgtatt actgtgcgag gactttatat 300
gatgcttttg atatctgggg ccaagggacc acggtcaccg tctcgagt 348
<210> 180
<211> 390
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 180
gaggtgcaac tggtggagtc tgggggaggc ttggtaaagc ctggggggtc ccttagactc 60
tcctgtgcag cctctggatt cactttcagt aacgcctgga tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggttggccgt attaaaagca aaactgatgg tgggacaaca 180
gactacgctg cacccgtgaa aggcagattc accatctcaa gagatgattc aaaaaacacg 240
ctgtatctgc aaatgaacag cctgaaaacc gaggacacag ccgtgtatta ctgtaccaca 300
gatcaaccgg agggatacta tggttcgggg agtgtctact actacggtat ggacgtctgg 360
ggccaaggga ccacggtcac cgtctcgagt 390
<210> 181
<211> 351
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 181
caggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt caccgtcagt agcaactaca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc tgaggacacg gctgtgtatt actgtgcgag agatctcgtt 300
gcctacggta tggacgtctg gggccaaggg accacggtca ccgtctcgag t 351
<210> 182
<211> 354
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 182
gaggtgcagc tggtgcagtc tggaggaggc ttgatccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctgggtt caccgtcagt agcaactaca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gccgtgtatt actgtgcgag agatctctta 300
gaagtagggg gtatggacgt ctggggccaa gggaccctgg tcaccgtctc gagt 354
<210> 183
<211> 321
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 183
gacatcgtga tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60
atcacttgtc gggcgagtca gggtattagc agctggttag cctggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240
gaagattttg caacttacta ttgtcaacag gctaacagtt tccctccggc tttcggccct 300
gggaccaaag tggatatcaa a 321
<210> 184
<211> 321
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 184
gccatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggcaagtca gagcattagc agctatttaa attggtatca gcagaaacca 120
gggaaagccc ctaagttcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180
aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240
gaagattttg caacttacta ctgtcaacag agtcacagta ccccgtacac ttttggccaa 300
gggaccaagg tggaaatcaa a 321
<210> 185
<211> 321
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 185
gacatcgtga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggcaagtca gagcattagc agctatttaa attggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180
aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240
gaagattttg caacttacta ctgtcaacag agttacagta cccctcggac gttcggccag 300
gggaccaagc tggagatcaa a 321
<210> 186
<211> 321
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 186
gccatccgga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggcaagtca gagcattagc agctatttaa attggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180
aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240
gaagattttg caacttacta ctgtcaacag agttacagta cccctcggac ttttggccaa 300
gggaccaagg tggaaatcaa a 321
<210> 187
<211> 321
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 187
gccatccgga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggcaagtca gagcattagc agctatttaa attggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180
aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240
gaagattttg caacttacta ctgtcaacag agttacagta ccccgtacac ttttggccag 300
gggaccaagc tggagatcaa a 321
<210> 188
<211> 324
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 188
gaaattgtgt tgacacagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60
ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120
cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca 180
gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240
cctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcctcgta cacttttggc 300
caggggacca agctggagat caaa 324
<210> 189
<211> 309
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 189
gccatccgga tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60
atcacttgtc gggcgagtca gggtattagc agctggttag cctggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240
gaagattttg caacttacta ttgtcaacag gctgaggctt tcggcggagg gaccaaggtg 300
gagatcaaa 309
<210> 190
<211> 318
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 190
gccatccagt tgacccagtc tccttccacc ctgtctgcat ctgtcggaga cagagtcacc 60
atcacttgcc gggccagtca gagtattaat tcctggttgg cctggtatca gcagaaacca 120
gggaaagccc ctaaactcct gatctataag gcgtctcatt tacaaagtgg cgtcccttca 180
aggttcagcg gcagtggatc tgggacagat ttcactctta ccatcagtag cctgcagcct 240
gatgattttg caatttatta ctgccaacag cataattctt atccgacctt cggccaaggg 300
accaaggtgg aaatcaaa 318
<210> 191
<211> 321
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 191
gaaattgtgt tgacgcagtc tccatccttc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggccagtca gggcattagc agttatttag cctggtatca gcaagaacca 120
gggaaagccc ctaagctcct gatctatgct gcatccactt tgcaaggtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagaa ttcactctca caatcagcag cctgcagcct 240
gaagattttg caacttatta ctgtcaacag cttaatagtt accctttcac tttcggcgga 300
gggaccaagg tggagatcaa a 321
<210> 192
<211> 321
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 192
gacatccagt tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggcaagtca gagcattagc agctatttaa attggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180
aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240
gaagattttg caacttacta ctgtcaacag agttacagta ccccgtacac ttttggccag 300
gggaccaagc tggagatcaa a 321
<210> 193
<211> 324
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 193
gccatccagt tgacccagtc tccatccttc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggccagtca gggcattagc agttatttag cctggtatca gcaaaaacca 120
gggaaagccc ctaagctcct gatctatgct gcatccactt tgcaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tggggcagaa ttcactctca caatcagcag cctgcagcct 240
gaagattttg caacttatta ctgtcaacag cttaatagtt accctccgta cacttttggc 300
caagggacca aggtggaaat caaa 324
<210> 194
<211> 321
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 194
gccatccagt tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggcaagtca gagcattagc agctatttaa attggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180
aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240
gaagattttg caacttacta ctgtcaacag agttacagta cactcctcac tttcggcgga 300
gggaccaagg tggagatcaa a 321
<210> 195
<211> 324
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 195
gacatcgtga tgacccagtc tccatccttc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggccagtca gggcattagc agttatttag cctggtatca gcaaaaacca 120
gggaaagccc ctaagctcct gatctatgct gcatccactt tgcaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagaa ttcactctca caatcagcag cctgcagcct 240
gaagattttg caacttatta ctgtcaacag cttaatagtt accctccgta cacttttggc 300
caagggacca aggtggaaat caaa 324
<210> 196
<211> 324
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 196
gaaattgtgt tgacgcagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60
ctctcctgcg gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120
cctggcctgg cgcccaggct cctcatctat gatgcatcca gcagggccac tggcatccca 180
gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240
cctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcaccgct cactttcggc 300
ggagggacca aggtggagat caaa 324
<210> 197
<211> 318
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 197
gacatccagt tgacccagtc tccctccacc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggccagtca ggctattagt aactggttgg cctggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatgag gcgtctaatt tagaaagtgg ggtcccatcg 180
aggttcagcg gcagtggttc tgggacagaa ttcactctca ccatcagcag cctgcagcct 240
gatgattttg caacttatta ctgccaacag tatggtaatt attggacgtt cggccaaggg 300
accaaggtgg aaatcaaa 318
<210> 198
<211> 321
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 198
gacatccagt tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggcaagtca gagcattagc agctatttaa attggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180
aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240
gaagattttg caacttacta ctgtcaacag agttacagta cccctctgac gttcggccag 300
gggaccaagc tggagatcaa a 321
<210> 199
<211> 321
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 199
gacatcgtga tgacccagtc ttcatcctcc ctgtctgcat ctgtaggaga cagggtcacc 60
atcacttgcc gggcaagtca gagcattagc agctatttaa attggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180
aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240
gaagattttg caacttacta ctgtcaacag agttacagta ccccgtacac ttttggccag 300
gggaccaagc tggagatcaa a 321
<210> 200
<211> 321
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 200
gccatccgga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggccagtca gactattact gactggttgg cctggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctataag gcgtctactt tagaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagaa ttcactctca ccatcagcag cctgcagcct 240
gatgatttcg caacttatta ctgccaacaa tataatagtt attcttgggc gttcggccaa 300
gggaccaagg tggaaatcaa a 321
<210> 201
<211> 321
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 201
gccatccgga tgacccagtt tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggccagtca gagtattggt agctggttgg cctggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctataag gcgtctagtt tagaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagaa ttcactctca ccatcagcag cctgcagcct 240
gatgattttg caacttatta ctgccaacag tataatagtt attctcacac ttttggccaa 300
gggaccaagg tggaaatcaa a 321
<210> 202
<211> 324
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 202
gacatcgtga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc aggcgagtca ggacattagc aactatttaa attggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctacgat gcatccaatt tggaaacagg ggtcccatca 180
aggttcagtg gaagtggatc tgggacagat tttactttca ccatcagcag cctgcagcct 240
gaagatattg caacatatta ctgtcaacag tatgataatc tccccttatt cactttcggc 300
cctgggacca aagtggatat caaa 324
<210> 203
<211> 336
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 203
gatattgtga tgacccagac tccactctcc ctgcccgtca cccctggaga gtcggcctcc 60
ctctcctgca ggtctagtca gagcctcctg cataggagtg gacacaacta tttggattgg 120
tacctgcaga agccagggca gtctccacag ctcctgattt atttgggttc tattcgggcc 180
tccggggtcc ctgacaggtt cagtggcagt ggatcaggca cagactttac actgaaaata 240
agtagagtgg aggctgagga tgttggggtt tattactgca tgcaaggtct acaacctccg 300
tacacttttg gccaagggac caaggtggaa atcaaa 336
<210> 204
<211> 321
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 204
gacatccagt tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggcaagtca gagcattagc agctatttaa attggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180
aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240
gaagattttg caacttacta ctgtcaacag agttacagta cccctcgcac ttttggccag 300
gggaccaagc tggagatcaa a 321
<210> 205
<211> 336
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 205
gatattgtga tgactcagcc tccactctcc ctgcccgtca cccctggaga gccggcctcc 60
atctcctgca ggtctagtca gagcctcctc catagtaatg gatacaacta tttggattgg 120
tacctgcaga agccagggca gtctccacag ctcctgatct atttgggttc taatcgggcc 180
tccggggtcc ctgacaggtt cagtggcagt ggatcaggca cagattttac actgaaaatc 240
agcagagtgg aggctgagga tgttggggtt tattactgca tgcaagctct acaaactccg 300
tacacttttg gccaggggac caagctggag atcaaa 336
<210> 206
<211> 324
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 206
gccatccgga tgacccagtc tccttccacc ctgtctgcat ctgtgggcga cagagtcacc 60
atcacttgcc gggccagtca gattattagt gactggttgg cctggtatca gcagagacca 120
ggggaagccc ctaagctcct catctataag gcatctaatt tacaaagtgg ggtcccatca 180
aggttcagcg gcagtgtatc tgggacagaa ttcactctca ccatcagcag cctgcagcct 240
gatgattttg cgacttatta ctgccaacaa tataatagtg attctgggca cacttttggc 300
caagggacca aggtggaaat caga 324
<210> 207
<211> 321
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 207
gacatccaga tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60
atcacttgtc gggcgagtca gggtattagc agctggttag cctggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatggt gcatccagtt tgcaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240
gaagattttg caacttacta ttgtcaacag gctaacagtt tccctcccac tttcggcgga 300
gggaccaagg tggagatcaa a 321
<210> 208
<211> 336
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 208
gatattgtga tgactcagcc tccactctcc ctgcccgtca cccctggaga gccggcctcc 60
atctcctgca ggtctagtca gagcctcctg catagtaatg gatacaacta tttggattgg 120
tacctgcaga agccagggca gtctccacag ctcctgatct atttgggttc taatcgggcc 180
tccggggtcc ctgacaggtt cagtggcagt ggatcaggca cagattttac actgaaaatc 240
agcagagtgg aggctgggga tgttggggtt tattactgca tgcaagctct acaaacccct 300
ttcactttcg gccctgggac caaagtggat atcaaa 336
<210> 209
<211> 324
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 209
gaaatagtga tgacgcagtc tccagacacc ctgtctttgt ctccagggga aagagccacc 60
ctctcctgca gggccagtga gagtgttagc agcagctact tagcctggta ccagcagaaa 120
cctggccagg ctcccaggct cctcatctat ggtgcatcca gtagggccac tggcatccca 180
gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240
cctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcacccta cacttttggc 300
caagggacca aggtggaaat caaa 324
<210> 210
<211> 339
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 210
gatattgtga tgactcagtc tccactctcc ctgcccgtca cccttggaca gccggcctcc 60
atctcctgca ggtctagtca aagcctcgta cacagtgatg gaaacaccta cttgaattgg 120
tttcagcaga ggccaggcca atctccaagg cgcctaattt ataaggtttc taaccgggac 180
tctggggtcc cagacagatt cagcggcagt gggtcaggca ctgatttcac actgaaaatc 240
agcagggtgg aggctgaaga tgttggggtt tattactgca tgcaaggtac acactggcct 300
ccgaacactt ttggccaagg gaccaaggtg gaaatcaaa 339
<210> 211
<211> 327
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 211
gccatccaga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggccagtca gagtattagt agctggttgg cctggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctataag gcgtctagtt tagaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagaa ttcactctca ccatcagcag cctgcagcct 240
gatgattttg caacttatta ctgccaacag tataatagtt attctgacat gtacactttt 300
ggccaaggga ccaaggtgga aatcaaa 327
<210> 212
<211> 336
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 212
gatattgtga tgactcagcc tccactctcc ctgcccgtca cccttggaca gccggcctcc 60
atctcctgca ggtctagtca aagcctcgta cacagtgatg gaaacaccta cttgaattgg 120
tttcagcaga ggccaggcca atctccaagg cgcctaattt ataaggtttc taaccgggac 180
tctggggtcc cagacagatt cagcggcagt gggtcaggca ctgatttcac actgaaaatc 240
agcagggtgg aggctgagga tgttggggtt tattactgca tgcaaggtac acactggcct 300
tacacttttg gccaagggac caaggtggaa atcaaa 336
<210> 213
<211> 321
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 213
gacatccagt tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggccagtca gggcattagc agttatttag cctggtatca gcaaaaacca 120
gggaaagccc ctaagctcct gatctatgct gcatccactt tgcaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240
gaagattttg caacttatta ctgtcaacag cttaatagtt accccttcac tttcggccct 300
gggaccaaag tggatatcaa a 321
<210> 214
<211> 324
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 214
gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggccagtca gggcattagc agttatttag cctggtatca gcaaaaacca 120
gggaaagccc ctaagctcct gatctatgct gcatccactt tgcaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240
gaagattttg caacttatta ctgtgaacag cttaagagtt accctccgta cacttttggc 300
caggggacca agctggagat caaa 324
<210> 215
<211> 224
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 215
Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Val Thr Val Ser Ser Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg His Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Leu Val Ser Ser Gly Met Asp Val Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser Asp Ile Val Met Thr Gln Ser Pro Ser Ser Val
115 120 125
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
130 135 140
Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala
145 150 155 160
Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro
165 170 175
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
180 185 190
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala
195 200 205
Asn Ser Phe Pro Pro Ala Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
210 215 220
<210> 216
<211> 239
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 216
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Glu Asp Ala Gly Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr
100 105 110
Pro Lys Ala His Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Met Val
115 120 125
Thr Val Ser Ser Ala Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
130 135 140
Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser
145 150 155 160
Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
165 170 175
Lys Phe Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser
180 185 190
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
195 200 205
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser His
210 215 220
Ser Thr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
225 230 235
<210> 217
<211> 239
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 217
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asp Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Glu Asp Ala Gly Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr
100 105 110
Pro Lys Ala His Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val
115 120 125
Thr Val Ser Ser Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser
130 135 140
Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser
145 150 155 160
Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
165 170 175
Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser
180 185 190
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
195 200 205
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr
210 215 220
Ser Thr Pro Arg Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
225 230 235
<210> 218
<211> 239
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 218
Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Glu Asp Ala Gly Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr
100 105 110
Pro Lys Ala His Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val
115 120 125
Thr Val Ser Ser Ala Ile Arg Met Thr Gln Ser Pro Ser Ser Leu Ser
130 135 140
Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser
145 150 155 160
Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
165 170 175
Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser
180 185 190
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
195 200 205
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr
210 215 220
Ser Thr Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
225 230 235
<210> 219
<211> 225
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 219
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Ser Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Leu Asp Ile Ala Gly Gly Met Asp Val Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ile Arg Met Thr Gln Ser Pro Ser Ser
115 120 125
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
130 135 140
Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys
145 150 155 160
Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val
165 170 175
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
180 185 190
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
195 200 205
Ser Tyr Ser Thr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile
210 215 220
Lys
225
<210> 220
<211> 225
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 220
Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Ser Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Leu Val Val Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu
115 120 125
Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln
130 135 140
Ser Val Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
145 150 155 160
Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile
165 170 175
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
180 185 190
Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln
195 200 205
Tyr Gly Ser Ser Ser Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile
210 215 220
Lys
225
<210> 221
<211> 220
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 221
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Ser Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Leu Val Val Phe Gly Met Asp Val Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser Ala Ile Arg Met Thr Gln Ser Pro Ser Ser Val
115 120 125
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
130 135 140
Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala
145 150 155 160
Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro
165 170 175
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
180 185 190
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala
195 200 205
Glu Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
210 215 220
<210> 222
<211> 228
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 222
Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asn Ser Gly Ala Thr Asn Phe Ala Gln Lys Phe
50 55 60
Arg Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Thr Thr Ala Tyr
65 70 75 80
Met Glu Met Ser Arg Leu Ile Ser Asp Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Arg Asp Arg Gly Phe Ser Ile Val Ser Tyr Ala Met Asp Val Trp
100 105 110
Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ile Gln Leu Thr Gln
115 120 125
Ser Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
130 135 140
Cys Arg Ala Ser Gln Ser Ile Asn Ser Trp Leu Ala Trp Tyr Gln Gln
145 150 155 160
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Lys Ala Ser His Leu
165 170 175
Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
180 185 190
Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Ile Tyr
195 200 205
Tyr Cys Gln Gln His Asn Ser Tyr Pro Thr Phe Gly Gln Gly Thr Lys
210 215 220
Val Glu Ile Lys
225
<210> 223
<211> 224
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 223
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Val Thr Val Ser Ser Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg His Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Leu Val Ser Ser Gly Met Asp Val Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser Glu Ile Val Leu Thr Gln Ser Pro Ser Phe Leu
115 120 125
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
130 135 140
Gly Ile Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Glu Pro Gly Lys Ala
145 150 155 160
Pro Lys Leu Leu Ile Tyr Ala Ala Ser Thr Leu Gln Gly Gly Val Pro
165 170 175
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile
180 185 190
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu
195 200 205
Asn Ser Tyr Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
210 215 220
<210> 224
<211> 235
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 224
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Ser Ala Tyr His Gly Asn Thr Asn Tyr Ala Gln Lys Leu
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Leu Ala Pro Ser Tyr Cys Gly Gly Asp Cys Tyr Pro Arg
100 105 110
Ala Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
130 135 140
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
145 150 155 160
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
165 170 175
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
180 185 190
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
195 200 205
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Tyr
210 215 220
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
225 230 235
<210> 225
<211> 225
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 225
Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Val Thr Val Ser Ser Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg His Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Leu Val Ser Ser Gly Met Asp Val Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu
115 120 125
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
130 135 140
Gly Ile Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala
145 150 155 160
Pro Lys Leu Leu Ile Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro
165 170 175
Ser Arg Phe Ser Gly Ser Gly Ser Gly Ala Glu Phe Thr Leu Thr Ile
180 185 190
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu
195 200 205
Asn Ser Tyr Pro Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
210 215 220
Lys
225
<210> 226
<211> 235
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 226
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Ser Gly Phe His Gly Asn Thr Asn Tyr Ala Gln Lys Leu
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Leu Ala Pro Ser Tyr Cys Gly Gly Asp Cys Tyr Pro Arg
100 105 110
Ala Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
130 135 140
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
145 150 155 160
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
165 170 175
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
180 185 190
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
195 200 205
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Leu Leu
210 215 220
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
225 230 235
<210> 227
<211> 225
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 227
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Gly Ser Asn
20 25 30
Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Leu Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Leu Val Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser Asp Ile Val Met Thr Gln Ser Pro Ser Phe Leu
115 120 125
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
130 135 140
Gly Ile Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala
145 150 155 160
Pro Lys Leu Leu Ile Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro
165 170 175
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile
180 185 190
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu
195 200 205
Asn Ser Tyr Pro Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
210 215 220
Lys
225
<210> 228
<211> 226
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 228
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ile Thr Val Ser Ser Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Ser Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Leu Gln Glu Arg Gly Gly Met Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser Glu Ile Val Leu Thr Gln Ser Pro Ala Thr
115 120 125
Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Gly Ala Ser
130 135 140
Gln Ser Val Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly
145 150 155 160
Leu Ala Pro Arg Leu Leu Ile Tyr Asp Ala Ser Ser Arg Ala Thr Gly
165 170 175
Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
180 185 190
Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln
195 200 205
Gln Tyr Gly Ser Ser Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu
210 215 220
Ile Lys
225
<210> 229
<211> 224
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 229
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ile Thr Val Ser Ser Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Ser Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Leu Gln Glu Arg Gly Gly Met Asp Val Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Asp Ile Gln Leu Thr Gln Ser Pro Ser Thr
115 120 125
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
130 135 140
Gln Ala Ile Ser Asn Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys
145 150 155 160
Ala Pro Lys Leu Leu Ile Tyr Glu Ala Ser Asn Leu Glu Ser Gly Val
165 170 175
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr
180 185 190
Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
195 200 205
Tyr Gly Asn Tyr Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
210 215 220
<210> 230
<211> 239
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 230
Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Glu Asp Ala Gly Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr
100 105 110
Pro Lys Ala His Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val
115 120 125
Thr Val Ser Ser Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser
130 135 140
Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser
145 150 155 160
Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
165 170 175
Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser
180 185 190
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
195 200 205
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr
210 215 220
Ser Thr Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
225 230 235
<210> 231
<211> 230
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 231
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Arg Ser Pro Ser Ile Ala Ala Ala Ala Asn Ala Phe Asp Ile
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Asp Ile Val Met Thr
115 120 125
Gln Ser Ser Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile
130 135 140
Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln
145 150 155 160
Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser
165 170 175
Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr
180 185 190
Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr
195 200 205
Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Tyr Thr Phe Gly Gln Gly
210 215 220
Thr Lys Leu Glu Ile Lys
225 230
<210> 232
<211> 229
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 232
Gln Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asn Ser Gly Ala Thr Asn Phe Ala Gln Lys Phe
50 55 60
Arg Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Thr Thr Ala Tyr
65 70 75 80
Met Glu Met Ser Arg Leu Ile Ser Asp Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Arg Asp Arg Gly Phe Ser Ile Val Ser Tyr Ala Met Asp Val Trp
100 105 110
Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ile Arg Met Thr Gln
115 120 125
Ser Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
130 135 140
Cys Arg Ala Ser Gln Thr Ile Thr Asp Trp Leu Ala Trp Tyr Gln Gln
145 150 155 160
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Lys Ala Ser Thr Leu
165 170 175
Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu
180 185 190
Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr
195 200 205
Tyr Cys Gln Gln Tyr Asn Ser Tyr Ser Trp Ala Phe Gly Gln Gly Thr
210 215 220
Lys Val Glu Ile Lys
225
<210> 233
<211> 229
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 233
Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asn Ser Gly Ala Thr Asn Phe Ala Gln Lys Phe
50 55 60
Arg Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Thr Thr Ala Tyr
65 70 75 80
Met Glu Met Ser Arg Leu Ile Ser Asp Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Arg Asp Arg Gly Phe Ser Ile Val Ser Tyr Ala Met Asp Val Trp
100 105 110
Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ile Arg Met Thr Gln
115 120 125
Phe Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
130 135 140
Cys Arg Ala Ser Gln Ser Ile Gly Ser Trp Leu Ala Trp Tyr Gln Gln
145 150 155 160
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Lys Ala Ser Ser Leu
165 170 175
Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu
180 185 190
Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr
195 200 205
Tyr Cys Gln Gln Tyr Asn Ser Tyr Ser His Thr Phe Gly Gln Gly Thr
210 215 220
Lys Val Glu Ile Lys
225
<210> 234
<211> 224
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 234
Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Asp Phe Thr Val Ser Ser Asn
20 25 30
Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Leu Ile Tyr Pro Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Leu Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Arg Gly Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser
115 120 125
Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp
130 135 140
Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
145 150 155 160
Lys Leu Leu Ile Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser
165 170 175
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser
180 185 190
Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp
195 200 205
Asn Leu Pro Leu Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
210 215 220
<210> 235
<211> 234
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 235
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Glu Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Val Gly Lys Arg Gly Val Phe Leu Gly Gly Met Asp Val Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Asp Ile Val Met Thr Gln
115 120 125
Thr Pro Leu Ser Leu Pro Val Thr Pro Gly Glu Ser Ala Ser Leu Ser
130 135 140
Cys Arg Ser Ser Gln Ser Leu Leu His Arg Ser Gly His Asn Tyr Leu
145 150 155 160
Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr
165 170 175
Leu Gly Ser Ile Arg Ala Ser Gly Val Pro Asp Arg Phe Ser Gly Ser
180 185 190
Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu
195 200 205
Asp Val Gly Val Tyr Tyr Cys Met Gln Gly Leu Gln Pro Pro Tyr Thr
210 215 220
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
225 230
<210> 236
<211> 228
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 236
Gln Val Gln Leu Gln Gln Trp Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ser Val Ser Gly Gly Ser Ile Thr Gln Ile
20 25 30
Ile Tyr Tyr Trp Ala Trp Ile Arg Gln Pro Pro Gly Arg Gly Leu Glu
35 40 45
Trp Ile Gly Ser Ile Tyr Tyr Arg Gly Ser Thr Ser Ser Asn Pro Ser
50 55 60
Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Asn Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Ala Val Arg His Asp Tyr Asn Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Asp Ile Gln Leu Thr Gln Ser
115 120 125
Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys
130 135 140
Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys
145 150 155 160
Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln
165 170 175
Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
180 185 190
Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr
195 200 205
Cys Gln Gln Ser Tyr Ser Thr Pro Arg Thr Phe Gly Gln Gly Thr Lys
210 215 220
Leu Glu Ile Lys
225
<210> 237
<211> 234
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 237
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Val Gly Lys Arg Gly Val Phe Leu Gly Gly Met Asp Val Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Asp Ile Val Met Thr Gln
115 120 125
Pro Pro Leu Ser Leu Pro Val Thr Pro Gly Glu Pro Ala Ser Ile Ser
130 135 140
Cys Arg Ser Ser Gln Ser Leu Leu His Ser Asn Gly Tyr Asn Tyr Leu
145 150 155 160
Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr
165 170 175
Leu Gly Ser Asn Arg Ala Ser Gly Val Pro Asp Arg Phe Ser Gly Ser
180 185 190
Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu
195 200 205
Asp Val Gly Val Tyr Tyr Cys Met Gln Ala Leu Gln Thr Pro Tyr Thr
210 215 220
Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
225 230
<210> 238
<211> 225
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 238
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Val Thr Val Ser Ser Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ser Gly Gly Thr Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Leu Gly Pro Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser Ala Ile Arg Met Thr Gln Ser Pro Ser Thr Leu
115 120 125
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
130 135 140
Ile Ile Ser Asp Trp Leu Ala Trp Tyr Gln Gln Arg Pro Gly Glu Ala
145 150 155 160
Pro Lys Leu Leu Ile Tyr Lys Ala Ser Asn Leu Gln Ser Gly Val Pro
165 170 175
Ser Arg Phe Ser Gly Ser Val Ser Gly Thr Glu Phe Thr Leu Thr Ile
180 185 190
Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr
195 200 205
Asn Ser Asp Ser Gly His Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
210 215 220
Arg
225
<210> 239
<211> 224
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 239
Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Arg Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Leu Val Val Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val
115 120 125
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
130 135 140
Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala
145 150 155 160
Pro Lys Leu Leu Ile Tyr Gly Ala Ser Ser Leu Gln Ser Gly Val Pro
165 170 175
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
180 185 190
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala
195 200 205
Asn Ser Phe Pro Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
210 215 220
<210> 240
<211> 234
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 240
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Val Gly Lys Arg Gly Val Phe Leu Gly Gly Met Asp Val Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Asp Ile Val Met Thr Gln
115 120 125
Pro Pro Leu Ser Leu Pro Val Thr Pro Gly Glu Pro Ala Ser Ile Ser
130 135 140
Cys Arg Ser Ser Gln Ser Leu Leu His Ser Asn Gly Tyr Asn Tyr Leu
145 150 155 160
Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr
165 170 175
Leu Gly Ser Asn Arg Ala Ser Gly Val Pro Asp Arg Phe Ser Gly Ser
180 185 190
Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Gly
195 200 205
Asp Val Gly Val Tyr Tyr Cys Met Gln Ala Leu Gln Thr Pro Phe Thr
210 215 220
Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
225 230
<210> 241
<211> 226
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 241
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Ser Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Leu Leu Glu Val Gly Gly Met Asp Val Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Glu Ile Val Met Thr Gln Ser Pro Asp Thr
115 120 125
Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser
130 135 140
Glu Ser Val Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly
145 150 155 160
Gln Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly
165 170 175
Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
180 185 190
Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln
195 200 205
Gln Tyr Gly Ser Ser Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu
210 215 220
Ile Lys
225
<210> 242
<211> 243
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 242
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Glu Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Thr Thr Asp Gln Pro Glu Gly Tyr Tyr Gly Ser Gly Ser Val
100 105 110
Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val
115 120 125
Ser Ser Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr
130 135 140
Leu Gly Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val
145 150 155 160
His Ser Asp Gly Asn Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly
165 170 175
Gln Ser Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn Arg Asp Ser Gly
180 185 190
Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
195 200 205
Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met
210 215 220
Gln Gly Thr His Trp Pro Pro Asn Thr Phe Gly Gln Gly Thr Lys Val
225 230 235 240
Glu Ile Lys
<210> 243
<211> 225
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 243
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Val Thr Val Ser Ser Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Thr Leu Tyr Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser Ala Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser
115 120 125
Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser
130 135 140
Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
145 150 155 160
Lys Leu Leu Ile Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser
165 170 175
Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser
180 185 190
Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn
195 200 205
Ser Tyr Ser Asp Met Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
210 215 220
Lys
225
<210> 244
<211> 242
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 244
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Thr Thr Asp Gln Pro Glu Gly Tyr Tyr Gly Ser Gly Ser Val
100 105 110
Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val
115 120 125
Ser Ser Asp Ile Val Met Thr Gln Pro Pro Leu Ser Leu Pro Val Thr
130 135 140
Leu Gly Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val
145 150 155 160
His Ser Asp Gly Asn Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly
165 170 175
Gln Ser Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn Arg Asp Ser Gly
180 185 190
Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
195 200 205
Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met
210 215 220
Gln Gly Thr His Trp Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu
225 230 235 240
Ile Lys
<210> 245
<211> 224
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 245
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Ser Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Leu Val Ala Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu
115 120 125
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
130 135 140
Gly Ile Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala
145 150 155 160
Pro Lys Leu Leu Ile Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro
165 170 175
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
180 185 190
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu
195 200 205
Asn Ser Tyr Pro Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
210 215 220
<210> 246
<211> 226
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 246
Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Ser Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Leu Leu Glu Val Gly Gly Met Asp Val Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
115 120 125
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
130 135 140
Gln Gly Ile Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys
145 150 155 160
Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val
165 170 175
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
180 185 190
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Glu Gln
195 200 205
Leu Lys Ser Tyr Pro Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu
210 215 220
Ile Lys
225
<210> 247
<211> 672
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 247
caggttcagc tggtgcagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggggt caccgtcagt agcaactaca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggccgatt caccatctcc agacacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc tgaggacacg gccgtgtatt actgtgcgag agatctggtg 300
tcgtccggta tggacgtctg gggccaaggg accacggtca ccgtctcgag tgacatcgtg 360
atgacccagt ctccatcttc cgtgtctgca tctgtaggag acagagtcac catcacttgt 420
cgggcgagtc agggtattag cagctggtta gcctggtatc agcagaaacc agggaaagcc 480
cctaagctcc tgatctatgc tgcatccagt ttgcaaagtg gggtcccatc aaggttcagc 540
ggcagtggat ctgggacaga tttcactctc accatcagca gcctgcagcc tgaagatttt 600
gcaacttact attgtcaaca ggctaacagt ttccctccgg ctttcggccc tgggaccaaa 660
gtggatatca aa 672
<210> 248
<211> 717
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 248
gaggtgcagc tggtggagtc cgggggaggc ttggtacagc ctggcaggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaagct 120
ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggtag cataggctat 180
gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240
ctgcaaatga acagtctgag agctgaggac acggccttgt attactgtgc aaaagaggat 300
gcggggtatt actatgatag tagtggttat tactacccta aagcccactg gtacttcgat 360
ctctggggcc gtggcacaat ggtcaccgtc tcgagtgcca tccagatgac ccagtctcca 420
tcctccctgt ctgcatctgt aggagacaga gtcaccatca cttgccgggc aagtcagagc 480
attagcagct atttaaattg gtatcagcag aaaccaggga aagcccctaa gttcctgatc 540
tatgctgcat ccagtttgca aagtggggtc ccatcaaggt tcagtggcag tggatctggg 600
acagatttca ctctcaccat cagcagtctg caacctgaag attttgcaac ttactactgt 660
caacagagtc acagtacccc gtacactttt ggccaaggga ccaaggtgga aatcaaa 717
<210> 249
<211> 717
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 249
gaggtgcagc tggtggagtc cgggggaggc ttggtacagc ctggcaggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaagct 120
ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggtag cataggctat 180
gcggactctg tgaagggccg attcaccatt tccagagaca acgccaagaa ctccctgtat 240
ctgcaaatgg acagtctgag agctgaggac acggccttgt attactgtgc aaaagaggat 300
gcggggtatt actatgatag tagtggttat tactacccta aagcccactg gtacttcgat 360
ctctggggcc gtggcaccct ggtcactgtc tcgagtgaca tcgtgatgac ccagtctcca 420
tcctccctgt ctgcatctgt aggagacaga gtcaccatca cttgccgggc aagtcagagc 480
attagcagct atttaaattg gtatcagcag aaaccaggga aagcccctaa gctcctgatc 540
tatgctgcat ccagtttgca aagtggggtc ccatcaaggt tcagtggcag tggatctggg 600
acagatttca ctctcaccat cagcagtctg caacctgaag attttgcaac ttactactgt 660
caacagagtt acagtacccc tcggacgttc ggccagggga ccaagctgga gatcaaa 717
<210> 250
<211> 717
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 250
caggttcagc tggtgcagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaagct 120
ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggtag cataggctat 180
gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240
ctgcaaatga acagtctgag agctgaggac acggccttgt attactgtgc aaaagaggat 300
gcggggtatt actatgatag tagtggttat tactacccta aagcccactg gtacttcgat 360
ctctggggcc gtggcaccct ggtcaccgtc tcgagtgcca tccggatgac ccagtctcca 420
tcctccctgt ctgcatctgt aggagacaga gtcaccatca cttgccgggc aagtcagagc 480
attagcagct atttaaattg gtatcagcag aaaccaggga aagcccctaa gctcctgatc 540
tatgctgcat ccagtttgca aagtggggtc ccatcaaggt tcagtggcag tggatctggg 600
acagatttca ctctcaccat cagcagtctg caacctgaag attttgcaac ttactactgt 660
caacagagtt acagtacccc tcggactttt ggccaaggga ccaaggtgga aatcaaa 717
<210> 251
<211> 675
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 251
gaggtgcaac tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt caccgtcagt agcaactaca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc tgaggacacg gctgtgtatt actgtgcgag agatctggat 300
atagccgggg gtatggacgt ctggggccaa gggaccctgg tcaccgtctc gagtgccatc 360
cggatgaccc agtctccatc ctccctgtct gcatctgtag gagacagagt caccatcact 420
tgccgggcaa gtcagagcat tagcagctat ttaaattggt atcagcagaa accagggaaa 480
gcccctaagc tcctgatcta tgctgcatcc agtttgcaaa gtggggtccc atcaaggttc 540
agtggcagtg gatctgggac agatttcact ctcaccatca gcagtctgca acctgaagat 600
tttgcaactt actactgtca acagagttac agtaccccgt acacttttgg ccaggggacc 660
aagctggaga tcaaa 675
<210> 252
<211> 675
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 252
gaggtgcagc tggtgcagtc tggaggaggc ttgatccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctgggtt caccgtcagt agcaactaca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gccgtgtatt actgtgcgag agacctagta 300
gtctacggta tggacgtctg gggccaaggg accacggtca ccgtctcgag tgaaattgtg 360
ttgacacagt ctccaggcac cctgtctttg tctccagggg aaagagccac cctctcctgc 420
agggccagtc agagtgttag cagcagctac ttagcctggt accagcagaa acctggccag 480
gctcccaggc tcctcatcta tggtgcatcc agcagggcca ctggcatccc agacaggttc 540
agtggcagtg ggtctgggac agacttcact ctcaccatca gcagactgga gcctgaagat 600
tttgcagtgt attactgtca gcagtatggt agctcctcgt acacttttgg ccaggggacc 660
aagctggaga tcaaa 675
<210> 253
<211> 660
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 253
gaggtgcagc tggtggagtc tggaggaggc ttgatccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctgggtt caccgtcagt agcaactaca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gccgtgtatt actgtgcgag agatctggtg 300
gtattcggta tggacgtctg gggccaaggg accacggtca ccgtctcgag tgccatccgg 360
atgacccagt ctccatcttc cgtgtctgca tctgtaggag acagagtcac catcacttgt 420
cgggcgagtc agggtattag cagctggtta gcctggtatc agcagaaacc agggaaagcc 480
cctaagctcc tgatctatgc tgcatccagt ttgcaaagtg gggtcccatc aaggttcagc 540
ggcagtggat ctgggacaga tttcactctc accatcagca gcctgcagcc tgaagatttt 600
gcaacttact attgtcaaca ggctgaggct ttcggcggag ggaccaaggt ggagatcaaa 660
<210> 254
<211> 684
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 254
gaggtgcagc tggtggagtc tggggctgag gtgaagaagc ctggggcctc agtgaaagtc 60
tcctgcaagg cttctggata caccttcacc ggttactata tccactgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggatgg atcaacccta acagtggtgc cacaaacttt 180
gcacagaagt ttcggggcag ggtcaccatg accagggaca cctccatcac cacagcctac 240
atggagatga gcaggctgat atctgacgac acggccgtgt atttctgtgc gagagatcga 300
ggcttcagta tcgtatccta cgctatggac gtctggggcc aagggaccac ggtcaccgtc 360
tcgagtgcca tccagttgac ccagtctcct tccaccctgt ctgcatctgt cggagacaga 420
gtcaccatca cttgccgggc cagtcagagt attaattcct ggttggcctg gtatcagcag 480
aaaccaggga aagcccctaa actcctgatc tataaggcgt ctcatttaca aagtggcgtc 540
ccttcaaggt tcagcggcag tggatctggg acagatttca ctcttaccat cagtagcctg 600
cagcctgatg attttgcaat ttattactgc caacagcata attcttatcc gaccttcggc 660
caagggacca aggtggaaat caaa 684
<210> 255
<211> 672
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 255
gaggtgcagc tggtggagac tggaggaggc ttggtccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggggt caccgtcagt agcaactaca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggccgatt caccatctcc agacacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc tgaggacacg gccgtgtatt actgtgcgag agatctggtg 300
tcgtccggta tggacgtctg gggccaaggg accacggtca ccgtctcgag tgaaattgtg 360
ttgacgcagt ctccatcctt cctgtctgca tctgtaggag acagagtcac catcacttgc 420
cgggccagtc agggcattag cagttattta gcctggtatc agcaagaacc agggaaagcc 480
cctaagctcc tgatctatgc tgcatccact ttgcaaggtg gggtcccatc aaggttcagc 540
ggcagtggat ctgggacaga attcactctc acaatcagca gcctgcagcc tgaagatttt 600
gcaacttatt actgtcaaca gcttaatagt taccctttca ctttcggcgg agggaccaag 660
gtggagatca aa 672
<210> 256
<211> 705
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 256
gaggtgcagc tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg cttctggtta cacctttacc agctatggta tcagctgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggatgg atcagcgctt accatggtaa cacaaactat 180
gcacagaagc tccagggcag agtcaccatg accacagaca catccacgag cacagcctac 240
atggagctga ggagcctgag atctgacgac acggccgtgt attactgtgc gagaggcctg 300
gccccatcat attgtggtgg tgactgctat cctcgggccc catttgacta ctggggccag 360
ggaaccctgg tcaccgtctc gagtgacatc cagttgaccc agtctccatc ctccctgtct 420
gcatctgtag gagacagagt caccatcact tgccgggcaa gtcagagcat tagcagctat 480
ttaaattggt atcagcagaa accagggaaa gcccctaagc tcctgatcta tgctgcatcc 540
agtttgcaaa gtggggtccc atcaaggttc agtggcagtg gatctgggac agatttcact 600
ctcaccatca gcagtctgca acctgaagat tttgcaactt actactgtca acagagttac 660
agtaccccgt acacttttgg ccaggggacc aagctggaga tcaaa 705
<210> 257
<211> 675
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 257
gaggtgcagc tggtgcagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggggt caccgtcagt agcaactaca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggccgatt caccatctcc agacacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc tgaggacacg gccgtgtatt actgtgcgag agatctggtg 300
tcgtccggta tggacgtctg gggccaaggg accctggtca ccgtctcgag tgccatccag 360
ttgacccagt ctccatcctt cctgtctgca tctgtaggag acagagtcac catcacttgc 420
cgggccagtc agggcattag cagttattta gcctggtatc agcaaaaacc agggaaagcc 480
cctaagctcc tgatctatgc tgcatccact ttgcaaagtg gggtcccatc aaggttcagc 540
ggcagtggat ctggggcaga attcactctc acaatcagca gcctgcagcc tgaagatttt 600
gcaacttatt actgtcaaca gcttaatagt taccctccgt acacttttgg ccaagggacc 660
aaggtggaaa tcaaa 675
<210> 258
<211> 705
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 258
gaggtgcagc tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg cttctggtta cacctttacc agctatggta tcagctgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggatgg atcagcggtt tccacggtaa cacaaactat 180
gcacagaagc tccagggcag agtcaccatg accacagaca catccacgag cacagcctac 240
atggagctga ggagcctgag atctgacgac acggccgtgt attactgtgc gagaggcctg 300
gccccatcat attgtggtgg tgactgctat cctcgggccc catttgacta ctggggccag 360
ggaaccctgg tcaccgtctc gagtgccatc cagttgaccc agtctccatc ctccctgtct 420
gcatctgtag gagacagagt caccatcact tgccgggcaa gtcagagcat tagcagctat 480
ttaaattggt atcagcagaa accagggaaa gcccctaagc tcctgatcta tgctgcatcc 540
agtttgcaaa gtggggtccc atcaaggttc agtggcagtg gatctgggac agatttcact 600
ctcaccatca gcagtctgca acctgaagat tttgcaactt actactgtca acagagttac 660
agtacactcc tcactttcgg cggagggacc aaggtggaga tcaaa 705
<210> 259
<211> 675
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 259
gaggtgcagc tggtggagac tggaggaggc ttgatccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctgggtt caccgtcggt agcaactaca tgaactgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcactt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gccgtgtatt actgtgcgag agacttagtc 300
tactacggta tggacgtctg gggccaaggg accacggtca ccgtctcgag tgacatcgtg 360
atgacccagt ctccatcctt cctgtctgca tctgtaggag acagagtcac catcacttgc 420
cgggccagtc agggcattag cagttattta gcctggtatc agcaaaaacc agggaaagcc 480
cctaagctcc tgatctatgc tgcatccact ttgcaaagtg gggtcccatc aaggttcagc 540
ggcagtggat ctgggacaga attcactctc acaatcagca gcctgcagcc tgaagatttt 600
gcaacttatt actgtcaaca gcttaatagt taccctccgt acacttttgg ccaagggacc 660
aaggtggaaa tcaaa 675
<210> 260
<211> 678
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 260
caggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggaat caccgtcagt agcaactaca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggcagatt cagcatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gctgtgtatt actgtgcgag agatcttcag 300
gagcgaggcg gtatggacgt ctggggccaa gggaccacgg tcaccgtctc gagtgaaatt 360
gtgttgacgc agtctccagc caccctgtct ttgtctccag gggaaagagc caccctctcc 420
tgcggggcca gtcagagtgt tagcagcagc tacttagcct ggtaccagca gaaacctggc 480
ctggcgccca ggctcctcat ctatgatgca tccagcaggg ccactggcat cccagacagg 540
ttcagtggca gtgggtctgg gacagacttc actctcacca tcagcagact ggagcctgaa 600
gattttgcag tgtattactg tcagcagtat ggtagctcac cgctcacttt cggcggaggg 660
accaaggtgg agatcaaa 678
<210> 261
<211> 673
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 261
caggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggaat caccgtcagt agcaactaca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggcagatt cagcatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gctgtgtatt actgtgcgag agatcttcag 300
gagcgaggcg gtatggacgt ctggggccaa gggaccctgg tcaccgtctc gagtgacatc 360
cagttgaccc agtctccctc caccctgtct gcatctgtag gagacagagt caccatcact 420
tgccgggcca gtcaggctat tagtaactgg ttggcctggt atcagcagaa accagggaaa 480
gcccctaagc tcctgatcta tgaggcgtct aatttagaaa gtggggtccc atcgaggttc 540
agcggcagtg gttctgggac agaattcact ctcaccatca gcagcctgca gcctgatgat 600
tttgcaactt attactgcca acagtatggt aattattgga cgttcggcca agggaccaag 660
gtggaaatca aag 673
<210> 262
<211> 719
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 262
caggtccagc tggtacagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaagct 120
ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggtag cataggctat 180
gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240
ctgcaaatga acagtctgag agctgaggac acggccttgt attactgtgc aaaagaggat 300
gcggggtatt actatgatag tagtggttat tactacccta aagcccactg gtacttcgat 360
ctctggggcc gtggcaccct ggtcaccgtc tcgagtggac atccagttga cccagtctcc 420
atcctccctg tctgcatctg taggagacag agtcaccatc acttgccggg caagtcagag 480
cattagcagc tatttaaatt ggtatcagca gaaaccaggg aaagccccta agctcctgat 540
ctatgctgca tccagtttgc aaagtggggt cccatcaagg ttcagtggca gtggatctgg 600
gacagatttc actctcacca tcagcagtct gcaacctgaa gattttgcaa cttactactg 660
tcaacagagt tacagtaccc ctctgacgtt cggccagggg accaagctgg agatcaaag 719
<210> 263
<211> 692
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 263
gaggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60
tcctgtgcag cctctggatt caccttcagt agctatgcta tgcactgggt ccgccaggct 120
ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactac 180
gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagccgatcc 300
cccagtatag cagcagccgc taatgctttt gatatctggg gccaagggac cacggtcacc 360
gtctcgagtg gacatcgtga tgacccagtc ttcatcctcc ctgtctgcat ctgtaggaga 420
cagggtcacc atcacttgcc gggcaagtca gagcattagc agctatttaa attggtatca 480
gcagaaacca gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg 540
ggtcccatca aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag 600
tctgcaacct gaagattttg caacttacta ctgtcaacag agttacagta ccccgtacac 660
ttttggccag gggaccaagc tggagatcaa ag 692
<210> 264
<211> 688
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 264
caggtgcagc tggtggagtc tggggctgag gtgaagaagc ctggggcctc agtgaaagtc 60
tcctgcaagg cttctggata caccttcacc ggttactata tccactgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggatgg atcaacccta acagtggtgc cacaaacttt 180
gcacagaagt ttcggggcag ggtcaccatg accagggaca cctccatcac cacagcctac 240
atggagatga gcaggctgat atctgacgac acggccgtgt atttctgtgc gagagatcga 300
ggcttcagta tcgtatccta cgctatggac gtctggggcc aagggaccac ggtcaccgtc 360
tcgagtgcca tccggatgac ccagtctcct tccaccctgt ctgcatctgt aggagacaga 420
gtcaccatca cttgccgggc cagtcagact attactgact ggttggcctg gtatcagcag 480
aaaccaggga aagcccctaa gctcctgatc tataaggcgt ctactttaga aagtggggtc 540
ccatcaaggt tcagcggcag tggatctggg acagaattca ctctcaccat cagcagcctg 600
cagcctgatg atttcgcaac ttattactgc caacaatata atagttattc ttgggcgttc 660
ggccaaggga ccaaggtgga aatcaaag 688
<210> 265
<211> 688
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 265
gaggtgcagc tggtggagtc cggggctgag gtgaagaagc ctggggcctc agtgaaagtc 60
tcctgcaagg cttctggata caccttcacc ggttactata tccactgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggatgg atcaacccta acagtggtgc cacaaacttt 180
gcacagaagt ttcggggcag ggtcaccatg accagggaca cctccatcac cacagcctac 240
atggagatga gcaggctgat atctgacgac acggccgtgt atttctgtgc gagagatcga 300
ggcttcagta tcgtatccta cgctatggac gtctggggcc aagggaccac ggtcaccgtc 360
tcgagtgcca tccggatgac ccagtttcct tccaccctgt ctgcatctgt aggagacaga 420
gtcaccatca cttgccgggc cagtcagagt attggtagct ggttggcctg gtatcagcag 480
aaaccaggga aagcccctaa gctcctgatc tataaggcgt ctagtttaga aagtggggtc 540
ccatcaaggt tcagcggcag tggatctggg acagaattca ctctcaccat cagcagcctg 600
cagcctgatg attttgcaac ttattactgc caacagtata atagttattc tcacactttt 660
ggccaaggga ccaaggtgga aatcaaag 688
<210> 266
<211> 674
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 266
caggtccagc tggtgcagtc tgggggaggc ttgatccagc ctggggggtc cctgagactc 60
tcctgtacag cctctgactt caccgtcagt agcaactaca tgacctgggt ccgccaggct 120
ccagggaagg gactggagtg ggtctcactt atttatcccg gtggtagcac atactacgca 180
gactccctga agggccgatt caccatctcc agagacaatt ccaagaacac gctatacctt 240
caaatgaaca gcctgagagt tgaggacacg gctgtgtatt actgtgcgag agaccggggc 300
gatgcatttg atatctgggg ccaagggacc acggtcaccg tctcgagtgg acatcgtgat 360
gacccagtct ccatcctccc tgtctgcatc tgtaggagac agagtcacca tcacttgcca 420
ggcgagtcag gacattagca actatttaaa ttggtatcag cagaaaccag ggaaagcccc 480
taagctcctg atctacgatg catccaattt ggaaacaggg gtcccatcaa ggttcagtgg 540
aagtggatct gggacagatt ttactttcac catcagcagc ctgcagcctg aagatattgc 600
aacatattac tgtcaacagt atgataatct ccccttattc actttcggcc ctgggaccaa 660
agtggatatc aaag 674
<210> 267
<211> 702
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 267
gaggtgcagc tggtggagtc cgggggaggc gtggtccagc ctgggaggtc cctgagactc 60
tcctgtgcag cgtctggatt caccttcagt acctatgcta tgcactgggt ccgccaggct 120
ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactac 180
gcagactccg tgaagggccg attcaccatc tccagagaca attccgagaa cacgctgtat 240
ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagagtagga 300
aaaagggggg ttttcctggg gggtatggac gtctggggcc aaggcaccct ggtcaccgtc 360
tcgagtgata ttgtgatgac ccagactcca ctctccctgc ccgtcacccc tggagagtcg 420
gcctccctct cctgcaggtc tagtcagagc ctcctgcata ggagtggaca caactatttg 480
gattggtacc tgcagaagcc agggcagtct ccacagctcc tgatttattt gggttctatt 540
cgggcctccg gggtccctga caggttcagt ggcagtggat caggcacaga ctttacactg 600
aaaataagta gagtggaggc tgaggatgtt ggggtttatt actgcatgca aggtctacaa 660
cctccgtaca cttttggcca agggaccaag gtggaaatca aa 702
<210> 268
<211> 684
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 268
caggtgcagc tacaacagtg gggcccagga ctggtgaagc cttcggagac cctgtccctc 60
acctgtagcg tctctggtgg ctccatcacg cagattattt actactgggc ctggatccgc 120
cagcccccag ggagggggct ggagtggatt gggagtatct actatagggg gagcacctcc 180
tccaacccgt ccctcaagag tcgagtcacc atatccgtag acacgtccaa gaaccagttc 240
tccctgaacc taacctctgt gaccgccgca gacacggctg tgtattactg tgcgagggcg 300
gttagacatg actacaacta ttttgactac tggggccagg gaaccctggt caccgtctcg 360
agtgacatcc agttgaccca gtctccatcc tccctgtctg catctgtagg agacagagtc 420
accatcactt gccgggcaag tcagagcatt agcagctatt taaattggta tcagcagaaa 480
ccagggaaag cccctaagct cctgatctat gctgcatcca gtttgcaaag tggggtccca 540
tcaaggttca gtggcagtgg atctgggaca gatttcactc tcaccatcag cagtctgcaa 600
cctgaagatt ttgcaactta ctactgtcaa cagagttaca gtacccctcg cacttttggc 660
caggggacca agctggagat caaa 684
<210> 269
<211> 702
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 269
gaggtgcagc tgttggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60
tcctgtgcag cgtctggatt caccttcagt acctatgcta tgcactgggt ccgccaggct 120
ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactac 180
gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagagtagga 300
aaaagggggg ttttcctggg gggtatggac gtctggggcc aagggaccct ggtcaccgtc 360
tcgagtgata ttgtgatgac tcagcctcca ctctccctgc ccgtcacccc tggagagccg 420
gcctccatct cctgcaggtc tagtcagagc ctcctccata gtaatggata caactatttg 480
gattggtacc tgcagaagcc agggcagtct ccacagctcc tgatctattt gggttctaat 540
cgggcctccg gggtccctga caggttcagt ggcagtggat caggcacaga ttttacactg 600
aaaatcagca gagtggaggc tgaggatgtt ggggtttatt actgcatgca agctctacaa 660
actccgtaca cttttggcca ggggaccaag ctggagatca aa 702
<210> 270
<211> 675
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 270
gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggagt caccgtcagt agcaactaca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatagcg gcggtaccac atactacgca 180
gactccgtga agggcagatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gctgtgtatt actgtgcgag agatctgggg 300
ccatacggta tggacgtctg gggccaaggg accacggtca ccgtctcgag tgccatccgg 360
atgacccagt ctccttccac cctgtctgca tctgtgggcg acagagtcac catcacttgc 420
cgggccagtc agattattag tgactggttg gcctggtatc agcagagacc aggggaagcc 480
cctaagctcc tcatctataa ggcatctaat ttacaaagtg gggtcccatc aaggttcagc 540
ggcagtgtat ctgggacaga attcactctc accatcagca gcctgcagcc tgatgatttt 600
gcgacttatt actgccaaca atataatagt gattctgggc acacttttgg ccaagggacc 660
aaggtggaaa tcaga 675
<210> 271
<211> 672
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 271
gaggtgcagc tggtgcagtc tggaggaggc ttgatccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctgggtt caccgtcagt aggaactaca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gccgtgtatt actgtgcgag agatctggtg 300
gtttacggta tggacgtctg gggccaaggg accacggtca ccgtctcgag tgacatccag 360
atgacccagt ctccatcttc cgtgtctgca tctgtaggag acagagtcac catcacttgt 420
cgggcgagtc agggtattag cagctggtta gcctggtatc agcagaaacc agggaaagcc 480
cctaagctcc tgatctatgg tgcatccagt ttgcaaagtg gggtcccatc aaggttcagc 540
ggcagtggat ctgggacaga tttcactctc accatcagca gcctgcagcc tgaagatttt 600
gcaacttact attgtcaaca ggctaacagt ttccctccca ctttcggcgg agggaccaag 660
gtggagatca aa 672
<210> 272
<211> 702
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 272
gaagtgcagc tggtggagtc tgggggaggc gtggtccagc ctggggggtc cctgagactc 60
tcctgtgcag cgtctggatt caccttcagt acctatgcta tgcactgggt ccgccaggct 120
ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactac 180
gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagagtagga 300
aaaagggggg ttttcctggg gggtatggac gtctggggcc aagggaccct ggtcaccgtc 360
tcgagtgata ttgtgatgac tcagcctcca ctctccctgc ccgtcacccc tggagagccg 420
gcctccatct cctgcaggtc tagtcagagc ctcctgcata gtaatggata caactatttg 480
gattggtacc tgcagaagcc agggcagtct ccacagctcc tgatctattt gggttctaat 540
cgggcctccg gggtccctga caggttcagt ggcagtggat caggcacaga ttttacactg 600
aaaatcagca gagtggaggc tggggatgtt ggggtttatt actgcatgca agctctacaa 660
acccctttca ctttcggccc tgggaccaaa gtggatatca aa 702
<210> 273
<211> 678
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 273
gaggtgcagc tggtggagac tggaggaggc ttgatccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctgggtt caccgtcagt agcaactaca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gccgtgtatt actgtgcgag agatctctta 300
gaagtagggg gtatggacgt ctggggccaa gggacaatgg tcaccgtctc gagtgaaata 360
gtgatgacgc agtctccaga caccctgtct ttgtctccag gggaaagagc caccctctcc 420
tgcagggcca gtgagagtgt tagcagcagc tacttagcct ggtaccagca gaaacctggc 480
caggctccca ggctcctcat ctatggtgca tccagtaggg ccactggcat cccagacagg 540
ttcagtggca gtgggtctgg gacagacttc actctcacca tcagcagact ggagcctgaa 600
gattttgcag tgtattactg tcagcagtat ggtagctcac cctacacttt tggccaaggg 660
accaaggtgg aaatcaaa 678
<210> 274
<211> 729
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 274
gaggtgcaac tggtggagtc tgggggaggc ttggtaaagc ctggggggtc ccttagactc 60
tcctgtgcag cctctgagtt cactttcagt aacgcctgga tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggttggccgt attaaaagca aaactgatgg tgggacaaca 180
gactacgctg cacccgtgaa aggcagattc accatctcaa gagatgattc aaaaaacacg 240
ctgtatctgc aaatgaacag cctgaaaacc gaggacacag ccgtgtatta ctgtaccaca 300
gatcaaccgg agggatacta tggttcgggg agtgtctact actacggtat ggacgtctgg 360
ggccaaggga ccacggtcac cgtctcgagt gatattgtga tgactcagtc tccactctcc 420
ctgcccgtca cccttggaca gccggcctcc atctcctgca ggtctagtca aagcctcgta 480
cacagtgatg gaaacaccta cttgaattgg tttcagcaga ggccaggcca atctccaagg 540
cgcctaattt ataaggtttc taaccgggac tctggggtcc cagacagatt cagcggcagt 600
gggtcaggca ctgatttcac actgaaaatc agcagggtgg aggctgaaga tgttggggtt 660
tattactgca tgcaaggtac acactggcct ccgaacactt ttggccaagg gaccaaggtg 720
gaaatcaaa 729
<210> 275
<211> 675
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 275
gaggtgcagc tggtggagac tggaggaggc ttgatccagc ctggggggtc cctgagactc 60
tcttgtgcag cctctggggt caccgtcagt agcaactaca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggccgatt caccatctcc agagacaatt ccaagaatac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gccgtgtatt actgtgcgag gactttatat 300
gatgcttttg atatctgggg ccaagggacc acggtcaccg tctcgagtgc catccagatg 360
acccagtctc cttccaccct gtctgcatct gtaggagaca gagtcaccat cacttgccgg 420
gccagtcaga gtattagtag ctggttggcc tggtatcagc agaaaccagg gaaagcccct 480
aagctcctga tctataaggc gtctagttta gaaagtgggg tcccatcaag gttcagcggc 540
agtggatctg ggacagaatt cactctcacc atcagcagcc tgcagcctga tgattttgca 600
acttattact gccaacagta taatagttat tctgacatgt acacttttgg ccaagggacc 660
aaggtggaaa tcaaa 675
<210> 276
<211> 726
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 276
gaggtgcaac tggtggagtc tgggggaggc ttggtaaagc ctggggggtc ccttagactc 60
tcctgtgcag cctctggatt cactttcagt aacgcctgga tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggttggccgt attaaaagca aaactgatgg tgggacaaca 180
gactacgctg cacccgtgaa aggcagattc accatctcaa gagatgattc aaaaaacacg 240
ctgtatctgc aaatgaacag cctgaaaacc gaggacacag ccgtgtatta ctgtaccaca 300
gatcaaccgg agggatacta tggttcgggg agtgtctact actacggtat ggacgtctgg 360
ggccaaggga ccacggtcac cgtctcgagt gatattgtga tgactcagcc tccactctcc 420
ctgcccgtca cccttggaca gccggcctcc atctcctgca ggtctagtca aagcctcgta 480
cacagtgatg gaaacaccta cttgaattgg tttcagcaga ggccaggcca atctccaagg 540
cgcctaattt ataaggtttc taaccgggac tctggggtcc cagacagatt cagcggcagt 600
gggtcaggca ctgatttcac actgaaaatc agcagggtgg aggctgagga tgttggggtt 660
tattactgca tgcaaggtac acactggcct tacacttttg gccaagggac caaggtggaa 720
atcaaa 726
<210> 277
<211> 672
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 277
caggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt caccgtcagt agcaactaca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc tgaggacacg gctgtgtatt actgtgcgag agatctcgtt 300
gcctacggta tggacgtctg gggccaaggg accacggtca ccgtctcgag tgacatccag 360
ttgacccagt ctccatcctc cctgtctgca tctgtaggag acagagtcac catcacttgc 420
cgggccagtc agggcattag cagttattta gcctggtatc agcaaaaacc agggaaagcc 480
cctaagctcc tgatctatgc tgcatccact ttgcaaagtg gggtcccatc aaggttcagc 540
ggcagtggat ctgggacaga tttcactctc accatcagca gcctgcagcc tgaagatttt 600
gcaacttatt actgtcaaca gcttaatagt taccccttca ctttcggccc tgggaccaaa 660
gtggatatca aa 672
<210> 278
<211> 678
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 278
gaggtgcagc tggtgcagtc tggaggaggc ttgatccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctgggtt caccgtcagt agcaactaca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gccgtgtatt actgtgcgag agatctctta 300
gaagtagggg gtatggacgt ctggggccaa gggaccctgg tcaccgtctc gagtgacatc 360
cagatgaccc agtctccatc ctccctgtct gcatctgtag gagacagagt caccatcact 420
tgccgggcca gtcagggcat tagcagttat ttagcctggt atcagcaaaa accagggaaa 480
gcccctaagc tcctgatcta tgctgcatcc actttgcaaa gtggggtccc atcaaggttc 540
agcggcagtg gatctgggac agatttcact ctcaccatca gcagcctgca gcctgaagat 600
tttgcaactt attactgtga acagcttaag agttaccctc cgtacacttt tggccagggg 660
accaagctgg agatcaaa 678
<210> 279
<211> 118
<212> PRT
<213> VH(Artificial Sequence)
<400> 279
Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Ser Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Leu His Val Val Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 280
<211> 116
<212> PRT
<213> VH(Artificial Sequence)
<400> 280
Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Glu Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Ser Arg Arg Gly Arg Asp Tyr Trp Gly Gln Gly Thr Met Val
100 105 110
Thr Val Ser Ser
115
<210> 281
<211> 118
<212> PRT
<213> VH(Artificial Sequence)
<400> 281
Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Ser Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Leu His Val Val Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 282
<211> 116
<212> PRT
<213> VH(Artificial Sequence)
<400> 282
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Arg Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Glu Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Ser Arg Arg Gly Arg Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 283
<211> 123
<212> PRT
<213> VH(Artificial Sequence)
<400> 283
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr
20 25 30
Trp Ile Ser Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ser Asp Ser Tyr Thr Asn Tyr Ser Pro Ser Phe
50 55 60
Gln Gly His Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Ile Leu Gly Val Asp Thr Ala Pro Ser Trp Gly Met Asp Val
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 284
<211> 117
<212> PRT
<213> VH(Artificial Sequence)
<400> 284
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Arg Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Leu Val Val Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser
115
<210> 285
<211> 117
<212> PRT
<213> VH(Artificial Sequence)
<400> 285
Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Arg Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Leu Val Val Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser
115
<210> 286
<211> 117
<212> PRT
<213> VH(Artificial Sequence)
<400> 286
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Arg Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Leu Val Val Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser
115
<210> 287
<211> 126
<212> PRT
<213> VH(Artificial Sequence)
<400> 287
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr
20 25 30
Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe
50 55 60
Gln Gly Gln Val Ile Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Ser Arg Asp Pro Ile Ile Ala Gln Gly Arg Thr Met Phe Asp Ala
100 105 110
Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser
115 120 125
<210> 288
<211> 126
<212> PRT
<213> VH(Artificial Sequence)
<400> 288
Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr
20 25 30
Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe
50 55 60
Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Ser Arg Asp Pro Ile Ile Ala Gln Gly Arg Thr Met Phe Asp Ala
100 105 110
Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser
115 120 125
<210> 289
<211> 126
<212> PRT
<213> VH(Artificial Sequence)
<400> 289
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr
20 25 30
Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Val Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe
50 55 60
Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Ser Arg Asp Pro Ile Ile Ala Gln Gly Arg Thr Met Phe Asp Ala
100 105 110
Phe Asp Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 290
<211> 108
<212> PRT
<213> VL(Artificial Sequence)
<400> 290
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Asp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 291
<211> 113
<212> PRT
<213> VL(Artificial Sequence)
<400> 291
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu Asp Ser
20 25 30
Asp Asp Gly Asn Thr Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln
35 40 45
Ser Pro Gln Leu Leu Ile Tyr Thr Leu Ser Tyr Arg Ala Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys
65 70 75 80
Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln
85 90 95
Arg Ile Glu Phe Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 292
<211> 108
<212> PRT
<213> VL(Artificial Sequence)
<400> 292
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 293
<211> 107
<212> PRT
<213> VL(Artificial Sequence)
<400> 293
Asp Ile Val Met Thr Gln Thr Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Asp Tyr Asn Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 294
<211> 112
<212> PRT
<213> VL(Artificial Sequence)
<400> 294
Asp Ile Val Met Thr Gln Pro Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala
85 90 95
Leu Gln Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 295
<211> 110
<212> PRT
<213> VL(Artificial Sequence)
<400> 295
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Arg Met Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 296
<211> 107
<212> PRT
<213> VL(Artificial Sequence)
<400> 296
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Ser Tyr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 297
<211> 106
<212> PRT
<213> VL(Artificial Sequence)
<400> 297
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Ser Tyr Pro Gly
85 90 95
Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
100 105
<210> 298
<211> 107
<212> PRT
<213> VL(Artificial Sequence)
<400> 298
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Ser Tyr Pro Phe
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 299
<211> 107
<212> PRT
<213> VL(Artificial Sequence)
<400> 299
Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Ser Tyr Pro Gln
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 300
<211> 107
<212> PRT
<213> VL(Artificial Sequence)
<400> 300
Ala Ile Arg Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Asn Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gln Asn Tyr Asn Ser Ala Pro Phe
85 90 95
Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
100 105
<210> 301
<211> 108
<212> PRT
<213> VL(Artificial Sequence)
<400> 301
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Arg Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 302
<211> 109
<212> PRT
<213> VL(Artificial Sequence)
<400> 302
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 303
<211> 8
<212> PRT
<213> VH_CDR1(Artificial Sequence)
<400> 303
Gly Phe Thr Phe Ser Ser Tyr Glu
1 5
<210> 304
<211> 8
<212> PRT
<213> VH_CDR1(Artificial Sequence)
<400> 304
Gly Tyr Ser Phe Thr Ser Tyr Trp
1 5
<210> 305
<211> 8
<212> PRT
<213> VH_CDR1(Artificial Sequence)
<400> 305
Gly Phe Thr Val Ser Arg Asn Tyr
1 5
<210> 306
<211> 8
<212> PRT
<213> VH_CDR2(Artificial Sequence)
<400> 306
Ile Ser Ser Ser Gly Ser Thr Ile
1 5
<210> 307
<211> 8
<212> PRT
<213> VH_CDR2(Artificial Sequence)
<400> 307
Ile Asp Pro Ser Asp Ser Tyr Thr
1 5
<210> 308
<211> 8
<212> PRT
<213> VH_CDR2(Artificial Sequence)
<400> 308
Ile Tyr Pro Gly Asp Ser Asp Thr
1 5
<210> 309
<211> 12
<212> PRT
<213> VH_CDR3(Artificial Sequence)
<400> 309
Ala Arg Asp Leu His Val Val Gly Ala Phe Asp Ile
1 5 10
<210> 310
<211> 9
<212> PRT
<213> VH_CDR3(Artificial Sequence)
<400> 310
Ala Thr Ser Arg Arg Gly Arg Asp Tyr
1 5
<210> 311
<211> 16
<212> PRT
<213> VH_CDR3(Artificial Sequence)
<400> 311
Ala Arg Ile Leu Gly Val Asp Thr Ala Pro Ser Trp Gly Met Asp Val
1 5 10 15
<210> 312
<211> 19
<212> PRT
<213> VH_CDR3(Artificial Sequence)
<400> 312
Ala Ser Arg Asp Pro Ile Ile Ala Gln Gly Arg Thr Met Phe Asp Ala
1 5 10 15
Phe Asp Ile
<210> 313
<211> 7
<212> PRT
<213> VL_CDR1(Artificial Sequence)
<400> 313
Gln Ser Val Ser Ser Ser Tyr
1 5
<210> 314
<211> 12
<212> PRT
<213> VL_CDR1(Artificial Sequence)
<400> 314
Gln Ser Leu Leu Asp Ser Asp Asp Gly Asn Thr Tyr
1 5 10
<210> 315
<211> 6
<212> PRT
<213> VL_CDR1(Artificial Sequence)
<400> 315
Gln Gly Ile Ser Asn Tyr
1 5
<210> 316
<211> 3
<212> PRT
<213> VL_CDR2(Artificial Sequence)
<400> 316
Thr Leu Ser
1
<210> 317
<211> 9
<212> PRT
<213> VL_CDR3(Artificial Sequence)
<400> 317
Gln Gln Tyr Gly Ser Ser Pro Asp Thr
1 5
<210> 318
<211> 9
<212> PRT
<213> VL_CDR3(Artificial Sequence)
<400> 318
Met Gln Arg Ile Glu Phe Pro Tyr Thr
1 5
<210> 319
<211> 9
<212> PRT
<213> VL_CDR3(Artificial Sequence)
<400> 319
Leu Gln Asp Tyr Asn Tyr Pro Trp Thr
1 5
<210> 320
<211> 9
<212> PRT
<213> VL_CDR3(Artificial Sequence)
<400> 320
Met Gln Ala Leu Gln Thr Pro Trp Thr
1 5
<210> 321
<211> 11
<212> PRT
<213> VL_CDR3(Artificial Sequence)
<400> 321
Gln Gln Tyr Gly Ser Ser Pro Arg Met Tyr Thr
1 5 10
<210> 322
<211> 9
<212> PRT
<213> VL_CDR3(Artificial Sequence)
<400> 322
Gln Gln Leu Asn Ser Tyr Pro Tyr Thr
1 5
<210> 323
<211> 8
<212> PRT
<213> VL_CDR3(Artificial Sequence)
<400> 323
Gln Gln Leu Asn Ser Tyr Pro Gly
1 5
<210> 324
<211> 9
<212> PRT
<213> VL_CDR3(Artificial Sequence)
<400> 324
Gln Gln Leu Asn Ser Tyr Pro Gln Thr
1 5
<210> 325
<211> 9
<212> PRT
<213> VL_CDR3(Artificial Sequence)
<400> 325
Gln Asn Tyr Asn Ser Ala Pro Phe Thr
1 5
<210> 326
<211> 9
<212> PRT
<213> VL_CDR3(Artificial Sequence)
<400> 326
Gln Gln Tyr Gly Ser Ser Pro Arg Thr
1 5
<210> 327
<211> 10
<212> PRT
<213> VL_CDR3(Artificial Sequence)
<400> 327
Gln Gln Tyr Gly Ser Ser Pro Pro Phe Thr
1 5 10
<210> 328
<211> 396
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 328
caggtccagc tggtacagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaagct 120
ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggtag cataggctat 180
gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240
ctgcaaatga acagtctgag agctgaggac acggccttgt attactgtgc aaaagaggat 300
gcggggtatt actatgatag tagtggttat tactacccta aagcccactg gtacttcgat 360
ctctggggcc gtggcaccct ggtcaccgtc tcgagt 396
<210> 329
<211> 366
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 329
gaggtgcagc tggtggagtc cggggctgag gtgaagaagc ctggggcctc agtgaaagtc 60
tcctgcaagg cttctggata caccttcacc ggttactata tccactgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggatgg atcaacccta acagtggtgc cacaaacttt 180
gcacagaagt ttcggggcag ggtcaccatg accagggaca cctccatcac cacagcctac 240
atggagatga gcaggctgat atctgacgac acggccgtgt atttctgtgc gagagatcga 300
ggcttcagta tcgtatccta cgctatggac gtctggggcc aagggaccac ggtcaccgtc 360
tcgagt 366
<210> 330
<211> 354
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 330
gaggtgcagc tggtgcagtc tggaggaggc ttgatccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctgggtt caccgtcagt agcaactaca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gccgtgtatt actgtgcgag agatctgcat 300
gtggtgggtg cttttgatat ctggggccaa gggaccacgg tcaccgtctc gagt 354
<210> 331
<211> 348
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 331
caggtccagc tggtacagtc tgggggaggc ttggtacagc ctggagggtc cctgagactc 60
tcctgtgcag cctctggatt caccttcagt agttatgaaa tgaactgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtttcatac attagtagta gtggtagtac catatactac 180
gcagactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctcactgtat 240
ctgcaaatga acagcctgag agccgaggac acggctgttt attactgtgc gaccagccgt 300
cgcggacggg actactgggg ccagggcaca atggtcaccg tctcgagt 348
<210> 332
<211> 354
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 332
gaggtgcagc tggtgcagtc tggaggaggc ttgatccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctgggtt caccgtcagt agcaactaca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gccgtgtatt actgtgcgag agatctgcat 300
gtggtgggtg cttttgatat ctggggccaa gggaccctgg tcaccgtctc gagt 354
<210> 333
<211> 348
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 333
gaggtgcagc tggtggagtc tgggggaggc ttggtacggc ctggagggtc cctgagactc 60
tcctgtgcag cctctggatt caccttcagt agttatgaaa tgaactgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtttcatac attagtagta gtggtagcac catatactac 180
gcagactctg tgaagggccg attcaccatc tccagagaca acgccaaaaa ctcactgtat 240
ctgcaaatga acagcctgag agccgaggac acggctgttt attactgtgc gaccagccgt 300
cgcggacggg actactgggg ccagggcacc ctggtcaccg tctcgagt 348
<210> 334
<211> 369
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 334
gaggtgcagc tggtgcagtc tggagcagag gtgaaaaagc ccggggagtc tctgaggatc 60
tcctgtaagg gttctggata cagctttacc agctactgga tcagctgggt gcgccagatg 120
cccgggaaag gcctggagtg gatggggagg attgatccta gtgactctta taccaactac 180
agcccgtcct tccaaggcca cgtcaccatc tcagctgaca agtccatcag cactgcctac 240
ctgcagtgga gcagcctgaa ggcctcggac accgccatgt attactgtgc gagaatttta 300
ggggtggata cagctccctc ttggggtatg gacgtctggg gccaagggac cctggtcacc 360
gtctcgagt 369
<210> 335
<211> 351
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 335
gaggtgcagc tggtgcagtc tggaggaggc ttgatccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctgggtt caccgtcagt aggaactaca tgagctgggt ccgccaggct 120
ccagggaagg gactggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gccgtgtatt actgtgcgag agatctggtg 300
gtttacggta tggacgtctg gggccaaggg accacggtca ccgtctcgag t 351
<210> 336
<211> 351
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 336
gaggtgcagc tggtggagac tggaggaggc ttgatccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctgggtt caccgtcagt aggaactaca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gccgtgtatt actgtgcgag agatctggtg 300
gtttacggta tggacgtctg gggccaaggg accacggtca ccgtctcgag t 351
<210> 337
<211> 351
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 337
caggtgcagc tggtgcagtc tgggggaggc ttgatccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctgggtt caccgtcagt aggaactaca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gccgtgtatt actgtgcgag agatctggtg 300
gtttacggta tggacgtctg gggccaaggg accacggtca ccgtctcgag t 351
<210> 338
<211> 351
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 338
gaggtgcagc tggtgcagtc tggaggaggc ttgatccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctgggtt caccgtcagt aggaactaca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gccgtgtatt actgtgcgag agatctggtg 300
gtttacggta tggacgtctg gggtcaaggg accacggtca ccgtctcgag t 351
<210> 339
<211> 351
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 339
gaggtgcagc tgttggagtc tgggggaggc ttgatccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctgggtt caccgtcagt aggaactaca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gccgtgtatt actgtgcgag agatctggtg 300
gtttacggta tggacgtctg gggccaaggg accacggtca ccgtctcgag t 351
<210> 340
<211> 378
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 340
caggtgcagc tggtgcaatc tggggcagag gtgaaaaagc ccggggagtc tctgaagatc 60
tcctgtaagg gttctggata cagctttacc agctactgga tcggctgggt gcgccagatg 120
cccgggaaag gcctggagtg gatggggatc atctatcctg gtgactctga taccagatac 180
agcccgtcct tccaaggcca ggtcatcatc tcagccgaca agtccatcag caccgcctac 240
ctgcagtgga gcagcctgaa ggcctcggac accgccatgt attactgtgc gagccgagac 300
ccaattatag cacaaggacg gacaatgttc gatgcttttg atatctgggg ccaagggaca 360
atggtcaccg tctcgagt 378
<210> 341
<211> 378
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 341
caaatgcagc tggtgcagtc tggggcagag gtgaaaaagc ccggggagtc tctgaagatc 60
tcctgtaagg gttctggata cagctttacc agctactgga tcggctgggt gcgccagatg 120
cccgggaaag gcctggagtg gatggggatc atctatcctg gtgactctga taccagatac 180
agcccgtcct tccaaggcca ggtcaccatc tcagccgaca agtccatcag caccgcctac 240
ctgcagtgga gcagcctgaa ggcctcggac accgccatgt attactgtgc gagccgagac 300
ccaattatag cacaaggacg gacaatgttc gatgcttttg atatctgggg ccaggggaca 360
atggtcaccg tctcgagt 378
<210> 342
<211> 378
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 342
caggtccagc tggtacagtc tggggcagag gtgaaaaagc ccggggagtc tctgaagatc 60
tcctgtaagg gttctggata cagctttacc agctactgga tcggctgggt gcgccagatg 120
cccgggaaag gcctggagtg gatgggggtc atctatcctg gtgactctga taccagatac 180
agcccgtcct tccaaggcca ggtcaccatc tcagccgaca agtccatcag caccgcctac 240
ctgcagtgga gcagcctgaa ggcctcggac accgccatgt attactgtgc gagccgagac 300
ccaattatag cacaaggacg gacaatgttc gatgcttttg atatctgggg ccaagggacc 360
ctggtcaccg tctcgagt 378
<210> 343
<211> 324
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 343
gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60
ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120
cctggccagg ctcccaggct cctcatctat ggcgcatcca gcagggccac tggcatccca 180
gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240
cctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcaccaga cacttttggc 300
caggggacca agctggagat caaa 324
<210> 344
<211> 339
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 344
gatattgtga tgacccagac tccactctcc ctgcccgtca cccctggaga gccggcctcc 60
atctcctgca ggtctagtca gagcctcttg gatagtgatg atggaaacac ctatttggac 120
tggtacctgc agaagccagg gcagtctcca cagctcctga tctatacgct ttcctatcgg 180
gcctctggag tcccagacag gttcagtggc agtgggtcag gcactgattt cacactgaaa 240
atcagcaggg tggaggctga ggatgttgga gtttattact gcatgcaacg tatagagttt 300
ccctacactt ttggccaggg gaccaagctg gagatcaaa 339
<210> 345
<211> 324
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 345
gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60
ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120
cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca 180
gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240
cctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcacctta cacttttggc 300
caagggacca aggtggaaat caaa 324
<210> 346
<211> 321
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 346
gatattgtga tgacccagac tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggcaagtca gggcattaga aatgatttag gctggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatgct gcatccagtt tacaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tggcacagat ttcactctca ccatcagcag cctgcagcct 240
gaagattttg caacttatta ctgtctacaa gattacaatt acccgtggac gttcggccaa 300
gggaccaagg tggaaatcaa a 321
<210> 347
<211> 336
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 347
gatattgtga tgactcagcc tccactctcc ctgcccgtca cccctggaga gccggcctcc 60
atctcctgca ggtctagtca gagcctcctg catagtaatg gatacaacta tttggattgg 120
tacctgcaga agccagggca gtctccacag ctcctgatct atttgggttc taatcgggcc 180
tccggggtcc ctgacaggtt cagtggcagt ggatcaggca cagattttac actgaaaatc 240
agcagagtgg aggctgagga tgttggggtt tattactgca tgcaagctct acaaactccg 300
tggacgttcg gccaggggac caagctggag atcaaa 336
<210> 348
<211> 330
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 348
gaaattgtgt tgacacagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60
ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120
cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca 180
gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240
cctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcaccacg aatgtacact 300
tttggccaag ggaccaaggt ggaaatcaaa 330
<210> 349
<211> 321
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 349
gacatccagt tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggccagtca gggcattagc agttatttag cctggtatca gcaaaaacca 120
gggaaagccc ctaagctcct gatctatgct gcatccactt tgcaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240
gaagattttg caacttatta ctgtcaacag cttaatagtt acccgtacac ttttggccag 300
gggaccaagc tggagatcaa a 321
<210> 350
<211> 318
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 350
gacatcgtga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggccagtca gggcattagc agttatttag cctggtatca gcaaaaacca 120
gggaaagccc ctaagctcct gatctatgct gcatccactt tgcaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240
gaagattttg caacttatta ctgtcaacag cttaatagtt accccggttt cggccctggg 300
accaaagtgg atatcaaa 318
<210> 351
<211> 321
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 351
gacatccagt tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggccagtca gggcattagc agttatttag cctggtatca gcaaaaacca 120
gggaaagccc ctaagctcct gatctatgct gcatccactt tgcaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240
gaagattttg caacttatta ctgtcaacag cttaatagtt accctttcac tttcggccag 300
gggaccaagc tggagatcaa a 321
<210> 352
<211> 321
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 352
gccatccagt tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggccagtca gggcattagc agttatttag cctggtatca gcaaaaacca 120
gggaaagccc ctaagctcct gatctatgct gcatccactt tgcaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240
gaagattttg caacttatta ctgtcaacag cttaatagtt accctcaaac gttcggccag 300
gggaccaagc tggagatcaa a 321
<210> 353
<211> 321
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 353
gccatccgga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggcgagtca gggcattagc aattatttag cctggtatca gcagaaacca 120
gggaaagttc ctaagctcct gatctatgct gcatccactt tgcaatcagg ggtcccatct 180
cggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240
gaagatgttg caacttatta ctgtcaaaac tataacagtg cccccttcac tttcggccct 300
gggaccaaag tggatatcaa a 321
<210> 354
<211> 324
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 354
gaaattgtgt tgacacagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60
ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120
cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca 180
gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240
cctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcaccgag aacgttcggc 300
caggggacca agctggagat caaa 324
<210> 355
<211> 327
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 355
gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60
ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120
cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca 180
gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240
cctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcacctcc attcactttc 300
ggccagggga ccaagctgga gatcaaa 327
<210> 356
<211> 226
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 356
Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Ser Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Leu His Val Val Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr
115 120 125
Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser
130 135 140
Gln Ser Val Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly
145 150 155 160
Gln Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly
165 170 175
Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
180 185 190
Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln
195 200 205
Gln Tyr Gly Ser Ser Pro Asp Thr Phe Gly Gln Gly Thr Lys Leu Glu
210 215 220
Ile Lys
225
<210> 357
<211> 229
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 357
Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Glu Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Ser Arg Arg Gly Arg Asp Tyr Trp Gly Gln Gly Thr Met Val
100 105 110
Thr Val Ser Ser Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro
115 120 125
Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser
130 135 140
Leu Leu Asp Ser Asp Asp Gly Asn Thr Tyr Leu Asp Trp Tyr Leu Gln
145 150 155 160
Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Thr Leu Ser Tyr Arg
165 170 175
Ala Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
180 185 190
Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr
195 200 205
Tyr Cys Met Gln Arg Ile Glu Phe Pro Tyr Thr Phe Gly Gln Gly Thr
210 215 220
Lys Leu Glu Ile Lys
225
<210> 358
<211> 226
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 358
Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Ser Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Leu His Val Val Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr
115 120 125
Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser
130 135 140
Gln Ser Val Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly
145 150 155 160
Gln Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly
165 170 175
Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
180 185 190
Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln
195 200 205
Gln Tyr Gly Ser Ser Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu
210 215 220
Ile Lys
225
<210> 359
<211> 223
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 359
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Arg Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Glu Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Ser Arg Arg Gly Arg Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Asp Ile Val Met Thr Gln Thr Pro Ser Ser Leu Ser
115 120 125
Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly
130 135 140
Ile Arg Asn Asp Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
145 150 155 160
Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser
165 170 175
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
180 185 190
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Asp Tyr
195 200 205
Asn Tyr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
210 215 220
<210> 360
<211> 235
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 360
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr
20 25 30
Trp Ile Ser Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ser Asp Ser Tyr Thr Asn Tyr Ser Pro Ser Phe
50 55 60
Gln Gly His Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Ile Leu Gly Val Asp Thr Ala Pro Ser Trp Gly Met Asp Val
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Asp Ile Val Met Thr
115 120 125
Gln Pro Pro Leu Ser Leu Pro Val Thr Pro Gly Glu Pro Ala Ser Ile
130 135 140
Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser Asn Gly Tyr Asn Tyr
145 150 155 160
Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile
165 170 175
Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro Asp Arg Phe Ser Gly
180 185 190
Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala
195 200 205
Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala Leu Gln Thr Pro Trp
210 215 220
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
225 230 235
<210> 361
<211> 227
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 361
Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Arg Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Leu Val Val Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu
115 120 125
Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln
130 135 140
Ser Val Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
145 150 155 160
Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile
165 170 175
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
180 185 190
Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln
195 200 205
Tyr Gly Ser Ser Pro Arg Met Tyr Thr Phe Gly Gln Gly Thr Lys Val
210 215 220
Glu Ile Lys
225
<210> 362
<211> 224
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 362
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Arg Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Leu Val Val Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu
115 120 125
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
130 135 140
Gly Ile Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala
145 150 155 160
Pro Lys Leu Leu Ile Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro
165 170 175
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
180 185 190
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu
195 200 205
Asn Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
210 215 220
<210> 363
<211> 223
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 363
Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Arg Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Leu Val Val Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu
115 120 125
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
130 135 140
Gly Ile Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala
145 150 155 160
Pro Lys Leu Leu Ile Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro
165 170 175
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
180 185 190
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu
195 200 205
Asn Ser Tyr Pro Gly Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
210 215 220
<210> 364
<211> 224
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 364
Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Arg Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Leu Val Val Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu
115 120 125
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
130 135 140
Gly Ile Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala
145 150 155 160
Pro Lys Leu Leu Ile Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro
165 170 175
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
180 185 190
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu
195 200 205
Asn Ser Tyr Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
210 215 220
<210> 365
<211> 224
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 365
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Arg Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Leu Val Val Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu
115 120 125
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
130 135 140
Gly Ile Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala
145 150 155 160
Pro Lys Leu Leu Ile Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro
165 170 175
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
180 185 190
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu
195 200 205
Asn Ser Tyr Pro Gln Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
210 215 220
<210> 366
<211> 233
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 366
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr
20 25 30
Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe
50 55 60
Gln Gly Gln Val Ile Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Ser Arg Asp Pro Ile Ile Ala Gln Gly Arg Thr Met Phe Asp Ala
100 105 110
Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Ala Ile
115 120 125
Arg Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg
130 135 140
Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Asn Tyr Leu Ala
145 150 155 160
Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile Tyr Ala
165 170 175
Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly
180 185 190
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
195 200 205
Val Ala Thr Tyr Tyr Cys Gln Asn Tyr Asn Ser Ala Pro Phe Thr Phe
210 215 220
Gly Pro Gly Thr Lys Val Asp Ile Lys
225 230
<210> 367
<211> 234
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 367
Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr
20 25 30
Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe
50 55 60
Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Ser Arg Asp Pro Ile Ile Ala Gln Gly Arg Thr Met Phe Asp Ala
100 105 110
Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Glu Ile
115 120 125
Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg
130 135 140
Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu
145 150 155 160
Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr
165 170 175
Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser
180 185 190
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu
195 200 205
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro Arg Thr
210 215 220
Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
225 230
<210> 368
<211> 235
<212> PRT
<213> VH_VL(Artificial Sequence)
<400> 368
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr
20 25 30
Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Val Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe
50 55 60
Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Ser Arg Asp Pro Ile Ile Ala Gln Gly Arg Thr Met Phe Asp Ala
100 105 110
Phe Asp Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Glu Ile
115 120 125
Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg
130 135 140
Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu
145 150 155 160
Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr
165 170 175
Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser
180 185 190
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu
195 200 205
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro Pro Phe
210 215 220
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
225 230 235
<210> 369
<211> 678
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 369
gaggtgcagc tggtgcagtc tggaggaggc ttgatccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctgggtt caccgtcagt agcaactaca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gccgtgtatt actgtgcgag agatctgcat 300
gtggtgggtg cttttgatat ctggggccaa gggaccacgg tcaccgtctc gagtgaaatt 360
gtgttgacgc agtctccagg caccctgtct ttgtctccag gggaaagagc caccctctcc 420
tgcagggcca gtcagagtgt tagcagcagc tacttagcct ggtaccagca gaaacctggc 480
caggctccca ggctcctcat ctatggcgca tccagcaggg ccactggcat cccagacagg 540
ttcagtggca gtgggtctgg gacagacttc actctcacca tcagcagact ggagcctgaa 600
gattttgcag tgtattactg tcagcagtat ggtagctcac cagacacttt tggccagggg 660
accaagctgg agatcaaa 678
<210> 370
<211> 687
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 370
caggtccagc tggtacagtc tgggggaggc ttggtacagc ctggagggtc cctgagactc 60
tcctgtgcag cctctggatt caccttcagt agttatgaaa tgaactgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtttcatac attagtagta gtggtagtac catatactac 180
gcagactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctcactgtat 240
ctgcaaatga acagcctgag agccgaggac acggctgttt attactgtgc gaccagccgt 300
cgcggacggg actactgggg ccagggcaca atggtcaccg tctcgagtga tattgtgatg 360
acccagactc cactctccct gcccgtcacc cctggagagc cggcctccat ctcctgcagg 420
tctagtcaga gcctcttgga tagtgatgat ggaaacacct atttggactg gtacctgcag 480
aagccagggc agtctccaca gctcctgatc tatacgcttt cctatcgggc ctctggagtc 540
ccagacaggt tcagtggcag tgggtcaggc actgatttca cactgaaaat cagcagggtg 600
gaggctgagg atgttggagt ttattactgc atgcaacgta tagagtttcc ctacactttt 660
ggccagggga ccaagctgga gatcaaa 687
<210> 371
<211> 678
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 371
gaggtgcagc tggtgcagtc tggaggaggc ttgatccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctgggtt caccgtcagt agcaactaca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gccgtgtatt actgtgcgag agatctgcat 300
gtggtgggtg cttttgatat ctggggccaa gggaccctgg tcaccgtctc gagtgaaatt 360
gtgttgacgc agtctccagg caccctgtct ttgtctccag gggaaagagc caccctctcc 420
tgcagggcca gtcagagtgt tagcagcagc tacttagcct ggtaccagca gaaacctggc 480
caggctccca ggctcctcat ctatggtgca tccagcaggg ccactggcat cccagacagg 540
ttcagtggca gtgggtctgg gacagacttc actctcacca tcagcagact ggagcctgaa 600
gattttgcag tgtattactg tcagcagtat ggtagctcac cttacacttt tggccaaggg 660
accaaggtgg aaatcaaa 678
<210> 372
<211> 669
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 372
gaggtgcagc tggtggagtc tgggggaggc ttggtacggc ctggagggtc cctgagactc 60
tcctgtgcag cctctggatt caccttcagt agttatgaaa tgaactgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtttcatac attagtagta gtggtagcac catatactac 180
gcagactctg tgaagggccg attcaccatc tccagagaca acgccaaaaa ctcactgtat 240
ctgcaaatga acagcctgag agccgaggac acggctgttt attactgtgc gaccagccgt 300
cgcggacggg actactgggg ccagggcacc ctggtcaccg tctcgagtga tattgtgatg 360
acccagactc catcctccct gtctgcatct gtaggagaca gagtcaccat cacttgccgg 420
gcaagtcagg gcattagaaa tgatttaggc tggtatcagc agaaaccagg gaaagcccct 480
aagctcctga tctatgctgc atccagttta caaagtgggg tcccatcaag gttcagcggc 540
agtggatctg gcacagattt cactctcacc atcagcagcc tgcagcctga agattttgca 600
acttattact gtctacaaga ttacaattac ccgtggacgt tcggccaagg gaccaaggtg 660
gaaatcaaa 669
<210> 373
<211> 705
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 373
gaggtgcagc tggtgcagtc tggagcagag gtgaaaaagc ccggggagtc tctgaggatc 60
tcctgtaagg gttctggata cagctttacc agctactgga tcagctgggt gcgccagatg 120
cccgggaaag gcctggagtg gatggggagg attgatccta gtgactctta taccaactac 180
agcccgtcct tccaaggcca cgtcaccatc tcagctgaca agtccatcag cactgcctac 240
ctgcagtgga gcagcctgaa ggcctcggac accgccatgt attactgtgc gagaatttta 300
ggggtggata cagctccctc ttggggtatg gacgtctggg gccaagggac cctggtcacc 360
gtctcgagtg atattgtgat gactcagcct ccactctccc tgcccgtcac ccctggagag 420
ccggcctcca tctcctgcag gtctagtcag agcctcctgc atagtaatgg atacaactat 480
ttggattggt acctgcagaa gccagggcag tctccacagc tcctgatcta tttgggttct 540
aatcgggcct ccggggtccc tgacaggttc agtggcagtg gatcaggcac agattttaca 600
ctgaaaatca gcagagtgga ggctgaggat gttggggttt attactgcat gcaagctcta 660
caaactccgt ggacgttcgg ccaggggacc aagctggaga tcaaa 705
<210> 374
<211> 681
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 374
gaggtgcagc tggtgcagtc tggaggaggc ttgatccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctgggtt caccgtcagt aggaactaca tgagctgggt ccgccaggct 120
ccagggaagg gactggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gccgtgtatt actgtgcgag agatctggtg 300
gtttacggta tggacgtctg gggccaaggg accacggtca ccgtctcgag tgaaattgtg 360
ttgacacagt ctccaggcac cctgtctttg tctccagggg aaagagccac cctctcctgc 420
agggccagtc agagtgttag cagcagctac ttagcctggt accagcagaa acctggccag 480
gctcccaggc tcctcatcta tggtgcatcc agcagggcca ctggcatccc agacaggttc 540
agtggcagtg ggtctgggac agacttcact ctcaccatca gcagactgga gcctgaagat 600
tttgcagtgt attactgtca gcagtatggt agctcaccac gaatgtacac ttttggccaa 660
gggaccaagg tggaaatcaa a 681
<210> 375
<211> 672
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 375
gaggtgcagc tggtggagac tggaggaggc ttgatccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctgggtt caccgtcagt aggaactaca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gccgtgtatt actgtgcgag agatctggtg 300
gtttacggta tggacgtctg gggccaaggg accacggtca ccgtctcgag tgacatccag 360
ttgacccagt ctccatcctc cctgtctgca tctgtaggag acagagtcac catcacttgc 420
cgggccagtc agggcattag cagttattta gcctggtatc agcaaaaacc agggaaagcc 480
cctaagctcc tgatctatgc tgcatccact ttgcaaagtg gggtcccatc aaggttcagc 540
ggcagtggat ctgggacaga tttcactctc accatcagca gcctgcagcc tgaagatttt 600
gcaacttatt actgtcaaca gcttaatagt tacccgtaca cttttggcca ggggaccaag 660
ctggagatca aa 672
<210> 376
<211> 669
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 376
caggtgcagc tggtgcagtc tgggggaggc ttgatccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctgggtt caccgtcagt aggaactaca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gccgtgtatt actgtgcgag agatctggtg 300
gtttacggta tggacgtctg gggccaaggg accacggtca ccgtctcgag tgacatcgtg 360
atgacccagt ctccatcctc cctgtctgca tctgtaggag acagagtcac catcacttgc 420
cgggccagtc agggcattag cagttattta gcctggtatc agcaaaaacc agggaaagcc 480
cctaagctcc tgatctatgc tgcatccact ttgcaaagtg gggtcccatc aaggttcagc 540
ggcagtggat ctgggacaga tttcactctc accatcagca gcctgcagcc tgaagatttt 600
gcaacttatt actgtcaaca gcttaatagt taccccggtt tcggccctgg gaccaaagtg 660
gatatcaaa 669
<210> 377
<211> 672
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 377
gaggtgcagc tggtgcagtc tggaggaggc ttgatccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctgggtt caccgtcagt aggaactaca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gccgtgtatt actgtgcgag agatctggtg 300
gtttacggta tggacgtctg gggtcaaggg accacggtca ccgtctcgag tgacatccag 360
ttgacccagt ctccatcctc cctgtctgca tctgtaggag acagagtcac catcacttgc 420
cgggccagtc agggcattag cagttattta gcctggtatc agcaaaaacc agggaaagcc 480
cctaagctcc tgatctatgc tgcatccact ttgcaaagtg gggtcccatc aaggttcagc 540
ggcagtggat ctgggacaga tttcactctc accatcagca gcctgcagcc tgaagatttt 600
gcaacttatt actgtcaaca gcttaatagt taccctttca ctttcggcca ggggaccaag 660
ctggagatca aa 672
<210> 378
<211> 672
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 378
gaggtgcagc tgttggagtc tgggggaggc ttgatccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctgggtt caccgtcagt aggaactaca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gccgtgtatt actgtgcgag agatctggtg 300
gtttacggta tggacgtctg gggccaaggg accacggtca ccgtctcgag tgccatccag 360
ttgacccagt ctccatcctc cctgtctgca tctgtaggag acagagtcac catcacttgc 420
cgggccagtc agggcattag cagttattta gcctggtatc agcaaaaacc agggaaagcc 480
cctaagctcc tgatctatgc tgcatccact ttgcaaagtg gggtcccatc aaggttcagc 540
ggcagtggat ctgggacaga tttcactctc accatcagca gcctgcagcc tgaagatttt 600
gcaacttatt actgtcaaca gcttaatagt taccctcaaa cgttcggcca ggggaccaag 660
ctggagatca aa 672
<210> 379
<211> 699
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 379
caggtgcagc tggtgcaatc tggggcagag gtgaaaaagc ccggggagtc tctgaagatc 60
tcctgtaagg gttctggata cagctttacc agctactgga tcggctgggt gcgccagatg 120
cccgggaaag gcctggagtg gatggggatc atctatcctg gtgactctga taccagatac 180
agcccgtcct tccaaggcca ggtcatcatc tcagccgaca agtccatcag caccgcctac 240
ctgcagtgga gcagcctgaa ggcctcggac accgccatgt attactgtgc gagccgagac 300
ccaattatag cacaaggacg gacaatgttc gatgcttttg atatctgggg ccaagggaca 360
atggtcaccg tctcgagtgc catccggatg acccagtctc catcctccct gtctgcatct 420
gtaggagaca gagtcaccat cacttgccgg gcgagtcagg gcattagcaa ttatttagcc 480
tggtatcagc agaaaccagg gaaagttcct aagctcctga tctatgctgc atccactttg 540
caatcagggg tcccatctcg gttcagcggc agtggatctg ggacagattt cactctcacc 600
atcagcagcc tgcagcctga agatgttgca acttattact gtcaaaacta taacagtgcc 660
cccttcactt tcggccctgg gaccaaagtg gatatcaaa 699
<210> 380
<211> 702
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 380
caaatgcagc tggtgcagtc tggggcagag gtgaaaaagc ccggggagtc tctgaagatc 60
tcctgtaagg gttctggata cagctttacc agctactgga tcggctgggt gcgccagatg 120
cccgggaaag gcctggagtg gatggggatc atctatcctg gtgactctga taccagatac 180
agcccgtcct tccaaggcca ggtcaccatc tcagccgaca agtccatcag caccgcctac 240
ctgcagtgga gcagcctgaa ggcctcggac accgccatgt attactgtgc gagccgagac 300
ccaattatag cacaaggacg gacaatgttc gatgcttttg atatctgggg ccaggggaca 360
atggtcaccg tctcgagtga aattgtgttg acacagtctc caggcaccct gtctttgtct 420
ccaggggaaa gagccaccct ctcctgcagg gccagtcaga gtgttagcag cagctactta 480
gcctggtacc agcagaaacc tggccaggct cccaggctcc tcatctatgg tgcatccagc 540
agggccactg gcatcccaga caggttcagt ggcagtgggt ctgggacaga cttcactctc 600
accatcagca gactggagcc tgaagatttt gcagtgtatt actgtcagca gtatggtagc 660
tcaccgagaa cgttcggcca ggggaccaag ctggagatca aa 702
<210> 381
<211> 705
<212> DNA
<213> VH_DNA_VL_DNA (Artificial Sequence)
<400> 381
caggtccagc tggtacagtc tggggcagag gtgaaaaagc ccggggagtc tctgaagatc 60
tcctgtaagg gttctggata cagctttacc agctactgga tcggctgggt gcgccagatg 120
cccgggaaag gcctggagtg gatgggggtc atctatcctg gtgactctga taccagatac 180
agcccgtcct tccaaggcca ggtcaccatc tcagccgaca agtccatcag caccgcctac 240
ctgcagtgga gcagcctgaa ggcctcggac accgccatgt attactgtgc gagccgagac 300
ccaattatag cacaaggacg gacaatgttc gatgcttttg atatctgggg ccaagggacc 360
ctggtcaccg tctcgagtga aattgtgttg acgcagtctc caggcaccct gtctttgtct 420
ccaggggaaa gagccaccct ctcctgcagg gccagtcaga gtgttagcag cagctactta 480
gcctggtacc agcagaaacc tggccaggct cccaggctcc tcatctatgg tgcatccagc 540
agggccactg gcatcccaga caggttcagt ggcagtgggt ctgggacaga cttcactctc 600
accatcagca gactggagcc tgaagatttt gcagtgtatt actgtcagca gtatggtagc 660
tcacctccat tcactttcgg ccaggggacc aagctggaga tcaaa 705
<210> 382
<211> 8
<212> PRT
<213> VH_CDR2(Artificial Sequence)
<400> 382
Ile Ser Trp Asn Ser Arg Ser Ile
1 5
<210> 383
<211> 8
<212> PRT
<213> VH_CDR2(Artificial Sequence)
<400> 383
Ile Ser Trp Asn Ser Tyr Ser Ile
1 5
<210> 384
<211> 132
<212> PRT
<213> VH(Artificial Sequence)
<400> 384
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Arg Ser Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Glu Asp Ala Gly Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr
100 105 110
Pro Lys Ala His Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val
115 120 125
Thr Val Ser Ser
130
<210> 385
<211> 132
<212> PRT
<213> VH(Artificial Sequence)
<400> 385
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Tyr Ser Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asp Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Glu Asp Ala Gly Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr
100 105 110
Pro Lys Ala His Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val
115 120 125
Thr Val Ser Ser
130
<210> 386
<211> 132
<212> PRT
<213> VH(Artificial Sequence)
<400> 386
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Tyr Ser Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Glu Asp Ala Gly Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr
100 105 110
Pro Lys Ala His Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val
115 120 125
Thr Val Ser Ser
130
<210> 387
<211> 118
<212> PRT
<213> VH(Artificial Sequence)
<400> 387
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ile Thr Val Ser Ser Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Leu Gln Glu Arg Gly Gly Met Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 388
<211> 396
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 388
gaggtgcagc tggtggagtc cgggggaggc ttggtacagc ctggcaggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaagct 120
ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtcggag cataggctat 180
gcggactctg tgaagggccg attcaccatt tccagagaca acgccaagaa ctccctgtat 240
ctgcaaatga acagtctgag agctgaggac acggccttgt attactgtgc aaaagaggat 300
gcggggtatt actatgatag tagtggttat tactacccta aagcccactg gtacttcgat 360
ctctggggcc gtggcaccct ggtcactgtc tcgagt 396
<210> 389
<211> 396
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 389
gaggtgcagc tggtggagtc cgggggaggc ttggtacagc ctggcaggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaagct 120
ccagggaagg gcctggagtg ggtctcaggt attagttgga atagttacag cataggctat 180
gcggactctg tgaagggccg attcaccatt tccagagaca acgccaagaa ctccctgtat 240
ctgcaaatgg acagtctgag agctgaggac acggccttgt attactgtgc aaaagaggat 300
gcggggtatt actatgatag tagtggttat tactacccta aagcccactg gtacttcgat 360
ctctggggcc gtggcaccct ggtcactgtc tcgagt 396
<210> 390
<211> 396
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 390
gaggtgcagc tggtggagtc cgggggaggc ttggtacagc ctggcaggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaagct 120
ccagggaagg gcctggagtg ggtctcaggt attagttgga atagttacag cataggctat 180
gcggactctg tgaagggccg attcaccatt tccagagaca acgccaagaa ctccctgtat 240
ctgcaaatga acagtctgag agctgaggac acggccttgt attactgtgc aaaagaggat 300
gcggggtatt actatgatag tagtggttat tactacccta aagcccactg gtacttcgat 360
ctctggggcc gtggcaccct ggtcactgtc tcgagt 396
<210> 391
<211> 354
<212> DNA
<213> VH_DNA(Artificial Sequence)
<400> 391
gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggaat caccgtcagt agcaactaca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggcagatt cactatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gctgtgtatt actgtgcgag agatcttcag 300
gagcgaggcg gtatggacgt ctggggccaa gggaccacgg tcaccgtctc gagt 354
<210> 392
<211> 9
<212> PRT
<213> VL_CDR3(Artificial Sequence)
<400> 392
Gln Leu Tyr Gly Ser Ser Ala Leu Thr
1 5
<210> 393
<211> 9
<212> PRT
<213> VL_CDR3(Artificial Sequence)
<400> 393
Gln His Tyr Gly Ser Ser Ala Leu Thr
1 5
<210> 394
<211> 9
<212> PRT
<213> VL_CDR3(Artificial Sequence)
<400> 394
Gln His Tyr Gly Ser Ser Pro Ala Thr
1 5
<210> 395
<211> 9
<212> PRT
<213> VL_CDR3(Artificial Sequence)
<400> 395
Gln His Tyr Gly Ser Ser Ala Ala Thr
1 5
<210> 396
<211> 9
<212> PRT
<213> VL_CDR3(Artificial Sequence)
<400> 396
Gln Leu Tyr Gly Ser Ser Ala Ala Thr
1 5
<210> 397
<211> 107
<212> PRT
<213> VL(Artificial Sequence)
<400> 397
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 398
<211> 108
<212> PRT
<213> VL(Artificial Sequence)
<400> 398
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Gly Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Leu Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Asp Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Leu Tyr Gly Ser Ser Ala
85 90 95
Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 399
<211> 108
<212> PRT
<213> VL(Artificial Sequence)
<400> 399
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Gly Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Leu Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Asp Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Gly Ser Ser Ala
85 90 95
Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 400
<211> 108
<212> PRT
<213> VL(Artificial Sequence)
<400> 400
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Gly Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Leu Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Asp Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Gly Ser Ser Pro
85 90 95
Ala Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 401
<211> 108
<212> PRT
<213> VL(Artificial Sequence)
<400> 401
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Gly Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Leu Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Asp Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Gly Ser Ser Ala
85 90 95
Ala Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 402
<211> 108
<212> PRT
<213> VL(Artificial Sequence)
<400> 402
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Gly Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Leu Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Asp Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Leu Tyr Gly Ser Ser Ala
85 90 95
Ala Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 403
<211> 321
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 403
gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggcaagtca gagcattagc agctatttaa attggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180
aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240
gaagattttg caacttacta ctgtcaacag agttacagta cccctcggac gttcggccag 300
gggaccaagc tggagatcaa a 321
<210> 404
<211> 324
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 404
gaaattgtgt tgacgcagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60
ctctcctgcg gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120
cctggcctgg cgcccaggct cctcatctat gatgcatcca gcagggccac tggcatccca 180
gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240
cctgaagatt ttgcagtgta ttactgtcag ctgtatggta gctcagccct cactttcggc 300
ggagggacca aggtggagat caaa 324
<210> 405
<211> 324
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 405
gaaattgtgt tgacgcagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60
ctctcctgcg gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120
cctggcctgg cgcccaggct cctcatctat gatgcatcca gcagggccac tggcatccca 180
gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240
cctgaagatt ttgcagtgta ttactgtcag cactatggta gctcagccct cactttcggc 300
ggagggacca aggtggagat caaa 324
<210> 406
<211> 324
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 406
gaaattgtgt tgacgcagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60
ctctcctgcg gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120
cctggcctgg cgcccaggct cctcatctat gatgcatcca gcagggccac tggcatccca 180
gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240
cctgaagatt ttgcagtgta ttactgtcag cactatggta gctcaccggc cactttcggc 300
ggagggacca aggtggagat caaa 324
<210> 407
<211> 324
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 407
gaaattgtgt tgacgcagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60
ctctcctgcg gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120
cctggcctgg cgcccaggct cctcatctat gatgcatcca gcagggccac tggcatccca 180
gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240
cctgaagatt ttgcagtgta ttactgtcag cactatggta gctcagccgc cactttcggc 300
ggagggacca aggtggagat caaa 324
<210> 408
<211> 324
<212> DNA
<213> VL_DNA(Artificial Sequence)
<400> 408
gaaattgtgt tgacgcagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60
ctctcctgcg gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120
cctggcctgg cgcccaggct cctcatctat gatgcatcca gcagggccac tggcatccca 180
gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240
cctgaagatt ttgcagtgta ttactgtcag ctgtatggta gctcagccgc cactttcggc 300
ggagggacca aggtggagat caaa 324

Claims (12)

1. An antibody capable of binding to the RBD region in the S1 subunit of Spike protein of the novel coronavirus SARS-CoV-2, thereby blocking the binding activity of the host cell membrane surface receptor ACE2 to the Spike protein; wherein the antibody comprises a heavy chain VH and a light chain VL, each comprising the variable regions CDR1, CDR2, and CDR 3;
the amino acid sequence of a VH variable region CDR1 of the antibody is shown as SEQ ID number 64, the amino acid sequence of a VH variable region CDR2 is shown as SEQ ID number 78, the amino acid sequence of a VH variable region CDR3 is shown as SEQ ID number 88, the amino acid sequence of a VL variable region CDR1 of the antibody is shown as SEQ ID number 106, the amino acid sequence of a VL variable region CDR2 is shown as SEQ ID number 120, and the amino acid sequence of a VL variable region CDR3 of the antibody is shown as SEQ ID number 128 or SEQ ID number 129; or, the amino acid sequence of the VH variable region CDR1 of the antibody is shown as SEQ ID number 69, the amino acid sequence of the VH variable region CDR2 is shown as SEQ ID number 77, and the amino acid sequence of the VH variable region CDR3 is shown as SEQ ID number 95, the amino acid sequence of the VL variable region CDR1 of the antibody is shown as SEQ ID number 107, the amino acid sequence of the VL variable region CDR2 of the antibody is shown as SEQ ID number 123, and the amino acid sequence of the VL variable region CDR3 of the antibody is shown as SEQ ID number 137.
2. An antibody according to claim 1, wherein said antibody is a neutralizing fully human antibody.
3. The antibody of claim 1, wherein the amino acid sequence of VH of said antibody is represented by SEQ ID number 2, and the amino acid sequence of VL is represented by SEQ ID number 32; or the amino acid sequence of VH of the antibody is shown as SEQ ID number 3, and the amino acid sequence of VL is shown as SEQ ID number 33; or the amino acid sequence of VH of the antibody is shown as SEQ ID number 4, and the amino acid sequence of VL is shown as SEQ ID number 34; or the amino acid sequence of VH of the antibody is shown as SEQ ID number 14, and the amino acid sequence of VL is shown as SEQ ID number 44.
4. A derivative antibody of the antibody according to any one of claims 1 to 3, wherein the derivative antibody is selected from one of the following (1) to (3):
(1) a single chain antibody obtained by linking VH and VL of an antibody according to any one of claims 1 to 3;
(2) a Fab comprising the VH and VL of the antibody of any one of claims 1 to 3;
(3) an intact antibody comprising the VH and VL of an antibody of any one of claims 1 to 3.
5. The derivative antibody according to claim 4, wherein the derivative antibody is an scFv single chain antibody, and the amino acid sequence of the scFv single chain antibody is selected from one of SEQ ID number 216, SEQ ID number 217, SEQ ID number 218 and SEQ ID number 228.
6. The derivatized antibody of claim 4, wherein the derivatized antibody is a whole IgG antibody; wherein the preparation steps of the complete IgG antibody comprise: the gene segments encoding the VH and VL are subcloned into human IgG1CH vector and light chain CL expression vector respectively, transfected into cells for expression and affinity purified.
7. A biomaterial related to the antibody according to any one of claims 1 to 3, wherein the biomaterial is selected from one of the following (A) to (B):
(A) a nucleic acid molecule encoding an antibody according to any one of claims 1 to 3 and/or a nucleic acid molecule encoding a derivatized antibody according to any one of claims 4 to 6;
(B) an expression cassette, a recombinant vector, a recombinant microorganism, a recombinant cell line comprising the nucleic acid molecule of (A).
8. The biomaterial according to claim 7, characterized in that the nucleic acid sequence encoding VH is shown as SEQ ID number 154, the nucleic acid sequence encoding VL is shown as SEQ ID number 184, the nucleic acid sequence encoding scFv single-chain antibody is shown as SEQ ID number 248; or the nucleic acid sequence for coding VH is shown as SEQ ID number 155, the nucleic acid sequence for coding VL is shown as SEQ ID number 185, and the nucleic acid sequence for coding scFv single-chain antibody is shown as SEQ ID number 249; or the nucleic acid sequence for coding VH is shown as SEQ ID number 156, the nucleic acid sequence for coding VL is shown as SEQ ID number 186, and the nucleic acid sequence for coding scFv single-chain antibody is shown as SEQ ID number 250; or the nucleic acid sequence for encoding VH is shown as SEQ ID number 166, the nucleic acid sequence for encoding VL is shown as SEQ ID number 196, and the nucleic acid sequence for encoding scFv single-chain antibody is shown as SEQ ID number 260.
9. An affinity matured antibody which binds to the RBD region in the S1 subunit of Spike protein of SARS-CoV-2, thereby blocking the binding activity of ACE2, a host cell membrane surface receptor, to the Spike protein; wherein the affinity matured antibody is obtained by affinity maturation of the antibody of any one of claims 1 to 3;
the amino acid sequence of the VH variable region CDR1 of the affinity matured antibody is shown as SEQ ID number 64, the amino acid sequence of the VH variable region CDR2 is shown as SEQ ID number 382 or SEQ ID number 383, and the amino acid sequence of the VH variable region CDR3 is shown as SEQ ID number 88, the amino acid sequence of the VL variable region CDR1 of the affinity matured antibody is shown as SEQ ID number 106, the amino acid sequence of the VL variable region CDR2 is shown as SEQ ID number 120, and the amino acid sequence of the VL variable region CDR3 is shown as SEQ ID number 129; or the amino acid sequence of the variable region CDR1 of the VH of the affinity matured antibody is shown in SEQ ID number 69, the amino acid sequence of the variable region CDR2 of the VH is shown in SEQ ID number 77 and the amino acid sequence of the variable region CDR3 of the VH is shown in SEQ ID number 95, the amino acid sequence of the variable region CDR1 of the VL of the affinity matured antibody is shown in SEQ ID number 107, the amino acid sequence of the variable region CDR2 of the VL is shown in SEQ ID number 123 and the amino acid sequence of the variable region CDR3 of the VL is selected from one of SEQ ID number 392, SEQ ID number 393, SEQ ID number 394, SEQ ID number 395 and SEQ ID number 396.
10. The affinity matured antibody of claim 9, wherein the amino acid sequence of the VH of the affinity matured antibody is selected from one of SEQ ID number 384, SEQ ID number 385 and SEQ ID number 386, and the amino acid sequence of the VL is shown as SEQ ID number 397; or the amino acid sequence of the VH of the affinity matured antibody is shown as SEQ ID number 387, and the amino acid sequence of the VL is selected from one of SEQ ID number 398, SEQ ID number 399, SEQ ID number 400, SEQ ID number 401 and SEQ ID number 402.
11. The affinity matured antibody of claim 10, wherein the nucleic acid sequence encoding the VH of the affinity matured antibody is selected from the group consisting of SEQ ID No.388, SEQ ID No.389, SEQ ID No.390, and the nucleic acid sequence encoding the VL of the affinity matured antibody is set forth in SEQ ID No. 403; or the nucleic acid sequence of the VH coding the affinity matured antibody is shown as SEQ ID number 391, and the nucleic acid sequence of the VL coding the affinity matured antibody is selected from one of SEQ ID number 404, SEQ ID number 405, SEQ ID number 406, SEQ ID number 407 and SEQ ID number 408.
12. Use of an antibody according to any one of claims 1 to 3, a derivatized antibody according to any one of claims 4 to 6, a biological material according to claim 7 or 8, or an affinity matured antibody according to any one of claims 9 to 11 for the preparation of a product for the treatment and/or prevention of the novel coronavirus SARS-CoV-2 and diseases caused thereby.
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