CN101541832A

CN101541832A - Human binding molecules capable of neutralizing influenza virus H5N1 and uses thereof

Info

Publication number: CN101541832A
Application number: CNA2007800412851A
Authority: CN
Inventors: E·N·范登布林克; C·A·德克吕夫; M·思罗斯比
Original assignee: Crucell Holand BV
Current assignee: Janssen Vaccines and Prevention BV
Priority date: 2006-09-07
Filing date: 2007-09-06
Publication date: 2009-09-23
Anticipated expiration: 2027-09-06
Also published as: CN101541832B

Abstract

The present invention relates to binding molecules such as human monoclonal antibodies that bind to influenza virus H5N1 and have neutralizing activity against influenza virus H5N1. The disclosure provides nucleic acid molecules encoding the antibodies, their sequences and compositions comprising the antibodies and methods of identifying or producing the ant ibodies. The antibodies can be used in the diagnosis, prophylaxis and/or treatment of an influenza virus H5N1 infection. In a preferred embodiment, the antibodies provide cross- subt ype protection in vivo, such that infections with H5, H2, H6, H9 and H1-based influenza subtypes can be prevented and/or treated.

Description

In the energy and the human binding molecules and the application thereof of influenza virus H 5 N 1

Invention field

The present invention relates to medical science.Especially, the present invention relates to the influenza virus H 5 N 1 diagnosis of infection, prevent and/or treat.

Background of invention

Influenza virus is made up of three types: A, B and C.Influenza virus A infects multiple birds and Mammals, comprises people, horse, marine mammal, pig, ferret and chicken.In animal, most of influenza virus As cause the slight local infection of respiratory tract and enteron aisle.Yet highly pathogenic influenza A strain such as H5N1 cause the poultry systemic infection, and mortality ratio can reach 100%.The animal that has infected influenza virus A has illustrated as influenza virus storehouse (reservoir) and some hypotypes usually and has crossed species barrier and infected person.

Influenza virus A can be divided into hypotype based on the allelic variation in the antigenicity zone of two genes of coded surface glycoprotein, and described surface glycoprotein is hemagglutinin (HA) and neuraminidase (NA), its by virus adhere to cell discharge essential.Other main viral protein comprises nucleoprotein, nucleocapsid structure albumen, membranin (M1 and M2), polysaccharase (PA, PB and PB2) and Nonstructural Protein (NS1 and NS2).

16 HA hypotypes (H1-H16) of present known influenza virus A and 9 NA (N1-N9) antigenicity variant.Previously known only three hypotypes at people's body-internal-circulation (H1N1, H1N2 and H3N2).Yet, reported that in recent years the pathogenic H5N1 hypotype of avian influenza virus A is crossed species barrier and infected person, cause some patients' death, as the Documentary Records in Hong Kong in 1997 and 2003.

In human body, the cell of avian influenza respiratory tract and enteron aisle, liver,spleen,kidney and other organ.The symptom of bird flu comprises heating, expiratory dyspnea (comprise and breathe hard and cough), lymphopenia, diarrhoea and glucose level adjusting difficulty.Opposite with seasonal influenza, the crowd who is in most in the risk is the health adult of formation crowd main body.Because some avian influenza virus A hypotype particularly highly pathogenic and attested its of H5N1 is crossed the ability that species barrier infects human body, therefore there are great economy and the public health risk relevant, comprise serious popularity and explosive the threat with these virus strain.The scale of this threat causes surpassing 50,000,000 people's death as influenza great outburst in 1918.

The effective vaccine that does not also have at present H5N1 to infect, therefore the passive immunotherapy that carries out with immunoglobulin (Ig) may be a kind of alternative strategy.It is reported that the application of passive immunization makes mortality ratio reduce by half during 1918.Therefore in view of they treatment benefits, need in the energy and the preferred human binding molecules of binding molecule of H5N1 for human body.The invention provides these binding molecules and disclosed them and can be used in the medical science, especially for diagnosis, prevent and/or treat during H5N1 infects.

Accompanying drawing is described

Fig. 1 shows the immunoblotting assay that uses antibody CR6307 (left part), CR6323 (middle portion) and CR5111 (right side part) that different hemagglutinin (HA) is carried out.The HA that will recombinate carries out reductibility SDS-PAGE and analyzes and immunoblotting assay.Swimming lane 1 illustrates the sHA of H5N1TV, swimming lane 2 illustrates reorganization HA, hypotype H5 (A/Vietnam/1203/2004 (H5N1)), swimming lane 3 illustrates reorganization HA, hypotype H3 (A/Wyoming/3/2003 (H3N2)), and swimming lane 4 illustrates reorganization HA, hypotype H1 (A/New Caledonia/20/99 (H1N1)).Also marked the position that to find HA0, HA1 and HA2 among the figure.

Fig. 2 illustrates the average clinical score of (embodiment 12) every group of mouse in the research, is wherein infecting the day before yesterday with influenza virus H 5 N 1, and with three-type-person H5N1 monoclonal antibody CR6261, CR6323 and CR6325 are with various dose prophylactic treatment mouse.

Fig. 3 is illustrated in and infects during back 21 days with the body weight change (embodiment 12) during the anti-H5N1 antibody prophylactic treatment mouse.

The number of survival mice during Fig. 4 is illustrated in the research (embodiment 12) of Fig. 2 and 3 not on the same group.

Fig. 5 is illustrated in the relation between mortality ratio in the research (embodiment 12) of Fig. 2-4 and resisting of giving-H5N1 antibody dosage.

Fig. 6 is illustrated in the average clinical score of (embodiment 13) every group of mouse in the research, wherein use lethal dose the influenza virus H 5 N 1 infecting mouse and metainfective different time points (4 hours, 1 day, 2 days and 3 days) with CR6261 anti--H5N1 monoclonal antibody or incoherent antibody CR2006 (after infection, giving in the 1st day) treatment.

Fig. 7 illustrates the survival number of every group of mouse in the described research of Fig. 6.All animals (1 animal in the 1st group) of 1-4 group all survive during whole research until infecting the back the 21st day.All animals of the 5th group are all dead at the 9th day.

Fig. 8 illustrates the mean body weight of every group of mouse during the described research of Fig. 6.Stopped to measure the 5th group of mouse body weight at the 9th day, because all mouse that should organize are dead this moment.Although the speed of every treated animal rehabilitation depends on treatment time, the mouse of survival all reached the normal type level on the 21st day in the 1-4 group after infection.

Fig. 9 illustrates the per-cent of surviving animals in every treated animal of a research, wherein use lethal dose H1N1 influenza infection mouse and different time points (infected preceding 1 day, infect back 1,2 and 3 day) with CR6261 anti--H5N1 monoclonal antibody or incoherent antibody CR57 (after infection, giving in the 1st day) treatment.

Figure 10 illustrates the mean body weight of every group of mouse during the described research of Fig. 9.Stopped to measure the 5th group of mouse body weight at the 9th day, because all mouse that should organize are dead this moment.Although the speed of every treated animal rehabilitation depends on treatment time, the mouse of survival all reached the normal type level on the 21st day in the 1-4 group after infection.

Invention is described

Hereinafter set forth the definition of some terms of the present invention's use.

As used herein, term " binding molecule " is meant complete immunoglobulin (Ig), comprise monoclonal antibody, as chimeric antibody, humanized antibody or human monoclonal antibodies, perhaps be meant antigen in conjunction with and/or variable domains, it comprises the binding partners immunoglobulin fragment of H5N1 for example that combines described immunoglobulin (Ig) with described complete immunoglobulin (Ig) competition specificity.Regardless of structure, described Fab is in conjunction with the same antigen of being discerned by described complete immunoglobulin (Ig).Fab can comprise peptide or the polypeptide with such aminoacid sequence, and described aminoacid sequence is at least 2,5,10,15,20,25,30,35,40,50,60,70,80,90,100,125,150,175,200 or 250 continuous amino acid residues of the aminoacid sequence of described binding molecule.

As used herein, term " binding molecule " comprises all immunoglobulin classes known in the art and subclass.Aminoacid sequence according to its heavy chain constant domain, binding molecule can be divided into the complete antibody of five kinds of primary categories: IgA, IgD, IgE, IgG and IgM, and the some of them classification can further be divided into subclass (isotype), for example IgA1, IgA2, IgG1, IgG2, IgG3 and IgG4.

Fab comprises Fab, F (ab '), F (ab ') 2, Fv, dAb, Fd, complementary determining region (CDR) fragment, single-chain antibody (scFv), divalence single-chain antibody, single chain variable fragment phage antibody, two special double-stranded antibody (diabody), three chain antibodies (triabody), four chain antibodies (tetrabody), contain and be enough to give with (many) peptides of (many) peptide specifics antigen bonded immunoglobulin fragment at least etc.Above-mentioned fragment can be synthesized and produced or produce or can be genetically engineered by recombinant DNA technology by enzyme or the complete immunoglobulin (Ig) of chemical cracking.Described production method is known in the art, for example incorporate into this paper for referencial use by E.Harlow and D, Lane (1988) editor's Antibodies:A LaboratoryManual, Cold Spring Harbor Labotatory, Cold Spring Harbor, New York.Binding molecule or its Fab can have one or more binding site.If there is more than one binding site, then described binding site can be same to each other or different to each other.

Binding molecule can be naked or unconjugated binding molecule, but also can be the part of immunoconjugates.Naked or unconjugated binding molecule is meant such binding molecule, it is not with effect part or mark is puted together, operably connect or physics or functional related in addition, and described effect part or mark for example are toxicant, radioactive substance, liposome, enzyme.That naked or unconjugated binding molecule is not got rid of is stabilized, polymerization, humanization or with (except the adhering to of effect components or mark) binding molecule of any alternate manner operation.Therefore, naked all being included in wherein with unconjugated binding molecule of all posttranslational modifications comprises it wherein being to produce modification and prepare the back by artificial importing modification at initial binding molecule by the cell that produces the reorganization binding molecule in the cellular environment that produces natural binding molecule.Certainly, term naked or unconjugated binding molecule be not precluded within and give the ability that described binding molecule and effector cell behind the body and/or molecule form functional cohesion biological action is necessary because some such interactions are performance.Effect group that is associated or mark lack so be used to be defined in naked or unconjugated binding molecule external rather than in vivo.

As used herein, the several samples type contained in term " biological sample ", comprises blood and other humoral sample of biological origin, and solid tissue sample such as biopsy sample or tissue culture are perhaps derived from wherein cell or its offspring.This term also is included in the sample of having handled by any way after the acquisition, for example uses some composition of agent treated, dissolving or enrichment such as protein or polynucleotide.The various clinical samples that derive from any species contained in this term, also comprises cultured cells, cell conditioned medium and cell lysates.

As used herein, term " complementary determining region (CDR) " is meant the sequence in the variable region of binding molecule such as immunoglobulin (Ig), and it constitutes antigen binding site usually to a great extent, aspect form and the charge distribution with the epi-position complementation of on antigen, discerning.The CDR district can be specific to the linear epitope of protein or protein fragments, discontinuous epi-position or conformational epitope, these epi-positions are present on the protein with its native conformation, perhaps are present on the protein with denatured form (for example by dissolving in SDS) in some cases.Epi-position also can be made up of proteinic posttranslational modification thing.

As used herein, term " disappearance " is meant with the parental generation molecule of normally natural generation and compares, lacks the change of one or more amino acid or nucleotide residue in aminoacid sequence or the nucleotide sequence respectively.

As used herein, term " regulate express nucleotide sequence " is meant that the encoding sequence that operably connects expresses necessary and/or influence the polynucleotide sequence of described encoding sequence expression in the specific host organism.The nucleotide sequence of regulate expressing can be to have active any nucleotide sequence and can be derived from coding and host organisms homology or allogenic proteinic gene in the host organisms of selecting, and described sequence for example is suitable transcriptional initiation sequence, terminator sequence, promoter sequence, enhancer sequence; Repressor or activator sequence; Effective RNA processing signal such as montage and polyadenylation signal; The sequence of stabilized cell matter mRNA; Strengthen the sequence (for example ribosome bind site) of translation efficiency; Strengthen the sequence of protein stability; And the sequence that when needing, strengthens protein secreting.Regulating the discriminating of the sequence of expressing knows with the those skilled in the art that base on practicality.

As used herein, term " functional variant " is meant such binding molecule, it is compared with the nucleotide sequence of parental generation binding molecule and/or aminoacid sequence and comprises one or more Nucleotide and/or reformed Nucleotide of amino acid and/or aminoacid sequence, still can compete in conjunction with described binding partners H5N1 for example and compare with the parental generation binding molecule.In other words, the amino acid of parental generation binding molecule and/or the not remarkably influenced of modification in the nucleotide sequence or change binding characteristic by described described binding molecule nucleotide sequence coded or that contain described aminoacid sequence, promptly described binding molecule still can be discerned and in conjunction with its target position.Described functional variant can have conserved sequence to be modified, and comprises Nucleotide and aminoacid replacement, interpolation and disappearance.These modifications can import by standard technique known in the art, for example directed mutagenesis and random PCR mediated mutagenesis, and can comprise natural and non-natural nucleotide and amino acid.

Conserved amino acid replaces and comprises that wherein amino-acid residue is by the replacement of another radical amino acid replacement with analog structure or chemical property.Family with amino-acid residue of similar side chain limits in the art.These families comprise amino acid with basic side chain (Methionin for example, arginine, Histidine), acid side-chain amino acid (aspartic acid for example, L-glutamic acid), no charge polarity side chain amino acid (l-asparagine for example, glutamine, Serine, Threonine, tyrosine, halfcystine, tryptophane), non-polar sidechain amino acid (glycine for example, L-Ala, Xie Ansuan, leucine, Isoleucine, proline(Pro), phenylalanine, methionine(Met)), β-branched building block amino acid (Threonine for example, Xie Ansuan, Isoleucine) and aromatic side chain amino acid (tyrosine for example, phenylalanine, tryptophane).Those skilled in the art understand other amino-acid residue family mode classification that also can use except above-mentioned family.In addition, variant can have nonconservative aminoacid replacement, and for example amino acid is by another radical amino acid replacement with different structure or chemical property.Similar little variation also can comprise aminoacid deletion or insertion, perhaps these two.Use computer program well known in the art can find to determine which amino-acid residue can be substituted, inserts or lack and do not eliminate the guidance of immunologic competence.

Sudden change in the nucleotide sequence can be the single change (point mutation) at a locus, and for example conversion or transversional mutation perhaps can insert, lack or change a plurality of Nucleotide at a locus.Produce one or more change in the locus of any number that in addition, can be in nucleotide sequence.Described sudden change can be undertaken by any appropriate method known in the art.

As used herein, term " host " is meant organism or the cell that has wherein imported carrier, and described carrier for example is cloning vector or expression vector.Described organism or cell can be protokaryon or most eukaryotes or cell.Should understand this term and not only be meant special object organism or cell, and can be the offspring of this organism or cell.Owing to sudden change or environmental influence cause some modification to occur in the generation subsequently, therefore in fact this offspring is perhaps inequality with described parental generation organism or cell, but it still is included in term as used herein " host's " the scope.

Term " people " is meant direct derived from human or based on human sequence's molecule when being used to describe binding molecule described herein.When binding molecule derived from or based on the human sequence and when being modified subsequently, think still that in this manual it is people's molecule.In other words, term " people " comprises having the such variable region and the binding molecule of constant region when being used to describe binding molecule, described variable region and constant region derived from human racial immunity sphaeroprotein sequence or based on the variable region or the constant region that occur in people or human lymphocyte and modify with some forms.Therefore, human binding molecules can comprise and not be that by ethnic group be immunoglobulin sequences amino acids coding residue, comprises to replace and/or disappearance (for example by at random external or site-specific mutagenesis method or the sudden change by somatic mutation method importing in the body).As used herein, " based on " be meant such situation, promptly nucleotide sequence can accurately copy from template, perhaps for example has micromutation by the fallibility PCR method, perhaps accurately mates through synthetic preparation and with described template or has a little modification.Semi-synthetic molecule based on the human sequence also is considered to people's molecule in this article.

Term " insertion " also is known as " interpolation ", is meant to compare with the parental generation sequence to cause adding the amino acid of one or more amino acid or nucleotide residue or the variation in the nucleotide sequence respectively.

Term " isolating " is meant such binding molecule when being used to describe binding molecule described herein, it is substantially free of other protein or polypeptide, does not particularly contain other binding molecule with different antigen-specifiies, and is substantially free of other cell material and/or chemicals.For example, when described binding molecule was the reorganization generation, it preferably was substantially free of substratum; When described binding molecule is when producing by chemical synthesis process, it preferably is substantially free of chemicals precursor or other chemicals, and promptly it is what to separate with chemicals precursor or other chemicals of participating in protein synthesis.Term " isolating " is meant that when being used to describe the nucleic acid molecule of coding binding molecule described herein the nucleotide sequence of the described binding molecule of wherein encoding does not contain other nucleotide sequence, particularly coding in conjunction with the nucleic acid molecule of the nucleotide sequence of the binding molecule of the binding partners except H5N1.In addition, term " isolating " is meant the nucleic acid molecule that separates basically with other cellular constituent, described other cellular constituent is and natural acid molecule natural cellular constituent that accompanies in its natural host, for example rrna, polysaccharase or with its natural genome sequence that is associated.In addition, " isolating " nucleic acid molecule such as cDNA molecule can be substantially free of other cell material or substratum when producing by recombinant technology, are substantially free of chemicals precursor or other chemicals when by chemosynthesis.

As used herein, term " monoclonal antibody " is meant the prepared product of single molecular antibody molecule.Monoclonal antibody is showed single binding specificity and affinity for defined epitope.Therefore, term " human monoclonal antibodies " is meant the antibody of showing single binding specificity, its have derived from or be immunoglobulin sequences or based on ethnic group derived from the variable region and the constant region of synthetic sequence fully.The preparation monoclonal antibody method has nothing to do.

As used herein, when term " natural generation " is used to describe an object, be meant the fact that can find this object at occurring in nature.For example, being present in separable is natural generation from natural source and without polypeptide or polynucleotide sequence in the artificial organism of having a mind to modify in the laboratory.

As used herein, term " nucleic acid molecule " is meant the polymerized form of Nucleotide, comprises the synthesized form that justice and antisense strand and above-mentioned molecule are arranged and the blended polymkeric substance of RNA, cDNA, genomic dna.Nucleotide is meant the modified forms of ribonucleotide, deoxyribonucleotide or arbitrary types of nuclear thuja acid.This term also comprises the DNA of strand and double chain form.In addition, polynucleotide can comprise the Nucleotide of the Nucleotide of the natural generation that links together by nucleotide bond natural generation and/or that non-natural takes place and modification arbitrary or these two.Described nucleic acid molecule can or can contain non-natural or the deutero-nucleotide base through chemistry or biochemical method modification, and this point those skilled in the art are easy to recognize.This modification comprises for example mark, methylate, the Nucleotide of one or more natural generation is replaced by analogue, modify between Nucleotide as no electric charge key (for example methylphosphonate, phosphotriester, phosphoramidate, carbamate etc.), electrically charged key (for example thiophosphatephosphorothioate, phosphorodithioate etc.), overhang (pendent moiety) (for example polypeptide), intercalator (for example acridine, psoralene etc.), sequestrant, alkylating agent, and the key of modifying (for example different nucleic acid of α etc.).This term also comprises any topological conformation, comprises strand, two strands, part duplex, triple helical, hair clip, annular and padlock conformation.This term also comprises the synthetic molecule, and its simulation polynucleotide are by hydrogen bond and other chemical interaction and in conjunction with the ability of specified sequence.This molecule is known in the art, comprises those molecules that for example wherein replace the phosphate bond in the molecular backbone chain with peptide bond.Comprise its complement when unless otherwise indicated, mentioning nucleotide sequence.Therefore, the nucleic acid molecule with particular sequence be interpreted as comprising its complementary strand with and complementary sequence.Described complementary strand also can be used for for example antisense therapy, hybridization probe and PCR primer.

Term " operably connect " is meant normally physical connection of two or more nucleotide sequence element, and function is associated each other.For example, if the promotor energy is initial or regulate transcribing or expressing of encoding sequence, then this promotor operably is connected with described encoding sequence, should understand described encoding sequence in this case in described promotor " under the control ".

" pharmaceutically-acceptable excipients " is meant any inert substance, and itself and bioactive molecule such as medicine, medicament or binding molecule combination are to prepare suitable or conventional formulation." pharmaceutically-acceptable excipients " be in used dosage and concentration for the avirulent vehicle of acceptor, and compatible with other composition of the preparation that comprises described medicine, medicament or binding molecule.Pharmaceutically-acceptable excipients is widespread use in the art.

As used herein, for example antibody and its binding partners for example mean that this interaction depends on for example existence of antigenic determinant or epi-position of ad hoc structure on the described binding partners during interaction between the antigen to term " specificity in conjunction with " when being used to describe binding molecule.In other words, antibody preferential in conjunction with or the identification binding partners, even also like this when described binding partners is present in the mixture of other molecule or organism.In conjunction with can be by covalently or non-covalently interacting or these two combination mediation.Again in other words, term " specificity in conjunction with " is meant with antigen or its segmental immunologic opsonin and combines, and is not that immunologic opsonin combines with other antigen.Can low affinity combine with other peptide or polypeptide with antigen immune specificity bonded binding molecule, for example determine by radioimmunoassay (RIA), enzyme-linked immunosorbent assay (ELISA), BIACORE or other measuring method known in the art.With antigen immune specificity bonded binding molecule or its fragment can with the related antigen cross reaction.Preferably, with antigen immune specificity bonded binding molecule or its fragment and other not cross reaction of antigen.

As used herein, " replacement " is meant that one or more amino acid or Nucleotide are respectively by different amino acid or nucleotide subsitution.

Term " treatment significant quantity " is meant that binding molecule described herein effectively prevents, improves and/or treat the amount of the illness that derives from the H5N1 infection.

Term " treatment " is meant that therapeutic treatment and prevention (prophylactic) or protection (preventative) measure are with cure diseases or make disease stop progress or postpone progression of disease at least.Need those objects of treatment comprise the object of illness due to suffering from H5N1 infects and wherein H5N1 infect and wait those objects of being prevented.Partly or completely the restorative object perhaps also needs treatment in H5N1 infects.Prevention comprises generation, development or the progress of the H5N1 propagation that suppresses or reduce or inhibition or reduction one or more symptom relevant with the H5N1 infection.

Term " carrier " is meant such nucleic acid molecule, and to wherein inserting another kind of nucleic acid molecule to import among the host, it will be replicated in the host, and be expressed in some cases.In other words, carrier can be transported connected nucleic acid molecule.Cloning vector and expression vector are included in term used herein " carrier " scope.Carrier includes but not limited to plasmid, clay, bacterial artificial chromosome (BAC) and yeast artificial chromosome (YAC) and derived from the carrier of phage or plant or animal (comprising the people) virus.Carrier comprises the replication orgin by host's identification of proposing, other regulatory region that also comprises promotor and discerned by described host in the situation of expression vector.The carrier that contains another nucleic acid molecule is by conversion, transfection or by using the virus mechanism of entering to be imported in the cell.Some carrier can be in the host that it is imported into self-replicating (carrier that for example has the bacterium replication orgin can duplicate in bacterium).Other carrier can be integrated in the host genome in importing the host time, thereby duplicates with host genome.

Summary of the invention

The invention provides can specificity in conjunction with influenza virus H 5 N 1 and present among the H5N1 and active human binding molecules.The present invention also provides and finishes the binding molecule that closes between the influenza virus sub-strain epi-position in the total hemagglutinin, and therefore relates to based on hypotype such as H5N1, the H1N1 of H5-, H1-, H2-, H6-and H9-influenza virus with contain the binding molecule of cross reaction between proteic other influenza virus strain of the HA with these defined epitopes.The invention still further relates to the nucleic acid molecule of the land of the described at least human binding molecules of coding.The present invention further provides the application of human binding molecules of the present invention in preventing and/or treating the object of suffering from the H5N1 infection or being in the H5N1 infection risk.In addition, the invention still further relates to the application of human binding molecules of the present invention in diagnosis/detection H5N1.

Describe in detail

First aspect the present invention relates to the energy specificity in conjunction with influenza virus A, the particularly binding molecule of influenza virus A hypotype H5N1.Preferably, described binding molecule is a human binding molecules.Preferably, binding molecule of the present invention presents the neutralization activity for influenza virus A hypotype H5N1.On the other hand, binding molecule of the present invention can specificity have the neutralization activity in conjunction with different influenza virus H 5 N 1 strains and/or to it.These strains can be the members of clade 1, clade 2 or the clade 3 of influenza virus H 5 N 1 strain.The phylogenetics analysis of carrying out with the HA gene of H5N1 of outburst in 2005 from 2004 is disclosed two different pedigrees (lineage) of HA gene, be called clade 1 and clade 2.Virus in each of these clade is distributed in the non-overlapping geographic area in Asia.H5N1 virus from Indochina is closely trooped in clade 1, and different with clade 1 isolate from the H5N1 strain isolated of some circumjacent states, belongs to the clade of more dispersing 2.Clade 1H5N1 virus is separated people and the bird from Vietnam, Thailand and Cambodia, but only separates from bird with Malaysia in Laos.Clade 2 viruses are just being found in the isolating virus from the bird of China, Indonesia, Japan and Korea S.2003 and 1997 in Hong Kong from bird and people isolating virus form clade 1 ' (also being classified as in the clade 1) and clade 3 (seeing WHOGlobal Influenza Program Surveillance Network, 2005) respectively.The aminoacid sequence difference of the hemagglutinin of described clade.The example of clade 1 strain includes but not limited to A/Hong Kong/213/03, A/Vietnam/1194/04, A/Vietnam/1203/04 and A/Thailand/1 (KAN-1)/2004.The example of clade 2 strains includes but not limited to A/Indonesia/5/05, A/bar headedgoose/Qinghai/1A/05, A/turkey/Turkey/1/05 and A/Anhui/1/05.The example of clade 3 strains includes but not limited to A/Hong Kong/156/97 and A/goose/Guangdong/1/96.Other strain is found in for example WHO Global Influenza Program Surveillance Network, 2005 and Http:// www.who.int/csr/disease/avian influenza/guidelines/recommendation Vaccine.pdfPreferably, binding molecule of the present invention can specificity have the neutralization activity in conjunction with clade 1, clade 2 and clade 3 strains and to it.Binding molecule energy specificity of the present invention is in conjunction with influenza virus H 5 N 1 survival, that live and/or infectivity or inactivation/attenuation form.The method that makes influenza virus H 5 N 1 inactivation/attenuation is known in the art, includes but not limited to formaldehyde, β-propionic acid lactone (BPL), Thiomersalate and/or UV treatment.

Binding molecule of the present invention also can specificity in conjunction with one or more fragment of influenza virus H 5 N 1, as the H5N1 protein that produces derived from one or more protein of hypotype H5N1 and/or (many) peptides or one or more reorganization and/or the prepared product of polypeptide.For treating and/or preventing the method that H5N1 infects, described binding molecule preferably can specificity can reach protein in conjunction with the surface of H5N1 and discharge necessary surface glycoprotein hemagglutinin (HA) and neuraminidase (NA) or membranin (M1 and M2) as adhering to for virus with cell.In specific embodiment, binding molecule energy specificity of the present invention is in conjunction with the HA molecule of H5N1 strain.They perhaps can specificity in conjunction with the HA1 and/or the HA2 subunit of HA molecule.They perhaps can specificity in conjunction with HA1 and/or the linearity on the HA2 subunit or the structure and/or the conformational epitope of HA molecule.Described HA molecule can produce and randomly separation from viral or reorganization by purifying before use.Perhaps, HA can express on the surface of cell.

For diagnostic purpose, binding molecule also can specificity in conjunction with non-existent protein on the H5N1 surface, comprise nucleoprotein, nucleocapsid structure albumen, polysaccharase (PA, PB and PB2) and Nonstructural Protein (NS1 and NS2).The nucleotide sequence of various H5N1 strains and/or proteinic aminoacid sequence are found in GenBank-database, NCBI influenza virus sequence library, influenza virus sequence library (ISD), EMBL-database and/or other database.Those skilled in the art are easy to find this sequence in database separately.

In another embodiment, binding molecule energy specificity of the present invention is in conjunction with the fragment of above-mentioned protein and/or polypeptide, and wherein said fragment comprises the antigenic determinant by binding molecule identification of the present invention at least.As used herein, " antigenic determinant " be can be with sufficiently high affinity in conjunction with binding molecule of the present invention to form the part of detectable antigen-binding molecule mixture.Binding molecule of the present invention can or can not specificity in conjunction with born of the same parents' outside part (being also referred to as solvable HA (sHA)) of HA at this paper.

Binding molecule of the present invention can be complete immunoglobulin molecules for example polyclone or monoclonal antibody or described binding molecule can be Fab, include but not limited to Fab, F (ab '), F (ab ') ₂, Fv, dAb, Fd, complementary determining region (CDR) fragment, single-chain antibody (scFv), divalence single-chain antibody, single chain variable fragment phage antibody, two special double-stranded antibody, three chain antibodies, four chain antibodies and containing at least are enough to give and segmental (many) peptides or its fragment of the specific antigens bonded immunoglobulin (Ig) of influenza virus H 5 N 1 strain.In preferred embodiments, binding molecule of the present invention is a human monoclonal antibodies.

Binding molecule of the present invention can use with unsegregated or isolating form.In addition, binding molecule of the present invention can be used separately or use in the mixture that comprises at least a binding molecule of the present invention (or its variant or fragment).In other words, described binding molecule can applied in any combination, for example as comprising two or more kinds of binding molecule of the present invention, its variant or segmental pharmaceutical composition.For example, have difference but the binding molecule of complementary activity can be combined in prevention, treatment or the diagnostic effect to reach hope in the treatment plan, but or also can be combined in prevention, treatment or the diagnostic effect to reach hope in the treatment plan having identical active binding molecule.Randomly, described mixture further comprises at least a other therapeutical agent.Preferably, described therapeutical agent such as M2 inhibitor (for example amantidine, Rimantadine (rimantadine)) and/or neuraminidase inhibitor (for example zanamivir (zanamivir), Oseltamivir (oseltamivir)) can be used for preventing and/or treating the influenza virus H 5 N 1 infection.

Typically, binding molecule of the present invention can be in conjunction with its binding partners, i.e. influenza virus H 5 N 1 or its fragment, affinity costant (K _dValue) is lower than 0.2 * 10 ^-4M, 1.0 * 10 ^-5M, 1.0 * 10 ^-6M, 1.0 * 10 ^-7M is preferably lower than 1.0 * 10 ^-8M is more preferably less than 1.0 * 10 ^-9M is more preferably less than 1.0 * 10 ^-10M, even more preferably less than 1.0 * 10 ^-11M especially preferably is lower than 1.0 * 10 ^-12M.Described affinity costant is according to the antibody type and can be different.For example, the affinity of IgM isotype is in conjunction with being meant about at least 1.0 * 10 ^-7The binding affinity of M.The affinity constant can be for example by using surface plasma resonance technology to measure, for example use the BIACORE system (Pharmacia Biosensor AB, Uppsala, Sweden).

Binding molecule of the present invention can be in conjunction with the soluble form for example influenza virus H 5 N 1 in sample or in the suspension or its fragment or can be in conjunction with combining with carrier or base material or adhering to influenza virus H 5 N 1 or its fragment that for example combines with microtitre flat board, film and pearl or adhere to.Carrier or base material can be made by glass, plastics (for example polystyrene), polysaccharide, nylon, soluble cotton or Teflon etc.The surface of this upholder can be solid phase or porous and can be any shape easily.In addition, described binding molecule can be in conjunction with the influenza virus H 5 N 1 of purifying/separation or non-purifying/non-separation form.

It is active that binding molecule of the present invention presents neutralization.The neutralization activity can measurement for example as described herein.Another kind of measurement neutralizes active measuring method for example at WHO Manual on Animal InfluenzaDiagnosis and Surveillance, Geneva:World Health Organisation, and 2005, describe among the version2002.5.The present invention relates to isolating human binding molecules, it can be discerned and in conjunction with the epi-position in the HA2 subunit of influenza hemagglutinin protein (HA), be characterised in that described binding molecule has the neutralization activity at the influenza virus of the HA that comprises the H5 hypotype.Contain the HA of this H5 hypotype and be that the example with influenza virus strain of the popular important strain that threatens is H5N1, H5N2, H5N8 and H5N9.In particularly preferably being at least and the binding molecule of H5N1 influenza virus strain.Preferably, described binding molecule of the present invention and the proteic epi-position that does not rely in the proteic HA1 subunit of HA that combines of described HA.Describe in the prior art field also in conjunction with the known murine antibody (C179) of identical epi-position in the HA2 structural domain also depend on the proteic HA1 structural domain of HA in the combining of epi-position.This is disadvantageous, because it has increased no longer the possibility by the escape mutant (escape mutant) of described antibody recognition.In addition, many antibody of the present invention (as CR6307 and CR6323) do not rely on conformational epitope, even can discern the HA2 epi-position (when being used for western blotting) of reduction form.This is better than the antibody of prior art, because when because the no matter sudden change of what sample and when importing conformational change in HA albumen in proteinic another part, this conformational change unlikely hinders combining of antibody of the present invention and HA2 epi-position; And when this sudden change takes place, conformation-dependent antibody very may not in conjunction with.

In another preferred embodiment, binding molecule of the present invention also has the neutralization activity for the influenza virus of the HA that comprises the H1 hypotype, and preferred wherein said binding molecule also has the neutralization activity for the influenza virus of the HA that comprises H2, H6 and/or H9 hypotype.This paper has disclosed the epi-position that exists in the HA2 epi-position that exists in binding molecule of the present invention and H5, H1, H2, H6 and the H9 hypotype and has interacted, and has disclosed binding molecule of the present invention because this epi-position is shared have cross neutralization between influenza virus sub-strain.Infer and to depend on specific part in the HA2 structural domain and combine (and not with HA1 in have a sudden change tendency another epi-position combine) binding molecule of the present invention between influenza virus sub-strain, have cross neutralization because seem its do not rely on HA1 in the combining of the structural domain that is obviously changed owing to antigenic drift.Those skilled in the art can determine the whether really cross reaction of HA albumen of antibody and different subtype based on content described herein, and also can determine they whether can be in vivo in and the influenza virus of different subtype.

Of the present invention another preferred aspect, binding molecule of the present invention is in conjunction with the epi-position in the HA2 subunit, and described epi-position is selected from one group that following aminoacid sequence forms: GVTNKVNSIIDK (SEQ IDNO:368), GVTNKVNSIINK (SEQ ID NO:369), GVTNKENSIIDK (SEQ IDNO:370), GVTNKVNRIIDK (SEQ ID NO:371), GITNKVNSVIEK (SEQ IDNO:372), GITNKENSVIEK (SEQ ID NO:373), GITNKVNSIIDK (SEQ IDNO:374) and KITSKVNNIVDK (SEQ ID NO:375).Can infer that from the data shown in the table 13 GVTNKVNSIIDK (the SEQ ID NO:368) epi-position that exists among some binding molecule CR6261, CR6325 of the present invention and CR6329 and the H5N1 interacts, and be not subjected to the obstruction that suddenlys change in the TGLRN epi-position among the HA1, this sudden change influences the combination of C179.In addition, some binding molecules such as CR6307 and CR6323 even are not subjected to the obstruction of escape mutant, sport L-glutamic acid (GVTNKENSIIDK (SEQ ID NO:370)) at the 6th Xie Ansuan as described in Okuno et al. (1993).This epi-position is the part of the α spiral of extension in the HA2 district.Predict that this infers the residue that the residue that is exposed to solvent in the epi-position most is runic underscore place: GVTNKENSIIDK (SEQ ID NO:370).The most accessible binding molecule of these amino acid, and therefore form the most important zone of epi-position.Identical of views with this, highlighted amino acid is being absolute conservative aspect homogeny and the position in the sequence that all present.The knowledge of this respect can be used for predicting do not have in the influenza virus sub-strain above-mentioned identical sequence in conjunction with epi-position (being H3, H7 and B strain).

Preferred binding molecule of the present invention is selected from as next group:

A) comprise the binding molecule in heavy chain CDR3 district shown in heavy chain CDR2 district shown in heavy chain CDR1 district shown in the SEQ ID NO:1, the SEQ ID NO:2 and the SEQ ID NO:3,

B) comprise the binding molecule in heavy chain CDR3 district shown in heavy chain CDR2 district shown in heavy chain CDR1 district shown in the SEQ ID NO:16, the SEQ ID NO:17 and the SEQ ID NO:18,

C) comprise the binding molecule in heavy chain CDR3 district shown in heavy chain CDR2 district shown in heavy chain CDR1 district shown in the SEQ ID NO:1, the SEQ ID NO:22 and the SEQ ID NO:23,

D) comprise the binding molecule in heavy chain CDR3 district shown in heavy chain CDR2 district shown in heavy chain CDR1 district shown in the SEQ ID NO:27, the SEQ ID NO:28 and the SEQ ID NO:29,

E) comprise the binding molecule in heavy chain CDR3 district shown in heavy chain CDR2 district shown in heavy chain CDR1 district shown in the SEQ ID NO:39, the SEQ ID NO:40 and the SEQ ID NO:41,

F) comprise the binding molecule in heavy chain CDR3 district shown in heavy chain CDR2 district shown in heavy chain CDR1 district shown in the SEQ ID NO:45, the SEQ ID NO:46 and the SEQ ID NO:47,

G) comprise the binding molecule in heavy chain CDR3 district shown in heavy chain CDR2 district shown in heavy chain CDR1 district shown in the SEQ ID NO:1, the SEQ ID NO:49 and the SEQ ID NO:50,

H) comprise the binding molecule in heavy chain CDR3 district shown in heavy chain CDR2 district shown in heavy chain CDR1 district shown in the SEQ ID NO:52, the SEQ ID NO:53 and the SEQ ID NO:54,

I) comprise the binding molecule in heavy chain CDR3 district shown in heavy chain CDR2 district shown in heavy chain CDR1 district shown in the SEQ ID NO:262, the SEQ ID NO:263 and the SEQ ID NO:264,

J) comprise the binding molecule in heavy chain CDR3 district shown in heavy chain CDR269 district shown in heavy chain CDR1 district shown in the SEQ ID NO:268, the SEQ ID NO:2 and the SEQ ID NO:270,

K) comprise the binding molecule in heavy chain CDR3 district shown in heavy chain CDR2 district shown in heavy chain CDR1 district shown in the SEQ ID NO:274, the SEQ ID NO:275 and the SEQ ID NO:276,

L) comprise the binding molecule in heavy chain CDR3 district shown in heavy chain CDR2 district shown in heavy chain CDR1 district shown in the SEQ ID NO:280, the SEQ ID NO:281 and the SEQ ID NO:282,

M) comprise the binding molecule in heavy chain CDR3 district shown in heavy chain CDR2 district shown in heavy chain CDR1 district shown in the SEQ ID NO:286, the SEQ ID NO:287 and the SEQ ID NO:288,

N) comprise the binding molecule in heavy chain CDR3 district shown in heavy chain CDR2 district shown in heavy chain CDR1 district shown in the SEQ ID NO:292, the SEQ ID NO:293 and the SEQ ID NO:294,

O) comprise the binding molecule in heavy chain CDR3 district shown in heavy chain CDR2 district shown in heavy chain CDR1 district shown in the SEQ ID NO:304, the SEQ ID NO:305 and the SEQ ID NO:306, and

P) comprise the binding molecule in heavy chain CDR3 district shown in heavy chain CDR2 district shown in heavy chain CDR1 district shown in the SEQ ID NO:310, the SEQ ID NO:311 and the SEQ ID NO:312.

In a preferred embodiment, binding molecule of the present invention is preferred for diagnosis, treats and/or prevents influenza infection as medicine.In aspect of this application, described influenza infection is because relevant with popularity outburst or have (seeing the table that WO 2007/045674 reaches wherein) due to the influenza virus of the potentiality of being correlated with popular outburst.Preferably, relevant with popularity outburst and can be selected from one group that forms by H1N1, H5N1, H5N2, H5N8, H5N9, based on the virus of H2 and H9N2 by the described influenza virus strain that binding molecule of the present invention is treated by the disease that these strains cause.

The invention still further relates to the pharmaceutical composition that comprises binding molecule of the present invention and pharmaceutically-acceptable excipients.

In another embodiment, the present invention relates to the application of binding molecule of the present invention in preparing the medicine of diagnosing, prevent and/or treat influenza infection.This infection can take place in microcommunity, but also can propagate at world wide in prevailing disease mode in season, perhaps more seriously spreads in the whole world, and millions of individualities are in danger.The invention provides to neutralize causes prevailing disease and the binding molecule of the infection of the global epiphytotics influenza virus strain of potential in this season.Importantly, can expect at present and utilize binding molecule of the present invention to play protection and therapeutic action for multiple influenza virus strain, because disclosed since with the combining of the epi-position of between the HA of the susceptible poison strain of various flows albumen, sharing, therefore can use the binding molecule of the present invention between these strains, to carry out cross-neutralization at present.This is particularly advantageous; because before infecting or give described binding molecule afterwards and can protect Mammals (disclosing) as embodiment, therefore not clear described infection whether by based on the causing of the strain of H1, H2, H5, H6 or H9 the time (at the commitment of morbidity) also play effect like this.Treat healthy workman, soldier and general population in the time of can using binding molecule prophylactic treatment of the present invention or infection.Potentially, binding molecule of the present invention can the huge stocks form preparation and storing because it provides the provide protection at different popular strains, and be favourable for preparing for contingent flu outbreak in the future.

In a preferred embodiment, the human binding molecules of the present invention wherein said human binding Molecule selected from the following group: a) contains a SEQ ID NO: 1 shows the amino acid sequence heavy chain CDR1 Region having SEQ ID NO: 2 shows the amino acid sequence of the heavy chain CDR2 region having SEQ ID NO: 3 The amino acid sequence shown in heavy chain CDR3 region having SEQ ID NO: 4 shows the amino acid sequence of a light Chain CDR1 region having SEQ ID NO: 5 shows the amino acid sequence and a light chain CDR2 region having SEQ ID NO: 6 shows the amino acid sequence of the light chain CDR3 region of the human binding molecules, b) contains a SEQ ID NO: 1 shows the amino acid sequence heavy chain CDR1 region having SEQ ID NO: 2 shows the ammonia Amino acid sequence of the heavy chain CDR2 region having SEQ ID NO: 3 shows the amino acid sequence of the heavy chain CDR3 Region having SEQ ID NO: 7 shows the amino acid sequence of the light chain CDR1 region having SEQ ID NO: 8 The amino acid sequence shown in a light chain CDR2 region, and with SEQ ID NO: 9 amino acid sequence shown The light chain CDR3 region of the human binding molecules, c) contains a SEQ ID NO: 1 amino acid sequence shown Heavy chain CDR1 region having SEQ ID NO: 2 shows the amino acid sequence heavy chain CDR2 region having SEQ ID NO: 3 shows the amino acid sequence of the heavy chain CDR3 region having SEQ ID NO: 10 shows the ammonia Amino acid sequence of the light chain CDR1 region having SEQ ID NO: 11 shows the amino acid sequence of the light chain CDR2 Area and having SEQ ID NO: 12 shows the amino acid sequence of the light chain CDR3 region of the human binding molecules, d) contains a SEQ ID NO: 1 shows the amino acid sequence heavy chain CDR1 region having SEQ ID NO: 2 shows the amino acid sequence of the heavy chain CDR2 region having SEQ ID NO: 3 shows the amino acid sequence The heavy chain CDR3 region having SEQ ID NO: 13 shows the amino acid sequence of the light chain CDR1 region, a With SEQ ID NO: 14 shows the amino acid sequence and a light chain CDR2 region having SEQ ID NO: 15 The amino acid sequence shown in light chain CDR3 region of the human binding molecules, e) contains a SEQ ID NO: 16 The amino acid sequence shown in heavy chain CDR1 region having SEQ ID NO: 17 shows the amino acid sequence of a heavy Chain CDR2 region having SEQ ID NO: 18 shows the amino acid sequence of the heavy chain CDR3 region having SEQ ID NO: 19 shows the amino acid sequence of the light chain CDR1 region having SEQ ID NO: 20 shown in A light chain CDR2 amino acid sequence region and having SEQ ID NO: 21 shows the amino acid sequence of the light chain CDR3 region of the human binding molecules, f) contains a SEQ ID NO: 1 heavy chain amino acid sequence shown CDR1 region having SEQ ID NO: 22 shows the amino acid sequence of the heavy chain CDR2 region having SEQ ID NO: 23 shows the amino acid sequence of the heavy chain CDR3 region having SEQ ID NO: 24 shows amino Acid sequence of the light chain CDR1 region having SEQ ID NO: 25 shows the amino acid sequence of the light chain CDR2 Area and having SEQ ID NO: 26 shows the amino acid sequence of the light chain CDR3 region of the human binding molecules, g) include having SEQ ID NO: 27 shows the amino acid sequence of the heavy chain CDR1 region having SEQ ID NO: 28 shows the amino acid sequence of the heavy chain CDR2 region having SEQ ID NO: 29 shows the amino acid sequence Column the heavy chain CDR3 region, having SEQ ID NO: 30 shows the amino acid sequence of the light chain CDR1 region, With SEQ ID NO: 31 shows the amino acid sequence and a light chain CDR2 region of SEQ ID NO: 32 shows the amino acid sequence of the light chain CDR3 region of the human binding molecules, h) included in SEQ ID NO: 1 in the amino acid sequence of the heavy chain CDR1 region having SEQ ID NO: 2 amino acid sequence shown The heavy chain CDR2 region having SEQ ID NO: 3 shows the amino acid sequence heavy chain CDR3 region, with With SEQ ID NO: 33 shows the amino acid sequence of the light chain CDR1 region having SEQ ID NO: 34 The amino acid sequence shown in area and has a light chain CDR2 SEQ ID NO: 35 shows the amino acid sequence of the light Chain CDR3 region of the human binding molecules, i) contains a SEQ ID NO: 1 heavy chain amino acid sequence shown CDR1 region having SEQ ID NO: 2 shows the amino acid sequence of the heavy chain CDR2 region having SEQ ID NO: 3 shows the amino acid sequence of the heavy chain CDR3 region having SEQ ID NO: 36 shows the amino acid sequence A light chain CDR1 region column, with SEQ ID NO: 37 shows the amino acid sequence of the light chain CDR2 region with And with SEQ ID NO: 38 shows the amino acid sequence of the light chain CDR3 region of the human binding molecules, j) packet Included with SEQ ID NO: 39 shows the amino acid sequence of the heavy chain CDR1 region having SEQ ID NO: 40 The amino acid sequence shown in heavy chain CDR2 region having SEQ ID NO: 41 shows the amino acid sequence of a heavy Chain CDR3 region having SEQ ID NO: 42 shows the amino acid sequence of the light chain CDR1 region having SEQ ID NO: 43 shows the amino acid sequence and a light chain CDR2 region having SEQ ID NO: 44 Shows the amino acid sequence of the human light chain CDR3 region binding molecule, k) contains a SEQ ID NO: 45 The amino acid sequence shown in the heavy chain CDR1 region having SEQ ID NO: 46 shows the amino acid sequence of the heavy chain CDR2 region having SEQ ID NO: 47 shows the amino acid sequence of the heavy chain CDR3 region having SEQ ID NO: 7 shows the amino acid sequence of the light chain CDR1 region having SEQ ID NO: 8 shows the amino acid A light chain CDR2 region sequence and having SEQ ID NO: 48 shows the amino acid sequence of the light chain CDR3 Human binding molecules zone, l) contains a SEQ ID NO: 1 shows the amino acid sequence heavy chain CDR1 Region having SEQ ID NO: 49 shows the amino acid sequence of the heavy chain CDR2 region having SEQ ID NO: 50 shows the amino acid sequence of the heavy chain CDR3 region having SEQ ID NO: 33 shows the amino acid sequence A light chain CDR1 region column, with SEQ ID NO: 34 shows the amino acid sequence of the light chain CDR2 region with And with SEQ ID NO: 51 shows the amino acid sequence of the light chain CDR3 region of the human binding molecules, m) Contains a SEQ ID NO: 52 shows the amino acid sequence of the heavy chain CDR1 region having SEQ ID NO: 53 shows the amino acid sequence of the heavy chain CDR2 region having SEQ ID NO: 54 shows the amino acid sequence Column heavy chain CDR3 region having SEQ ID NO: 55 shows the amino acid sequence of the light chain CDR1 region, With SEQ ID NO: 56 shows the amino acid sequence and a light chain CDR2 region of SEQ ID NO: 57 shows the amino acid sequence of the light chain CDR3 region of the human binding molecules, n) contains a SEQ ID NO: 262 amino acid sequence as shown in a heavy chain CDR1 region having SEQ ID NO: 263 amino acids shown in CDR2 region of the heavy chain sequence having SEQ ID NO: 264 as shown in the heavy chain CDR3 amino acid sequence Region having SEQ ID NO: 265 amino acid sequence as shown in a light chain CDR1 region having SEQ ID NO: 266 amino acid sequence shown, and a light chain CDR2 region having SEQ ID NO: 267 shown in amino Acid sequence of the light chain CDR3 region of the human binding molecules, o) contains a SEQ ID NO: 268 shows the ammonia Amino acid sequence of the heavy chain CDR1 region having SEQ ID NO: 269 in a heavy chain amino acid sequence shown CDR2 region having SEQ ID NO: 270 amino acid sequence shown in heavy chain CDR3 region having SEQ ID NO: 271 amino acid sequence as shown in a light chain CDR1 region having SEQ ID NO: 272 shows the ammonia Amino acid sequence and a light chain CDR2 region having SEQ ID NO: 273 and the light chain amino acid sequence shown CDR3 region of the human binding molecules, p) contains a SEQ ID NO: 274 in a heavy chain amino acid sequence shown CDR1 region having SEQ ID NO: 275 amino acid sequence shown in heavy chain CDR2 region having SEQ ID NO: 276 amino acid sequence shown in heavy chain CDR3 region having SEQ ID NO: 277 shows the ammonia Amino acid sequence of the light chain CDR1 region having SEQ ID NO: 278 and the light chain amino acid sequence shown And a CDR2 region having SEQ ID NO: 279 amino acid sequence as shown in a light chain CDR3 region of the human colon Covalent, q) contains a SEQ ID NO: 280 amino acid sequence as shown in a heavy chain CDR1 region, a With SEQ ID NO: 281 amino acid sequence shown in heavy chain CDR2 region having SEQ ID NO: 282 The amino acid sequence shown in heavy chain CDR3 region having SEQ ID NO: 283 amino acid sequence shown A light chain CDR1 region having SEQ ID NO: 284 amino acid sequence shown, and a light chain CDR2 region With SEQ ID NO: 285 amino acid sequence shown in a light chain CDR3 region of the human binding molecules, r) contains With SEQ ID NO: 286 amino acid sequence shown in heavy chain CDR1 region having SEQ ID NO: 287 The amino acid sequence shown in heavy chain CDR2 region having SEQ ID NO: 288 amino acid sequence shown Heavy chain CDR3 region having SEQ ID NO: 289 amino acid sequence shown in a light chain CDR1 region, a With SEQ ID NO: 290 amino acid sequence shown, and a light chain CDR2 region of SEQ ID NO: 291 amino acid sequence as shown in a light chain CDR3 region of the human binding molecules, s) contained in SEQ ID NO: 292 amino acid sequence as shown in a heavy chain CDR1 region having SEQ ID NO: 293 amino acids shown in CDR2 region of the heavy chain sequence having SEQ ID NO: 294 as shown in the heavy chain CDR3 amino acid sequence Region having SEQ ID NO: 295 amino acid sequence as shown in a light chain CDR1 region having SEQ ID NO: 296 amino acid sequence shown, and a light chain CDR2 region having SEQ ID NO: 297 shown in amino Acid sequence of the light chain CDR3 region of the human binding molecules, t) contains a SEQ ID NO: 304 shown in amino Acid sequence of the heavy chain CDR1 region having SEQ ID NO: 305 amino acid sequence shown in heavy chain CDR2 Region having SEQ ID NO: 306 amino acid sequence shown in heavy chain CDR3 region having SEQ ID NO: 307 amino acid sequence as shown in a light chain CDR1 region having SEQ ID NO: 308 amino acids shown in A light chain CDR2 region sequence and having SEQ ID NO: 309 and the light chain amino acid sequence shown CDR3 region of the human binding molecules, u) contains a SEQ ID NO: 310 in a heavy chain amino acid sequence shown CDR1 region having SEQ ID NO: 311 amino acid sequence shown in heavy chain CDR2 region having SEQ ID NO: 312 amino acid sequence shown in heavy chain CDR3 region, having SEQ ID NO: 313 shows the ammonia Amino acid sequence of the light chain CDR1 region having SEQ ID NO: 314 and the light chain amino acid sequence shown And a CDR2 region having SEQ ID NO: 315 amino acid sequence as shown in a light chain CDR3 region of the human colon Covalent, v) contains a SEQ ID NO: 238 amino acid sequence as shown in a heavy chain CDR1 region, a With SEQ ID NO: 239 amino acid sequence shown in heavy chain CDR2 region having SEQ ID NO: 240 The amino acid sequence shown in heavy chain CDR3 region having SEQ ID NO: 241 amino acid sequence shown A light chain CDR1 region having SEQ ID NO: 242 amino acid sequence shown, and a light chain CDR2 region With SEQ ID NO: 243 amino acid sequence shown in a light chain CDR3 region of the human binding molecules, w) package Included with SEQ ID NO: 244 amino acid sequence shown in heavy chain CDR1 region having SEQ ID NO: 245 amino acid sequence shown in heavy chain CDR2 region having SEQ ID NO: 246 amino acids shown in The heavy chain CDR3 region sequence having SEQ ID NO: 247 as shown in a light chain CDR1 amino acid sequence Region having SEQ ID NO: 248 amino acid sequence shown, and a light chain CDR2 region of SEQ ID NO: 249 amino acid sequence as shown in a light chain CDR3 region of the human binding molecules, x) contains a SEQ ID NO: 250 amino acid sequence as shown in a heavy chain CDR1 region having SEQ ID NO: 251 amino acids shown in CDR2 region of the heavy chain sequence having SEQ ID NO: 252 as shown in the heavy chain CDR3 amino acid sequence Region having SEQ ID NO: 253 amino acid sequence as shown in a light chain CDR1 region having SEQ ID NO: 254 amino acid sequence shown, and a light chain CDR2 region having SEQ ID NO: 255 shown in amino Acid sequence of the light chain CDR3 region of the human binding molecules, y) contains a SEQ ID NO: 256 shows the ammonia Amino acid sequence of the heavy chain CDR1 region having SEQ ID NO: 257 in a heavy chain amino acid sequence shown CDR2 region having SEQ ID NO: 258 amino acid sequence shown in heavy chain CDR3 region having SEQ ID NO: 259 amino acid sequence as shown in a light chain CDR1 region having SEQ ID NO: 260 shows the ammonia Amino acid sequence and a light chain CDR2 region having SEQ ID NO: 261 and the light chain amino acid sequence shown CDR3 region of the human binding molecules, and z) contains a SEQ ID NO: 298 amino acid sequence shown The heavy chain CDR1 region having SEQ ID NO: 299 amino acid sequence shown in heavy chain CDR2 region, With SEQ ID NO: 300 as shown in the heavy chain CDR3 amino acid sequence region having SEQ ID NO: 301 The amino acid sequence shown in a light chain CDR1 region having SEQ ID NO: 302 amino acid sequence shown And a light chain CDR2 region having SEQ ID NO: 303 amino acid sequence shown in a light chain CDR3 region Human binding molecules. ...

In specific embodiment, binding molecule of the present invention comprises heavy chain CDR1 district with aminoacid sequence shown in the SEQ ID NO:1, have the heavy chain CDR2 district of aminoacid sequence shown in the SEQ ID NO:2 and have the heavy chain CDR3 district of aminoacid sequence shown in the SEQ ID NO:3.The CDR district of binding molecule of the present invention is shown in the table 7.According to Kabat et al. (1991), the CDR district is the sequence of immunology protein of interest matter.In embodiments of the invention, binding molecule can comprise two, three, four, five or all six CDR districts that this paper discloses.Preferably, binding molecule of the present invention comprises at least two CDR that this paper discloses.

In one embodiment, it is that VH1-69 (sees Tomlinson IM that binding molecule of the present invention comprises the VH kind, Williams SC, Ignatovitch O, Corbett SJ, Winter G.V-BASESequence Directory.Cambridge United Kingdom:MRC Centre for ProteinEngineering (1997)).In another embodiment, binding molecule of the present invention comprises heavy chain, and described heavy chain comprises and has the variable heavy chain of aminoacid sequence that is selected from as in next group: SEQ IDNO:59, SEQ ID NO:61, SEQ ID NO:63, SEQ ID NO:65, SEQ ID NO:67, SEQ ID NO:69, SEQ ID NO:71, SEQ ID NO:73, SEQ ID NO:75, SEQ IDNO:77, SEQ ID NO:79, SEQ ID NO:81, SEQ ID NO:83, SEQ ID NO:317, SEQ ID NO:321, SEQ ID NO:325, SEQ ID NO:329, SEQ ID NO:333, SEQID NO:337, SEQ ID NO:341, SEQ ID NO:345, SEQ ID NO:349, SEQ IDNO:353, SEQ ID NO:357, SEQ ID NO:361 and SEQ ID NO:365.In another embodiment, binding molecule of the present invention comprises light chain, and described light chain comprises and has the variable light chain of aminoacid sequence that is selected from as in next group: SEQ ID NO:85, SEQ ID NO:87, SEQ IDNO:89, SEQ ID NO:91, SEQ ID NO:93, SEQ ID NO:95, SEQ ID NO:97, SEQ ID NO:99, SEQ ID NO:101, SEQ ID NO:103, SEQ ID NO:105, SEQ IDNO:107, SEQ ID NO:109, SEQ ID NO:319, SEQ ID NO:323, SEQ ID NO:327, SEQ ID NO:331, SEQ ID NO:335, SEQ ID NO:339, SEQ ID NO:343, SEQID NO:347, SEQ ID NO:351, SEQ ID NO:355, SEQ ID NO:359, SEQ IDNO:363 and SEQ ID NO:367.Table 8 has been listed the heavy chain and the variable region of light chain of binding molecule of the present invention.

Another aspect of the present invention comprises the functional variant of binding molecule described herein.If variant can combine influenza virus H 5 N 1 or its fragment with parental generation binding molecule competition specificity, then think the functional variant that this variant molecule is a binding molecule of the present invention.In other words, described functional variant still can be in conjunction with influenza virus H 5 N 1 or its fragment.Preferably, the competitive specificity combination of described functional variant energy is by different influenza virus H 5 N 1 strain or its fragments of parental generation binding molecule specificity bonded at least two (or more a plurality of).In addition, if certain molecule has the active influenza virus H 5 N 1 of neutralization, preferably has the neutralization activity at least two (or a plurality of) influenza virus H 5 N 1 strain it for the parental generation binding molecule, think that then this molecule is the functional variant of binding molecule of the present invention.Functional variant include but not limited to the primary structure sequence similar substantially, but for example contain in the parental generation binding molecule derivative that chemistry in the undiscovered external or body and/or biological chemistry are modified.This modification comprise covalent attachment, lipid or the lipid derivate of acetylize, acidylate, Nucleotide or nucleotide derivative covalent attachment, crosslinked, disulfide linkage formation, glycosylation, hydroxylation, methylate, oxidation, Pegylation, proteolysis processing, phosphorylation etc.

Perhaps, functional variant can be a binding molecule of the present invention, it comprises such aminoacid sequence, and described aminoacid sequence is compared the combination that contains one or more amino acid whose replacement, insertion, disappearance or this modification with the aminoacid sequence of parental generation binding molecule.In addition, functional variant can comprise the brachymemma of aminoacid sequence at N-terminal or C-terminal or these two ends.Functional variant of the present invention is compared with the parental generation binding molecule can have identical or different, higher or lower binding affinity, but still can be in conjunction with influenza virus H 5 N 1 or its fragment.For example, functional variant of the present invention is compared with the parental generation binding molecule for influenza virus H 5 N 1 or its fragment and can be had the binding affinity that increases or reduce.Preferably, the variable region includes but not limited to that the aminoacid sequence in framework region, hypervariable region, particularly CDR3 district is modified.Usually, light chain and variable region of heavy chain comprise three hypervariable regions, comprise three CDR, and more conservative zone, promptly so-called framework region (FR).The hypervariable region comprises from the amino-acid residue of CDR with from the amino-acid residue of hypermutation ring.Functional variant within the scope of the present invention and parental generation binding molecule described herein have about at least 50% to about 99%, preferably about at least 60% to about 99%, more preferably about at least 70% to about 99% even more preferably about at least 80% to about 99%, most preferably about at least 90% to about 99%, particularly about at least 95% to about 99%, and about at least 97% to about 99% amino acid sequence homology particularly.Computerized algorithm well known by persons skilled in the art such as Gap or Bestfit can be used for best the arranged amido acid sequence to compare and precisely similar or identical amino-acid residue.Functional variant can change parental generation binding molecule or its a part of acquisition by using common molecular biology method known in the art, and described method includes but not limited to mutagenesis, site-directed mutagenesis and heavy chain and/or the light chain reorganization method that fallibility PCR, oligonucleotide instruct.In one embodiment, functional variant of the present invention has the neutralization activity for influenza virus H 5 N 1.Active the comparing with the parental generation binding molecule of described neutralization can be identical or higher or lower.After this, when using term (people) binding molecule, it also contains the functional variant of described (people) binding molecule.

On the other hand, the present invention includes immunoconjugates, the molecule that promptly comprises at least one binding molecule described herein and further comprise at least one mark such as detectable part/material.The invention still further relates to the mixture of immunoconjugates of the present invention or the mixture of at least a immunoconjugates of the present invention and another molecule, described another molecule such as therapeutical agent or another binding molecule or immunoconjugates.In another embodiment, immunoconjugates of the present invention can comprise more than one mark.These marks can be same to each other or different to each other, and can combine with binding molecule non-covalently/put together.Described mark also can directly combine with human binding molecules/put together by covalent linkage.Perhaps, described mark can connect compound by one or more and combines/put together with described binding molecule.The conjugation techniques of mark and binding molecule is well known to those skilled in the art.

The mark of immunoconjugates of the present invention can be a therapeutical agent, but they also can be detectable part/materials.The mark that is suitable for treating and/or preventing can be other binding molecule of toxin or its funtion part, microbiotic, enzyme, enhancing phagolysis or immunostimulation.The immunoconjugates diagnosticability ground that comprises detectable substance be used for for example evaluating object whether influenza virus infection H5N1 strain or the generation of infecting as the part monitoring influenza virus H 5 N 1 of clinical experiment program or progress for example to determine the effect of TA scheme.Yet they also can be used for other detection and/or analysis and/or diagnostic purpose.Detectable part/material includes but not limited to enzyme, prothetic group, fluorescent material, luminescent material, bioluminescent material, radio active material, positron emitting metal and on-radiation paramagnetic metal ion.Depend on the particular detection/analysis/diagnostic techniques and/or for example immunohistochemical staining (tissue) sample, flow cytometry, the detection of laser scanning cytometry, fluorescence immunoassay, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), biological assay (for example phagolysis mensuration), the western blotting application etc. of method of use for the mark that detects and/or analysis and/or diagnostic purpose are used for the mark binding molecule.Be well known to those skilled in the art for detection known in the art/analysis/diagnostic techniques and/or the suitable mark of method.

In addition, human binding molecules of the present invention or immunoconjugates also can be attached on the solid support, and it is used in particular for influenza virus H 5 N 1 or its segmental external immunoassay or purifying.This solid support can be porous or atresia, plane or nonplanar.Binding molecule of the present invention can merge so that purifying with flag sequence such as peptide.The example of described flag sequence includes but not limited to six histidine marks, hemagglutinin (HA) mark, myc mark or flag mark.Perhaps, a kind of antibody can be puted together formation antibody allos conjugate (heteroconjugate) with another kind of antibody.On the other hand, binding molecule of the present invention can be puted together with one or more antigen/adhere to.Preferably, these antigens are the antigen by the immune system recognition of the object that has given binding molecule-antigen conjugate.Described antigen can be mutually the same, but also can be different.It is known in the art making the conjugation methods that adheres to antigen and binding molecule, includes but not limited to use linking agent.Binding molecule of the present invention will cause for the strong T cell of described conjugate in conjunction with influenza virus H 5 N 1 and the antigen that is attached to binding molecule attacks the destruction that finally causes influenza virus H 5 N 1.

Chemistry produces the immunoconjugates except puting together by direct or indirect (for example passing through joint), and described immunoconjugates can be used as fusion rotein and produces, and described fusion rotein comprises binding molecule of the present invention and suitable mark.Fusion rotein can produce by means known in the art, for example by making up nucleic acid molecule and expressing generations of recombinating of described nucleic acid molecule subsequently, described nucleic acid molecule comprises the nucleotide sequence of the nucleotide sequence of in-frame coding binding molecule and the appropriate flags of encoding.

The present invention provides the nucleic acid molecule of encode at least a binding molecule of the present invention, its functional variant or immunoconjugates on the other hand.This nucleic acid molecule can for example be used for as above-mentioned affinity maturation method as intermediate to clone.In a preferred embodiment, described nucleic acid molecule is an isolated or purified.

The technician will recognize that the functional variant of these nucleic acid molecule also is a part of the present invention.Functional variant is such nucleotide sequence, it directly can be translated so that the aminoacid sequence identical with the sequence of translating from the parental generation nucleic acid molecule to be provided by using the standard genetic code.

Preferably, described nucleic acid molecule encoding comprises the binding molecule in above-mentioned CDR district.In another embodiment, described nucleic acid molecule encoding comprises 2,3,4,5 or even the binding molecule in all 6 CDR districts of binding molecule of the present invention.

In another embodiment, described nucleic acid molecule encoding comprises the binding molecule of heavy chain, and described heavy chain comprises above-mentioned variable heavy chain sequence.In another embodiment, described nucleic acid molecule encoding comprises the binding molecule of light chain, and described light chain comprises above-mentioned variable sequence of light chain.The nucleotides sequence of binding molecule of the present invention is listed in the embodiment chapters and sections to be provided (seeing for example table 6 and table 8).

The present invention provides carrier on the other hand, i.e. nucleic acid construct, and it comprises one or more nucleic acid molecule of the present invention.Carrier can be derived from plasmid such as F, R1, RP1, Col, pBR322, TOL, Ti etc.; Clay; Phage such as lambda particles phage, lambdoid phage, M13, Mu, P1, P22, Q β, T-even, T-odd, T2, T4, T7 etc.; Plant virus.Carrier can be used for the clone and/or expresses binding molecule of the present invention, even can be used for the gene therapy purpose.The present invention also comprises the carrier that comprises one or more nucleic acid molecule of the present invention that operably is connected with one or more expression adjusting nucleic acid molecule.The selection of carrier depend on subsequently the reorganization program and the host of use.Carrier is imported in the host cell and can realize by the following method: transfection, lipofectamin transfection or the electroporation of calcium phosphate transfection, virus infection, the mediation of DEAE-dextran.Carrier can self-replicating or can be duplicated with its karyomit(e) that is integrated into wherein.Preferably, described carrier contains one or more selective marker.The selection of mark depends on the host cell of selection, although as well known to the skilled person-this is not vital for the present invention.Described mark includes but not limited to the thymidine kinase gene (HSV-TK) of kantlex, Xin Meisu, tetracycline, Totomycin, zeocin, hsv, the dihydrofolate reductase gene (dhfr) of mouse.The present invention also comprises such carrier, and it comprises one or more nucleic acid molecule that can be used for the coding human binding molecules that one or more nucleic acid molecule of the protein of separation of human binding molecule or peptide operably is connected with coding.These protein or peptide include but not limited to polyhistidine, green fluorescent protein, luciferase and the beta-galactosidase enzymes of glutathione-S-transferase, maltose binding protein, bond.

The host of carrier of containing one or more copy of above-mentioned carrier is another aspect of the present invention.Preferably, described host is a host cell.Host cell includes but not limited to come from the cell of Mammals, plant, insect, fungi or bacterium.Bacterial cell includes but not limited to the cell of gram-positive microorganism or Gram-negative bacteria, for example some bacterial classifications of enterobacter such as intestinal bacteria (E.coli) and Rhodopseudomonas.In the fungal cell, preferably use yeast cell.Expression in yeast can realize described yeast strain such as pichia pastoris phaff (Pichia pastoris), yeast saccharomyces cerevisiae (Saccharomyces cerevisiae) and multiple-shaped nuohan inferior yeast (Hansenula polymorpha) by using yeast strain.In addition, insect cell such as fruit bat and Sf9 cell can be used as host cell.In addition, host cell can be a vegetable cell, for example the cell of farm crop such as forest plants, food and raw-material vegetable cell perhaps are provided, as cereal grass or medicinal plant, the perhaps cell of ornamental plant, the perhaps cell of bouquet root farm crop (flower bulb crop).(transgenosis) plant or the vegetable cell that transform produce by currently known methods, and for example agriculture bacillus mediated transgenosis, leaf dish transform, shift the protoplast transformation of carrying out, electroporation, ultrasonic, microinjection or bolistic gene transfer method by polyoxyethylene glycol inductive DNA.In addition, appropriate expression system can be a rhabdovirus system.The present invention preferably uses the expression system of mammalian cell, for example Chinese hamster ovary (CHO) cell, COS cell, bhk cell, NSO cell or Bowes melanoma cells.Mammalian cell provides the expressed protein with posttranslational modification, and is the most similar to the natural molecule in Mammals source.Owing to the present invention relates to the molecule of administration of human, therefore preferred especially people's expression system fully.Therefore, preferred host cell is people's cell.The example of people's cell is HeLa, 911, AT1080, A549,293 and the HEK293T cell.In preferred embodiments, but the people produces the funtion part at least of nucleotide sequence that cell comprises the encoding adenovirus E 1 district of expression-form.In a more preferred embodiment, described host cell derived from human retina and with the nucleic acid immortalization that comprises the adenovirus E 1 sequence, 911 cells or be deposited on February 29th, 1996 and be positioned at CAMR for example, Salisbury, Wiltshire SP4 OJG, clone in the European cell culture center of GreatBritain (European Collection of Cell Cultures (ECACC)), preserving number is 96022940, with PER.

(PER.C6 is the registered trademark of Crucell Holland B.V.) trade mark is sold.Be the application's purpose, " PER.C6 cell " is meant cell or the progenitor cell with preserving number 96022940 preservations, and go down to posterity and offspring and filial generation in the upstream of the progenitor cell of preservation cell or downstream, and the derivative of any aforementioned cell.The generation of recombinant protein can be carried out according to method well known in the art in host cell.With PER.

The cell that trade mark is sold is described as being applied among the WO 00/63403 of production platform of protein of interest matter, and it is for referencial use that described document is incorporated this paper into its full content.

The method that produces binding molecule of the present invention is another part of the present invention.Described method comprises the steps: a) to cultivate host of the present invention under the condition that is of value to the binding molecule expression, b) randomly reclaim the binding molecule of expressing.The binding molecule of expressing can reclaim from cell-free extract, but preferably reclaims from substratum.Above-mentioned production method also can be used for producing the functional variant of binding molecule of the present invention and/or immunoconjugates.The method that reclaims protein such as binding molecule from cell-free extract or substratum is well known to those skilled in the art.By the obtainable binding molecule of aforesaid method, its functional variant and/or immunoconjugates also is a part of the present invention.

Perhaps, after expressing in host such as host cell, binding molecule of the present invention and immunoconjugates can or use in cell free translation system derived from the RNA nucleic acid of dna molecular of the present invention is synthetic by the synthetic generation of conventional peptide synthesizer and produce.By above-mentioned synthetic production method or the obtainable binding molecule of cell free translation system and immunoconjugates also is a part of the present invention.

In another embodiment, binding molecule of the present invention also can produce in transgenic nonhuman mammal such as rabbit, goat or ox, and for example its Ruzhong is entered in secretion.

In another embodiment, binding molecule of the present invention, preferred specificity can be produced by the transgenic nonhuman mammal of expressing human immunoglobulin gene such as transgenic mice or rabbit in conjunction with influenza virus H 5 N 1 or its segmental human binding molecules.Preferably, described transgenic nonhuman mammal has such genome, and it comprises as people's heavy chain transgenosis of above-mentioned coding all or part human binding molecules and people's light chain transgenosis.Described transgenic nonhuman mammal can be used influenza virus H 5 N 1 purifying or enrichment or its segmental prepared product immunization.The scheme of immunization non-human mammal is fully set up in this area.See Using Antibodies:A Laboratory Manual, Edited by:E.Harlow, D.Lane (1998), Cold Spring Harbor Laboratory, Cold Spring Harbor, New York and Current Protocols in Immunology, Edited by:J.E.Coligan, A.M.Kruisbeek, D.H.Margulies, E.M.Shevach, W.Strober (2001), John Wiley ﹠amp; Sons Inc., New York, it is for referencial use that described document is all incorporated this paper into.Immunization scheme generally includes or does not have the repeatedly immunization of adjuvant, and described adjuvant such as Freund's complete adjuvant and Freund's incomplete adjuvant also can comprise the naked DNA methods of vaccination.In another embodiment, described human binding molecules is produced by B cell, plasmocyte and/or memory cell derived from described transgenic animal.In another embodiment, described human binding molecules is produced by hybridoma, and described hybridoma is to merge by B cell that derives from above-mentioned transgenic nonhuman mammal and immortalized cells to prepare.The human binding molecules that can derive from B cell, plasmocyte and the hybridoma of above-mentioned transgenic nonhuman mammal and can derive from above-mentioned transgenic nonhuman mammal, B cell, plasmocyte and/or memory cell and hybridoma also is a part of the present invention.

On the other hand, the invention provides the method for specificity of differentiating in conjunction with the nucleic acid molecule of the binding molecule of influenza virus H 5 N 1 or this binding molecule of encoding, described binding molecule for example is human binding molecules such as human monoclonal antibodies or its fragment, described method comprises the steps: that (a) contacts (genetic package) the lip-deep binding molecule set of reproducible heredity packing being of value under the bonded condition with influenza virus H 5 N 1 or its fragment, (b) select at least once and influenza virus H 5 N 1 or the reproducible heredity packing of its fragment bonded, (c) from influenza virus H 5 N 1 or the uncombined reproducible heredity packing of its fragment separate and recovery is packed with influenza virus H 5 N 1 or the reproducible heredity of its fragment bonded.As used herein, reproducible hereditary packing can be protokaryon or eukaryote, comprises cell, spore, yeast, bacterium, virus, (bacterium) phage, rrna and polysome.Preferred reproducible heredity packing is a phage.Described binding molecule for example strand Fv is illustrated on the reproducible heredity packing, and promptly they are attached to group or the molecule that is positioned at reproducible heredity packing outside surface.Described reproducible heredity packing is the unit that can screen, and it comprises the screened binding molecule for the treatment of that is connected with the nucleic acid molecule of coding binding molecule.Described nucleic acid molecule (for example as carrier) or external (for example by PCR, transcribe and translate) in vivo duplicates.Duplicating in the body can be self-replicating (with regard to cell), duplicates (with regard to virus) or the two duplicates (with regard to phagemid) by means of host and helper virus by means of host's factor.The reproducible heredity packing of showing the binding molecule set is to form like this, and the nucleic acid molecule that is about to coding external source binding molecule to be demonstrated imports in the genome of reproducible heredity packing to form fusion rotein with intrinsic protein from the outside surface normal expression of reproducible heredity packing.Described Expression of Fusion Protein, be transported to outside surface and assembling and cause the external source binding molecule to be showed from the outside surface of reproducible heredity packing.

Selection step in the inventive method can be carried out with influenza virus H 5 N 1, described virus be live and still have infectivity or an inactivation.The inactivation of influenza virus H 5 N 1 can be undertaken by virally inactivated method well known to those skilled in the art, for example uses formaldehyde, β-propionic acid lactone (BPL), Thiomersalate and/or UV treatment.Detect influenza virus H 5 N 1 whether be still alive, infective and/or can survive or partially or completely the method for inactivation be well known to those skilled in the art.The influenza virus H 5 N 1 that uses in the aforesaid method can be unsegregated, for example is present in the serum and/or blood of infected individuality.The influenza virus H 5 N 1 that uses also can separate from the cell culture in suitable culture medium.

In one embodiment, influenza virus H 5 N 1 is when packing with reproducible heredity in suspension when contacting.Perhaps, when coming in contact, they also can with the carrier coupling.In one embodiment, can carry out at the influenza virus H 5 N 1 strain of same clade with further selection for the first time.Perhaps, can carry out (for example select for the first time to carry out at clade 1 strain, selection is for the second time carried out at

clade

2 or 3 strains) for the first time at the influenza virus H 5 N 1 strain of Different Evolutionary branch with further selection.

Perhaps, select step for example to carry out under the condition of cell membrane preparations, reorganization H5N1 albumen or polypeptide, the fusion rotein that comprises H5N1 albumen or polypeptide, the protein of express recombinant H5N1 or the cell of polypeptide etc. in the fragment that has influenza virus H 5 N 1.The outer expose portion of the born of the same parents of these protein or polypeptide also can be with the material that elects.The fragment of influenza virus H 5 N 1 can be fixed on the suitable material before using or can use by suspension.In one embodiment, described selection can be carried out at the different fragments of influenza virus H 5 N 1 or the fragment of different influenza virus H 5 N 1 strains.Find that suitable selection combination is well known to those skilled in the art.Can select by ELISA or FACS.

Again on the one hand, the invention provides the method for specificity that obtain in conjunction with the nucleic acid molecule of influenza virus H 5 N 1 strain or its segmental binding molecule or this binding molecule of encoding, wherein said method comprises the steps: a) to carry out the method for above-mentioned discriminating binding molecule, b) separates the nucleic acid molecule of the described binding molecule and/or the described binding molecule of encoding from the reproducible heredity packing that reclaims.The set of the binding molecule on the reproducible hereditary surface of package can be the set of scFv or Fab.In case determine or differentiated new scFv or Fab with the method for the nucleic acid molecule of the above-mentioned discriminating binding molecule or the described binding molecule of encoding, then can from bacterium or phage, separate the DNA of described scFv of coding or Fab and wish the construct of specific scFv, divalence scFv, Fab or complete human normal immunoglobulin (for example IgG, IgA or IgM) with standard molecular biological technique combination results coding.These construct transfections can be advanced in the clone, finally can produce complete human monoclonal antibodies and (see Huls et al., 1999; Boel et al., 2000).

As previously mentioned, preferred reproducible heredity packing is a phage.Discriminated union acquisition (people) binding molecule for example phage display method of (people) monoclonal antibody is well known to those skilled in the art.Described method is for example in U.S. Patent No. 5,696,108; Burton and Barbas, 1994; De Kruif et al., 1995b; With Phage Display:A Laboratory Manual.Edited by:CF Barbas, DR Burton, JKScott and GJ Silverman (2001), Cold Spring Harbor Laboratory Press, ColdSpring Harbor describes among the New York.It is for referencial use that all these reference are all incorporated this paper into its full content.In order to make up phage display library, make being integrated on the preferred filobactivirus of phage, the particulate surface of human monoclonal antibodies heavy chain and chain variable region gene (see de Kruif et al., 1995b) with for example strand Fv (scFv) or Fab formal representation.The big library typical case of the segmental phage of expressing antibodies is contained and is surpassed 1.0 * 10 ⁹Plant antibodies specific, and can be from the immunoglobulin (Ig) V district assembling of the bone-marrow-derived lymphocyte of immunity or non-immune individuality, expressing.In a particular of the present invention, the phage library of binding molecule, preferred scFv phage library are to prepare from the RNA of cell from separating, described cell get own through inoculation influenza virus (for example H5N1), recently inoculate incoherent pathogenic agent, experience the cell of the object that influenza virus H 5 N 1 infects or derive from the cell of healthy individual recently.RNA can separate from marrow or peripheral blood, and preferable separation is from peripheral blood lymphocyte or isolating B cell or even the subgroup such as the memory B cell of B cell.Described object can be an animal, preferred people.In a preferred embodiment, described library can be from the immunoglobulin (Ig) V district assembling of being expressed by the IgM memory B cell.

Perhaps, phage display library can be from making up the immune globulin variable region of outer body assembling to import the additional antibody diversity in library (semi-synthetic library).For example, the dna sequence dna that in those molecular domains important (for example CDR district), contains synthetic that produce, randomization or incomplete randomization in the variable region of assembled in vitro for antibodies specific.The phage antibody that is specific to influenza virus H 5 N 1 can be selected from the library, by virus or its fragment are exposed to phage library so that in conjunction with expressing the phage that is specific to described virus or its segmental antibody fragment.Unconjugated phage is removed by washing, and the phage of elution of bound also breeds subsequently with ehec infection.Usually need repeatedly select and breed circulation to be enough to the enrichment specificity in conjunction with described virus or its segmental phage.If desired, before phage library is exposed to described virus or its fragment, can be at first by phage library is exposed to non-target material subdue as the virus of different strains or its fragment (being non-H5N1 influenza virus) as described in phage library.These subdue (subtractor) virus or its fragment can combine with solid phase or can be in suspension.Can for example be optional added the H5N1 albumen of other material or the compounding mixture of (many) peptides also at selecting phage, described complex antigen with combining of complex antigen.One or more protein of expression of influenza virus H5N1 or the host cell of (many) peptides also can be used to select purpose.Use the phage display method of these host cells to be expanded in the following way and to improve, described mode is to subdue incoherent binding substances by the host cell that adds the excessive host cell that does not comprise target molecule or comprise the non-target molecule similar but different with target molecule during screening, thereby increases the chance of finding relevant binding molecule powerfully.Certainly, described subdue can be before with virus or the screening of its fragment, during or carry out afterwards.Described method is called Method (

Be the registered trademark of Crucell Holland B.V., also see and incorporate this paper United States Patent (USP) for referencial use 6,265,150 into).

Again on the one hand, the invention provides the potential method that has for the active binding molecule of neutralization of the influenza virus H 5 N 1 strain of influenza virus H 5 N 1,

preferred clade

1,2 at least and 3 that obtains, described method comprises the steps: that (a) carries out as the method for above-mentioned acquisition specificity in conjunction with the nucleic acid molecule of influenza virus H 5 N 1 or its segmental binding molecule or this binding molecule of encoding, (b) the isolating binding molecule of check for described virus, preferably whether to have a neutralization for the influenza virus H 5 N 1 strain of clade 1 at least and 2 active.Whether the check binding molecule has the active measuring method of neutralization is known in the artly (to see WHO Manual on Animal Influenza Diagnosis and Surveillance, Geneva:World Health Organisation, 2005version 2002.5).

On the other hand, the present invention relates to by aforesaid method obtainable have the neutralization active binding molecule.

Again on the one hand, the invention provides and comprise the preferred human monoclonal antibodies of binding molecule of the present invention at least, the composition of its functional variant, immunoconjugates of the present invention at least or its combination at least.In addition, described composition can comprise stable molecule such as albumin or polyoxyethylene glycol or salt.Preferably, used salt be keep binding molecule hope biologic activity and do not cause the salt of any undesirable toxic action.If desired, human binding molecules of the present invention can wrap by among a kind of material or on to protect its effect that avoids acid maybe can make other natural or non-natural condition effect of described binding molecule inactivation.

On the one hand, the invention provides the composition that comprises at least a nucleic acid molecule of the present invention again.Described composition can comprise the aqueous solution as containing the aqueous solution of salt (for example NaCl or as above-mentioned salt), stain remover (for example SDS) and/or other suitable component.

In addition, the present invention relates to pharmaceutical composition, it comprises at least a binding molecule such as human monoclonal antibodies of the present invention (or its function fragment or variant), at least a immunoconjugates of the present invention, at least a composition of the present invention or its combination.Pharmaceutical composition of the present invention further comprises at least a pharmaceutically-acceptable excipients.Pharmaceutically-acceptable excipients is well known to those skilled in the art.Pharmaceutical composition of the present invention can further comprise at least a other therapeutical agent.Proper drug also is well known to those skilled in the art.

In one embodiment, described pharmaceutical composition can comprise two or more for influenza virus H 5 N 1 have the neutralization active binding molecule.In one embodiment, when applied in any combination, it is active that described binding molecule presents collaborative neutralization.In other words, described composition comprise at least two kinds have the neutralization active binding molecule, be characterised in that described binding molecule in and influenza virus H 5 N 1 in play synergy.As used herein, term " is worked in coordination with " and is meant when applied in any combination, the adduction the when compound action of binding molecule is higher than independent the application.Described synergistic binding molecule can be in conjunction with the different structure on the identical or different fragment of influenza virus H 5 N 1.Calculating synergistic mode is to calculate by combinatorial index.The notion of combinatorial index (CI) is described by Chou and Talalay (1984).Described composition also can comprise and has neutralization active a kind of binding molecule and a kind of non-neutral H5N1 specific binding molecules.Described non-neutral and neutrality H5N1 specific binding molecules in and influenza virus H 5 N 1 in also can act synergistically.

Pharmaceutical composition of the present invention can further comprise at least a other therapeutical agent, preventive and/or diagnostic reagent.Preferably, described pharmaceutical composition comprises at least a other preventive and/or therapeutical agent.Preferably, described further therapeutical agent and/or preventive are to prevent and/or treat the medicament that influenza virus H 5 N 1 infects and/or derive from the illness of this infection.Described therapeutical agent and/or preventive include but not limited to antiviral agent.This medicament can be binding molecule, small molecules, organic or inorganic compound, enzyme, polynucleotide sequence, antiviral peptide etc.Other medicament that is used for the treatment of influenza virus infection H5N1 patient at present is M2 inhibitor (for example amantidine, Rimantadine) and/or neuraminidase inhibitor (for example zanamivir, Oseltamivir).These medicaments can with binding molecule applied in any combination of the present invention.The experimental phase can prevent and/or treat that influenza virus H 5 N 1 infects and/or derive from the medicament of the illness of this infection also can be as can be used for other therapeutical agent of the present invention and/or preventive.

Binding molecule of the present invention or drug regimen can detect at suitable animal model system before being used for human body.This animal model system includes but not limited to mouse, ferret (ferret) and monkey.

Typically, pharmaceutical composition must be aseptic and stable under production and storage requirement.Binding molecule of the present invention, immunoconjugates, nucleic acid molecule or composition can be powder types, rebuild in suitable pharmaceutically-acceptable excipients before carrying or when carrying (reconstitution).In the situation of the sterilized powder that is used for preparing sterile injectable solution, preferred manufacturing procedure is vacuum-drying and lyophilize (freeze-drying), produces the activeconstituents powder and adds from any other of previous filtration sterilization solution and wishes composition.

Binding molecule of the present invention, immunoconjugates, nucleic acid molecule or composition can add or mix so that the unitary dose of injectable forms to be provided when perhaps, can or be carried in solution and before carrying with suitable pharmaceutically-acceptable excipients.Preferably, the pharmaceutically-acceptable excipients of using among the present invention is suitable for high drug level, can keep adequate liquidity, and can postpone if desired the time to absorb.

The selection that the best of pharmaceutical composition gives approach is subjected to the influence of some factors, and described factor comprises the relation of the therapeutic action of the plasma concentration of the emergency of physical-chemical property, clinical condition of bioactive molecule in the composition and bioactive molecule and hope.For example, if desired, binding molecule of the present invention can prepare with carrier, avoids snap-out release to protect it, and sustained release preparation for example comprises implant, through skin patch and micro encapsulation delivery system.Can use biodegradable, biocompatible polymkeric substance, for example ethylene-vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoesters and poly(lactic acid).In addition, perhaps must give described binding molecule by described binding molecule or with these materials or compound with material that prevents described human binding molecules inactivation or compound bag.For example, described binding molecule can give object in suitable carriers, and described carrier for example is liposome or thinner.

The approach of giving can be divided into two kinds of main types: oral and parenteral gives.Preferably give approach and be intravenous administration or by sucking.

Oral dosage form can be formulated as tablet (tablets), tablet (troches), lozenge (lozenges), aqueous solution suspension or oil suspension, dispersible powder or particle, milk sap, hard capsule, soft gelatin capsule, syrup or elixir, pill, dragee, liquid, gel or slurry agent (slurries).These prescriptions can contain drug excipient, include but not limited to inert diluent, granulating agent and decomposition agent, wedding agent, lubricant, sanitas, pigment, seasonings or sweeting agent, vegetables oil or mineral oil, moistening agent and thickening material.

Pharmaceutical composition of the present invention also can be formulated as and is used for parenteral admin.The preparation of parenteral admin can be that the aqueous solution or non-aqueous solution etc. ooze aseptic nontoxic injection or primer solution or form of suspension.Described solution or suspension can be included in used dosage and concentration for the nontoxic material of acceptor, for example 1,3 butylene glycol, Ringer ' s solution, Hank ' s solution, isotonic sodium chlorrde solution, oil, lipid acid, local anesthetic, sanitas, damping fluid, thickening material or solubilizing agent, water soluble antioxidant, oil-soluble inhibitor and metal chelator.

On the other hand, binding molecule of the present invention such as human monoclonal antibodies (its function fragment and variant), immunoconjugates, composition or pharmaceutical composition can be used as medicine.Therefore, the method for using binding molecule of the present invention, immunoconjugates, composition or medicine composite for curing and/or flu-prevention virus H5N1 to infect is another part of the present invention.Above-mentioned molecule can be used in influenza virus H 5 N 1 diagnosis of infection, prevention, treatment or its combination.Their are fit to that treatment experience influenza virus H 5 N 1 infects but still untreated patient and treated or treated the patient that influenza virus H 5 N 1 infects.They can be used for such patient, for example health care practitioner, the relatives that infect object, (bird) raiser etc.

Above-mentioned molecule or composition can with other molecule combined utilization that can be used for diagnosing, preventing and/or treating.They can be in external, stripped (ex vivo) or use in vivo.For example, binding molecule of the present invention such as human monoclonal antibodies (or its functional variant), immunoconjugates, composition or pharmaceutical composition can give jointly with the vaccine (if can obtain) of influenza virus H 5 N 1.Perhaps, vaccine also can give before or after the molecule of the present invention giving.Replace vaccine, antiviral agent also can with binding molecule combined utilization of the present invention.Suitable antiviral agent be above-mentioned those.

Described molecule typical case is formulated in composition of the present invention and the pharmaceutical composition with treatment or diagnosis significant quantity.Perhaps, they can be prepared separately and give.For example, other molecule such as antiviral agent can general be used, and binding molecule of the present invention can give by intravenously.

Can adjust dosage regimen so that best required replying (for example treatment is replied) to be provided.Suitable dosage ranges can for example be the 0.1-100mg/kg body weight, preferred 0.5-15mg/kg body weight.In addition, for example can give once to inject, give in time repeatedly separate doses or can reduce or increase dosage in proportion according to the emergency of treatment situation.Molecule of the present invention and composition are preferably aseptic.Make that the method for these molecules and composition sterile is known in the art.Other molecule that is used to diagnose, prevent and/or treat can be to give with binding molecule similar administration schedule of the present invention.If give other molecule separately, then can be before giving one or more human binding molecules of the present invention or pharmaceutical composition (for example 2 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 7 days, 2 weeks, before 4 weeks or 6 weeks), while or (for example 2 minutes afterwards, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 7 days, 2 weeks, after 4 weeks or 6 weeks) give the patient.Accurate dosage regimen for people patient is picked out during clinical experiment usually.

When as interior therapeutic agent administration of human; human binding molecules and the pharmaceutical composition that comprises described human binding molecules are useful especially and normally preferred because acceptor for the immunne response of administered antibodies be lower than basically usually give monoclonal mouse, the replying of chimeric or humanization binding molecule.

On the other hand, the present invention relates to binding molecule of the present invention such as neutrality human monoclonal antibodies (its function fragment and variant), immunoconjugates, nucleic acid molecule, composition or pharmaceutical composition and be used for diagnosing, prevent, treat that influenza virus H 5 N 1 infects or the application of the medicine of its combination in preparation.

Next, test kit also is a part of the present invention, and described test kit comprises at least a binding molecule of the present invention such as neutrality human monoclonal antibodies (its function fragment and variant), at least a immunoconjugates, at least a nucleic acid molecule, at least a composition, at least a pharmaceutical composition, at least a carrier, at least a host or its combination.Randomly, the mentioned component of test kit of the present invention is packaged in the suitable containers, and indicates diagnosis, prevents and/or treats the appointment illness.Mentioned component can be stored in unitary dose or the multi-dose container, stores with the preferred aseptic aqueous solution form of the aqueous solution or as the preferred sterile freeze-drying preparation form of freeze-drying to be rebuild.Described container can be made by various materials, for example glass or plastics, and can have the aseptic hole (for example container can be the bottle of the intravenous injection solution bag or the stopper that can be pierced through by hypodermic needle) that enters.Described test kit can further comprise a plurality of containers, wherein comprises the acceptable damping fluid of medicine.Described test kit can further be included as commercial and other required material of user, the substratum that comprises other damping fluid, thinner, strainer, syringe needle, syringe, one or more suitable host, even may comprise at least a other therapeutical agent, preventive or diagnostic reagent.The subsidiary specification sheets that comprises in the commercial package of treatment, prevention or diagnostic products usually of this test kit, this specification sheets contains the information relevant for the indication of for example application of this treatment, prevention or diagnostic products, using method, dosage, production, administration, contraindication and/or precaution.

The invention further relates to the method for influenza virus H 5 N 1 in the test sample, wherein said method comprises the steps: that (a) contacts of the present invention binding molecule (its function fragment and variant) or the immunoconjugates of sample with the diagnosis significant quantity, (b) determine described binding molecule or immunoconjugates whether specificity in conjunction with the molecule of sample.Described sample can be the biological sample that infects object from (potential), include but not limited to blood, serum, stool, saliva, pharynx nasalis aspirate (nasophargyal aspirates), bronchial lavage thing (bronchial lavages), urine, tissue or other biologic material, perhaps abiology sample such as water, beverage etc.Described (potential) infects object can be the people, but also can detect the situation that exists of described virus to the animal that suspection is carried influenza virus H 5 N 1, uses human binding molecules of the present invention or immunoconjugates to carry out.At first can handle so that it is more suitable for detection method sample.Processing means that the sample that suspection is contained and/or contain described virus handles, and this virus resolves into antigenicity composition such as protein, (many) peptides or other antigenicity fragment thus.Preferably, human binding molecules of the present invention or immunoconjugates and sample are contacted under the condition that forms immunocomplex between the virus that perhaps exists in human binding molecules and the sample or its antigenicity composition making.The formation that detects and measure described immunocomplex by suitable method then, the formation of described immunocomplex represents to exist in the sample described virus.This method comprises homogeneous and heterogeneous in conjunction with immunoassay, for example radioimmunoassay (RIA), ELISA, immunofluorescence method, immunohistochemical method, FACS, BIACORE and western blot analysis.

The determination techniques of preferred determination techniques, especially extensive clinical screening patients serum and blood and blood derived product is ELISA and western blotting technology.Preferred especially ELISA test.In order to be used as reagent, binding molecule of the present invention or immunoconjugates are combined on the internal surface in microtitre hole expediently at these measuring methods.Binding molecule of the present invention or immunoconjugates can directly be combined on the microtitre hole.Yet the maximum combined in binding molecule of the present invention or immunoconjugates and hole can be by with adding binding molecule of the present invention after many Methionin pre-treatment hole or immunoconjugates is realized.In addition, binding molecule of the present invention or immunoconjugates can be by known way and hole covalent attachment.Usually, use binding molecule or the immunoconjugates of 0.01-100 μ g/ml to be used to wrap quilt, but also can use greater concn and lower amount.Then sample is added in the hole with binding molecule of the present invention or immunoconjugates bag quilt.

In addition, binding molecule of the present invention can be used for differentiating the specificity integrated structure of influenza virus H 5 N 1.Described integrated structure can be the epi-position on protein and/or the polypeptide.They can be linear, but also can be structure and/or conformation.In one embodiment, described integrated structure can be analyzed by PEPSCAN analytical procedure (see WO 84/03564, WO 93/09872, Slootstra et al., 1996).Perhaps, can be at the random peptide library that can comprise in conjunction with the peptide screening of binding molecule of the present invention from the proteinic peptide of influenza virus H 5 N 1.Integrated structure/peptide/epi-position of finding can and be used to diagnose influenza virus H 5 N 1 to infect as vaccine.The fragment except protein and/or polypeptide by described binding molecule bonded situation in, integrated structure can pass through mass spectroscopy, high performance liquid chromatography and magnetic nuclear resonance method is differentiated.

On the other hand, the invention provides the screening specificity in conjunction with method by the binding molecule (or its function fragment or variant) of the epi-position of the identical influenza virus H 5 N 1 of human binding molecules bonded epi-position of the present invention, wherein said method comprises the steps: that (a) will treat that screened binding molecule, binding molecule of the present invention contact with influenza virus H 5 N 1 or its fragment, (b) measures and treats whether screened binding molecule can combine influenza virus H 5 N 1 or its fragment with binding molecule competition specificity of the present invention.In further step, can determine to compete specificity and whether have the neutralization activity in conjunction with influenza virus H 5 N 1 or its segmental screened binding molecule.Can combine influenza virus H 5 N 1 with binding molecule of the present invention competition specificity or its segmental binding molecule is another part of the present invention.In above-mentioned screening method, " specificity is in conjunction with identical epi-position " also comprises specificity combination and binding molecule bonded epi-position of the present invention basic (substantially) or basic (essentially) identical epi-position.Blocking-up or compete binding molecule of the present invention and influenza virus H 5 N 1 bonded ability typical case and be meant and treat that screened binding molecule combines epi-position or the binding site on the binding site structure eclipsed influenza virus H 5 N 1 on the influenza virus H 5 N 1 of discerning with binding molecule immunologic opsonin of the present invention.Perhaps, this be meant treat screened binding molecule in conjunction with by the binding site of binding molecule immunologic opsonin identification of the present invention very approaching epi-position or binding site or suppress combining of binding molecule of the present invention and influenza virus H 5 N 1 on spatial disposition.

Usually, competitive inhibition is measured by such measuring method, wherein antigen composition is promptly comprised influenza virus H 5 N 1 or its segmental composition and is binding molecule of the present invention with reference to binding molecule and treats that screened binding molecule mixes.Usually, treat the excessive existence of screened binding molecule.Scheme based on ELISA and western blotting is applicable in this easy competitiveness research.By using species or isotype secondary antibody, those skilled in the art can only detect bonded with reference to binding molecule, and its combination is owing to the existence for the treatment of screened binding molecule of discerning identical epi-position basically reduces.Carrying out with reference to binding molecule and treating in the competitive research of the binding molecule that carries out between screened any binding molecule (no matter species or isotype), those skilled in the art can be at first with detectable mark to the reference binding molecule in addition mark to carry out discriminating subsequently, described mark for example is a vitamin H, enzyme labelling, radio-labeling or other mark, the binding molecule of differentiating by these competitive assay method (competitive binding molecule or cross reaction binding molecules) includes but not limited to that combination is the antibody of binding molecule bonded epi-position of the present invention or binding site by the reference binding molecule, antibody fragment and other wedding agents, and in conjunction with described with reference to the very approaching epi-position of binding molecule bonded epi-position or the antibody of binding site, antibody fragment and other wedding agents, described treat screened binding molecule with reference to binding molecule between competitive the combination taken place.Preferably, when competitive binding molecule of the present invention during excessive the existence, combine with reference to the specificity of binding molecule suppressing with the target of selection, the inhibition degree at least 10%, preferably at least 25%, more preferably at least 50%, more preferably 75%-90% or higher at least.In conjunction with binding molecule bonded epi-position of the present invention approximately, the discriminating of one or more competitive binding molecule of basic (substantially), basic (essentially) or identical epi-position is a kind of simple and clear technological method.Owing to the discriminating of competitive binding molecule and reference binding molecule are that binding molecule of the present invention compares and determines, therefore should understand in fact do not need to determine by any way described with reference to binding molecule and competitive binding molecule bonded epi-position to differentiate competitive binding molecule in conjunction with or essentially identical epi-position identical with reference binding molecule bonded epi-position.

Embodiment

For illustration the present invention, provide following embodiment.The scope that described embodiment does not limit the present invention in any way.

Embodiment 1

The RNA that use is extracted from memory B cell makes up the scFv phage display library

Collect peripheral blood by venipuncture from the normal health donor and place EDTA anti-freezing sample hose.Blood sample (45ml) with PBS dilution twice, is got on the 10ml Ficoll-Hypaque (Pharmacia) that is placed in such as 30ml, at 900 * g uninterrupted centrifugal 20 minutes of room temperature.Carefully take out the supernatant on the white layer that contains lymphocyte and thrombocyte fraction.Then, should layer is careful take out (～10ml), move in the new 50ml test tube, with 40ml PBS washing 3 times, and in room temperature centrifugal 10 minutes of 400 * g to remove thrombocyte.The lymphocytic precipitation that contains that obtains is resuspended in the RPMI substratum that contains 2%FBS, determines cell count by method for cell count.Use CD24, CD27 and surperficial IgM to serve as a mark to about 1 * 10 ⁸Individual lymphocyte dyes to carry out the fluorocyte sorting to separate the IgM memory B cell.The Becton Dickinson DigitalVantage device that use is set to Yield Mode carries out physical memory B cell sorting and separates.Lymphocyte is little fine and close group from FSC/SSC window control (gated).Memory B cell (CD24+/CD27+) separates with inmature (naive) B cell (CD24+/CD27-) and memory T cell (CD24-/CD27+) subsequently.Then, use IgM to express and from switch memory B cell (IgM-), separate IgM memory B cell (IgM+).In this step, the sorting in independent sample hose of IgM memory B cell.With 1 * 10 ⁵Individual cell harvesting with its at 400 * g centrifugal 10 minutes, and extracts cracking in the solution at the total RNA of 500 μ lTRIZOL after sorting is finished in DMEM/50%FBS.Use 200 μ l chloroforms and isopropanol precipitating method from cracked solution, to extract RNA, describe in detail as TRIZOL solution scheme.Then, using 1 μ l PelletPaint (Novogen) strengthens and manifests precipitation process.Whole RNA prepared products are dissolved in the ultrapure water (Invitrogen) of 23 μ l DEPC processing, and carry out the cDNA conversion with SuperScript III reversed transcriptive enzyme (Invitrogen).1 μ l Random Hexamers (500ng/ μ l) (Promega) is added in the RNA sample, mix, and in heat lid PCR instrument, unwind 5 minutes at 65 ℃.It is cold that sample is gone up speed at wet ice (wet-ice), adds following composition: 8 μ l 5X RT damping fluid (250mM Tris-HCl pH 8.3,375mMKCl, 15mM MgCl ₂), 2 μ l dNTP (every kind of 10mM) (Invitrogen), 2 μ l DTT (100mM), 2 μ l RNAse inhibitor (40U/ μ l) (Promega), 2 μ l SuperScript III (200U/ μ l) are (Invitrogen).At first the mixture that obtains is incubated 5 minutes in room temperature, moves to then in the heat lid PCR instrument 50 ℃ of operations 1 hour.Carried out 15 minutes and termination reaction until 75 ℃ by heating.The cDNA that obtains is diluted to 200 μ l with ultrapure water ,-20 ℃ of storages until further use.

Use two-wheeled pcr amplification method, use as shown in Table 1 and Table 2 primer sets with separating immune globulin VH and VL district from donor reservoir (repertoire) separately.The amplification composition that uses in the pcr amplification program is as follows: 5 μ l cDNA templates, 32.75 μ l ultrapure waters, every kind of primer of 2.5 μ l (10 μ M), 5 μ l10X PCR damping fluids (200mM Tris-HCl pH 8.4,500mM KCl), 1.5 μ l MgCl ₂(50mM), 0.5 μ l dNTP (every kind of 25mM), 0.25 μ l Taq polysaccharase (5U/ μ l) is (Invitrogen).The first round amplification that primer sets shown in the use table 1 is carried out cDNA separately produces 7,6 and 9 products of about 650 base pairs respectively for VH, V κ and V λ district.For the amplification of IgM memory B cell VH district, use the constant combination of primers OHl-OH7 of OCM.The thermal cycling program of first round amplification is: 2 minutes 96 ℃ (denaturing step), 30 circulations are as follows: 30 seconds 96 ℃/30 seconds 55 ℃/60 seconds 72 ℃, 72 ℃ of final extensions in 10 minutes, and 4 ℃ of coolings.The product application of sample on 1% sepharose and use gel-extraction column (Qiagen) therefrom to separate, is eluted among the 50 μ l 1mM Tris-HCl pH 8.0.First round amplified production with 10% (5 μ l) carries out second and takes turns amplification, the primer shown in the use table 2.These primers extend with restriction site, make separately VL and VH district directed cloning advance among the Vector for Phage Display PDV-C06.Second to take turns the pcr amplification program as follows: 2 minutes 96 ℃ (denaturing step), 30 following circulations: 30 seconds 96 ℃/30 seconds 60 ℃/60 seconds 72 ℃, 10 minutes 72 ℃ of final extensions, and 4 ℃ of coolings.At first gather second according to the natural appearance of the J sections of in the immunoglobulin gene product, finding and take turns amplified production (～350 base pair), produce 7,6 and 9 set (see Table 3 and table 4) respectively for VH, V κ and V λ variable region.For the stdn that obtains immunoglobulin sequences in the immune library distributes, gather according to 6 V κ of percentage mix and 9 V lambda light chains that table 3 is mentioned.This single final VL set (3 μ g) is spent the night with SalI and the digestion of NotI restriction enzyme, application of sample is in 1.5% sepharose (～350 base pair) and use Qiagen gel extraction post therefrom to separate, in the following PDV-C06 carrier (～5000 base pair) that is connected SalI-NotI cutting: 10 μ l PDV-C06 carriers (50ng/ μ l), 7 μ l VL insert body (10ng/ μ l), 5 μ l 10X connect damping fluid (NEB), 2.5 T4 dna ligase (400U/ μ l) (NEB), 25.5 μ l ultrapure waters (carrier is 1: 2 with insertion body ratio).In 16 ℃ of water-baths, connect and spend the night.Then, water doubles sample volume, (Invitrogen) extract with isopyknic phenol-chloroform-primary isoamyl alcohol (75: 24: 1), use chloroform (Merck) to extract subsequently, and precipitate 2 hours at-20 ℃ with 1 μ l Pellet Paint (Novogen), 10 μ l sodium acetates (3M pH 5.0) and 100 μ l Virahols.Subsequently that the sample that obtains is centrifugal 30 minutes at 4 ℃ at 20.000 * g.Precipitation 70% washing with alcohol that obtains was 20.000 * g in room temperature centrifugal 10 minutes.Remove ethanol by vacuum take-off, will be deposited in the air drying several minutes, be dissolved in then in the 50 μ l damping fluids that contain 10mM Tris-HCl (pH 8.0).1 μ l connects mixture and is used for being set at 1.7kV, 200Ohm in refrigerative 0.1cm electroporation pipe (Biorad) use, (time constant～4, Genepulser II equipment (Biorad) 5msec) transforms 40 μ l TG-1 electroreception attitude cells (Stratagene) to 25 μ F.After pulse, the SOC substratum (Invitrogen) that contains 5% (w/v) glucose (Sigma) with 37 ℃ 1000 μ l washes bacterium from the electroporation pipe immediately, is transferred in the 15ml round bottom culture test tube.500 μ l SOC/ glucose in addition are used for from the remaining bacterium of electroporation pipe flushing, and it is added in the culture test tube.By in the shaking table incubator, just in time reclaiming bacterium in 1 hour in the 220rpm cultivation at 37 ℃.The bacterium that transforms is plated in the square culture dish of big 240mm (NUNC), contain 200ml 2TY agar (16g/l bacto-tryptone in the described culture dish, the 10g/l bacterium is used yeast extract, 5g/l NaCl, 15g/l agar, pH 7.0) added 50 μ g/ml penbritins and 5% (w/v) glucose (Sigma).1-1000 times of diluent is plated on the 15cm culture dish that contains same medium to count.Continue to repeat 20 these Transformation Program, whole libraries are plated on 30 large square culture dish grow overnight in 37 ℃ of culturing room (culture stove) totally.Typically, use such scheme to obtain about 1 * 10 ⁷Cfu.Get each dull and stereotyped bacterium and place 10ml 2TY substratum by scraping gently from flat board results intermediate VL light chain library.The cell quality is measured by OD600 and is determined that the bacterium of 2 times of 500OD is used for plasmid DNA and prepares in a large number, uses two P500maxiprep posts (Qiagen) to instruct according to manufacturer and carries out.

Similar with the VL variable region, at first take turns the VH-JH product and mix to obtain normal J sections use distribution (seeing Table 4), to produce to be called the inferior set of 7 VH of PH1-PH7 with second.This set of percentage mix shown in the use table 4 distributes to obtain standardized sequence, obtains a VH fraction, it is digested with SfiI and XhoI restriction enzyme and be connected in the PDV-VL intermediate library that the SfiI-XhoI as above-mentioned acquisition cuts.The setting that connects, purification process, TG1 subsequently transform and the results of bacterium with at VL intermediate library described consistent (seeing above).The primer sets that use is positioned at the both sides, VH-VL district of insertion detects final library (about 5 * 10 by bacterium colony PCR ⁶Cfu) insertion frequency.Bacterium colony above 95% illustrates correct length and inserts body (seeing Table 5).Bacterium colony PCR product is used for subsequently dna sequence analysis to detect the bacterium colony per-cent that sequence variation and evaluation illustrate complete ORF.This per-cent typical case surpasses 70% (seeing Table 5).Also analyzed the mutation frequency in the V gene.In 50 sequences, it is not kind to be configuration that 47 sequences (94%) are arranged, and the expression ripening process is also consistent with memory phenotype as the B cell in the RNA source in library.At last, use CT helper phage (seeing WO 02/103012) save and increase described library and be used for carrying out phage antibody and select by elutriation method hereinafter described.

Embodiment 2

Carry selection at the segmental phage of strand Fv of H5N1

Use the antibody phage display libraries and the common display technique of bacteriophage and basic of basic as above-mentioned structure as United States Patent (USP) 6,265,150 and WO 98/15833 (it is for referencial use that these two pieces of documents are all incorporated this paper into) described

Choice of technology antibody fragment.In addition, described method of WO 02/103012 (it is for referencial use to incorporate this paper into) and helper phage are used for the present invention.

At reorganization hemagglutinin (HA) hypotype H5 (A/Vietnam/1203/2004 that in insect cell, uses baculovirus vector to produce; See SEQ ID NO:110) select (Protein Sciences, CT, USA).From the aminoacid sequence of the HA of isolate A/Vietnam/1194/2004 (H5N1TV) and come the consensus amino acid sequences of the representative HA of comfortable Indonesia and Chinese isolating strain (H5N1IC) to be shown in SEQ ID NO:111 and SEQ ID NO:112 respectively.Also select at solvable reorganization HA (sHA) from H5N1.Use the standard DNA clone technology in the expression vector that contains myc-and his-mark, clone following sequence: (solvable) sequence of (sHA) partly outside the HA born of the same parents of encoding from isolate A/Vietnam/1194/2004 (H5N1), this sequence is represented the HA (sHA of H5N1TV that differentiates in 2004 in Thailand and Vietnam's isolated influenza virus stain (clade 1), SEQ ID NO:113), and represent 2003/2004 year consensus sequence at the HA soluble part of Indonesia and Chinese isolating H5N1 strain (clade 2) (sHA of H5N1IC, SEQ ID NO:114).H5N1TV is different at 9 amino acid positions with the HA of H5N1IC, all is arranged in the HA1 subunit of described molecule.Use standard technique in the PER.C6 cell, to carry out the DNA transfection with instantaneous and/or stably express.Use HisTrap ^TMFF post (Amersham Biosciences) instructs by metal chelate affinity chromatography purifying sHA from culture supernatant according to manufacturer.

HA antigen (reorganization HA and the sHA of H5N1TV) is diluted (5.0 μ g/ml) in PBS, add MaxiSorp ^TMAmong the Nunc-Immuno Tubes (Nunc), on runner 4 ℃ of incubated overnight.Turn these immune test tubes (immunotubes) also with sealing damping fluid (2% skim-milk (ELK) in PBS) washing 3 times.Subsequently immune test tube is filled up with the sealing damping fluid, room temperature insulation 1-2 hour.In addition, immune test tube is spent the night with anti--myc antibody sandwich and with the sealing damping fluid insulation of the sHA of the H5N1TV that contains 5 μ g/ml myc-marks.Equal portions (500-1000 μ l, 0.5 * 10 of phage display library with set ¹³-1 * 10 ¹³Cfu uses CT helper phage amplification (seeing WO02/103012)) in the sealing damping fluid of the foetal calf serum of having added 10% non-heated and inactivated and 2% mice serum, sealed 1-2 hour in room temperature.The phage library of sealing is added in the immune test tube,, wash to remove unconjugated phage with lavation buffer solution (0.05% (v/v) Tween-20 in PBS) room temperature insulation 2 hours.The bonded phage by being incubated 10 minutes at the 100mM of room temperature and 1ml triethylamine (TEA) from antigen separately wash-out.Subsequently, the phage of wash-out is mixed with the 1M Tris-HCl of 0.5ml (pH 7.5) with in and pH.This mixture is used to infect at 37 ℃ and grows to the XL1-Blue culture of Escherichia coli that OD600nm is about 0.3 5ml.Make phage infect the XL1-Blue bacterium 30 minutes at 37 ℃.Then with this mixture room temperature centrifugal 10 minutes with 3000 * g, bacterial precipitation is resuspended in 0.5ml 2-Tryptones yeast extract (2TY) substratum.The bacterial suspension that obtains is assigned in two 2TY agar plates adding tsiklomitsin, penbritin and glucose.Flat board after 37 ℃ of incubated overnight, is scraped from flat board and to be got the phage library that bacterium colony is used to prepare enrichment, as described in DeKruif et al. (1995a) and WO 02/103012, carry out substantially.In brief, be used to inoculate the 2TY substratum that contains penbritin, tsiklomitsin and glucose with scraping the bacterium of getting, growing to OD 600nm at 37 ℃ is～0.3.Add the CT helper phage, make its bacterial infection, afterwards substratum is replaced by the 2TY that contains penbritin, tsiklomitsin and kantlex.Continue incubated overnight at 30 ℃.Second day, degerm by centrifugal from the 2TY substratum, removing, use the phage in polyoxyethylene glycol (PEG) the 6000/NaCl precipitation substratum afterwards.At last, phage is dissolved among the 2ml PBS with 1% bovine serum albumin (BSA), filtration sterilization also is used for the next round selection.

Perhaps use total length HA express cell system to carry out the phage selection.For this reason, use and to contain from the complete encoding sequence of the total length HA of isolate A/Vietnam/1194/2004 (H5N1TV) and representative expression vector transfection PER.C6 cell at the consensus sequence of the total length HA of Indonesia and Chinese isolating H5N1 strain (H5N1IC).Use anti-HA antibody and each phage to select the parallel HA expression (data not shown goes out) of carrying out flow cytometry with the PER.C6 cell of assurance H5N1TV-and H5N1IC-transfection.With 10 * 10 ⁶The PER.C6 cell of individual untransfected is resuspended in the phage library of 0.5ml set and adds in the 0.5ml PER.C6 substratum of 4%ELK, is incubated 1 hour with 5rpm at 4 ℃ in rolling type rotor (end-over-endrotor).To the PER.C6 cell mixture of phage library/untransfected 4 ℃ with 300 * g after centrifugal 5 minutes, the supernatant that contains phage is with 10 * 10 ⁶The PER.C6 cell of untransfected carries out subduing the second time.The phage prepared product and 1 * 10 that to subdue subsequently ⁶The PER.C6 cytomixis of individual expression HA is incubated 2 hours with 5rpm at 4 ℃ in the rolling type rotor.Subsequently cell was rotated 2 minutes at 3000 * g, cell precipitation is resuspended among the 1ml PBS/0.05%Tween-20 with the unconjugated phage of flush away.With cell at 3000 * g centrifugal 2 minutes, repeated washing was 5 times again.After each washing, cell is moved in the new test tube.The bonded phage by with the 100mM TEA of 1ml in the rolling type rotor with 5rpm room temperature insulation 10 minutes and from the antigen wash-out.Cell with 3000 * g rotation 2 minutes, is transferred to the phage of wash-out in the 50ml test tube that contains 0.5ml 1MTris-HCl (pH 7.5).Save and breed as above-mentioned phage wash-out.Carrying out two-wheeled before separating each single chain variable fragment phage antibody selects.After second took turns selection, each intestinal bacteria bacterium colony was used to prepare the mono-clonal phage antibody.Basically make each bacterium colony in 96 hole flat boards, grow to logarithmic phase, and infect, make phage antibody produce afterwards and spend the night with the VCS-M13 helper phage.The supernatant that contains phage antibody is directly used among the ELISA with in conjunction with HA antigen.Perhaps phage antibody is carried out PEG/NaCl-precipitation and filtration sterilization to carry out the fluidic cell quantitative analysis.

Embodiment 3

The affirmation of HA specific single-chain phage antibody

The specificity of the single chain variable fragment phage antibody of the selection that affirmation obtains in above-mentioned screening method in ELISA promptly combines with HA is antigenic.For this reason, with the reorganization HA of baculovirus expression (ProteinSciences, CT, USA) and the sHA of the purifying of H5N1TV and H5NlIC bag by Maxisorp ^TMThe ELISA flat board.To resist-myc mA 9E 10 (Roche) is fixed on Maxisorp ^TMOn the ELISA flat board as negative control antigen.Bag by after flat board contained washing 3 times among the PBS of 0.1%v/v Tween-20 and containing among the PBS of 3%BSA or 2%ELK and sealing 1 hour in room temperature.The single chain variable fragment phage antibody of selecting is incubated 1 hour to obtain the phage antibody of sealing in containing the equal-volume PBS of 4%ELK.Turned letter is dull and stereotyped, with PBS/0.1%Tween-20 washing 3 times, the single chain variable fragment phage antibody that seals is added in the hand-hole.Be incubated 1 hour, dull and stereotyped with the PBS/0.1%Tween-20 washing, use anti--M13 antibody test bonded phage antibody (using OD492nm to measure) with peroxidase conjugated.In contrast, do not use the corresponding program of single chain variable fragment phage antibody and use negative control single chain variable fragment phage antibody simultaneously.Single chain variable fragment phage antibody from 92 uniquenesses the selection that different HA antigens carry out, obtaining to be specific to reorganization HA or sHA with IgM memory B cell library.

Perhaps, use the reactivity of fluidic cell quantitative analysis detection at the single-chain antibody of selecting with the combining of PER.C6 cell of expressing HA.The sedimentary phage of PEG/NaCl is mixed with isopyknic PBS/2%ELK, sealed on ice 30 minutes.The phage of sealing is added (the PER.C6 cell of the PER.C6 cell of untransfected and expression HA) in the sedimentary cell, be incubated 1 hour on ice.Cell is washed 3 times with PBS/1%BSA; centrifugal 1 minute subsequently at 300 * g, use biotinylated anti--M13 antibody (Fitzgerald) and use streptavidin-described single chain variable fragment phage antibody of phycoerythrin conjugate (Caltag) observation to combine subsequently with cell.The selection that the PER.C6 cell of use expression HA carries out provides the single chain variable fragment phage antibody of 24 uniquenesses, does not identify these antibody during using different reorganization HA albumen to select.

Embodiment 4

The evaluation of HA specificity scFv

From specific single-chain phage antibody (scFv) clone who selects, obtain plasmid DNA, according to standard technique definite kernel thuja acid and aminoacid sequence.The nucleotide sequence of described scFv and aminoacid sequence and VH and VL gene homogeny (seeing Tomlinson IM et al.V-BASE Sequence Directoty.Cambridge United Kingdom:MRC Centre for Protein Engineering (1997)) are shown in table 6.The CDR district of described HA specific immunoglobulin is shown in table 7.

Embodiment 5

From the strand Fv that selects, make up complete human normal immunoglobulin molecule (human monoclonal antibodies)

By restriction digestion directly the heavy chain of the described scFv of clone and variable region of light chain with expression among IgG expression vector pIg-C911-HC γ 1 (seeing SEQ ID No:141), pIG-C909-C κ (seeing SEQ ID NO:142) or pIg-C910-C λ (seeing SEQ ID No:143).Confirm the nucleotide sequence of all constructs according to standard technique well known by persons skilled in the art.The gained expression construct of coding human IgG1's heavy chain and light chain is made up transient expression in the 293T cell, use the acquisition of standard purification method and produce the supernatant that contains human IgG1's antibody.With described human IgG1's antibody in 10-0.003 μ g/ml concentration range at H5 titration (data not shown goes out).The SARS-CoV specific antibody is antibody in contrast.The IgG1 molecule illustrates the pattern of reactivity identical with single chain variable fragment phage antibody.

Illustrated in the table 8 Nucleotide of the heavy chain of antibody of following title and light chain and aminoacid sequence with and heavy chain and variable region of light chain: CR6141, CR6255, CR6257, CR6260, CR6261, CR6262, CR6268, CR6272, CR6296, CR6301, CR6307, CR6310, CR6314, CR6323, CR6325, CR6327, CR6328, CR6329, CR6331, CR6332, CR6334, CR6336, CR6339, CR6342, CR6343 and CR6344.Subsequently by the flow cytometry analysis anti--the combining of the PER.C6 cell of HA IgG and expression HA.Analyze antibody and HA bonded flow cytometry show antibody CR6255, CR6257, CR6260, CR6261, CR6262, CR6268, CR6307, CR6310, CR6314, CR6323, CR6325, CR6331 and CR6344 combine expression HA (H5N1TV)-PER.C6 cell (seeing Table 9).Antibody CR6261 and CR6344 also demonstrate with the control cells of untransfected and combine, and still the signal that obtains is than hanging down about 10 times (seeing Table 9) with the signal that combines acquisition of the PER.C6 cell of expressing HA (H5N1TV).Do not observe control antibodies CR3014 and express the cell of HA and combining of untransfected control cells.

Embodiment 6

The H5N1 specific IgG is for the external neutralizing effect (virus neutralization's mensuration) of H5N1 influenza virus

In order to determine whether the IgG that selects can block H5N1 and infect, and carries out external virus neutralization and measures (VNA).(ATCC CCL-34) carries out VNA to mdck cell.Mdck cell is cultivated in mdck cell substratum (the MEM substratum has been added microbiotic, 20mM Hepes and 0.15% (w/v) sodium bicarbonate (MEM substratum fully), adds 10% (v/v) foetal calf serum).With the H5N1 permutatation strain NIBRG-14 dilution of using in this mensuration is 4 * 10 ³TCID50/ml (the every ml of 50% tissue culture infective dose) tires, and calculates according to the method for Spearman and Karber and tires.With IgG prepared product (200 μ g/ml) in bipartite hole in complete MEM substratum 2 times (1: 2-1: 16) of serial dilutions.25 μ l IgG diluent is separately mixed with 25 μ l viral suspensions (100TCID50/25 μ l), 37 ℃ of insulations 1 hour.Then this suspension is moved in duplicate in the complete MEM substratum of 50 μ l of the 96 hole flat boards that contain the MDCK culture that converges.Before using, mdck cell is seeded in the mdck cell substratum, density is 3 * 10 ⁴The every hole of individual cell, growth reach until cell to be converged, and with 300-350 μ l PBS (pH 7.4) washing, and adds the complete MEM substratum of 50 μ l at last in each hole.The cell of inoculation was cultivated 3-4 days at 33 ℃, and a situation arises to observe cytopathic effect (CPE) every day.This CPE and positive control (cell of NIBRG-14-inoculation) and negative control (cell that simulation is inoculated) are compared.Do not exist CPF to be restricted to provide protection in each cell culture fully.Sheep anti-A/Vietnam/1194/04H5N1 influenza virus HA (04/214, NIBSC) in this mensuration, be used as positive control.

In addition, use immunohistochemical method to detect the situation that exists of virus in the culture.For this reason, discard culture supernatant, cell is fixed 15 minutes with 40% (v/v) acetone and 60% (v/v) methyl alcohol.The fixed cell is at the sealing damping fluid (200mMNaCl that adds 2% (w/v) BSA and 5% (v/v) lowlenthal serum, 0.2% (w/v) bovine serum albumin (BSA), 0.01% Thiomersalate, 0.2% (v/v) Tween-20,20mM Tris-HCl, pH 7.45) in 37 ℃ of sealings 30 minutes.Subsequently, cell and the 50 μ l mouse anti influenza virus A monoclonal antibody mixtures (Chemicon) that dilute at 1: 1000 are incubated 1 hour at 37 ℃ in lavation buffer solution.After with lavation buffer solution washing 3 times, be added in the goat anti-mouse IgG (Jackson) of 50 μ l biotin-conjugated of dilution in 1: 1000 in the lavation buffer solution, 37 ℃ of insulations 1 hour.After with lavation buffer solution washing 3 times, be added in the 50 μ l streptavidins-peroxidase conjugated thing (Calbiochem) of dilution in 1: 3000 in the lavation buffer solution, 37 ℃ of insulations 30 minutes.After with lavation buffer solution washing 3 times, use and contain 1 μ l H ₂O ₂The AEC solution of/1ml AEC solution (0.12% (w/v) 3-amino-9-ethyl carbazole, 30% (v/v) N-N-dimethyl formamide and 70% (v/v) acetate buffer) observation dyeing situation.Again with after the lavation buffer solution washing 3 times, in microscopically analysis dyeing situation.

The anti-HA antibody of the people who is called CR6255, CR6257, CR6260, CR6261, CR6262, CR6268, CR6307, CR6310, CR6314, CR6323, CR6325, CR6331 and CR6344 is carried out above-mentioned VNA.All antibody all in and H5N1 permutatation strain NIBRG-14.The concentration (μ g/ml) of these antibody protections MDCK culture antagonism CPE is shown in the table 10.In observing the hole of CPE, confirm exist (data not shown goes out) of virus by Cell immunohistochemical staining method.

Render a service for the neutralization of determining the H5N1 specific IgG more accurately, repeat to measure, but specifically the IgG prepared product is further diluted with the external virus neutralization that NIBRG-14 carries out.With IgG prepared product (200 μ g/ml) in complete MEM substratum 2 times of serial dilutions (1: 1-1: 512), in quadruplicate hole as above-mentioned VNA in detecting.The people who determines following title in VNA is anti--and the neutralization of H5N1 antibody renders a service: CR6255, CR6257, CR6260, CR6261, CR6262, CR6268, CR6272, CR6307, CR6310, CR6314, CR6323, CR6325, CR6327, CR6328, CR6329, CR6331, CR6332, CR6334, CR6336, CR6339, CR6342, CR6343 and CR6344.Except CR6272 and CR6339, all antibody all in and H5N1 permutatation strain NIBRG-14.The concentration (μ g/l is under the condition that has 100TCID50 virus) of these antibody protections MDCK culture antagonism CPE is shown in the table 11.In observing the hole of CPE, confirm exist (data not shown goes out) of virus by Cell immunohistochemical staining method.

Embodiment 7

The immunoblotting assay of H5N1 specific IgG

In order further to study the specificity of anti-HA antibody, different reorganization hemagglutinin influenza virus A antigen is carried out SDS-PAGE under reductive condition, carry out anti-HA immunoblotting assay subsequently.The HA0 polypeptide is made up of HA1 and HA2 subunit.Antibody CR5111, a kind of H5N1-specificity control antibodies, the HA1 subunit of the sHA of identification H5N1TV and complete (uncracked) HA0 polypeptide (seeing Fig. 1, right side, swimming lane 1).In addition, the HA1 subunit of CR5111 identification reorganization HA, the hypotype H5 (A/Vietnam/1203/2004 (H5N1) that described reorganization HA is to use baculovirus vector to produce in insect cell, see SEQ ID NO:110) (Protein Sciences, CT, USA) (Fig. 1, the right side, swimming lane 2).Uncracked HA0 polypeptide does not detect in this HA prepared product.In swimming lane 1 and the swimming lane 2 between the HA subunit size difference can be explained by the different glycosylation effect of the HA that expresses in insect cell and the PER.C6 cell.The CR5111 nonrecognition is HA1 and/or the HA0 polypeptide of the reorganization HA of hypotype H1 (A/New Caledonia/20/99 (H1N1)) (seeing Fig. 1, right side, swimming lane 4) or hypotype H3 (A/Wyoming/3/2003 (H3N2)) (Fig. 1, right side, swimming lane 3).

The sHA (seeing Fig. 1, left side and middle portion, swimming lane 1) of antibody CR6307 and CR6323 identification H5N1TV and reorganization HA (the HA2 subunit of A/Vietnam/1203/2004 (H5N1) (seeing Fig. 1, left side and middle portion, swimming lane 2) of hypotype H5.Interesting ground, when the HA2 subunit is complete when existing, uncracked HA0 polypeptide is not identified.Obviously being become when the HA0 cracking by the epi-position of CR6307 and CR6323 identification can be approaching.In addition, the HA2 subunit of the reorganization HA of antibody CR6307 and CR6323 identification hypotype H1 (A/New Caledonia/20/99 (H1N1)) (is seen Fig. 1, left side and middle portion, swimming lane 4), but the HA2 subunit of the reorganization HA of nonrecognition hypotype H3 (A/Wyoming/3/2003 (H3N2)) (is seen Fig. 1, left side and middle portion, swimming lane 3), these two reorganization HA all in insect cell, use baculovirus vector produce (Protein Sciences, CT, USA).Because the binding site of neutralizing antibody CR6307 and CR6323 is guarded in the influenza virus A strain of hypotype H1 and H5, the molecule that therefore comprises described binding site can be considered to induce the vaccine of extensive cross reactivity resisiting influenza virus antibody response (a part).

After antibody CR6307 and CR6323, the antibody that is called CR6141, CR6296 and CR6301 is used for immunoblotting assay.Each antibody in these three antibody all can be in conjunction with sHA and the hypotype H5 (A/Vietnam/1203/2004 of H5N1TV; H5N1) the HA2 subunit (data not shown goes out) of reorganization HA.

Embodiment 8

Determine the specific facs analysis of subunit of H5N1 specific IgG

In order to assess of the contribution of HA1 subunit for anti--H5N1 antibodies, measure, wherein the HA1 subunit discharges from the PER.C6 cell of expressing HA.The PER.C6 cell of expressing HA is washed 3 times with PBS (pH 7.4), and in acidifying PBS (pH 4.9), be incubated 10 minutes.Subsequently, cell with PBS (pH 7.4) washing, is used in 10 μ g/ml trypsin treatment 10 minutes among the PBS (pH 7.4) so that the HA0 molecule is cracked into HA1 and the HA2 subunit that disulfide linkage connects.At last, cell is among the 20mM DTT among the PBS (pH 7.4) that insulation 20 minutes is to discharge the HA1 subunit from the HA2 subunit of film grappling.The cell that untreated and sour/trypsinase/DTT the handles PBS washed twice that contains 1%w/vBSA.In order to carry out the fluidic cell quantitative analysis, each dyeing uses 2.5 * 10 ⁵Individual cell.Observe with negative control antibody CR3014 and handle and untreated cell dye-free.In conjunction with the HA1 subunit, it makes the PER.C6 cell dyeing of untreated expression HA to antibody CR5111 in immunoblotting assay, and the cell of handling unrecognized (data not shown goes out).This result provides the further evidence of CR5111 identification HA1 subunit.Processing and untreated cell are by antibody CR6307 and CR6323 similarity degree dyeing (data not shown goes out).The release of HA1 subunit does not obviously influence the combination of these antibody, and further confirmation derives from the result of the immunoblotting assay of described antibodies HA2 subunit.Antibody CR6325 and CR6331 be in conjunction with untreated cell, and reduce (data not shown goes out) with comparing with combining obviously of the cell of handling in conjunction with untreated cell.Because conformational change and obviously reducing, described conformational change is to connect the disulfide linkage of HA1 and HA2 subunit and inductive by acid treatment or by reduction to this results suggest antibody for the affinity of its epi-position.

Embodiment 9

Utilize phage antibody and IgG to carry out the hemagglutinin competitive ELISA

In order to differentiate antibody, carry out the hemagglutinin competitive ELISA in conjunction with non-overlapped noncompetitive epi-position.With Nunc-Immuno ^TMMaxisorp F96 flat board is used in 0.5 μ g/ml hypotype H5 among the PBS, and (the reorganization HA of A/Vietnam/1203/2004 (H5N 1) (Protein Sciences) is spent the night at 4 ℃ of bags.Flush away does not wrap the protein of quilt, afterwards the hole is sealed 1 hour in room temperature with the 300 μ l PBS (lock solution) that contain the 2%w/v skim-milk.Discard lock solution, the 10 μ g/ml that are incorporated in 50 μ l in the lock solution in each hole resisted-H5N1IgG, room temperature insulation 1 hour.Be incorporated in 50 μ l phage antibodies in the lock solution subsequently in each hole, concentration is the twice of the concentration that causes 50% maximum combined (determining in formerly measuring), is incubated 1 hour again in room temperature.With the PBS washing hole that contains 0.1%v/v Tween-20 3 times.Use the anti--M13 antibody test bonded phage antibody of peroxidase conjugated.As above-mentioned washing hole once more and by the OPD reagent (Sigma) that the adds 100 μ l ELISA that further develops the color.Reaction is by adding 50 μ l 1M H ₂SO ₄And stop the OD that measures then at 492nm.Exist under the condition of IgG, the combination of phage antibody does not exist the combination under the IgG condition to be set at 100% to represent with the bonded per-cent under the condition that does not have IgG.The phage antibody SC05-111 of epi-position and corresponding IgG CR5111 are with comparing in the HA1 subunit of identification H5 hemagglutinin.

The result shows that most of phage antibodies and IgG are in conjunction with the overlapping epi-position (data not shown goes out) on the reorganization HA of hypotype H5 (A/Vietnam/1203/2004 (H5N1)).The combination of SC05-111 phage antibody is blocked by CR5111IgG, but can't help any other IgG blocking-up, points out other IgG identification the epi-position different with the land of CR5111.5 IgG CR6262, CR6272, CR6307, CR6339 and CR6343 combine (the residue combination more than 25%) with remaining IgG than the competition of low degree ground.For IgG CR6262, CR6272, CR6339 and CR6343, this can be explained by the low affinity for HA.This is promptly more effectively competed by other IgG corresponding to the phage antibody of these antibody by such observed result support.The combination of phage antibody SC06-307 is blocked by IgG CR6307, but other IgG is lower to its influence.This prompting SC06-307 and the epi-position different unique epi-position of CR6307 identification with other IgG identification.

Embodiment 10

Use the cross reactivity ELISA of anti--J5N1 IgG

Whether the epi-position of-H5N1 antibody anti-in order to detect is guarded in the HA except hypotype H5, carries out hemagglutinin cross reactivity ELISA.With Nunc-Immuno ^TMMaxisorp F96 flat board (Nunc) is spent the night at 4 ℃ of bags with following material: the reorganization HA of 0.5 μ g/ml hypotype H1 (A/NewCaledonia/20/99 (H1N1)), hypotype H3 (A/Wyoming/3/03 (H3N2)), hypotype H5 (A/Vietnam/1203/04 (H5N1)), hypotype H7 (A/Netherlands/219/03 (H7N7)) and hypotype H9 (A/Hong Kong/1073/99 (H9N2)) (Protein Sciences Corp.) in PBS.In addition, the viral prepared product of BPL-inactivation that will contain the HA of the A/New Caledonia/20/99 (H1N1) of 0.5 μ g/ml and permutatation strain NIBRG-14 (A/Vietnam/1194/04 (H5N1)) wraps on flat board in PBS and is spent the night.With the PBS washing hole that contains 0.1%v/v Tween-20 3 times to remove the protein that does not wrap quilt, subsequently with the 300 μ l PBS (lock solution) that contain the 2%w/v skim-milk room temperature sealing 1 hour.Discard lock solution, the 5 μ g/ml that every hole is incorporated in 100 μ l in the lock solution resisted-H5N1 antibody, room temperature insulation 1 hour.With the PBS washing hole that contains 0.1%v/v Tween-20 3 times, use the mouse anti human IgG antibody (Jackson) of peroxidase conjugated to detect bonded antibody.Develop the color as described above and measure.Table 12 illustrates all anti--H5N1IgG all in conjunction with the reorganization HA of the viral prepared product of NIBRG-14 of hypotype H5 (A/Vietnam/1203/2004 (H5N1)) and BPL-inactivation, and the latter contains the HA of toxic strain A/Vietnam/1194/2004 (H5N1).The reorganization HA of hypotype H3 and H7 is not by the anti--H5N1IgG identification of any detection.Interesting ground, all anti--H5N1 IgG are all in conjunction with the reorganization HA of the viral prepared product of the strain A/New Caledonia/20/99 (H1N1) of hypotype H1 and H9 and BPL-inactivation except CR5111 and CR6307.This epi-position that shows most of resisting-H5N1 IgG is guarded in the HA of different subtype molecule.

Embodiment 11

The epitope mapping of anti--H5N1 IgG

Okuno et al. (1993) and Smimov et al. (1999) confirm the existence of the total epi-position that the HA of influenza virus A hypotype H1, H2 and H5 shares and at the mouse monoclonal antibody C179 of this epi-position neutralizing effect to these hypotypes.This conformational epitope is made up of two different loci that are arranged in HA1 and HA2 subunit.These two sites are closely adjacent in the middle of the dried district of HA molecule.Whether discern this epi-position in order to assess aforementioned anti-HA antibody, be created in the HA molecule that contains aminoacid replacement in this zone.

Be the zone of the 47-58 residue of the 318-322 position residue that comprises the HA1 subunit and HA2 subunit (amino acid numbering as Okuno et al.1999 as described in) by the epi-position of antibody C179 (Takara Bio Inc.) identification by ownership.The escape virus that contains such HA is no longer by C179 identification and neutralization, and described HA has the replacement of Thr to Lys or in the 52nd replacement with Val to Glu of HA2 subunit the 318th of HA1 subunit.These sudden changes (the 318th Thr to Lys, mutant I; The 52nd Val to Glu, mutant II), the Leu to Met that the HA1 subunit is the 320th replaces (mutant III, Met320 is present in the zone, 318-322 position of HA1 of hypotype H3 and H7), the Ser to Arg that the HA2 subunit is the 54th replaces (mutant IV, Arg54 is present in the zone, 47-58 position of HA2 of hypotype H3 and H7) and the Asp to Asn of the 57th of HA2 subunit replace (mutant V, Asn57 is present in the zone, 47-58 position of HA2 of strain A/Hong Kong/156/97 (H5N1)) import among the total length HA of isolate A/Vietnam/1194/2004 (H5N1TV), and dye at the PER.C6 transit cell.The anti-HA antibody of C179 and people passes through the FACA analysis and evaluation with combining of the PER.C6 cell of expressing these mutant as described above.The anti-H5 sheep serum of the antibody CR5111 of epi-position and polyclone confirms the PER.C6 cell expressing H5N1TV and the HA mutant (data not shown goes out) of transfection in the anti-HA1 subunit.Observe with negative control antibody CR3014 or under the condition that does not have antibody dye-free (data not shown goes out).As desired, antibody C179 nonrecognition mutant I and II, it has the aminoacid replacement (see Okuno et al., 1993) identical with HA in the C179 escape virus.In addition, C179 debond mutant IV, and C179 is unaffected with combining of mutant III and V.Observe similar pattern of reactivity at antibody CR6342, this prompting antibody C179 and the similar epi-position of CR6342 identification.Antibody CR6261, CR6325 and CR6329 identification all mutant except mutant II.The epi-position of this prompting antibody CR6261, CR6325 and CR6329 is different with the epi-position of C179.Because the combination of these antibody is not eliminated in the replacement in the HA1 subunit, so its epi-position is arranged in the HA2 subunit probably.Antibody CR6307 and CR6323 discern all mutant, and also the epi-position with C179 is different to point out the epi-position of these antibody.About the overview of the sequence of mutant and antibodies shown in the table 13.In a word, the result shows that antibody CR6261, CR6325, CR6329, CR6307 and CR6323 are in the combination also and the ideal candidate of influenza virus, and it has sudden change and so is no longer neutralized by this antibody in the epi-position by mouse monoclonal antibody C179 identification.

Embodiment 12

The prophylactic activity that the anti-in vivo H5N1 of causing death of human IgG monoclonal antibody attacks

Give the influenza virus H 5 N 1 strain A/HongKong/156/97 of mouse lethal dose prophylactic effect with research human monoclonal IgG antibody CR6261, CR6323 and CR6325.Be the antibody of every mouse through the peritoneal injection various dose the day before yesterday at 8 treated animals that infect every group of 10 mouse.As negative control, one group of incoherent control antibodies of injected in mice (CR3014).Monitoring clinical symptom, weight loss and mortality ratio are until infecting back 21 days.Carrying out this research is in order to evaluate the anti-H5N1 IgG of described monoclonal human antibody prophylactic effect in vivo.

The H5N1 strain derives from the 3 years old children who suffers from respiratory system disease at first.Should virus on mdck cell, go down to posterity twice.Be used for infecting mouse batch [8.1log TCID tires ₅₀/ ml] in the chicken embryo, breed once.

With 80 female 7 age in week the Balb/c mouse be divided into 8 groups, 10 every group, before attacking, carry out following injection for every mouse with H5N1 virus:

1.15mg/kg CR6261.

2.5mg/kg CR6261.

3.2mg/kg CR6261.

4.0.7mg/kg CR6261.

5.15mg/kg CR6323.

6.15mg/kg CR6325

7.500 μ l rabbit resists-H5N3 immune serum (100 * dilution)

8.15mg/kg CR3014.

All animals are conformed and raised 6 days, begin one's study afterwards.Infecting the day before yesterday with H5N1 virus, giving 500 μ l antibody by peritoneal injection.Used 25LD at the 0th day ₅₀Inoculation animal in virus (about 50 μ l) intranasal, and proceed 21 days.The actual dose of the virus that gives derives from the several same sample of finishing remaining inoculum behind the animal inoculation pvaccination and assessment by titration.The virus titer of inoculum (TCID50/mL) is determined on mdck cell.Be not intended to take place the inactivation of virus during the results are shown in preparation or giving described inoculum.The 8th group as negative control.Injected incoherent monoclonal antibody (CR3014) at the 0th day for this treated animal.The 7th group of supposition is as positive control.Rabbit polyclonal serum antibody for the anti-H5N3 influenza virus generation of this group injected in mice.

Monitored clinical symptom and body weight behind the virus inoculation in the-1 day until the 21st day every day.(0=does not have clinical symptom to clinical symptom with points-scoring system scoring and record; 1=is by hair coarse (rough coat); 2=is coarse by hair, the reactive reduction, and operating period is obedient to; 3=is coarse by hair, rolls, and firmly breathes, and operating period is obedient to; 4=is coarse by hair, rolls, and firmly breathes, and is not retracted into the downward state of stomach when placing down dorsad).The animal of survival was the 21st day euthanasia and get blood.For serum analysis IgG antibody horizontal, collected the blood sample of every mouse at the 0th day.Prepare serum according to standard program.To infect back serum in order producing, from the animal of survival, to collect blood on the 21st day.Serum is stored in-20 ℃ ± 2 ℃ until the existence of analyzing special viral antibody.Use the H5N1 HK/97 substrate of 4HAU to detect serum in duplicate.Tire with the dilution expression reciprocal of the highest serum that HI is shown, begin at 1/10 extent of dilution.

During conforming, all mouse all be enliven and also look like healthy, not shown disease indication.Calculate average clinical score (total clinical score is divided by every group of surviving animals number) every day, the results are shown in Fig. 2 (every group of average clinical score), table 14 (clinical score) and table 15 (respiratory distress).After infection the 3rd day, in group (the 8th group), observe negative clinical symptom and take place with negative control Ab CR3014 inoculation.Respiratory distress is record first at the 6th day, continues 1-4 days.In the mouse (the 6th group) that the CR6325 with 15mg/kg handles, do not observe clinical symptom.In the 5th group (CR6323), mouse illustrated slight clinical symptom (score 1) and in death next day at 5-8 days.In the 1st group, a mouse was death in the 13rd day, but previous not shown any clinical symptom.The Ab dosage of higher CR6261 and later generation clinical symptom and lower average clinical score are relevant.In lowest dose level (0.7mg/kg) group, observe respiratory distress, but in higher dosage (2,5 and 15mg/kg) group, do not observe.All mouse all are illustrated in 9-13 days (the 2nd, 3 and 5 group) or be improved since the 17th day (the 4th group) its clinical condition.Serious disease and death subsequently took place in the mouse (the 7th group) of injection rabbit polyclonal antibody in 3 days, show that rabbit antibody can not bring into play anti-infectious provide protection in vivo.The 10th day to two animal euthanasias (the 4th group only reaches the 8th group) and be not used further to research in the serious disease because this animal is thought suffering from (score 4).

The H5N1 infected animals illustrates weight loss (Fig. 3) in various degree.Proportional weight loss is constantly relevant with antibody dosage with outbreak.In the group with the maximum dose level antibody treatment, As time goes on body weight is stable increases the weight increase unanimity relevant with the age.The animal groups of inoculation lowest dose level CR6261 is than the quicker reduction of animal groups body weight of accepting higher dosage antibody.In than low dose group, the total amount of weight loss is bigger, and mean body weight and inchoate aspect heavy phase are than reducing about 15% and 40% respectively in inoculation 2 and the group of 0.7mg/kg CR6261.In than low dose group, showing mean body weight when animal illustrates some clinical symptom improvement increases.

Fig. 4 illustrates the number of mice of every group of survival every day.There is between administered antibodies amount and the mean survival time dose response relationship clearly.Fig. 5 illustrates the mortality ratio of dose response mode.In lowest dose level group (0.7mg/kg) with accept in the mouse group of negative control antibody CR3014, at inoculation first dead mouse after 7 days.When giving the CR6261 antibody of 0.7mg/kg, be lower than 50% animal and protected and avoid death.Yet when giving the antibody of maximum dose level, 9-10 mouse survival.Nos mouse survival in the negative control group (CR3014) shows that what use in this research is 100% deadly challenge dose really.

Whether can present anti-infectious complete provide protection in order to evaluate IgG antibody, carry out HI and measure, use the serum of collecting from the mouse of the CR6261 (the 1st group) that accepts 15mg/kg at the 21st day to measure.Though these data should show that mouse does not have clinical manifestation, have experienced the H5N1 infection.

These results illustrate the three-type-person at least of discriminating as described herein and exploitation, and anti--H5N1 antibody (CR6261, CR6323 and CR6325) all can provide the provide protection that resists the lethal dose influenza virus H 5 N 1 in vivo independently.Observe the clear dose response relationship between CR6261 antibody amount that gives and mean survival time.The result shows when at the every kind of monoclonal anti that infects the detection give mouse 15mg/kg dosage the day before yesterday-H5N1IgG antibody, the clinical manifestation that described antibody all can prevent H5N1 to infect in mouse.

Embodiment 13

Infect the endogenous protective and the therapeutic action of back administration of human monoclonal anti-H5N1 antibody at the influenza virus H 5 N 1 of lethal dose

After infection, study in the model to detect for example interior therapeutic effect of the deadly H5N1 A/HK/97 influenza viruse attack of CR6261 antagonism of monoclonal antibody as herein described.Described virus is batch used identical with embodiment 12 with type and mouse age.As negative control, one group of incoherent control antibodies of injected in mice (CR2006).Monitoring clinical symptom, weight loss situation and mortality ratio are until infecting the back the 21st day.

With 58 female 7 the week age Balb/c mouse be divided into 5 groups, as described below after infection different steps accept antibody:

1.10 only mouse gave 15mg/kg CR6261 in back 4 hours in infection

2.14 only mouse gave 15mg/kg CR6261 in back 1 day in infection

3.10 only mouse gave 15mg/kg CR6261 in back 2 days in infection

4.10 only mouse gave 15mg/kg CR6261 in back 3 days in infection

5.14 only mouse gave 15mg/kg CR2006 in back 1 day in infection.

All animals are conformed and raised 6 days, begin one's study afterwards.At the 0th day was animal via intranasal vaccination 25LD ₅₀H5N1 influenza virus (about 50 μ l) and monitored 21 days.The several same sample of remaining inoculum after the actual dose of the virus that gives derives from the inoculation animal and finishes by titration and assessment.The virus titer of inoculum (TCID50/mL) is determined on mdck cell.The result shows in preparation or is not intended to take place virally inactivated during giving inoculum.Give 500 μ l antibody at postvaccinal particular point in time by peritoneal injection.The 5th group as negative control.Animal was injected incoherent monoclonal antibody (CR2006) on the 1st day in this group after infection.

Evaluated clinical symptom and body weight until the 21st day every day from the-1 day.Clinical symptom is as scoring as described in the embodiment 12, and the score scope is 0-4.The animal of survival was the 21st day quilt row euthanasia and get blood.In order to evaluate pathological change, after attack, put to death 4 animals of the 2nd group and the 5th group on the 6th day.These animals have carried out preselected at the 0th day, and settle respectively with other animal.For this reason, the 2nd group and the 5th group has 14 animals, 10 animals of residue after selection when beginning.Behind virus inoculation, evaluated clinical symptom and body weight in the-1 day until the 21st day every day.

All animals all are that just looking at of enlivening is healthy during conforming, ned.Calculate average clinical score (total clinical score is divided by every group of surviving animals number) every day, the results are shown in Fig. 6 (every group of average clinical score), table 16 (clinical score) and table 17 (respiratory distress).Obviously, all groups all are included in and infect the mouse that the back illustrated clinical symptom on the 1st day.According to the time that gives antibody, described clinical symptom is eliminated, and or else clinical symptom all exists in the 15th day all group.In control group 5, the 9th day all animals serious clinical symptom and the equal dead or quilt row euthanasia of all animals appear all, because these animals reach clinical score 4.This shows that what give animal is the influenza virus of lethal dose.In the 1st group, animal was accepted antibody in back 4 hours in infection, and clinical symptom does not appear in some animals, and clinical symptom appears in other animal.The number of the animal that the clinical symptom that can mark occurs is provided in the table 16.Because influenza virus can have remarkable effect for respiratory organs, therefore also measure the respiratory distress situation and in table 17, provide.Fig. 7 and table 18 illustrate the surviving animals number and the mortality ratio of all groups respectively.Because unknown cause, accepted in the 1st group of antibody an animal in back 4 hours death in the 10th day in infection.Behind influenza infection, accept all residue animals all survivals and healthy in the animal groups of antibody at the 21st day.This is high-visible the weight data that obtains from all mouse.Fig. 8 is illustrated in the mean body weight of every group of mouse during 21 days of research.Although the body weight of all mouse all reduces when infecting, the weight recovery of mouse is to normal level after giving antibody.Obviously, return to the selection of time that the normal type level depends on Antybody therapy, reach normal level in the rapid rehabilitation of animal of exposure treatment in back 4 hours and at the 7th day; Animal in infection treatment in back 3 days reached its normal type at the 17th day.All animals all reach similar and healthy body weight when research finishes promptly the 21st day.Obviously, the animal of accepting negative control antibody does not recover body weight, then stops measuring death in the 9th day.

These results show after with lethal dose H5N1 influenza viruse attack, and the monoclonal antibody of the anti-H5N1 influenza virus of disclosing with the present invention after infection for example CR6261 is treated and can be saved mammalian object, as this paper as shown in the mouse.Even stage late, infected the level that described antibody still can make clinical symptom fall back and no longer can monitor to clinical symptom back 3 days.It is shocking after infection the 21st day, all animals through Antybody therapy all reach normal type level and not shown any remaining clinical symptom.

Embodiment 14

Use is anti-by cross-protection in the deadly body of attacking of allos influenza virus sub-strain at the monoclonal antibody of the HA of H5N1

The single epi-position in the HA2 structural domain of H5 hemagglutinin is obviously discerned in (embodiment 11) as previously mentioned, antibody more of the present invention.Embodiment 7 illustrate some binding molecule of the present invention can non-conformation mode and the HA2 epi-position interact, as if in other words, the folded form of hemagglutinin does not hinder the neutralization activity and the provide protection of these antibody that the present invention discloses.

That part of sequence of the proteic no antigen drift of influenza virus hemagglutinin known in the art tendency (change of immune determining area in antigenic drift=described proteinic HA1 zone causes the annual influenza virus vaccine that upgrades of needs).Be contained among the aminoacid sequence GVTNKVNSIIDK (SEQ ID NO:368 sees Table 13) by the epi-position among the HA2 of CR6261, CR6325 and CR6329 identification, also be present in the hemagglutinin of H1 and H9 hypotype, see Table 22.Embodiment 10 illustrates the HA of the non-H5 of being limited to of interaction of binding molecule of the present invention and epi-position, also can discern the HA (seeing Table 12) of H1 and H9.Therefore, binding molecule of the present invention is discerned the epi-position in a plurality of HA albumen that are present in different influenza virus serotypes.

In order to study the cross-application that these antibody are used for interior therapeutic, in mouse, experimentize, consistent with the dosage regimen of the experiment of describing among the embodiment 13.In this experiment, give the another kind of influenza virus H1N1 of the high lethal dose of mouse, this virus and popular outburst in 1918, relevant at seasonality infection human body at present.Subsequently, with antibody of the present invention CR6261 treatment mouse for example, clinical symptom, respiratory distress and the body weight of monitoring mouse totally 3 weeks after infection.As mentioned below, these binding molecules can be saved the H5N1 mice infected, also can save the mammalian object that H1N1 infects.

After infection, study in the model to detect for example interior therapeutic effect of the deadly H1N1 A/WSN/33 influenza viruse attack of CR6261 antagonism of monoclonal antibody.This virus batch derives from ATCC (VR-219) and propagation is once in the chicken embryo.Tire and be 8.5log TCID ₅₀/ ml.As negative control, one group of incoherent monoclonal antibody of injected in mice (IgG1, λ are called CR57, the negative control antibody of isotype coupling).Monitoring clinical symptom, weight loss and mortality ratio are until infecting back 21 days.

The Balb/c mouse in 50 female 6-8 ages in week is divided into 5 groups, as described belowly accepts antibody infecting relevant different steps:

1.10 only mouse gave 15mg/kg CR6261 in preceding 1 day in infection

2.10 only mouse gave 15mg/kg CR6261 in back 1 day in infection

3.10 only mouse gave 15mg/kg CR6261 in back 2 days in infection

4.10 only mouse gave 15mg/kg CR6261 in back 3 days in infection

5.10 only mouse gave 15mg/kg negative control CR57 in back 1 day in infection

All animals are conformed and raised at least 4 days, begin one's study afterwards.At the 0th day was lethal dose H1N1 virus (the 6.6log TCID of the about 50 μ l of animal inoculation pvaccination ₅₀25 * LD ₅₀Equivalent) also monitoring.Before inoculation/afterwards fixed time point gives 500 μ l antibody by peritoneal injection.The general health situation of monitoring mouse during studying.Evaluated clinical symptom and body weight until the 21st day every day from the-1 day.Utilize

embodiment

12 and 13 described grading systems that clinical symptom is marked, the score scope is 0-4.The animal of survival was the 21st day quilt row euthanasia and get blood.

Table 19 provides every group mortality ratio, is illustrated in the mouse number of living in each study group during the research.Two mouse dead soon after inoculation (at the 1st day, the 2nd group one, the 3rd group one) get rid of it as specifying in advance in the research project from analyze.All mouse in the control group 5 are all dead at the 9th day, with the research of before having carried out with H5N1 the same (seeing Table 18).This deadly challenge dose H1N1 per-cent of the animal of survival down draws in Fig. 9.The number of the mouse of relevant clinical symptom provides in table 20 shown in every group.Do not observe clinical symptom in the 1st group, and clinical symptom appears in some mouse in the 2nd, 3 and 4 group, these symptoms are completely dissolve in the 14th day after inoculation.All mouse of the 5th group began to occur clinical symptom at the 2nd day.This organizes no mouse rehabilitation.The number of mouse that the respiratory distress symptom of

score

2 or 3 occurs provides in table 21.In the 1-4 group, after the 13rd day, do not observe clinical symptom, and serious respiratory distress all appears in all remaining mouse in the control group 5.

Figure 10 illustrates the mean body weight of mouse in each study group.Obviously, in the 5th group after the 8th day no take off data can provide.From this figure as can be seen, accept anti--H5N1 antibody and all from clinical symptom all mouse of rehabilitation all reached its expection body weight level at the 21st day.

Before or after infecting, give described antibody and can protect these mouse.Obviously, infective dose is quite high: 25 * LD ₅₀Dosage shows when described antibody height in lung and tires when existing, and very strong antiviral provide protection is provided.This is clinical relevant because highly pathogenic virus such as H5N1 copy as after infection that height is tired and the human body of these high viral loads and infection in the frequent serious consequence that occurs relevant.In addition, all protected mouse are along with the time all returns to one's perfect health from this causes death infection.Therefore infer that the of the present invention anti--H5N1 antibody (as CR6261, CR6325 and CR6329) in conjunction with (single) epi-position in the HA2 district that does not have the antigenic drift tendency provides the body that resists multiple influenza virus serotype interior cross-protection, no longer need be at the suddenly change antibody in susceptibility HA1 district of height.The epi-position that should understand among the HA that is not subjected to exist only in H5 influenza virus serotype limits, and binding molecule of the present invention also can be used for preventing or treat all influenza virus serotypes such as the H1N1 that contains identical epi-position in the stable region of HA2 and comprise H2, H6 and the influenza virus of H9 hemagglutinin.

Embodiment 15

Affinity research

Use the surface plasma resonance analysis to carry out affinity research, (Biacore AB Sweden) carries out with 75 μ l/ minute flow velocitys as running buffer to use the BIAcore3000 analytical system to use HBS-EP at 25 ℃ and 37 ℃.Use the amine coupling method with IgG be fixed on research grade CM54-flow channel (Fc) sensor chip (Biacore AB, Sweden) on.The HA of the H5N1 virus (A/Vietnam/1203/2004) of the different amounts of injection is to analyze the binding interactions between described HA albumen and the fixed IgG.Use 20mM NaOH regeneration to remove bonded HA when finishing each the measurement, make residue fixed IgG on the chip simultaneously.

Determine the affinity constant of CR6261, CR6323 and CR6325 antibody.The HA (per injection 100 μ l) of 4 times of dilutions of five kinds of concentration of injection dissociated 3600 seconds subsequently, used 10 μ l 20mMNaOH regeneration.Use 1: 1 (Langmuir) model-fitting gained data.Yet, can not calculate accurate dissociation constant (KD).This is owing to cause in the calculating due to the unacceptable error at 25 ℃ of low-down dissociation rates (even measure with the measuring method of expansion).When 37 ℃ of repeated experiments, the recognizable generation of dissociating, but still be not enough to accurately measure KD.Experimentize to determine the accurate KD of antibody.These are the affinity in single digit nM scope at least according to estimates, are likely the affinity in the pM scope.These experiments illustrate binding molecule of the present invention and have high affinity for its epi-position that exists in the influenza virus HA albumen.

The nucleic acid that this paper is called SEQ ID NO:58-143, SEQ ID NO:212-237 and SEQID NO:316-367 and the detailed description of aminoacid sequence hereinafter are provided.

SEQ ID NO：58

gaggtgcagc tggtggagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaagtc 60

tcttgcaagg cttctggagg ccccttccgc agctatgcta tcagctgggt gcgacaggcc 120

cctggacaag ggcctgagtg gatgggaggg atcatcccta tttttggtac aacaaaatac 180

gcaccgaagt tccagggcag agtcacgatt accgcggacg atttcgcggg cacagtttac 240

atggagctga gcagcctgcg atctgaggac acggccatgt actactgtgc gaaacatatg 300

gggtaccagg tgcgcgaaac tatggacgtc tggggcaaag ggaccacggt caccgtctcg 360

agtgctagca ccaagggccc cagcgtgttc cccctggccc ccagcagcaa gagcaccagc 420

ggcggcacag ccgccctggg ctgcctggtg aaggactact tccccgagcc cgtgaccgtg 480

agctggaaca gcggcgcctt gaccagcggc gtgcacacct tccccgccgt gctgcagagc 540

agcggcctgt acagcctgag cagcgtggtg accgtgccca gcagcagcct gggcacccag 600

acctacatct gcaacgtgaa ccacaagccc agcaacacca aggtggacaa acgcgtggag 660

cccaagagct gcgacaagac ccacacctgc cccccctgcc ctgcccccga gctgctgggc 720

ggaccctccg tgttcctgtt cccccccaag cccaaggaca ccctcatgat cagccggacc 780

cccgaggtga cctgcgtggt ggtggacgtg agccacgagg accccgaggt gaagttcaac 840

tggtacgtgg acggcgtgga ggtgcacaac gccaagacca agccccggga ggagcagtac 900

aacagcacct accgggtggt gagcgtgctc accgtgctgc accaggactg gctgaacggc 960

aaggagtaca agtgcaaggt gagcaacaag gccctgcctg cccccatcga gaagaccatc 1020

agcaaggcca agggccagcc ccgggagccc caggtgtaca ccctgccccc cagccgggag 1080

gagatgacca agaaccaggt gtccctcacc tgtctggtga agggcttcta ccccagcgac 1140

atcgccgtgg agtgggagag caacggccag cccgagaaca actacaagac caccccccct 1200

gtgctggaca gcgacggcag cttcttcctg tacagcaagc tcaccgtgga caagagccgg 1260

tggcagcagg gcaacgtgtt cagctgcagc gtgatgcacg aggccctgca caaccactac 1320

acccagaaga gcctgagcct gagccccggc aag 1353

SEQ ID NO：59

E V Q L V E S G A E V K K P G S S V K V S C K A S G G P F R S Y A I S W V R Q

A P G Q G P E W M G G I I P I F G T T K Y A P K F Q G R V T I T A D D F A G T

V Y M E L S S L R S E D T A M Y Y C A K H M G Y Q V R E T M D V W G K G T T V

T V S S A S T K G P S V F P L A P S S K S T S G G T A A L G C L V K D Y F P E

P V T V S W N S G A L T S G V H T F P A V L Q S S G L Y S L S S V V T V P S S

S L G T Q T Y I C N V N H K P S N T K V D K R V E P K S C D K T H T C P P C P

A P E L L G G P S V F L F P P K P K D T L M I S R T P E V T C V V V D V S H E

D P E V K F N W Y V D G V E V H N A K T K P R E E Q Y N S T Y

R V V S V L T V L H Q D W L N G K E Y K C K V S N K A L P A P I E K T I S K A

K G Q P R E P Q V Y T L P P S R E E M T K N Q V S L T C L V K G F Y P S D I A

V E W E S N G Q P E N N Y K T T P P V L D S D G S F F L Y S K L T V D K S R W

Q Q G N V F S C S V M H E A L H N H Y T Q K S L S L S P G K

SEQ ID NO：60

caggtccagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaagtc 60

tcttgcaagg cttctggagg ccccttccgc agctatgcta tcagctgggt gcgacaggcc 120

cctggacaag ggcctgagtg gatgggaggg atcatcccta tttttggtac aacaaaatac 180

gcaccgaagt tccagggcag agtcacgatt accgcggacg atttcgcggg cacagtttac 240

atggagctga gcagcctgcg atctgaggac acggccatgt actactgtgc gaaacatatg 300

gggtaccagg tgcgcgaaac tatggacgtc tggggcaaag ggaccacggt caccgtctcg 360

agtgctagca ccaagggccc cagcgtgttc cccctggccc ccagcagcaa gagcaccagc 420

ggcggcacag ccgccctggg ctgcctggtg aaggactact tccccgagcc cgtgaccgtg 480

agctggaaca gcggcgcctt gaccagcggc gtgcacacct tccccgccgt gctgcagagc 540

agcggcctgt acagcctgag cagcgtggtg accgtgccca gcagcagcct gggcacccag 600

acctacatct gcaacgtgaa ccacaagccc agcaacacca aggtggacaa acgcgtggag 660

cccaagagct gcgacaagac ccacacctgc cccccctgcc ctgcccccga gctgctgggc 720

ggaccctccg tgttcctgtt cccccccaag cccaaggaca ccctcatgat cagccggacc 780

cccgaggtga cctgcgtggt ggtggacgtg agccacgagg accccgaggt gaagttcaac 840

tggtacgtgg acggcgtgga ggtgcacaac gccaagacca agccccggga ggagcagtac 900

aacagcacct accgggtggt gagcgtgctc accgtgctgc accaggactg gctgaacggc 960

aaggagtaca agtgcaaggt gagcaacaag gccctgcctg cccccatcga gaagaccatc 1020

agcaaggcca agggccagcc ccgggagccc caggtgtaca ccctgccccc cagccgggag 1080

gagatgacca agaaccaggt gtccctcacc tgtctggtga agggcttcta ccccagcgac 1140

atcgccgtgg agtgggagag caacggccag cccgagaaca actacaagac caccccccct 1200

gtgctggaca gcgacggcag cttcttcctg tacagcaagc tcaccgtgga caagagccgg 1260

tggcagcagg gcaacgtgtt cagctgcagc gtgatgcacg aggccctgca caaccactac 1320

acccagaaga gcctgagcct gagccccggc aag 1353

SEQ ID NO：61

Q V Q L V Q S G A E V K K P G S S V K V S C K A S G G P F R S Y A I S W V R Q

A P G Q G P E W M G G I I P I F G T T K Y A P K F Q G R V T I T A D D F A G T

V Y M E L S S L R S E D T A M Y Y C A K H M G Y Q V R E T M D V W G K G T T V

T V S S A S T K G P S V F P L A P S S K S T S G G T A A L G C L V K D Y F P E

P V T V S W N S G A L T S G V H T F P A V L Q S S G L Y S L S S V V T V P S S

S L G T Q T Y I C N V N H K P S N T K V D K R V E P K S C D K T H T C P P C P

A P E L L G G P S V F L F P P K P K D T L M I S R T P E V T C V V V D V S H E

D P E V K F N W Y V D G V E V H N A K T K P R E E Q Y N S T Y R V V S V L T V

L H Q D W L N G K E Y K C K V S N K A L P A P I E K T I S K A K G Q P R E P Q

V Y T L P P S R E E M T K N Q V S L T C L V K G F Y P S D I A V E W E S N G Q

P E N N Y K T T P P V L D S D G S F F L Y S K L T V D K S R W Q Q G N V F S C

S V M H E A L H N H Y T Q K S L S L S P G K

SEQ ID NO：62

gaggtgcagc tggtggagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaagtc 60

tcttgcaagg cttctggagg ccccttccgc agctatgcta tcagctgggt gcgacaggcc 120

cctggacaag ggcctgagtg gatgggaggg atcatcccta tttttggtac aacaaaatac 180

gcaccgaagt tccagggcag agtcacgatt accgcggacg atttcgcggg cacagtttac 240

atggagctga gcagcctgcg atctgaggac acggccatgt actactgtgc gaaacatatg 300

gggtaccagg tgcgcgaaac tatggacgtc tggggcaaag ggaccacggt caccgtctcg 360

agtgctagca ccaagggccc cagcgtgttc cccctggccc ccagcagcaa gagcaccagc 420

ggcggcacag ccgccctggg ctgcctggtg aaggactact tccccgagcc cgtgaccgtg 480

agctggaaca gcggcgcctt gaccagcggc gtgcacacct tccccgccgt gctgcagagc 540

agcggcctgt acagcctgag cagcgtggtg accgtgccca gcagcagcct gggcacccag 600

acctacatct gcaacgtgaa ccacaagccc agcaacacca aggtggacaa acgcgtggag 660

cccaagagct gcgacaagac ccacacctgc cccccctgcc ctgcccccga gctgctgggc 720

ggaccctccg tgttcctgtt cccccccaag cccaaggaca ccctcatgat cagccggacc 780

cccgaggtga cctgcgtggt ggtggacgtg agccacgagg accccgaggt gaagttcaac 840

tggtacgtgg acggcgtgga ggtgcacaac gccaagacca agccccggga ggagcagtac 900

aacagcacct accgggtggt gagcgtgctc accgtgctgc accaggactg gctgaacggc 960

aaggagtaca agtgcaaggt gagcaacaag gccctgcctg cccccatcga gaagaccatc 1020

agcaaggcca agggccagcc ccgggagccc caggtgtaca ccctgccccc cagccgggag 1080

gagatgacca agaaccaggt gtccctcacc tgtctggtga agggcttcta ccccagcgac 1140

atcgccgtgg agtgggagag caacggccag cccgagaaca actacaagac caccccccct 1200

gtgctggaca gcgacggcag cttcttcctg tacagcaagc tcaccgtgga caagagccgg 1260

tggcagcagg gcaacgtgtt cagctgcagc gtgatgcacg aggccctgca caaccactac 1320

acccagaaga gcctgagcct gagccccggc aag 1353

SEQ ID NO：63

E V Q L V E S G A E V K K P G S S V K V S C K A S G G P F R S Y A I S W V R Q

A P G Q G P E W M G G I I P I F G T T K Y A P K F Q G R V T I T A D D F A G T

V Y M E L S S L R S E D T A M Y Y C A K H M G Y Q V R E T M D V W G K G T T V

T V S S A S T K G P S V F P L A P S S K S T S G G T A A L G C L V K D Y F P E

P V T V S W N S G A L T S G V H T F P A V L Q S S G L Y S L S S V V T V P S S

S L G T Q T Y I C N V N H K P S N T K V D K R V E P K S C D K T H T C P P C P

A P E L L G G P S V F L F P P K P K D T L M I S R T P E V T C V V V D V S H E

D P E V K F N W Y V D G V E V H N A K T K P R E E Q Y N S T Y R V V S V L T V

L H Q D W L N G K E Y K C K V S N K A L P A P I E K T I S K A K G Q P R E P Q

V Y T L P P S R E E M T K N Q V S L T C L V K G F Y P S D I A V E W E S N G Q

P E N N Y K T T P P V L D S D G S F F L Y S K L T V D K S R W Q Q G N V F S C

S V M H E A L H N H Y T Q K S L S L S P G K

SEQ ID NO：64

gaggtgcagc tggtggagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaagtc 60

tcttgcaagg cttctggagg ccccttccgc agctatgcta tcagctgggt gcgacaggcc 120

cctggacaag ggcctgagtg gatgggaggg atcatcccta tttttggtac aacaaaatac 180

gcaccgaagt tccagggcag agtcacgatt accgcggacg atttcgcggg cacagtttac 240

atggagctga gcagcctgcg atctgaggac acggccatgt actactgtgc gaaacatatg 300

gggtaccagg tgcgcgaaac tatggacgtc tggggcaaag ggaccacggt caccgtctcg 360

agtgctagca ccaagggccc cagcgtgttc cccctggccc ccagcagcaa gagcaccagc 420

ggcggcacag ccgccctggg ctgcctggtg aaggactact tccccgagcc cgtgaccgtg 480

agctggaaca gcggcgcctt gaccagcggc gtgcacacct tccccgccgt gctgcagagc 540

agcggcctgt acagcctgag cagcgtggtg accgtgccca gcagcagcct gggcacccag 600

acctacatct gcaacgtgaa ccacaagccc agcaacacca aggtggacaa acgcgtggag 660

cccaagagct gcgacaagac ccacacctgc cccccctgcc ctgcccccga gctgctgggc 720

ggaccctccg tgttcctgtt cccccccaag cccaaggaca ccctcatgat cagccggacc 780

cccgaggtga cctgcgtggt ggtggacgtg agccacgagg accccgaggt gaagttcaac 840

tggtacgtgg acggcgtgga ggtgcacaac gccaagacca agccccggga ggagcagtac 900

aacagcacct accgggtggt gagcgtgctc accgtgctgc accaggactg gctgaacggc 960

aaggagtaca agtgcaaggt gagcaacaag gccctgcctg cccccatcga gaagaccatc 1020

agcaaggcca agggccagcc ccgggagccc caggtgtaca ccctgccccc cagccgggag 1080

gagatgacca agaaccaggt gtccctcacc tgtctggtga agggcttcta ccccagcgac 1140

atcgccgtgg agtgggagag caacggccag cccgagaaca actacaagac caccccccct 1200

gtgctggaca gcgacggcag cttcttcctg tacagcaagc tcaccgtgga caagagccgg 1260

tggcagcagg gcaacgtgtt cagctgcagc gtgatgcacg aggccctgca caaccactac 1320

acccagaaga gcctgagcct gagccccggc aag 1353

SEQ ID NO：65

E V Q L V E S G A E V K K P G S S V K V S C K A S G G P F R S Y A I S W V R Q

A P G Q G P E W M G G I I P I F G T T K Y A P K F Q G R V T I T A D D F A G T

V Y M E L S S L R S E D T A M Y Y C A K H M G Y Q V R E T M D V W G K G T T V

T V S S A S T K G P S V F P L A P S S K S T S G G T A A L G C L V K D Y F P E

P V T V S W N S G A L T S G V H T F P A V L Q S S G L Y S L S S V V T V P S S

S L G T Q T Y I C N V N H K P S N T K V D K R V E P K S C D K T H T C P P C P

A P E L L G G P S V F L F P P K P K D T L M I S R T P E V T C V V V D V S H E

D P E V K F N W Y V D G V E V H N A K T K P R E E Q Y N S T Y R V V S V L T V

L H Q D W L N G K E Y K C K V S N K A L P A P I E K T I S K A K G Q P R E P Q

V Y T L P P S R E E M T K N Q V S L T C L V K G F Y P S D I A V E W E S N G Q

P E N N Y K T T P P V L D S D G S F F L Y S K L T V D K S R W Q Q G N V F S C

S V M H E A L H N H Y T Q K S L S L S P G K

SEQ ID NO：66

caggtacagc tgcagcagtc aggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60

tcctgcaagg tttccggagt cattttcagc ggcagtgcga tcagctgggt gcgacaggcc 120

cctggacaag gccttgagtg gatgggaggg atcagccctc tctttggcac aacaaattac 180

gcacaaaagt tccagggcag agtcacgatt accgcggacc aatccacgaa cacaacctac 240

atggaggtga acagcctgag atatgaggac acggccgtgt atttctgtgc gcgaggtcca 300

aaatattaca gtgagtacat ggacgtctgg ggcaaaggga ccacggtcac cgtctcgagt 360

gctagcacca agggccccag cgtgttcccc ctggccccca gcagcaagag caccagcggc 420

ggcacagccg ccctgggctg cctggtgaag gactacttcc ccgagcccgt gaccgtgagc 480

tggaacagcg gcgccttgac cagcggcgtg cacaccttcc ccgccgtgct gcagagcagc 540

ggcctgtaca gcctgagcag cgtggtgacc gtgcccagca gcagcctggg cacccagacc 600

tacatctgca acgtgaacca caagcccagc aacaccaagg tggacaaacg cgtggagccc 660

aagagctgcg acaagaccca cacctgcccc ccctgccctg cccccgagct gctgggcgga 720

ccctccgtgt tcctgttccc ccccaagccc aaggacaccc tcatgatcag ccggaccccc 780

gaggtgacct gcgtggtggt ggacgtgagc cacgaggacc ccgaggtgaa gttcaactgg 840

tacgtggacg gcgtggaggt gcacaacgcc aagaccaagc cccgggagga gcagtacaac 900

agcacctacc gggtggtgag cgtgctcacc gtgctgcacc aggactggct gaacggcaag 960

gagtacaagt gcaaggtgag caacaaggcc ctgcctgccc ccatcgagaa gaccatcagc 1020

aaggccaagg gccagccccg ggagccccag gtgtacaccc tgccccccag ccgggaggag 1080

atgaccaaga accaggtgtc cctcacctgt ctggtgaagg gcttctaccc cagcgacatc 1140

gccgtggagt gggagagcaa cggccagccc gagaacaact acaagaccac cccccctgtg 1200

ctggacagcg acggcagctt cttcctgtac agcaagctca ccgtggacaa gagccggtgg 1260

cagcagggca acgtgttcag ctgcagcgtg atgcacgagg ccctgcacaa ccactacacc 1320

cagaagagcc tgagcctgag ccccggcaag 1350

SEQ ID NO：67

Q V Q L Q Q S G A E V K K P G S S V K V S C K V S G V I F S G S A I S W V R Q

A P G Q G L E W M G G I S P L F G T T N Y A Q K F Q G R V T I T A D Q S T N T

T Y M E V N S L R Y E D T A V Y F C A R G P K Y Y S E Y M D V W G K G T T V T

V S S A S T K G P S V F P L A P S S K S T S G G T A A L G C L V K D Y F P E P

V T V S W N S G A L T S G V H T F P A V L Q S S G L Y S L S S V V T V P S S S

L G T Q T Y I C N V N H K P S N T K V D K R V E P K S C D K T H T C P P C P A

P E L L G G P S V F L F P P K P K D T L M I S R T P E V T C V V V D V S H E D

P E V K F N W Y V D G V E V H N A K T K P R E E Q Y N S T Y R V V S V L T V L

H Q D W L N G K E Y K C K V S N K A L P A P I E K T I S K A K G Q P R E P Q V

Y T L P P S R E E M T K N Q V S L T C L V K G F Y P S D I A V E W E S N G Q P

E N N Y K T T P P V L D S D G S F F L Y S K L T V D K S R W Q Q G N V F S C S

V M H E A L H N H Y T Q K S L S L S P G K

SEQ ID NO：68

caggtccagc tggtacagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60

tcctgcaagg cttctggagg caccttcagt agttatgcta tcagctgggt gcgacaggcc 120

cctggacaag ggcttgagtg gatgggagga atcatgggta tgtttggcac aactaactac 180

gcacagaagt tccagggcag agtcacgatt accgcggacg aattcacgag cgcagcctac 240

atggagctga ggagcctgag atctgaggac acggccgtct actactgtgc gaggtctagt 300

ggttattacc ccgaatactt ccaggactgg ggccagggca ccctggtcac cgtctcgagt 360

gctagcacca agggccccag cgtgttcccc ctggccccca gcagcaagag caccagcggc 420

ggcacagccg ccctgggctg cctggtgaag gactacttcc ccgagcccgt gaccgtgagc 480

tggaacagcg gcgccttgac cagcggcgtg cacaccttcc ccgccgtgct gcagagcagc 540

ggcctgtaca gcctgagcag cgtggtgacc gtgcccagca gcagcctggg cacccagacc 600

tacatctgca acgtgaacca caagcccagc aacaccaagg tggacaaacg cgtggagccc 660

aagagctgcg acaagaccca cacctgcccc ccctgccctg cccccgagct gctgggcgga 720

ccctccgtgt tcctgttccc ccccaagccc aaggacaccc tcatgatcag ccggaccccc 780

gaggtgacct gcgtggtggt ggacgtgagc cacgaggacc ccgaggtgaa gttcaactgg 840

tacgtggacg gcgtggaggt gcacaacgcc aagaccaagc cccgggagga gcagtacaac 900

agcacctacc gggtggtgag cgtgctcacc gtgctgcacc aggactggct gaacggcaag 960

gagtacaagt gcaaggtgag caacaaggcc ctgcctgccc ccatcgagaa gaccatcagc 1020

aaggccaagg gccagccccg ggagccccag gtgtacaccc tgccccccag ccgggaggag 1080

atgaccaaga accaggtgtc cctcacctgt ctggtgaagg gcttctaccc cagcgacatc 1140

gccgtggagt gggagagcaa cggccagccc gagaacaact acaagaccac cccccctgtg 1200

ctggacagcg acggcagctt cttcctgtac agcaagctca ccgtggacaa gagccggtgg 1260

cagcagggca acgtgttcag ctgcagcgtg atgcacgagg ccctgcacaa ccactacacc 1320

cagaagagcc tgagcctgag ccccggcaag 1350

SEQ ID NO：69

Q V Q L V Q S G A E V K K P G S S V K V S C K A S G G T F S S Y A I S W V R Q

A P G Q G L E W M G G I M G M F G T T N Y A Q K F Q G R V T I T A D E F T S A

A Y M E L R S L R S E D T A V Y Y C A R S S G Y Y P E Y F Q D W G Q G T L V T

V S S A S T K G P S V F P L A P S S K S T S G G T A A L G C L V K D Y F P E P

V T V S W N S G A L T S G V H T F P A V L Q S S G L Y S L S S V V T V P S S S

L G T Q T Y I C N V N H K P S N T K V D K R V E P K S C D K T H T C P P C P A

P E L L G G P S V F L F P P K P K D T L M I S R T P E V T C V V V D V S H E D

P E V K F N W Y V D G V E V H N A K T K P R E E Q Y N S T Y R V V S V L T V L

H Q D W L N G K E Y K C K V S N K A L P A P I E K T I S K A K G Q P R E P Q V

Y T L P P S R E E M T K N Q V S L T C L V K G F Y P S D I A V E W E S N G Q P

E N N Y K T T P P V L D S D G S F F L Y S K L T V D K S R W Q Q G N V F S C S

V M H E A L H N H Y T Q K S L S L S P G K

SEQ ID NO：70

caggtccagc tggtgcagtc tgggggaggc ctggtcaagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt caccttcagt agctatagca tgaactgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcatcc attagtagta gtagtagtta catatactac 180

gtagactcag tgaagggccg attcaccatc tccagagaca acgccaagaa ctcactgtat 240

ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagaggtggt 300

gggagctacg gggcctacga aggctttgac tactggggcc agggcaccct ggtcaccgtc 360

tcgagtgcta gcaccaaggg ccccagcgtg ttccccctgg cccccagcag caagagcacc 420

agcggcggca cagccgccct gggctgcctg gtgaaggact acttccccga gcccgtgacc 480

gtgagctgga acagcggcgc cttgaccagc ggcgtgcaca ccttccccgc cgtgctgcag 540

agcagcggcc tgtacagcct gagcagcgtg gtgaccgtgc ccagcagcag cctgggcacc 600

cagacctaca tctgcaacgt gaaccacaag cccagcaaca ccaaggtgga caaacgcgtg 660

gagcccaaga gctgcgacaa gacccacacc tgccccccct gccctgcccc cgagctgctg 720

ggcggaccct ccgtgttcct gttccccccc aagcccaagg acaccctcat gatcagccgg 780

acccccgagg tgacctgcgt ggtggtggac gtgagccacg aggaccccga ggtgaagttc 840

aactggtacg tggacggcgt ggaggtgcac aacgccaaga ccaagccccg ggaggagcag 900

tacaacagca cctaccgggt ggtgagcgtg ctcaccgtgc tgcaccagga ctggctgaac 960

ggcaaggagt acaagtgcaa ggtgagcaac aaggccctgc ctgcccccat cgagaagacc 1020

atcagcaagg ccaagggcca gccccgggag ccccaggtgt acaccctgcc ccccagccgg 1080

gaggagatga ccaagaacca ggtgtccctc acctgtctgg tgaagggctt ctaccccagc 1140

gacatcgccg tggagtggga gagcaacggc cagcccgaga acaactacaa gaccaccccc 1200

cctgtgctgg acagcgacgg cagcttcttc ctgtacagca agctcaccgt ggacaagagc 1260

cggtggcagc agggcaacgt gttcagctgc agcgtgatgc acgaggccct gcacaaccac 1320

tacacccaga agagcctgag cctgagcccc ggcaag 1356

SEQ ID NO：71

Q V Q L V Q S G G G L V K P G G S L R L S C A A S G F T F S S Y S M N W V R Q

A P G K G L E W V S S I S S S S S Y I Y Y V D S V K G R F T I S R D N A K N S

L Y L Q M N S L R A E D T A V Y Y C A R G G G S Y G A Y E G F D Y W G Q G T L

V T V S S A S T K G P S V F P L A P S S K S T S G G T A A L G C L V K D Y F P

E P V T V S W N S G A L T S G V H T F P A V L Q S S G L Y S L S S V V T V P S

S S L G T Q T Y I C N V N H K P S N T K V D K R V E P K S C D K T H T C P P C

P A P E L L G G P S V F L F P P K P K D T L M I S R T P E V T C V V V D V S H

E D P E V K F N W Y V D G V E V H N A K T K P R E E Q Y N S T Y R V V S V L T

V L H Q D W L N G K E Y K C K V S N K A L P A P I E K T I S K A K G Q P R E P

Q V Y T L P P S R E E M T K N Q V S L T C L V K G F Y P S D I A V E W E S N G

Q P E N N Y K T T P P V L D S D G S F F L Y S K L T V D K S R W Q Q G N V F S

C S V M H E A L H N H Y T Q K S L S L S P G K

SEQ ID NO：72

gaggtgcagc tggtggagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaagtc 60

tcttgcaagg cttctggagg ccccttccgc agctatgcta tcagctgggt gcgacaggcc 120

cctggacaag ggcctgagtg gatgggaggg atcatcccta tttttggtac aacaaaatac 180

gcaccgaagt tccagggcag agtcacgatt accgcggacg atttcgcggg cacagtttac 240

atggagctga gcagcctgcg atctgaggac acggccatgt actactgtgc gaaacatatg 300

gggtaccagg tgcgcgaaac tatggacgtc tggggcaaag ggaccacggt caccgtctcg 360

agtgctagca ccaagggccc cagcgtgttc cccctggccc ccagcagcaa gagcaccagc 420

ggcggcacag ccgccctggg ctgcctggtg aaggactact tccccgagcc cgtgaccgtg 480

agctggaaca gcggcgcctt gaccagcggc gtgcacacct tccccgccgt gctgcagagc 540

agcggcctgt acagcctgag cagcgtggtg accgtgccca gcagcagcct gggcacccag 600

acctacatct gcaacgtgaa ccacaagccc agcaacacca aggtggacaa acgcgtggag 660

cccaagagct gcgacaagac ccacacctgc cccccctgcc ctgcccccga gctgctgggc 720

ggaccctccg tgttcctgtt cccccccaag cccaaggaca ccctcatgat cagccggacc 780

cccgaggtga cctgcgtggt ggtggacgtg agccacgagg accccgaggt gaagttcaac 840

tggtacgtgg acggcgtgga ggtgcacaac gccaagacca agccccggga ggagcagtac 900

aacagcacct accgggtggt gagcgtgctc accgtgctgc accaggactg gctgaacggc 960

aaggagtaca agtgcaaggt gagcaacaag gccctgcctg cccccatcga gaagaccatc 1020

agcaaggcca agggccagcc ccgggagccc caggtgtaca ccctgccccc cagccgggag 1080

gagatgacca agaaccaggt gtccctcacc tgtctggtga agggcttcta ccccagcgac 1140

atcgccgtgg agtgggagag caacggccag cccgagaaca actacaagac caccccccct 1200

gtgctggaca gcgacggcag cttcttcctg tacagcaagc tcaccgtgga caagagccgg 1260

tggcagcagg gcaacgtgtt cagctgcagc gtgatgcacg aggccctgca caaccactac 1320

acccagaaga gcctgagcct gagccccggc aag 1353

SEQ ID NO：73

E V Q L V E S G A E V K K P G S S V K V S C K A S G G P F R S Y A I S W V R Q

A P G Q G P E W M G G I I P I F G T T K Y A P K F Q G R V T I T A D D F A G T

V Y M E L S S L R S E D T A M Y Y C A K H M G Y Q V R E T M D V W G K G T T V

T V S S A S T K G P S V F P L A P S S K S T S G G T A A L G C L V K D Y F P E

P V T V S W N S G A L T S G V H T F P A V L Q S S G L Y S L S S V V T V P S S

S L G T Q T Y I C N V N H K P S N T K V D K R V E P K S C D K T H T C P P C P

A P E L L G G P S V F L F P P K P K D T L M I S R T P E V T C V V V D V S H E

D P E V K F N W Y V D G V E V H N A K T K P R E E Q Y N S T Y R V V S V L T V

L H Q D W L N G K E Y K C K V S N K A L P A P I E K T I S K A K G Q P R E P Q

V Y T L P P S R E E M T K N Q V S L T C L V K G F Y P S D I A V E W E S N G Q

P E N N Y K T T P P V L D S D G S F F L Y S K L T V D K S R W Q Q G N V F S C

S V M H E A L H N H Y T Q K S L S L S P G K

SEQ ID NO：74

gaggtgcagc tggtggagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaagtc 60

tcttgcaagg cttctggagg ccccttccgc agctatgcta tcagctgggt gcgacaggcc 120

cctggacaag ggcctgagtg gatgggaggg atcatcccta tttttggtac aacaaaatac 180

gcaccgaagt tccagggcag agtcacgatt accgcggacg atttcgcggg cacagtttac 240

atggagctga gcagcctgcg atctgaggac acggccatgt actactgtgc gaaacatatg 300

gggtaccagg tgcgcgaaac tatggacgtc tggggcaaag ggaccacggt caccgtctcg 360

agtgctagca ccaagggccc cagcgtgttc cccctggccc ccagcagcaa gagcaccagc 420

ggcggcacag ccgccctggg ctgcctggtg aaggactact tccccgagcc cgtgaccgtg 480

agctggaaca gcggcgcctt gaccagcggc gtgcacacct tccccgccgt gctgcagagc 540

agcggcctgt acagcctgag cagcgtggtg accgtgccca gcagcagcct gggcacccag 600

acctacatct gcaacgtgaa ccacaagccc agcaacacca aggtggacaa acgcgtggag 660

cccaagagct gcgacaagac ccacacctgc cccccctgcc ctgcccccga gctgctgggc 720

ggaccctccg tgttcctgtt cccccccaag cccaaggaca ccctcatgat cagccggacc 780

cccgaggtga cctgcgtggt ggtggacgtg agccacgagg accccgaggt gaagttcaac 840

tggtacgtgg acggcgtgga ggtgcacaac gccaagacca agccccggga ggagcagtac 900

aacagcacct accgggtggt gagcgtgctc accgtgctgc accaggactg gctgaacggc 960

aaggagtaca agtgcaaggt gagcaacaag gccctgcctg cccccatcga gaagaccatc 1020

agcaaggcca agggccagcc ccgggagccc caggtgtaca ccctgccccc cagccgggag 1080

gagatgacca agaaccaggt gtccctcacc tgtctggtga agggcttcta ccccagcgac 1140

atcgccgtgg agtgggagag caacggccag cccgagaaca actacaagac caccccccct 1200

gtgctggaca gcgacggcag cttcttcctg tacagcaagc tcaccgtgga caagagccgg 1260

tggcagcagg gcaacgtgtt cagctgcagc gtgatgcacg aggccctgca caaccactac 1320

acccagaaga gcctgagcct gagccccggc aag 1353

SEQ ID NO：75

E V Q L V E S G A E V K K P G S S V K V S C K A S G G P F R S Y A I S W V R Q

A P G Q G P E W M G G I I P I F G T T K Y A P K F Q G R V T I T A D D F A G T

V Y M E L S S L R S E D T A M Y Y C A K H M G Y Q V R E T M D V W G K G T T V

T V S S A S T K G P S V F P L A P S S K S T S G G T A A L G C L V K D Y F P E

P V T V S W N S G A L T S G V H T F P A V L Q S S G L Y S L S S V V T V P S S

S L G T Q T Y I C N V N H K P S N T K V D K R V E P K S C D K T H T C P P C P

A P E L L G G P S V F L F P P K P K D T L M I S R T P E V T C V V V D V S H E

D P E V K F N W Y V D G V E V H N A K T K P R E E Q Y N S T Y R V V S V L T V

L H Q D W L N G K E Y K C K V S N K A L P A P I E K T I S K A K G Q P R E P Q

V Y T L P P S R E E M T K N Q V S L T C L V K G F Y P S D I A V E W E S N G Q

P E N N Y K T T P P V L D S D G S F F L Y S K L T V D K S R W Q Q G N V F S C

S V M H E A L H N H Y T Q K S L S L S P G K

SEQ ID NO：76

gaggtgcagc tggtggagtc tggggctgag gtgaagaagc cagggtcctc ggtgaaggtc 60

tcctgtaagg cctctggagg caccttctcc agctatggta tcagctgggt gcgacaggcc 120

cctggacaag ggcttgagtg gatgggagac atcatcggta tgtttggttc aacaaactac 180

gcacagaact tccagggcag actcacgatt accgcggacg aatccacgag cacagcctac 240

atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagaagtagt 300

ggttattacc ctgcatacct cccccactgg ggccagggca ccttggtcac cgtctcgagt 360

gctagcacca agggccccag cgtgttcccc ctggccccca gcagcaagag caccagcggc 420

ggcacagccg ccctgggctg cctggtgaag gactacttcc ccgagcccgt gaccgtgagc 480

tggaacagcg gcgccttgac cagcggcgtg cacaccttcc ccgccgtgct gcagagcagc 540

ggcctgtaca gcctgagcag cgtggtgacc gtgcccagca gcagcctggg cacccagacc 600

tacatctgca acgtgaacca caagcccagc aacaccaagg tggacaaacg cgtggagccc 660

aagagctgcg acaagaccca cacctgcccc ccctgccctg cccccgagct gctgggcgga 720

ccctccgtgt tcctgttccc ccccaagccc aaggacaccc tcatgatcag ccggaccccc 780

gaggtgacct gcgtggtggt ggacgtgagc cacgaggacc ccgaggtgaa gttcaactgg 840

tacgtggacg gcgtggaggt gcacaacgcc aagaccaagc cccgggagga gcagtacaac 900

agcacctacc gggtggtgag cgtgctcacc gtgctgcacc aggactggct gaacggcaag 960

gagtacaagt gcaaggtgag caacaaggcc ctgcctgccc ccatcgagaa gaccatcagc 1020

aaggccaagg gccagccccg ggagccccag gtgtacaccc tgccccccag ccgggaggag 1080

atgaccaaga accaggtgtc cctcacctgt ctggtgaagg gcttctaccc cagcgacatc 1140

gccgtggagt gggagagcaa cggccagccc gagaacaact acaagaccac cccccctgtg 1200

ctggacagcg acggcagctt cttcctgtac agcaagctca ccgtggacaa gagccggtgg 1260

cagcagggca acgtgttcag ctgcagcgtg atgcacgagg ccctgcacaa ccactacacc 1320

cagaagagcc tgagcctgag ccccggcaag 1350

SEQ ID NO：77

E V Q L V E S G A E V K K P G S S V K V S C K A S G G T F S S Y G I S W V R Q

A P G Q G L E W M G D I I G M F G S T N Y A Q N F Q G R L T I T A D E S T S T

A Y M E L S S L R S E D T A V Y Y C A R S S G Y Y P A Y L P H W G Q G T L V T

V S S A S T K G P S V F P L A P S S K S T S G G T A A L G C L V K D Y F P E P

V T V S W N S G A L T S G V H T F P A V L Q S S G L Y S L S S V V T V P S S S

L G T Q T Y I C N V N H K P S N T K V D K R V E P K S C D K T H T C P P C P A

P E L L G G P S V F L F P P K P K D T L M I S R T P E V T C V V V D V S H E D

P E V K F N W Y V D G V E V H N A K T K P R E E Q Y N S T Y R V V S V L T V L

H Q D W L N G K E Y K C K V S N K A L P A P I E K T I S K A K G Q P R E P Q V

Y T L P P S R E E M T K N Q V S L T C L V K G F Y P S D I A V E W E S N G Q P

E N N Y K T T P P V L D S D G S F F L Y S K L T V D K S R W Q Q G N V F S C S

V M H E A L H N H Y T Q K S L S L S P G K

SEQ ID NO：78

gaggtgcagc tggtggagtc tggggctgag gtgaagaagc cggggtcctc ggtgaaggtc 60

tcctgcaagg cttctggagg caccttcagc ttctattcta tgagctgggt gcgacaggcc 120

cctggacaag gacttgagtg gatgggaggg atcatcccta tgtttggtac aacaaactac 180

gcacagaagt tccagggcag agtcacgatt accgcggtcg aatccacgag cacagcctac 240

atggaggtga gcagcctgag atctgaggac acggccgttt attactgtgc gagaggtgat 300

aagggtatct actactacta catggacgtc tggggcaaag ggaccacggt caccgtctcg 360

agtgctagca ccaagggccc cagcgtgttc cccctggccc ccagcagcaa gagcaccagc 420

ggcggcacag ccgccctggg ctgcctggtg aaggactact tccccgagcc cgtgaccgtg 480

agctggaaca gcggcgcctt gaccagcggc gtgcacacct tccccgccgt gctgcagagc 540

agcggcctgt acagcctgag cagcgtggtg accgtgccca gcagcagcct gggcacccag 600

acctacatct gcaacgtgaa ccacaagccc agcaacacca aggtggacaa acgcgtggag 660

cccaagagct gcgacaagac ccacacctgc cccccctgcc ctgcccccga gctgctgggc 720

ggaccctccg tgttcctgtt cccccccaag cccaaggaca ccctcatgat cagccggacc 780

cccgaggtga cctgcgtggt ggtggacgtg agccacgagg accccgaggt gaagttcaac 840

tggtacgtgg acggcgtgga ggtgcacaac gccaagacca agccccggga ggagcagtac 900

aacagcacct accgggtggt gagcgtgctc accgtgctgc accaggactg gctgaacggc 960

aaggagtaca agtgcaaggt gagcaacaag gccctgcctg cccccatcga gaagaccatc 1020

agcaaggcca agggccagcc ccgggagccc caggtgtaca ccctgccccc cagccgggag 1080

gagatgacca agaaccaggt gtccctcacc tgtctggtga agggcttcta ccccagcgac 1140

atcgccgtgg agtgggagag caacggccag cccgagaaca actacaagac caccccccct 1200

gtgctggaca gcgacggcag cttcttcctg tacagcaagc tcaccgtgga caagagccgg 1260

tggcagcagg gcaacgtgtt cagctgcagc gtgatgcacg aggccctgca caaccactac 1320

acccagaaga gcctgagcct gagccccggc aag 1353

SEQ ID NO：79

E V Q L V E S G A E V K K P G S S V K V S C K A S G G T F S F Y S M S W V R Q

A P G Q G L E W M G G I I P M F G T T N Y A Q K F Q G R V T I T A V E S T S T

A Y M E V S S L R S E D T A V Y Y C A R G D K G I Y Y Y Y M D V W G K G T T V

T V S S A S T K G P S V F P L A P S S K S T S G G T A A L G C L V K D Y F P E

P V T V S W N S G A L T S G V H T F P A V L Q S S G L Y S L S S V V T V P S S

S L G T Q T Y I C N V N H K P S N T K V D K R V E P K S C D K T H T C P P C P

A P E L L G G P S V F L F P P K P K D T L M I S R T P E V T C V V V D V S H E

D P E V K F N W Y V D G V E V H N A K T K P R E E Q Y N S T Y R V V S V L T V

L H Q D W L N G K E Y K C K V S N K A L P A P I E K T I S K A K G Q P R E P Q

V Y T L P P S R E E M T K N Q V S L T C L V K G F Y P S D I A V E W E S N G Q

P E N N Y K T T P P V L D S D G S F F L Y S K L T V D K S R W Q Q G N V F S C

S V M H E A L H N H Y T Q K S L S L S P G K

SEQ ID NO：80

gaggtgcagc tggtggagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60

tcctgcaagg cttctggagg caccttcagc agctatgcta tcagctgggt gcgacaggcc 120

cctggacaag ggcttgagtg gatgggaggg atcatcggta tgttcggtac agcaaactac 180

gcacagaagt tccagggcag agtcacgatt accgcggacg aatttacgag cacagcctac 240

atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagaggaaat 300

tattactatg agagtagtct cgactactgg ggccagggaa ccctggtcac cgtctcgagt 360

gctagcacca agggccccag cgtgttcccc ctggccccca gcagcaagag caccagcggc 420

ggcacagccg ccctgggctg cctggtgaag gactacttcc ccgagcccgt gaccgtgagc 480

tggaacagcg gcgccttgac cagcggcgtg cacaccttcc ccgccgtgct gcagagcagc 540

ggcctgtaca gcctgagcag cgtggtgacc gtgcccagca gcagcctggg cacccagacc 600

tacatctgca acgtgaacca caagcccagc aacaccaagg tggacaaacg cgtggagccc 660

aagagctgcg acaagaccca cacctgcccc ccctgccctg cccccgagct gctgggcgga 720

ccctccgtgt tcctgttccc ccccaagccc aaggacaccc tcatgatcag ccggaccccc 780

gaggtgacct gcgtggtggt ggacgtgagc cacgaggacc ccgaggtgaa gttcaactgg 840

tacgtggacg gcgtggaggt gcacaacgcc aagaccaagc cccgggagga gcagtacaac 900

agcacctacc gggtggtgag cgtgctcacc gtgctgcacc aggactggct gaacggcaag 960

gagtacaagt gcaaggtgag caacaaggcc ctgcctgccc ccatcgagaa gaccatcagc 1020

aaggccaagg gccagccccg ggagccccag gtgtacaccc tgccccccag ccgggaggag 1080

atgaccaaga accaggtgtc cctcacctgt ctggtgaagg gcttctaccc cagcgacatc 1140

gccgtggagt gggagagcaa cggccagccc gagaacaact acaagaccac cccccctgtg 1200

ctggacagcg acggcagctt cttcctgtac agcaagctca ccgtggacaa gagccggtgg 1260

cagcagggca acgtgttcag ctgcagcgtg atgcacgagg ccctgcacaa ccactacacc 1320

cagaagagcc tgagcctgag ccccggcaag 1350

SEQ ID NO：81

E V Q L V E S G A E V K K P G S S V K V S C K A S G G T F S S Y A I S W V R Q

A P G Q G L E W M G G I I G M F G T A N Y A Q K F Q G R V T I T A D E F T S T

A Y M E L S S L R S E D T A V Y Y C A R G N Y Y Y E S S L D Y W G Q G T L V T

V S S A S T K G P S V F P L A P S S K S T S G G T A A L G C L V K D Y F P E P

V T V S W N S G A L T S G V H T F P A V L Q S S G L Y S L S S V V T V P S S S

L G T Q T Y I C N V N H K P S N T K V D K R V E P K S C D K T H T C P P C P A

P E L L G G P S V F L F P P K P K D T L M I S R T P E V T C V V V D V S H E D

P E V K F N W Y V D G V E V H N A K T K P R E E Q Y N S T Y R V V S V L T V L

H Q D W L N G K E Y K C K V S N K A L P A P I E K T I S K A K G Q P R E P Q V

Y T L P P S R E E M T K N Q V S L T C L V K G F Y P S D I A V E W E S N G Q P

E N N Y K T T P P V L D S D G S F F L Y S K L T V D K S R W Q Q G N V F S C S

V M H E A L H N H Y T Q K S L S L S P G K

SEQ ID NO：82

caggtgcagc tggtgcagtctggggctgag gtgaagaagc ctgggtcctc ggtgagagtc 60

tcctgcaagg cttctggaag catcttcaga aactatgcta tgagctgggt gcgacaggcc 120

cctggacaag ggcttgagtg gatgggaggg atcatcgcta tttttgggac accaaagtac 180

gcacagaagt tccagggcag agtcacgatt accgcggacg aatcgacgag cactgtctac 240

atggaactga gcggactgag atctgaggac acggccatgt attactgtgc gaggattccc 300

cactataatt ttggttcggg gagttatttc gactactggg gccagggaac cctggtcacc 360

gtctcgagtg ctagcaccaa gggccccagc gtgttccccc tggcccccag cagcaagagc 420

accagcggcg gcacagccgc cctgggctgc ctggtgaagg actacttccc cgagcccgtg 480

accgtgagct ggaacagcgg cgccttgacc agcggcgtgc acaccttccc cgccgtgctg 540

cagagcagcg gcctgtacag cctgagcagc gtggtgaccg tgcccagcag cagcctgggc 600

acccagacct acatctgcaa cgtgaaccac aagcccagca acaccaaggt ggacaaacgc 660

gtggagccca agagctgcga caagacccac acctgccccc cctgccctgc ccccgagctg 720

ctgggcggac cctccgtgtt cctgttcccc cccaagccca aggacaccct catgatcagc 780

cggacccccg aggtgacctg cgtggtggtg gacgtgagcc acgaggaccc cgaggtgaag 840

ttcaactggt acgtggacgg cgtggaggtg cacaacgcca agaccaagcc ccgggaggag 900

cagtacaaca gcacctaccg ggtggtgagc gtgctcaccg tgctgcacca ggactggctg 960

aacggcaagg agtacaagtg caaggtgagc aacaaggccc tgcctgcccc catcgagaag 1020

accatcagca aggccaaggg ccagccccgg gagccccagg tgtacaccct gccccccagc 1080

cgggaggaga tgaccaagaa ccaggtgtcc ctcacctgtc tggtgaaggg cttctacccc 1140

agcgacatcg ccgtggagtg ggagagcaac ggccagcccg agaacaacta caagaccacc 1200

ccccctgtgc tggacagcga cggcagcttc ttcctgtaca gcaagctcac cgtggacaag 1260

agccggtggc agcagggcaa cgtgttcagc tgcagcgtga tgcacgaggc cctgcacaac 1320

cactacaccc agaagagcct gagcctgagc cccggcaag 1359

SEQ ID NO：83

Q V Q L V Q S G A E V K K P G S S V R V S C K A S G S I F R N Y A M S W V R Q

A P G Q G L E W M G G I I A I F G T P K Y A Q K F Q G R V T I T A D E S T S T

V Y M E L S G L R S E D T A M Y Y C A R I P H Y N F G S G S Y F D Y W G Q G T

L V T V S S A S T K G P S V F P L A P S S K S T S G G T A A L G C L V K D Y F

P E P V T V S W N S G A L T S G V H T F P A V L Q S S G L Y S L S S V V T V P

S S S L G T Q T Y I C N V N H K P S N T K V D K R V E P K S C D K T H T C P P

C P A P E L L G G P S V F L F P P K P K D T L M I S R T P E V T C V V V D V S

H E D P E V K F N W Y V D G V E V H N A K T K P R E E Q Y N S T Y R V V S V L

T V L H Q D W L N G K E Y K C K V S N K A L P A P I E K T I S K A K G Q P R E

P Q V Y T L P P S R E E M T K N Q V S L T C L V K G F Y P S D I A V E W E S N

G Q P E N N Y K T T P P V L D S D G S F F L Y S K L T V D K S R W Q Q G N V F

S C S V M H E A L H N H Y T Q K S L S L S P G K

SEQ ID NO：84

tcctatgtgc tgactcagcc accctcagcg tctgggaccc ccgggcagag ggtcaccatc 60

tcttgttctg gaagcacgtt caacatcgga agtaatgctg tagactggta ccggcagctc 120

ccaggaacgg cccccaaact cctcatctat agtaataatc agcggccctc aggggtccct 180

gaccgattct ctggctccag gtctggcacc tcagcctccc tggccatcag tgggctccag 240

tctgaggatg aggctgatta ttactgtgca gcatgggatg acatcctgaa tgttccggta 300

ttcggcggag ggaccaagct gaccgtccta ggtgcggccg caggccagcc caaggccgct 360

cccagcgtga ccctgttccc cccctcctcc gaggagctgc aggccaacaa ggccaccctg 420

gtgtgcctca tcagcgactt ctaccctggc gccgtgaccg tggcctggaa ggccgacagc 480

agccccgtga aggccggcgt ggagaccacc acccccagca agcagagcaa caacaagtac 540

gccgccagca gctacctgag cctcaccccc gagcagtgga agagccaccg gagctacagc 600

tgccaggtga cccacgaggg cagcaccgtg gagaagaccg tggcccccac cgagtgcagc 660

SEQ ID NO：85

S Y V L T Q P P S A S G T P G Q R V T I S C S G S T F N I G S N A V D W Y R Q

L P G T A P K L L I Y S N N Q R P S G V P D R F S G S R S G T S A S L A I S G

L Q S E D E A D Y Y C A A W D D I L N V P V F G G G T K L T V L G A A A G Q P

K A A P S V T L F P P S S E E L Q A N K A T L V C L I S D F Y P G A V T V A W

K A D S S P V K A G V E T T T P S K Q S N N K Y A A S S Y L S L T P E Q W K S

H R S Y S C Q V T H E G S T V E K T V A P T E C S

SEQ ID NO：86

cagtctgccc tgactcagcc tgccgccgtg tctgggtctc ctggacagtc gatcaccatc 60

tcctgcactg gaaccagcag tgacgttggt ggttataact atgtctcctg gtaccaacag 120

cacccaggca aagcccccaa actcatgatt tatgaggtca gtaatcggcc ctcaggggtt 180

tctaatcgct tctctggctc caagtctggc aacacggcct ccctgaccat ctctgggctc 240

caggctgagg acgaggctga ttattactgc agctcatata caagcagcag cacttatgtc 300

ttcggaactg ggaccaaggt caccgtccta ggtgcggccg caggccagcc caaggccgct 360

cccagcgtga ccctgttccc cccctcctcc gaggagctgc aggccaacaa ggccaccctg 420

gtgtgcctca tcagcgactt ctaccctggc gccgtgaccg tggcctggaa ggccgacagc 480

agccccgtga aggccggcgt ggagaccacc acccccagca agcagagcaa caacaagtac 540

gccgccagca gctacctgag cctcaccccc gagcagtgga agagccaccg gagctacagc 600

tgccaggtga cccacgaggg cagcaccgtg gagaagaccg tggcccccac cgagtgcagc 660

SEQ ID NO：87

Q S A L T Q P A A V S G S P G Q S I T I S C T G T S S D V G G Y N Y V S W Y Q

Q H P G K A P K L M I Y E V S N R P S G V S N R F S G S K S G N T A S L T I S

G L Q A E D E A D Y Y C S S Y T S S S T Y V F G T G T K V T V L G A A A G Q P

K A A P S V T L F P P S S E E L Q A N K A T L V C L I S D F Y P G A V T V A W

K A D S S P V K A G V E T T T P S K Q S N N K Y A A S S Y L S L T P E Q W K S

H R S Y S C Q V T H E G S T V E K T V A P T E C S

SEQ ID NO：88

tcctatgtgc tgactcagcc accctcagtc tctgggaccc ccgggcagag ggtcaccatc 60

tcttgctctg gaagccgctc caacgtcgga gataattctg tatattggta tcaacacgtc 120

ccagaaatgg cccccaaact cctcgtctat aagaatactc aacggccctc aggagtccct 180

gcccggtttt ccggctccaa gtctggcact tcagcctccc tggccatcat tggcctccag 240

tccggcgatg aggctgatta ttattgtgtg gcatgggatg acagcgtaga tggctatgtc 300

ttcggatctg ggaccaaggt caccgtccta ggtgcggccg caggccagcc caaggccgct 360

cccagcgtga ccctgttccc cccctcctcc gaggagctgc aggccaacaa ggccaccctg 420

gtgtgcctca tcagcgactt ctaccctggc gccgtgaccg tggcctggaa ggccgacagc 480

agccccgtga aggccggcgt ggagaccacc acccccagca agcagagcaa caacaagtac 540

gccgccagca gctacctgag cctcaccccc gagcagtgga agagccaccg gagctacagc 600

tgccaggtga cccacgaggg cagcaccgtg gagaagaccg tggcccccac cgagtgcagc 660

SEQ ID NO：89

S Y V L T Q P P S V S G T P G Q R V T I S C S G S R S N V G D N S V Y W Y Q H

V P E M A P K L L V Y K N T Q R P S G V P A R F S G S K S G T S A S L A I I G

L Q S G D E A D Y Y C V A W D D S V D G Y V F G S G T K V T V L G A A A G Q P

K A A P S V T L F P P S S E E L Q A N K A T L V C L I S D F Y P G A V T V A W

K A D S S P V K A G V E T T T P S K Q S N N K Y A A S S Y L S L T P E Q W K S

H R S Y S C Q V T H E G S T V E K T V A P T E C S

SEQ ID NO：90

cagtctgtgt tgacgcagcc gccctcagtg tctgcggccc caggacagaa ggtcaccatc 60

tcctgctctg gaagcagctc caacattggg aatgattatg tatcctggta ccagcagctc 120

ccaggaacag cccccaaact cctcatttat gacaataata agcgaccctc agggattcct 180

gaccgattct ctggctccaa gtctggcacg tcagccaccc tgggcatcac cggactccag 240

actggggacg aggccaacta ttactgcgca acatgggatc gccgcccgac tgcttatgtt 300

gtcttcggcg gagggaccaa gctgaccgtc ctaggtgcgg ccgcaggcca gcccaaggcc 360

gctcccagcg tgaccctgtt ccccccctcc tccgaggagc tgcaggccaa caaggccacc 420

ctggtgtgcc tcatcagcga cttctaccct ggcgccgtga ccgtggcctg gaaggccgac 480

agcagccccg tgaaggccgg cgtggagacc accaccccca gcaagcagag caacaacaag 540

tacgccgcca gcagctacct gagcctcacc cccgagcagt ggaagagcca ccggagctac 600

agctgccagg tgacccacga gggcagcacc gtggagaaga ccgtggcccc caccgagtgc 660

agc 663

SEQ ID NO：91

Q S V L T Q P P S V S A A P G Q K V T I S C S G S S S N I G N D Y V S W Y Q Q

L P G T A P K L L I Y D N N K R P S G I P D R F S G S K S G T S A T L G I T G

L Q T G D E A N Y Y C A T W D R R P T A Y V V F G G G T K L T V L G A A A G Q

P K A A P S V T L F P P S S E E L Q A N K A T L V C L I S D F Y P G A V T V A

W K A D S S P V K A G V E T T T P S K Q S N N K Y A A S S Y L S L T P E Q W K

S H R S Y S C Q V T H E G S T V E K T V A P T E C S

SEQ ID NO：92

gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60

atcacttgcc gggcgagtca gggcattagc agttatttag cctggtatca gcagaagcca 120

gggaaagttc ctacactcct gatctatgat gcatccactt tgcgatcagg ggtcccatct 180

cgcttcagtg gcagtggatc tgcgacagat ttcactctca ccatcagcag cctgcagcct 240

gaagatgttg caacttatta ctgtcaaagg tataacagtg cccccccgat caccttcggc 300

caagggacac gactggagat taaacgtgcg gccgcaccca gcgtgttcat cttccccccc 360

tccgacgagc agctgaagag cggcaccgcc agcgtggtgt gcctgctgaa caacttctac 420

ccccgggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480

gagagcgtga ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctcacc 540

ctgagcaagg ccgactacga gaagcacaag gtgtacgcct gcgaggtgac ccaccagggc 600

ctgagcagcc ccgtgaccaa gagcttcaac cggggcgagt gt 642

SEQ ID NO：93

D I Q M T Q S P S S L S A S V G D R V T I T C R A S Q G I S S Y L A W Y Q Q K

P G K V P T L L I Y D A S T L R S G V P S R F S G S G S A T D F T L T I S S L

Q P E D V A T Y Y C Q R Y N S A P P I T F G Q G T R L E I K R A A A P S V F I

F P P S D E Q L K S G T A S V V C L L N N F Y P R E A K V Q W K V D N A L Q S

G N S Q E S V T E Q D S K D S T Y S L S S T L T L S K A D Y E K H K V Y A C E

V T H Q G L S S P V T K S F N R G E C

SEQ ID NO：94

cagtctgtgc tgactcagcc accctcagag tccgtgtccc caggacagac agccagcgtc 60

acctgctctg gacataaatt gggggataaa tatgtttcgt ggtatcagca gaagccaggc 120

cagtcccctg tattactcat ctatcaagat aacaggcggc cctcagggat ccctgagcga 180

ttcataggct ccaactctgg gaacacagcc actctgacca tcagcgggac ccaggctctg 240

gatgaggctg actattactg tcaggcgtgg gacagcagca ctgcggtttt cggcggaggg 300

accaagctga ccgtcctagg tgcggccgca ggccagccca aggccgctcc cagcgtgacc 360

ctgttccccc cctcctccga ggagctgcag gccaacaagg ccaccctggt gtgcctcatc 420

agcgacttct accctggcgc cgtgaccgtg gcctggaagg ccgacagcag ccccgtgaag 480

gccggcgtgg agaccaccac ccccagcaag cagagcaaca acaagtacgc cgccagcagc 540

tacctgagcc tcacccccga gcagtggaag agccaccgga gctacagctg ccaggtgacc 600

cacgagggca gcaccgtgga gaagaccgtg gcccccaccg agtgcagc 648

SEQ ID NO：95

Q S V L T Q P P S E S V S P G Q T A S V T C S G H K L G D K Y V S W Y Q Q K P

G Q S P V L L I Y Q D N R R P S G I P E R F I G S N S G N T A T L T I S G T Q

A L D E A D Y Y C Q A W D S S T A V F G G G T K L T V L G A A A G Q P K A A P

S V T L F P P S S E E L Q A N K A T L V C L I S D F Y P G A V T V A W K A D S

S P V K A G V E T T T P S K Q S N N K Y A A S S Y L S L T P E Q W K S H R S Y

S C Q V T H E G S T V E K T V A P T E C S

SEQ ID NO：96

gaaattgtgc tgactcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60

ctctcctgca gggccagtca gcgtgttagc agctacttag cctggtacca acagaaacct 120

ggccaggctc ccaggctcct catctatggt gcatccacca gggccgctgg catcccagac 180

aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag actggagcct 240

gaagattctg cagtgtatta ctgtcagcag tatggtagga caccgctcac tttcggcgga 300

gggaccaagg tggagatcaa acgtgcggcc gcacccagcg tgttcatctt ccccccctcc 360

gacgagcagc tgaagagcgg caccgccagc gtggtgtgcc tgctgaacaa cttctacccc 420

cgggaggcca aggtgcagtg gaaggtggac aacgccctgc agagcggcaa cagccaggag 480

agcgtgaccg agcaggacag caaggactcc acctacagcc tgagcagcac cctcaccctg 540

agcaaggccg actacgagaa gcacaaggtg tacgcctgcg aggtgaccca ccagggcctg 600

agcagccccg tgaccaagag cttcaaccgg ggcgagtgt 639

SEQ ID NO：97

E I V L T Q S P G T L S L S P G E R A T L S C R A S Q R V S S Y L A W Y Q Q K

P G Q A P R L L I Y G A S T R A A G I P D R F S G S G S G T D F T L T I S R L

E P E D S A V Y Y C Q Q Y G R T P L T F G G G T K V E I K R A A A P S V F I F

P P S D E Q L K S G T A S V V C L L N N F Y P R E A K V Q W K V D N A L Q S G

N S Q E S V T E Q D S K D S T Y S L S S T L T L S K A D Y E K H K V Y A C E V

T H Q G L S S P V T K S F N R G E C

SEQ ID NO：98

tcctatgtgc tgactcagcc accctcggtg tcagtggccc caggacagac ggccaggatt 60

acctgtgggg gaaacaacat tggaagtaaa agtgtgcact ggtaccagca gaagccaggc 120

caggcccctg tgctggtcgt ctatgatgat agcgaccggc cctcagggat ccctgagcga 180

ttctctggct ccaactctgg gaacacggcc accctgacca tcagcagggt cgaagccggg 240

gatgaggccg actattactg tcaggtgtgg gatagtagta gtgatcatgc tgtgttcgga 300

ggaggcaccc agctgaccgt cctcggtgcg gccgcaggcc agcccaaggc cgctcccagc 360

gtgaccctgt tccccccctc ctccgaggag ctgcaggcca acaaggccac cctggtgtgc 420

ctcatcagcg acttctaccc tggcgccgtg accgtggcct ggaaggccga cagcagcccc 480

gtgaaggccg gcgtggagac caccaccccc agcaagcaga gcaacaacaa gtacgccgcc 540

agcagctacc tgagcctcac ccccgagcag tggaagagcc accggagcta cagctgccag 600

gtgacccacg agggcagcac cgtggagaag accgtggccc ccaccgagtg cagc 654

SEQ ID NO：99

S Y V L T Q P P S V S V A P G Q T A R I T C G G N N I G S K S V H W Y Q Q K P

G Q A P V L V V Y D D S D R P S G I P E R F S G S N S G N T A T L T I S R V E

A G D E A D Y Y C Q V W D S S S D H A V F G G G T Q L T V L G A A A G Q P K A

A P S V T L F P P S S E E L Q A N K A T L V C L I S D F Y P G A V T V A W K A

D S S P V K A G V E T T T P S K Q S N N K Y A A S S Y L S L T P E Q W K S H R

S Y S C Q V T H E G S T V E K T V A P T E C S

SEQ ID NO：100

tcctatgtgc tgactcagcc accctcagcg tctgggaccc ccgggcagag ggtcaccatc 60

tcttgttctg gaagcagctc caacatcgga agtaattatg tatactggta ccagcagctc 120

ccaggcacgg cccccaaact cctcatctat agggatggtc agcggccctc aggggtccct 180

gaccgattct ctggctccaa gtctggcacc tcagcctccc tggccatcag tggactccgg 240

tccgatgatg aggctgatta ttactgtgca acatgggatg acaacctgag tggtccagta 300

ttcggcggag ggaccaagct gaccgtccta ggtgcggccg caggccagcc caaggccgct 360

cccagcgtga ccctgttccc cccctcctcc gaggagctgc aggccaacaa ggccaccctg 420

gtgtgcctca tcagcgactt ctaccctggc gccgtgaccg tggcctggaa ggccgacagc 480

agccccgtga aggccggcgt ggagaccacc acccccagca agcagagcaa caacaagtac 540

gccgccagca gctacctgag cctcaccccc gagcagtgga agagccaccg gagctacagc 600

tgccaggtga cccacgaggg cagcaccgtg gagaagaccg tggcccccac cgagtgcagc 660

SEQ ID NO：101

S Y V L T Q P P S A S G T P G Q R V T I S C S G S S S N I G S N Y V Y W Y Q Q

L P G T A P K L L I Y R D G Q R P S G V P D R F S G S K S G T S A S L A I S G

L R S D D E A D Y Y C A T W D D N L S G P V F G G G T K L T V L G A A A G Q P

K A A P S V T L F P P S S E E L Q A N K A T L V C L I S D F Y P G A V T V A W

K A D S S P V K A G V E T T T P S K Q S N N K Y A A S S Y L S L T P E Q W K S

H R S Y S C Q V T H E G S T V E K T V A P T E C S

SEQ ID NO：102

gaaattgtgt tgacccagtc 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 gctcacccag aactttcggc 300

ggagggacca aggtggagat caaacgtgcg gccgcaccca gcgtgttcat cttccccccc 360

tccgacgagc agctgaagag cggcaccgcc agcgtggtgt gcctgctgaa caacttctac 420

ccccgggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480

gagagcgtga ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctcacc 540

ctgagcaagg ccgactacga gaagcacaag gtgtacgcct gcgaggtgac ccaccagggc 600

ctgagcagcc ccgtgaccaa gagcttcaac cggggcgagt gt 642

SEQ ID NO：103

E I V L T Q S P G T L S L S P G E R A T L S C R A S Q S V S S S Y L A W Y Q Q

K P G Q A P R L L I Y G A S S R A T G I P D R F S G S G S G T D F T L T I S R

L E P E D F A V Y Y C Q Q Y G S S P R T F G G G T K V E I K R A A A P S V F I

F P P S D E Q L K S G T A S V V C L L N N F Y P R E A K V Q W K V D N A L Q S

G N S Q E S V T E Q D S K D S T Y S L S S T L T L S K A D Y E K H K V Y A C E

V T H Q G L S S P V T K S F N R G E C

SEQ ID NO：104

cagtctgccc tgactcagcc tgcctccgtg tctgggtctc ctggacagtc gatcaccatc 60

tcctgcactg gaaccagcag tgacgttggt ggttataact atgtctcctg gtaccaacag 120

cacccaggca aagcccccaa actcatgatt tatgaggtca gtaatcggcc ctcaggggtt 180

tctaatcgct tctctggctc caagtctggc aacacggcct ccctgaccat ctctgggctc 240

caggctgagg acgaggctga ttattactgc agctcatata caagcagcag cactcttgtc 300

ttcggaactg ggaccaaggt caccgtccta ggtgcggccg caggccagcc caaggccgct 360

cccagcgtga ccctgttccc cccctcctcc gaggagctgc aggccaacaa ggccaccctg 420

gtgtgcctca tcagcgactt ctaccctggc gccgtgaccg tggcctggaa ggccgacagc 480

agccccgtga aggccggcgt ggagaccacc acccccagca agcagagcaa caacaagtac 540

gccgccagca gctacctgag cctcaccccc gagcagtgga agagccaccg gagctacagc 600

tgccaggtga cccacgaggg cagcaccgtg gagaagaccg tggcccccac cgagtgcagc 660

SEQ ID NO：105

Q S A L T Q P A S V S G S P G Q S I T I S C T G T S S D V G G Y N Y V S W Y Q

Q H P G K A P K L M I Y E V S N R P S G V S N R F S G S K S G N T A S L T I S

G L Q A E D E A D Y Y C S S Y T S S S T L V F G T G T K V T V L G A A A G Q P

K A A P S V T L F P P S S E E L Q A N K A T L V C L I S D F Y P G A V T V A W

K A D S S P V K A G V E T T T P S K Q S N N K Y A A S S Y L S L T P E Q W K S

H R S Y S C Q V T H E G S T V E K T V A P T E C S

SEQ ID NO：106

cagtctgtcg tgacgcagcc gccctcggtg tcagtggccc caggacagac ggccaggatt 60

acctgtgggg gaaacaacat tggaagtaaa agtgtgcact ggtaccagca gaagccaggc 120

caggcccctg tgctggtcgt ctatgatgat agcgaccggc cctcagggat ccctgagcga 180

ttctctggct ccaactctgg gaacacggcc accctgacca tcagcagggt cgaagccggg 240

gatgaggccg actattactg tcaggtgtgg gatagtagta gtgatcatta tgtcttcgga 300

actgggacca aggtcaccgt cctaggtgcg gccgcaggcc agcccaaggc cgctcccagc 360

gtgaccctgt tccccccctc ctccgaggag ctgcaggcca acaaggccac cctggtgtgc 420

ctcatcagcg acttctaccc tggcgccgtg accgtggcct ggaaggccga cagcagcccc 480

gtgaaggccg gcgtggagac caccaccccc agcaagcaga gcaacaacaa gtacgccgcc 540

agcagctacc tgagcctcac ccccgagcag tggaagagcc accggagcta cagctgccag 600

gtgacccacg agggcagcac cgtggagaag accgtggccc ccaccgagtg cagc 654

SEQ ID NO：107

Q S V V T Q P P S V S V A P G Q T A R I T C G G N N I G S K S V H W Y Q Q K P

G Q A P V L V V Y D D S D R P S G I P E R F S G S N S G N T A T L T I S R V E

A G D E A D Y Y C Q V W D S S S D H Y V F G T G T K V T V L G A A A G Q P K A

A P S V T L F P P S S E E L Q A N K A T L V C L I S D F Y P G A V T V A W K A

D S S P V K A G V E T T T P S K Q S N N K Y A A S S Y L S L T P E Q W K S H R

S Y S C Q V T H E G S T V E K T V A P T E C S

SEQ ID NO：108

actgtgttga cacagccgcc ctcagtgtct ggggccccag ggcagagggt caccatctcc 60

tgcactggga gcagctccaa catcggggca ggttatgatg tacactggta ccagcagctt 120

ccaggaacag cccccaaact cctcatctat ggtaacagca atcggccctc aggggtccct 180

gaccgattct ctggctccaa gtctggcacg tcagccaccc tgggcatcac cggactccag 240

actggggacg aggccgatta ttactgcgga acatgggata gcagcctgag tgcttatgtc 300

ttcggaactg ggaccaaggt caccgtccta ggtgcggccg caggccagcc caaggccgct 360

cccagcgtga ccctgttccc cccctcctcc gaggagctgc aggccaacaa ggccaccctg 420

gtgtgcctca tcagcgactt ctaccctggc gccgtgaccg tggcctggaa ggccgacagc 480

agccccgtga aggccggcgt ggagaccacc acccccagca agcagagcaa caacaagtac 540

gccgccagca gctacctgag cctcaccccc gagcagtgga agagccaccg gagctacagc 600

tgccaggtga cccacgaggg cagcaccgtg gagaagaccg tggcccccac cgagtgcagc 660

SEQ ID NO：109

T V L T Q P P S V S G A P G Q R V T I S C T G S S S N I G A G Y D V H W Y Q Q

L P G T A P K L L I Y G N S N R P S G V P D R F S G S K S G T S A T L G I T G

L Q T G D E A D Y Y C G T W D S S L S A Y V F G T G T K V T V L G A A A G Q P

K A A P S V T L F P P S S E E L Q A N K A T L V C L I S D F Y P G A V T V A W

K A D S S P V K A G V E T T T P S K Q S N N K Y A A S S Y L S L T P E Q W K S

H R S Y S C Q V T H E G S T V E K T V A P T E C S

SEQ ID NO：110

M E K I V L L F A I V S L V K S D Q I C I G Y H A N N S T E Q V D T I M E K N

V T V T H A Q D I L E K K H N G K L C D L D G V K P L I L R D C S V A G W L L

G N P M C D E F I N V P E W S Y I V E K A N P V N D L C Y P G D F N D Y E E L

K H L L S R I N H F E K I Q I I P K S S W S S H E A S L G V S S A C P Y Q G K

S S F F R N V V W L I K K N S T Y P T I K R S Y N N T N Q E D L L V L W G I H

H P N D A A E Q T K L Y Q N P T T Y I S V G T S T L N Q R L V P R I A T R S K

V N G Q S G R M E F F W T I L K P N D A I N F E S N G N F I A P E Y A Y K I V

K K G D S T I M K S E L E Y G N C N T K C Q T P M G A I N S S M P F H N I H P

L T I G E C P K Y V K S N R L V L A T G L R N S P Q R E R R R K K R G L F G A

I A G F I E G G W Q G M V D G W Y G Y H H S N E Q G S G Y A A D K E S T Q K A

I D G V T N K V N S I I D K M N T Q F E A V G R E F N N L E R R I E N L N K K

M E D G F L D V W T Y N A E L L V L M E N E R T L D F H D S N V K N L Y D K V

R L Q L R D N A K E L G N G C F E F Y H K C D N E C M E S V R N G T Y D Y P Q

Y S E E A R L K R E E I S G V K L E S I G I Y Q I L S I Y S T V A S S L A L A

I M V A G L S L W M C S N G S L Q C R

SEQ ID NO：111

M E K I V L L F A I V S L V K S D Q I C I G Y H A N N S T E Q V D T I M E K N

V T V T H A Q D I L E K T H N G K L C D L D G V K P L I L R D C S V A G W L L

G N P M C D E F I N V P E W S Y I V E K A N P V N D L C Y P G D F N D Y E E L

K H L L S R I N H F E K I Q I I P K S S W S S H E A S L G V S S A C P Y Q G K

S S F F R N V V W L I K K N S T Y P T I K R S Y N N T N Q E D L L V L W G I H

H P N D A A E Q T K L Y Q N P T T Y I S V G T S T L N Q R L V P R I A T R S K

V N G Q S G R M E F F W T I L K P N D A I N F E S N G N F I A P E Y A Y K I V

K K G D S T I M K S E L E Y G N C N T K C Q T P M G A I N S S M P F H N I H P

L T I G E C P K Y V K S N R L V L A T G L R N S P Q R E R R R K K R G L F G A

I A G F I E G G W Q G M V D G W Y G Y H H S N E Q G S G Y A A D K E S T Q K A

I D G V T N K V N S I I D K M N T Q F E A V G R E F N N L E R R I E N L N K K

M E D G F L D V W T Y N A E L L V L M E N E R T L D F H D S N V K N L Y D K V

R L Q L R D N A K E L G N G C F E F Y H K C D N E C M E S V R N G T Y D Y P Q

Y S E E A R L K R E E I S G V K L E S I G I Y Q I L S I Y S T V A S S L A L A

I M V A G L S L W M C S N G S L Q C R

SEQ ID NO：112

M E K I V L L L A I V S L V K S D Q I C I G Y H A N N S T E Q V D T I M E K N

V T V T H A Q D I L E K T H N G K L C D L D G V K P L I L R D C S V A G W L L

G N P M C D E F I N V P E W S Y I V E K A N P A N D L C Y P G N F N D Y E E L

K H L L S R I N H F E K I Q I I P K S S W S D H E A S S G V S S A C P Y Q G K

S S F F R N V V W L I K K N S S Y P T I K R S Y N N T N Q E D L L V L W G I H

H P N D A A E Q T R L Y Q N P T T Y I S V G T S T L N Q R L V P K I A T R S K

V N G Q S G R M E F F W T I L K P N D A I N F E S N G N F I A P E Y A Y K I V

K K G D S A I M K S E L E Y G N C N T K C Q T P M G A I N S S M P F H N I H P

L T I G E C P K Y V K S N R L V L A T G L R N S P Q R E R R R K K R G L F G A

I A G F I E G G W Q G M V D G W Y G Y H H S N E Q G S G Y A A D K E S T Q K A

I D G V T N K V N S I I D K M N T Q F E A V G R E F N N L E R R I E N L N K K

M E D G F L D V W T Y N A E L L V L M E N E R T L D F H D S N V K N L Y D K V

R L Q L R D N A K E L G N G C F E F Y H K C D N E C M E S V R N G T Y D Y P Q

Y S E E A R L K R E E I S G V K L E S I G I Y Q I L S I Y S T V A S S L A L A

I M V A G L S L W M C S N G S L Q C R

SEQ ID NO：113

M E K I V L L F A I V S L V K S D Q I C I G Y H A N N S T E Q V D T I M E K N

V T V T H A Q D I L E K T H N G K L C D L D G V K P L I L R D C S V A G W L L

G N P M C D E F I N V P E W S Y I V E K A N P V N D L C Y P G D F N D Y E E L

K H L L S R I N H F E K I Q I I P K S S W S S H E A S L G V S S A C P Y Q G K

S S F F R N V V W L I K K N S T Y P T I K R S Y N N T N Q E D L L V L W G I H

H P N D A A E Q T K L Y Q N P T T Y I S V G T S T L N Q R L V P R I A T R S K

V N G Q S G R M E F F W T I L K P N D A I N F E S N G N F I A P E Y A Y K I V

K K G D S T I M K S E L E Y G N C N T K C Q T P M G A I N S S M P F H N I H P

L T I G E C P K Y V K S N R L V L A T G L R N S P Q R E R R R K K R G L F G A

I A G F I E G G W Q G M V D G W Y G Y H H S N E Q G S G Y A A D K E S T Q K A

I D G V T N K V N S I I D K M N T Q F E A V G R E F N N L E R R I E N L N K K

M E D G F L D V W T Y N A E L L V L M E N E R T L D F H D S N V K N L Y D K V

R L Q L R D N A K E L G N G C F E F Y H K C D N E C M E S V R N G T Y D Y P Q

Y S E E A R L K R E E I S G V K L E S I G I Y Q I Q H S G G R S S L E G P R F

E Q K L I S E E D L N M H T G H H H H H H

SEQ ID NO：114

M E K I V L L L A I V S L V K S D Q I C I G Y H A N N S T E Q V D T I M E K N

V T V T H A Q D I L E K T H N G K L C D L D G V K P L I L R D C S V A G W L L

G N P M C D E F I N V P E W S Y I V E K A N P A N D L C Y P G N F N D Y E E L

K H L L S R I N H F E K I Q I I P K S S W S D H E A S S G V S S A C P Y Q G K

S S F F R N V V W L I K K N S S Y P T I K R S Y N N T N Q E D L L V L W G I H

H P N D A A E Q T R L Y Q N P T T Y I S V G T S T L N Q R L V P K I A T R S K

V N G Q S G R M E F F W T I L K P N D A I N F E S N G N F I A P E Y A Y K I V

K K G D S A I M K S E L E Y G N C N T K C Q T P M G A I N S S M P F H N I H P

L T I G E C P K Y V K S N R L V L A T G L R N S P Q R E R R R K K R G L F G A

I A G F I E G G W Q G M V D G W Y G Y H H S N E Q G S G Y A A D K E S T Q K A

I D G V T N K V N S I I D K M N T Q F E A V G R E F N N L E R R I E N L N K K

M E D G F L D V W T Y N A E L L V L M E N E R T L D F H D S N V K N L Y D K V

R L Q L R D N A K E L G N G C F E F Y H K C D N E C M E S V R N G T Y D Y P Q

Y S E E A R L K R E E I S G V K L E S I G I Y Q I Q H S G G R S S L E G P R F

E Q K L I S E E D L N M H T G H H H H H H

SEQ ID NO：115

gaggtgcagc tggtggagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaagtc 60

tcttgcaagg cttctggagg ccccttccgc agctatgcta tcagctgggt gcgacaggcc 120

cctggacaag ggcctgagtg gatgggaggg atcatcccta tttttggtac aacaaaatac 180

gcaccgaagt tccagggcag agtcacgatt accgcggacg atttcgcggg cacagtttac 240

atggagctga gcagcctgcg atctgaggac acggccatgt actactgtgc gaaacatatg 300

gggtaccagg tgcgcgaaac tatggacgtc tggggcaaag ggaccacggt caccgtctcg 360

agcggtacgg gcggttcagg cggaaccggc agcggcactg gcgggtcgac gtcctatgtg 420

ctgactcagc caccctcagc gtctgggacc cccgggcaga gggtcaccat ctcttgttct 480

ggaagcacgt tcaacatcgg aagtaatgct gtagactggt accggcagct cccaggaacg 540

gcccccaaac tcctcatcta tagtaataat cagcggccct caggggtccc tgaccgattc 600

tctggctcca ggtctggcac ctcagcctcc ctggccatca gtgggctcca gtctgaggat 660

gaggctgatt attactgtgc agcatgggatg acatcctga atgttccggt attcggcgga 720

gggaccaagc tgaccgtcct aggt 744

SEQ ID NO：116

E V Q L V E S G A E V K K P G S S V K V S C K A S G G P F R S Y A I S W V R Q

A P G Q G P E W M G G I I P I F G T T K Y A P K F Q G R V T I T A D D F A G T

V Y M E L S S L R S E D T A M Y Y C A K H M G Y Q V R E T M D V W G K G T T V

T V S S G T G G S G G T G S G T G G S T S Y V L T Q P P S A S G T P G Q R V T

I S C S G S T F N I G S N A V D W Y R Q L P G T A P K L L I Y S N N Q R P S G

V P D R F S G S R S G T S A S L A I S G L Q S E D E A D Y Y C A A W D D I L N

V P V F G G G T K L T V L G

SEQ ID NO：117

caggtccagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaagtc 60

tcttgcaagg cttctggagg ccccttccgc agctatgcta tcagctgggt gcgacaggcc 120

cctggacaag ggcctgagtg gatgggaggg atcatcccta tttttggtac aacaaaatac 180

gcaccgaagt tccagggcag agtcacgatt accgcggacg atttcgcggg cacagtttac 240

atggagctga gcagcctgcg atctgaggac acggccatgt actactgtgc gaaacatatg 300

gggtaccagg tgcgcgaaac tatggacgtc tggggcaaag ggaccacggt caccgtctcg 360

agcggtacgg gcggttcagg cggaaccggc agcggcactg gcgggtcgac gcagtctgcc 420

ctgactcagc ctgccgccgt gtctgggtct cctggacagt cgatcaccat ctcctgcact 480

ggaaccagca gtgacgttgg tggttataac tatgtctcct ggtaccaaca gcacccaggc 540

aaagccccca aactcatgat ttatgaggtc agtaatcggc cctcaggggt ttctaatcgc 600

ttctctggct ccaagtctgg caacacggcc tccctgacca tctctgggct ccaggctgag 660

gacgaggctg attattactg cagctcatat acaagcagca gcacttatgt cttcggaact 720

gggaccaagg tcaccgtcct aggt 744

SEQ ID NO：118

Q V Q L V Q S G A E V K K P G S S V K V S C K A S G G P F R S Y A I S W V R Q

A P G Q G P E W M G G I I P I F G T T K Y A P K F Q G R V T I T A D D F A G T

V Y M E L S S L R S E D T A M Y Y C A K H M G Y Q V R E T M D V W G K G T T V

T V S S G T G G S G G T G S G T G G S T Q S A L T Q P A A V S G S P G Q S I T

I S C T G T S S D V G G Y N Y V S W Y Q Q H P G K A P K L M I Y E V S N R P S

G V S N R F S G S K S G N T A S L T I S G L Q A E D E A D Y Y C S S Y T S S S

T Y V F G T G T K V T V L G

SEQ ID NO：119

gaggtgcagc tggtggagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaagtc 60

tcttgcaagg cttctggagg ccccttccgc agctatgcta tcagctgggt gcgacaggcc 120

cctggacaag ggcctgagtg gatgggaggg atcatcccta tttttggtac aacaaaatac 180

gcaccgaagt tccagggcag agtcacgatt accgcggacg atttcgcggg cacagtttac 240

atggagctga gcagcctgcg atctgaggac acggccatgt actactgtgc gaaacatatg 300

gggtaccagg tgcgcgaaac tatggacgtc tggggcaaag ggaccacggt caccgtctcg 360

agcggtacgg gcggttcagg cggaaccggc agcggcactg gcgggtcgac gtcctatgtg 420

ctgactcagc caccctcagt ctctgggacc cccgggcaga gggtcaccat ctcttgctct 480

ggaagccgct ccaacgtcgg agataattct gtatattggt atcaacacgt cccagaaatg 540

gcccccaaac tcctcgtcta taagaatact caacggccct caggagtccc tgcccggttt 600

tccggctcca agtctggcac ttcagcctcc ctggccatca ttggcctcca gtccggcgat 660

gaggctgatt attattgtgt ggcatgggat gacagcgtag atggctatgt cttcggatct 720

gggaccaagg tcaccgtcct aggt 744

SEQ ID NO：120

E V Q L V E S G A E V K K P G S S V K V S C K A S G G P F R S Y A I S W V R Q

A P G Q G P E W M G G I IP I F G T T K Y A P K F Q G R V T I T A D D F A G T

V Y M E L S S L R S E D T A M Y Y C A K H M G Y Q V R E T M D V W G K G T T V

T V S S G T G G S G G T G S G T G G S T S Y V L T Q P P S V S G T P G Q R V T

I S C S G S R S N V G D N S V Y W Y Q H V P E M A P K L L V Y K N T Q R P S G

V P A R F S G S K S G T S A S L A I I G L Q S G D E A D Y Y C V A W D D S V D

G Y V F G S G T K V T V L G

SEQ ID NO：121

gaggtgcagc tggtggagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaagtc 60

tcttgcaagg cttctggagg ccccttccgc agctatgcta tcagctgggt gcgacaggcc 120

cctggacaag ggcctgagtg gatgggaggg atcatcccta tttttggtac aacaaaatac 180

gcaccgaagt tccagggcag agtcacgatt accgcggacg atttcgcggg cacagtttac 240

atggagctga gcagcctgcg atctgaggac acggccatgt actactgtgc gaaacatatg 300

gggtaccagg tgcgcgaaac tatggacgtc tggggcaaag ggaccacggt caccgtctcg 360

agcggtacgg gcggttcagg cggaaccggc agcggcactg gcgggtcgac gcagtctgtg 420

ttgacgcagc cgccctcagt gtctgcggcc ccaggacaga aggtcaccat ctcctgctct 480

ggaagcagct ccaacattgg gaatgattat gtatcctggt accagcagct cccaggaaca 540

gcccccaaac tcctcattta tgacaataat aagcgaccct cagggattcc tgaccgattc 600

tctggctcca agtctggcac gtcagccacc ctgggcatca ccggactcca gactggggac 660

gaggccaact attactgcgc aacatgggat cgccgcccga ctgcttatgt tgtcttcggc 720

ggagggacca agctgaccgt cctaggt 747

SEQ ID NO：122

E V Q L V E S G A E V K K P G S S V K V S C K A S G G P F R S Y A I S W V R Q

A P G Q G P E W M G G I I P I F G T T K Y A P K F Q G R V T I T A D D F A G T

V Y M E L S S L R S E D T A M Y Y C A K H M G Y Q V R E T M D V W G K G T T V

T V S S G T G G S G G T G S G T G G S T Q S V L T Q P P S V S A A P G Q K V T

I S C S G S S S N I G N D Y V S W Y Q Q L P G T A P K L L I Y D N N K R P S G

I P D R F S G S K S G T S A T L G I T G L Q T G D E A N Y Y C A T W D R R P T

A Y V V F G G G T K L T V L G

SEQ ID NO：123

caggtacagc tgcagcagtc aggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60

tcctgcaagg tttccggagt cattttcagc ggcagtgcga tcagctgggt gcgacaggcc 120

cctggacaag gccttgagtg gatgggaggg atcagccctc tctttggcac aacaaattac 180

gcacaaaagt tccagggcag agtcacgatt accgcggacc aatccacgaa cacaacctac 240

atggaggtga acagcctgag atatgaggac acggccgtgt atttctgtgc gcgaggtcca 300

aaatattaca gtgagtacat ggacgtctgg ggcaaaggga ccacggtcac cgtctcgagc 360

ggtacgggcg gttcaggcgg aaccggcagc ggcactggcg ggtcgacgga catccagatg 420

acccagtctc catcctccct gtctgcatct gtaggagaca gagtcaccat cacttgccgg 480

gcgagtcagg gcattagcag ttatttagcc tggtatcagc agaagccagg gaaagttcct 540

acactcctga tctatgatgc atccactttg cgatcagggg tcccatctcg cttcagtggc 600

agtggatctg cgacagattt cactctcacc atcagcagcc tgcagcctga agatgttgca 660

acttattact gtcaaaggta taacagtgcc cccccgatca ccttcggcca agggacacga 720

ctggagatta aacgt 735

SEQ ID NO：124

Q V Q L Q Q S G A E V K K P G S S V K V S C K V S G V I F S G S A I S W V R Q

A P G Q G L E W M G G I S P L F G T T N Y A Q K F Q G R V T I T A D Q S T N T

T Y M E V N S L R Y E D T A V Y F C A R G P K Y Y S E Y M D V W G K G T T V T

V S S G T G G S G G T G S G T G G S T D I Q M T Q S P S S L S A S V G D R V T

I T C R A S Q G I S S Y L A W Y Q Q K P G K V P T L L I Y D A S T L R S G V P

S R F S G S G S A T D F T L T I S S L Q P E D V A T Y Y C Q R Y N S A P P I T

F G Q G T R L E I K R

SEQ ID NO：125

caggtccagc tggtacagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60

tcctgcaagg cttctggagg caccttcagt agttatgcta tcagctgggt gcgacaggcc 120

cctggacaag ggcttgagtg gatgggagga atcatgggta tgtttggcac aactaactac 180

gcacagaagt tccagggcag agtcacgatt accgcggacg aattcacgag cgcagcctac 240

atggagctga ggagcctgag atctgaggac acggccgtct actactgtgc gaggtctagt 300

ggttattacc ccgaatactt ccaggactgg ggccagggca ccctggtcac cgtctcgagc 360

ggtacgggcg gttcaggcgg aaccggcagc ggcactggcg ggtcgacgca gtctgtgctg 420

actcagccac cctcagagtc cgtgtcccca ggacagacag ccagcgtcac ctgctctgga 480

cataaattgg gggataaata tgtttcgtgg tatcagcaga agccaggcca gtcccctgta 540

ttactcatct atcaagataa caggcggccc tcagggatcc ctgagcgatt cataggctcc 600

aactctggga acacagccac tctgaccatc agcgggaccc aggctctgga tgaggctgac 660

tattactgtc aggcgtggga cagcagcact gcggttttcg gcggagggac caagctgacc 720

gtcctaggt 729

SEQ ID NO：126

Q V Q L V Q S G A E V K K P G S S V K V S C K A S G G T F S S Y A I S W V R Q

A P G Q G L E W M G G I M G M F G T T N Y A Q K F Q G R V T I T A D E F T S A

A Y M E L R S L R S E D T A V Y Y C A R S S G Y Y P E Y F Q D W G Q G T L V T

V S S G T G G S G G T G S G T G G S T Q S V L T Q P P S E S V S P G Q T A S V

T C S G H K L G D K Y V S W Y Q Q K P G Q S P V L L I Y Q D N R R P S G I P E

R F I G S N S G N T A T L T I S G T Q A L D E A D Y Y C Q A W D S S T A V F G

G G T K L T V L G

SEQ ID NO：127

caggtccagc tggtgcagtc tgggggaggc ctggtcaagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt caccttcagt agctatagca tgaactgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcatcc attagtagta gtagtagtta catatactac 180

gtagactcag tgaagggccg attcaccatc tccagagaca acgccaagaa ctcactgtat 240

ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagaggtggt 300

gggagctacg gggcctacga aggctttgac tactggggcc agggcaccct ggtcaccgtc 360

tcgagcggta cgggcggttc aggcggaacc ggcagcggca ctggcgggtc gacggaaatt 420

gtgctgactc agtctccagg caccctgtct ttgtctccag gggaaagagc caccctctcc 480

tgcagggcca gtcagcgtgt tagcagctac ttagcctggt accaacagaa acctggccag 540

gctcccaggc tcctcatcta tggtgcatcc accagggccg ctggcatccc agacaggttc 600

agtggcagtg ggtctgggac agacttcact ctcaccatca gcagactgga gcctgaagat 660

tctgcagtgt attactgtca gcagtatggt aggacaccgc tcactttcgg cggagggacc 720

aaggtggaga tcaaacgt 738

SEQ ID NO：128

Q V Q L V Q S G G G L V K P G G S L R L S C A A S G F T F S S Y S M N W V R Q

A P G K G L E W V S S I S S S S S Y I Y Y V D S V K G R F T I S R D N A K N S

L Y L Q M N S L R A E D T A V Y Y C A R G G G S Y G A Y E G F D Y W G Q G T L

V T V S S G T G G S G G T G S G T G G S T E I V L T Q S P G T L S L S P G E R

A T L S C R A S Q R V S S Y L A W Y Q Q K P G Q A P R L L I Y G A S T R A A G

I P D R F S G S G S G T D F T L T I S R L E P E D S A V Y Y C Q Q Y G R T P L

T F G G G T K V E I K R

SEQ ID NO：129

gaggtgcagc tggtggagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaagtc 60

tcttgcaagg cttctggagg ccccttccgc agctatgcta tcagctgggt gcgacaggcc 120

cctggacaag ggcctgagtg gatgggaggg atcatcccta tttttggtac aacaaaatac 180

gcaccgaagt tccagggcag agtcacgatt accgcggacg atttcgcggg cacagtttac 240

atggagctga gcagcctgcg atctgaggac acggccatgt actactgtgc gaaacatatg 300

gggtaccagg tgcgcgaaac tatggacgtc tggggcaaag ggaccacggt caccgtctcg 360

agcggtacgg gcggttcagg cggaaccggc agcggcactg gcgggtcgac gtcctatgtg 420

ctgactcagc caccctcggt gtcagtggcc ccaggacaga cggccaggat tacctgtggg 480

ggaaacaaca ttggaagtaa aagtgtgcac tggtaccagc agaagccagg ccaggcccct 540

gtgctggtcg tctatgatga tagcgaccgg ccctcaggga tccctgagcg attctctggc 600

tccaactctg ggaacacggc caccctgacc atcagcaggg tcgaagccgg ggatgaggcc 660

gactattact gtcaggtgtg ggatagtagt agtgatcatg ctgtgttcgg aggaggcacc 720

cagctgaccg tcctcggt 738

SEQ ID NO：130

E V Q L V E S G A E V K K P G S S V K V S C K A S G G P F R S Y A I S W V R Q

A P G Q G P E W M G G I I P I F G T T K Y A P K F Q G R V T I T A D D F A G T

V Y M E L S S L R S E D T A M Y Y C A K H M G Y Q V R E T M D V W G K G T T V

T V S S G T G G S G G T G S G T G G S T S Y V L T Q P P S V S V A P G Q T A R

I T C G G N N I G S K S V H W Y Q Q K P G Q A P V L V V Y D D S D R P S G I P

E R F S G S N S G N T A T L T I S R V E A G D E A D Y Y C Q V W D S S S D H A

V F G G G T Q L T V L G

SEQ ID NO：131

gaggtgcagc tggtggagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaagtc 60

tcttgcaagg cttctggagg ccccttccgc agctatgcta tcagctgggt gcgacaggcc 120

cctggacaag ggcctgagtg gatgggaggg atcatcccta tttttggtac aacaaaatac 180

gcaccgaagt tccagggcag agtcacgatt accgcggacg atttcgcggg cacagtttac 240

atggagctga gcagcctgcg atctgaggac acggccatgt actactgtgc gaaacatatg 300

gggtaccagg tgcgcgaaac tatggacgtc tggggcaaag ggaccacggt caccgtctcg 360

agcggtacgg gcggttcagg cggaaccggc agcggcactg gcgggtcgac gtcctatgtg 420

ctgactcagc caccctcagc gtctgggacc cccgggcaga gggtcaccat ctcttgttct 480

ggaagcagct ccaacatcgg aagtaattat gtatactggt accagcagct cccaggcacg 540

gcccccaaac tcctcatcta tagggatggt cagcggccct caggggtccc tgaccgattc 600

tctggctcca agtctggcac ctcagcctcc ctggccatca gtggactccg gtccgatgat 660

gaggctgatt attactgtgc aacatgggat gacaacctga gtggtccagt attcggcgga 720

gggaccaagc tgaccgtcct aggt 744

SEQID NO：132

E V Q L V E S G A E V K K P G S S V K V S C K A S G G P F R S Y A I S W V R Q

A P G Q G P E W M G G I I P I F G T T K Y A P K F Q G R V T I T A D D F A G T

V Y M E L S S L R S E D T A M Y Y C A K H M G Y Q V R E T M D V W G K G T T V

T V S S G T G G S G G T G S G T G G S T S Y V L T Q P P S A S G T P G Q R V T

I S C S G S S S N I G S N Y V Y W Y Q Q L P G T A P K L L I Y R D G Q R P S G

V P D R F S G S K S G T S A S L A I S G L R S D D E A D Y Y C A T W D D N L S

G P V F G G G T K L T V L G

SEQ ID NO：133

gaggtgcagc tggtggagtc tggggctgag gtgaagaagc cagggtcctc ggtgaaggtc 60

tcctgtaagg cctctggagg caccttctcc agctatggta tcagctgggt gcgacaggcc 120

cctggacaag ggcttgagtg gatgggagac atcatcggta tgtttggttc aacaaactac 180

gcacagaact tccagggcag actcacgatt accgcggacg aatccacgag cacagcctac 240

atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagaagtagt 300

ggttattacc ctgcatacct cccccactgg ggccagggca ccttggtcac cgtctcgagc 360

ggtacgggcg gttcaggcgg aaccggcagc ggcactggcg ggtcgacgga aattgtgttg 420

acccagtctc caggcaccct gtctttgtct ccaggggaaa gagccaccct ctcctgcagg 480

gccagtcaga gtgttagcag cagctactta gcctggtacc agcagaaacc tggccaggct 540

cccaggctcc tcatctatgg tgcatccagc agggccactg gcatcccaga caggttcagt 600

ggcagtgggt ctgggacaga cttcactctc accatcagca gactggagcc tgaagatttt 660

gcagtgtatt actgtcagca gtatggtagc tcacccagaa ctttcggcgg agggaccaag 720

gtggagatca aacgt 735

SEQ ID NO：134

E V Q L V E S G A E V K K P G S S V K V S C K A S G G T F S S Y G I S W V R Q

A P G Q G L E W M G D I I G M F G S T N Y A Q N F Q G R L T I T A D E S T S T

A Y M E L S S L R S E D T A V Y Y C A R S S G Y Y P A Y L P H W G Q G T L V T

V S S G T G G S G G T G S G T G G S T E I V L T Q S P G T L S L S P G E R A T

L S C R A S Q S V S S S Y L A W Y Q Q K P G Q A P R L L I Y G A S S R A T G I

P D R F S G S G S G T D F T L T I S R L E P E D F A V Y Y C Q Q Y G S S P R T

F G G G T K V E I K R

SEQ ID NO：135

gaggtgcagc tggtggagtc tggggctgag gtgaagaagc cggggtcctc ggtgaaggtc 60

tcctgcaagg cttctggagg caccttcagc ttctattcta tgagctgggt gcgacaggcc 120

cctggacaag gacttgagtg gatgggaggg atcatcccta tgtttggtac aacaaactac 180

gcacagaagt tccagggcag agtcacgatt accgcggtcg aatccacgag cacagcctac 240

atggaggtga gcagcctgag atctgaggac acggccgttt attactgtgc gagaggtgat 300

aagggtatct actactacta catggacgtc tggggcaaag ggaccacggt caccgtctcg 360

agcggtacgg gcggttcagg cggaaccggc agcggcactg gcgggtcgac gcagtctgcc 420

ctgactcagc ctgcctccgt gtctgggtct cctggacagt cgatcaccat ctcctgcact 480

ggaaccagca gtgacgttgg tggttataac tatgtctcct ggtaccaaca gcacccaggc 540

aaagccccca aactcatgat ttatgaggtc agtaatcggc cctcaggggt ttctaatcgc 600

ttctctggct ccaagtctgg caacacggcc tccctgacca tctctgggct ccaggctgag 660

gacgaggctg attattactg cagctcatat acaagcagca gcactcttgt cttcggaact 720

gggaccaagg tcaccgtcct aggt 744

SEQ ID NO：136

E V Q L V E S G A E V K K P G S S V K V S C K A S G G T F S F Y S M S W V R Q

A P G Q G L E W M G G I I P M F G T T N Y A Q K F Q G R V T I T A V E S T S T

A Y M E V S S L R S E D T A V Y Y C A R G D K G I Y Y Y Y M D V W G K G T T V

T V S S G T G G S G G T G S G T G G S T Q S A L T Q P A S V S G S P G Q S I T

I S C T G T S S D V G G Y N Y V S W Y Q Q H P G K A P K L M I Y E V S N R P S

G V S N R F S G S K S G N T A S L T I S G L Q A E D E A D Y Y C S S Y T S S S

T L V F G T G T K V T V L G

SEQ ID NO：137

gaggtgcagc tggtggagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60

tcctgcaagg cttctggagg caccttcagc agctatgcta tcagctgggt gcgacaggcc 120

cctggacaag ggcttgagtg gatgggaggg atcatcggta tgttcggtac agcaaactac 180

gcacagaagt tccagggcag agtcacgatt accgcggacg aatttacgag cacagcctac 240

atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagaggaaat 300

tattactatg agagtagtct cgactactgg ggccagggaa ccctggtcac cgtctcgagc 360

ggtacgggcg gttcaggcgg aaccggcagc ggcactggcg ggtcgacgca gtctgtcgtg 420

acgcagccgc cctcggtgtc agtggcccca ggacagacgg ccaggattac ctgtggggga 480

aacaacattg gaagtaaaag tgtgcactgg taccagcaga agccaggcca ggcccctgtg 540

ctggtcgtct atgatgatag cgaccggccc tcagggatcc ctgagcgatt ctctggctcc 600

aactctggga acacggccac cctgaccatc agcagggtcg aagccgggga tgaggccgac 660

tattactgtc aggtgtggga tagtagtagt gatcattatg tcttcggaac tgggaccaag 720

gtcaccgtcc taggt 735

SEQ ID NO：138

E V Q L V E S G A E V K K P G S S V K V S C K A S G G T F S S Y A I S W V R Q

A P G Q G L E W M G G I I G M F G T A N Y A Q K F Q G R V T I T A D E F T S T

A Y M E L S S L R S E D T A V Y Y C A R G N Y Y Y E S S L D Y W G Q G T L V T

V S S G T G G S G G T G S G T G G S T Q S V V T Q P P S V S V A P G Q T A R I

T C G G N N I G S K S V H W Y Q Q K P G Q A P V L V V Y D D S D R P S G I P E

R F S G S N S G N T A T L T I S R V E A G D E A D Y Y C Q V W D S S S D H Y V

F G T G T K V T V L G

SEQ ID NO：139

caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgagagtc 60

tcctgcaagg cttctggaag catcttcaga aactatgcta tgagctgggt gcgacaggcc 120

cctggacaag ggcttgagtg gatgggaggg atcatcgcta tttttgggac accaaagtac 180

gcacagaagt tccagggcag agtcacgatt accgcggacg aatcgacgag cactgtctac 240

atggaactga gcggactgag atctgaggac acggccatgt attactgtgc gaggattccc 300

cactataatt ttggttcggg gagttatttc gactactggg gccagggaac cctggtcacc 360

gtctcgagcg gtacgggcgg ttcaggcgga accggcagcg gcactggcgg gtcgacgact 420

gtgttgacac agccgccctc agtgtctggg gccccagggc agagggtcac catctcctgc 480

actgggagca gctccaacat cggggcaggt tatgatgtac actggtacca gcagcttcca 540

ggaacagccc ccaaactcct catctatggt aacagcaatc ggccctcagg ggtccctgac 600

cgattctctg gctccaagtc tggcacgtca gccaccctgg gcatcaccgg actccagact 660

ggggacgagg ccgattatta ctgcggaaca tgggatagca gcctgagtgc ttatgtcttc 720

ggaactggga ccaaggtcac cgtcctaggt 750

SEQ ID NO：140

Q V Q L V Q S G A E V K K P G S S V R V S C K A S G S I F R N Y A M S W V R Q

A P G Q G L E W M G G I I A I F G T P K Y A Q K F Q G R V T I T A D E S T S T

V Y M E L S G L R S E D T A M Y Y C A R I P H Y N F G S G S Y F D Y W G Q G T

L V T V S S G T G G S G G T G S G T G G S T T V L T Q P P S V S G A P G Q R V

T I S C T G S S S N I G A G Y D V H W Y Q Q L P G T A P K L L I Y G N S N R P

S G V P D R F S G S K S G T S A T L G I T G L Q T G D E A D Y Y C G T W D S S

L S A Y V F G T G T K V T V L G

SEQ ID NO：141

tcgacggatc gggagatctc ccgatcccct atggtgcact ctcagtacaa tctgctctga 60

tgccgcatag ttaagccagt atctgctccc tgcttgtgtg ttggaggtcg ctgagtagtg 120

cgcgagcaaa atttaagcta caacaaggc aaggcttgacc gacaattgca tgaagaatct 180

gcttagggtt aggcgttttg cgctgcttcg ctaggtggtc aatattggcc attagccata 240

ttattcattg gttatatagc ataaatcaat attggctatt ggccattgca tacgttgtat 300

ccatatcata atatgtacat ttatattggc tcatgtccaa cattaccgcc atgttgacat 360

tgattattga ctagttatta atagtaatca attacggggt cattagttca tagcccatat 420

atggagttcc gcgttacata acttacggta aatggcccgc ctggctgacc gcccaacgac 480

ccccgcccat tgacgtcaat aatgacgtat gttcccatag taacgccaat agggactttc 540

cattgacgtc aatgggtgga gtatttacgg taaactgccc acttggcagt acatcaagtg 600

tatcatatgc caagtacgcc ccctattgac gtcaatgacg gtaaatggcc cgcctggcat 660

tatgcccagt acatgacctt atgggacttt cctacttggc agtacatcta cgtattagtc 720

atcgctatta ccatggtgat gcggttttgg cagtacatca atgggcgtgg atagcggttt 780

gactcacggg gatttccaag tctccacccc attgacgtca atgggagttt gttttggcac 840

caaaatcaac gggactttcc aaaatgtcgt aacaactccg ccccattgac gcaaatgggc 900

ggtaggcgtg tacggtggga ggtctatata agcagagctc gtttagtgaa ccgtcagatc 960

gcctggagac gccatccacg ctgttttgac ctccatagaa gacaccggga ccgatccagc 1020

ctccgcggcc gggaacggtg cattggaagc tggcctggat atcctgactc tcttaggtag 1080

ccttgcagaa gttggtcgtg aggcactggg caggtaagta tcaaggttac aagacaggtt 1140

taaggagatc aatagaaact gggcttgtcg agacagagaa gactcttgcg tttctgatag 1200

gcacctattg gtcttactga catccacttt gcctttctct ccacaggtgt ccactcccag 1260

ttcaattaca gctcgccacc atgggatgga gctgtatcat cctcttcttg gtactgctgc 1320

tggcccagcc ggccagtgac cttgaccggt gcaccacttt tgatgatgtt caagctccta 1380

attacactca acatacttca tctatgaggg gggtttacta tcctgatgaa atttttagat 1440

cggacactct ttatttaact caggatttat ttcttccatt ttattctaat gttacagggt 1500

ttcatactat taatcatacg tttggcaacc ctgtcatacc ttttaaggat ggtatttatt 1560

ttgctgccac agagaaatca aatgttgtcc gtggttgggt ttttggttct accatgaaca 1620

acaagtcaca gtcggtgatt attattaaca attctactaa tgttgttata cgagcatgta 1680

actttgaatt gtgtgacaac cctttctttg ctgtttctaa acccatgggt acacagacac 1740

atactatgat attcgataat gcatttaatt gcactttcga gtacatatct gatgcctttt 1800

cgcttgatgt ttcagaaaag tcaggtaatt ttaaacactt acgagagttt gtgtttaaaa 1860

ataaagatgg gtttctctat gtttataagg gctatcaacc tatagatgta gttcgtgatc 1920

taccttctgg ttttaacact ttgaaaccta tttttaagtt gcctcttggt attaacatta 1980

caaattttag agccattctt acagcctttt cacctgctca agacatttgg ggcacgtcag 2040

ctgcagccta ttttgttggc tatttaaagc caactacatt tatgctcaag tatgatgaaa 2100

atggtacaat cacagatgct gttgattgtt ctcaaaatcc acttgctgaa ctcaaatgct 2160

ctgttaagag ctttgagatt gacaaaggaa tttaccagac ctctaatttc agggttgttc 2220

cctcaggaga tgttgtgaga ttccctaata ttacaaactt gtgtcctttt ggagaggttt 2280

ttaatgctac taaattccct tctgtctatg catgggagag aaaaaaaatt tctaattgtg 2340

ttgctgatta ctctgtgctc tacaactcaa catttttttc aacctttaag tgctatggcg 2400

tttctgccac taagttgaat gatctttgct tctccaatgt ctatgcagat tcttttgtag 2460

tcaagggaga tgatgtaaga caaatagcgc caggacaaac tggtgttatt gctgattata 2520

attataaatt gccagatgat ttcatgggtt gtgtccttgc ttggaatact aggaacattg 2580

atgctacttc aactggtaat tataattata aatataggta tcttagacat ggcaagctta 2640

ggccctttga gagagacata tctaatgtgc ctttctcccc tgatggcaaa ccttgcaccc 2700

cacctgctct taattgttat tggccattaa atgattatgg tttttacacc actactggca 2760

ttggctacca accttacaga gttgtagtac tttcttttga acttttaaat gcaccggcca 2820

cggtttgtgg accaaaatta tccactgacc ttattaagaa ccagtgtgtc aattttaatt 2880

ttaatggact cactggtact ggtgtgttaa ctccttcttc aaagagattt caaccatttc 2940

aacaatttgg ccgtgatgtt tctgatttca ctgattccgt tcgagatcct aaaacatctg 3000

aaatattaga catttcacct tgctcttttg ggggtgtaag tgtaattaca cctggaacaa 3060

atgcttcatc tgaagttgct gttctatatc aagatgttaa ctgcactgat gtttctacag 3120

caattcatgc agatcaactc acaccagctt ggcgcatata ttctactgga aacaatgtat 3180

tccagactca ggcaggctgt cttataggag ctgagcatgt cgacacttct tatgagtgcg 3240

acattcctat tggagctggc atttgtgcta gttaccatac agtttcttta ttacgtagta 3300

ctagccaaaa atctattgtg gcttatacta tgtctttagg tgctgatagt tcaattgctt 3360

actctaataa caccattgct atacctacta acttttcaat tagcattact acagaagtaa 3420

tgcctgtttc tatggctaaa acctccgtag attgtaatat gtacatctgc ggagattcta 3480

ctgaatgtgc taatttgctt ctccaatatg gtagcttttg cacacaacta aatcgtgcac 3540

tctcaggtat tgctgctgaa caggatcgca acacacgtga agtgttcgct caagtcaaac 3600

aaatgtacaa aaccccaact ttgaaatatt ttggtggttt taatttttca caaatattac 3660

ctgaccctct aaagccaact aagaggtctt ttattgagga cttgctcttt aataaggtga 3720

cactcgctga tgctggcttc atgaagcaat atggcgaatg cctaggtgat attaatgcta 3780

gagatctcat ttgtgcgcag aagttcaatg gacttacagt gttgccacct ctgctcactg 3840

atgatatgat tgctgcctac actgctgctc tagttagtgg tactgccact gctggatgga 3900

catttggtgc tggcgctgct cttcaaatac cttttgctat gcaaatggca tataggttca 3960

atggcattgg agttacccaa aatgttctct atgagaacca aaaacaaatc gccaaccaat 4020

ttaacaaggc gattagtcaa attcaagaat cacttacaac aacatcaact gcattgggca 4080

agctgcaaga cgttgttaac cagaatgctc aagcattaaa cacacttgtt aaacaactta 4140

gctctaattt tggtgcaatt tcaagtgtgc taaatgatat cctttcgcga cttgataaag 4200

tcgaggcgga ggtacaaatt gacaggttaa ttacaggcag acttcaaagc cttcaaacct 4260

atgtaacaca acaactaatc agggctgctg aaatcagggc ttctgctaat cttgctgcta 4320

ctaaaatgtc tgagtgtgtt cttggacaat caaaaagagt tgacttttgt ggaaagggct 4380

accaccttat gtccttccca caagcagccc cgcatggtgt tgtcttccta catgtcacgt 4440

atgtgccatc ccaggagagg aacttcacca cagcgccagc aatttgtcat gaaggcaaag 4500

catacttccc tcgtgaaggt gtttttgtgt ttaatggcac ttcttggttt attacacaga 4560

ggaacttctt ttctccacaa ataattacta cagacaatac atttgtctca ggaaattgtg 4620

atgtcgttat tggcatcatt aacaacacag tttatgatcc tctgcaacct gagcttgact 4680

cattcaaaga agagctggac aagtacttca aaaatcatac atcaccagat gttgattttg 4740

gcgacatttc aggcattaac gcttctgtcg tcaacattca aaaagaaatt gaccgcctca 4800

atgaggtcgc taaaaattta aatgaatcac tcattgacct tcaagaactg ggaaaatatg 4860

agcaatatat taaatggcct ctcgacgaac aaaaactcat ctcagaagag gatctgaatg 4920

ctgtgggcca ggacacgcag gaggtcatcg tggtgccaca ctccttgccc tttaaggtgg 4980

tggtgatctc agccatcctg gccctggtgg tgctcaccat catctccctt atcatcctca 5040

tcatgctttg gcagaagaag ccacgttagg cggccgctcg agtgctagca ccaagggccc 5100

cagcgtgttc cccctggccc ccagcagcaa gagcaccagc ggcggcacag ccgccctggg 5160

ctgcctggtg aaggactact tccccgagcc cgtgaccgtg agctggaaca gcggcgcctt 5220

gaccagcggc gtgcacacct tccccgccgt gctgcagagc agcggcctgt acagcctgag 5280

cagcgtggtg accgtgccca gcagcagcct gggcacccag acctacatct gcaacgtgaa 5340

ccacaagccc agcaacacca aggtggacaa acgcgtggag cccaagagct gcgacaagac 5400

ccacacctgc cccccctgcc ctgcccccga gctgctgggc ggaccctccg tgttcctgtt 5460

cccccccaag cccaaggaca ccctcatgat cagccggacc cccgaggtga cctgcgtggt 5520

ggtggacgtg agccacgagg accccgaggt gaagttcaac tggtacgtgg acggcgtgga 5580

ggtgcacaac gccaagacca agccccggga ggagcagtac aacagcacct accgggtggt 5640

gagcgtgctc accgtgctgc accaggactg gctgaacggc aaggagtaca agtgcaaggt 5700

gagcaacaag gccctgcctg cccccatcga gaagaccatc agcaaggcca agggccagcc 5760

ccgggagccc caggtgtaca ccctgccccc cagccgggag gagatgacca agaaccaggt 5820

gtccctcacc tgtctggtga agggcttcta ccccagcgac atcgccgtgg agtgggagag 5880

caacggccag cccgagaaca actacaagac caccccccct gtgctggaca gcgacggcag 5940

cttcttcctg tacagcaagc tcaccgtgga caagagccgg tggcagcagg gcaacgtgtt 6000

cagctgcagc gtgatgcacg aggccctgca caaccactac acccagaaga gcctgagcct 6060

gagccccggc aagtgataat ctagagggcc cgtttaaacc cgctgatcag cctcgactgt 6120

gccttctagt tgccagccat ctgttgtttg cccctccccc gtgccttcct tgaccctgga 6180

aggtgccact cccactgtcc tttcctaata aaatgaggaa attgcatcgc attgtctgag 6240

taggtgtcat tctattctgg ggggtggggt ggggcaggac agcaaggggg aggattggga 6300

agacaatagc aggcatgctg gggatgcggt gggctctatg gcttctgagg cggaaagaac 6360

cagctggggc tctagggggt atccccacgc gccctgtagc ggcgcattaa gcgcggcggg 6420

tgtggtggtt acgcgcagcg tgaccgctac acttgccagc gccctagcgc ccgctccttt 6480

cgctttcttc ccttcctttc tcgccacgtt cgccggcttt ccccgtcaag ctctaaatcg 6540

ggggctccct ttagggttcc gatttagtgc tttacggcac ctcgacccca aaaaacttga 6600

ttagggtgat ggttcacgta gtgggccatc gccctgatag acggtttttc gccctttgac 6660

gttggagtcc acgttcttta atagtggact cttgttccaa actggaacaa cactcaaccc 6720

tatctcggtc tattcttttg atttataagg gattttgccg atttcggcct attggttaaa 6780

aaatgagctg atttaacaaa aatttaacgc gaattaattc tgtggaatgt gtgtcagtta 6840

gggtgtggaa agtccccagg ctccccagca ggcagaagta tgcaaagcat gcatctcaat 6900

tagtcagcaa ccaggtgtgg aaagtcccca ggctccccag caggcagaag tatgcaaagc 6960

atgcatctca attagtcagc aaccatagtc ccgcccctaa ctccgcccat cccgccccta 7020

actccgccca gttccgccca ttctccgccc catggctgac taattttttt tatttatgca 7080

gaggccgagg ccgcctctgc ctctgagcta ttccagaagt agtgaggagg cttttttgga 7140

ggcctaggct tttgcaaaaa gctcccggga gcttgtatat ccattttcgg atctgatcaa 7200

gagacaggat gaggatcgtt tcgcatgatt gaacaagatg gattgcacgc aggttctccg 7260

gccgcttggg tggagaggct attcggctat gactgggcac aacagacaat cggctgctct 7320

gatgccgccg tgttccggct gtcagcgcag gggcgcccgg ttctttttgt caagaccgac 7380

ctgtccggtg ccctgaatga actgcaggac gaggcagcgc ggctatcgtg gctggccacg 7440

acgggcgttc cttgcgcagc tgtgctcgac gttgtcactg aagcgggaag ggactggctg 7500

ctattgggcg aagtgccggg gcaggatctc ctgtcatctc accttgctcc tgccgagaaa 7560

gtatccatca tggctgatgc aatgcggcgg ctgcatacgc ttgatccggc tacctgccca 7620

ttcgaccacc aagcgaaaca tcgcatcgag cgagcacgta ctcggatgga agccggtctt 7680

gtcgatcagg atgatctgga cgaagagcat caggggctcg cgccagccga actgttcgcc 7740

aggctcaagg cgcgcatgcc cgacggcgag gatctcgtcg tgacccatgg cgatgcctgc 7800

ttgccgaata tcatggtgga aaatggccgc ttttctggat tcatcgactg tggccggctg 7860

ggtgtggcgg accgctatca ggacatagcg ttggctaccc gtgatattgc tgaagagctt 7920

ggcggcgaat gggctgaccg cttcctcgtg ctttacggta tcgccgctcc cgattcgcag 7980

cgcatcgcct tctatcgcct tcttgacgag ttcttctgag cgggactctg gggttcgaaa 8040

tgaccgacca agcgacgccc aacctgccat cacgagattt cgattccacc gccgccttct 8100

atgaaaggtt gggcttcgga atcgttttcc gggacgccgg ctggatgatc ctccagcgcg 8160

gggatctcat gctggagttc ttcgcccacc ccaacttgtt tattgcagct tataatggtt 8220

acaaataaag caatagcatc acaaatttca caaataaagc atttttttca ctgcattcta 8280

gttgtggttt gtccaaactc atcaatgtat cttatcatgt ctgtataccg tcgacctcta 8340

gctagagctt ggcgtaatca tggtcatagc tgtttcctgt gtgaaattgt tatccgctca 8400

caattccaca caacatacga gccggaagca taaagtgtaa agcctggggt gcctaatgag 8460

tgagctaact cacattaatt gcgttgcgct cactgcccgc tttccagtcg ggaaacctgt 8520

cgtgccagct gcattaatga atcggccaac gcgcggggag aggcggtttg cgtattgggc 8580

gctcttccgc ttcctcgctc actgactcgc tgcgctcggt cgttcggctg cggcgagcgg 8640

tatcagctca ctcaaaggcg gtaatacggt tatccacaga atcaggggat aacgcaggaa 8700

agaacatgtg agcaaaaggc cagcaaaagg ccaggaaccg taaaaaggcc gcgttgctgg 8760

cgtttttcca taggctccgc ccccctgacg agcatcacaa aaatcgacgc tcaagtcaga 8820

ggtggcgaaa cccgacagga ctataaagat accaggcgtt tccccctgga agctccctcg 8880

tgcgctctcc tgttccgacc ctgccgctta ccggatacct gtccgccttt ctcccttcgg 8940

gaagcgtggc gctttctcat agctcacgct gtaggtatct cagttcggtg taggtcgttc 9000

gctccaagct gggctgtgtg cacgaacccc ccgttcagcc cgaccgctgc gccttatccg 9060

gtaactatcg tcttgagtcc aacccggtaa gacacgactt atcgccactg gcagcagcca 9120

ctggtaacag gattagcaga gcgaggtatg taggcggtgc tacagagttc ttgaagtggt 9180

ggcctaacta cggctacact agaagaacag tatttggtat ctgcgctctg ctgaagccag 9240

ttaccttcgg aaaaagagtt ggtagctctt gatccggcaa acaaaccacc gctggtagcg 9300

gtttttttgt ttgcaagcag cagattacgc gcagaaaaaa aggatctcaa gaagatcctt 9360

tgatcttttc tacggggtct gacgctcagt ggaacgaaaa ctcacgttaa gggattttgg 9420

tcatgagatt atcaaaaagg atcttcacct agatcctttt aaattaaaaa tgaagtttta 9480

aatcaatcta aagtatatat gagtaaactt ggtctgacag ttaccaatgc ttaatcagtg 9540

aggcacctat ctcagcgatc tgtctatttc gttcatccat agttgcctga ctccccgtcg 9600

tgtagataac tacgatacgg gagggcttac catctggccc cagtgctgca atgataccgc 9660

gagacccacg ctcaccggct ccagatttat cagcaataaa ccagccagcc ggaagggccg 9720

agcgcagaag tggtcctgca actttatccg cctccatcca gtctattaat tgttgccggg 9780

aagctagagt aagtagttcg ccagttaata gtttgcgcaa cgttgttgcc attgctacag 9840

gcatcgtggt gtcacgctcg tcgtttggta tggcttcatt cagctccggt tcccaacgat 9900

caaggcgagt tacatgatcc cccatgttgt gcaaaaaagc ggttagctcc ttcggtcctc 9960

cgatcgttgt cagaagtaag ttggccgcag tgttatcact catggttatg gcagcactgc 10020

ataattctct tactgtcatg ccatccgtaa gatgcttttc tgtgactggt gagtactcaa 10080

ccaagtcatt ctgagaatag tgtatgcggc gaccgagttg ctcttgcccg gcgtcaatac 10140

gggataatac cgcgccacat agcagaactt taaaagtgct catcattgga aaacgttctt 10200

cggggcgaaa actctcaagg atcttaccgc tgttgagatc cagttcgatg taacccactc 10260

gtgcacccaa ctgatcttca gcatctttta ctttcaccag cgtttctggg tgagcaaaaa 10320

caggaaggca aaatgccgca aaaaagggaa taagggcgac acggaaatgt tgaatactca 10380

tactcttcct ttttcaatat tattgaagca tttatcaggg ttattgtctc atgagcggat 10440

acatatttga atgtatttag aaaaataaac aaataggggt tccgcgcaca tttccccgaa 10500

aagtgccacc tgacg 10515

SEQ ID NO：142

tcgacggatc gggagatctc ccgatcccct atggtgcact ctcagtacaa tctgctctga 60

tgccgcatag ttaagccagt atctgctccc tgcttgtgtg ttggaggtcg ctgagtagtg 120

cgcgagcaaa atttaagcta caacaaggca aggcttgacc gacaattgtt aattaacatg 180

aagaatctgc ttagggttag gcgttttgcg ctgcttcgct aggtggtcaa tattggccat 240

tagccatatt attcattggt tatatagcat aaatcaatat tggctattgg ccattgcata 300

cgttgtatcc atatcataat atgtacattt atattggctc atgtccaaca ttaccgccat 360

gttgacattg attattgact agttattaat agtaatcaat tacggggtca ttagttcata 420

gcccatatat ggagttccgc gttacataac ttacggtaaa tggcccgcct ggctgaccgc 480

ccaacgaccc ccgcccattg acgtcaataa tgacgtatgt tcccatagta acgccaatag 540

ggactttcca ttgacgtcaa tgggtggagt atttacggta aactgcccac ttggcagtac 600

atcaagtgta tcatatgcca agtacgcccc ctattgacgt caatgacggt aaatggcccg 660

cctggcatta tgcccagtac atgaccttat gggactttcc tacttggcag tacatctacg 720

tattagtcat cgctattacc atggtgatgc ggttttggca gtacatcaat gggcgtggat 780

agcggtttga ctcacgggga tttccaagtc tccaccccat tgacgtcaat gggagtttgt 840

tttggcacca aaatcaacgg gactttccaa aatgtcgtaa caactccgcc ccattgacgc 900

aaatgggcgg taggcgtgta cggtgggagg tctatataag cagagctcgt ttagtgaacc 960

gtcagatcgc ctggagacgc catccacgct gttttgacct ccatagaaga caccgggacc 1020

gatccagcct ccgcggccgg gaacggtgca ttggaatcga tgactctctt aggtagcctt 1080

gcagaagttg gtcgtgaggc actgggcagg taagtatcaa ggttacaaga caggtttaag 1140

gagatcaata gaaactgggc ttgtcgagac agagaagact cttgcgtttc tgataggcac 1200

ctattggtct tactgacatc cactttgcct ttctctccac aggtgtccac tcccagttca 1260

attacagctc gccaccatgc ggctgcccgc ccagctgctg ggccttctca tgctgtgggt 1320

gcccgcctcg agatctatcg atgcatgcca tggtaccaag cttgccacca tgagcagcag 1380

ctcttggctg ctgctgagcc tggtggccgt gacagccgcc cagagcacca tcgaggagca 1440

ggccaagacc ttcctggaca agttcaacca cgaggccgag gacctgttct accagagcag 1500

cctggccagc tggaactaca acaccaacat caccgaggag aacgtgcaga acatgaacaa 1560

cgccggcgac aagtggagcg ccttcctgaa ggagcagagc acactggccc agatgtaccc 1620

cctgcaggag atccagaacc tgaccgtgaa gctgcagctg caggccctgc agcagaacgg 1680

cagcagcgtg ctgagcgagg acaagagcaa gcggctgaac accatcctga acaccatgtc 1740

caccatctac agcaccggca aagtgtgcaa ccccgacaac ccccaggagt gcctgctgct 1800

ggagcccggc ctgaacgaga tcatggccaa cagcctggac tacaacgagc ggctgtgggc 1860

ctgggagagc tggcggagcg aagtgggcaa gcagctgcgg cccctgtacg aggagtacgt 1920

ggtgctgaag aacgagatgg ccagggccaa ccactacgag gactacggcg actactggag 1980

aggcgactac gaagtgaacg gcgtggacgg ctacgactac agcagaggcc agctgatcga 2040

ggacgtggag cacaccttcg aggagatcaa gcctctgtac gagcacctgc acgcctacgt 2100

gcgggccaag ctgatgaacg cctaccccag ctacatcagc cccatcggct gcctgcccgc 2160

ccacctgctg ggcgacatgt ggggccggtt ctggaccaac ctgtacagcc tgaccgtgcc 2220

cttcggccag aagcccaaca tcgacgtgac cgacgccatg gtggaccagg cctgggacgc 2280

ccagcggatc ttcaaggagg ccgagaagtt cttcgtgagc gtgggcctgc ccaacatgac 2340

ccagggcttt tgggagaaca gcatgctgac cgaccccggc aatgtgcaga aggccgtgtg 2400

ccaccccacc gcctgggacc tgggcaaggg cgacttccgg atcctgatgt gcaccaaagt 2460

gaccatggac gacttcctga ccgcccacca cgagatgggc cacatccagt acgacatggc 2520

ctacgccgcc cagcccttcc tgctgcggaa cggcgccaac gagggctttc acgaggccgt 2580

gggcgagatc atgagcctga gcgccgccac ccccaagcac ctgaagagca tcggcctgct 2640

gagccccgac ttccaggagg acaacgagac cgagatcaac ttcctgctga agcaggccct 2700

gaccatcgtg ggcaccctgc ccttcaccta catgctggag aagtggcggt ggatggtgtt 2760

taagggcgag atccccaagg accagtggat gaagaagtgg tgggagatga agcgggagat 2820

cgtgggcgtg gtggagcccg tgccccacga cgagacctac tgcgaccccg ccagcctgtt 2880

ccacgtgagc aacgactact ccttcatccg gtactacacc cggaccctgt accagttcca 2940

gttccaggag gccctgtgcc aggccgccaa gcacgagggc cccctgcaca agtgcgacat 3000

cagcaacagc accgaggccg gacagaaact gttcaacatg ctgcggctgg gcaagagcga 3060

gccctggacc ctggccctgg agaatgtggt gggcgccaag aacatgaatg tgcgccccct 3120

gctgaactac ttcgagcccc tgttcacctg gctgaaggac cagaacaaga acagcttcgt 3180

gggctggagc accgactgga gcccctacgc cgaccagagc atcaaagtgc ggatcagcct 3240

gaagagcgcc ctgggcgaca aggcctacga gtggaacgac aacgagatgt acctgttccg 3300

gagcagcgtg gcctatgcca tgcggcagta cttcctgaaa gtgaagaacc agatgatcct 3360

gttcggcgag gaggacgtga gagtggccaa cctgaagccc cggatcagct tcaacttctt 3420

cgtgaccgcc cccaagaacg tgagcgacat catcccccgg accgaagtgg agaaggccat 3480

ccggatgagc cggagccgga tcaacgacgc cttccggctg aacgacaact ccctggagtt 3540

cctgggcatc cagcccaccc tgggccctcc caaccagccc cccgtgagca tctggctgat 3600

cgtgtttggc gtggtgatgg gcgtgatcgt ggtgggaatc gtgatcctga tcttcaccgg 3660

catccgggac cggaagaaga agaacaaggc ccggagcggc gagaacccct acgccagcat 3720

cgatatcagc aagggcgaga acaaccccgg cttccagaac accgacgacg tgcagaccag 3780

cttctgataa tctagaacga gctcgaattc gaagcttctg cagacgcgtc gacgtcatat 3840

ggatccgata tcgccgtggc ggccgcaccc agcgtgttca tcttcccccc ctccgacgag 3900

cagctgaaga gcggcaccgc cagcgtggtg tgcctgctga acaacttcta cccccgggag 3960

gccaaggtgc agtggaaggt ggacaacgcc ctgcagagcg gcaacagcca ggagagcgtg 4020

accgagcagg acagcaagga ctccacctac agcctgagca gcaccctcac cctgagcaag 4080

gccgactacg agaagcacaa ggtgtacgcc tgcgaggtga cccaccaggg cctgagcagc 4140

cccgtgacca agagcttcaa ccggggcgag tgttaataga cttaagttta aaccgctgat 4200

cagcctcgac tgtgccttct agttgccagc catctgttgt ttgcccctcc cccgtgcctt 4260

ccttgaccct ggaaggtgcc actcccactg tcctttccta ataaaatgag gaaattgcat 4320

cgcattgtct gagtaggtgt cattctattc tggggggtgg ggtggggcag gacagcaagg 4380

gggaggattg ggaagacaat agcaggcatg ctggggatgc ggtgggctct atggcttctg 4440

aggcggaaag aaccagctgg ggctctaggg ggtatcccca cgcgccctgt agcggcgcat 4500

taagcgcggc gggtgtggtg gttacgcgca gcgtgaccgc tacacttgcc agcgccctag 4560

cgcccgctcc tttcgctttc ttcccttcct ttctcgccac gttcgccggc tttccccgtc 4620

aagctctaaa tcgggggctc cctttagggt tccgatttag tgctttacgg cacctcgacc 4680

ccaaaaaact tgattagggt gatggttcac gtagtgggcc atcgccctga tagacggttt 4740

ttcgcccttt gacgttggag tccacgttct ttaatagtgg actcttgttc caaactggaa 4800

caacactcaa ccctatctcg gtctattctt ttgatttata agggattttg gccatttcgg 4860

cctattggtt aaaaaatgag ctgatttaac aaaaatttaa cgcgaattaa ttctgtggaa 4920

tgtgtgtcag ttagggtgtg gaaagtcccc aggctcccca gcaggcagaa gtatgcaaag 4980

catgcatctc aattagtcag caaccaggtg tggaaagtcc ccaggctccc cagcaggcag 5040

aagtatgcaa agcatgcatc tcaattagtc agcaaccata gtcccgcccc taactccgcc 5100

catcccgccc ctaactccgc ccagttccgc ccattctccg ccccatggct gactaatttt 5160

ttttatttat gcagaggccg aggccgcctc tgcctctgag ctattccaga agtagtgagg 5220

aggctttttt ggaggcctag gcttttgcaa aaagctcccg ggagcttgta tatccatttt 5280

cggatctgat cagcacgtga tgaaaaagcc tgaactcacc gcgacgtctg tcgagaagtt 5340

tctgatcgaa aagttcgaca gcgtctccga cctgatgcag ctctcggagg gcgaagaatc 5400

tcgtgctttc agcttcgatg taggagggcg tggatatgtc ctgcgggtaa atagctgcgc 5460

cgatggtttc tacaaagatc gttatgttta tcggcacttt gcatcggccg cgctcccgat 5520

tccggaagtg cttgacattg gggaattcag cgagagcctg acctattgca tctcccgccg 5580

tgcacagggt gtcacgttgc aagacctgcc tgaaaccgaa ctgcccgctg ttctgcagcc 5640

ggtcgcggag gccatggatg cgatcgctgc ggccgatctt agccagacga gcgggttcgg 5700

cccattcgga ccacaaggaa tcggtcaata cactacatgg cgtgatttca tatgcgcgat 5760

tgctgatccc catgtgtatc actggcaaac tgtgatggac gacaccgtca gtgcgtccgt 5820

cgcgcaggct ctcgatgagc tgatgctttg ggccgaggac tgccccgaag tccggcacct 5880

cgtgcacgcg gatttcggct ccaacaatgt cctgacggac aatggccgca taacagcggt 5940

cattgactgg agcgaggcga tgttcgggga ttcccaatac gaggtcgcca acatcttctt 6000

ctggaggccg tggttggctt gtatggagca gcagacgcgc tacttcgagc ggaggcatcc 6060

ggagcttgca ggatcgccgc ggctccgggc gtatatgctc cgcattggtc ttgaccaact 6120

ctatcagagc ttggttgacg gcaatttcga tgatgcagct tgggcgcagg gtcgatgcga 6180

cgcaatcgtc cgatccggag ccgggactgt cgggcgtaca caaatcgccc gcagaagcgc 6240

ggccgtctgg accgatggct gtgtagaagt actcgccgat agtggaaacc gacgccccag 6300

cactcgtccg agggcaaagg aatagcacgt gctacgagat ttcgattcca ccgccgcctt 6360

ctatgaaagg ttgggcttcg gaatcgtttt ccgggacgcc ggctggatga tcctccagcg 6420

cggggatctc atgctggagt tcttcgccca ccccaacttg tttattgcag cttataatgg 6480

ttacaaataa agcaatagca tcacaaattt cacaaataaa gcattttttt cactgcattc 6540

tagttgtggt ttgtccaaac tcatcaatgt atcttatcat gtctgtatac cgtcgacctc 6600

tagctagagc ttggcgtaat catggtcata gctgtttcct gtgtgaaatt gttatccgct 6660

cacaattcca cacaacatac gagccggaag cataaagtgt aaagcctggg gtgcctaatg 6720

agtgagctaa ctcacattaa ttgcgttgcg ctcactgccc gctttccagt cgggaaacct 6780

gtcgtgccag ctgcattaat gaatcggcca acgcgcgggg agaggcggtt tgcgtattgg 6840

gcgctcttcc gcttcctcgc tcactgactc gctgcgctcg gtcgttcggc tgcggcgagc 6900

ggtatcagct cactcaaagg cggtaatacg gttatccaca gaatcagggg ataacgcagg 6960

aaagaacatg tgagcaaaag gccagcaaaa ggccaggaac cgtaaaaagg ccgcgttgct 7020

ggcgtttttc cataggctcc gcccccctga cgagcatcac aaaaatcgac gctcaagtca 7080

gaggtggcga aacccgacag gactataaag ataccaggcg tttccccctg gaagctccct 7140

cgtgcgctct cctgttccga ccctgccgct taccggatac ctgtccgcct ttctcccttc 7200

gggaagcgtg gcgctttctc atagctcacg ctgtaggtat ctcagttcgg tgtaggtcgt 7260

tcgctccaag ctgggctgtg tgcacgaacc ccccgttcag cccgaccgct gcgccttatc 7320

cggtaactat cgtcttgagt ccaacccggt aagacacgac ttatcgccac tggcagcagc 7380

cactggtaac aggattagca gagcgaggta tgtaggcggt gctacagagt tcttgaagtg 7440

gtggcctaac tacggctaca ctagaagaac agtatttggt atctgcgctc tgctgaagcc 7500

agttaccttc ggaaaaagag ttggtagctc ttgatccggc aaacaaacca ccgctggtag 7560

cggttttttt gtttgcaagc agcagattac gcgcagaaaa aaaggatctc aagaagatcc 7620

tttgatcttt tctacggggt ctgacgctca gtggaacgaa aactcacgtt aagggatttt 7680

ggtcatgaga ttatcaaaaa ggatcttcac ctagatcctt ttaaattaaa aatgaagttt 7740

taaatcaatc taaagtatat atgagtaaac ttggtctgac agttaccaat gcttaatcag 7800

tgaggcacct atctcagcga tctgtctatt tcgttcatcc atagttgcct gactccccgt 7860

cgtgtagata actacgatac gggagggctt accatctggc cccagtgctg caatgatacc 7920

gcgagaccca cgctcaccgg ctccagattt atcagcaata aaccagccag ccggaagggc 7980

cgagcgcaga agtggtcctg caactttatc cgcctccatc cagtctatta attgttgccg 8040

ggaagctaga gtaagtagtt cgccagttaa tagtttgcgc aacgttgttg ccattgctac 8100

aggcatcgtg gtgtcacgct cgtcgtttgg tatggcttca ttcagctccg gttcccaacg 8160

atcaaggcga gttacatgat cccccatgtt gtgcaaaaaa gcggttagct ccttcggtcc 8220

tccgatcgtt gtcagaagta agttggccgc agtgttatca ctcatggtta tggcagcact 8280

gcataattct cttactgtca tgccatccgt aagatgcttt tctgtgactg gtgagtactc 8340

aaccaagtca ttctgagaat agtgtatgcg gcgaccgagt tgctcttgcc cggcgtcaat 8400

acgggataat accgcgccac atagcagaac tttaaaagtg ctcatcattg gaaaacgttc 8460

ttcggggcga aaactctcaa ggatcttacc gctgttgaga tccagttcga tgtaacccac 8520

tcgtgcaccc aactgatctt cagcatcttt tactttcacc agcgtttctg ggtgagcaaa 8580

aacaggaagg caaaatgccg caaaaaaggg aataagggcg acacggaaat gttgaatact 8640

catactcttc ctttttcaat attattgaag catttatcag ggttattgtc tcatgagcgg 8700

atacatattt gaatgtattt agaaaaataa acaaataggg gttccgcgca catttccccg 8760

aaaagtgcca cctgacg 8777

SEQ ID NO：143

tcgacggatc gggagatctc ccgatcccct atggtgcact ctcagtacaa tctgctctga 60

tgccgcatag ttaagccagt atctgctccc tgcttgtgtg ttggaggtcg ctgagtagtg 120

cgcgagcaaa atttaagcta caacaaggca aggcttgacc gacaattgtt aattaacatg 180

aagaatctgc ttagggttag gcgttttgcg ctgcttcgct aggtggtcaa tattggccat 240

tagccatatt attcattggt tatatagcat aaatcaatat tggctattgg ccattgcata 300

cgttgtatcc atatcataat atgtacattt atattggctc atgtccaaca ttaccgccat 360

gttgacattg attattgact agttattaat agtaatcaat tacggggtca ttagttcata 420

gcccatatat ggagttccgc gttacataac ttacggtaaa tggcccgcct ggctgaccgc 480

ccaacgaccc ccgcccattg acgtcaataa tgacgtatgt tcccatagta acgccaatag 540

ggactttcca ttgacgtcaa tgggtggagt atttacggta aactgcccac ttggcagtac 600

atcaagtgta tcatatgcca agtacgcccc ctattgacgt caatgacggt aaatggcccg 660

cctggcatta tgcccagtac atgaccttat gggactttcc tacttggcag tacatctacg 720

tattagtcat cgctattacc atggtgatgc ggttttggca gtacatcaat gggcgtggat 780

agcggtttga ctcacgggga tttccaagtc tccaccccat tgacgtcaat gggagtttgt 840

tttggcacca aaatcaacgg gactttccaa aatgtcgtaa caactccgcc ccattgacgc 900

aaatgggcgg taggcgtgta cggtgggagg tctatataag cagagctcgt ttagtgaacc 960

gtcagatcgc ctggagacgc catccacgct gttttgacct ccatagaaga caccgggacc 1020

gatccagcct ccgcggccgg gaacggtgca ttggaatcga tgactctctt aggtagcctt 1080

gcagaagttg gtcgtgaggc actgggcagg taagtatcaa ggttacaaga caggtttaag 1140

gagatcaata gaaactgggc ttgtcgagac agagaagact cttgcgtttc tgataggcac 1200

ctattggtct tactgacatc cactttgcct ttctctccac aggtgtccac tcccagttca 1260

attacagctc gccaccatgc ggttctccgc tcagctgctg ggccttctgg tgctgtggat 1320

tcccggcgtc tcgagatcta tcgatgcatg ccatggtacc aagcttgcca ccatgagcag 1380

cagctcttgg ctgctgctga gcctggtggc cgtgacagcc gcccagagca ccatcgagga 1440

gcaggccaag accttcctgg acaagttcaa ccacgaggcc gaggacctgt tctaccagag 1500

cagcctggcc agctggaact acaacaccaa catcaccgag gagaacgtgc agaacatgaa 1560

caacgccggc gacaagtgga gcgccttcct gaaggagcag agcacactgg cccagatgta 1620

ccccctgcag gagatccaga acctgaccgt gaagctgcag ctgcaggccc tgcagcagaa 1680

cggcagcagc gtgctgagcg aggacaagag caagcggctg aacaccatcc tgaacaccat 1740

gtccaccatc tacagcaccg gcaaagtgtg caaccccgac aacccccagg agtgcctgct 1800

gctggagccc ggcctgaacg agatcatggc caacagcctg gactacaacg agcggctgtg 1860

ggcctgggag agctggcgga gcgaagtggg caagcagctg cggcccctgt acgaggagta 1920

cgtggtgctg aagaacgaga tggccagggc caaccactac gaggactacg gcgactactg 1980

gagaggcgac tacgaagtga acggcgtgga cggctacgac tacagcagag gccagctgat 2040

cgaggacgtg gagcacacct tcgaggagat caagcctctg tacgagcacc tgcacgccta 2100

cgtgcgggcc aagctgatga acgcctaccc cagctacatc agccccatcg gctgcctgcc 2160

cgcccacctg ctgggcgaca tgtggggccg gttctggacc aacctgtaca gcctgaccgt 2220

gcccttcggc cagaagccca acatcgacgt gaccgacgcc atggtggacc aggcctggga 2280

cgcccagcgg atcttcaagg aggccgagaa gttcttcgtg agcgtgggcc tgcccaacat 2340

gacccagggc ttttgggaga acagcatgct gaccgacccc ggcaatgtgc agaaggccgt 2400

gtgccacccc accgcctggg acctgggcaa gggcgacttc cggatcctga tgtgcaccaa 2460

agtgaccatg gacgacttcc tgaccgccca ccacgagatg ggccacatcc agtacgacat 2520

ggcctacgcc gcccagccct tcctgctgcg gaacggcgcc aacgagggct ttcacgaggc 2580

cgtgggcgag atcatgagcc tgagcgccgc cacccccaag cacctgaaga gcatcggcct 2640

gctgagcccc gacttccagg aggacaacga gaccgagatc aacttcctgc tgaagcaggc 2700

cctgaccatc gtgggcaccc tgcccttcac ctacatgctg gagaagtggc ggtggatggt 2760

gtttaagggc gagatcccca aggaccagtg gatgaagaag tggtgggaga tgaagcggga 2820

gatcgtgggc gtggtggagc ccgtgcccca cgacgagacc tactgcgacc ccgccagcct 2880

gttccacgtg agcaacgact actccttcat ccggtactac acccggaccc tgtaccagtt 2940

ccagttccag gaggccctgt gccaggccgc caagcacgag ggccccctgc acaagtgcga 3000

catcagcaac agcaccgagg ccggacagaa actgttcaac atgctgcggc tgggcaagag 3060

cgagccctgg accctggccc tggagaatgt ggtgggcgcc aagaacatga atgtgcgccc 3120

cctgctgaac tacttcgagc ccctgttcac ctggctgaag gaccagaaca agaacagctt 3180

cgtgggctgg agcaccgact ggagccccta cgccgaccag agcatcaaag tgcggatcag 3240

cctgaagagc gccctgggcg acaaggccta cgagtggaac gacaacgaga tgtacctgtt 3300

ccggagcagc gtggcctatg ccatgcggca gtacttcctg aaagtgaaga accagatgat 3360

cctgttcggc gaggaggacg tgagagtggc caacctgaag ccccggatca gcttcaactt 3420

cttcgtgacc gcccccaaga acgtgagcga catcatcccc cggaccgaag tggagaaggc 3480

catccggatg agccggagcc ggatcaacga cgccttccgg ctgaacgaca actccctgga 3540

gttcctgggc atccagccca ccctgggccc tcccaaccag ccccccgtga gcatctggct 3600

gatcgtgttt ggcgtggtga tgggcgtgat cgtggtggga atcgtgatcc tgatcttcac 3660

cggcatccgg gaccggaaga agaagaacaa ggcccggagc ggcgagaacc cctacgccag 3720

catcgatatc agcaagggcg agaacaaccc cggcttccag aacaccgacg acgtgcagac 3780

cagcttctga taatctagaa cgagctcgaa ttcgaagctt ctgcagacgc gtcgacgtca 3840

tatggatccg atatcgccgt ggcggccgca ggccagccca aggccgctcc cagcgtgacc 3900

ctgttccccc cctcctccga ggagctgcag gccaacaagg ccaccctggt gtgcctcatc 3960

agcgacttct accctggcgc cgtgaccgtg gcctggaagg ccgacagcag ccccgtgaag 4020

gccggcgtgg agaccaccac ccccagcaag cagagcaaca acaagtacgc cgccagcagc 4080

tacctgagcc tcacccccga gcagtggaag agccaccgga gctacagctg ccaggtgacc 4140

cacgagggca gcaccgtgga gaagaccgtg gcccccaccg agtgcagcta atagacttaa 4200

gtttaaaccg ctgatcagcc tcgactgtgc cttctagttg ccagccatct gttgtttgcc 4260

cctcccccgt gccttccttg accctggaag gtgccactcc cactgtcctt tcctaataaa 4320

atgaggaat tgcatcgcat tgtctgagta ggtgtcattc tattctgggg ggtggggtgg 4380

ggcaggacag caagggggag gattgggaag acaatagcag gcatgctggg gatgcggtgg 4440

gctctatggc ttctgaggcg gaaagaacca gctggggctc tagggggtat ccccacgcgc 4500

cctgtagcgg cgcattaagc gcggcgggtg tggtggttac gcgcagcgtg accgctacac 4560

ttgccagcgc cctagcgccc gctcctttcg ctttcttccc ttcctttctc gccacgttcg 4620

ccggctttcc ccgtcaagct ctaaatcggg ggctcccttt agggttccga tttagtgctt 4680

tacggcacct cgaccccaaa aaacttgatt agggtgatgg ttcacgtagt gggccatcgc 4740

cctgatagac ggtttttcgc cctttgacgt tggagtccac gttctttaat agtggactct 4800

tgttccaaac tggaacaaca ctcaacccta tctcggtcta ttcttttgat ttataaggga 4860

ttttggccat ttcggcctat tggttaaaaa atgagctgat ttaacaaaaa tttaacgcga 4920

attaattctg tggaatgtgt gtcagttagg gtgtggaaag tccccaggct ccccagcagg 4980

cagaagtatg caaagcatgc atctcaatta gtcagcaacc aggtgtggaa agtccccagg 5040

ctccccagca ggcagaagta tgcaaagcat gcatctcaat tagtcagcaa ccatagtccc 5100

gcccctaact ccgcccatcc cgcccctaac tccgcccagt tccgcccatt ctccgcccca 5160

tggctgacta atttttttta tttatgcaga ggccgaggcc gcctctgcct ctgagctatt 5220

ccagaagtag tgaggaggct tttttggagg cctaggcttt tgcaaaaagc tcccgggagc 5280

ttgtatatcc attttcggat ctgatcagca cgtgatgaaa aagcctgaac tcaccgcgac 5340

gtctgtcgag aagtttctga tcgaaaagtt cgacagcgtc tccgacctga tgcagctctc 5400

ggagggcgaa gaatctcgtg ctttcagctt cgatgtagga gggcgtggat atgtcctgcg 5460

ggtaaatagc tgcgccgatg gtttctacaa agatcgttat gtttatcggc actttgcatc 5520

ggccgcgctc ccgattccgg aagtgcttga cattggggaa ttcagcgaga gcctgaccta 5580

ttgcatctcc cgccgtgcac agggtgtcac gttgcaagac ctgcctgaaa ccgaactgcc 5640

cgctgttctg cagccggtcg cggaggccat ggatgcgatc gctgcggccg atcttagcca 5700

gacgagcggg ttcggcccat tcggaccgca aggaatcggt caatacacta catggcgtga 5760

tttcatatgc gcgattgctg atccccatgt gtatcactgg caaactgtga tggacgacac 5820

cgtcagtgcg tccgtcgcgc aggctctcga tgagctgatg ctttgggccg aggactgccc 5880

cgaagtccgg cacctcgtgc acgcggattt cggctccaac aatgtcctga cggacaatgg 5940

ccgcataaca gcggtcattg actggagcga ggcgatgttc ggggattccc aatacgaggt 6000

cgccaacatc ttcttctgga ggccgtggtt ggcttgtatg gagcagcaga cgcgctactt 6060

cgagcggagg catccggagc ttgcaggatc gccgcggctc cgggcgtata tgctccgcat 6120

tggtcttgac caactctatc agagcttggt tgacggcaat ttcgatgatg cagcttgggc 6180

gcagggtcga tgcgacgcaa tcgtccgatc cggagccggg actgtcgggc gtacacaaat 6240

cgcccgcaga agcgcggccg tctggaccga tggctgtgta gaagtactcg ccgatagtgg 6300

aaaccgacgc cccagcactc gtccgagggc aaaggaatag cacgtgctac gagatttcga 6360

ttccaccgcc gccttctatg aaaggttggg cttcggaatc gttttccggg acgccggctg 6420

gatgatcctc cagcgcgggg atctcatgct ggagttcttc gcccacccca acttgtttat 6480

tgcagcttat aatggttaca aataaagcaa tagcatcaca aatttcacaa ataaagcatt 6540

tttttcactg cattctagtt gtggtttgtc caaactcatc aatgtatctt atcatgtctg 6600

tataccgtcg acctctagct agagcttggc gtaatcatgg tcatagctgt ttcctgtgtg 6660

aaattgttat ccgctcacaa ttccacacaa catacgagcc ggaagcataa agtgtaaagc 6720

ctggggtgcc taatgagtga gctaactcac attaattgcg ttgcgctcac tgcccgcttt 6780

ccagtcggga aacctgtcgt gccagctgca ttaatgaatc ggccaacgcg cggggagagg 6840

cggtttgcgt attgggcgct cttccgcttc ctcgctcact gactcgctgc gctcggtcgt 6900

tcggctgcgg cgagcggtat cagctcactc aaaggcggta atacggttat ccacagaatc 6960

aggggataac gcaggaaaga acatgtgagc aaaaggccag caaaaggcca ggaaccgtaa 7020

aaaggccgcg ttgctggcgt ttttccatag gctccgcccc cctgacgagc atcacaaaaa 7080

tcgacgctca agtcagaggt ggcgaaaccc gacaggacta taaagatacc aggcgtttcc 7140

ccctggaagc tccctcgtgc gctctcctgt tccgaccctg ccgcttaccg gatacctgtc 7200

cgcctttctc ccttcgggaa gcgtggcgct ttctcatagc tcacgctgta ggtatctcag 7260

ttcggtgtag gtcgttcgct ccaagctggg ctgtgtgcac gaaccccccg ttcagcccga 7320

ccgctgcgcc ttatccggta actatcgtct tgagtccaac ccggtaagac acgacttatc 7380

gccactggca gcagccactg gtaacaggat tagcagagcg aggtatgtag gcggtgctac 7440

agagttcttg aagtggtggc ctaactacgg ctacactaga agaacagtat ttggtatctg 7500

cgctctgctg aagccagtta ccttcggaaa aagagttggt agctcttgat ccggcaaaca 7560

aaccaccgct ggtagcggtt tttttgtttg caagcagcag attacgcgca gaaaaaaagg 7620

atctcaagaa gatcctttga tcttttctac ggggtctgac gctcagtgga acgaaaactc 7680

acgttaaggg attttggtca tgagattatc aaaaaggatc ttcacctaga tccttttaaa 7740

ttaaaaatga agttttaaat caatctaaag tatatatgag taaacttggt ctgacagtta 7800

ccaatgctta atcagtgagg cacctatctc agcgatctgt ctatttcgtt catccatagt 7860

tgcctgactc cccgtcgtgt agataactac gatacgggag ggcttaccat ctggccccag 7920

tgctgcaatg ataccgcgag acccacgctc accggctcca gatttatcag caataaacca 7980

gccagccgga agggccgagc gcagaagtgg tcctgcaact ttatccgcct ccatccagtc 8040

tattaattgt tgccgggaag ctagagtaag tagttcgcca gttaatagtt tgcgcaacgt 8100

tgttgccatt gctacaggca tcgtggtgtc acgctcgtcg tttggtatgg cttcattcag 8160

ctccggttcc caacgatcaa ggcgagttac atgatccccc atgttgtgca aaaaagcggt 8220

tagctccttc ggtcctccga tcgttgtcag aagtaagttg gccgcagtgt tatcactcat 8280

ggttatggca gcactgcata attctcttac tgtcatgcca tccgtaagat gcttttctgt 8340

gactggtgag tactcaacca agtcattctg agaatagtgt atgcggcgac cgagttgctc 8400

ttgcccggcg tcaatacggg ataataccgc gccacatagc agaactttaa aagtgctcat 8460

cattggaaaa cgttcttcgg ggcgaaaact ctcaaggatc ttaccgctgt tgagatccag 8520

ttcgatgtaa cccactcgtg cacccaactg atcttcagca tcttttactt tcaccagcgt 8580

ttctgggtga gcaaaaacag gaaggcaaaa tgccgcaaaa aagggaataa gggcgacacg 8640

gaaatgttga atactcatac tcttcctttt tcaatattat tgaagcattt atcagggtta 8700

ttgtctcatg agcggataca tatttgaatg tatttagaaa aataaacaaa taggggttcc 8760

gcgcacattt ccccgaaaag tgccacctga cg 8792

SEQ ID NO：212

gaggtccagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60

tcctgcaagg cttctgggta caccttcacc ggctactatg tgtactgggt gcgacaggcc 120

cctggacaag ggcttgagtg gatgggatgg atcagcgctt acaatggtaa cacaaactat 180

gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240

atggagctga gcagcctgag atctgaagac acggctgtgt attactgtgc gagaagtaga 300

tccctggacg tctggggcca agggaccacg gtcaccgtct cgagcggtac gggcggttca 360

ggcggaaccg gcagcggcac tggcgggtcg acggatgttg tgatgactca gtctccagac 420

tccctggctg tgtctctggg cgagagggcc accatcaact gcaagtccag ccagagtgtt 480

ttatacagct ccaacaataa gaactactta gcttggtacc agcagaaacc aggacagcct 540

cctaagctgc tcatttactg ggcatctacc cgggaatccg gggtccctga ccgattcagt 600

ggcagcgggt ctgggacaga tttcactctc accatcagca gcctgcaggc tgaagatgtg 660

gcagtttatt actgtcagca atattatagt actcctctca ctttcggcgg agggaccaaa 720

gtggatatca aacgt 735

SEQ ID NO：213

E V Q L V Q S G A E V K K P G A S V K V S C K A S G Y T F T G Y Y V Y W V R Q

A P G Q G L E W M G W I S A Y N G N T N Y A Q K F Q G R V T I T A D K S T S T

A Y M E L S S L R S E D T A V Y Y C A R S R S L D V W G Q G T T V T V S S G T

G G S G G T G S G T G G S T D V V M T Q S P D S L A V S L G E R A T I N C K S

S Q S V L Y S S N N K N Y L A W Y Q Q K P G Q P P K L L I Y W A S T R E S G V

P D R F S G S G S G T D F T L T I S S L Q A E D V A V Y Y C Q Q Y Y S T P L T

F G G G T K V D I K R

SEQ ID NO：214

cagatgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60

tcctgcaagg cttctggagg caccttctcc agttatgcta tcacctgggt gcgacaggcc 120

cctggacaag ggcttgagtg gatgggaggg atcatcggta tgtttggttc aacaaactac 180

gcacagaact tccagggcag agtcacgatt accgcggacg aatccacgag cacagcctac 240

atggagctga gcagcctcag atctgaggac acggccgtgt attactgtgc gagaagtact 300

ggttattacc ctgcatacct ccaccactgg ggccagggca ccctggtcac cgtctcgagc 360

ggtacgggcg gttcaggcgg aaccggcagc ggcactggcg ggtcgacgca gtctgccctg 420

actcagcctc gctcagtgtc cgggtctcct ggacagtcag tcaccatctc ctgcactgga 480

accagcagtg atgttggtgg ttataactat gtctcctggt accaacagca cccaggcaaa 540

gcccccaaac tcatgattta tgatgtcagt aagcggccct caggggtccc tgatcgcttc 600

tctggctcca agtctggcaa cacggcctcc ctgaccatct ctgggctcca ggctgaggat 660

gaggctgatt attactgcag ctcatataca agcagcagca ctcatgtctt cggaactggg 720

accaaggtca ccgtcctagg t 741

SEQ ID NO：215

Q M Q L V Q S G A E V K K P G S S V K V S C K A S G G T F S S Y A I T W V R Q

A P G Q G L E W M G G I I G M F G S T N Y A Q N F Q G R V T I T A D E S T S T

A Y M E L S S L R S E D T A V Y Y C A R S T G Y Y P A Y L H H W G Q G T L V T

V S S G T G G S G G T G S G T G G S T Q S A L T Q P R S V S G S P G Q S V T I

S C T G T S S D V G G Y N Y V S W Y Q Q H P G K A P K L M I Y D V S K R P S G

V P D R F S G S K S G N T A S L T I S G L Q A E D E A D Y Y C S S Y T S S S T

H V F G T G T K V T V L G

SEQ ID NO：216

gaggtgcagc tggtggagac cggggctgag gtgaagaagc ctggggcctc agtgaaggtt 60

tcctgcaagg catctggata caccttcacc agctactata tgcactgggt gcgacaggcc 120

cctggacaag ggcttgagtg gatgggatgg atcaacccta acagtggtgg cacaaactat 180

gcacagaagt ttcagggcag ggtcaccatg accagggaca cgtccatcag cacagcctac 240

atggagctga gcaggctgag atctgacgac acggccgtgt attactgtgc gagagagggg 300

aaatggggac ctcaagcggc ttttgatatc tggggccaag ggacaatggt caccgtctcg 360

agcggtacgg gcggttcagg cggaaccggc agcggcactg gcgggtcgac ggaaattgtg 420

atgacgcagt ctccaggcac cctgtctttg tctccagggg aaagagccac cctctcctgc 480

agggccagtc agagtgttag cagcagctac ttagcctggt accagcagaa acctggccag 540

gctcccaggc tcctcatcta tgatgcatcc agcagggcca ctgacatccc agacaggttc 600

agtggcagtg ggtctgggac agacttcact ctcaccatca gcagactgga gcctgaagat 660

tttgcagtgt attactgtca gcagtatggt agctcacttt ggacgttcgg ccaagggacc 720

aaggtggaga tcaaacgt 738

SEQ ID NO：217

E V Q L V E T G A E V K K P G A S V K V S C K A S G Y T F T S Y Y M H W V R Q

A P G Q G L E W M G W I N P N S G G T N Y A Q K F Q G R V T M T R D T S I S T

A Y M E L S R L R S D D T A V Y Y C A R E G K W G P Q A A F D I W G Q G T M V

T V S S G T G G S G G T G S G T G G S T E I V M T Q S P G T L S L S P G E R A

T L S C R A S Q S V S S S Y L A W Y Q Q K P G Q A P R L L I Y D A S S R A T D

I P D R F S G S G S G T D F T L T I S R L E P E D F A V Y Y C Q Q Y G S S L W

T F G Q G T K V E I K R

SEQ ID NO：218

gaggtgcagc tggtagagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc atctatgcca tgagctgggt ccgccaggca 120

ccagggaagg ggctggagtg ggtctcagct attagtagta gtggtgatag cacatactac 180

gcagactccg tgaagggccg gttcaccatc tccagagaca acgccaggaa cacgctgtat 240

ctgcaaatga acagtctgag agccgaggac acggctgtgt attactgtgc gagagcgtat 300

ggctacacgt tcgacccctg gggccaggga accctggtca ccgtctcgag cggtacgggc 360

ggttcaggcg gaaccggcag cggcactggc gggtcgacgg aaattgtgct gactcagtct 420

ccactctccc tgcccgtcac ccctggagag ccggcctcca tctcctgcag gtctagtcag 480

agcctcctgc atagtaatgg atacaactat ttggattggt acctgcagaa gccagggcag 540

tctccacagc tcctgatcta tttgggttct aatcgggcct ccggggtccc tgacaggttc 600

agtggcagtg gatcaggcac agattttaca ctgaaaatca gcagagtgga ggctgaggat 660

gttggggttt attactgcat gcaagctcta caaactcccc tcactttcgg cggagggacc 720

aaggtggaga tcaaacgt 738

SEQ ID NO：219

E V Q L V E S G G G L V Q P G G S L R L S C A A S G F T F S I Y A M S W V R Q

A P G K G L E W V S A I S S S G D S T Y Y A D S V K G R F T I S R D N A R N T

L Y L Q M N S L R A E D T A V Y Y C A R A Y G Y T F D P W G Q G T L V T V S S

G T G G S G G T G S G T G G S T E I V L T Q S P L S L P V T P G E P A S I S C

R S S Q S L L H S N G Y N Y L D W Y L Q K P G Q S P Q L L I Y L G S N R A S G

V P D R F S G S G S G T D F T L K I S R V E A E D V G V Y Y C M Q A L Q T P L

T F G G G T K V E I K R

SEQ ID NO：220

gaggtgcagc tggtggagac cggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60

tcctgcaagg cctctggagg caccttcagg acccatgcta tcagttgggt gcgacaggcc 120

cctggacaag ggcttgagtg gatgggaggg atcatcgcta tcttcggaac agcaaactac 180

gcacagaagt tccagggcag aatcacgatt accgcggacg aatccacgag tacagcctac 240

atggagctga gcagcctgag atctgaggac acggccgtgt atttctgtgc gagaggcagt 300

ggttatcata tatcgacacc ctttgacaac tggggccagg gaaccctggt caccgtctcg 360

agcggtacgg gcggttcagg cggaaccggc agcggcactg gcgggtcgac gtcctatgtg 420

ctgactcagc caccctcggt gtcagtggcc ccaggacaga cggccaggat tacctgtggg 480

ggaaacaaca ttggaagtaa aggtgtgcac tggtaccagc agaagcctgg ccaggcccct 540

gtgctggtcg tctatgatga tagcgaccgg ccctcaggga tccctgagcg attctctggc 600

tccaactctg ggaacacggc caccctgacc atcagcaggg tcgaagccgg ggatgaggcc 660

gactattact gtcaggtgtg ggatagtagt agtgatcatg tggtattcgg cggagggacc 720

aagctgaccg tcctaggt 738

SEQ ID NO：221

E V Q L V E T G A E V K K P G S S V K V S C K A S G G T F R T H A I S W V R Q

A P G Q G L E W M G G I I A I F G T A N Y A Q K F Q G R I T I T A D E S T S T

A Y M E L S S L R S E D T A V Y F C A R G S G Y H I S T P F D N W G Q G T L V

T V S S G T G G S G G T G S G T G G S T S Y V L T Q P P S V S V A P G Q T A R

I T C G G N N I G S K G V H W Y Q Q K P G Q A P V L V V Y D D S D R P S G I P

E R F S G S N S G N T A T L T I S R V E A G D E A D Y Y C Q V W D S S S D H V

V F G G G T K L T V L G

SEQ ID NO：222

gaggtgcagc tggtggagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60

tcctgcaagg cttctggaca catcttcagc ggctatgcaa tcagttgggt gcgacaggcc 120

cctggacaag ggcttgagtg gatgggaggg atcatcccta tctttggtac aacaaactac 180

gcacagaagt tccagggcag agtcacgatt accgcggacc aatccacgag cacagcctac 240

atggacctga gcaacttgag atctgaggac acggccgtct attactgtgc gagagtgaaa 300

gatggatatt gtactcttac cagctgccct gtcggctggt acttcgatct ctggggccgt 360

ggcaccctgg tcactgtctc gagcggtacg ggcggttcag gcggaaccgg cagcggcact 420

ggcgggtcga cggaaattgt gatgacgcag tctccaggca ccctgtcttt gtctccaggg 480

gaaagagcca ccctctcgtg cagggccagt cagagtgtta gcagcagcta cttagcctgg 540

taccagcaga aacctggcca ggctcccagg ctcctcatct ttggtgcctc cagcagggcc 600

actggcatcc cagacaggtt cagtggcagt gggtctggga cagacttcac tctcaccatc 660

agcagactgg agcctgaaga ttttgcagtg tattactgtc agcagtatgg tagctcactc 720

actttcggcg gagggaccaa gctggagatc aaacgt 756

SEQ ID NO：223

E V Q L V E S G A E V K K P G S S V K V S C K A S G H I F S G Y A I S W V R Q

A P G Q G L E W M G G I I P I F G T T N Y A Q K F Q G R V T I T A D Q S T S T

A Y M D L S N L R S E D T A V Y Y C A R V K D G Y C T L T S C P V G W Y F D L

W G R G T L V T V S S G T G G S G G T G S G T G G S T E I V M T Q S P G T L S

L S P G E R A T L S C R A S Q S V S S S Y L A W Y Q Q K P G Q A P R L L I F G

A S S R A T G I P D R F S G S G S G T D F T L TIS R L E P E D F A V Y Y C Q

Q Y G S S L T F G G G T K L E I K R

SEQ ID NO：224

gaggtccagc tggtacagtc tggggctgag gttaagaagc ctgggtcctc ggtgaaggtc 60

tcctgcaagg cttctggagg catcttcaga agcaattcta tcagttgggt gcgacaggcc 120

cctgggcaag ggcttgagtg gatgggaggg atcttcgctc ttttcggaac aacagactac 180

gcgcagaagt tccagggcag agtcacgatt accgcggacg aatcttcgac cacagtctac 240

ctggagctga gtagcctgac atctgaggac acggccgttt attactgtgc gagaggcagt 300

ggctacacca cacgcaacta ctttgactac tggggccagg gcaccctggt caccgtctcg 360

agcggtacgg gcggttcagg cggaaccggc agcggcactg gcgggtcgac ggaaattgtg 420

ctgactcagt ctccaggcac cctgtctttg tctccagggg aaagagccac actctcctgc 480

agggccagtc agagtgttag cagcaactac ttaggctggt accagcagaa acctggccag 540

gctcccaggc tcctgatcta tggtgcatcc agcagggcca gtggcatccc agacaggttc 600

agtggcggtg ggtctgggac agacttcact ctcaccatca gcagactgga gcctgaagat 660

tttgcagtgt attactgtca gcagtatggt agctcacccc tcactttcgg cggagggacc 720

aaggtggaga tcaaacgt 738

SEQ ID NO：225

E V Q L V Q S G A E V K K P G S S V K V S C K A S G G I F R S N S I S W V R Q

A P G Q G L E W M G G I F A L F G T T D Y A Q K F Q G R V T I T A D E S S T T

V Y L E L S S L T S E D T A V Y Y C A R G S G Y T T R N Y F D Y W G Q G T L V

T V S S G T G G S G G T G S G T G G S T E I V L T Q S P G T L S L S P G E R A

T L S C R A S Q S V S S N Y L G W Y Q Q K P G Q A P R L L I Y G A S S R A S G

I P D R F S G G G S G T D F T L T I S R L E P E D F A V Y Y C Q Q Y G S S P L

T F G G G T K V E I K R

SEQ ID NO：226

caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtaaaggtc 60

tcctgcaagg cttctggagg ccccttccgc aattttgcta tcaactgggt gcgacaggcc 120

cctggacaag ggcttgagtg gatgggaggg atcatcgctg tctttgggac gacaaagtac 180

gcacataagt tccagggcag agtcaccatc accgcggacg actccacaaa tacagcttac 240

atggagctgg gcagcctgaa atctgaggac acggccgtgt attactgtgc gagaggtccc 300

cactactact cctcctacat ggacgtctgg ggcgaaggga ccacggtcac cgtctcgagc 360

ggtacgggcg gttcaggcgg aaccggcagc ggcactggcg ggtcgacgga catccagttg 420

acccagtctc catcctccct gtctgcatct gtaggagaca gagtcaccat cacttgccgg 480

gcgagtcagg gcattagcac ttatttagcc tggtatcagc agaaacccgg gaaagttcct 540

aaactcctga tctatgctgc atccactttg caatcagggg tcccatctcg gttcagtggc 600

agtggatctg ggacagattt cactctcacc atcagcagcc tgcagcctga agatgttgca 660

acttattact gtcaaaagta taacagtgcc ccttctttcg gccctgggac caaagtggat 720

atcaaacgt 729

SEQ ID NO：227

Q V Q L V Q S G A E V K K P G S S V K V S C K A S G G P F R N F A I N W V R Q

A P G Q G L E W M G G I I A V F G T T K Y A H K F Q G R V T I T A D D S T N T

A Y M E L G S L K S E D T A V Y Y C A R G P H Y Y S S Y M D V W G E G T T V T

V S S G T G G S G G T G S G T G G S T D I Q L T Q S P S S L S A S V G D R V T

I T C R A S Q G I S T Y L A W Y Q Q K P G K V P K L L I Y A A S T L Q S G V P

S R F S G S G S G T D F T L T I S S L Q P E D V A T Y Y C Q K Y N S A P S F G

P G T K V D I K R

SEQ ID NO：228

gaggtgcagc tggtggagac tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60

ccctgcaaat cttctggaag ccccttcagg agtaatgctg tcagctgggt gcgacaggcc 120

cccggacaag ggcttgagtg ggtgggagga atcctcggtg tctttggttc accaagctac 180

gcacagaagt tccagggcag agtcacgatt accgcggacg aatccaccaa cacagtccac 240

atggagctga gaggtttgag atctgaggac acggccgtgt attattgtgc gagaggtcct 300

acctactact actcctacat ggacgtctgg ggcaaaggga ccacggtcac cgtctcgagc 360

ggtacgggcg gttcaggcgg aaccggcagc ggcactggcg ggtcgacgtc ctatgtgctg 420

actcagccac cctcggagtc agtggcccca ggacagacgg ccaggattac ctgtggggga 480

aataacattg gaagaaatag tgtgcactgg tatcagcaga agccaggcca ggcccctgtg 540

ctggtcgtgt atgatgatag cgaccggccc tcagggatcc ctgagcgatt ttctggctcc 600

aagtctggga acacggccac cctgattatc agcagggtcg aagtcgggga tgaggccgac 660

tactactgtc aggtgtggca tagtagtagt gatcattatg tcttcggaac tgggaccaag 720

gtcaccgtcc taggt 735

SEQ ID NO：229

E V Q L V E T G A E V K K P G S S V K V P C K S S G S P F R S N A V S W V R Q

A P G Q G L E W V G G I L G V F G S P S Y A Q K F Q G R V T I T A D E S T N T

V H M E L R G L R S E D T A V Y Y C A R G P T Y Y Y S Y M D V W G K G T T V T

V S S G T G G S G G T G S G T G G S T S Y V L T Q P P S E S V A P G Q T A R I

T C G G N N I G R N S V H W Y Q Q K P G Q A P V L V V Y D D S D R P S G I P E

R F S G S K S G N T A T L I I S R V E V G D E A D Y Y C Q V W H S S S D H Y V

F G T G T K V T V L G

SEQ ID NO：230

cagatgcagc tggtacaatc tggagctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60

tcctgcaagg cttctggagg caccttcagc agctatgcta tcagctgggt gcgacaggcc 120

cctggacaag ggcttgagtg gatgggaggg atcttcggta tgtttgggac agcaaactac 180

gcgcagaagt tccagggcag agtcacgatt accgcggacg aattcacgag cgcggcctac 240

atggagctga gcagcctggg atctgaggac acggccatgt attactgtgc gaggtctagt 300

ggttattacc cccaatactt ccaggactgg ggccagggca ccctggtcac cgtctcgagc 360

ggtacgggcg gttcaggcgg aaccggcagc ggcactggcg ggtcgacgga aattgtgatg 420

acacagtctc caggcaccct gtctttgtct ccagggcaaa gagccaccct ctcctgcagg 480

gccagtcaga gtgttagcag cagctactta gcctggtacc agcagaaacc tggccaggct 540

cccagactcc tcatgtatgg tgcatccagc agggccactg gcatcccaga caggttcagt 600

ggcagtgggt ctgggacaga cttcactctc accatcagca gactggagcc tgaagatttt 660

gcagtgtatt actgtcagca gtatggtagc tcatcgctca ctttcggcgg agggaccaag 720

ctggagatca aacgt 735

SEQ ID NO：231

Q M Q L V Q S G A E V K K P G S S V K V S C K A S G G T F S S Y A I S W V R Q

A P G Q G L E W M G G I F G M F G T A N Y A Q K F Q G R V T I T A D E F T S A

A Y M E L S S L G S E D T A M Y Y C A R S S G Y Y P Q Y F Q D W G Q G T L V T

V S S G T G G S G G T G S G T G G S T E I V M T Q S P G T L S L S P G Q R A T

L S C R A S Q S V S S S Y L A W Y Q Q K P G Q A P R L L M Y G A S S R A T G I

P D R F S G S G S G T D F T L T I S R L E P E D F A V Y Y C Q Q Y G S S S L T

F G G G T K L E I K R

SEQ ID NO：232

gaggtgcagc tggtggagtc cggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60

tcctgcaagg cttctggagg catcttcaac agttatgcta tcagctgggt gcgacaggcc 120

cctggacaag ggcttgagtg gatgggaggc atcatcgcta tctttcatac accaaagtac 180

gcacagaagt tccagggcag agtcacgatt accgcggacg aatccacgaa cacagcctac 240

atggaactga gaagcctgaa atctgaggac acggccctgt attactgtgc gagagggtcc 300

acttacgatt tttcgagtgg ccttgactac tggggccagg gaaccctggt caccgtctcg 360

agcggtacgg gcggttcagg cggaaccggc agcggcactg gcgggtcgac gcaggcaggg 420

ctgactcagc caccctcggt gtcagtggcc ccaggacaga cggccaggat tacctgtggg 480

ggaaacaaca ttggaagtaa aagtgtgcac tggtaccagc agaagccagg ccaggcccct 540

gtcctagtcg tctatgatga tagcgaccgg ccctcaggga tccctgagcg attctctggc 600

tccaactctg ggaacacggc caccctgacc atcagcaggg tcgaagccgg ggatgaggcc 660

gactattact gtcaggtgtg ggatagtagt agtgatcatg tggtattcgg cggagggacc 720

aagctgaccg tcctaggt 738

SEQ ID NO：233

E V Q L V E S G A E V K K P G S S V K V S C K A S G G I F N S Y A I S W V R Q

A P G Q G L E W M G G I I A I F H T P K Y A Q K F Q G R V T I T A D E S T N T

A Y M E L R S L K S E D T A L Y Y C A R G S T Y D F S S G L D Y W G Q G T L V

T V S S G T G G S G G T G S G T G G S T Q A G L T Q P P S V S V A P G Q T A R

I T C G G N N I G S K S V H W Y Q Q K P G Q A P V L V V Y D D S D R P S G I P

E R F S G S N S G N T A T L T I S R V E A G D E A D Y Y C Q V W D S S S D H V

V F G G G T K L T V L G

SEQ ID NO：234

caggtccagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60

tcctgcaagg cttctggagg cttcttcagc agctatgcta tcagctgggt gcgccaggcc 120

cctggacaag gacttgagtg gatggggggg gtcatcccta tctttcgtac agcaaactac 180

gcacagaact tccagggcag agtcaccatt accgcggacg aattcacatc gtatatggag 240

ctgagcagcc tgagatctga cgacacggcc gtgtattact gtgcgaggtt gaattaccat 300

gattcgggga cttattataa cgccccccgg ggctggttcg acccctgggg ccagggaacc 360

ctggtcaccg tctcgagcgg tacgggcggt tcaggcggaa ccggcagcgg cactggcggg 420

tcgacggaca tccagatgac ccagtctcca gactccctgg ctgtgtctct gggcgagaag 480

gccaccatca actgcaagtc cagccagagt attttaaaca gctccaacaa taagaactac 540

ttagcttggt accagcagaa accaggacag cctcctaagc tgctcattta ctgggcatct 600

acccgggaat ccggggtccc tgaccgattc agtggcagcg ggtctgggac agatttcact 660

ctcaccatca gcagcctgca ggctgaagat gtggcagttt attactgtca gcaatattat 720

agtagtccgc cgacgttcgg ccaagggacc aaggtggaaa tcaaacgt 768

SEQ ID NO：235

Q V Q L V Q S G A E V K K P G S S V K V S C K A S G G F F S S Y A I S W V R Q

A P G Q G L E W M G G V I P I F R T A N Y A Q N F Q G R V T I T A D E F T S Y

M E L S S L R S D D T A V Y Y C A R L N Y H D S G T Y Y N A P R G W F D P W G

Q G T L V T V S S G T G G S G G T G S G T G G S T D I Q M T Q S P D S L A V S

L G E K A T I N C K S S Q S I L N S S N N K N Y L A W Y Q Q K P G Q P P K L L

I Y W A S T R E S G V P D R F S G S G S G T D F T L T I S S L Q A E D V A V Y

Y C Q Q Y Y S S P P T F G Q G T K V E I K R

SEQ ID NO：236

caggtccagc tggtgcagtc tggagctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60

tcctgcaagg cttctggagt caccttcagt tactatgcta tgagctgggt gcgacaggcc 120

cctggacaag ggcttgagtg gatgggagga atcagcccta tgtttgggac aacaacctac 180

gcacagaagt tccagggcag agtcacgatt actgcggacg actccacgag tacagcctac 240

atggaggtga ggagcctgag atctgaggac acggccgtgt attactgtgc gagatcttcg 300

aattactatg atagtgtata tgactactgg ggccagggaa ccctggtcac cgtctcgagc 360

ggtacgggcg gttcaggcgg aaccggcagc ggcactggcg ggtcgacgca gtctgtcgtg 420

acgcagccgc cctcggagtc agtggcccca ggacagacgg ccaggattac ctgtggggga 480

cataacattg gaagtaatag tgtgcactgg taccagcaga agccaggcca ggcccctgtg 540

ctggtcgtgt atgataatag cgaccggccc tcagggatcc ctgagcgatt ctctggctcc 600

aactctggga acacggccac cctgaccatc agcagggtcg aagccgggga tgaggccgac 660

tattactgtc aggtgtgggg tagtagtagt gaccattatg tcttcggaac tgggaccaag 720

gtcaccgtcc taggt 735

SEQ ID NO：237

Q V Q L V Q S G A E V K K P G S S V K V S C K A S G V T F S Y Y A M S W V R Q

A P G Q G L E W M G G I S P M F G T T T Y A Q K F Q G R V T I T A D D S T S T

A Y M E V R S L R S E D T A V Y Y C A R S S N Y Y D S V Y D Y W G Q G T L V T

V S S G T G G S G G T G S G T G G S T Q S V V T Q P P S E S V A P G Q T A R I

T C G G H N I G S N S V H W Y Q Q K P G Q A P V L V V Y D N S D R P S G I P E

R F S G S N S G N T A T L T I S R V E A G D E A D Y Y C Q V W G S S S D H Y V

F G T G T K V T V L G

SEQ ID NO：316

gaggtccagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60

tcctgcaagg cttctgggta caccttcacc ggctactatg tgtactgggt gcgacaggcc 120

cctggacaag ggcttgagtg gatgggatgg atcagcgctt acaatggtaa cacaaactat 180

gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240

atggagctga gcagcctgag atctgaagac acggctgtgt attactgtgc gagaagtaga 300

tccctggacg tctggggcca agggaccacg gtcaccgtct cgagtgctag caccaagggc 360

cccagcgtgt tccccctggc ccccagcagc aagagcacca gcggcggcac agccgccctg 420

ggctgcctgg tgaaggacta cttccccgag cccgtgaccg tgagctggaa cagcggcgcc 480

ttgaccagcg gcgtgcacac cttccccgcc gtgctgcaga gcagcggcct gtacagcctg 540

agcagcgtgg tgaccgtgcc cagcagcagc ctgggcaccc agacctacat ctgcaacgtg 600

aaccacaagc ccagcaacac caaggtggac aaacgcgtgg agcccaagag ctgcgacaag 660

acccacacct gccccccctg ccctgccccc gagctgctgg gcggaccctc cgtgttcctg 720

ttccccccca agcccaagga caccctcatg atcagccgga cccccgaggt gacctgcgtg 780

gtggtggacg tgagccacga ggaccccgag gtgaagttca actggtacgt ggacggcgtg 840

gaggtgcaca acgccaagac caagccccgg gaggagcagt acaacagcac ctaccgggtg 900

gtgagcgtgc tcaccgtgct gcaccaggac tggctgaacg gcaaggagta caagtgcaag 960

gtgagcaaca aggccctgcc tgcccccatc gagaagacca tcagcaaggc caagggccag 1020

ccccgggagc cccaggtgta caccctgccc cccagccggg aggagatgac caagaaccag 1080

gtgtccctca cctgtctggt gaagggcttc taccccagcg acatcgccgt ggagtgggag 1140

agcaacggcc agcccgagaa caactacaag accacccccc ctgtgctgga cagcgacggc 1200

agcttcttcc tgtacagcaa gctcaccgtg gacaagagcc ggtggcagca gggcaacgtg 1260

ttcagctgca gcgtgatgca cgaggccctg cacaaccact acacccagaa gagcctgagc 1320

ctgagccccg gcaag 1335

SEQ ID NO：317

E V Q L V Q S G A E V K K P G A S V K V S C K A S G Y T F T G Y Y V Y W V R Q

A P G Q G L E W M G W I S A Y N G N T N Y A Q K F Q G R V T I T A D K S T S T

A Y M E L S S L R S E D T A V Y Y C A R S R S L D V W G Q G T T V T V S S A S

T K G P S V F P L A P S S K S T S G G T A A L G C L V K D Y F P E P V T V S W

N S G A L T S G V H T F P A V L Q S S G L Y S L S S V V T V P S S S L G T Q T

Y I C N V N H K P S N T K V D K R V E P K S C D K T H T C P P C P A P E L L G

G P S V F L F P P K P K D T L M I S R T P E V T C V V V D V S H E D P E V K F

N W Y V D G V E V H N A K T K P R E E Q Y N S T Y R V V S V L T V L H Q D W L

N G K E Y K C K V S N K A L P A P I E K T I S K A K G Q P R E P Q V Y T L P P

S R E E M T K N Q V S L T C L V K G F Y P S D I A V E W E S N G Q P E N N Y K

T T P P V L D S D G S F F L Y S K L T V D K S R W Q Q G N V F S C S V M H E A

L H N H Y T Q K S L S L S P G K

SEQ ID NO：318

gatgttgtga tgactcagtc tccagactcc ctggctgtgt ctctgggcga gagggccacc 60

atcaactgca agtccagcca gagtgtttta tacagctcca acaataagaa ctacttagct 120

tggtaccagc agaaaccagg acagcctcct aagctgctca tttactgggc atctacccgg 180

gaatccgggg tccctgaccg attcagtggc agcgggtctg ggacagattt cactctcacc 240

atcagcagcc tgcaggctga agatgtggca gtttattact gtcagcaata ttatagtact 300

cctctcactt tcggcggagg gaccaaagtg gatatcaaac gtgcggccgc acccagcgtg 360

ttcatcttcc ccccctccga cgagcagctg aagagcggca ccgccagcgt ggtgtgcctg 420

ctgaacaact tctacccccg ggaggccaag gtgcagtgga aggtggacaa cgccctgcag 480

agcggcaaca gccaggagag cgtgaccgag caggacagca aggactccac ctacagcctg 540

agcagcaccc tcaccctgag caaggccgac tacgagaagc acaaggtgta cgcctgcgag 600

gtgacccacc agggcctgag cagccccgtg accaagagct tcaaccgggg cgagtgt 657

SEQ ID NO：319

D V V M T Q S P D S L A V S L G E R A T I N C K S S Q S V L Y S S N N K N Y L

A W Y Q Q K P G Q P P K L L I Y W A S T R E S G V P D R F S G S G S G T D F T

L T I S S L Q A E D V A V Y Y C Q Q Y Y S T P L T F G G G T K V D I K R A A A

P S V F I F P P S D E Q L K S G T A S V V C L L N N F Y P R E A K V Q W K V D

N A L Q S G N S Q E S V T E Q D S K D S T Y S L S S T L T L S K A D Y E K H K

V Y A C E V T H Q G L S S P V T K S F N R G E C

SEQ ID NO：320

cagatgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60

tcctgcaagg cttctggagg caccttctcc agttatgcta tcacctgggt gcgacaggcc 120

cctggacaag ggcttgagtg gatgggaggg atcatcggta tgtttggttc aacaaactac 180

gcacagaact tccagggcag agtcacgatt accgcggacg aatccacgag cacagcctac 240

atggagctga gcagcctcag atctgaggac acggccgtgt attactgtgc gagaagtact 300

ggttattacc ctgcatacct ccaccactgg ggccagggca ccctggtcac cgtctcgagt 360

gctagcacca agggccccag cgtgttcccc ctggccccca gcagcaagag caccagcggc 420

ggcacagccg ccctgggctg cctggtgaag gactacttcc ccgagcccgt gaccgtgagc 480

tggaacagcg gcgccttgac cagcggcgtg cacaccttcc ccgccgtgct gcagagcagc 540

ggcctgtaca gcctgagcag cgtggtgacc gtgcccagca gcagcctggg cacccagacc 600

tacatctgca acgtgaacca caagcccagc aacaccaagg tggacaaacg cgtggagccc 660

aagagctgcg acaagaccca cacctgcccc ccctgccctg cccccgagct gctgggcgga 720

ccctccgtgt tcctgttccc ccccaagccc aaggacaccc tcatgatcag ccggaccccc 780

gaggtgacct gcgtggtggt ggacgtgagc cacgaggacc ccgaggtgaa gttcaactgg 840

tacgtggacg gcgtggaggt gcacaacgcc aagaccaagc cccgggagga gcagtacaac 900

agcacctacc gggtggtgag cgtgctcacc gtgctgcacc aggactggct gaacggcaag 960

gagtacaagt gcaaggtgag caacaaggcc ctgcctgccc ccatcgagaa gaccatcagc 1020

aaggccaagg gccagccccg ggagccccag gtgtacaccc tgccccccag ccgggaggag 1080

atgaccaaga accaggtgtc cctcacctgt ctggtgaagg gcttctaccc cagcgacatc 1140

gccgtggagt gggagagcaa cggccagccc gagaacaact acaagaccac cccccctgtg 1200

ctggacagcg acggcagctt cttcctgtac agcaagctca ccgtggacaa gagccggtgg 1260

cagcagggca acgtgttcag ctgcagcgtg atgcacgagg ccctgcacaa ccactacacc 1320

cagaagagcc tgagcctgag ccccggcaag 1350

SEQ ID NO：321

Q M Q L V Q S G A E V K K P G S S V K V S C K A S G G T F S S Y A I T W V R Q

A P G Q G L E W M G G I I G M F G S T N Y A Q N F Q G R V T I T A D E S T S T

A Y M E L S S L R S E D T A V Y Y C A R S T G Y Y P A Y L H H W G Q G T L V T

V S S A S T K G P S V F P L A P S S K S T S G G T A A L G C L V K D Y F P E P

V T V S W N S G A L T S G V H T F P A V L Q S S G L Y S L S S V V T V P S S S

L G T Q T Y I C N V N H K P S N T K V D K R V E P K S C D K T H T C P P C P A

P E L L G G P S V F L F P P K P K D T L M I S R T P E V T C V V V D V S H E D

P E V K F N W Y V D G V E V H N A K T K P R E E Q Y N S T Y R V V S V L T V L

H Q D W L N G K E Y K C K V S N K A L P A P I E K T I S K A K G Q P R E P Q V

Y T L P P S R E E M T K N Q V S L T C L V K G F Y P S D I A V E W E S N G Q P

E N N Y K T T P P V L D S D G S F F L Y S K L T V D K S R W Q Q G N V F S C S

V M H E A L H N H Y T Q K S L S L S P G K

SEQ ID NO：322

cagtctgccc tgactcagcc tcgctcagtg tccgggtctc ctggacagtc agtcaccatc 60

tcctgcactg gaaccagcag tgatgttggt ggttataact atgtctcctg gtaccaacag 120

cacccaggca aagcccccaa actcatgatt tatgatgtca gtaagcggcc ctcaggggtc 180

cctgatcgct tctctggctc caagtctggc aacacggcct ccctgaccat ctctgggctc 240

caggctgagg atgaggctga ttattactgc agctcatata caagcagcag cactcatgtc 300

ttcggaactg ggaccaaggt caccgtccta ggtgcggccg caggccagcc caaggccgct 360

cccagcgtga ccctgttccc cccctcctcc gaggagctgc aggccaacaa ggccaccctg 420

gtgtgcctca tcagcgactt ctaccctggc gccgtgaccg tggcctggaa ggccgacagc 480

agccccgtga aggccggcgt ggagaccacc acccccagca agcagagcaa caacaagtac 540

gccgccagca gctacctgag cctcaccccc gagcagtgga agagccaccg gagctacagc 600

tgccaggtga cccacgaggg cagcaccgtg gagaagaccg tggcccccac cgagtgcagc 660

SEQ ID NO：323

Q S A L T Q P R S V S G S P G Q S V T I S C T G T S S D V G G Y N Y V S W Y Q

Q H P G K A P K L M I Y D V S K R P S G V P D R F S G S K S G N T A S L T I S

G L Q A E D E A D Y Y C S S Y T S S S T H V F G T G T K V T V L G A A A G Q P

K A A P S V T L F P P S S E E L Q A N K A T L V C L I S D F Y P G A V T V A W

K A D S S P V K A G V E T T T P S K Q S N N K Y A A S S Y L S L T P E Q W K S

H R S Y S C Q V T H E G S T V E K T V A P T E C S

SEQ ID NO：324

gaggtgcagc tggtggagac cggggctgag gtgaagaagc ctggggcctc agtgaaggtt 60

tcctgcaagg catctggata caccttcacc agctactata tgcactgggt gcgacaggcc 120

cctggacaag ggcttgagtg gatgggatgg atcaacccta acagtggtgg cacaaactat 180

gcacagaagt ttcagggcag ggtcaccatg accagggaca cgtccatcag cacagcctac 240

atggagctga gcaggctgag atctgacgac acggccgtgt attactgtgc gagagagggg 300

aaatggggac ctcaagcggc ttttgatatc tggggccaag ggacaatggt caccgtctcg 360

agtgctagca ccaagggccc cagcgtgttc cccctggccc ccagcagcaa gagcaccagc 420

ggcggcacag ccgccctggg ctgcctggtg aaggactact tccccgagcc cgtgaccgtg 480

agctggaaca gcggcgcctt gaccagcggc gtgcacacct tccccgccgt gctgcagagc 540

agcggcctgt acagcctgag cagcgtggtg accgtgccca gcagcagcct gggcacccag 600

acctacatct gcaacgtgaa ccacaagccc agcaacacca aggtggacaa acgcgtggag 660

cccaagagct gcgacaagac ccacacctgc cccccctgcc ctgcccccga gctgctgggc 720

ggaccctccg tgttcctgtt cccccccaag cccaaggaca ccctcatgat cagccggacc 780

cccgaggtga cctgcgtggt ggtggacgtg agccacgagg accccgaggt gaagttcaac 840

tggtacgtgg acggcgtgga ggtgcacaac gccaagacca agccccggga ggagcagtac 900

aacagcacct accgggtggt gagcgtgctc accgtgctgc accaggactg gctgaacggc 960

aaggagtaca agtgcaaggt gagcaacaag gccctgcctg cccccatcga gaagaccatc 1020

agcaaggcca agggccagcc ccgggagccc caggtgtaca ccctgccccc cagccgggag 1080

gagatgacca agaaccaggt gtccctcacc tgtctggtga agggcttcta ccccagcgac 1140

atcgccgtgg agtgggagag caacggccag cccgagaaca actacaagac caccccccct 1200

gtgctggaca gcgacggcag cttcttcctg tacagcaagc tcaccgtgga caagagccgg 1260

tggcagcagg gcaacgtgtt cagctgcagc gtgatgcacg aggccctgca caaccactac 1320

acccagaaga gcctgagcct gagccccggc aag 1353

SEQ ID NO：325

E V Q L V E T G A E V K K P G A S V K V S C K A S G Y T F T S Y Y M H W V R Q

A P G Q G L E W M G W I N P N S G G T N Y A Q K F Q G R V T M T R D T S I S T

A Y M E L S R L R S D D T A V Y Y C A R E G K W G P Q A A F D I W G Q G T M V

T V S S A S T K G P S V F P L A P S S K S T S G G T A A L G C L V K D Y F P E

P V T V S W N S G A L T S G V H T F P A V L Q S S G L Y S L S S V V T V P S S

S L G T Q T Y I C N V N H K P S N T K V D K R V E P K S C D K T H T C P P C P

A P E L L G G P S V F L F P P K P K D T L M I S R T P E V T C V V V D V S H E

D P E V K F N W Y V D G V E V H N A K T K P R E E Q Y N S T Y R V V S V L T V

L H Q D W L N G K E Y K C K V S N K A L P A P I E K T I S K A K G Q P R E P Q

V Y T L P P S R E E M T K N Q V S L T C L V K G F Y P S D I A V E W E S N G Q

P E N N Y K T T P P V L D S D G S F F L Y S K L T V D K S R W Q Q G N V F S C

S V M H E A L H N H Y T Q K S L S L S P G K

SEQ ID NO：326

gaaattgtga tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60

ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120

cctggccagg ctcccaggct cctcatctat gatgcatcca gcagggccac tgacatccca 180

gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240

cctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcactttg gacgttcggc 300

caagggacca aggtggagat caaacgtgcg gccgcaccca gcgtgttcat cttccccccc 360

tccgacgagc agctgaagag cggcaccgcc agcgtggtgt gcctgctgaa caacttctac 420

ccccgggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480

gagagcgtga ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctcacc 540

ctgagcaagg ccgactacga gaagcacaag gtgtacgcct gcgaggtgac ccaccagggc 600

ctgagcagcc ccgtgaccaa gagcttcaac cggggcgagt gt 642

SEQ ID NO：327

E I V M T Q S P G T L S L S P G E R A T L S C R A S Q S V S S S Y L A W Y Q Q

K P G Q A P R L L I Y D A S S R A T D I P D R F S G S G S G T D F T L T I S R

L E P E D F A V Y Y C Q Q Y G S S L W T F G Q G T K V E I K R A A A P S V F I

F P P S D E Q L K S G T A S V V C L L N N F Y P R E A K V Q W K V D N A L Q S

G N S Q E S V T E Q D S K D S T Y S L S S T L T L S K A D Y E K H K V Y A C E

V T H Q G L S S P V T K S F N R G E C

SEQ ID NO：328

gaggtgcagc tggtagagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc atctatgcca tgagctgggt ccgccaggca 120

ccagggaagg ggctggagtg ggtctcagct attagtagta gtggtgatag cacatactac 180

gcagactccg tgaagggccg gttcaccatc tccagagaca acgccaggaa cacgctgtat 240

ctgcaaatga acagtctgag agccgaggac acggctgtgt attactgtgc gagagcgtat 300

ggctacacgt tcgacccctg gggccaggga accctggtca ccgtctcgag tgctagcacc 360

aagggcccca gcgtgttccc cctggccccc agcagcaaga gcaccagcgg cggcacagcc 420

gccctgggct gcctggtgaa ggactacttc cccgagcccg tgaccgtgag ctggaacagc 480

ggcgccttga ccagcggcgt gcacaccttc cccgccgtgc tgcagagcag cggcctgtac 540

agcctgagca gcgtggtgac cgtgcccagc agcagcctgg gcacccagac ctacatctgc 600

aacgtgaacc acaagcccag caacaccaag gtggacaaac gcgtggagcc caagagctgc 660

gacaagaccc acacctgccc cccctgccct gcccccgagc tgctgggcgg accctccgtg 720

ttcctgttcc cccccaagcc caaggacacc ctcatgatca gccggacccc cgaggtgacc 780

tgcgtggtgg tggacgtgag ccacgaggac cccgaggtga agttcaactg gtacgtggac 840

ggcgtggagg tgcacaacgc caagaccaag ccccgggagg agcagtacaa cagcacctac 900

cgggtggtga gcgtgctcac cgtgctgcac caggactggc tgaacggcaa ggagtacaag 960

tgcaaggtga gcaacaaggc cctgcctgcc cccatcgaga agaccatcag caaggccaag 1020

ggccagcccc gggagcccca ggtgtacacc ctgcccccca gccgggagga gatgaccaag 1080

aaccaggtgt ccctcacctg tctggtgaag ggcttctacc ccagcgacat cgccgtggag 1140

tgggagagca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggacagc 1200

gacggcagct tcttcctgta cagcaagctc accgtggaca agagccggtg gcagcagggc 1260

aacgtgttca gctgcagcgt gatgcacgag gccctgcaca accactacac ccagaagagc 1320

ctgagcctga gccccggcaa g 1341

SEQ ID NO：329

E V Q L V E S G G G L V Q P G G S L R L S C A A S G F T F S I Y A M S W V R Q

A P G K G L E W V S A I S S S G D S T Y Y A D S V K G R F T I S R D N A R N T

L Y L Q M N S L R A E D T A V Y Y C A R A Y G Y T F D P W G Q G T L V T V S S

A S T K G P S V F P L A P S S K S T S G G T A A L G C L V K D Y F P E P V T V

S W N S G A L T S G V H T F P A V L Q S S G L Y S L S S V V T V P S S S L G T

Q T Y I C N V N H K P S N T K V D K R V E P K S C D K T H T C P P C P A P E L

L G G P S V F L F P P K P K D T L M I S R T P E V T C V V V D V S H E D P E V

K F N W Y V D G V E V H N A K T K P R E E Q Y N S T Y R V V S V L T V L H Q D

W L N G K E Y K C K V S N K A L P A P I E K T I S K A K G Q P R E P Q V Y T L

P P S R E E M T K N Q V S L T C L V K G F Y P S D I A V E W E S N G Q P E N N

Y K T T P P V L D S D G S F F L Y S K L T V D K S R W Q Q G N V F S C S V M H

E A L H N H Y T Q K S L S L S P G K

SEQ ID NO：330

gaaattgtgc tgactcagtc 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 acaactccc 300

ctcactttcg gcggagggac caaggtggag atcaaacgtg cggccgcacc cagcgtgttc 360

atcttccccc cctccgacga gcagctgaag agcggcaccg ccagcgtggt gtgcctgctg 420

aacaacttct acccccggga ggccaaggtg cagtggaagg tggacaacgc cctgcagagc 480

ggcaacagcc aggagagcgt gaccgagcag gacagcaagg actccaccta cagcctgagc 540

agcaccctca ccctgagcaa ggccgactac gagaagcaca aggtgtacgc ctgcgaggtg 600

acccaccagg gcctgagcag ccccgtgacc aagagcttca accggggcga gtgt 654

SEQ ID NO：331

E I V L T Q S P L S L P V T P G E P A S I S C R S S Q S L L H S N G Y N Y L D

W Y L Q K P G Q S P Q L L I Y L G S N R A S G V P D R F S G S G S G T D F T L

K I S R V E A E D V G V Y Y C M Q A L Q T P L T F G G G T K V E I K R A A A P

S V F I F P P S D E Q L K S G T A S V V C L L N N F Y P R E A K V Q W K V D N

A L Q S G N S Q E S V T E Q D S K D S T Y S L S S T L T L S K A D Y E K H K V

Y A C E V T H Q G L S S P V T K S F N R G E C

SEQ ID NO：332

gaggtgcagc tggtggagac cggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60

tcctgcaagg cctctggagg caccttcagg acccatgcta tcagttgggt gcgacaggcc 120

cctggacaag ggcttgagtg gatgggaggg atcatcgcta tcttcggaac agcaaactac 180

gcacagaagt tccagggcag aatcacgatt accgcggacg aatccacgag tacagcctac 240

atggagctga gcagcctgag atctgaggac acggccgtgt atttctgtgc gagaggcagt 300

ggttatcata tatcgacacc ctttgacaac tggggccagg gaaccctggt caccgtctcg 360

agtgctagca ccaagggccc cagcgtgttc cccctggccc ccagcagcaa gagcaccagc 420

ggcggcacag ccgccctggg ctgcctggtg aaggactact tccccgagcc cgtgaccgtg 480

agctggaaca gcggcgcctt gaccagcggc gtgcacacct tccccgccgt gctgcagagc 540

agcggcctgt acagcctgag cagcgtggtg accgtgccca gcagcagcct gggcacccag 600

acctacatct gcaacgtgaa ccacaagccc agcaacacca aggtggacaa acgcgtggag 660

cccaagagct gcgacaagac ccacacctgc cccccctgcc ctgcccccga gctgctgggc 720

ggaccctccg tgttcctgtt cccccccaag cccaaggaca ccctcatgat cagccggacc 780

cccgaggtga cctgcgtggt ggtggacgtg agccacgagg accccgaggt gaagttcaac 840

tggtacgtgg acggcgtgga ggtgcacaac gccaagacca agccccggga ggagcagtac 900

aacagcacct accgggtggt gagcgtgctc accgtgctgc accaggactg gctgaacggc 960

aaggagtaca agtgcaaggt gagcaacaag gccctgcctg cccccatcga gaagaccatc 1020

agcaaggcca agggccagcc ccgggagccc caggtgtaca ccctgccccc cagccgggag 1080

gagatgacca agaaccaggt gtccctcacc tgtctggtga agggcttcta ccccagcgac 1140

atcgccgtgg agtgggagag caacggccag cccgagaaca actacaagac caccccccct 1200

gtgctggaca gcgacggcag cttcttcctg tacagcaagc tcaccgtgga caagagccgg 1260

tggcagcagg gcaacgtgtt cagctgcagc gtgatgcacg aggccctgca caaccactac 1320

acccagaaga gcctgagcctgagccccggc aag 1353

SEQ ID NO：333

E V Q L V E T G A E V K K P G S S V K V S C K A S G G T F R T H A I S W V R Q

A P G Q G L E W M G G I I A I F G T A N Y A Q K F Q G R I T I T A D E S T S T

A Y M E L S S L R S E D T A V Y F C A R G S G Y H I S T P F D N W G Q G T L V

T V S S A S T K G P S V F P L A P S S K S T S G G T A A L G C L V K D Y F P E

P V T V S W N S G A L T S G V H T F P A V L Q S S G L Y S L S S V V T V P S S

S L G T Q T Y I C N V N H K P S N T K V D K R V E P K S C D K T H T C P P C P

A P E L L G G P S V F L F P P K P K D T L M I S R T P E V T C V V V D V S H E

D P E V K F N W Y V D G V E V H N A K T K P R E E Q Y N S T Y R V V S V L T V

L H Q D W L N G K E Y K C K V S N K A L P A P I E K T I S K A K G Q P R E P Q

V Y T L P P S R E E M T K N Q V S L T C L V K G F Y P S D I A V E W E S N G Q

P E N N Y K T T P P V L D S D G S F F L Y S K L T V D K S R W Q Q G N V F S C

S V M H E A L H N H Y T Q K S L S L S P G K

SEQ ID NO：334

tcctatgtgc tgactcagcc accctcggtg tcagtggccc caggacagac ggccaggatt 60

acctgtgggg gaaacaacat tggaagtaaa ggtgtgcact ggtaccagca gaagcctggc 120

caggcccctg tgctggtcgt ctatgatgat agcgaccggc cctcagggat ccctgagcga 180

ttctctggct ccaactctgg gaacacggcc accctgacca tcagcagggt cgaagccggg 240

gatgaggccg actattactg tcaggtgtgg gatagtagta gtgatcatgt ggtattcggc 300

ggagggacca agctgaccgt cctaggtgcg gccgcaggcc agcccaaggc cgctcccagc 360

gtgaccctgt tccccccctc ctccgaggag ctgcaggcca acaaggccac cctggtgtgc 420

ctcatcagcg acttctaccc tggcgccgtg accgtggcct ggaaggccga cagcagcccc 480

gtgaaggccg gcgtggagac caccaccccc agcaagcaga gcaacaacaa gtacgccgcc 540

agcagctacc tgagcctcac ccccgagcag tggaagagcc accggagcta cagctgccag 600

gtgacccacg agggcagcac cgtggagaag accgtggccc ccaccgagtg cagc 654

SEQ ID NO：335

S Y V L T Q P P S V S V A P G Q T A R I T C G G N N I G S K G V H W Y Q Q K P

G Q A P V L V V Y D D S D R P S G I P E R F S G S N S G N T A T L T I S R V E

A G D E A D Y Y C Q V W D S S S D H V V F G G G T K L T V L G A A A G Q P K A

A P S V T L F P P S S E E L Q A N K A T L V C L I S D F Y P G A V T V A W K A

D S S P V K A G V E T T T P S K Q S N N K Y A A S S Y L S L T P E Q W K S H R

S Y S C Q V T H E G S T V E K T V A P T E C S

SEQ ID NO：336

gaggtgcagc tggtggagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60

tcctgcaagg cttctggaca catcttcagc ggctatgcaa tcagttgggt gcgacaggcc 120

cctggacaag ggcttgagtg gatgggaggg atcatcccta tctttggtac aacaaactac 180

gcacagaagt tccagggcag agtcacgatt accgcggacc aatccacgag cacagcctac 240

atggacctga gcaacttgag atctgaggac acggccgtct attactgtgc gagagtgaaa 300

gatggatatt gtactcttac cagctgccct gtcggctggt acttcgatct ctggggccgt 360

ggcaccctgg tcactgtctc gagtgctagc accaagggcc ccagcgtgtt ccccctggcc 420

cccagcagca agagcaccag cggcggcaca gccgccctgg gctgcctggt gaaggactac 480

ttccccgagc ccgtgaccgt gagctggaac agcggcgcct tgaccagcgg cgtgcacacc 540

ttccccgccg tgctgcagag cagcggcctg tacagcctga gcagcgtggt gaccgtgccc 600

agcagcagcc tgggcaccca gacctacatc tgcaacgtga accacaagcc cagcaacacc 660

aaggtggaca aacgcgtgga gcccaagagc tgcgacaaga cccacacctg ccccccctgc 720

cctgcccccg agctgctggg cggaccctcc gtgttcctgt tcccccccaa gcccaaggac 780

accctcatga tcagccggac ccccgaggtg acctgcgtgg tggtggacgt gagccacgag 840

gaccccgagg tgaagttcaa ctggtacgtg gacggcgtgg aggtgcacaa cgccaagacc 900

aagccccggg aggagcagta caacagcacc taccgggtgg tgagcgtgct caccgtgctg 960

caccaggact ggctgaacgg caaggagtac aagtgcaagg tgagcaacaa ggccctgcct 1020

gcccccatcg agaagaccat cagcaaggcc aagggccagc cccgggagcc ccaggtgtac 1080

accctgcccc ccagccggga ggagatgacc aagaaccagg tgtccctcac ctgtctggtg 1140

aagggcttct accccagcga catcgccgtg gagtgggaga gcaacggcca gcccgagaac 1200

aactacaaga ccaccccccc tgtgctggac agcgacggca gcttcttcct gtacagcaag 1260

ctcaccgtgg acaagagccg gtggcagcag ggcaacgtgt tcagctgcag cgtgatgcac 1320

gaggccctgc acaaccacta cacccagaag agcctgagcc tgagccccgg caag 1374

SEQ ID NO：337

E V Q L V E S G A E V K K P G S S V K V S C K A S G H I F S G Y A I S W V R Q

A P G Q G L E W M G G I I P I F G T T N Y A Q K F Q G R V T I T A D Q S T S T

A Y M D L S N L R S E D T A V Y Y C A R V K D G Y C T L T S C P V G W Y F D L

W G R G T L V T V S S A S T K G P S V F P L A P S S K S T S G G T A A L G C L

V K D Y F P E P V T V S W N S G A L T S G V H T F P A V L Q S S G L Y S L S S

V V T V P S S S L G T Q T Y I C N V N H K P S N T K V D K R V E P K S C D K T

H T C P P C P A P E L L G G P S V F L F P P K P K D T L M I S R T P E V T C V

V V D V S H E D P E V K F N W Y V D G V E V H N A K T K P R E E Q Y N S T Y R

V V S V L T V L H Q D W L N G K E Y K C K V S N K A L P A P I E K T I S K A K

G Q P R E P Q V Y T L P P S R E E M T K N Q V S L T C L V K G F Y P S D I A V

E W E S N G Q P E N N Y K T T P P V L D S D G S F F L Y S K L T V D K S R W Q

Q G N V F S C S V M H E A L H N H Y T Q K S L S L S P G K

SEQ ID NO：338

gaaattgtga tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60

ctctcgtgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120

cctggccagg ctcccaggct cctcatcttt ggtgcctcca gcagggccac tggcatccca 180

gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240

cctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcactcac tttcggcgga 300

gggaccaagc tggagatcaa acgtgcggcc gcacccagcg tgttcatctt ccccccctcc 360

gacgagcagc tgaagagcgg caccgccagc gtggtgtgcc tgctgaacaa cttctacccc 420

cgggaggcca aggtgcagtg gaaggtggac aacgccctgc agagcggcaa cagccaggag 480

agcgtgaccg agcaggacag caaggactcc acctacagcc tgagcagcac cctcaccctg 540

agcaaggccg actacgagaa gcacaaggtg tacgcctgcg aggtgaccca ccagggcctg 600

agcagccccg tgaccaagag cttcaaccgg ggcgagtgt 639

SEQ ID NO：339

E I V M T Q S P G T L S L S P G E R A T L S C R A S Q S V S S S Y L A W Y Q Q

K P G Q A P R L L I F G A S S R A T G I P D R F S G S G S G T D F T L T I S R

L E P E D F A V Y Y C Q Q Y G S S L T F G G G T K L E I K R A A A P S V F I F

P P S D E Q L K S G T A S V V C L L N N F Y P R E A K V Q W K V D N A L Q S G

N S Q E S V T E Q D S K D S T Y S L S S T L T L S K A D Y E K H K V Y A C E V

T H Q G L S S P V T K S F N R G E C

SEQ ID NO：340

gaggtccagc tggtacagtc tggggctgag gttaagaagc ctgggtcctc ggtgaaggtc 60

tcctgcaagg cttctggagg catcttcaga agcaattcta tcagttgggt gcgacaggcc 120

cctgggcaag ggcttgagtg gatgggaggg atcttcgctc ttttcggaac aacagactac 180

gcgcagaagt tccagggcag agtcacgatt accgcggacg aatcttcgac cacagtctac 240

ctggagctga gtagcctgac atctgaggac acggccgttt attactgtgc gagaggcagt 300

ggctacacca cacgcaacta ctttgactac tggggccagg gcaccctggt caccgtctcg 360

agtgctagca ccaagggccc cagcgtgttc cccctggccc ccagcagcaa gagcaccagc 420

ggcggcacag ccgccctggg ctgcctggtg aaggactact tccccgagcc cgtgaccgtg 480

agctggaaca gcggcgcctt gaccagcggc gtgcacacct tccccgccgt gctgcagagc 540

agcggcctgt acagcctgag cagcgtggtg accgtgccca gcagcagcct gggcacccag 600

acctacatct gcaacgtgaa ccacaagccc agcaacacca aggtggacaa acgcgtggag 660

cccaagagct gcgacaagac ccacacctgc cccccctgcc ctgcccccga gctgctgggc 720

ggaccctccg tgttcctgtt cccccccaag cccaaggaca ccctcatgat cagccggacc 780

cccgaggtga cctgcgtggt ggtggacgtg agccacgagg accccgaggt gaagttcaac 840

tggtacgtgg acggcgtgga ggtgcacaac gccaagacca agccccggga ggagcagtac 900

aacagcacct accgggtggt gagcgtgctc accgtgctgc accaggactg gctgaacggc 960

aaggagtaca agtgcaaggt gagcaacaag gccctgcctg cccccatcga gaagaccatc 1020

agcaaggcca agggccagcc ccgggagccc caggtgtaca ccctgccccc cagccgggag 1080

gagatgacca agaaccaggt gtccctcacc tgtctggtga agggcttcta ccccagcgac 1140

atcgccgtgg agtgggagag caacggccag cccgagaaca actacaagac caccccccct 1200

gtgctggaca gcgacggcag cttcttcctg tacagcaagc tcaccgtgga caagagccgg 1260

tggcagcagg gcaacgtgtt cagctgcagc gtgatgcacg aggccctgca caaccactac 1320

acccagaaga gcctgagcct gagccccggc aag 1353

SEQ ID NO：341

E V Q L V Q S G A E V K K P G S S V K V S C K A S G G I F R S N S I S W V R Q

A P G Q G L E W M G G I F A L F G T T D Y A Q K F Q G R V T I T A D E S S T T

V Y L E L S S L T S E D T A V Y Y C A R G S G Y T T R N Y F D Y W G Q G T L V

T V S S A S T K G P S V F P L A P S S K S T S G G T A A L G C L V K D Y F P E

P V T V S W N S G A L T S G V H T F P A V L Q S S G L Y S L S S V V T V P S S

S L G T Q T Y I C N V N H K P S N T K V D K R V E P K S C D K T H T C P P C P

A P E L L G G P S V F L F P P K P K D T L M I S R T P E V T C V V V D V S H E

D P E V K F N W Y V D G V E V H N A K T K P R E E Q Y N S T Y R V V S V L T V

L H Q D W L N G K E Y K C K V S N K A L P A P I E K T I S K A K G Q P R E P Q

V Y T L P P S R E E M T K N Q V S L T C L V K G F Y P S D I A V E W E S N G Q

P E N N Y K T T P P V L D S D G S F F L Y S K L T V D K S R W Q Q G N V F S C

S V M H E A L H N H Y T Q K S L S L S P G K

SEQ ID NO：342

gaaattgtgc tgactcagtc tccaggcacc ctgtctttgt ctccagggga aagagccaca 60

ctctcctgca gggccagtca gagtgttagc agcaactact taggctggta ccagcagaaa 120

cctggccagg ctcccaggct cctgatctat ggtgcatcca gcagggccag tggcatccca 180

gacaggttca gtggcggtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240

cctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcacccct cactttcggc 300

ggagggacca aggtggagat caaacgtgcg gccgcaggcc agcccaaggc cgctcccagc 360

gtgaccctgt tccccccctc ctccgaggag ctgcaggcca acaaggccac cctggtgtgc 420

ctcatcagcg acttctaccc tggcgccgtg accgtggcct ggaaggccga cagcagcccc 480

gtgaaggccg gcgtggagac caccaccccc agcaagcaga gcaacaacaa gtacgccgcc 540

agcagctacc tgagcctcac ccccgagcag tggaagagcc accggagcta cagctgccag 600

gtgacccacg agggcagcac cgtggagaag accgtggccc ccaccgagtg cagc 654

SEQ ID NO：343

E I V L T Q S P G T L S L S P G E R A T L S C R A S Q S V S S N Y L G W Y Q Q

K P G Q A P R L L I Y G A S S R A S GI P D R F S G G G S G T D F T L T I S R

L E P E D F A V Y Y C Q Q Y G S S P L T F G G G T K V E I K R A A A G Q P K A

A P S V T L F P P S S E E L Q A N K A T L V C L I S D F Y P G A V T V A W K A

D S S P V K A G V E T T T P S K Q S N N K Y A A S S Y L S L T P E Q W K S H R

S Y S C Q V T H E G S T V E K T V A P T E C S

SEQ ID NO：344

caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtaaaggtc 60

tcctgcaagg cttctggagg ccccttccgc aattttgcta tcaactgggt gcgacaggcc 120

cctggacaag ggcttgagtg gatgggaggg atcatcgctg tctttgggac gacaaagtac 180

gcacataagt tccagggcag agtcaccatc accgcggacg actccacaaa tacagcttac 240

atggagctgg gcagcctgaa atctgaggac acggccgtgt attactgtgc gagaggtccc 300

cactactact cctcctacat ggacgtctgg ggcgaaggga ccacggtcac cgtctcgagt 360

gctagcacca agggccccag cgtgttcccc ctggccccca gcagcaagag caccagcggc 420

ggcacagccg ccctgggctg cctggtgaag gactacttcc ccgagcccgt gaccgtgagc 480

tggaacagcg gcgccttgac cagcggcgtg cacaccttcc ccgccgtgct gcagagcagc 540

ggcctgtaca gcctgagcag cgtggtgacc gtgcccagca gcagcctggg cacccagacc 600

tacatctgca acgtgaacca caagcccagc aacaccaagg tggacaaacg cgtggagccc 660

aagagctgcg acaagaccca cacctgcccc ccctgccctg cccccgagct gctgggcgga 720

ccctccgtgt tcctgttccc ccccaagccc aaggacaccc tcatgatcag ccggaccccc 780

gaggtgacct gcgtggtggt ggacgtgagc cacgaggacc ccgaggtgaa gttcaactgg 840

tacgtggacg gcgtggaggt gcacaacgcc aagaccaagc cccgggagga gcagtacaac 900

agcacctacc gggtggtgag cgtgctcacc gtgctgcacc aggactggct gaacggcaag 960

gagtacaagt gcaaggtgag caacaaggcc ctgcctgccc ccatcgagaa gaccatcagc 1020

aaggccaagg gccagccccg ggagccccag gtgtacaccc tgccccccag ccgggaggag 1080

atgaccaaga accaggtgtc cctcacctgt ctggtgaagg gcttctaccc cagcgacatc 1140

gccgtggagt gggagagcaa cggccagccc gagaacaact acaagaccac cccccctgtg 1200

ctggacagcg acggcagctt cttcctgtac agcaagctca ccgtggacaa gagccggtgg 1260

cagcagggca acgtgttcag ctgcagcgtg atgcacgagg ccctgcacaa ccactacacc 1320

cagaagagcc tgagcctgag ccccggcaag 1350

SEQ ID NO：345

Q V Q L V Q S G A E V K K P G S S V K V S C K A S G G P F R N F A I N W V R Q

A P G Q G L E W M G G I I A V F G T T K Y A H K F Q G R V T I T A D D S T N T

A Y M E L G S L K S E D T A V Y Y C A R G P H Y Y S S Y M D V W G E G T T V T

V S S A S T K G P S V F P L A P S S K S T S G G T A A L G C L V K D Y F P E P

V T V S W N S G A L T S G V H T F P A V L Q S S G L Y S L S S V V T V P S S S

L G T Q T Y I C N V N H K P S N T K V D K R V E P K S C D K T H T C P P C P A

P E L L G G P S V F L F P P K P K D T L M I S R T P E V T C V V V D V S H E D

P E V K F N W Y V D G V E V H N A K T K P R E E Q Y N S T Y R V V S V L T V L

H Q D W L N G K E Y K C K V S N K A L P A P I E K T I S K A K G Q P R E P Q V

Y T L P P S R E E M T K N Q V S L T C L V K G F Y P S D I A V E W E S N G Q P

E N N Y K T T P P V L D S D G S F F L Y S K L T V D K S R W Q Q G N V F S C S

V M H E A L H N H Y T Q K S L S L S P G K

SEQ ID NO：346

gacatccagt tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60

atcacttgcc gggcgagtca gggcattagc acttatttag cctggtatca gcagaaaccc 120

gggaaagttc ctaaactcct gatctatgct gcatccactt tgcaatcagg ggtcccatct 180

cggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240

gaagatgttg caacttatta ctgtcaaaag tataacagtg ccccttcttt cggccctggg 300

accaaagtgg atatcaaacg tgcggccgca cccagcgtgt tcatcttccc cccctccgac 360

gagcagctga agagcggcac cgccagcgtg gtgtgcctgc tgaacaactt ctacccccgg 420

gaggccaagg tgcagtggaa ggtggacaac gccctgcaga gcggcaacag ccaggagagc 480

gtgaccgagc aggacagcaa ggactccacc tacagcctga gcagcaccct caccctgagc 540

aaggccgact acgagaagca caaggtgtac gcctgcgagg tgacccacca gggcctgagc 600

agccccgtga ccaagagctt caaccggggc gagtgt 636

SEQ ID NO：347

D I Q L T Q S P S S L S A S V G D R V T I T C R A S Q G I S T Y L A W Y Q Q K

P G K V P K L L I Y A A S T L Q S G V P S R F S G S G S G T D F T L T I S S L

Q P E D V A T Y Y C Q K Y N S A P S F G P G T K V D I K R A A A P S V F I F P

P S D E Q L K S G T A S V V C L L N N F Y P R E A K V Q W K V D N A L Q S G N

S Q E S V T E Q D S K D S T Y S L S S T L T L S K A D Y E K H K V Y A C E V T

H Q G L S S P V T K S F N R G E C

SEQ ID NO：348

gaggtgcagc tggtggagac tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60

ccctgcaaat cttctggaag ccccttcagg agtaatgctg tcagctgggt gcgacaggcc 120

cccggacaag ggcttgagtg ggtgggagga atcctcggtg tctttggttc accaagctac 180

gcacagaagt tccagggcag agtcacgatt accgcggacg aatccaccaa cacagtccac 240

atggagctga gaggtttgag atctgaggac acggccgtgt attattgtgc gagaggtcct 300

acctactact actcctacat ggacgtctgg ggcaaaggga ccacggtcac cgtctcgagt 360

gctagcacca agggccccag cgtgttcccc ctggccccca gcagcaagag caccagcggc 420

ggcacagccg ccctgggctg cctggtgaag gactacttcc ccgagcccgt gaccgtgagc 480

tggaacagcg gcgccttgac cagcggcgtg cacaccttcc ccgccgtgct gcagagcagc 540

ggcctgtaca gcctgagcag cgtggtgacc gtgcccagca gcagcctggg cacccagacc 600

tacatctgca acgtgaacca caagcccagc aacaccaagg tggacaaacg cgtggagccc 660

aagagctgcg acaagaccca cacctgcccc ccctgccctg cccccgagct gctgggcgga 720

ccctccgtgt tcctgttccc ccccaagccc aaggacaccc tcatgatcag ccggaccccc 780

gaggtgacct gcgtggtggt ggacgtgagc cacgaggacc ccgaggtgaa gttcaactgg 840

tacgtggacg gcgtggaggt gcacaacgcc aagaccaagc cccgggagga gcagtacaac 900

agcacctacc gggtggtgag cgtgctcacc gtgctgcacc aggactggct gaacggcaag 960

gagtacaagt gcaaggtgag caacaaggcc ctgcctgccc ccatcgagaa gaccatcagc 1020

aaggccaagg gccagccccg ggagccccag gtgtacaccc tgccccccag ccgggaggag 1080

atgaccaaga accaggtgtc cctcacctgt ctggtgaagg gcttctaccc cagcgacatc 1140

gccgtggagt gggagagcaa cggccagccc gagaacaact acaagaccac cccccctgtg 1200

ctggacagcg acggcagctt cttcctgtac agcaagctca ccgtggacaa gagccggtgg 1260

cagcagggca acgtgttcag ctgcagcgtg atgcacgagg ccctgcacaa ccactacacc 1320

cagaagagcc tgagcctgag ccccggcaag 1350

SEQ ID NO：349

E V Q L V E T G A E V K K P G S S V K V P C K S S G S P F R S N A V S W V R Q

A P G Q G L E W V G G I L G V F G S P S Y A Q K F Q G R V T I T A D E S T N T

V H M E L R G L R S E D T A V Y Y C A R G P T Y Y Y S Y M D V W G K G T T V T

V S S A S T K G P S V F P L A P S S K S T S G G T A A L G C L V K D Y F P E P

V T V S W N S G A L T S G V H T F P A V L Q S S G L Y S L S S V V T V P S S S

L G T Q T Y I C N V N H K P S N T K V D K R V E P K S C D K T H T C P P C P A

P E L L G G P S V F L F P P K P K D T L M I S R T P E V T C V V V D V S H E D

P E V K F N W Y V D G V E V H N A K T K P R E E Q Y N S T Y R V V S V L T V L

H Q D W L N G K E Y K C K V S N K A L P A P I E K T I S K A K G Q P R E P Q V

Y T L P P S R E E M T K N Q V S L T C L V K G F Y P S D I A V E W E S N G Q P

E N N Y K T T P P V L D S D G S F F L Y S K L T V D K S R W Q Q G N V F S C S

V M H E A L H N H Y T Q K S L S L S P G K

SEQ ID NO：350

tcctatgtgc tgactcagcc accctcggag tcagtggccc caggacagac ggccaggatt 60

acctgtgggg gaaataacat tggaagaaat agtgtgcact ggtatcagca gaagccaggc 120

caggcccctg tgctggtcgt gtatgatgat agcgaccggc cctcagggat ccctgagcga 180

ttttctggct ccaagtctgg gaacacggcc accctgatta tcagcagggt cgaagtcggg 240

gatgaggccg actactactg tcaggtgtgg catagtagta gtgatcatta tgtcttcgga 300

actgggacca aggtcaccgt cctaggtgcg gccgcaggcc agcccaaggc cgctcccagc 360

gtgaccctgt tccccccctc ctccgaggag ctgcaggcca acaaggccac cctggtgtgc 420

ctcatcagcg acttctaccc tggcgccgtg accgtggcct ggaaggccga cagcagcccc 480

gtgaaggccg gcgtggagac caccaccccc agcaagcaga gcaacaacaa gtacgccgcc 540

agcagctacc tgagcctcac ccccgagcag tggaagagcc accggagcta cagctgccag 600

gtgacccacg agggcagcac cgtggagaag accgtggccc ccaccgagtg cagc 654

SEQ ID NO：351

S Y V L T Q P P S E S V A P G Q T A R I T C G G N N I G R N S V H W Y Q Q K P

G Q A P V L V V Y D D S D R P S G I P E R F S G S K S G N T A T L I I S R V E

V G D E A D Y Y C Q V W H S S S D H Y V F G T G T K V T V L G A A A G Q P K A

A P S V T L F P P S S E E L Q A N K A T L V C L I S D F Y P G A V T V A W K A

D S S P V K A G V E T T T P S K Q S N N K Y A A S S Y L S L T P E Q W K S H R

S Y S C Q V T H E G S T V E K T V A P T E C S

SEQ ID NO：352

cagatgcagc tggtacaatc tggagctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60

tcctgcaagg cttctggagg caccttcagc agctatgcta tcagctgggt gcgacaggcc 120

cctggacaag ggcttgagtg gatgggaggg atcttcggta tgtttgggac agcaaactac 180

gcgcagaagt tccagggcag agtcacgatt accgcggacg aattcacgag cgcggcctac 240

atggagctga gcagcctggg atctgaggac acggccatgt attactgtgc gaggtctagt 300

ggttattacc cccaatactt ccaggactgg ggccagggca ccctggtcac cgtctcgagt 360

gctagcacca agggccccag cgtgttcccc ctggccccca gcagcaagag caccagcggc 420

ggcacagccg ccctgggctg cctggtgaag gactacttcc ccgagcccgt gaccgtgagc 480

tggaacagcg gcgccttgac cagcggcgtg cacaccttcc ccgccgtgct gcagagcagc 540

ggcctgtaca gcctgagcag cgtggtgacc gtgcccagca gcagcctggg cacccagacc 600

tacatctgca acgtgaacca caagcccagc aacaccaagg tggacaaacg cgtggagccc 660

aagagctgcg acaagaccca cacctgcccc ccctgccctg cccccgagct gctgggcgga 720

ccctccgtgt tcctgttccc ccccaagccc aaggacaccc tcatgatcag ccggaccccc 780

gaggtgacct gcgtggtggt ggacgtgagc cacgaggacc ccgaggtgaa gttcaactgg 840

tacgtggacg gcgtggaggt gcacaacgcc aagaccaagc cccgggagga gcagtacaac 900

agcacctacc gggtggtgag cgtgctcacc gtgctgcacc aggactggct gaacggcaag 960

gagtacaagt gcaaggtgag caacaaggcc ctgcctgccc ccatcgagaa gaccatcagc 1020

aaggccaagg gccagccccg ggagccccag gtgtacaccc tgccccccag ccgggaggag 1080

atgaccaaga accaggtgtc cctcacctgt ctggtgaagg gcttctaccc cagcgacatc 1140

gccgtggagt gggagagcaa cggccagccc gagaacaact acaagaccac cccccctgtg 1200

ctggacagcg acggcagctt cttcctgtac agcaagctca ccgtggacaa gagccggtgg 1260

cagcagggca acgtgttcag ctgcagcgtg atgcacgagg ccctgcacaa ccactacacc 1320

cagaagagcc tgagcctgag ccccggcaag 1350

SEQ ID NO：353

Q M Q L V Q S G A E V K K P G S S V K V S C K A S G G T F S S Y A I S W V R Q

A P G Q G L E W M G G I F G M F G T A N Y A Q K F Q G R V T I T A D E F T S A

A Y M E L S S L G S E D T A M Y Y C A R S S G Y Y P Q Y F Q D W G Q G T L V T

V S S A S T K G P S V F P L A P S S K S T S G G T A A L G C L V K D Y F P E P

V T V S W N S G A L T S G V H T F P A V L Q S S G L Y S L S S V V T V P S S S

L G T Q T Y I C N V N H K P S N T K V D K R V E P K S C D K T H T C P P C P A

P E L L G G P S V F L F P P K P K D T L M I S R T P E V T C V V V D V S H E D

P E V K F N W Y V D G V E V H N A K T K P R E E Q Y N S T Y R V V S V L T V L

H Q D W L N G K E Y K C K V S N K A L P A P I E K T I S K A K G Q P R E P Q V

Y T L P P S R E E M T K N Q V S L T C L V K G F Y P S D I A V E W E S N G Q P

E N N Y K T T P P V L D S D G S F F L Y S K L T V D K S R W Q Q G N V F S C S

V M H E A L H N H Y T Q K S L S L S P G K

SEQ ID NO：354

gaaattgtga tgacacagtc tccaggcacc ctgtctttgt ctccagggca aagagccacc 60

ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120

cctggccagg ctcccagact cctcatgtat ggtgcatcca gcagggccac tggcatccca 180

gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240

cctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcatcgct cactttcggc 300

ggagggacca agctggagat caaacgtgcg gccgcaccca gcgtgttcat cttccccccc 360

tccgacgagc agctgaagag cggcaccgcc agcgtggtgt gcctgctgaa caacttctac 420

ccccgggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480

gagagcgtga ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctcacc 540

ctgagcaagg ccgactacga gaagcacaag gtgtacgcct gcgaggtgac ccaccagggc 600

ctgagcagcc ccgtgaccaa gagcttcaac cggggcgagtgt 642

SEQ ID NO：355

E I V M T Q S P G T L S L S P G Q R A T L S C R A S Q S V S S S Y L A W Y Q Q

K P G Q A P R L L M Y G A S S R A T G I P D R F S G S G S G T D F T L T I S R

L E P E D F A V Y Y C Q Q Y G S S S L T F G G G T K L E I K R A A A P S V F I

F P P S D E Q L K S G T A S V V C L L N N F Y P R E A K V Q W K V D N A L Q S

G N S Q E S V T E Q D S K D S T Y S L S S T L T L S K A D Y E K H K V Y A C E

V T H Q G L S S P V T K S F N R G E C

SEQ ID NO：356

gaggtgcagc tggtggagtc cggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60

tcctgcaagg cttctggagg catcttcaac agttatgcta tcagctgggt gcgacaggcc 120

cctggacaag ggcttgagtg gatgggaggc atcatcgcta tctttcatac accaaagtac 180

gcacagaagt tccagggcag agtcacgatt accgcggacg aatccacgaa cacagcctac 240

atggaactga gaagcctgaa atctgaggac acggccctgt attactgtgc gagagggtcc 300

acttacgatt tttcgagtgg ccttgactac tggggccagg gaaccctggt caccgtctcg 360

agtgctagca ccaagggccc cagcgtgttc cccctggccc ccagcagcaa gagcaccagc 420

ggcggcacag ccgccctggg ctgcctggtg aaggactact tccccgagcc cgtgaccgtg 480

agctggaaca gcggcgcctt gaccagcggc gtgcacacct tccccgccgt gctgcagagc 540

agcggcctgt acagcctgag cagcgtggtg accgtgccca gcagcagcct gggcacccag 600

acctacatct gcaacgtgaa ccacaagccc agcaacacca aggtggacaa acgcgtggag 660

cccaagagct gcgacaagac ccacacctgc cccccctgcc ctgcccccga gctgctgggc 720

ggaccctccg tgttcctgtt cccccccaag cccaaggaca ccctcatgat cagccggacc 780

cccgaggtga cctgcgtggt ggtggacgtg agccacgagg accccgaggt gaagttcaac 840

tggtacgtgg acggcgtgga ggtgcacaac gccaagacca agccccggga ggagcagtac 900

aacagcacct accgggtggt gagcgtgctc accgtgctgc accaggactg gctgaacggc 960

aaggagtaca agtgcaaggt gagcaacaag gccctgcctg cccccatcga gaagaccatc 1020

agcaaggcca agggccagcc ccgggagccc caggtgtaca ccctgccccc cagccgggag 1080

gagatgacca agaaccaggt gtccctcacc tgtctggtga agggcttcta ccccagcgac 1140

atcgccgtgg agtgggagag caacggccag cccgagaaca actacaagac caccccccct 1200

gtgctggaca gcgacggcag cttcttcctg tacagcaagc tcaccgtgga caagagccgg 1260

tggcagcagg gcaacgtgtt cagctgcagc gtgatgcacg aggccctgca caaccactac 1320

acccagaaga gcctgagcct gagccccggc aag 1353

SEQ ID NO：357

E V Q L V E S G A E V K K P G S S V K V S C K A S G G I F N S Y A I S W V R Q

A P G Q G L E W M G G I I A I F H T P K Y A Q K F Q G R V T I T A D E S T N T

A Y M E L R S L K S E D T A L Y Y C A R G S T Y D F S S G L D Y W G Q G T L V

T V S S A S T K G P S V F P L A P S S K S T S G G T A A L G C L V K D Y F P E

P V T V S W N S G A L T S G V H T F P A V L Q S S G L Y S L S S V V T V P S S

S L G T Q T Y I C N V N H K P S N T K V D K R V E P K S C D K T H T C P P C P

A P E L L G G P S V F L F P P K P K D T L M I S R T P E V T C V V V D V S H E

D P E V K F N W Y V D G V E V H N A K T K P R E E Q Y N S T Y R V V S V L T V

L H Q D W L N G K E Y K C K V S N K A L P A P I E K T I S K A K G Q P R E P Q

V Y T L P P S R E E M T K N Q V S L T C L V K G F Y P S D I A V E W E S N G Q

P E N N Y K T T P P V L D S D G S F F L Y S K L T V D K S R W Q Q G N V F S C

S V M H E A L H N H Y T Q K S L S L S P G K

SEQ ID NO：358

caggcagggc tgactcagcc accctcggtg tcagtggccc caggacagac ggccaggatt 60

acctgtgggg gaaacaacat tggaagtaaa agtgtgcact ggtaccagca gaagccaggc 120

caggcccctg tcctagtcgt ctatgatgat agcgaccggc cctcagggat ccctgagcga 180

ttctctggct ccaactctgg gaacacggcc accctgacca tcagcagggt cgaagccggg 240

gatgaggccg actattactg tcaggtgtgg gatagtagta gtgatcatgt ggtattcggc 300

ggagggacca agctgaccgt cctaggtgcg gccgcaggcc agcccaaggc cgctcccagc 360

gtgaccctgt tccccccctc ctccgaggag ctgcaggcca acaaggccac cctggtgtgc 420

ctcatcagcg acttctaccc tggcgccgtg accgtggcct ggaaggccga cagcagcccc 480

gtgaaggccg gcgtggagac caccaccccc agcaagcaga gcaacaacaa gtacgccgcc 540

agcagctacc tgagcctcac ccccgagcag tggaagagcc accggagcta cagctgccag 600

gtgacccacg agggcagcac cgtggagaag accgtggccc ccaccgagtg cagc 654

SEQ ID NO：359

Q A G L T Q P P S V S V A P G Q T A R I T C G G N N I G S K S V H W Y Q Q K P

G Q A P V L V V Y D D S D R P S G I P E R F S G S N S G N T A T L T I S R V E

A G D E A D Y Y C Q V W D S S S D H V V F G G G T K L T V L G A A A G Q P K A

A P S V T L F P P S S E E L Q A N K A T L V C L I S D F Y P G A V T V A W K A

D S S P V K A G V E T T T P S K Q S N N K Y A A S S Y L S L T P E Q W K S H R

S Y S C Q V T H E G S T V E K T V A P T E C S

SEQ ID NO：360

caggtccagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60

tcctgcaagg cttctggagg cttcttcagc agctatgcta tcagctgggt gcgccaggcc 120

cctggacaag gacttgagtg gatggggggg gtcatcccta tctttcgtac agcaaactac 180

gcacagaact tccagggcag agtcaccatt accgcggacg aattcacatc gtatatggag 240

ctgagcagcc tgagatctga cgacacggcc gtgtattact gtgcgaggtt gaattaccat 300

gattcgggga cttattataa cgccccccgg ggctggttcg acccctgggg ccagggaacc 360

ctggtcaccg tctcgagtgc tagcaccaag ggccccagcg tgttccccct ggcccccagc 420

agcaagagca ccagcggcgg cacagccgcc ctgggctgcc tggtgaagga ctacttcccc 480

gagcccgtga ccgtgagctg gaacagcggc gccttgacca gcggcgtgca caccttcccc 540

gccgtgctgc agagcagcgg cctgtacagc ctgagcagcg tggtgaccgt gcccagcagc 600

agcctgggca cccagaccta catctgcaac gtgaaccaca agcccagcaa caccaaggtg 660

gacaaacgcg tggagcccaa gagctgcgac aagacccaca cctgcccccc ctgccctgcc 720

cccgagctgc tgggcggacc ctccgtgttc ctgttccccc ccaagcccaa ggacaccctc 780

atgatcagcc ggacccccga ggtgacctgc gtggtggtgg acgtgagcca cgaggacccc 840

gaggtgaagt tcaactggta cgtggacggc gtggaggtgc acaacgccaa gaccaagccc 900

cgggaggagc agtacaacag cacctaccgg gtggtgagcg tgctcaccgt gctgcaccag 960

gactggctga acggcaagga gtacaagtgc aaggtgagca acaaggccct gcctgccccc 1020

atcgagaaga ccatcagcaa ggccaagggc cagccccggg agccccaggt gtacaccctg 1080

ccccccagcc gggaggagat gaccaagaac caggtgtccc tcacctgtct ggtgaagggc 1140

ttctacccca gcgacatcgc cgtggagtgg gagagcaacg gccagcccga gaacaactac 1200

aagaccaccc cccctgtgct ggacagcgac ggcagcttct tcctgtacag caagctcacc 1260

gtggacaaga gccggtggca gcagggcaac gtgttcagct gcagcgtgat gcacgaggcc 1320

ctgcacaacc actacaccca gaagagcctg agcctgagcc ccggcaag 1368

SEQ ID NO：361

Q V Q L V Q S G A E V K K P G S S V K V S C K A S G G F F S S Y A I S W V R Q

A P G Q G L E W M G G V I P I F R T A N Y A Q N F Q G R V T I T A D E F T S Y

M E L S S L R S D D T A V Y Y C A R L N Y H D S G T Y Y N A P R G W F D P W G

Q G T L V T V S S A S T K G P S V F P L A P S S K S T S G G T A A L G C L V K

D Y F P E P V T V S W N S G A L T S G V H T F P A V L Q S S G L Y S L S S V V

T V P S S S L G T Q T Y I C N V N H K P S N T K V D K R V E P K S C D K T H T

C P P C P A P E L L G G P S V F L F P P K P K D T L M I S R T P E V T C V V V

D V S H E D P E V K F N W Y V D G V E V H N A K T K P R E E Q Y N S T Y R V V

S V L T V L H Q D W L N G K E Y K C K V S N K A L P A P I E K T I S K A K G Q

P R E P Q V Y T L P P S R E E M T K N Q V S L T C L V K G F Y P S D I A V E W

E S N G Q P E N N Y K T T P P V L D S D G S F F L Y S K L T V D K S R W Q Q G

N V F S C S V M H E A L H N H Y T Q K S L S L S P G K

SEQ ID NO：362

gacatccaga tgacccagtc tccagactcc ctggctgtgt ctctgggcga gaaggccacc 60

atcaactgca agtccagcca gagtatttta aacagctcca acaataagaa ctacttagct 120

tggtaccagc agaaaccagg acagcctcct aagctgctca tttactgggc atctacccgg 180

gaatccgggg tccctgaccg attcagtggc agcgggtctg ggacagattt cactctcacc 240

atcagcagcc tgcaggctga agatgtggca gtttattact gtcagcaata ttatagtagt 300

ccgccgacgt tcggccaagg gaccaaggtg gaaatcaaac gtgcggccgc acccagcgtg 360

ttcatcttcc ccccctccga cgagcagctg aagagcggca ccgccagcgt ggtgtgcctg 420

ctgaacaact tctacccccg ggaggccaag gtgcagtgga aggtggacaa cgccctgcag 480

agcggcaaca gccaggagag cgtgaccgag caggacagca aggactccac ctacagcctg 540

agcagcaccc tcaccctgag caaggccgac tacgagaagc acaaggtgta cgcctgcgag 600

gtgacccacc agggcctgag cagccccgtg accaagagct tcaaccgggg cgagtgt 657

SEQ ID NO：363

D I Q M T Q S P D S L A V S L G E K A T I N C K S S Q S I L N S S N N K N Y L

A W Y Q Q K P G Q P P K L L I Y W A S T R E S G V P D R F S G S G S G T D F T

L T I S S L Q A E D V A V Y Y C Q Q Y Y S S P P T F G Q G T K V E I K R A A A

P S V F I F P P S D E Q L K S G T A S V V C L L N N F Y P R E A K V Q W K V D

N A L Q S G N S Q E S V T E Q D S K D S T Y S L S S T L T L S K A D Y E K H K

V Y A C E V T H Q G L S S P V T K S F N R G E C

SEQ ID NO：364

caggtccagc tggtgcagtc tggagctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60

tcctgcaagg cttctggagt caccttcagt tactatgcta tgagctgggt gcgacaggcc 120

cctggacaag ggcttgagtg gatgggagga atcagcccta tgtttgggac aacaacctac 180

gcacagaagt tccagggcag agtcacgatt actgcggacg actccacgag tacagcctac 240

atggaggtga ggagcctgag atctgaggac acggccgtgt attactgtgc gagatcttcg 300

aattactatg atagtgtata tgactactgg ggccagggaa ccctggtcac cgtctcgagt 360

gctagcacca agggccccag cgtgttcccc ctggccccca gcagcaagag caccagcggc 420

ggcacagccg ccctgggctg cctggtgaag gactacttcc ccgagcccgt gaccgtgagc 480

tggaacagcg gcgccttgac cagcggcgtg cacaccttcc ccgccgtgct gcagagcagc 540

ggcctgtaca gcctgagcag cgtggtgacc gtgcccagca gcagcctggg cacccagacc 600

tacatctgca acgtgaacca caagcccagc aacaccaagg tggacaaacg cgtggagccc 660

aagagctgcg acaagaccca cacctgcccc ccctgccctg cccccgagct gctgggcgga 720

ccctccgtgt tcctgttccc ccccaagccc aaggacaccc tcatgatcag ccggaccccc 780

gaggtgacct gcgtggtggt ggacgtgagc cacgaggacc ccgaggtgaa gttcaactgg 840

tacgtggacg gcgtggaggt gcacaacgcc aagaccaagc cccgggagga gcagtacaac 900

agcacctacc gggtggtgag cgtgctcacc gtgctgcacc aggactggct gaacggcaag 960

gagtacaagt gcaaggtgag caacaaggcc ctgcctgccc ccatcgagaa gaccatcagc 1020

aaggccaagg gccagccccg ggagccccag gtgtacaccc tgccccccag ccgggaggag 1080

atgaccaaga accaggtgtc cctcacctgt ctggtgaagg gcttctaccc cagcgacatc 1140

gccgtggagt gggagagcaa cggccagccc gagaacaact acaagaccac cccccctgtg 1200

ctggacagcg acggcagctt cttcctgtac agcaagctca ccgtggacaa gagccggtgg 1260

cagcagggca acgtgttcag ctgcagcgtg atgcacgagg ccctgcacaa ccactacacc 1320

cagaagagcc tgagcctgag ccccggcaag 1350

SEQ ID NO：365

Q V Q L V Q S G A E V K K P G S S V K V S C K A S G V T F S Y Y A M S W V R Q

A P G Q G L E W M G G I S P M F G T T T Y A Q K F Q G R V T I T A D D S T S T

A Y M E V R S L R S E D T A V Y Y C A R S S N Y Y D S V Y D Y W G Q G T L V T

V S S A S T K G P S V F P L A P S S K S T S G G T A A L G C L V K D Y F P E P

V T V S W N S G A L T S G V H T F P A V L Q S S G L Y S L S S V V T V P S S S

L G T Q T Y I C N V N H K P S N T K V D K R V E P K S C D K T H T C P P C P A

P E L L G G P S V F L F P P K P K D T L M I S R T P E V T C V V V D V S H E D

P E V K F N W Y V D G V E V H N A K T K P R E E Q Y N S T Y R V V S V L T V L

H Q D W L N G K E Y K C K V S N K A L P A P I E K T I S K A K G Q P R E P Q V

Y T L P P S R E E M T K N Q V S L T C L V K G F Y P S D I A V E W E S N G Q P

E N N Y K T T P P V L D S D G S F F L Y S K L T V D K S R W Q Q G N V F S C S

V M H E A L H N H Y T Q K S L S L S P G K

SEQ ID NO：366

cagtctgtcg tgacgcagcc gccctcggag tcagtggccc caggacagac ggccaggatt 60

acctgtgggg gacataacat tggaagtaat agtgtgcact ggtaccagca gaagccaggc 120

caggcccctg tgctggtcgt gtatgataat agcgaccggc cctcagggat ccctgagcga 180

ttctctggct ccaactctgg gaacacggcc accctgacca tcagcagggt cgaagccggg 240

gatgaggccg actattactg tcaggtgtgg ggtagtagta gtgaccatta tgtcttcgga 300

actgggacca aggtcaccgt cctaggtgcg gccgcaggcc agcccaaggc cgctcccagc 360

gtgaccctgt tccccccctc ctccgaggag ctgcaggcca acaaggccac cctggtgtgc 420

ctcatcagcg acttctaccc tggcgccgtg accgtggcct ggaaggccga cagcagcccc 480

gtgaaggccg gcgtggagac caccaccccc agcaagcaga gcaacaacaa gtacgccgcc 540

agcagctacc tgagcctcac ccccgagcag tggaagagcc accggagcta cagctgccag 600

gtgacccacg agggcagcac cgtggagaag accgtggccc ccaccgagtg cagc 654

SEQ ID NO：367

Q S V V T Q P P S E S V A P G Q T A R I T C G G H N I G S N S V H W Y Q Q

K P G Q A P V L V V Y D N S D R P S G I P E R F S G S N S G N T A T L T I S R

V E A G D E A D Y Y C Q V W G S S S D H Y V F G T G T K V T V L G A A A G Q P

K A A P S V T L F P P S S E E L Q A N K A T L V C L I S D F Y P G A V T V A W

K A D S S P V K A G V E T T T P S K Q S N N K Y A A S S Y L S L T P E Q W K S

H R S Y S C Q V T H E G S T V E K T V A P T E C S

Table 1: first round V κ, V λ and VH amplification

The primer title	The primer nucleotide sequence	SEQ ID NO：
The primer title	The primer nucleotide sequence	SEQ ID NO：	OK1(HuVK1B)	GAC ATC CAG WTG ACC CAG TCT CC	144
OK2(HuVK2)	GAT GTT GTG ATG ACT CAG TCT CC	145	OK1(HuVK1B)	GAC ATC CAG WTG ACC CAG TCT CC	144
OK2(HuVK2)	GAT GTT GTG ATG ACT CAG TCT CC	145	OK3(HuVK2B2)	GAT ATT GTG ATG ACC CAG ACT CC	146
OK4(HuVK3B)	GAA ATT GTG WTG ACR CAG TCT CC	147	OK3(HuVK2B2)	GAT ATT GTG ATG ACC CAG ACT CC	146
OK4(HuVK3B)	GAA ATT GTG WTG ACR CAG TCT CC	147	OK5(HuVK5)	GAA ACG ACA CTC ACG CAG TCT CC	148
OK6(HuVK6)	GAA ATT GTG CTG ACT CAG TCT CC	149	OK5(HuVK5)	GAA ACG ACA CTC ACG CAG TCT CC	148
OK6(HuVK6)	GAA ATT GTG CTG ACT CAG TCT CC	149	OCK(HuCK)	ACAC TCT CCC CTG TTG AAG CTC TT	150
OL1(HuVL1A) ^*	CAG TCT GTG CTG ACT CAG CCA CC	151	OCK(HuCK)	ACAC TCT CCC CTG TTG AAG CTC TT	150
OL1(HuVL1A) ^*	CAG TCT GTG CTG ACT CAG CCA CC	151	OL1(HuVL1B) ^*	CAG TCT GTG YTG ACG CAG CCG CC	152
OL1(HuVL1C) ^*	CAG TCT GTC GTG ACG CAG CCG CC	153	OL1(HuVL1B) ^*	CAG TCT GTG YTG ACG CAG CCG CC	152
OL1(HuVL1C) ^*	CAG TCT GTC GTG ACG CAG CCG CC	153	OL2(HuVL2B)	CAG TCT GCC CTG ACT CAG CC	154
OL3(HuVL3A)	TCC TAT GWG CTG ACT CAG CCA CC	155	OL2(HuVL2B)	CAG TCT GCC CTG ACT CAG CC	154
OL3(HuVL3A)	TCC TAT GWG CTG ACT CAG CCA CC	155	OL4(HuVL3B)	TCT TCT GAG CTG ACT CAG GAC CC	156
OL5(HuVL4B)	CAG CYT GTG CTG ACT CAA TC	157	OL4(HuVL3B)	TCT TCT GAG CTG ACT CAG GAC CC	156
OL5(HuVL4B)	CAG CYT GTG CTG ACT CAA TC	157	OL6(HuVL5)	CAG GCT GTG CTG ACT CAG CCG TC	158
OL7(HuVL6)	AAT TTT ATG CTG ACT CAG CCC CA	159	OL6(HuVL5)	CAG GCT GTG CTG ACT CAG CCG TC	158
OL7(HuVL6)	AAT TTT ATG CTG ACT CAG CCC CA	159	OL8(HuVL7/8)	CAG RCT GTG GTG ACY CAG GAG CC	160
OL9(HuVL9)#	CWG CCT GTG CTG ACT CAG CCM CC	161	OL8(HuVL7/8)	CAG RCT GTG GTG ACY CAG GAG CC	160
OL9(HuVL9)#	CWG CCT GTG CTG ACT CAG CCM CC	161	OL9(HuVL10)#	CAG GCA GGG CTG ACT CAG	162
OCL(H uCL2)X	TGA ACA TTC TGT AGG GGC CAC TG	163	OL9(HuVL10)#	CAG GCA GGG CTG ACT CAG	162
OCL(H uCL2)X	TGA ACA TTC TGT AGG GGC CAC TG	163	OCL(HuCL7)X	AGA GCA TTC TGC AGG GGC CAC TG	164
OH1(HuVH1B7A)+	CAG RTG CAG CTG GTG CAR TCT GG	165	OCL(HuCL7)X	AGA GCA TTC TGC AGG GGC CAC TG	164
OH1(HuVH1B7A)+	CAG RTG CAG CTG GTG CAR TCT GG	165	OH1(HuVH1C)+	SAG GTC CAG CTG GTR CAG TCT GG	166
OH2(HuVH2B)	CAG RTC ACC TTG AAG GAG TCT GG	167	OH1(HuVH1C)+	SAG GTC CAG CTG GTR CAG TCT GG	166
OH2(HuVH2B)	CAG RTC ACC TTG AAG GAG TCT GG	167	OH3(HuVH3A)	GAG GTG CAG CTG GTG GAG	168
OH4(HuVH3C)	GAG GTG CAG CTG GTG GAG WCY GG	169	OH3(HuVH3A)	GAG GTG CAG CTG GTG GAG	168
OH4(HuVH3C)	GAG GTG CAG CTG GTG GAG WCY GG	169	OH5(HuVH4B)	CAG GTG CAG CTA CAG CAG TGG GG	170

OH6(HuVH4C)	CAG STG CAG CTG CAG GAG TCS GG	171
OH6(HuVH4C)	CAG STG CAG CTG CAG GAG TCS GG	171	OH7(HuVH6A)	CAG GTA CAG CTG CAG CAG TCA GG	172
OCM(HuCIgM)	TGG AAG AGG CAC GTT CTT TTC TTT	173	OH7(HuVH6A)	CAG GTA CAG CTG CAG CAG TCA GG	172

^*Mix with 1: 1: 1 ratio

# mixes with 1: 1 ratio

X mixes with 1: 1 ratio

+ mix with 1: 1 ratio

Table 2: second takes turns V κ, V λ and VH amplification

The primer title	The primer nucleotide sequence	SEQ ID NO
The primer title	The primer nucleotide sequence	SEQ ID NO	OK1S(HuVK1B-SAL)	TGA GCA CAC AGG TCG ACG GAC ATC CAG WTG ACC CAG TCT CC	174
OK2S(HuVK2-SAL)	TGA GCA CAC AGG TCG ACG GAT GTT GTG ATG ACT CAG TCT CC	175	OK1S(HuVK1B-SAL)	TGA GCA CAC AGG TCG ACG GAC ATC CAG WTG ACC CAG TCT CC	174
OK2S(HuVK2-SAL)	TGA GCA CAC AGG TCG ACG GAT GTT GTG ATG ACT CAG TCT CC	175	OK3S(HuVK2B2-SAL)	TGA GCA CAC AGG TCG ACG GAT ATT GTG ATG ACC CAG ACT CC	176
OK4S(HuVK3B-SAL)	TGA GCA CAC AGG TCG ACG GAA ATT GTG WTG ACR CAG TCT CC	177	OK3S(HuVK2B2-SAL)	TGA GCA CAC AGG TCG ACG GAT ATT GTG ATG ACC CAG ACT CC	176
OK4S(HuVK3B-SAL)	TGA GCA CAC AGG TCG ACG GAA ATT GTG WTG ACR CAG TCT CC	177	OK5S(HuVK5-SAL)	TGA GCA CAC AGG TCG ACG GAA ACG ACA CTC ACG CAG TCT CC	178
OK6S(HuVK6-SAL)	TGA GCA CAC AGG TCG ACG GAA ATT GTG CTG ACT CAG TCTCC	179	OK5S(HuVK5-SAL)	TGA GCA CAC AGG TCG ACG GAA ACG ACA CTC ACG CAG TCT CC	178
OK6S(HuVK6-SAL)	TGA GCA CAC AGG TCG ACG GAA ATT GTG CTG ACT CAG TCTCC	179	OJK1(HuJK1-NOT)	GAG TCA TTC TCG ACT TGC GGC CGC ACG TTT GAT TTC CAC CTT GGT CCC	180
OJK2(HuJK2-NOT)	GAG TCA TTC TCG ACT TGC GGC CGC ACG TTT GAT CTC CAG CTT GGT CCC	181	OJK1(HuJK1-NOT)		180
OJK2(HuJK2-NOT)		181	OJK3(HuJK3-NOT)	GAG TCA TTC TCG ACT TGC GGC CGC ACG TTT GAT ATC CAC TTT GGT CCC	182
OJK4(HuJK4-NOT)	GAG TCA TTC TCG ACT TGC GGC CGC ACG TTT GAT CTC CAC CTT GGT CCC	183	OJK3(HuJK3-NOT)		182
OJK4(HuJK4-NOT)		183	OJK5(HuJK5-NOT)	GAG TCA TTC TCG ACT TGC GGC CGC ACG TTT AAT CTC CAG TCG TGT CCC	184
OL1S(HuVL1A-SAL) ^*	TGA GCA CAC AGG TCG ACG CAG TCT GTG CTG ACT CAG CCA CC	185	OJK5(HuJK5-NOT)		184
OL1S(HuVL1A-SAL) ^*	TGA GCA CAC AGG TCG ACG CAG TCT GTG CTG ACT CAG CCA CC	185	OL1S(HuVL1B-SAL) ^*	TGA GCA CAC AGG TCG ACG CAG TCT GTG YTG ACG CAG CCG CC	186
OL1S(HuVL1C-SAL) ^*	TGA GCA CAC AGG TCG ACG CAG TCT GTC GTG ACG CAG CCG CC	187	OL1S(HuVL1B-SAL) ^*	TGA GCA CAC AGG TCG ACG CAG TCT GTG YTG ACG CAG CCG CC	186
OL1S(HuVL1C-SAL) ^*	TGA GCA CAC AGG TCG ACG CAG TCT GTC GTG ACG CAG CCG CC	187	OL2S(HuVL2B-SAL)	TGA GCA CAC AGG TCG ACG CAG TCT GCC CTG ACT CAG CC	188
OL3S(HuVL3A-SAL)	TGA GCA CAC AGG TCG ACG TCC TAT GWG CTG ACT CAG CCA CC	189	OL2S(HuVL2B-SAL)	TGA GCA CAC AGG TCG ACG CAG TCT GCC CTG ACT CAG CC	188
OL3S(HuVL3A-SAL)	TGA GCA CAC AGG TCG ACG TCC TAT GWG CTG ACT CAG CCA CC	189	OL4S(HuVL3B-SAL)	TGA GCA CAC AGG TCG ACG TCT TCT GAG CTG ACT CAG GAC CC	190
OL5S(HuVL4B-SAL)	TGA GCA CAC AGG TCG ACG CAG CYT GTG CTG ACT CAA TC	191	OL4S(HuVL3B-SAL)	TGA GCA CAC AGG TCG ACG TCT TCT GAG CTG ACT CAG GAC CC	190
OL5S(HuVL4B-SAL)	TGA GCA CAC AGG TCG ACG CAG CYT GTG CTG ACT CAA TC	191	OL6S(HuVL5-SAL)	TGA GCA CAC AGG TCG ACG CAG GCT GTG CTG ACT CAG CCG TC	192
OL7S(HuVL6-SAL)	TGA GCA CAC AGG TCG ACG AAT TTT ATG CTG ACT CAG CCC CA	193	OL6S(HuVL5-SAL)	TGA GCA CAC AGG TCG ACG CAG GCT GTG CTG ACT CAG CCG TC	192
OL7S(HuVL6-SAL)	TGA GCA CAC AGG TCG ACG AAT TTT ATG CTG ACT CAG CCC CA	193	OL8S(HuVL7/8-SAL)	TGA GCA CAC AGG TCG ACG CAG RCT GTG GTG ACY CAG GAG CC	194
OL9S(HuVL9-SAL)#	TGA GCA CAC AGG TCG ACG CWG CCT GTG	195	OL8S(HuVL7/8-SAL)	TGA GCA CAC AGG TCG ACG CAG RCT GTG GTG ACY CAG GAG CC	194

	CTG ACT CAG CCM CC
	CTG ACT CAG CCM CC		OL9S(HuVL10-SAL)#	TGA GCA CAC AGG TCG ACG CAG GCA GGG CTG ACT CAG	196
OJL1(HuJL1-NOT)	GAG TCA TTC TCG ACT TGC GGC CGC ACC TAG GAC GGT GAC CTT GGT CCC	197	OL9S(HuVL10-SAL)#	TGA GCA CAC AGG TCG ACG CAG GCA GGG CTG ACT CAG	196
OJL1(HuJL1-NOT)		197	OJL2(HuJL2/3-NOT)	GAG TCA TTC TCG ACT TGC GGC CGC ACC TAG GAC GGT CAG CTT GGT CCC	198
OJL3(HuJL7-NOT)	GAG TCA TTC TCG ACT TGC GGC CGC ACC GAG GAC GGT CAG CTG GGT GCC	199	OJL2(HuJL2/3-NOT)		198
OJL3(HuJL7-NOT)		199	OH1S(HuVH1B-SFI)+	GTC CTC GCA ACT GCG GCC CAG CCG GCC ATG GCC CAG RTG CAG CTG GTG CAR TCT GG	200
OH1S(HuVH1C-SF1)+	GTC CTC GCA ACT GCG GCC CAG CCG GCC ATG GCC SAG GTC CAG CTG GTR CAG TCT GG	201	OH1S(HuVH1B-SFI)+		200
OH1S(HuVH1C-SF1)+		201	OH2S(HuVH2B-SFI)	GTC CTC GCA ACT GCG GCC CAG CCG GCC ATG GCC CAG RTC ACC TTG AAG GAG TCT GG	202
OH3S(HuVH3A-SFI)	GTC CTC GCA ACT GCG GCC CAG CCG GCC ATG GCC GAG GTG CAG CTG GTG GAG	203	OH2S(HuVH2B-SFI)		202
OH3S(HuVH3A-SFI)		203	OH4S(HuVH3C-SFI)	GTC CTC GCA ACT GCG GCC CAG CCG GCC ATG GCC GAG GTG CAG CTG GTG GAG WCY GG	204
OH5S(HuVH4B-SFI)	GTC CTC GCA ACT GCG GCC CAG CCG GCC ATG GCC CAG GTG CAG CTA CAG CAG TGG GG	205	OH4S(HuVH3C-SFI)		204
OH5S(HuVH4B-SFI)		205	OH6S(HuVH4C-SFI)	GTC CTC GCA ACT GCG GCC CAG CCG GCC ATG GCC CAG STG CAG CTG CAG GAG TCS GG	206
OH7S(HuVH6A-SFI)	GTC CTC GCA ACT GCG GCC CAG CCG GCC ATG GCC CAG GTA CAG CTG CAG CAG TCA GG	207	OH6S(HuVH4C-SFI)		206
OH7S(HuVH6A-SFI)		207	OJH1(HuJH1/2-XHO)	GAG TCA TTC TCG ACT CGA GAC RGT GAC CAG GGTG CC	208
OJH2(HuJH3-XHO)	GAG TCA TTC TCG ACT CGA GAC GGT GAC CAT TGT CCC	209	OJH1(HuJH1/2-XHO)	GAG TCA TTC TCG ACT CGA GAC RGT GAC CAG GGTG CC	208
OJH2(HuJH3-XHO)	GAG TCA TTC TCG ACT CGA GAC GGT GAC CAT TGT CCC	209	OJH3(HuJH4/5-XHO)	GAG TCA TTC TCG ACT CGA GAC GGT GAC CAG GGT TCC	210
OJH4(HuJH6-XHO)	GAG TCA TTC TCG ACT CGA GAC GGT GAC CGT GGT CCC	211	OJH3(HuJH4/5-XHO)	GAG TCA TTC TCG ACT CGA GAC GGT GAC CAG GGT TCC	210

^*Mix with 1: 1: 1 ratio

# mixes with 1: 1 ratio

+ mix with 1: 1 ratio

Table 3. second is taken turns the amplification of VL district and is summarized

Table 4. second is taken turns the amplification of VH district and is summarized

Table 5: the feature in individual IgM memory B cell library

The data of table 6:HA specific single-chain Fv

Title scFv	SEQ ID NO (nucleotide sequence)	SEQ ID NO (aminoacid sequence) ^*	The VH-locus	The VL-locus
Title scFv	SEQ ID NO (nucleotide sequence)	SEQ ID NO (aminoacid sequence) ^*	The VH-locus	The VL-locus	SC06-141	212	213 (Vh 1-115； Vl 132-245)	VH1(1-18)	VKIV(B3)
SC06-255	115	116 (Vh 1-121； Vl 138-248)	VH1(1-69)	VL1(V1-16)	SC06-141	212	213 (Vh 1-115； Vl 132-245)	VH1(1-18)	VKIV(B3)
SC06-255	115	116 (Vh 1-121； Vl 138-248)	VH1(1-69)	VL1(V1-16)	SC06-257	117	118 (Vh 1-121； Vl 138-248)	VH1(1-69)	VL2(V1-4)
SC06-260	119	120 (Vh 1-121； Vl 138-248)	VH1(1-69)	VL1(V1-17)	SC06-257	117	118 (Vh 1-121； Vl 138-248)	VH1(1-69)	VL2(V1-4)
SC06-260	119	120 (Vh 1-121； Vl 138-248)	VH1(1-69)	VL1(V1-17)	SC06-261	121	122 (Vh 1-121； Vl 138-249)	VH1(1-69)	VL1(V1-19)
SC06-262	123	124 (Vh 1-120； Vl 137-245)	VH1(1-69)	VKI(A20)	SC06-261	121	122 (Vh 1-121； Vl 138-249)	VH1(1-69)	VL1(V1-19)
SC06-262	123	124 (Vh 1-120； Vl 137-245)	VH1(1-69)	VKI(A20)	SC06-268	125	126 (Vh 1-120； Vl 137-243)	VH1(1-69)	VL3(V2-1)
SC06-272	214	215 (Vh 1-120； Vl 137-247)	VH1(1-69)	VL2(V1-3)	SC06-268	125	126 (Vh 1-120； Vl 137-243)	VH1(1-69)	VL3(V2-1)
SC06-272	214	215 (Vh 1-120； Vl 137-247)	VH1(1-69)	VL2(V1-3)	SC06-296	216	217 (Vh 1-121； Vl 138-246)	VH1(1-2)	VKIII(A27)
SC06-301	218	219 (Vh 1-117； Vl 134-246)	VH1(3-23)	VKII(A3)	SC06-296	216	217 (Vh 1-121； Vl 138-246)	VH1(1-2)	VKIII(A27)
SC06-301	218	219 (Vh 1-117； Vl 134-246)	VH1(3-23)	VKII(A3)	SC06-307	127	128 (Vh 1-122； Vl 139-246)	VH3(3-21)	VKIII(A27)
SC06-310	129	130 (Vh 1-121； Vl 138-246)	VH1(1-69)	VL3(V2-14)	SC06-307	127	128 (Vh 1-122； Vl 139-246)	VH3(3-21)	VKIII(A27)
SC06-310	129	130 (Vh 1-121； Vl 138-246)	VH1(1-69)	VL3(V2-14)	SC06-314	131	132 (Vh 1-121； Vl 138-248)	VH1(1-69)	VL1(V1-17)
SC06-323	133	134 (Vh 1-120； Vl 137-245)	VH1(1-69)	VKIII(A27)	SC06-314	131	132 (Vh 1-121； Vl 138-248)	VH1(1-69)	VL1(V1-17)
SC06-323	133	134 (Vh 1-120； Vl 137-245)	VH1(1-69)	VKIII(A27)	SC06-325	135	136 (Vh 1-121； Vl 138-248)	VH1(1-69)	VL2(V1-4)
SC06-327	220	221 (Vh 1-121； Vl 138-246)	VH1(1-69)	VL3(V2-14)	SC06-325	135	136 (Vh 1-121； Vl 138-248)	VH1(1-69)	VL2(V1-4)
SC06-327	220	221 (Vh 1-121； Vl 138-246)	VH1(1-69)	VL3(V2-14)	SC06-328	222	223 (Vh 1-128； Vl 145-252)	VH1(1-69)	VKIII(A27)
SC06-329	224	225 (Vh 1-121； Vl 138-246)	VH1(1-69)	VKIII(A27)	SC06-328	222	223 (Vh 1-128； Vl 145-252)	VH1(1-69)	VKIII(A27)
SC06-329	224	225 (Vh 1-121； Vl 138-246)	VH1(1-69)	VKIII(A27)	SC06-331	137	138 (Vh 1-120；	VH1(1-69)	VL3(V2-14)

		Vl 137-245)
		Vl 137-245)			SC06-332	226	227 (Vh 1-120； Vl 137-243)	VH1(1-69)	VKI(A20)
SC06-334	228	229 (Vh 1-120； Vl 137-245)	VH1(1-69)	VL3(V2-14)	SC06-332	226	227 (Vh 1-120； Vl 137-243)	VH1(1-69)	VKI(A20)
SC06-334	228	229 (Vh 1-120； Vl 137-245)	VH1(1-69)	VL3(V2-14)	SC06-336	230	231 (Vh 1-120； Vl 137-245)	VH1(1-69)	VKIII(A27)
SC06-339	232	233 (Vh 1-121； Vl 138-246)	VH1(1-69)	VL3(V2-14)	SC06-336	230	231 (Vh 1-120； Vl 137-245)	VH1(1-69)	VKIII(A27)
SC06-339	232	233 (Vh 1-121； Vl 138-246)	VH1(1-69)	VL3(V2-14)	SC06-342	234	235 (Vh 1-126； Vl 143-256)	VH1(1-69)	VKIV(B3)
SC06-343	236	237 (Vh 1-120； Vl 137-245)	VH1(1-69)	VL3(V2-14)	SC06-342	234	235 (Vh 1-126； Vl 143-256)	VH1(1-69)	VKIV(B3)
SC06-343	236	237 (Vh 1-120； Vl 137-245)	VH1(1-69)	VL3(V2-14)	SC06-344	139	140 (Vh 1-123； Vl 140-250)	VH1(1-69)	VL1(V1-13)

^*The amino acid of forming variable region of heavy chain (VH) and variable region of light chain (VL) shown in the bracket

The data in the CDR district of table 7:HA specific immunoglobulin.SEQ ID NO provides in bracket

Title scFv	HCDR1	HCDR2	HCDR3	LCDR1	LCDR2	LCDR3
Title scFv	HCDR1	HCDR2	HCDR3	LCDR1	LCDR2	LCDR3	SC06-141	GYYVY (238)	WISAYNGNTNY AQKFQG (239)	SRSLDV (240)	KSSQSVLYSSN NKNYLA (241)	WASTRES (242)	QQYYSTPLT (243)
SC06-255	SYAIS(1)	GIIPIFGTTKY APKFQG(2)	HMGYQVRET MDV(3)	SGSTFNIGSNA VD(4)	SNNQRPS (5)	AAWDDILNV PV(6)	SC06-141	GYYVY (238)	WISAYNGNTNY AQKFQG (239)	SRSLDV (240)	KSSQSVLYSSN NKNYLA (241)	WASTRES (242)	QQYYSTPLT (243)
SC06-255	SYAIS(1)	GIIPIFGTTKY APKFQG(2)	HMGYQVRET MDV(3)	SGSTFNIGSNA VD(4)	SNNQRPS (5)	AAWDDILNV PV(6)	SC06-257	SYAIS(1)	GIIPIFGTTKY APKFQG(2)	HMGYQVRET MDV(3)	TGTSSDVGGYN YVS(7)	EVSNRPS (8)	SSYTSSSTY V(9)
SC06-260	SYAIS(1)	GIIPIFGTTKY APKFQG(2)	HMGYQVRET MDV(3)	SGSRSNVGDNS VY(10)	KNTQRPS (11)	VAWDDSVDG YV(12)	SC06-257	SYAIS(1)	GIIPIFGTTKY APKFQG(2)	HMGYQVRET MDV(3)	TGTSSDVGGYN YVS(7)	EVSNRPS (8)	SSYTSSSTY V(9)
SC06-260	SYAIS(1)	GIIPIFGTTKY APKFQG(2)	HMGYQVRET MDV(3)	SGSRSNVGDNS VY(10)	KNTQRPS (11)	VAWDDSVDG YV(12)	SC06-261	SYAIS(1)	GIIPIFGTTKY APKFQG(2)	HMGYQVRET MDV(3)	SGSSSNIGNDY VS(13)	DNNKRPS (14)	ATWDRRPTA YVV(15)
SC06-262	GSAIS(16)	GISPLFGTTNY AQKFQG(17)	GPKYYSEYM DV(18)	RASQGISSYLA (19)	DASTLRS (20)	QRYNSAPPI T(21)	SC06-261	SYAIS(1)	GIIPIFGTTKY APKFQG(2)	HMGYQVRET MDV(3)	SGSSSNIGNDY VS(13)	DNNKRPS (14)	ATWDRRPTA YVV(15)
SC06-262	GSAIS(16)	GISPLFGTTNY AQKFQG(17)	GPKYYSEYM DV(18)	RASQGISSYLA (19)	DASTLRS (20)	QRYNSAPPI T(21)	SC06-268	SYAIS(1)	GIMGMFGTTNY AQKFQG(22)	SSGYYPEYF QD(23)	SGHKLGDKYVS (24)	QDNRRPS (25)	QAWDSSTAV (26)
SC06-272	SYAIT (244)	GIIGMFGSTNY AQNFQG (245)	STGYYPAYL HH(246)	TGTSSDVGGYN YVS(247)	DVSKRPS (248)	SSYTSSSTH V(249)	SC06-268	SYAIS(1)	GIMGMFGTTNY AQKFQG(22)	SSGYYPEYF QD(23)	SGHKLGDKYVS (24)	QDNRRPS (25)	QAWDSSTAV (26)
SC06-272	SYAIT (244)	GIIGMFGSTNY AQNFQG (245)	STGYYPAYL HH(246)	TGTSSDVGGYN YVS(247)	DVSKRPS (248)	SSYTSSSTH V(249)	SC06-296	SYYMH (250)	WINPNSGGTNY AQKFQG (251)	EGKWGPQAA FDI(252)	RASQSVSSSYL A(253)	DASSRAT (254)	QQYGSSLW (255)
SC06-301	IYAMS (256)	AISSSGDSTYY ADSVKG (257)	AYGYTFDP (258)	RSSQSLLHSNG YNYLD(259)	LGSNRAS (260)	MQALQTPL (261)	SC06-296	SYYMH (250)	WINPNSGGTNY AQKFQG (251)	EGKWGPQAA FDI(252)	RASQSVSSSYL A(253)	DASSRAT (254)	QQYGSSLW (255)
SC06-301	IYAMS (256)	AISSSGDSTYY ADSVKG (257)	AYGYTFDP (258)	RSSQSLLHSNG YNYLD(259)	LGSNRAS (260)	MQALQTPL (261)	SC06-307	SYSMN(27)	SISSSSSYIYY VDSVKG(28)	GGGSYGAYE GFDY(29)	RASQRVSSYLA (30)	GASTRAA (31)	QQYGRTPLT (32)
SC06-310	SYAIS(1)	GIIPIFGTTKY APKFQG(2)	HMGYQVRET MDV(3)	GGNNIGSKSVH (33)	DDSDRPS (34)	QVWDSSSDH AV(35)	SC06-307	SYSMN(27)	SISSSSSYIYY VDSVKG(28)	GGGSYGAYE GFDY(29)	RASQRVSSYLA (30)	GASTRAA (31)	QQYGRTPLT (32)
SC06-310	SYAIS(1)	GIIPIFGTTKY APKFQG(2)	HMGYQVRET MDV(3)	GGNNIGSKSVH (33)	DDSDRPS (34)	QVWDSSSDH AV(35)	SC06-314	SYAIS(1)	GIIPIFGTTKY APKFQG(2)	HMGYQVRET MDV(3)	SGSSSNIGSNY VY(36)	RDGQRPS (37)	ATWDDNLSG PV(38)
SC06-323	SYGIS(39)	DIIGMFGSTNY AQNFQG(40)	SSGYYPAYL PH(41)	RASQSVSSSYL A(42)	GASSRAT (43)	QQYGSSPRT (44)	SC06-314	SYAIS(1)	GIIPIFGTTKY APKFQG(2)	HMGYQVRET MDV(3)	SGSSSNIGSNY VY(36)	RDGQRPS (37)	ATWDDNLSG PV(38)
SC06-323	SYGIS(39)	DIIGMFGSTNY AQNFQG(40)	SSGYYPAYL PH(41)	RASQSVSSSYL A(42)	GASSRAT (43)	QQYGSSPRT (44)	SC06-325	FYSMS(45)	GIIPMFGTTNY AQKFQG(46)	GDKGIYYYY MDV(47)	TGTSSDVGGYN YVS(7)	EVSNRPS (8)	SSYTSSSTL V(48)
SC06-327	THAIS (262)	GIIAIFGTANY AQKFQG (263)	GSGYHISTP FDN(264)	GGNNIGSKGVH (265)	DDSDRPS (266)	QVWDSSSDH VV(267)	SC06-325	FYSMS(45)	GIIPMFGTTNY AQKFQG(46)	GDKGIYYYY MDV(47)	TGTSSDVGGYN YVS(7)	EVSNRPS (8)	SSYTSSSTL V(48)

SC06-328	GYAIS (268)	GIIPIFGTTNY AQKFQG (269)	VKDGYCTLT SCPVGWYFD L(270)	RASQSVSSSYL A(271)	GASSRAT (272)	QQYGSSLT (273)
SC06-328	GYAIS (268)	GIIPIFGTTNY AQKFQG (269)	VKDGYCTLT SCPVGWYFD L(270)	RASQSVSSSYL A(271)	GASSRAT (272)	QQYGSSLT (273)	SC06-329	SNSIS (274)	GIFALFGTTDY AQKFQG (275)	GSGYTTRNY FDY(276)	RASQSVS SNYL G(277)	GASSRAS (278)	QQYGSSPLT (279)
SC06-331	SYAIS(1)	GIIGMFGTANY AQKFQG(49)	GNYYYESSL DY(50)	GGNNIGSKSVH (33)	DDSDRPS (34)	QVWDSSSDH YV(51)	SC06-329	SNSIS (274)	GIFALFGTTDY AQKFQG (275)	GSGYTTRNY FDY(276)	RASQSVS SNYL G(277)	GASSRAS (278)	QQYGSSPLT (279)
SC06-331	SYAIS(1)	GIIGMFGTANY AQKFQG(49)	GNYYYESSL DY(50)	GGNNIGSKSVH (33)	DDSDRPS (34)	QVWDSSSDH YV(51)	SC06-332	NFAIN (280)	GIIAVFGTTKY AHKFQG (281)	GPHYYSSYM DV(282)	RASQGISTYLA (283)	AASTLQS (284)	QKYNSAPS (285)
SC06-334	SNAVS (286)	GILGVFGS PSY AQKFQG (287)	GPTYYYSYM DV(288)	GGNNIGRNSVH (289)	DDSDRPS (290)	QVWHSSSDH YV(291)	SC06-332	NFAIN (280)	GIIAVFGTTKY AHKFQG (281)	GPHYYSSYM DV(282)	RASQGISTYLA (283)	AASTLQS (284)	QKYNSAPS (285)
SC06-334	SNAVS (286)	GILGVFGS PSY AQKFQG (287)	GPTYYYSYM DV(288)	GGNNIGRNSVH (289)	DDSDRPS (290)	QVWHSSSDH YV(291)	SC06-336	SYAIS (292)	GIFGMFGTANY AQKFQG (293)	SSGYYPQYF QD(294)	RASQSVSSSYL A(295)	GASSRAT (296)	QQYGSSSLT (297)
SC06-339	SYAIS (298)	GIIAIFHTPKY AQKFQG (299)	GSTYDFSSG LDY(300)	GGNNIGSKSVH (301)	DDSDRPS (302)	QVWDSSSDH VV(303)	SC06-336	SYAIS (292)	GIFGMFGTANY AQKFQG (293)	SSGYYPQYF QD(294)	RASQSVSSSYL A(295)	GASSRAT (296)	QQYGSSSLT (297)
SC06-339	SYAIS (298)	GIIAIFHTPKY AQKFQG (299)	GSTYDFSSG LDY(300)	GGNNIGSKSVH (301)	DDSDRPS (302)	QVWDSSSDH VV(303)	SC06-342	SYAIS (304)	GVIPIFRTANY AQNFQG (305)	LNYHDSGTY YNAPRGWFD P(306)	KSSQSILNSSN NKNYLA (307)	WASTRES (308)	QQYYSSPPT (309)
SC06-343	YYAMS (310)	GISPMFGTTTY AQKFQG (311)	SSNYYDSVY DY(312)	GGHNIGSNSVH (313)	DNSDRPS (314)	QVWGSSSDH YV(315)	SC06-342	SYAIS (304)	GVIPIFRTANY AQNFQG (305)	LNYHDSGTY YNAPRGWFD P(306)	KSSQSILNSSN NKNYLA (307)	WASTRES (308)	QQYYSSPPT (309)
SC06-343	YYAMS (310)	GISPMFGTTTY AQKFQG (311)	SSNYYDSVY DY(312)	GGHNIGSNSVH (313)	DNSDRPS (314)	QVWGSSSDH YV(315)	SC06-344	NYAMS(52)	GIIAIFGTPKY AQKFQG(53)	IPHYNFGSG SYFDY(54)	TGSSSNIGAGY DVH (55)	GNSNRPS (56)	GTWDSSLSA YV(57)

The data of table 8.HA specific IgG

Title IgG	Nucleotide sequence SEQ ID NO heavy chain	The SEQ ID NO of aminoacid sequence ^*Heavy chain	The SEQ ID NO light chain of nucleotide sequence	The SEQ ID NO of aminoacid sequence ^*Light chain
Title IgG	Nucleotide sequence SEQ ID NO heavy chain	The SEQ ID NO of aminoacid sequence ^*Heavy chain	The SEQ ID NO light chain of nucleotide sequence	The SEQ ID NO of aminoacid sequence ^*Light chain	CR6141	316	317 (Vh 1-115)	318	319 (Vl 1-114)
CR6255	58	59 (Vh 1-121)	84	85 (Vl 1-111)	CR6141	316	317 (Vh 1-115)	318	319 (Vl 1-114)
CR6255	58	59 (Vh 1-121)	84	85 (Vl 1-111)	CR6257	60	61 (Vh 1-121)	86	87 (Vl 1-111)
CR6260	62	63 (Vh 1-121)	88	89 (Vl 1-111)	CR6257	60	61 (Vh 1-121)	86	87 (Vl 1-111)
CR6260	62	63 (Vh 1-121)	88	89 (Vl 1-111)	CR6261	64	65 (Vh 1-121)	90	91 (Vl 1-112)
CR6262	66	67 (Vh 1-120)	92	93 (Vl 1-109)	CR6261	64	65 (Vh 1-121)	90	91 (Vl 1-112)
CR6262	66	67 (Vh 1-120)	92	93 (Vl 1-109)	CR6268	68	69 (Vh 1-120)	94	95 (Vl 1-107)
CR6272	320	321 (Vh 1-120)	322	323 (Vl 1-111)	CR6268	68	69 (Vh 1-120)	94	95 (Vl 1-107)
CR6272	320	321 (Vh 1-120)	322	323 (Vl 1-111)	CR6296	324	325 (Vh 1-121)	326	327 (Vl 1-109)
CR6301	328	329 (Vh 1-117)	330	331 (Vl 1-113)	CR6296	324	325 (Vh 1-121)	326	327 (Vl 1-109)
CR6301	328	329 (Vh 1-117)	330	331 (Vl 1-113)	CR6307	70	71 (Vh 1-122)	96	97 (Vl 1-108)
CR6310	72	73 (Vh 1-121)	98	99 (Vl 1-109)	CR6307	70	71 (Vh 1-122)	96	97 (Vl 1-108)
CR6310	72	73 (Vh 1-121)	98	99 (Vl 1-109)	CR6314	74	75 (Vh 1-121)	100	101 (Vl 1-111)
CR6323	76	77 (Vh 1-120)	102	103 (Vl 1-109)	CR6314	74	75 (Vh 1-121)	100	101 (Vl 1-111)
CR6323	76	77 (Vh 1-120)	102	103 (Vl 1-109)	CR6325	78	79 (Vh 1-121)	104	105 (Vl 1-111)
CR6327	332	333 (Vh 1-121)	334	335 (Vl 1-109)	CR6325	78	79 (Vh 1-121)	104	105 (Vl 1-111)
CR6327	332	333 (Vh 1-121)	334	335 (Vl 1-109)	CR6328	336	337 (Vh 1-128)	338	339 (Vl 1-108)
CR6329	340	341 (Vh 1-121)	342	343 (Vl 1-109)	CR6328	336	337 (Vh 1-128)	338	339 (Vl 1-108)
CR6329	340	341 (Vh 1-121)	342	343 (Vl 1-109)	CR6331	80	81 (Vh 1-120)	106	107 (Vl 1-109)
CR6332	344	345 (Vh 1-120)	346	347 (Vl 1-107)	CR6331	80	81 (Vh 1-120)	106	107 (Vl 1-109)
CR6332	344	345 (Vh 1-120)	346	347 (Vl 1-107)	CR6334	348	349 (Vh 1-120)	350	351 (Vl 1-109)
CR6336	352	353 (Vh 1-120)	354	355 (Vl 1-109)	CR6334	348	349 (Vh 1-120)	350	351 (Vl 1-109)
CR6336	352	353 (Vh 1-120)	354	355 (Vl 1-109)	CR6339	356	357 (Vh 1-121)	358	359 (Vl 1-109)
CR6342	360	361 (Vh 1-126)	362	363 (Vl 1-114)	CR6339	356	357 (Vh 1-121)	358	359 (Vl 1-109)
CR6342	360	361 (Vh 1-126)	362	363 (Vl 1-114)	CR6343	364	365 (Vh 1-120)	366	367 (Vl 1-109)
CR6344	82	83 (Vh 1-123)	108	109 (Vl 1-111)	CR6343	364	365 (Vh 1-120)	366	367 (Vl 1-109)

Table 9.IgG is to the combination of the PER.C6 cell of expression HA (H5N1TV)

^*Be illustrated in the facs analysis that carries out in the independent experiment

The effectiveness of the anti-HA antibody of table 10. in NAT is measured

Antibody	Concentration (μ g/ml)
Antibody	Concentration (μ g/ml)	CR6255	25
CR6257	12.5	CR6255	25
CR6257	12.5	CR6260	12.5
CR6261	12.5	CR6260	12.5
CR6261	12.5	CR6262	100
CR6268	50	CR6262	100
CR6268	50	CR6307	50
CR6314	12.5	CR6307	50
CR6314	12.5	CR6323	50
CR6325	12.5	CR6323	50
CR6325	12.5	CR6344	25
CR6310	25	CR6344	25
CR6310	25	CR6331	100
CR4098	- ^*	CR6331	100

^*Do not observe neutralization at 50 μ g/ml

The effectiveness of the anti-HA antibody of table 11. in NAT is measured

Antibody	Concentration (μ g/ml)
Antibody	Concentration (μ g/ml)	CR6255	3.12
CR6257	1.56	CR6255	3.12
CR6257	1.56	CR6260	3.12
CR6261	0.78	CR6260	3.12
CR6261	0.78	CR6262	25
CR6268	6.25	CR6262	25
CR6268	6.25	CR6272	-
CR6307	25	CR6272	-
CR6307	25	CR6310	6.25
CR6314	3.12	CR6310	6.25
CR6314	3.12	CR6323	6.25
CR6325	6.25	CR6323	6.25
CR6325	6.25	CR6327	6.25
CR6328	25	CR6327	6.25
CR6328	25	CR6329	3.12
CR6331	25	CR6329	3.12
CR6331	25	CR6332	12.5
CR6334	6.25	CR6332	12.5
CR6334	6.25	CR6336	25
CR6339	-	CR6336	25
CR6339	-	CR6342	6.25
CR6343	50	CR6342	6.25
CR6343	50	CR6344	25

-be meant at 100 μ g/ml and do not observe neutralization

Anti--H5N1 IgG that table 12. is measured by ELISA (OD 492nm) is to the cross reactivity .ND of the HA molecule of different HA hypotypes: determine

	H1	H3	H5	H7	H9	BPL-inact. A/NC/20/99 (H1N1)	BPL-inact. NIBRG14 (H5N1)
	H1	H3	H5	H7	H9	BPL-inact. A/NC/20/99 (H1N1)	BPL-inact. NIBRG14 (H5N1)	CR6255	1.91	0.08	1.44	0.22	1.97	1.38	1.18
CR6257	1.93	0.08	1.37	0.16	2.06	1.34	1.21	CR6255	1.91	0.08	1.44	0.22	1.97	1.38	1.18
CR6257	1.93	0.08	1.37	0.16	2.06	1.34	1.21	CR6260	1.88	0.08	1.45	0.19	2.00	1.34	1.17
CR6261	2.04	0.07	1.44	0.31	2.32	1.46	1.41	CR6260	1.88	0.08	1.45	0.19	2.00	1.34	1.17
CR6261	2.04	0.07	1.44	0.31	2.32	1.46	1.41	CR6262	1.48	0.09	1.02	0.17	1.93	0.51	0.35
CR6268	1.78	0.08	1.30	0.15	2.16	1.39	1.13	CR6262	1.48	0.09	1.02	0.17	1.93	0.51	0.35
CR6268	1.78	0.08	1.30	0.15	2.16	1.39	1.13	CR6272	0.81	0.07	0.58	0.15	0.96	0.92	0.79
CR6307	0.22	0.11	0.99	0.22	0.17	0.23	0.50	CR6272	0.81	0.07	0.58	0.15	0.96	0.92	0.79
CR6307	0.22	0.11	0.99	0.22	0.17	0.23	0.50	CR6310	1.92	0.08	1.37	0.18	2.17	1.31	1.00
CR6314	1.93	0.07	1.48	0.25	2.21	1.37	1.42	CR6310	1.92	0.08	1.37	0.18	2.17	1.31	1.00
CR6314	1.93	0.07	1.48	0.25	2.21	1.37	1.42	CR6323	2.32	0.07	1.89	0.15	2.27	1.40	0.93
CR6325	1.42	0.07	1.30	0.17	2.04	1.09	1.20	CR6323	2.32	0.07	1.89	0.15	2.27	1.40	0.93
CR6325	1.42	0.07	1.30	0.17	2.04	1.09	1.20	CR6327	1.75	0.08	1.11	0.14	1.93	1.16	0.73
CR6328	2.43	0.07	1.78	0.16	2.38	1.39	0.98	CR6327	1.75	0.08	1.11	0.14	1.93	1.16	0.73
CR6328	2.43	0.07	1.78	0.16	2.38	1.39	0.98	CR6329	1.98	0.08	1.43	0.17	2.16	1.04	1.01
CR6331	1.75	0.06	1.32	0.16	2.02	1.25	0.92	CR6329	1.98	0.08	1.43	0.17	2.16	1.04	1.01
CR6331	1.75	0.06	1.32	0.16	2.02	1.25	0.92	CR6332	2.20	0.15	1.65	0.26	2.11	1.20	1.11
CR6334	2.04	0.07	1.19	0.15	1.82	1.13	0.91	CR6332	2.20	0.15	1.65	0.26	2.11	1.20	1.11
CR6334	2.04	0.07	1.19	0.15	1.82	1.13	0.91	CR6336	1.92	0.10	1.41	0.18	2.02	1.09	0.94
CR6339	1.25	0.07	0.81	0.14	1.96	0.94	0.50	CR6336	1.92	0.10	1.41	0.18	2.02	1.09	0.94
CR6339	1.25	0.07	0.81	0.14	1.96	0.94	0.50	CR6342	1.99	0.09	1.25	0.17	2.13	1.32	0.90
CR6343	1.28	0.07	0.76	0.15	1.88	0.91	0.64	CR6342	1.99	0.09	1.25	0.17	2.13	1.32	0.90
CR6343	1.28	0.07	0.76	0.15	1.88	0.91	0.64	CR6344	1.80	0.09	1.31	0.18	2.15	1.31	0.96
CR5111	0.08	0.07	1.57	0.15	0.17	0.09	0.81	CR6344	1.80	0.09	1.31	0.18	2.15	1.31	0.96
CR5111	0.08	0.07	1.57	0.15	0.17	0.09	0.81	CR3014	0.08	0.07	0.09	0.17	0.16	0.09	0.11
No IgG	0.13	0.08	0.09	0.15	0.16	0.09	0.14	CR3014	0.08	0.07	0.09	0.17	0.16	0.09	0.11
No IgG	0.13	0.08	0.09	0.15	0.16	0.09	0.14	Sheep anti H5	ND	ND	ND	0.90	2.07	2.62	2.93

The epitope mapping of the anti-HA antibody of table 13. people.

	HA1	HA2	CR5111	CR6342 C179	CR6307 CR6323	CR6261 CR6325 CR6329
	HA1	HA2	CR5111	CR6342 C179	CR6307 CR6323	CR6261 CR6325 CR6329	H5N1TV	TGLRN	GVTNKVNSIIDK	+	+	+	+
MutantI	K----	------------	+	-	+	+	H5N1TV	TGLRN	GVTNKVNSIIDK	+	+	+	+
MutantI	K----	------------	+	-	+	+	MutantII	-----	-----E------	+	-	+	-
MutantIII	--M--	------------	+	+	+	+	MutantII	-----	-----E------	+	-	+	-
MutantIII	--M--	------------	+	+	+	+	MutantIV	-----	-------R----	+	-	+	+
Mutant V	-----	----------N-	+	+	+	+	MutantIV	-----	-------R----	+	-	+	+

The sequence of the HA2 epi-position in the different influenza virus sub-strains of table 22..Amino acid represent H2N2 escape mutants (the mutant II of underscore; Table 13) Xie Ansuan in (V) → L-glutamic acid (E) replaces

	HA2	SEQ ID NO：
	HA2	SEQ ID NO：	H5N1： A/Vietnam/1203/2004	GVTNKVNSIIDK	368
H5N1： A/Hong Kong/156/97	GVTNKVNSIINK	369	H5N1： A/Vietnam/1203/2004	GVTNKVNSIIDK	368
H5N1： A/Hong Kong/156/97	GVTNKVNSIINK	369	H5N2： A/mald/PA/84	GVTNKVNSIIDK	368
H1N1： A/PR/8/34 A/South Carolina/1/1918 A/WSN/33 A/New Caledonia/20/99 A/Bangkok/10/83 A/Yamagata/120/86	GITNKVNSVIEK	372	H5N2： A/mald/PA/84	GVTNKVNSIIDK	368
	GITNKVNSVIEK	372	H2N2： A/Okuda/57 A/Kumamoto/1/65 A/Korea/426/68 A/Izumi/5/65	GITNKVNSVIEK	372
H2N2： A/Izumi/5/65(R)	GITNKENSVIEK	373		GITNKVNSVIEK	372
H2N2： A/Izumi/5/65(R)	GITNKENSVIEK	373	H6N2： A/Mallard/Netherlands/16/99	GITNKVNSIIDK	374
H9N2： A/Hong Kong/1073/99	KITSKVNNIVDK	375	H6N2： A/Mallard/Netherlands/16/99	GITNKVNSIIDK	374
H9N2： A/Hong Kong/1073/99	KITSKVNNIVDK	375	H3N2： A/Aichi/2/68	QINGKLNRVIEK	376
H3N2： A/Fukuoka/C29/85	QINGKLNRLIEK	377	H3N2： A/Aichi/2/68	QINGKLNRVIEK	376

Reference

Boel E et al.(2000)，Functional human monoclonal antibodies of allisotypes constructed from phage display library-derived single-chain Fvantibody fragments.J.Immunol.Methods 239：153-166

Burton DR and Barbas CF(1994)，Human antibodies from combinatoriallibraries.Adv.Immunol.57：191-280

Chou TC and P Talalay(1984)Quantitative analysis of dose-effectrelationships：the combined effects of multiple drugs or enzyme inhibitors.AdvEnzyme Regul 22：27-55

De Kruif J et al.(1995a)，Rapid selection of cell subpopulation-specifichuman monoclonal antibodies from a synthetic phage antibody library.Proc NatlAcad Sci USA 92：3938

De Kruif J et al.(1995b)Selection and application of human single-chainFv antibody fragments from a semi-synthetic phage antibody display librarywith designed CDR3 regions.J.Mol.Biol.248：97-105.

Huls G et al.(1999)Antitumor immune effector mechanisms recruited byphage display-derived fully human IgG1 and IgA1 monoclonal antibodies.Cancer Res 59：5778-5784

Okuno Y et al(1993)A common neutralizing epitope conserved betweenthe hemagglutinins of Influenza A virus H1 and H2 strains.J.Virol.67：2552-2558.

Slootstra JW et al.(1996)Structural aspects of antibody-antigen interactionrevealed through small random peptide libraries.Mol.Divers.1：87-96.

Smirnov YA et al(1999)An epitope shared by the hemagglutinins of H1，H2，H5and H6subtypes of influenza A virus.Acta Virol.43：237-244.

The World Health Organization Global Influenza Program SurveillanceNetwork(2005)，Evolution of H5N1 Avian Influenza Viruses in Asia.EmergInfect Dis 11：1515-1521

Sequence table

＜110〉Krusal Holland N.V

＜120〉in the energy and the human binding molecules and the application thereof of influenza virus H 5 N 1

<130>0145 WO 00 ORD

<140>PCT/EP2007/059356

<141>2007-09-06

<150>US 60/842,930

<151>2006-09-07

<150>EP 06120316.2

<151>2006-09-07

<150>EP 06120644.7

<151>2006-09-14

<150>EP 06125107.0

<151>2006-11-30

<150>EP 07111235.3

<151>2007-06-28

<160>377

<170>PatentIn version 3.3

<210>1

<211>5

<212>PRT

<213>Homo sapiens

<400> 1

Ser Tyr Ala Ile Ser

1 5

<210>2

<211>17

<212>PRT

<213>Homo sapiens

<400>2

Gly Ile Ile Pro Ile Phe Gly Thr Thr Lys Tyr Ala Pro Lys Phe Gln

1 5 10 15

Gly

<210>3

<211> 12

<212>PRT

<213>Homo sapiens

<400>3

His Met Gly Tyr Gln Val Arg Glu Thr Met Asp Val

1 5 10

<210>4

<211>13

<212>PRT

<213>Homo sapiens

<400>4

Ser Gly Ser Thr Phe Asn Ile Gly Ser Asn Ala Val Asp

1 5 10

<210>5

<211>7

<212>PRT

<213>Homo sapiens

<400>5

Ser Asn Asn Gln Arg Pro Ser

1 5

<210>6

<211>11

<212>PRT

<213>Homo sapiens

<400>6

Ala Ala Trp Asp Asp Ile Leu Asn Val Pro Val

1 5 10

<210>7

<211>14

<212>PRT

<213>Homo sapiens

<400>7

Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser

1 5 10

<210>8

<211>7

<212>PRT

<213>Homo sapiens

<400>8

Glu Val Ser Asn Arg Pro Ser

1 5

<210>9

<211>10

<212>PRT

<213>Homo sapiens

<400>9

Ser Ser Tyr Thr Ser Ser Ser Thr Tyr Val

1 5 10

<210>10

<211>13

<212>PRT

<213>Homo sapiens

<400>10

Ser Gly Ser Arg Ser Asn Val Gly Asp Asn Ser Val Tyr

1 5 10

<210>11

<211>7

<212>PRT

<213>Homo sapiens

<400>11

Lys Asn Thr Gln Arg Pro Ser

1 5

<210>12

<211>11

<212>PRT

<213>Homo sapiens

<400>12

Val Ala Trp Asp Asp Ser Val Asp Gly Tyr Val

1 5 10

<210>13

<211>13

<212>PRT

<213>Homo sapiens

<400>13

Ser Gly Ser Ser Ser Asn Ile Gly Asn Asp Tyr Val Ser

1 5 10

<210>14

<211>7

<212>PRT

<213>Homo sapiens

<400>14

Asp Asn Asn Lys Arg Pro Ser

1 5

<210>15

<211>12

<212>PRT

<213>Homo sapiens

<400>15

Ala Thr Trp Asp Arg Arg Pro Thr Ala Tyr Val Val

1 5 10

<210>16

<211>5

<212>PRT

<213>Homo sapiens

<400>16

Gly Ser Ala Ile Ser

1 5

<210>17

<211>17

<212>PRT

<213>Homo sapiens

<400>17

Gly Ile Ser Pro Leu Phe Gly Thr Thr Asn Tyr Ala Gln Lys Phe Gln

1 5 10 15

Gly

<210>18

<211>11

<212>PRT

<213>Homo sapiens

<400>18

Gly Pro Lys Tyr Tyr Ser Glu Tyr Met Asp Val

1 5 10

<210>19

<211>11

<212>PRT

<213>Homo sapiens

<400>19

Arg Ala Ser Gln Gly Ile Ser Ser Tyr Leu Ala

1 5 10

<210>20

<211>7

<212>PRT

<213>Homo sapiens

<400>20

Asp Ala Ser Thr Leu Arg Ser

1 5

<210>21

<211>10

<212>PRT

<213>Homo sapiens

<400>21

Gln Arg Tyr Asn Ser Ala Pro Pro Ile Thr

1 5 10

<210>22

<211>17

<212>PRT

<213>Homo sapiens

<400>22

Gly Ile Met Gly Met Phe Gly Thr Thr Asn Tyr Ala Gln Lys Phe Gln

1 5 10 15

Gly

<210>23

<211>11

<212>PRT

<213>Homo sapiens

<400>23

Ser Ser Gly Tyr Tyr Pro Glu Tyr Phe Gln Asp

1 5 10

<210>24

<211>11

<212>PRT

<213>Homo sapiens

<400>24

Ser Gly His Lys Leu Gly Asp Lys Tyr Val Ser

1 5 10

<210>25

<211>7

<212>PRT

<213>Homo sapiens

<400>25

Gln Asp Asn Arg Arg Pro Ser

1 5

<210>26

<211>9

<212>PRT

<213>Homo sapiens

<400>26

Gln Ala Trp Asp Ser Ser Thr Ala Val

1 5

<210>27

<211>5

<212>PRT

<213>Homo sapiens

<400>27

Ser Tyr Ser Met Asn

1 5

<210>28

<211>17

<212>PRT

<213>Homo sapiens

<400>28

Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Val Asp Ser Val Lys

1 5 10 15

Gly

<210>29

<211>13

<212>PRT

<213>Homo sapiens

<400>29

Gly Gly Gly Ser Tyr Gly Ala Tyr Glu Gly Phe Asp Tyr

1 5 10

<210>30

<211>11

<212>PRT

<213>Homo sapiens

<400>30

Arg Ala Ser Gln Arg Val Ser Ser Tyr Leu Ala

1 5 10

<210>31

<211>7

<212>PRT

<213>Homo sapiens

<400>31

Gly Ala Ser Thr Arg Ala Ala

1 5

<210>32

<211>9

<212>PRT

<213>Homo sapiens

<400>32

Gln Gln Tyr Gly Arg Thr Pro Leu Thr

1 5

<210>33

<211>11

<212>PRT

<213>Homo sapiens

<400>33

Gly Gly Asn Asn Ile Gly Ser Lys Ser Val His

1 5 10

<210>34

<211>7

<212>PRT

<213>Homo sapiens

<400>34

Asp Asp Ser Asp Arg Pro Ser

1 5

<210>35

<211>11

<212>PRT

<213>Homo sapiens

<400>35

Gln Val Trp Asp Ser Ser Ser Asp His Ala Val

1 5 10

<210>36

<211>13

<212>PRT

<213>Homo sapiens

<400>36

Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Tyr Val Tyr

1 5 10

<210>37

<211>7

<212>PRT

<213>Homo sapiens

<400>37

Arg Asp Gly Gln Arg Pro Ser

1 5

<210>38

<211>11

<212>PRT

<213>Homo sapiens

<400>38

Ala Thr Trp Asp Asp Asn Leu Ser Gly Pro Val

1 5 10

<210>39

<211>5

<212>PRT

<213>Homo sapiens

<400>39

Ser Tyr Gly Ile Ser

1 5

<210>40

<211>17

<212>PRT

<213>Homo sapiens

<400>40

Asp Ile Ile Gly Met Phe Gly Ser Thr Asn Tyr Ala Gln Asn Phe Gln

1 5 10 15

Gly

<210>41

<211>11

<212>PRT

<213>Homo sapiens

<400>41

Ser Ser Gly Tyr Tyr Pro Ala Tyr Leu Pro His

1 5 10

<210>42

<211>12

<212>PRT

<213>Homo sapiens

<400>42

Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala

1 5 10

<210>43

<211>7

<212>PRT

<213>Homo sapiens

<400>43

Gly Ala Ser Ser Arg Ala Thr

1 5

<210>44

<211>9

<212>PRT

<213>Homo sapiens

<400>44

Gln Gln Tyr Gly Ser Ser Pro Arg Thr

1 5

<210>45

<211>5

<212>PRT

<213>Homo sapiens

<400>45

Phe Tyr Ser Met Ser

1 5

<210>46

<211>17

<212>PRT

<213>Homo sapiens

<400>46

Gly Ile Ile Pro Met Phe Gly Thr Thr Asn Tyr Ala Gln Lys Phe Gln

1 5 10 15

Gly

<210>47

<211>12

<212>PRT

<213>Homo sapiens

<400>47

Gly Asp Lys Gly Ile Tyr Tyr Tyr Tyr Met Asp Val

1 5 10

<210>48

<211>10

<212>PRT

<213>Homo sapiens

<400>48

Ser Ser Tyr Thr Ser Ser Ser Thr Leu Val

1 5 10

<210>49

<211>17

<212>PRT

<213>Homo sapiens

<400>49

Gly Ile Ile Gly Met Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe Gln

1 5 10 15

Gly

<210>50

<211>11

<212>PRT

<213>Homo sapiens

<400>50

Gly Asn Tyr Tyr Tyr Glu Ser Ser Leu Asp Tyr

1 5 10

<210>51

<211>11

<212>PRT

<213>Homo sapiens

<400>51

Gln Val Trp Asp Ser Ser Ser Asp His Tyr Val

1 5 10

<210>52

<211>5

<212>PRT

<213>Homo sapiens

<400>52

Asn Tyr Ala Met Ser

1 5

<210>53

<211>17

<212>PRT

<213>Homo sapiens

<400>53

Gly Ile Ile Ala Ile Phe Gly Thr Pro Lys Tyr Ala Gln Lys Phe Gln

1 5 10 15

Gly

<210>54

<211>14

<212>PRT

<213>Homo sapiens

<400>54

Ile Pro His Tyr Asn Phe Gly Ser Gly Ser Tyr Phe Asp Tyr

1 5 10

<210>55

<211>14

<212>PRT

<213>Homo sapiens

<400>55

Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly Tyr Asp Val His

1 5 10

<210>56

<211>7

<212>PRT

<213>Homo sapiens

<400>56

Gly Asn Ser Asn Arg Pro Ser

1 5

<210>57

<211>11

<212>PRT

<213>Homo sapiens

<400>57

Gly Thr Trp Asp Ser Ser Leu Ser Ala Tyr Val

1 5 10

<210>58

<211>1353

Ser Asn Asn Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu

180 185 190

Gln Trp Lys Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly

195 200 205

Ser Thr Val Glu Lys Thr Val Ala Pro Thr Glu Cys Ser

210 215 220

<210>92

<211>642

<212>DNA

<213>Homo sapiens

<220>

<221>CDS

<222>(1)..(642)

210

<210>93

<211>214

<212>PRT

<213>Homo sapiens

<400>93

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 Val Pro Thr Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Thr Leu Arg Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Ala 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 Arg Tyr Asn Ser Ala Pro Pro

85 90 95

Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Arg Ala Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210>94

<211>648

<212>DNA

<213>Homo sapiens

<220>

<221>CDS

<222>(11)..(648)

<400>94

<210>95

<211>216

<212>PRT

<213>Homo sapiens

<400>95

Gln Ser Val Leu Thr Gln Pro Pro Ser Glu Ser Val Ser Pro Gly Gln

1 5 10 15

Thr Ala Ser Val Thr Cys Ser Gly His Lys Leu Gly Asp Lys Tyr Val

20 25 30

Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Val Leu Leu Ile Tyr

35 40 45

Gln Asp Asn Arg Arg Pro Ser Gly Ile Pro Glu Arg Phe Ile Gly Ser

50 55 60

Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Leu

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Gln Ala Trp Asp Ser Ser Thr Ala Val

85 90 95

Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Ala Ala Ala Gly Gln

100 105 110

Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu

115 120 125

Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr

130 135 140

Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys

145 150 155 160

Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr

165 170 175

Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His

180 185 190

Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys

195 200 205

Thr Val Ala Pro Thr Glu Cys Ser

210 215

<210>96

<211>639

<212>DNA

<213>Homo sapiens

<220>

<221>CDS

<222>(1)..(639)

<210>97

<211>213

<212>PRT

<213>Homo sapiens

<400>97

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 Arg Val Ser Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Gly Ala Ser Thr Arg Ala Ala Gly Ile Pro Asp Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro

65 70 75 80

Glu Asp Ser Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Arg Thr Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Ala Ala Ala Pro

100 105 110

Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr

115 120 125

Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys

130 135 140

Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu

145 150 155 160

Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser

165 170 175

Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala

180 185 190

Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe

195 200 205

Asn Arg Gly Glu Cys

210

<210>98

<211>654

<212>DNA

<213>Homo sapiens

<220>

<221>CDS

<222>(1)..(654)

<210>99

<211>218

<212>PRT

<213>Homo sapiens

<400>99

Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Gln

1 5 10 15

Thr Ala Arg Ile Thr Cys Gly Gly Asn Asn Ile Gly Ser Lys Ser Val

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Val Tyr

35 40 45

Asp Asp Ser Asp Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser

50 55 60

Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Asp His

85 90 95

Ala Val Phe Gly Gly Gly Thr Gln Leu Thr Val Leu Gly Ala Ala Ala

100 105 110

Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser

115 120 125

Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp

130 135 140

Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro

145 150 155 160

Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn

165 170 175

Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys

180 185 190

Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val

195 200 205

Glu Lys Thr Val Ala Pro Thr Glu Cys Ser

210 215

<210>100

<211>660

<212>DNA

<213>Homo sapiens

<220>

<221>CDS

<222>(1)..(660)

<210>101

<211>220

<212>PRT

<213>Homo sapiens

<400>101

Ser Tyr Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln

1 5 10 15

Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn

20 25 30

Tyr Val Tyr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu

35 40 45

Ile Tyr Arg Asp Gly Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser

50 55 60

Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg

65 70 75 80

Ser Asp Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Asp Asn Leu

85 90 95

Ser Gly Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Ala

100 105 110

Ala Ala Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro

115 120 125

Ser Ser Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile

130 135 140

Ser Asp Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser

145 150 155 160

Ser Pro Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser

165 170 175

Asn Asn Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln

180 185 190

Trp Lys Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser

195 200 205

Thr Val Glu Lys Thr Val Ala Pro Thr Glu Cys Ser

210 215 220

<210>102

<211>642

<212>DNA

<213>Homo sapiens

<220>

<221>CDS

<222>(1)..(642)

<210>103

<211>214

<212>PRT

<213>Homo sapiens

<400>103

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 Gly Gly Thr Lys Val Glu Ile Lys Arg Ala Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210>104

<211>660

<212>DNA

<213>Homo sapiens

<220>

<221>CDS

<222>(1)..(660)

<210>105

<211>220

<212>PRT

<213>Homo sapiens

<400>105

Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln

1 5 10 15

Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr

20 25 30

Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu

35 40 45

Met Ile Tyr Glu Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe

50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu

65 70 75 80

Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser

85 90 95

Ser Thr Leu Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu Gly Ala

100 105 110

Ala Ala Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro

115 120 125

Ser Ser Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile

130 135 140

Ser Asp Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser

145 150 155 160

Ser Pro Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser

165 170 175

Asn Asn Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln

180 185 190

Trp Lys Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser

195 200 205

Thr Val Glu Lys Thr Val Ala Pro Thr Glu Cys Ser

210 215 220

<210>106

<211>654

<212>DNA

<213>Homo sapiens

<220>

<221>CDS

<222>(1)..(654)

<210>107

<211>218

<212>PRT

<213>Homo sapiens

<400>107

Gln Ser Val Val Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Gln

1 5 10 15

Thr Ala Arg Ile Thr Cys Gly Gly Asn Asn Ile Gly Ser Lys Ser Val

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Val Tyr

35 40 45

Asp Asp Ser Asp Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser

50 55 60

Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Asp His

85 90 95

Tyr Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu Gly Ala Ala Ala

100 105 110

Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser

115 120 125

Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp

130 135 140

Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro

145 150 155 160

Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn

165 170 175

Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys

180 185 190

Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val

195 200 205

Glu Lys Thr Val Ala Pro Thr Glu Cys Ser

210 215

<210>108

<211>660

<212>DNA

<213>Homo sapiens

<220>

<221>CDS

<222>(1)..(660)

<210>109

<211>220

<212>PRT

<213>Homo sapiens

<400>109

Thr Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln Arg

1 5 10 15

Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly Tyr

20 25 30

Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu

35 40 45

Ile Tyr Gly Asn Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe Ser

50 55 60

Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln

65 70 75 80

Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ser Ser Leu

85 90 95

Ser Ala Tyr Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu Gly Ala

100 105 110

Ala Ala Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro

115 120 125

Ser Ser Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile

130 135 140

Ser Asp Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser

145 150 155 160

Ser Pro Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser

165 170 175

Asn Asn Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln

180 185 190

Trp Lys Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser

195 200 205

Thr Val Glu Lys Thr Val Ala Pro Thr Glu Cys Ser

210 215 220

<210>110

<211>565

<212>PRT

<213>Influenza A virus

<220>

<221>MISC_FEATURE

<222>(1)..(565)

<223>HA protein of influenza virus H5N1 isolate A/Vietnam/1203/2004

<400>110

Met Glu Lys Ile Val Leu Leu Phe Ala Ile Val Ser Leu Val Lys Ser

1 5 10 15

Asp Gln Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Glu Gln Val

20 25 30

Asp Thr Ile Met Glu Lys Asn Val Thr Val Thr His Ala Gln Asp Ile

35 40 45

Leu Glu Lys Lys His Asn Gly Lys Leu Cys Asp Leu Asp Gly Val Lys

50 55 60

Pro Leu Ile Leu Arg Asp Cys Ser Val Ala Gly Trp Leu Leu Gly Asn

65 70 75 80

Pro Met Cys Asp Glu Phe Ile Asn Val Pro Glu Trp Ser Tyr Ile Val

85 90 95

Glu Lys Ala Asn Pro Val Asn Asp Leu Cys Tyr Pro Gly Asp Phe Asn

100 105 110

Asp Tyr Glu Glu Leu Lys His Leu Leu Ser Arg Ile Asn His Phe Glu

115 120 125

Lys Ile Gln Ile Ile Pro Lys Ser Ser Trp Ser Ser His Glu Ala Ser

130 135 140

Leu Gly Val Ser Ser Ala Cys Pro Tyr Gln Gly Lys Ser Ser Phe Phe

145 150 155 160

Arg Asn Val Val Trp Leu Ile Lys Lys Asn Ser Thr Tyr Pro Thr Ile

165 170 175

Lys Arg Ser Tyr Asn Asn Thr Asn Gln Glu Asp Leu Leu Val Leu Trp

180 185 190

Gly Ile His His Pro Asn Asp Ala Ala Glu Gln Thr Lys Leu Tyr Gln

195 200 205

Asn Pro Thr Thr Tyr Ile Ser Val Gly Thr Ser Thr Leu Asn Gln Arg

210 215 220

Leu Val Pro Arg Ile Ala Thr Arg Ser Lys Val Asn Gly Gln Ser Gly

225 230 235 240

Arg Met Glu Phe Phe Trp Thr Ile Leu Lys Pro Asn Asp Ala Ile Asn

245 250 255

Phe Glu Ser Asn Gly Asn Phe Ile Ala Pro Glu Tyr Ala Tyr Lys Ile

260 265 270

Val Lys Lys Gly Asp Ser Thr Ile Met Lys Ser Glu Leu Glu Tyr Gly

275 280 285

Asn Cys Asn Thr Lys Cys Gln Thr Pro Met Gly Ala Ile Asn Ser Ser

290 295 300

Met Pro Phe His Asn Ile His Pro Leu Thr Ile Gly Glu Cys Pro Lys

305 310 315 320

Tyr Val Lys Ser Asn Arg Leu Val Leu Ala Thr Gly Leu Arg Asn Ser

325 330 335

Pro Gln Arg Glu Arg Arg Arg Lys Lys Arg Gly Leu Phe Gly Ala Ile

340 345 350

Ala Gly Phe Ile Glu Gly Gly Trp Gln Gly Met Val Asp Gly Trp Tyr

355 360 365

Gly Tyr His His Ser Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Lys

370 375 380

Glu Ser Thr Gln Lys Ala Ile Asp Gly Val Thr Asn Lys Val Asn Ser

385 390 395 400

Ile Ile Asp Lys Met Asn Thr Gln Phe Glu Ala Val Gly Arg Glu Phe

405 410 415

Asn Asn Leu Glu Arg Arg Ile Glu Asn Leu Asn Lys Lys Met Glu Asp

420 425 430

Gly Phe Leu Asp Val Trp Thr Tyr Asn Ala Glu Leu Leu Val Leu Met

435 440 445

Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn Val Lys Asn Leu

450 455 460

Tyr Asp Lys Val Arg Leu Gln Leu Arg Asp Asn Ala Lys Glu Leu Gly

465 470 475 480

Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asp Asn Glu Cys Met Glu

485 490 495

Ser Val Arg Asn Gly Thr Tyr Asp Tyr Pro Gln Tyr Ser Glu Glu Ala

500 505 510

Arg Leu Lys Arg Glu Glu Ile Ser Gly Val Lys Leu Glu Ser Ile Gly

515 520 525

Ile Tyr Gln Ile Leu Ser Ile Tyr Ser Thr Val Ala Ser Ser Leu Ala

530 535 540

Leu Ala Ile Met Val Ala Gly Leu Ser Leu Trp Met Cys Ser Asn Gly

545 550 555 560

Ser Leu Gln Cys Arg

565

<210>111

<211>565

<212>PRT

<213>Influenza A virus

<220>

<221>MISC_FEATURE

<223>HA protein of influenza virus H5N1 isolate A/Vietnam/1194/2004

(H5N1TV)

<400>111

Met Glu Lys Ile Val Leu Leu Phe Ala Ile Val Ser Leu Val Lys Ser

1 5 10 15

Asp Gln Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Glu Gln Val

20 25 30

Asp Thr Ile Met Glu Lys Asn Val Thr Val Thr His Ala Gln Asp Ile

35 40 45

Leu Glu Lys Thr His Asn Gly Lys Leu Cys Asp Leu Asp Gly Val Lys

50 55 60

Pro Leu Ile Leu Arg Asp Cys Ser Val Ala Gly Trp Leu Leu Gly Asn

65 70 75 80

Pro Met Cys Asp Glu Phe Ile Asn Val Pro Glu Trp Ser Tyr Ile Val

85 90 95

Glu Lys Ala Asn Pro Val Asn Asp Leu Cys Tyr Pro Gly Asp Phe Asn

100 105 110

Asp Tyr Glu Glu Leu Lys His Leu Leu Ser Arg Ile Asn His Phe Glu

115 120 125

Lys Ile Gln Ile Ile Pro Lys Ser Ser Trp Ser Ser His Glu Ala Ser

130 135 140

Leu Gly Val Ser Ser Ala Cys Pro Tyr Gln Gly Lys Ser Ser Phe Phe

145 150 155 160

Arg Asn Val Val Trp Leu Ile Lys Lys Asn Ser Thr Tyr Pro Thr Ile

165 170 175

Lys Arg Ser Tyr Asn Asn Thr Asn Gln Glu Asp Leu Leu Val Leu Trp

180 185 190

Gly Ile His His Pro Asn Asp Ala Ala Glu Gln Thr Lys Leu Tyr Gln

195 200 205

Asn Pro Thr Thr Tyr Ile Ser Val Gly Thr Ser Thr Leu Asn Gln Arg

210 215 220

Leu Val Pro Arg Ile Ala Thr Arg Ser Lys Val Asn Gly Gln Ser Gly

225 230 235 240

Arg Met Glu Phe Phe Trp Thr Ile Leu Lys Pro Asn Asp Ala Ile Asn

245 250 255

Phe Glu Ser Asn Gly Asn Phe Ile Ala Pro Glu Tyr Ala Tyr Lys Ile

260 265 270

Val Lys Lys Gly Asp Ser Thr Ile Met Lys Ser Glu Leu Glu Tyr Gly

275 280 285

Asn Cys Asn Thr Lys Cys Gln Thr Pro Met Gly Ala Ile Asn Ser Ser

290 295 300

Met Pro Phe His Asn Ile His Pro Leu Thr Ile Gly Glu Cys Pro Lys

305 310 315 320

Tyr Val Lys Ser Asn Arg Leu Val Leu Ala Thr Gly Leu Arg Asn Ser

325 330 335

Pro Gln Arg Glu Arg Arg Arg Lys Lys Arg Gly Leu Phe Gly Ala Ile

340 345 350

Ala Gly Phe Ile Glu Gly Gly Trp Gln Gly Met Val Asp Gly Trp Tyr

355 360 365

Gly Tyr His His Ser Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Lys

370 375 380

Glu Ser Thr Gln Lys Ala Ile Asp Gly Val Thr Asn Lys Val Asn Ser

385 390 395 400

Ile Ile Asp Lys Met Asn Thr Gln Phe Glu Ala Val Gly Arg Glu Phe

405 410 415

Asn Asn Leu Glu Arg Arg Ile Glu Asn Leu Asn Lys Lys Met Glu Asp

420 425 430

Gly Phe Leu Asp Val Trp Thr Tyr Asn Ala Glu Leu Leu Val Leu Met

435 440 445

Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn Val Lys Asn Leu

450 455 460

Tyr Asp Lys Val Arg Leu Gln Leu Arg Asp Asn Ala Lys Glu Leu Gly

465 470 475 480

Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asp Asn Glu Cys Met Glu

485 490 495

Ser Val Arg Asn Gly Thr Tyr Asp Tyr Pro Gln Tyr Ser Glu Glu Ala

500 505 510

Arg Leu Lys Arg Glu Glu Ile Ser Gly Val Lys Leu Glu Ser Ile Gly

515 520 525

Ile Tyr Gln Ile Leu Ser Ile Tyr Ser Thr Val Ala Ser Ser Leu Ala

530 535 540

Leu Ala Ile Met Val Ala Gly Leu Ser Leu Trp Met Cys Ser Asn Gly

545 550 555 560

Ser Leu Gln Cys Arg

565

<210>112

<211>565

<212>PRT

<213>Influenza A virus

<220>

<221>MISC_FEATURE

<223>Consensus amino acid sequence representing HAs from strains

isolated in Indonesia and China (H5N1IC)

<400>112

Met Glu Lys Ile Val Leu Leu Leu Ala Ile Val Ser Leu Val Lys Ser

1 5 10 15

Asp Gln Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Glu Gln Val

20 25 30

Asp Thr Ile Met Glu Lys Asn Val Thr Val Thr His Ala Gln Asp Ile

35 40 45

Leu Glu Lys Thr His Asn Gly Lys Leu Cys Asp Leu Asp Gly Val Lys

50 55 60

Pro Leu Ile Leu Arg Asp Cys Ser Val Ala Gly Trp Leu Leu Gly Asn

65 70 75 80

Pro Met Cys Asp Glu Phe Ile Asn Val Pro Glu Trp Ser Tyr Ile Val

85 90 95

Glu Lys Ala Asn Pro Ala Asn Asp Leu Cys Tyr Pro Gly Asn Phe Asn

100 105 110

Asp Tyr Glu Glu Leu Lys His Leu Leu Ser Arg Ile Asn His Phe Glu

115 120 125

Lys Ile Gln Ile Ile Pro Lys Ser Ser Trp Ser Asp His Glu Ala Ser

130 135 140

Ser Gly Val Ser Ser Ala Cys Pro Tyr Gln Gly Lys Ser Ser Phe Phe

145 150 155 160

Arg Asn Val Val Trp Leu Ile Lys Lys Asn Ser Ser Tyr Pro Thr Ile

165 170 175

Lys Arg Ser Tyr Asn Asn Thr Asn Gln Glu Asp Leu Leu Val Leu Trp

180 185 190

Gly Ile His His Pro Asn Asp Ala Ala Glu Gln Thr Arg Leu Tyr Gln

195 200 205

Asn Pro Thr Thr Tyr Ile Ser Val Gly Thr Ser Thr Leu Asn Gln Arg

210 215 220

Leu Val Pro Lys Ile Ala Thr Arg Ser Lys Val Asn Gly Gln Ser Gly

225 230 235 240

Arg Met Glu Phe Phe Trp Thr Ile Leu Lys Pro Asn Asp Ala Ile Asn

245 250 255

Phe Glu Ser Asn Gly Asn Phe Ile Ala Pro Glu Tyr Ala Tyr Lys Ile

260 265 270

Val Lys Lys Gly Asp Ser Ala Ile Met Lys Ser Glu Leu Glu Tyr Gly

275 280 285

Asn Cys Asn Thr Lys Cys Gln Thr Pro Met Gly Ala Ile Asn Ser Ser

290 295 300

Met Pro Phe His Asn Ile His Pro Leu Thr Ile Gly Glu Cys Pro Lys

305 310 315 320

Tyr Val Lys Ser Asn Arg Leu Val Leu Ala Thr Gly Leu Arg Asn Ser

325 330 335

Pro Gln Arg Glu Arg Arg Arg Lys Lys Arg Gly Leu Phe Gly Ala Ile

340 345 350

Ala Gly Phe Ile Glu Gly Gly Trp Gln Gly Met Val Asp Gly Trp Tyr

355 360 365

Gly Tyr His His Ser Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Lys

370 375 380

Glu Ser Thr Gln Lys Ala Ile Asp Gly Val Thr Asn Lys Val Asn Ser

385 390 395 400

Ile Ile Asp Lys Met Asn Thr Gln Phe Glu Ala Val Gly Arg Glu Phe

405 410 415

Asn Asn Leu Glu Arg Arg Ile Glu Asn Leu Asn Lys Lys Met Glu Asp

420 425 430

Gly Phe Leu Asp Val Trp Thr Tyr Asn Ala Glu Leu Leu Val Leu Met

435 440 445

Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn Val Lys Asn Leu

450 455 460

Tyr Asp Lys Val Arg Leu Gln Leu Arg Asp Asn Ala Lys Glu Leu Gly

465 470 475 480

Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asp Asn Glu Cys Met Glu

485 490 495

Ser Val Arg Asn Gly Thr Tyr Asp Tyr Pro Gln Tyr Ser Glu Glu Ala

500 505 510

Arg Leu Lys Arg Glu Glu Ile Ser Gly Val Lys Leu Glu Ser Ile Gly

515 520 525

Ile Tyr Gln Ile Leu Ser Ile Tyr Ser Thr Val Ala Ser Ser Leu Ala

530 535 540

Leu Ala Ile Met Val Ala Gly Leu Ser Leu Trp Met Cys Ser Asn Gly

545 550 555 560

Ser Leu Gln Cys Arg

565

<210>113

<211>567

<212>PRT

<213>Influenza A virus

<220>

<221>MISC_FEATURE

<223>Soluble part of HA from H5N1TV

<220>

<221>MISC_FEATURE

<222>(533)..(546)

<223>Spacer

<220>

<221>MISC_FEATURE

<222>(547)..(556)

<223>Myc-tag

<220>

<221>MISC)FEATURE

<222>(557)..(561)

<223>Spacer

<220>

<221>MISC)FEATURE

<222>(562)..(567)

<223>His-tag

<400>113

Met Glu Lys Ile Val Leu Leu Phe Ala Ile Val Ser Leu Val Lys Ser

1 5 10 15

Asp Gln Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Glu Gln Val

20 25 30

Asp Thr Ile Met Glu Lys Asn Val Thr Val Thr His Ala Gln Asp Ile

35 40 45

Leu Glu Lys Thr His Asn Gly Lys Leu Cys Asp Leu Asp Gly Val Lys

50 55 60

Pro Leu Ile Leu Arg Asp Cys Ser Val Ala Gly Trp Leu Leu Gly Asn

65 70 75 80

Pro Met Cys Asp Glu Phe Ile Asn Val Pro Glu Trp Ser Tyr Ile Val

85 90 95

Glu Lys Ala Asn Pro Val Asn Asp Leu Cys Tyr Pro Gly Asp Phe Asn

100 105 110

Asp Tyr Glu Glu Leu Lys His Leu Leu Ser Arg Ile Asn His Phe Glu

115 120 125

Lys Ile Gln Ile Ile Pro Lys Ser Ser Trp Ser Ser His Glu Ala Ser

130 135 140

Leu Gly Val Ser Ser Ala Cys Pro Tyr Gln Gly Lys Ser Ser Phe Phe

145 150 155 160

Arg Asn Val Val Trp Leu Ile Lys Lys Asn Ser Thr Tyr Pro Thr Ile

165 170 175

Lys Arg Ser Tyr Asn Asn Thr Asn Gln Glu Asp Leu Leu Val Leu Trp

180 185 190

Gly Ile His His Pro Asn Asp Ala Ala Glu Gln Thr Lys Leu Tyr Gln

195 200 205

Asn Pro Thr Thr Tyr Ile Ser Val Gly Thr Ser Thr Leu Asn Gln Arg

210 215 220

Leu Val Pro Arg Ile Ala Thr Arg Ser Lys Val Asn Gly Gln Ser Gly

225 230 235 240

Arg Met Glu Phe Phe Trp Thr Ile Leu Lys Pro Asn Asp Ala Ile Asn

245 250 255

Phe Glu Ser Asn Gly Asn Phe Ile Ala Pro Glu Tyr Ala Tyr Lys Ile

260 265 270

Val Lys Lys Gly Asp Ser Thr Ile Met Lys Ser Glu Leu Glu Tyr Gly

275 280 285

Asn Cys Asn Thr Lys Cys Gln Thr Pro Met Gly Ala Ile Asn Ser Ser

290 295 300

Met Pro Phe His Asn Ile His Pro Leu Thr Ile Gly Glu Cys Pro Lys

305 310 315 320

Tyr Val Lys Ser Asn Arg Leu Val Leu Ala Thr Gly Leu Arg Asn Ser

325 330 335

Pro Gln Arg Glu Arg Arg Arg Lys Lys Arg Gly Leu Phe Gly Ala Ile

340 345 350

Ala Gly Phe Ile Glu Gly Gly Trp Gln Gly Met Val Asp Gly Trp Tyr

355 360 365

Tyr His His Ser Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Lys Gly

370 375 380

Glu Ser Thr Gln Lys Ala Ile Asp Gly Val Thr Asn Lys Val Asn Ser

385 390 395 400

Ile Ile Asp Lys Met Asn Thr Gln Phe Glu Ala Val Gly Arg Glu Phe

405 410 415

Asn Asn Leu Glu Arg Arg Ile Glu Asn Leu Asn Lys Lys Met Glu Asp

420 425 430

Gly Phe Leu Asp Val Trp Thr Tyr Asn Ala Glu Leu Leu Val Leu Met

435 440 445

Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn Val Lys Asn Leu

450 455 460

Tyr Asp Lys Val Arg Leu Gln Leu Arg Asp Asn Ala Lys Glu Leu Gly

465 470 475 480

Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asp Asn Glu Cys Met Glu

485 490 495

Ser Val Arg Asn Gly Thr Tyr Asp Tyr Pro Gln Tyr Ser Glu Glu Ala

500 505 510

Arg Leu Lys Arg Glu Glu Ile Ser Gly Val Lys Leu Glu Ser Ile Gly

515 520 525

Ile Tyr Gln Ile Gln His Ser Gly Gly Arg Ser Ser Leu Glu Gly Pro

530 535 540

Arg Phe Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu Asn Met His Thr

545 550 555 560

Gly His His His His His His

565

<210>114

<211>567

<212>PRT

<213>Influenza A virus

<220>

<221>MISC_FEATURE

<223>Soluble part of HA from H5N1IC

<220>

<221>MISC_FEATURE

<222>(533)..(546)

<223>Spacer

<220>

<221>MISC_FEATURE

<222>(547)..(556)

<223>Myc-tag

<220>

<221>MISC_FEATURE

<222>(557)..(561)

<223>Spacer

<220>

<221>MISC_FEATURE

<222>(562)..(567)

<223>His-tag

<400>114

Met Glu Lys Ile Val Leu Leu Leu Ala Ile Val Ser Leu Val Lys Ser

1 5 10 15

Asp Gln Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Glu Gln Val

20 25 30

Asp Thr Ile Met Glu Lys Asn Val Thr Val Thr His Ala Gln Asp Ile

35 40 45

Leu Glu Lys Thr His Asn Gly Lys Leu Cys Asp Leu Asp Gly Val Lys

50 55 60

Pro Leu Ile Leu Arg Asp Cys Ser Val Ala Gly Trp Leu Leu Gly Asn

65 70 75 80

Pro Met Cys Asp Glu Phe Ile Asn Val Pro Glu Trp Ser Tyr Ile Val

85 90 95

Glu Lys Ala Asn Pro Ala Asn Asp Leu Cys Tyr Pro Gly Asn Phe Asn

100 105 110

Asp Tyr Glu Glu Leu Lys His Leu Leu Ser Arg Ile Asn His Phe Glu

115 120 125

Lys Ile Gln Ile Ile Pro Lys Ser Ser Trp Ser Asp His Glu Ala Ser

130 135 140

Ser Gly Val Ser Ser Ala Cys Pro Tyr Gln Gly Lys Ser Ser Phe Phe

145 150 155 160

Arg Asn Val Val Trp Leu Ile Lys Lys Asn Ser Ser Tyr Pro Thr Ile

165 170 175

Lys Arg Ser Tyr Asn Asn Thr Asn Gln Glu Asp Leu Leu Val Leu Trp

180 185 190

Gly Ile His His Pro Asn Asp Ala Ala Glu Gln Thr Arg Leu Tyr Gln

195 200 205

Asn Pro Thr Thr Tyr Ile Ser Val Gly Thr Ser Thr Leu Asn Gln Arg

210 215 220

Leu Val Pro Lys Ile Ala Thr Arg Ser Lys Val Asn Gly Gln Ser Gly

225 230 235 240

Arg Met Glu Phe Phe Trp Thr Ile Leu Lys Pro Asn Asp Ala Ile Asn

245 250 255

Phe Glu Ser Asn Gly Asn Phe Ile Ala Pro Glu Tyr Ala Tyr Lys Ile

260 265 270

Val Lys Lys Gly Asp Ser Ala Ile Met Lys Ser Glu Leu Glu Tyr Gly

275 280 285

Asn Cys Asn Thr Lys Cys Gln Thr Pro Met Gly Ala Ile Asn Ser Ser

290 295 300

Met Pro Phe His Asn Ile His Pro Leu Thr Ile Gly Glu Cys Pro Lys

305 310 315 320

Tyr Val Lys Ser Asn Arg Leu Val Leu Ala Thr Gly Leu Arg Asn Ser

325 330 335

Pro Gln Arg Glu Arg Arg Arg Lys Lys Arg Gly Leu Phe Gly Ala Ile

340 345 350

Ala Gly Phe Ile Glu Gly Gly Trp Gln Gly Met Val Asp Gly Trp Tyr

355 360 365 365

Gly Tyr His His Ser Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Lys

370 375 380

Glu Ser Thr Gln Lys Ala Ile Asp Gly Val Thr Asn Lys Val Asn Ser

385 390 395 400

Ile Ile Asp Lys Met Asn Thr Gln Phe Glu Ala Val Gly Arg Glu Phe

405 410 415

Asn Asn Leu Glu Arg Arg Ile Glu Asn Leu Asn Lys Lys Met Glu Asp

420 425 430

Gly Phe Leu Asp Val Trp Thr Tyr Asn Ala Glu Leu Leu Val Leu Met

435 440 445

Glu Asn Glu Arg Thr Leu Asp Phe His Asp Ser Asn Val Lys Asn Leu

450 455 460

Tyr Asp Lys Val Arg Leu Gln Leu Arg Asp Asn Ala Lys Glu Leu Gly

465 470 475 480

Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asp Asn Glu Cys Met Glu

485 495 495

Ser Val Arg Asn Gly Thr Tyr Asp Tyr Pro Gln Tyr Ser Glu Glu Ala

500 505 510

Arg Leu Lys Arg Glu Glu Ile Ser Gly Val Lys Leu Glu Ser Ile Gly

515 520 525

Ile Tyr Gln Ile Gln His Ser Gly Gly Arg Ser Ser Leu Glu Gly Pro

530 535 540

Arg Phe Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu Asn Met His Thr

545 550 555 560

Gly His His His His His His

565

<210>115

<211>744

<212>DNA

<213>Artificial

<220>

<223>SC06-255

<220>

<221>CDS

<222>(1)..(744)

gcc tcc ctg gcc atc agt ggg ctc cag tct gag gat gag gct gat tat 672

Ala Ser Leu Ala Ile Ser Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr

210 215 220

tac tgt gca gca tgg gat gac atc ctg aat gtt ccg gta ttc ggc gga 720

Tyr Cys Ala Ala Trp Asp Asp Ile Leu Asn Val Pro Val Phe Gly Gly

225 230 235 240

ggg acc aag ctg acc gtc cta ggt 744

Gly Thr Lys Leu Thr Val Leu Gly

245

<210>116

<211>248

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>116

Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Pro Phe Arg Ser Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Pro Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Ile Phe Gly Thr Thr Lys Tyr Ala Pro Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Asp Phe Ala Gly Thr Val Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Lys His Met Gly Tyr Gln Val Arg Glu Thr Met Asp Val Trp Gly

100 105 110

Lys Gly Thr Thr Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly

115 120 125

Thr Gly Ser Gly Thr Gly Gly Ser Thr Ser Tyr Val Leu Thr Gln Pro

130 135 140

Pro Ser Ala Ser Gly Thr Pro Gly Gln Arg Val Thr Ile Ser Cys Ser

145 150 155 160

Gly Ser Thr Phe Asn Ile Gly Ser Asn Ala Val Asp Trp Tyr Arg Gln

165 170 175

Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr Ser Asn Asn Gln Arg

180 185 190

Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Arg Ser Gly Thr Ser

195 200 205

Ala Ser Leu Ala Ile Ser Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr

210 215 220

Tyr Cys Ala Ala Trp Asp Asp Ile Leu Asn Val Pro Val Phe Gly Gly

225 230 235 240

Gly Thr Lys Leu Thr Val Leu Gly

245

<210>117

<211>744

<212>DNA

<213>Artificial

<220>

<223>SC06-257

<220>

<221>CDS

<222>(1)..(744)

acg gcc tcc ctg acc atc tct ggg ctc cag gct gag gac gag gct gat 672

Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp

210 215 220

tat tac tgc agc tca tat aca agc agc agc act tat gtc ttc gga act 720

Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser Ser Thr Tyr Val Phe Gly Thr

225 230 235 240

ggg acc aag gtc acc gtc cta ggt 744

Gly Thr Lys Val Thr Val Leu Gly

245

<210>118

<211>248

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>118

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Pro Phe Arg Ser Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Pro Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Ile Phe Gly Thr Thr Lys Tyr Ala Pro Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Asp Phe Ala Gly Thr Val Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Lys His Met Gly Tyr Gln Val Arg Glu Thr Met Asp Val Trp Gly

100 105 110

Lys Gly Thr Thr Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly

115 120 125

Thr Gly Ser Gly Thr Gly Gly Ser Thr Gln Ser Ala Leu Thr Gln Pro

130 135 140

Ala Ala Val Ser Gly Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr

145 150 155 160

Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln

165 170 175

Gln His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr Glu Val Ser Asn

180 185 190

Arg Pro Ser Gly Val Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn

195 200 205

Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp

210 215 220

Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser Ser Thr Tyr Val Phe Gly Thr

225 230 235 240

Gly Thr Lys Val Thr Val Leu Gly

245

<210>119

<211>744

<212>DNA

<213>Artificial

<220>

<223>SC06-260

<220>

<221>CDS

<222>(1)..(744)

Ala Ser Leu Ala Ile Ile Gly Leu Gln Ser Gly Asp Glu Ala Asp Tyr

210 215 220

tat tgt gtg gca tgg gat gac agc gta gat ggc tat gtc ttc gga tct 720

Tyr Cys Val Ala Trp Asp Asp Ser Val Asp Gly Tyr Val Phe Gly Ser

225 230 235 240

ggg acc aag gtc acc gtc cta ggt 744

Gly Thr Lys Val Thr Val Leu Gly

245

<210>120

<211>248

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>120

Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Pro Phe Arg Ser Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Pro Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Ile Phe Gly Thr Thr Lys Tyr Ala Pro Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Asp Phe Ala Gly Thr Val Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Lys His Met Gly Tyr Gln Val Arg Glu Thr Met Asp Val Trp Gly

100 105 110

Lys Gly Thr Thr Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly

115 120 125

Thr Gly Ser Gly Thr Gly Gly Ser Thr Ser Tyr Val Leu Thr Gln Pro

130 135 140

Pro Ser Val Ser Gly Thr Pro Gly Gln Arg Val Thr Ile Ser Cys Ser

145 150 155 160

Gly Ser Arg Ser Asn Val Gly Asp Asn Ser Val Tyr Trp Tyr Gln His

165 170 175

Val Pro Glu Met Ala Pro Lys Leu Leu Val Tyr Lys Asn Thr Gln Arg

180 185 190

Pro Ser Gly Val Pro Ala Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser

195 200 205

Ala Ser Leu Ala Ile Ile Gly Leu Gln Ser Gly Asp Glu Ala Asp Tyr

210 215 220

Tyr Cys Val Ala Trp Asp Asp Ser Val Asp Gly Tyr Val Phe Gly Ser

225 230 235 240

Gly Thr Lys Val Thr Val Leu Gly

245

<210>121

<211>747

<212>DNA

<213>Artificial

<220>

<223>SC06-261

<220>

<221>CDS

<222>(1)..(747)

210 215 220

tac tgc gca aca tgg gat cgc cgc ccg act gct tat gtt gtc ttc ggc 720

Tyr Cys Ala Thr Trp Asp Arg Arg Pro Thr Ala Tyr Val Val Phe Gly

225 230 235 240

gga ggg acc aag ctg acc gtc cta ggt 747

Gly Gly Thr Lys Leu Thr Val Leu Gly

245

<210>122

<211>249

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>122

Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Pro Phe Arg Ser Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Pro Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Ile Phe Gly Thr Thr Lys Tyr Ala Pro Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Asp Phe Ala Gly Thr Val Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Lys His Met Gly Tyr Gln Val Arg Glu Thr Met Asp Val Trp Gly

100 105 110

Lys Gly Thr Thr Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly

115 120 125

Thr Gly Ser Gly Thr Gly Gly Ser Thr Gln Ser Val Leu Thr Gln Pro

130 135 140

Pro Ser Val Ser Ala Ala Pro Gly Gln Lys Val Thr Ile Ser Cys Ser

145 150 155 160

Gly Ser Ser Ser Asn Ile Gly Asn Asp Tyr Val Ser Trp Tyr Gln Gln

165 175 175

Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr Asp Asn Asn Lys Arg

180 185 190

Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser

195 200 205

Ala Thr Leu Gly Ile Thr Gly Leu Gln Thr Gly Asp Glu Ala Asn Tyr

210 215 220

Tyr Cys Ala Thr Trp Asp Arg Arg Pro Thr Ala Tyr Val Val Phe Gly

225 230 235 240

Gly Gly Thr Lys Leu Thr Val Leu Gly

245

<210>123

<211>735

<212>DNA

<213>Artificial

<220>

<223>SC06-262

<220>

<221>CDS

<222>(1)..(735)

caa agg tat aac agt gcc ccc ccg atc acc ttc ggc caa ggg aca cga 720

Gln Arg Tyr Asn Ser Ala Pro Pro Ile Thr Phe Gly Gln Gly Thr Arg

225 230 235 240

ctg gag att aaa cgt 735

Leu Glu Ile Lys Arg

245

<210>124

<211>245

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>124

Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Val Ser Gly Val Ile Phe Ser Gly Ser

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ser Pro Leu Phe Gly Thr Thr Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Gln Ser Thr Asn Thr Thr Tyr

65 70 75 80

Met Glu Val Asn Ser Leu Arg Tyr Glu Asp Thr Ala Val Tyr Phe Cys

85 90 95

Ala Arg Gly Pro Lys Tyr Tyr Ser Glu Tyr Met Asp Val Trp Gly Lys

100 105 110

Gly Thr Thr Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly Thr

115 120 125

Gly Ser Gly Thr Gly Gly Ser Thr Asp Ile Gln Met Thr Gln Ser Pro

130 135 140

Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg

145 150 155 160

Ala Ser Gln Gly Ile Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro

165 170 175

Gly Lys Val Pro Thr Leu Leu Ile Tyr Asp Ala Ser Thr Leu Arg Ser

180 185 190

Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Ala Thr Asp Phe Thr

195 200 205

Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys

210 215 220

Gln Arg Tyr Asn Ser Ala Pro Pro Ile Thr Phe Gly Gln Gly Thr Arg

225 230 235 240

Leu Glu Ile Lys Arg

245

<210>125

<211>729

<212>DNA

<213>Artificial

<220>

<223>SC06-268

<220>

<221>CDS

<222>(1)..(729)

gcg tgg gac agc agc act gcg gtt ttc ggc gga ggg acc aag ctg acc 720

Ala Trp Asp Ser Ser Thr Ala Val Phe Gly Gly Gly Thr Lys Leu Thr

225 230 235 240

gtc cta ggt 729

Val Leu Gly

<210>126

<211>243

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>126

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Met Gly Met Phe Gly Thr Thr Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Phe Thr Ser Ala Ala Tyr

65 70 75 80

Met Glu Leu Arg Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Ser Gly Tyr Tyr Pro Glu Tyr Phe Gln Asp Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly Thr

115 120 125

Gly Ser Gly Thr Gly Gly Ser Thr Gln Ser Val Leu Thr Gln Pro Pro

130 135 140

Ser Glu Ser Val Ser Pro Gly Gln Thr Ala Ser Val Thr Cys Ser Gly

145 150 155 160

His Lys Leu Gly Asp Lys Tyr Val Ser Trp Tyr Gln Gln Lys Pro Gly

165 170 175

Gln Ser Pro Val Leu Leu Ile Tyr Gln Asp Asn Arg Arg Pro Ser Gly

180 185 190

Ile Pro Glu Arg Phe Ile Gly Ser Asn Ser Gly Asn Thr Ala Thr Leu

195 200 205

Thr Ile Ser Gly Thr Gln Ala Leu Asp Glu Ala Asp Tyr Tyr Cys Gln

210 215 220

Ala Trp Asp Ser Ser Thr Ala Val Phe Gly Gly Gly Thr Lys Leu Thr

225 230 235 240

Val Leu Gly

<210>127

<211>738

<212>DNA

<213>Artificial

<220>

<223>SC06-307

<220>

<221>CDS

<222>(1)..(738)

Tyr Cys Gln Gln Tyr Gly Arg Thr Pro Leu Thr Phe Gly Gly Gly Thr

225 230 235 240

aag gtg gag atc aaa cgt 738

Lys Val Glu Ile Lys Arg

245

<210>128

<211>246

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>128

Gln Val Gln Leu Val Gln 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 Ser Tyr

20 25 30

Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Val 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 Arg Gly Gly Gly Ser Tyr Gly Ala Tyr Glu Gly Phe Asp Tyr Trp

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly

115 120 125

Gly Thr Gly Ser Gly Thr Gly Gly Ser Thr Glu Ile Val Leu Thr Gln

130 135 140

Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser

145 150 155 160

Cys Arg Ala Ser Gln Arg Val Ser Ser Tyr Leu Ala Trp Tyr Gln Gln

165 170 175

Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Thr Arg

180 185 190

Ala Ala Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp

195 200 205

Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Ser Ala Val Tyr

210 215 220

Tyr Cys Gln Gln Tyr Gly Arg Thr Pro Leu Thr Phe Gly Gly Gly Thr

225 230 235 240

Lys Val Glu Ile Lys Arg

245

<210>129

<211>738

<212>DNA

<213>Artificial

<220>

<223>SC06-310

<220>

<221>CDS

<222>(1)..(738)

225 230 235 240

cag ctg acc gtc ctc ggt 738

Gln Leu Thr Val Leu Gly

245

<210>130

<211>246

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>130

Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Pro Phe Arg Ser Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Pro Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Ile Phe Gly Thr Thr Lys Tyr Ala Pro Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Asp Phe Ala Gly Thr Val Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Lys His Met Gly Tyr Gln Val Arg Glu Thr Met Asp Val Trp Gly

100 105 110

Lys Gly Thr Thr Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly

115 120 125

Thr Gly Ser Gly Thr Gly Gly Ser Thr Ser Tyr Val Leu Thr Gln Pro

130 135 140

Pro Ser Val Ser Val Ala Pro Gly Gln Thr Ala Arg Ile Thr Cys Gly

145 150 155 160

Gly Asn Asn Ile Gly Ser Lys Ser Val His Trp Tyr Gln Gln Lys Pro

165 170 175

Gly Gln Ala Pro Val Leu Val Val Tyr Asp Asp Ser Asp Arg Pro Ser

180 185 190

Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn Thr Ala Thr

195 200 205

Leu Thr Ile Ser Arg Val Glu Ala Gly Asp Glu Ala Asp Tyr Tyr Cys

210 215 220

Gln Val Trp Asp Ser Ser Ser Asp His Ala Val Phe Gly Gly Gly Thr

225 230 235 240

Gln Leu Thr Val Leu Gly

245

<210>131

<211>744

<212>DNA

<213>Artificial

<220>

<223>SC06-314

<220>

<221>CDS

<222>(1)..(744)

ggg acc aag ctg acc gtc cta ggt 744

Gly Thr Lys Leu Thr Val Leu Gly

245

<210>132

<211>248

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>132

Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Pro Phe Arg Ser Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Pro Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Ile Phe Gly Thr Thr Lys Tyr Ala Pro Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Asp Phe Ala Gly Thr Val Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Lys His Met Gly Tyr Gln Val Arg Glu Thr Met Asp Val Trp Gly

100 105 110

Lys Gly Thr Thr Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly

115 120 125

Thr Gly Ser Gly Thr Gly Gly Ser Thr Ser Tyr Val Leu Thr Gln Pro

130 135 140

Pro Ser Ala Ser Gly Thr Pro Gly Gln Arg Val Thr Ile Ser Cys Ser

145 150 155 160

Gly Ser Ser Ser Asn Ile Gly Ser Asn Tyr Val Tyr Trp Tyr Gln Gln

165 170 175

Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr Arg Asp Gly Gln Arg

180 185 190

Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser

195 200 205

Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Asp Asp Glu Ala Asp Tyr

210 215 220

Tyr Cys Ala Thr Trp Asp Asp Asn Leu Ser Gly Pro Val Phe Gly Gly

225 230 235 240

Gly Thr Lys Leu Thr Val Leu Gly

245

<210>133

<211>735

<212>DNA

<213>Artificial

<220>

<223>SC06-323

<220>

<221>CDS

<222>(1)..(735)

gtg gag atc aaa cgt 735

Val Glu Ile Lys Arg

245

<210>134

<211>245

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>134

Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser 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 Asp Ile Ile Gly Met Phe Gly Ser Thr Asn Tyr Ala Gln Asn Phe

50 55 60

Gln Gly Arg Leu Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Ser Gly Tyr Tyr Pro Ala Tyr Leu Pro His Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly Thr

115 120 125

Gly Ser Gly Thr Gly Gly Ser Thr Glu Ile Val Leu Thr Gln Ser Pro

130 135 140

Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg

145 150 155 160

Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys

165 170 175

Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala

180 185 190

Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe

195 200 205

Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr

210 215 220

Cys Gln Gln Tyr Gly Ser Ser Pro Arg Thr Phe Gly Gly Gly Thr Lys

225 230 235 240

Val Glu Ile Lys Arg

245

<210>135

<211>744

<212>DNA

<213>Artificial

<220>

<223>SC06-325

<220>

<221>CDS

<222>(1)..(744)

Gly Thr Lys Val Thr Val Leu Gly

245

<210>136

<211>248

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>136

Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Phe Tyr

20 25 30

Ser Met Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Met Phe Gly Thr Thr Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Val Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Val Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Asp Lys Gly Ile Tyr Tyr Tyr Tyr Met Asp Val Trp Gly

100 105 110

Lys Gly Thr Thr Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly

115 120 125

Thr Gly Ser Gly Thr Gly Gly Ser Thr Gln Ser Ala Leu Thr Gln Pro

130 135 140

Ala Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr

145 150 155 160

Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln

165 170 175

Gln His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr Glu Val Ser Asn

180 185 190

Arg Pro Ser Gly Val Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn

195 200 205

Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp

210 215 220

Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser Ser Thr Leu Val Phe Gly Thr

225 230 235 240

Gly Thr Lys Val Thr Val Leu Gly

245

<210>137

<211>735

<212>DNA

<213>Artificial

<220>

<223>SC06-331

<220>

<221>CDS

<222>(1)..(735)

245

<210>138

<211>245

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>138

Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Gly Met Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Phe Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Asn Tyr Tyr Tyr Glu Ser Ser Leu Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly Thr

115 120 125

Gly Ser Gly Thr Gly Gly Ser Thr Gln Ser Val Val Thr Gln Pro Pro

130 135 140

Ser Val Ser Val Ala Pro Gly Gln Thr Ala Arg Ile Thr Cys Gly Gly

145 150 155 160

Asn Asn Ile Gly Ser Lys Ser Val His Trp Tyr Gln Gln Lys Pro Gly

165 170 175

Gln Ala Pro Val Leu Val Val Tyr Asp Asp Ser Asp Arg Pro Ser Gly

180 185 190

Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn Thr Ala Thr Leu

195 200 205

Thr Ile Ser Arg Val Glu Ala Gly Asp Glu Ala Asp Tyr Tyr Cys Gln

210 215 220

Val Trp Asp Ser Ser Ser Asp His Tyr Val Phe Gly Thr Gly Thr Lys

225 230 235 240

Val Thr Val Leu Gly

245

<210>139

<211>750

<212>DNA

<213>Artificial

<220>

<223>SC06-344

<220>

<221>CDS

<222>(1)..(750)

<210>140

<211>250

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>140

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Arg Val Ser Cys Lys Ala Ser Gly Ser Ile Phe Arg Asn Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Ala Ile Phe Gly Thr Pro Lys Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Val Tyr

65 70 75 80

Met Glu Leu Ser Gly Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg Ile Pro His Tyr Asn Phe Gly Ser Gly Ser Tyr Phe Asp Tyr

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Thr Gly Gly Ser

115 120 125

Gly Gly Thr Gly Ser Gly Thr Gly Gly Ser Thr Thr Val Leu Thr Gln

130 135 140

Pro Pro Ser Val Ser Gly Ala Pro Gly Gln Arg Val Thr Ile Ser Cys

145 150 155 160

Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly Tyr Asp Val His Trp Tyr

165 170 175

Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr Gly Asn Ser

180 185 190

Asn Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly

195 200 205

Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln Thr Gly Asp Glu Ala

210 215 220

Asp Tyr Tyr Cys Gly Thr Trp Asp Ser Ser Leu Ser Ala Tyr Val Phe

225 230 235 240

Gly Thr Gly Thr Lys Val Thr Val Leu Gly

245 250

<210>141

<211>10515

<212>DNA

<213>Artificial

<220>

<223>Vector pIg-C911-HCgammal

<220>

<221>misc_feature

<222>(1326)..(5076)

<223>Stuffer

<400>141

tcgacggatc gggagatctc ccgatcccct atggtgcact ctcagtacaa tctgctctga 60

tgccgcatag ttaagccagt atctgctccc tgcttgtgtg ttggaggtcg ctgagtagtg 120

cgcgagcaaa atttaagcta caacaaggca aggcttgacc gacaattgca tgaagaatct 180

gcttagggtt aggcgttttg cgctgcttcg ctaggtggtc aatattggcc attagccata 240

ttattcattg gttatatagc ataaatcaat attggctatt ggccattgca tacgttgtat 300

ccatatcata atatgtacat ttatattggc tcatgtccaa cattaccgcc atgttgacat 360

tgattattga ctagttatta atagtaatca attacggggt cattagttca tagcccatat 420

atggagttcc gcgttacata acttacggta aatggcccgc ctggctgacc gcccaacgac 480

ccccgcccat tgacgtcaat aatgacgtat gttcccatag taacgccaat agggactttc 540

cattgacgtc aatgggtgga gtatttacgg taaactgccc acttggcagt acatcaagtg 600

tatcatatgc caagtacgcc ccctattgac gtcaatgacg gtaaatggcc cgcctggcat 660

tatgcccagt acatgacctt atgggacttt cctacttggc agtacatcta cgtattagtc 720

atcgctatta ccatggtgat gcggttttgg cagtacatca atgggcgtgg atagcggttt 780

gactcacggg gatttccaag tctccacccc attgacgtca atgggagttt gttttggcac 840

caaaatcaac gggactttcc aaaatgtcgt aacaactccg ccccattgac gcaaatgggc 900

ggtaggcgtg tacggtggga ggtctatata agcagagctc gtttagtgaa ccgtcagatc 960

gcctggagac gccatccacg ctgttttgac ctccatagaa gacaccggga ccgatccagc 1020

ctccgcggcc gggaacggtg cattggaagc tggcctggat atcctgactc tcttaggtag 1080

ccttgcagaa gttggtcgtg aggcactggg caggtaagta tcaaggttac aagacaggtt 1140

taaggagatc aatagaaact gggcttgtcg agacagagaa gactcttgcg tttctgatag 1200

gcacctattg gtcttactga catccacttt gcctttctct ccacaggtgt ccactcccag 1260

ttcaattaca gctcgccacc atgggatgga gctgtatcat cctcttcttg gtactgctgc 1320

tggcccagcc ggccagtgac cttgaccggt gcaccacttt tgatgatgtt caagctccta 1380

attacactca acatacttca tctatgaggg gggtttacta tcctgatgaa atttttagat 1440

cggacactct ttatttaact caggatttat ttcttccatt ttattctaat gttacagggt 1500

ttcatactat taatcatacg tttggcaacc ctgtcatacc ttttaaggat ggtatttatt 1560

ttgctgccac agagaaatca aatgttgtcc gtggttgggt ttttggttct accatgaaca 1620

acaagtcaca gtcggtgatt attattaaca attctactaa tgttgttata cgagcatgta 1680

actttgaatt gtgtgacaac cctttctttg ctgtttctaa acccatgggt acacagacac 1740

atactatgat attcgataat gcatttaatt gcactttcga gtacatatct gatgcctttt 1800

cgcttgatgt ttcagaaaag tcaggtaatt ttaaacactt acgagagttt gtgtttaaaa 1860

ataaagatgg gtttctctat gtttataagg gctatcaacc tatagatgta gttcgtgatc 1920

taccttctgg ttttaacact ttgaaaccta tttttaagtt gcctcttggt attaacatta 1980

caaattttag agccattctt acagcctttt cacctgctca agacatttgg ggcacgtcag 2040

ctgcagccta ttttgttggc tatttaaagc caactacatt tatgctcaag tatgatgaaa 2100

atggtacaat cacagatgct gttgattgtt ctcaaaatcc acttgctgaa ctcaaatgct 2160

ctgttaagag ctttgagatt gacaaaggaa tttaccagac ctctaatttc agggttgttc 2220

cctcaggaga tgttgtgaga ttccctaata ttacaaactt gtgtcctttt ggagaggttt 2280

ttaatgctac taaattccct tctgtctatg catgggagag aaaaaaaatt tctaattgtg 2340

ttgctgatta ctctgtgctc tacaactcaa catttttttc aacctttaag tgctatggcg 2400

tttctgccac taagttgaat gatctttgct tctccaatgt ctatgcagat tcttttgtag 2460

tcaagggaga tgatgtaaga caaatagcgc caggacaaac tggtgttatt gctgattata 2520

attataaatt gccagatgat ttcatgggtt gtgtccttgc ttggaatact aggaacattg 2580

atgctacttc aactggtaat tataattata aatataggta tcttagacat ggcaagctta 2640

ggccctttga gagagacata tctaatgtgc ctttctcccc tgatggcaaa ccttgcaccc 2700

cacctgctct taattgttat tggccattaa atgattatgg tttttacacc actactggca 2760

ttggctacca accttacaga gttgtagtac tttcttttga acttttaaat gcaccggcca 2820

cggtttgtgg accaaaatta tccactgacc ttattaagaa ccagtgtgtc aattttaatt 2880

ttaatggact cactggtact ggtgtgttaa ctccttcttc aaagagattt caaccatttc 2940

aacaatttgg ccgtgatgtt tctgatttca ctgattccgt tcgagatcct aaaacatctg 3000

aaatattaga catttcacct tgctcttttg ggggtgtaag tgtaattaca cctggaacaa 3060

atgcttcatc tgaagttgct gttctatatc aagatgttaa ctgcactgat gtttctacag 3120

caattcatgc agatcaactc acaccagctt ggcgcatata ttctactgga aacaatgtat 3180

tccagactca ggcaggctgt cttataggag ctgagcatgt cgacacttct tatgagtgcg 3240

acattcctat tggagctggc atttgtgcta gttaccatac agtttcttta ttacgtagta 3300

ctagccaaaa atctattgtg gcttatacta tgtctttagg tgctgatagt tcaattgctt 3360

actctaataa caccattgct atacctacta acttttcaat tagcattact acagaagtaa 3420

tgcctgtttc tatggctaaa acctccgtag attgtaatat gtacatctgc ggagattcta 3480

ctgaatgtgc taatttgctt ctccaatatg gtagcttttg cacacaacta aatcgtgcac 3540

tctcaggtat tgctgctgaa caggatcgca acacacgtga agtgttcgct caagtcaaac 3600

aaatgtacaa aaccccaact ttgaaatatt ttggtggttt taatttttca caaatattac 3660

ctgaccctct aaagccaact aagaggtctt ttattgagga cttgctcttt aataaggtga 3720

cactcgctga tgctggcttc atgaagcaat atggcgaatg cctaggtgat attaatgcta 3780

gagatctcat ttgtgcgcag aagttcaatg gacttacagt gttgccacct ctgctcactg 3840

atgatatgat tgctgcctac actgctgctc tagttagtgg tactgccact gctggatgga 3900

catttggtgc tggcgctgct cttcaaatac cttttgctat gcaaatggca tataggttca 3960

atggcattgg agttacccaa aatgttctct atgagaacca aaaacaaatc gccaaccaat 4020

ttaacaaggc gattagtcaa attcaagaat cacttacaac aacatcaact gcattgggca 4080

agctgcaaga cgttgttaac cagaatgctc aagcattaaa cacacttgtt aaacaactta 4140

gctctaattt tggtgcaatt tcaagtgtgc taaatgatat cctttcgcga cttgataaag 4200

tcgaggcgga ggtacaaatt gacaggttaa ttacaggcag acttcaaagc cttcaaacct 4260

atgtaacaca acaactaatc agggctgctg aaatcagggc ttctgctaat cttgctgcta 4320

ctaaaatgtc tgagtgtgtt cttggacaat caaaaagagt tgacttttgt ggaaagggct 4380

accaccttat gtccttccca caagcagccc cgcatggtgt tgtcttccta catgtcacgt 4440

atgtgccatc ccaggagagg aacttcacca cagcgccagc aatttgtcat gaaggcaaag 4500

catacttccc tcgtgaaggt gtttttgtgt ttaatggcac ttcttggttt attacacaga 4560

ggaacttctt ttctccacaa ataattacta cagacaatac atttgtctca ggaaattgtg 4620

atgtcgttat tggcatcatt aacaacacag tttatgatcc tctgcaacct gagcttgact 4680

cattcaaaga agagctggac aagtacttca aaaatcatac atcaccagat gttgattttg 4740

gcgacatttc aggcattaac gcttctgtcg tcaacattca aaaagaaatt gaccgcctca 4800

atgaggtcgc taaaaattta aatgaatcac tcattgacct tcaagaactg ggaaaatatg 4860

agcaatatat taaatggcct ctcgacgaac aaaaactcat ctcagaagag gatctgaatg 4920

ctgtgggcca ggacacgcag gaggtcatcg tggtgccaca ctccttgccc tttaaggtgg 4980

tggtgatctc agccatcctg gccctggtgg tgctcaccat catctccctt atcatcctca 5040

tcatgctttg gcagaagaag ccacgttagg cggccgctcg agtgctagca ccaagggccc 5100

cagcgtgttc cccctggccc ccagcagcaa gagcaccagc ggcggcacag ccgccctggg 5160

ctgcctggtg aaggactact tccccgagcc cgtgaccgtg agctggaaca gcggcgcctt 5220

gaccagcggc gtgcacacct tccccgccgt gctgcagagc agcggcctgt acagcctgag 5280

cagcgtggtg accgtgccca gcagcagcct gggcacccag acctacatct gcaacgtgaa 5340

ccacaagccc agcaacacca aggtggacaa acgcgtggag cccaagagct gcgacaagac 5400

ccacacctgc cccccctgcc ctgcccccga gctgctgggc ggaccctccg tgttcctgtt 5460

cccccccaag cccaaggaca ccctcatgat cagccggacc cccgaggtga cctgcgtggt 5520

ggtggacgtg agccacgagg accccgaggt gaagttcaac tggtacgtgg acggcgtgga 5580

ggtgcacaac gccaagacca agccccggga ggagcagtac aacagcacct accgggtggt 5640

gagcgtgctc accgtgctgc accaggactg gctgaacggc aaggagtaca agtgcaaggt 5700

gagcaacaag gccctgcctg cccccatcga gaagaccatc agcaaggcca agggccagcc 5760

ccgggagccc caggtgtaca ccctgccccc cagccgggag gagatgacca agaaccaggt 5820

gtccctcacc tgtctggtga agggcttcta ccccagcgac atcgccgtgg agtgggagag 5880

caacggccag cccgagaaca actacaagac caccccccct gtgctggaca gcgacggcag 5940

cttcttcctg tacagcaagc tcaccgtgga caagagccgg tggcagcagg gcaacgtgtt 6000

cagctgcagc gtgatgcacg aggccctgca caaccactac acccagaaga gcctgagcct 6060

gagccccggc aagtgataat ctagagggcc cgtttaaacc cgctgatcag cctcgactgt 6120

gccttctagt tgccagccat ctgttgtttg cccctccccc gtgccttcct tgaccctgga 6180

aggtgccact cccactgtcc tttcctaata aaatgaggaa attgcatcgc attgtctgag 6240

taggtgtcat tctattctgg ggggtggggt ggggcaggac agcaaggggg aggattggga 6300

agacaatagc aggcatgctg gggatgcggt gggctctatg gcttctgagg cggaaagaac 6360

cagctggggc tctagggggt atccccacgc gccctgtagc ggcgcattaa gcgcggcggg 6420

tgtggtggtt acgcgcagcg tgaccgctac acttgccagc gccctagcgc ccgctccttt 6480

cgctttcttc ccttcctttc tcgccacgtt cgccggcttt ccccgtcaag ctctaaatcg 6540

ggggctccct ttagggttcc gatttagtgc tttacggcac ctcgacccca aaaaacttga 6600

ttagggtgat ggttcacgta gtgggccatc gccctgatag acggtttttc gccctttgac 6660

gttggagtcc acgttcttta atagtggact cttgttccaa actggaacaa cactcaaccc 6720

tatctcggtc tattcttttg atttataagg gattttgccg atttcggcct attggttaaa 6780

aaatgagctg atttaacaaa aatttaacgc gaattaattc tgtggaatgt gtgtcagtta 6840

gggtgtggaa agtccccagg ctccccagca ggcagaagta tgcaaagcat gcatctcaat 6900

tagtcagcaa ccaggtgtgg aaagtcccca ggctccccag caggcagaag tatgcaaagc 6960

atgcatctca attagtcagc aaccatagtc ccgcccctaa ctccgcccat cccgccccta 7020

actccgccca gttccgccca ttctccgccc catggctgac taattttttt tatttatgca 7080

gaggccgagg ccgcctctgc ctctgagcta ttccagaagt agtgaggagg cttttttgga 7140

ggcctaggct tttgcaaaaa gctcccggga gcttgtatat ccattttcgg atctgatcaa 7200

gagacaggat gaggatcgtt tcgcatgatt gaacaagatg gattgcacgc aggttctccg 7260

gccgcttggg tggagaggct attcggctat gactgggcac aacagacaat cggctgctct 7320

gatgccgccg tgttccggct gtcagcgcag gggcgcccgg ttctttttgt caagaccgac 7380

ctgtccggtg ccctgaatga actgcaggac gaggcagcgc ggctatcgtg gctggccacg 7440

acgggcgttc cttgcgcagc tgtgctcgac gttgtcactg aagcgggaag ggactggctg 7500

ctattgggcg aagtgccggg gcaggatctc ctgtcatctc accttgctcc tgccgagaaa 7560

gtatccatca tggctgatgc aatgcggcgg ctgcatacgc ttgatccggc tacctgccca 7620

ttcgaccacc aagcgaaaca tcgcatcgag cgagcacgta ctcggatgga agccggtctt 7680

gtcgatcagg atgatctgga cgaagagcat caggggctcg cgccagccga actgttcgcc 7740

aggctcaagg cgcgcatgcc cgacggcgag gatctcgtcg tgacccatgg cgatgcctgc 7800

ttgccgaata tcatggtgga aaatggccgc ttttctggat tcatcgactg tggccggctg 7860

ggtgtggcgg accgctatca ggacatagcg ttggctaccc gtgatattgc tgaagagctt 7920

ggcggcgaat gggctgaccg cttcctcgtg ctttacggta tcgccgctcc cgattcgcag 7980

cgcatcgcct tctatcgcct tcttgacgag ttcttctgag cgggactctg gggttcgaaa 8040

tgaccgacca agcgacgccc aacctgccat cacgagattt cgattccacc gccgccttct 8100

atgaaaggtt gggcttcgga atcgttttcc gggacgccgg ctggatgatc ctccagcgcg 8160

gggatctcat gctggagttc ttcgcccacc ccaacttgtt tattgcagct tataatggtt 8220

acaaataaag caatagcatc acaaatttca caaataaagc atttttttca ctgcattcta 8280

gttgtggttt gtccaaactc atcaatgtat cttatcatgt ctgtataccg tcgacctcta 8340

gctagagctt ggcgtaatca tggtcatagc tgtttcctgt gtgaaattgt tatccgctca 8400

caattccaca caacatacga gccggaagca taaagtgtaa agcctggggt gcctaatgag 8460

tgagctaact cacattaatt gcgttgcgct cactgcccgc tttccagtcg ggaaacctgt 8520

cgtgccagct gcattaatga atcggccaac gcgcggggag aggcggtttg cgtattgggc 8580

gctcttccgc ttcctcgctc actgactcgc tgcgctcggt cgttcggctg cggcgagcgg 8640

tatcagctca ctcaaaggcg gtaatacggt tatccacaga atcaggggat aacgcaggaa 8700

agaacatgtg agcaaaaggc cagcaaaagg ccaggaaccg taaaaaggcc gcgttgctgg 8760

cgtttttcca taggctccgc ccccctgacg agcatcacaa aaatcgacgc tcaagtcaga 8820

ggtggcgaaa cccgacagga ctataaagat accaggcgtt tccccctgga agctccctcg 8880

tgcgctctcc tgttccgacc ctgccgctta ccggatacct gtccgccttt ctcccttcgg 8940

gaagcgtggc gctttctcat agctcacgct gtaggtatct cagttcggtg taggtcgttc 9000

gctccaagct gggctgtgtg cacgaacccc ccgttcagcc cgaccgctgc gccttatccg 9060

gtaactatcg tcttgagtcc aacccggtaa gacacgactt atcgccactg gcagcagcca 9120

ctggtaacag gattagcaga gcgaggtatg taggcggtgc tacagagttc ttgaagtggt 9180

ggcctaacta cggctacact agaagaacag tatttggtat ctgcgctctg ctgaagccag 9240

ttaccttcgg aaaaagagtt ggtagctctt gatccggcaa acaaaccacc gctggtagcg 9300

gtttttttgt ttgcaagcag cagattacgc gcagaaaaaa aggatctcaa gaagatcctt 9360

tgatcttttc tacggggtct gacgctcagt ggaacgaaaa ctcacgttaa gggattttgg 9420

tcatgagatt atcaaaaagg atcttcacct agatcctttt aaattaaaaa tgaagtttta 9480

aatcaatcta aagtatatat gagtaaactt ggtctgacag ttaccaatgc ttaatcagtg 9540

aggcacctat ctcagcgatc tgtctatttc gttcatccat agttgcctga ctccccgtcg 9600

tgtagataac tacgatacgg gagggcttac catctggccc cagtgctgca atgataccgc 9660

gagacccacg ctcaccggct ccagatttat cagcaataaa ccagccagcc ggaagggccg 9720

agcgcagaag tggtcctgca actttatccg cctccatcca gtctattaat tgttgccggg 9780

aagctagagt aagtagttcg ccagttaata gtttgcgcaa cgttgttgcc attgctacag 9840

gcatcgtggt gtcacgctcg tcgtttggta tggcttcatt cagctccggt tcccaacgat 9900

caaggcgagt tacatgatcc cccatgttgt gcaaaaaagc ggttagctcc ttcggtcctc 9960

cgatcgttgt cagaagtaag ttggccgcag tgttatcact catggttatg gcagcactgc 10020

ataattctct tactgtcatg ccatccgtaa gatgcttttc tgtgactggt gagtactcaa 10080

ccaagtcatt ctgagaatag tgtatgcggc gaccgagttg ctcttgcccg gcgtcaatac 10140

gggataatac cgcgccacat agcagaactt taaaagtgct catcattgga aaacgttctt 10200

cggggcgaaa actctcaagg atcttaccgc tgttgagatc cagttcgatg taacccactc 10260

gtgcacccaa ctgatcttca gcatctttta ctttcaccag cgtttctggg tgagcaaaaa 10320

caggaaggca aaatgccgca aaaaagggaa taagggcgac acggaaatgt tgaatactca 10380

tactcttcct ttttcaatat tattgaagca tttatcaggg ttattgtctc atgagcggat 10440

acatatttga atgtatttag aaaaataaac aaataggggt tccgcgcaca tttccccgaa 10500

aagtgccacc tgacg 10515

<210>142

<211>8777

<212>DNA

<213>Artificial

<220>

<223>Vector pIg-C909-Ckappa

<220>

<221>misc_feature

<222>(1328)..(3860)

<223>Stuffer

<400>142

tcgacggatc gggagatctc ccgatcccct atggtgcact ctcagtacaa tctgctctga 60

tgccgcatag ttaagccagt atctgctccc tgcttgtgtg ttggaggtcg ctgagtagtg 120

cgcgagcaaa atttaagcta caacaaggca aggcttgacc gacaattgtt aattaacatg 180

aagaatctgc ttagggttag gcgttttgcg ctgcttcgct aggtggtcaa tattggccat 240

tagccatatt attcattggt tatatagcat aaatcaatat tggctattgg ccattgcata 300

cgttgtatcc atatcataat atgtacattt atattggctc atgtccaaca ttaccgccat 360

gttgacattg attattgact agttattaat agtaatcaat tacggggtca ttagttcata 420

gcccatatat ggagttccgc gttacataac ttacggtaaa tggcccgcct ggctgaccgc 480

ccaacgaccc ccgcccattg acgtcaataa tgacgtatgt tcccatagta acgccaatag 540

ggactttcca ttgacgtcaa tgggtggagt atttacggta aactgcccac ttggcagtac 600

atcaagtgta tcatatgcca agtacgcccc ctattgacgt caatgacggt aaatggcccg 660

cctggcatta tgcccagtac atgaccttat gggactttcc tacttggcag tacatctacg 720

tattagtcat cgctattacc atggtgatgc ggttttggca gtacatcaat gggcgtggat 780

agcggtttga ctcacgggga tttccaagtc tccaccccat tgacgtcaat gggagtttgt 840

tttggcacca aaatcaacgg gactttccaa aatgtcgtaa caactccgcc ccattgacgc 900

aaatgggcgg taggcgtgta cggtgggagg tctatataag cagagctcgt ttagtgaacc 960

gtcagatcgc ctggagacgc catccacgct gttttgacct ccatagaaga caccgggacc 1020

gatccagcct ccgcggccgg gaacggtgca ttggaatcga tgactctctt aggtagcctt 1080

gcagaagttg gtcgtgaggc actgggcagg taagtatcaa ggttacaaga caggtttaag 1140

gagatcaata gaaactgggc ttgtcgagac agagaagactcttgcgtttc tgataggcac 1200

ctattggtct tactgacatc cactttgcct ttctctccac aggtgtccac tcccagttca 1260

attacagctc gccaccatgc ggctgcccgc ccagctgctg ggccttctca tgctgtgggt 1320

gcccgcctcg agatctatcg atgcatgcca tggtaccaag cttgccacca tgagcagcag 1380

ctcttggctg ctgctgagcc tggtggccgt gacagccgcc cagagcacca tcgaggagca 1440

ggccaagacc ttcctggaca agttcaacca cgaggccgag gacctgttct accagagcag 1500

cctggccagc tggaactaca acaccaacat caccgaggag aacgtgcaga acatgaacaa 1560

cgccggcgac aagtggagcg ccttcctgaa ggagcagagc acactggccc agatgtaccc 1620

cctgcaggag atccagaacc tgaccgtgaa gctgcagctg caggccctgc agcagaacgg 1680

cagcagcgtg ctgagcgagg acaagagcaa gcggctgaac accatcctga acaccatgtc 1740

caccatctac agcaccggca aagtgtgcaa ccccgacaac ccccaggagt gcctgctgct 1800

ggagcccggc ctgaacgaga tcatggccaa cagcctggac tacaacgagc ggctgtgggc 1860

ctgggagagc tggcggagcg aagtgggcaa gcagctgcgg cccctgtacg aggagtacgt 1920

ggtgctgaag aacgagatgg ccagggccaa ccactacgag gactacggcg actactggag 1980

aggcgactac gaagtgaacg gcgtggacgg ctacgactac agcagaggcc agctgatcga 2040

ggacgtggag cacaccttcg aggagatcaa gcctctgtac gagcacctgc acgcctacgt 2100

gcgggccaag ctgatgaacg cctaccccag ctacatcagc cccatcggct gcctgcccgc 2160

ccacctgctg ggcgacatgt ggggccggtt ctggaccaac ctgtacagcc tgaccgtgcc 2220

cttcggccag aagcccaaca tcgacgtgac cgacgccatg gtggaccagg cctgggacgc 2280

ccagcggatc ttcaaggagg ccgagaagtt cttcgtgagc gtgggcctgc ccaacatgac 2340

ccagggcttt tgggagaaca gcatgctgac cgaccccggc aatgtgcaga aggccgtgtg 2400

ccaccccacc gcctgggacc tgggcaaggg cgacttccgg atcctgatgt gcaccaaagt 2460

gaccatggac gacttcctga ccgcccacca cgagatgggc cacatccagt acgacatggc 2520

ctacgccgcc cagcccttcc tgctgcggaa cggcgccaac gagggctttc acgaggccgt 2580

gggcgagatc atgagcctga gcgccgccac ccccaagcac ctgaagagca tcggcctgct 2640

gagccccgac ttccaggagg acaacgagac cgagatcaac ttcctgctga agcaggccct 2700

gaccatcgtg ggcaccctgc ccttcaccta catgctggag aagtggcggt ggatggtgtt 2760

taagggcgag atccccaagg accagtggat gaagaagtgg tgggagatga agcgggagat 2820

cgtgggcgtg gtggagcccg tgccccacga cgagacctac tgcgaccccg ccagcctgtt 2880

ccacgtgagc aacgactact ccttcatccg gtactacacc cggaccctgt accagttcca 2940

gttccaggag gccctgtgcc aggccgccaa gcacgagggc cccctgcaca agtgcgacat 3000

cagcaacagc accgaggccg gacagaaact gttcaacatg ctgcggctgg gcaagagcga 3060

gccctggacc ctggccctgg agaatgtggt gggcgccaag aacatgaatg tgcgccccct 3120

gctgaactac ttcgagcccc tgttcacctg gctgaaggac cagaacaaga acagcttcgt 3180

gggctggagc accgactgga gcccctacgc cgaccagagc atcaaagtgc ggatcagcct 3240

gaagagcgcc ctgggcgaca aggcctacga gtggaacgac aacgagatgt acctgttccg 3300

gagcagcgtg gcctatgcca tgcggcagta cttcctgaaa gtgaagaacc agatgatcct 3360

gttcggcgag gaggacgtga gagtggccaa cctgaagccc cggatcagct tcaacttctt 3420

cgtgaccgcc cccaagaacg tgagcgacat catcccccgg accgaagtgg agaaggccat 3480

ccggatgagc cggagccgga tcaacgacgc cttccggctg aacgacaact ccctggagtt 3540

cctgggcatc cagcccaccc tgggccctcc caaccagccc cccgtgagca tctggctgat 3600

cgtgtttggc gtggtgatgg gcgtgatcgt ggtgggaatc gtgatcctga tcttcaccgg 3660

catccgggac cggaagaaga agaacaaggc ccggagcggc gagaacccct acgccagcat 3720

cgatatcagc aagggcgaga acaaccccgg cttccagaac accgacgacg tgcagaccag 3780

cttctgataa tctagaacga gctcgaattc gaagcttctg cagacgcgtc gacgtcatat 3840

ggatccgata tcgccgtggc ggccgcaccc agcgtgttca tcttcccccc ctccgacgag 3900

cagctgaaga gcggcaccgc cagcgtggtg tgcctgctga acaacttcta cccccgggag 3960

gccaaggtgc agtggaaggt ggacaacgcc ctgcagagcg gcaacagcca ggagagcgtg 4020

accgagcagg acagcaagga ctccacctac agcctgagca gcaccctcac cctgagcaag 4080

gccgactacg agaagcacaa ggtgtacgcc tgcgaggtga cccaccaggg cctgagcagc 4140

cccgtgacca agagcttcaa ccggggcgag tgttaataga cttaagttta aaccgctgat 4200

cagcctcgac tgtgccttct agttgccagc catctgttgt ttgcccctcc cccgtgcctt 4260

ccttgaccct ggaaggtgcc actcccactg tcctttccta ataaaatgag gaaattgcat 4320

cgcattgtct gagtaggtgt cattctattc tggggggtgg ggtggggcag gacagcaagg 4380

gggaggattg ggaagacaat agcaggcatg ctggggatgc ggtgggctct atggcttctg 4440

aggcggaaag aaccagctgg ggctctaggg ggtatcccca cgcgccctgt agcggcgcat 4500

taagcgcggc gggtgtggtg gttacgcgca gcgtgaccgc tacacttgcc agcgccctag 4560

cgcccgctcc tttcgctttc ttcccttcct ttctcgccac gttcgccggc tttccccgtc 4620

aagctctaaa tcgggggctc cctttagggt tccgatttag tgctttacgg cacctcgacc 4680

ccaaaaaact tgattagggt gatggttcac gtagtgggcc atcgccctga tagacggttt 4740

ttcgcccttt gacgttggag tccacgttct ttaatagtgg actcttgttc caaactggaa 4800

caacactcaa ccctatctcg gtctattctt ttgatttata agggattttg gccatttcgg 4860

cctattggtt aaaaaatgag ctgatttaac aaaaatttaa cgcgaattaa ttctgtggaa 4920

tgtgtgtcag ttagggtgtg gaaagtcccc aggctcccca gcaggcagaa gtatgcaaag 4980

catgcatctc aattagtcag caaccaggtg tggaaagtcc ccaggctccc cagcaggcag 5040

aagtatgcaa agcatgcatc tcaattagtc agcaaccata gtcccgcccc taactccgcc 5100

catcccgccc ctaactccgc ccagttccgc ccattctccg ccccatggct gactaatttt 5160

ttttatttat gcagaggccg aggccgcctc tgcctctgag ctattccaga agtagtgagg 5220

aggctttttt ggaggcctag gcttttgcaa aaagctcccg ggagcttgta tatccatttt 5280

cggatctgat cagcacgtga tgaaaaagcc tgaactcacc gcgacgtctg tcgagaagtt 5340

tctgatcgaa aagttcgaca gcgtctccga cctgatgcag ctctcggagg gcgaagaatc 5400

tcgtgctttc agcttcgatg taggagggcg tggatatgtc ctgcgggtaa atagctgcgc 5460

cgatggtttc tacaaagatc gttatgttta tcggcacttt gcatcggccg cgctcccgat 5520

tccggaagtg cttgacattg gggaattcag cgagagcctg acctattgca tctcccgccg 5580

tgcacagggt gtcacgttgc aagacctgcc tgaaaccgaa ctgcccgctg ttctgcagcc 5640

ggtcgcggag gccatggatg cgatcgctgc ggccgatctt agccagacga gcgggttcgg 5700

cccattcgga ccacaaggaa tcggtcaata cactacatgg cgtgatttca tatgcgcgat 5760

tgctgatccc catgtgtatc actggcaaac tgtgatggac gacaccgtca gtgcgtccgt 5820

cgcgcaggct ctcgatgagc tgatgctttg ggccgaggac tgccccgaag tccggcacct 5880

cgtgcacgcg gatttcggct ccaacaatgt cctgacggac aatggccgca taacagcggt 5940

cattgactgg agcgaggcga tgttcgggga ttcccaatac gaggtcgcca acatcttctt 6000

ctggaggccg tggttggctt gtatggagca gcagacgcgc tacttcgagc ggaggcatcc 6060

ggagcttgca ggatcgccgc ggctccgggc gtatatgctc cgcattggtc ttgaccaact 6120

ctatcagagc ttggttgacg gcaatttcga tgatgcagct tgggcgcagg gtcgatgcga 6180

cgcaatcgtc cgatccggag ccgggactgt cgggcgtaca caaatcgccc gcagaagcgc 6240

ggccgtctgg accgatggct gtgtagaagt actcgccgat agtggaaacc gacgccccag 6300

cactcgtccg agggcaaagg aatagcacgt gctacgagat ttcgattcca ccgccgcctt 6360

ctatgaaagg ttgggcttcg gaatcgtttt ccgggacgcc ggctggatga tcctccagcg 6420

cggggatctc atgctggagt tcttcgccca ccccaacttg tttattgcag cttataatgg 6480

ttacaaataa agcaatagca tcacaaattt cacaaataaa gcattttttt cactgcattc 6540

tagttgtggt ttgtccaaac tcatcaatgt atcttatcat gtctgtatac cgtcgacctc 6600

tagctagagc ttggcgtaat catggtcata gctgtttcct gtgtgaaatt gttatccgct 6660

cacaattcca cacaacatac gagccggaag cataaagtgt aaagcctggg gtgcctaatg 6720

agtgagctaa ctcacattaa ttgcgttgcg ctcactgccc gctttccagt cgggaaacct 6780

gtcgtgccag ctgcattaat gaatcggcca acgcgcgggg agaggcggtt tgcgtattgg 6840

gcgctcttcc gcttcctcgc tcactgactc gctgcgctcg gtcgttcggc tgcggcgagc 6900

ggtatcagct cactcaaagg cggtaatacg gttatccaca gaatcagggg ataacgcagg 6960

aaagaacatg tgagcaaaag gccagcaaaa ggccaggaac cgtaaaaagg ccgcgttgct 7020

ggcgtttttc cataggctcc gcccccctga cgagcatcac aaaaatcgac gctcaagtca 7080

gaggtggcga aacccgacag gactataaag ataccaggcg tttccccctg gaagctccct 7140

cgtgcgctct cctgttccga ccctgccgct taccggatac ctgtccgcct ttctcccttc 7200

gggaagcgtg gcgctttctc atagctcacg ctgtaggtat ctcagttcgg tgtaggtcgt 7260

tcgctccaag ctgggctgtg tgcacgaacc ccccgttcag cccgaccgct gcgccttatc 7320

cggtaactat cgtcttgagt ccaacccggt aagacacgac ttatcgccac tggcagcagc 7380

cactggtaac aggattagca gagcgaggta tgtaggcggt gctacagagt tcttgaagtg 7440

gtggcctaac tacggctaca ctagaagaac agtatttggt atctgcgctc tgctgaagcc 7500

agttaccttc ggaaaaagag ttggtagctc ttgatccggc aaacaaacca ccgctggtag 7560

cggttttttt gtttgcaagc agcagattac gcgcagaaaa aaaggatctc aagaagatcc 7620

tttgatcttt tctacggggt ctgacgctca gtggaacgaa aactcacgtt aagggatttt 7680

ggtcatgaga ttatcaaaaa ggatcttcac ctagatcctt ttaaattaaa aatgaagttt 7740

taaatcaatc taaagtatat atgagtaaac ttggtctgac agttaccaat gcttaatcag 7800

tgaggcacct atctcagcga tctgtctatt tcgttcatcc atagttgcct gactccccgt 7860

cgtgtagata actacgatac gggagggctt accatctggc cccagtgctg caatgatacc 7920

gcgagaccca cgctcaccgg ctccagattt atcagcaata aaccagccag ccggaagggc 7980

cgagcgcaga agtggtcctg caactttatc cgcctccatc cagtctatta attgttgccg 8040

ggaagctaga gtaagtagtt cgccagttaa tagtttgcgc aacgttgttg ccattgctac 8100

aggcatcgtg gtgtcacgct cgtcgtttgg tatggcttca ttcagctccg gttcccaacg 8160

atcaaggcga gttacatgat cccccatgtt gtgcaaaaaa gcggttagct ccttcggtcc 8220

tccgatcgtt gtcagaagta agttggccgc agtgttatca ctcatggtta tggcagcact 8280

gcataattct cttactgtca tgccatccgt aagatgcttt tctgtgactg gtgagtactc 8340

aaccaagtca ttctgagaat agtgtatgcg gcgaccgagt tgctcttgcc cggcgtcaat 8400

acgggataat accgcgccac atagcagaac tttaaaagtg ctcatcattg gaaaacgttc 8460

ttcggggcga aaactctcaa ggatcttacc gctgttgaga tccagttcga tgtaacccac 8520

tcgtgcaccc aactgatctt cagcatcttt tactttcacc agcgtttctg ggtgagcaaa 8580

aacaggaagg caaaatgccg caaaaaaggg aataagggcg acacggaaat gttgaatact 8640

catactcttc ctttttcaat attattgaag catttatcag ggttattgtc tcatgagcgg 8700

atacatattt gaatgtattt agaaaaataa acaaataggg gttccgcgca catttccccg 8760

aaaagtgcca cctgacg 8777

<210>143

<211>8792

<212>DNA

<213>Artificial

<220>

<223>Vector pIg-C910-Clambda

<220>

<221>misc_feature

<222>(1330)..(3869)

<223>Stuffer

<400>143

tcgacggatc gggagatctc ccgatcccct atggtgcact ctcagtacaa tctgctctga 60

tgccgcatag ttaagccagt atctgctccc tgcttgtgtg ttggaggtcg ctgagtagtg 120

cgcgagcaaa atttaagcta caacaaggca aggcttgacc gacaattgtt aattaacatg 180

aagaatctgc ttagggttag gcgttttgcg ctgcttcgct aggtggtcaa tattggccat 240

tagccatatt attcattggt tatatagcat aaatcaatat tggctattgg ccattgcata 300

cgttgtatcc atatcataat atgtacattt atattggctc atgtccaaca ttaccgccat 360

gttgacattg attattgact agttattaat agtaatcaat tacggggtca ttagttcata 420

gcccatatat ggagttccgc gttacataac ttacggtaaa tggcccgcct ggctgaccgc 480

ccaacgaccc ccgcccattg acgtcaataa tgacgtatgt tcccatagta acgccaatag 540

ggactttcca ttgacgtcaa tgggtggagt atttacggta aactgcccac ttggcagtac 600

atcaagtgta tcatatgcca agtacgcccc ctattgacgt caatgacggt aaatggcccg 660

cctggcatta tgcccagtac atgaccttat gggactttcc tacttggcag tacatctacg 720

tattagtcat cgctattacc atggtgatgc ggttttggca gtacatcaat gggcgtggat 780

agcggtttga ctcacgggga tttccaagtc tccaccccat tgacgtcaat gggagtttgt 840

tttggcacca aaatcaacgg gactttccaa aatgtcgtaa caactccgcc ccattgacgc 900

aaatgggcgg taggcgtgta cggtgggagg tctatataag cagagctcgt ttagtgaacc 960

gtcagatcgc ctggagacgc catccacgct gttttgacct ccatagaaga caccgggacc 1020

gatccagcct ccgcggccgg gaacggtgca ttggaatcga tgactctctt aggtagcctt 1080

gcagaagttg gtcgtgaggc actgggcagg taagtatcaa ggttacaaga caggtttaag 1140

gagatcaata gaaactgggc ttgtcgagac agagaagact cttgcgtttc tgataggcac 1200

ctattggtct tactgacatc cactttgcct ttctctccac aggtgtccac tcccagttca 1260

attacagctc gccaccatgc ggttctccgc tcagctgctg ggccttctgg tgctgtggat 1320

tcccggcgtc tcgagatcta tcgatgcatg ccatggtacc aagcttgcca ccatgagcag 1380

cagctcttgg ctgctgctga gcctggtggc cgtgacagcc gcccagagca ccatcgagga 1440

gcaggccaag accttcctgg acaagttcaa ccacgaggcc gaggacctgt tctaccagag 1500

cagcctggcc agctggaact acaacaccaa catcaccgag gagaacgtgc agaacatgaa 1560

caacgccggc gacaagtgga gcgccttcct gaaggagcag agcacactgg cccagatgta 1620

ccccctgcag gagatccaga acctgaccgt gaagctgcag ctgcaggccc tgcagcagaa 1680

cggcagcagc gtgctgagcg aggacaagag caagcggctg aacaccatcc tgaacaccat 1740

gtccaccatc tacagcaccg gcaaagtgtg caaccccgac aacccccagg agtgcctgct 1800

gctggagccc ggcctgaacg agatcatggc caacagcctg gactacaacg agcggctgtg 1860

ggcctgggag agctggcgga gcgaagtggg caagcagctg cggcccctgt acgaggagta 1920

cgtggtgctg aagaacgaga tggccagggc caaccactac gaggactacg gcgactactg 1980

gagaggcgac tacgaagtga acggcgtgga cggctacgac tacagcagag gccagctgat 2040

cgaggacgtg gagcacacct tcgaggagat caagcctctg tacgagcacc tgcacgccta 2100

cgtgcgggcc aagctgatga acgcctaccc cagctacatc agccccatcg gctgcctgcc 2160

cgcccacctg ctgggcgaca tgtggggccg gttctggacc aacctgtaca gcctgaccgt 2220

gcccttcggc cagaagccca acatcgacgt gaccgacgcc atggtggacc aggcctggga 2280

cgcccagcgg atcttcaagg aggccgagaa gttcttcgtg agcgtgggcc tgcccaacat 2340

gacccagggc ttttgggaga acagcatgct gaccgacccc ggcaatgtgc agaaggccgt 2400

gtgccacccc accgcctggg acctgggcaa gggcgacttc cggatcctga tgtgcaccaa 2460

agtgaccatg gacgacttcc tgaccgccca ccacgagatg ggccacatcc agtacgacat 2520

ggcctacgcc gcccagccct tcctgctgcg gaacggcgcc aacgagggct ttcacgaggc 2580

cgtgggcgag atcatgagcc tgagcgccgc cacccccaag cacctgaaga gcatcggcct 2640

gctgagcccc gacttccagg aggacaacga gaccgagatc aacttcctgc tgaagcaggc 2700

cctgaccatc gtgggcaccc tgcccttcac ctacatgctg gagaagtggc ggtggatggt 2760

gtttaagggc gagatcccca aggaccagtg gatgaagaag tggtgggaga tgaagcggga 2820

gatcgtgggc gtggtggagc ccgtgcccca cgacgagacc tactgcgacc ccgccagcct 2880

gttccacgtg agcaacgact actccttcat ccggtactac acccggaccc tgtaccagtt 2940

ccagttccag gaggccctgt gccaggccgc caagcacgag ggccccctgc acaagtgcga 3000

catcagcaac agcaccgagg ccggacagaa actgttcaac atgctgcggc tgggcaagag 3060

cgagccctgg accctggccc tggagaatgt ggtgggcgcc aagaacatga atgtgcgccc 3120

cctgctgaac tacttcgagc ccctgttcac ctggctgaag gaccagaaca agaacagctt 3180

cgtgggctgg agcaccgact ggagccccta cgccgaccag agcatcaaag tgcggatcag 3240

cctgaagagc gccctgggcg acaaggccta cgagtggaac gacaacgaga tgtacctgtt 3300

ccggagcagc gtggcctatg ccatgcggca gtacttcctg aaagtgaaga accagatgat 3360

cctgttcggc gaggaggacg tgagagtggc caacctgaag ccccggatca gcttcaactt 3420

cttcgtgacc gcccccaaga acgtgagcga catcatcccc cggaccgaag tggagaaggc 3480

catccggatg agccggagcc ggatcaacga cgccttccgg ctgaacgaca actccctgga 3540

gttcctgggc atccagccca ccctgggccc tcccaaccag ccccccgtga gcatctggct 3600

gatcgtgttt ggcgtggtga tgggcgtgat cgtggtggga atcgtgatcc tgatcttcac 3660

cggcatccgg gaccggaaga agaagaacaa ggcccggagc ggcgagaacc cctacgccag 3720

catcgatatc agcaagggcg agaacaaccc cggcttccag aacaccgacg acgtgcagac 3780

cagcttctga taatctagaa cgagctcgaa ttcgaagctt ctgcagacgc gtcgacgtca 3840

tatggatccg atatcgccgt ggcggccgca ggccagccca aggccgctcc cagcgtgacc 3900

ctgttccccc cctcctccga ggagctgcag gccaacaagg ccaccctggt gtgcctcatc 3960

agcgacttct accctggcgc cgtgaccgtg gcctggaagg ccgacagcag ccccgtgaag 4020

gccggcgtgg agaccaccac ccccagcaag cagagcaaca acaagtacgc cgccagcagc 4080

tacctgagcc tcacccccga gcagtggaag agccaccgga gctacagctg ccaggtgacc 4140

cacgagggca gcaccgtgga gaagaccgtg gcccccaccg agtgcagcta atagacttaa 4200

gtttaaaccg ctgatcagcc tcgactgtgc cttctagttg ccagccatct gttgtttgcc 4260

cctcccccgt gccttccttg accctggaag gtgccactcc cactgtcctt tcctaataaa 4320

atgaggaaat tgcatcgcat tgtctgagta ggtgtcattc tattctgggg ggtggggtgg 4380

ggcaggacag caagggggag gattgggaag acaatagcag gcatgctggg gatgcggtgg 4440

gctctatggc ttctgaggcg gaaagaacca gctggggctc tagggggtat ccccacgcgc 4500

cctgtagcgg cgcattaagc gcggcgggtg tggtggttac gcgcagcgtg accgctacac 4560

ttgccagcgc cctagcgccc gctcctttcg ctttcttccc ttcctttctc gccacgttcg 4620

ccggctttcc ccgtcaagct ctaaatcggg ggctcccttt agggttccga tttagtgctt 4680

tacggcacct cgaccccaaa aaacttgatt agggtgatgg ttcacgtagt gggccatcgc 4740

cctgatagac ggtttttcgc cctttgacgt tggagtccac gttctttaat agtggactct 4800

tgttccaaac tggaacaaca ctcaacccta tctcggtcta ttcttttgat ttataaggga 4860

ttttggccat ttcggcctat tggttaaaaa atgagctgat ttaacaaaaa tttaacgcga 4920

attaattctg tggaatgtgt gtcagttagg gtgtggaaag tccccaggct ccccagcagg 4980

cagaagtatg caaagcatgc atctcaatta gtcagcaacc aggtgtggaa agtccccagg 5040

ctccccagca ggcagaagta tgcaaagcat gcatctcaat tagtcagcaa ccatagtccc 5100

gcccctaact ccgcccatcc cgcccctaac tccgcccagt tccgcccatt ctccgcccca 5160

tggctgacta atttttttta tttatgcaga ggccgaggcc gcctctgcct ctgagctatt 5220

ccagaagtag tgaggaggct tttttggagg cctaggcttt tgcaaaaagc tcccgggagc 5280

ttgtatatcc attttcggat ctgatcagca cgtgatgaaa aagcctgaac tcaccgcgac 5340

gtctgtcgag aagtttctga tcgaaaagtt cgacagcgtc tccgacctga tgcagctctc 5400

ggagggcgaa gaatctcgtg ctttcagctt cgatgtagga gggcgtggat atgtcctgcg 5460

ggtaaatagc tgcgccgatg gtttctacaa agatcgttat gtttatcggc actttgcatc 5520

ggccgcgctc ccgattccgg aagtgcttga cattggggaa ttcagcgaga gcctgaccta 5580

ttgcatctcc cgccgtgcac agggtgtcac gttgcaagac ctgcctgaaa ccgaactgcc 5640

cgctgttctg cagccggtcg cggaggccat ggatgcgatc gctgcggccg atcttagcca 5700

gacgagcggg ttcggcccat tcggaccgca aggaatcggt caatacacta catggcgtga 5760

tttcatatgc gcgattgctg atccccatgt gtatcactgg caaactgtga tggacgacac 5820

cgtcagtgcg tccgtcgcgc aggctctcga tgagctgatg ctttgggccg aggactgccc 5880

cgaagtccgg cacctcgtgc acgcggattt cggctccaac aatgtcctga cggacaatgg 5940

ccgcataaca gcggtcattg actggagcga ggcgatgttc ggggattccc aatacgaggt 6000

cgccaacatc ttcttctgga ggccgtggtt ggcttgtatg gagcagcaga cgcgctactt 6060

cgagcggagg catccggagc ttgcaggatc gccgcggctc cgggcgtata tgctccgcat 6120

tggtcttgac caactctatc agagcttggt tgacggcaat ttcgatgatg cagcttgggc 6180

gcagggtcga tgcgacgcaa tcgtccgatc cggagccggg actgtcgggc gtacacaaat 6240

cgcccgcaga agcgcggccg tctggaccga tggctgtgta gaagtactcg ccgatagtgg 6300

aaaccgacgc cccagcactc gtccgagggc aaaggaatag cacgtgctac gagatttcga 6360

ttccaccgcc gccttctatg aaaggttggg cttcggaatc gttttccggg acgccggctg 6420

gatgatcctc cagcgcgggg atctcatgct ggagttcttc gcccacccca acttgtttat 6480

tgcagcttat aatggttaca aataaagcaa tagcatcaca aatttcacaa ataaagcatt 6540

tttttcactg cattctagtt gtggtttgtc caaactcatc aatgtatctt atcatgtctg 6600

tataccgtcg acctctagct agagcttggc gtaatcatgg tcatagctgt ttcctgtgtg 6660

aaattgttat ccgctcacaa ttccacacaa catacgagcc ggaagcataa agtgtaaagc 6720

ctggggtgcc taatgagtga gctaactcac attaattgcg ttgcgctcac tgcccgcttt 6780

ccagtcggga aacctgtcgt gccagctgca ttaatgaatc ggccaacgcg cggggagagg 6840

cggtttgcgt attgggcgct cttccgcttc ctcgctcact gactcgctgc gctcggtcgt 6900

tcggctgcgg cgagcggtat cagctcactc aaaggcggta atacggttat ccacagaatc 6960

aggggataac gcaggaaaga acatgtgagc aaaaggccag caaaaggcca ggaaccgtaa 7020

aaaggccgcg ttgctggcgt ttttccatag gctccgcccc cctgacgagc atcacaaaaa 7080

tcgacgctca agtcagaggt ggcgaaaccc gacaggacta taaagatacc aggcgtttcc 7140

ccctggaagc tccctcgtgc gctctcctgt tccgaccctg ccgcttaccg gatacctgtc 7200

cgcctttctc ccttcgggaa gcgtggcgct ttctcatagc tcacgctgta ggtatctcag 7260

ttcggtgtag gtcgttcgct ccaagctggg ctgtgtgcac gaaccccccg ttcagcccga 7320

ccgctgcgcc ttatccggta actatcgtct tgagtccaac ccggtaagac acgacttatc 7380

gccactggca gcagccactg gtaacaggat tagcagagcg aggtatgtag gcggtgctac 7440

agagttcttg aagtggtggc ctaactacgg ctacactaga agaacagtat ttggtatctg 7500

cgctctgctg aagccagtta ccttcggaaa aagagttggt agctcttgat ccggcaaaca 7560

aaccaccgct ggtagcggtt tttttgtttg caagcagcag attacgcgca gaaaaaaagg 7620

atctcaagaa gatcctttga tcttttctac ggggtctgac gctcagtgga acgaaaactc 7680

acgttaaggg attttggtca tgagattatc aaaaaggatc ttcacctaga tccttttaaa 7740

ttaaaaatga agttttaaat caatctaaag tatatatgag taaacttggt ctgacagtta 7800

ccaatgctta atcagtgagg cacctatctc agcgatctgt ctatttcgtt catccatagt 7860

tgcctgactc cccgtcgtgt agataactac gatacgggag ggcttaccat ctggccccag 7920

tgctgcaatg ataccgcgag acccacgctc accggctcca gatttatcag caataaacca 7980

gccagccgga agggccgagc gcagaagtgg tcctgcaact ttatccgcct ccatccagtc 8040

tattaattgt tgccgggaag ctagagtaag tagttcgcca gttaatagtt tgcgcaacgt 8100

tgttgccatt gctacaggca tcgtggtgtc acgctcgtcg tttggtatgg cttcattcag 8160

ctccggttcc caacgatcaa ggcgagttac atgatccccc atgttgtgca aaaaagcggt 8220

tagctccttc ggtcctccga tcgttgtcag aagtaagttg gccgcagtgt tatcactcat 8280

ggttatggca gcactgcata attctcttac tgtcatgcca tccgtaagat gcttttctgt 8340

gactggtgag tactcaacca agtcattctg agaatagtgt atgcggcgac cgagttgctc 8400

ttgcccggcg tcaatacggg ataataccgc gccacatagc agaactttaa aagtgctcat 8460

cattggaaaa cgttcttcgg ggcgaaaact ctcaaggatc ttaccgctgt tgagatccag 8520

ttcgatgtaa cccactcgtg cacccaactg atcttcagca tcttttactt tcaccagcgt 8580

ttctgggtga gcaaaaacag gaaggcaaaa tgccgcaaaa aagggaataa gggcgacacg 8640

gaaatgttga atactcatac tcttcctttt tcaatattat tgaagcattt atcagggtta 8700

ttgtctcatg agcggataca tatttgaatg tatttagaaa aataaacaaa taggggttcc 8760

gcgcacattt ccccgaaaag tgccacctga cg 8792

<210>144

<211>23

<212>DNA

<213>Artificial

<220>

<223>Primer OK1(HuVK1B)

<400>144

gacatccagw tgacccagtc tcc 23

<210>145

<211>23

<212>DNA

<213>Artificial

<220>

<223>Primer OK2(HuVK2)

<400>145

gatgttgtga tgactcagtc tcc 23

<210>146

<211>23

<212>DNA

<213>Artificial

<220>

<223>Primer OK3(HuVK2B2)

<400>146

gatattgtga tgacccagac tcc 23

<210>147

<211>23

<212>DNA

<213>Artificial

<220>

<223>Primer OK4(HuVK3B)

<400>147

gaaattgtgw tgacrcagtc tcc 23

<210>148

<211>23

<212>DNA

<213>Artificial

<220>

<223>Primer OK5(HuVK5)

<400>148

gaaacgacac tcacgcagtc tcc 23

<210>149

<211>23

<212>DNA

<213>Artificial

<220>

<223>Primer OK6(HuVK6)

<400>149

gaaattgtgc tgactcagtc tcc 23

<210>150

<211>24

<212>DNA

<213>Artificial

<220>

<223>Primer OCK(HuCK)

<400>150

acactctccc ctgttgaagc tctt 24

<210>151

<211>23

<212>DNA

<213>Artificial

<220>

<223>Primer OL1(HuVL1A)

<400>151

cagtctgtgc tgactcagcc acc 23

<210>152

<211>23

<212>DNA

<213>Artificial

<220>

<223>Primer OL1(HuVL1B)

<400>152

cagtctgtgy tgacgcagcc gcc 23

<210>153

<211>23

<212>DNA

<213>Artificial

<220>

<223>Primer OL1(HuVL1C)

<400>153

cagtctgtcg tgacgcagcc gcc 23

<210>154

<211>20

<212>DNA

<213>Artificial

<220>

<223>OL2(HuVL2B)

<400>154

cagtctgccc tgactcagcc 20

<210>155

<211>23

<212>DNA

<213>Artificial

<220>

<223>OL3(HuVL3A)

<400>155

tcctatgwgc tgactcagcc acc 23

<210>156

<211>23

<212>DNA

<213>Artificial

<220>

<223>OL4(HuVL3B)

<400>156

tcttctgagc tgactcagga ccc 23

<210>157

<211>20

<212>DNA

<213>Artificial

<220>

<223>OL5(HuVL4B)

<400>157

cagcytgtgc tgactcaatc 20

<210>158

<211>23

<212>DNA

<213>Artificial

<220>

<223>OL6(HuVL5)

<400>158

caggctgtgc tgactcagcc gtc 23

<210>159

<211>23

<212>DNA

<213>Artificial

<220>

<223>OL7(HuVL6)

<400>159

aattttatgc tgactcagcc cca 23

<210>160

<211>23

<212>DNA

<213>Artificial

<220>

<223>OL8(HuVL7/8)

<400>160

cagrctgtgg tgacycagga gcc 23

<210>161

<211>23

<212>DNA

<213>Artificial

<220>

<223>OL9(HuVL9)

<400>161

cwgcctgtgc tgactcagcc mcc 23

<210>162

<211>18

<212>DNA

<213>Artificial

<220>

<223>OL9(HuVL10)

<400>162

caggcagggc tgactcag 18

<210>163

<211>23

<212>DNA

<213>Artificial

<220>

<223>OCL(HuCL2)

<400>163

tgaacattct gtaggggcca ctg 23

<210>164

<211>23

<212>DNA

<213>Artificial

<220>

<223>OCL(HuCL7)

<400>164

agagcattct gcaggggcca ctg 23

<210>165

<211>23

<212>DNA

<213>Artificial

<220>

<223>OH1(HuVH1B7A)

<400>165

cagrtgcagc tggtgcartc tgg 23

<210>166

<211>23

<212>DNA

<213>Artificial

<220>

<223>OH1(HuVH1C)

<400>166

saggtccagc tggtrcagtc tgg 23

<210>167

<211>23

<212>DNA

<213>Artificial

<220>

<223>OH2(HuVH2B)

<400>167

cagrtcacct tgaaggagtc tgg 23

<210>168

<211>18

<212>DNA

<213>Artificial

<220>

<223>OH3(HuVH3A)

<400>168

gaggtgcagc tggtggag 18

<210>169

<211>23

<212>DNA

<213>Artificial

<220>

<223>OH4(HuVH3C)

<400>169

gaggtgcagc tggtggagwc ygg 23

<210>170

<211>23

<212>DNA

<213>Artificial

<220>

<223>OH5(HuVH4B)

<400>170

caggtgcagc tacagcagtg ggg 23

<210>171

<211>23

<212>DNA

<213>Artificial

<220>

<223>OH6(HuVH4C)

<400>171

cagstgcagc tgcaggagtc sgg 23

<210>172

<211>23

<212>DNA

<213>Artificial

<220>

<223>OH7(HuVH6A)

<400>172

caggtacagc tgcagcagtc agg 23

<210>173

<211>24

<212>DNA

<213>Artificial

<220>

<223>OCM(HuCIgM)

<400>173

tggaagaggc acgttctttt cttt 24

<210>174

<211>41

<212>DNA

<213>Artificial

<220>

<223>OK1S(HuVK1B-SAL)

<400>174

tgagcacaca ggtcgacgga catccagwtg acccagtctc c 41

<210>175

<211>41

<212>DNA

<213>Artificial

<220>

<223>OK2S(HuVK2-SAL)

<400>175

tgagcacaca ggtcgacgga tgttgtgatg actcagtctc c 41

<210>176

<211>41

<212>DNA

<213>Artificial

<220>

<223>OK3S(HuVK2B2-SAL)

<400>176

tgagcacaca ggtcgacgga tattgtgatg acccagactc c 41

<210>177

<211>41

<212>DNA

<213>Artificial

<220>

<223>OK4S(HuVK3B-SAL)

<400>177

tgagcacaca ggtcgacgga aattgtgwtg acrcagtctc c 41

<210>178

<211>41

<212>DNA

<213>Artificial

<220>

<223>OK5S(HuVK5-SAL)

<400>178

tgagcacaca ggtcgacgga aacgacactc acgcagtctc c 41

<210>179

<211>41

<212>DNA

<213>Artificial

<220>

<223>OK6S(HuVK6-SAL)

<400>179

tgagcacaca ggtcgacgga aattgtgctg actcagtctc c 41

<210>180

<211>48

<212>DNA

<213>Artificial

<220>

<223>OJK1(HuJK1-NOT)

<400>180

gagtcattct cgacttgcgg ccgcacgttt gatttccacc ttggtccc 48

<210>181

<211>48

<212>DNA

<213>Artificial

<220>

<223>OJK2(HuJK2-NOT)

<400>181

gagtcattct cgacttgcgg ccgcacgttt gatctccagc ttggtccc 48

<210>182

<211>48

<212>DNA

<213>Artificial

<220>

<223>OJK3(HuJK3-NOT)

<400>182

gagtcattct cgacttgcgg ccgcacgttt gatatccact ttggtccc 48

<210>183

<211>48

<212>DNA

<213>Artificial

<220>

<223>OJK4(HuJK4-NOT)

<400>183

gagtcattct cgacttgcgg ccgcacgttt gatctccacc ttggtccc 48

<210>184

<211>48

<212>DNA

<213>Artificial

<220>

<223>OJK5(HuJK5-NOT)

<400>184

gagtcattct cgacttgcgg ccgcacgttt aatctccagt cgtgtccc 48

<210>185

<211>41

<212>DNA

<213>Artificial

<220>

<223>OL1S(HuVL1A-SAL)

<400>185

tgagcacaca ggtcgacgca gtctgtgctg actcagccac c 41

<210>186

<211>41

<212>DNA

<213>Artificial

<220>

<223>OL1S(HuVL1B-SAL)

<400>186

tgagcacaca ggtcgacgca gtctgtgytg acgcagccgc c 41

<210>187

<211>41

<212>DNA

<213>Artificial

<220>

<223>OL1S(HuVL1C-SAL)

<400>187

tgagcacaca ggtcgacgca gtctgtcgtg acgcagccgc c 41

<210>188

<211>38

<212>DNA

<213>Artificial

<220>

<223>OL2S(HuVL2B-SAL)

<400>188

tgagcacaca ggtcgacgca gtctgccctg actcagcc 38

<210>189

<211>41

<212>DNA

<213>Artificial

<220>

<223>OL3S(HuVL3A-SAL)

<400>189

tgagcacaca ggtcgacgtc ctatgwgctg actcagccac c 41

<210>190

<211>41

<212>DNA

<213>Artificial

<220>

<223>OL4S(HuVL3B-SAL)

<400>190

tgagcacaca ggtcgacgtc ttctgagctg actcaggacc c 41

<210>191

<211>38

<212>DNA

<213>Artificial

<220>

<223>OL5S(HuVL4B-SAL)

<400>191

tgagcacaca ggtcgacgca gcytgtgctg actcaatc 38

<210>192

<211>41

<212>DNA

<213>Artificial

<220>

<223>OL6S(HuVL5-SAL)

<400>192

tgagcacaca ggtcgacgca ggctgtgctg actcagccgt c 41

<210>193

<211>41

<212>DNA

<213>Artificial

<220>

<223>OL7S(HuVL6-SAL)

<400>193

tgagcacaca ggtcgacgaa ttttatgctg actcagcccc a 41

<210>194

<211>41

<212>DNA

<213>Artificial

<220>

<223>OL8S(HuVL7/8-SAL)

<400>194

tgagcacaca ggtcgacgca grctgtggtg acycaggagc c 41

<210>195

<211>41

<212>DNA

<213>Artificial

<220>

<223>OL9S(HuVL9-SAL)

<400>195

tgagcacaca ggtcgacgcw gcctgtgctg actcagccmc c 41

<210>196

<211>36

<212>DNA

<213>Artificial

<220>

<223>OL9S(HuVL10-SAL)

<400>196

tgagcacaca ggtcgacgca ggcagggctg actcag 36

<210>197

<211>48

<212>DNA

<213>Artificial

<220>

<223>OJL1(HuJL1-NOT)

<400>197

gagtcattct cgacttgcgg ccgcacctag gacggtgacc ttggtccc 48

<210>198

<211>48

<212>DNA

<213>Artificial

<220>

<223>OJL2(HuJL2/3-NOT)

<400>198

gagtcattct cgacttgcgg ccgcacctag gacggtcagc ttggtccc 48

<210>199

<211>48

<212>DNA

<213>Artificial

<220>

<223>OJL3(HuJL7-NOT)

<400>199

gagtcattct cgacttgcgg ccgcaccgag gacggtcagc tgggtgcc 48

<210>200

<211>56

<212>DNA

<213>Artificial

<220>

<223>OH1S(HuVH1B-SFI)

<400>200

gtcctcgcaa ctgcggccca gccggccatg gcccagrtgc agctggtgca rtctgg 56

<210>201

<211>56

<212>DNA

<213>Artificial

<220>

<223>OH1S(HuVH1C-SFI)

<400>201

gtcctcgcaa ctgcggccca gccggccatg gccsaggtcc agctggtrca gtctgg 56

<210>202

<211>56

<212>DNA

<213>Artificial

<220>

<223>OH2S(HuVH2B-SFI)

<400>202

gtcctcgcaa ctgcggccca gccggccatg gcccagrtca ccttgaagga gtctgg 56

<210>203

<211>51

<212>DNA

<213>Artificial

<220>

<223>OH3S(HuVH3A-SFI)

<400>203

gtcctcgcaa ctgcggccca gccggccatg gccgaggtgc agctggtgga g 51

<210>204

<211>56

<212>DNA

<213>Artificial

<220>

<223>OH4S(HuVH3C-SFI)

<400>204

gtcctcgcaa ctgcggccca gccggccatg gccgaggtgc agctggtgga gwcygg 56

<210>205

<211>56

<212>DNA

<213>Artificial

<220>

<223>OH5S(HuVH4B-SFI)

<400>205

gtcctcgcaa ctgcggccca gccggccatg gcccaggtgc agctacagca gtgggg 56

<210>206

<211>56

<212>DNA

<213>Artificial

<220>

<223>OH6S(HuVH4C-SFI)

<400>206

gtcctcgcaa ctgcggccca gccggccatg gcccagstgcagctgcagga gtcsgg 56

<210>207

<211>56

<212>DNA

<213>Artificial

<220>

<223>OH7S(HuVH6A-SFI)

<400>207

gtcctcgcaa ctgcggccca gccggccatg gcccaggtac agctgcagca gtcagg 56

<210>208

<211>36

<212>DNA

<213>Artificial

<220>

<223>OJH1(HuJH1/2-XHO)

<400>208

gagtcattct cgactcgaga crgtgaccag ggtgcc 36

<210>209

<211>36

<212>DNA

<213>Artificial

<220>

<223>OJH2(HuJH3-XHO)

<400>209

gagtcattct cgactcgaga cggtgaccat tgtccc 36

<210>210

<211>36

<212>DNA

<213>Artificial

<220>

<223>OJH3(HuJH4/5-XHO)

<400>210

gagtcattct cgactcgaga cggtgaccag ggttcc 36

<210>211

<211>36

<212>DNA

<213>Artificial

<220>

<223>OJH4(HuJH6-XHO)

<400>211

gagtcattct cgactcgaga cggtgaccgt ggtccc 36

<210>212

<211>735

<212>DNA

<213>Artificial

<220>

<223>SC06-141

<220>

<221>CDS

<222>(1)..(735)

<210>213

<211>245

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>213

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 Gly Tyr

20 25 30

Tyr Val Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Arg Ser Leu Asp Val Trp Gly Gln Gly Thr Thr Val Thr

100 105 110

Val Ser Ser Gly Thr Gly Gly Ser Gly Gly Thr Gly Ser Gly Thr Gly

115 120 125

Gly Ser Thr Asp Val Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val

130 135 140

Ser Leu Gly Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val

145 150 155 160

Leu Tyr Ser Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys

165 170 175

Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu

180 185 190

Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe

195 200 205

Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr

210 215 220

Cys Gln Gln Tyr Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys

225 230 235 240

Val Asp Ile Lys Arg

245

<210>214

<211>741

<212>DNA

<213>Artificial

<220>

<223>SC06-272

<220>

<221>CDS

<222>(1)..(741)

<210>215

<211>247

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>215

Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr

20 25 30

Ala Ile Thr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Gly Met Phe Gly Ser Thr Asn Tyr Ala Gln Asn Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Thr Gly Tyr Tyr Pro Ala Tyr Leu His His Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly Thr

115 120 125

Gly Ser Gly Thr Gly Gly Ser Thr Gln Ser Ala Leu Thr Gln Pro Arg

130 135 140

Ser Val Ser Gly Ser Pro Gly Gln Ser Val Thr Ile Ser Cys Thr Gly

145 150 155 160

Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln

165 170 175

His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr Asp Val Ser Lys Arg

180 185 190

Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr

195 200 205

Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr

210 215 220

Tyr Cys Ser Ser Tyr Thr Ser Ser Ser Thr His Val Phe Gly Thr Gly

225 230 235 240

Thr Lys Val Thr Val Leu Gly

245

<210>216

<211>738

<212>DNA

<213>Artificial

<220>

<223>SC06-296

<220>

<221>CDS

<222>(1)..(738)

<210>217

<211>246

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>217

Glu Val Gln Leu Val Glu Thr 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

Tyr Met 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 Gly Thr Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Glu Gly Lys Trp Gly Pro Gln Ala Ala Phe Asp Ile Trp Gly

100 105 110

Gln Gly Thr Met Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly

115 120 125

Thr Gly Ser Gly Thr Gly Gly Ser Thr Glu Ile Val Met Thr Gln Ser

130 135 140

Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys

145 150 155 160

Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln

165 170 175

Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Asp Ala Ser Ser Arg

180 185 190

Ala Thr Asp Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp

195 200 205

Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr

210 215 220

Tyr Cys Gln Gln Tyr Gly Ser Ser Leu Trp Thr Phe Gly Gln Gly Thr

225 230 235 240

Lys Val Glu Ile Lys Arg

245

<210>218

<211>738

<212>DNA

<213>Artificial

<220>

<223>SC06-301

<220>

<221>CDS

<222>(1)..(738)

<210>219

<211>246

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<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 Phe Ser Ile Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Ser Ser Gly Asp Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg 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 Ala Tyr Gly Tyr Thr Phe Asp Pro Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly Thr Gly Ser Gly

115 120 125

Thr Gly Gly Ser Thr Glu Ile Val Leu Thr Gln Ser Pro Leu Ser Leu

130 135 140

Pro Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln

145 150 155 160

Ser Leu Leu His Ser Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln

165 170 175

Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg

180 185 190

Ala Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp

195 200 205

Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr

210 215 220

Tyr Cys Met Gln Ala Leu Gln Thr Pro Leu Thr Phe Gly Gly Gly Thr

225 230 235 240

Lys Val Glu Ile Lys Arg

245

<210>220

<211>738

<212>DNA

<213>Artificial

<220>

<223>SC06-327

<220>

<221>CDS

<222>(1)..(738)

<210>221

<211>246

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>221

Glu Val Gln Leu Val Glu Thr Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Arg Thr His

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Ala Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Ile Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys

85 90 95

Ala Arg Gly Ser Gly Tyr His Ile Ser Thr Pro Phe Asp Asn Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly

115 120 125

Thr Gly Ser Gly Thr Gly Gly Ser Thr Ser Tyr Val Leu Thr Gln Pro

130 135 140

Pro Ser Val Ser Val Ala Pro Gly Gln Thr Ala Arg Ile Thr Cys Gly

145 150 155 160

Gly Asn Asn Ile Gly Ser Lys Gly Val His Trp Tyr Gln Gln Lys Pro

165 170 175

Gly Gln Ala Pro Val Leu Val Val Tyr Asp Asp Ser Asp Arg Pro Ser

180 185 190

Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn Thr Ala Thr

195 200 205

Leu Thr Ile Ser Arg Val Glu Ala Gly Asp Glu Ala Asp Tyr Tyr Cys

210 215 220

Gln Val Trp Asp Ser Ser Ser Asp His Val Val Phe Gly Gly Gly Thr

225 230 235 240

Lys Leu Thr Val Leu Gly

245

<210>222

<211>756

<212>DNA

<213>Artificial

<220>

<223>SC06-328

<220>

<221>CDS

<222>(1)..(756)

<210>223

<211>252

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>223

Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly His Ile Phe Ser Gly Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Ile Phe Gly Thr Thr Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Gln Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Asp Leu Ser Asn Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Val Lys Asp Gly Tyr Cys Thr Leu Thr Ser Cys Pro Val Gly

100 105 110

Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser

115 120 125

Gly Thr Gly Gly Ser Gly Gly Thr Gly Ser Gly Thr Gly Gly Ser Thr

130 135 140

Glu Ile Val Met Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

145 150 155 160

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

165 170 175

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

180 185 190

Ile Phe Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

195 200 205

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

210 215 220

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Leu

225 230 235 240

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg

245 250

<210>224

<211>738

<212>DNA

<213>Artificial

<220>

<223>SC06-329

<220>

<221>CDS

<222>(1)..(738)

<210>225

<211>246

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>225

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Ile Phe Arg Ser Asn

20 25 30

Ser Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Phe Ala Leu Phe Gly Thr Thr Asp Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Ser Thr Thr Val Tyr

65 70 75 80

Leu Glu Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Ser Gly Tyr Thr Thr Arg Asn Tyr Phe Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly

115 120 125

Thr Gly Ser Gly Thr Gly Gly Ser Thr Glu Ile Val Leu Thr Gln Ser

130 135 140

Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys

145 150 155 160

Arg Ala Ser Gln Ser Val Ser Ser Asn Tyr Leu Gly Trp Tyr Gln Gln

165 170 175

Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg

180 185 190

Ala Ser Gly Ile Pro Asp Arg Phe Ser Gly Gly Gly Ser Gly Thr Asp

195 200 205

Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr

210 215 220

Tyr Cys Gln Gln Tyr Gly Ser Ser Pro Leu Thr Phe Gly Gly Gly Thr

225 230 235 240

Lys Val Glu Ile Lys Arg

245

<210>226

<211>729

<212>DNA

<213>Artificial

<220>

<223>SC06-332

<220>

<221>CDS

<222>(1)..(729)

<210>227

<211>243

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>227

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Pro Phe Arg Asn Phe

20 25 30

Ala Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Ala Val Phe Gly Thr Thr Lys Tyr Ala His Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Asp Ser Thr Asn Thr Ala Tyr

65 70 75 80

Met Glu Leu Gly Ser Leu Lys Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Pro His Tyr Tyr Ser Ser Tyr Met Asp Val Trp Gly Glu

100 105 110

Gly Thr Thr Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly Thr

115 120 125

Gly Ser Gly Thr Gly Gly Ser Thr Asp Ile Gln Leu Thr Gln Ser Pro

130 135 140

Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg

145 150 155 160

Ala Ser Gln Gly Ile Ser Thr Tyr Leu Ala Trp Tyr Gln Gln Lys Pro

165 170 175

Gly Lys Val Pro Lys Leu Leu Ile Tyr Ala Ala Ser Thr Leu Gln Ser

180 185 190

Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr

195 200 205

Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys

210 215 220

Gln Lys Tyr Asn Ser Ala Pro Ser Phe Gly Pro Gly Thr Lys Val Asp

225 230 235 240

Ile Lys Arg

<210>228

<211>735

<212>DNA

<213>Artificial

<220>

<223>SC06-334

<220>

<221>CDS

<222>(1)..(735)

<210>229

<211>245

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>229

Glu Val Gln Leu Val Glu Thr Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Sar Val Lys Val Pro Cys Lys Ser Ser Gly Ser Pro Phe Arg Ser Asn

20 25 30

Ala Val Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu GluTrp Val

35 40 45

Gly Gly Ile Leu Gly Val Phe Gly Ser Pro Ser Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Asn Thr Val His

65 70 75 80

Met Glu Leu Arg Gly Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Pro Thr Tyr Tyr Tyr Ser Tyr Met Asp Val Trp Gly Lys

100 105 110

Gly Thr Thr Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly Thr

115 120 125

Gly Ser Gly Thr Gly Gly Ser Thr Ser Tyr Val Leu Thr Gln Pro Pro

130 135 140

Ser Glu Ser Val Ala Pro Gly Gln Thr Ala Arg Ile Thr Cys Gly Gly

145 150 155 160

Asn Asn Ile Gly Arg Asn Ser Val His Trp Tyr Gln Gln Lys Pro Gly

165 170 175

Gln Ala Pro Val Leu Val Val Tyr Asp Asp Ser Asp Arg Pro Ser Gly

180 185 190

Ile Pro Glu Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Thr Leu

195 200 205

Ile Ile Ser Arg Val Glu Val Gly Asp Glu Ala Asp Tyr Tyr Cys Gln

210 215 220

Val Trp His Ser Ser Ser Asp His Tyr Val Phe Gly Thr Gly Thr Lys

225 230 235 240

Val Thr Val Leu Gly

245

<210>230

<211>735

<212>DNA

<213>Artificial

<220>

<223>SC06-336

<220>

<221>CDS

<222>(1)..(735)

<210>231

<211>245

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>231

Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Phe Gly Met Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Phe Thr Ser Ala Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Gly Ser Glu Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg Ser Ser Gly Tyr Tyr Pro Gln Tyr Phe Gln Asp Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly Thr

115 120 125

Gly Ser Gly Thr Gly Gly Ser Thr Glu Ile Val Met Thr Gln Ser Pro

130 135 140

Gly Thr Leu Ser Leu Ser Pro Gly Gln Arg Ala Thr Leu Ser Cys Arg

145 150 155 160

Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys

165 170 175

Pro Gly Gln Ala Pro Arg Leu Leu Met Tyr Gly Ala Ser Ser Arg Ala

180 185 190

Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe

195 200 205

Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr

210 215 220

Cys Gln Gln Tyr Gly Ser Ser Ser Leu Thr Phe Gly Gly Gly Thr Lys

225 230 235 240

Leu Glu Ile Lys Arg

245

<210>232

<211>738

<212>DNA

<213>Artificial

<220>

<223>SC06-339

<220>

<221>CDS

<222>(1)..(738)

<210>233

<211>246

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>233

Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Ile Phe Asn Ser Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Ala Ile Phe His Thr Pro Lys Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Asn Thr Ala Tyr

65 70 75 80

Met Glu Leu Arg Ser Leu Lys Ser Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Gly Ser Thr Tyr Asp Phe Ser Ser Gly Leu Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly

115 120 125

Thr Gly Ser Gly Thr Gly Gly Ser Thr Gln Ala Gly Leu Thr Gln Pro

130 135 140

Pro Ser Val Ser Val Ala Pro Gly Gln Thr Ala Arg Ile Thr Cys Gly

145 150 155 160

Gly Asn Asn Ile Gly Ser Lys Ser Val His Trp Tyr Gln Gln Lys Pro

165 170 175

Gly Gln Ala Pro Val Leu Val Val Tyr Asp Asp Ser Asp Arg Pro Ser

180 185 190

Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn Thr Ala Thr

195 200 205

Leu Thr Ile Ser Arg Val Glu Ala Gly Asp Glu Ala Asp Tyr Tyr Cys

210 215 220

Gln Val Trp Asp Ser Ser Ser Asp His Val Val Phe Gly Gly Gly Thr

225 230 235 240

Lys Leu Thr Val Leu Gly

245

<210>234

<211>768

<212>DNA

<213>Artificial

<220>

<223>SC06-342

<220>

<221>CDS

<222>(1)..(768)

<210>235

<211>256

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>235

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Phe Phe Ser Ser Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Val Ile Pro Ile Phe Arg Thr Ala Asn Tyr Ala Gln Asn Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Phe Thr Ser Tyr Met Glu

65 70 75 80

Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg

85 90 95

Leu Asn Tyr His Asp Ser Gly Thr Tyr Tyr Asn Ala Pro Arg Gly Trp

100 105 110

Phe Asp Pro Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Thr

115 120 125

Gly Gly Ser Gly Gly Thr Gly Ser Gly Thr Gly Gly Ser Thr Asp Ile

130 135 140

Gln Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly Glu Lys

145 150 155 160

Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Ile Leu Asn Ser Ser Asn

165 170 175

Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro

170 185 190

Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val Pro Asp

195 200 205

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser

210 215 220

Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Tyr Tyr

225 230 235 240

Ser Ser Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg

245 250 255

<210>236

<211>735

<212>DNA

<213>Artificial

<220>

<223>SC06-343

<220>

<221>CDS

<222>(1)..(735)

<210>237

<211>245

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>237

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Val Thr Phe Ser Tyr Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ser Pro Met Phe Gly Thr Thr Thr Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Asp Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Val Arg Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Ser Asn Tyr Tyr Asp Ser Val Tyr Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly Thr

115 120 125

Gly Ser Gly Thr Gly Gly Ser Thr Gln Ser Val Val Thr Gln Pro Pro

130 135 140

Ser Glu Ser Val Ala Pro Gly Gln Thr Ala Arg Ile Thr Cys Gly Gly

145 150 155 160

His Asn Ile Gly Ser Asn Ser Val His Trp Tyr Gln Gln Lys Pro Gly

165 170 175

Gln Ala Pro Val Leu Val Val Tyr Asp Asn Ser Asp Arg Pro Ser Gly

180 185 190

Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn Thr Ala Thr Leu

195 200 205

Thr Ile Ser Arg Val Glu Ala Gly Asp Glu Ala Asp Tyr Tyr Cys Gln

210 215 220

Val Trp Gly Ser Ser Ser Asp His Tyr Val Phe Gly Thr Gly Thr Lys

225 230 235 240

Val Thr Val Leu Gly

245

<210>238

<211>5

<212>PRT

<213>Homo sapiens

<400>238

Gly Tyr Tyr Val Tyr

1 5

<210>239

<211>17

<212>PRT

<213>Homo sapiens

<400>239

Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Phe Gln

1 5 10 15

Gly

<210>240

<211>6

<212>PRT

<213>Homo sapiens

<400>240

Ser Arg Ser Leu Asp Val

1 5

<210>241

<211>17

<212>PRT

<213>Homo sapiens

<400>241

Lys Ser Ser Gln Ser Val Leu Tyr Ser Ser Asn Asn Lys Asn Tyr Leu

1 5 10 15

Ala

<210>242

<211>7

<212>PRT

<213>Homo sapiens

<400>242

Trp Ala Ser Thr Arg Glu Ser

1 5

<210>243

<211>9

<212>PRT

<213>Homo sapiens

<400>243

Gln Gln Tyr Tyr Ser Thr Pro Leu Thr

1 5

<210>244

<211>5

<212>PRT

<213>Homo sapiens

<400>244

Ser Tyr Ala Ile Thr

1 5

<210>245

<211>17

<212>PRT

<213>Homo sapiens

<400>245

Gly Ile Ile Gly Met Phe Gly Ser Thr Asn Tyr Ala Gln Asn Phe Gln

1 5 10 15

Gly

<210>246

<211>11

<212>PRT

<213>Homo sapiens

<400>246

Ser Thr Gly Tyr Tyr Pro Ala Tyr Leu His His

1 5 10

<210>247

<211>14

<212>PRT

<213>Homo sapiens

<400>247

Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser

1 5 10

<210>248

<211>7

<212>PRT

<213>Homo sapiens

<400>248

Asp Val Ser Lys Arg Pro Ser

1 5

<210>249

<211>10

<212>PRT

<213>Homo sapiens

<400>249

Ser Ser Tyr Thr Ser Ser Ser Thr His Val

1 5 10

<210>250

<211>5

<212>PRT

<213>Homo sapiens

<400>250

Ser Tyr Tyr Met His

1 5

<210>251

<211>17

<212>PRT

<213>Homo sapiens

<400>251

Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe Gln

1 5 10 15

Gly

<210>252

<211>12

<212>PRT

<213>Homo sapiens

<400>252

Glu Gly Lys Trp Gly Pro Gln Ala Ala Phe Asp Ile

1 5 10

<210>253

<211>12

<212>PRT

<213>Homo sapiens

<400>253

Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala

1 5 10

<210>254

<211>7

<212>PRT

<213>Homo sapiens

<400>254

Asp Ala Ser Ser Arg Ala Thr

1 5

<210>255

<211>8

<212>PRT

<213>Homo sapiens

<400>255

Gln Gln Tyr Gly Ser Ser Leu Trp

1 5

<210>256

<211>5

<212>PRT

<213>Homo sapiens

<400>256

Ile Tyr Ala Met Ser

1 5

<210>257

<211>17

<212>PRT

<213>Homo sapiens

<400>257

Ala Ile Ser Ser Ser Gly Asp Ser Thr Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210>258

<211>8

<212>PRT

<213>Homo sapiens

<400>258

Ala Tyr Gly Tyr Thr Phe Asp Pro

1 5

<210>259

<211>16

<212>PRT

<213>Homo sapiens

<400>259

Arg Ser Ser Gln Ser Leu Leu His Ser Asn Gly Tyr Asn Tyr Leu Asp

1 5 10 15

<210>260

<211>7

<212>PRT

<213>Homo sapiens

<400>260

Leu Gly Ser Asn Arg Ala Ser

1 5

<210>261

<211>8

<212>PRT

<213>Homo sapiens

<400>261

Met Gln Ala Leu Gln Thr Pro Leu

1 5

<210>262

<211>5

<212>PRT

<213>Homo sapiens

<400>262

Thr His Ala Ile Ser

1 5

<210>263

<211>17

<212>PRT

<213>Homo sapiens

<400>263

Gly Ile Ile Ala Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe Gln

1 5 10 15

Gly

<210>264

<211>12

<212>PRT

<213>Homo sapiens

<400>264

Gly Ser Gly Tyr His Ile Ser Thr Pro Phe Asp Asn

1 5 10

<210>265

<211>11

<212>PRT

<213>Homo sapiens

<400>265

Gly Gly Asn Asn Ile Gly Ser Lys Gly Val His

1 5 10

<210>266

<211>7

<212>PRT

<213>Homo sapiens

<400>266

Asp Asp Ser Asp Arg Pro Ser

1 5

<210>267

<211>11

<212>PRT

<213>Homo sapiens

<400>267

Gln Val Trp Asp Ser Ser Ser Asp His Val Val

1 5 10

<210>268

<211>5

<212>PRT

<213>Homo sapiens

<400>268

Gly Tyr Ala Ile Ser

1 5

<210>269

<211>17

<212>PRT

<213>Homo sapiens

<400>269

Gly Ile Ile Pro Ile Phe Gly Thr Thr Asn Tyr Ala Gln Lys Phe Gln

1 5 10 15

Gly

<210>270

<211>19

<212>PRT

<213>Homo sapiens

<400>270

Val Lys Asp Gly Tyr Cys Thr Leu Thr Ser Cys Pro Val Gly Trp Tyr

1 5 10 15

Phe Asp Leu

<210>271

<211>12

<212>PRT

<213>Homo sapiens

<400>271

Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala Arg

1 5 10

<210>272

<211>7

<212>PRT

<213>Homo sapiens

<400>272

Gly Ala Ser Ser Arg Ala Thr

1 5

<210>273

<211>8

<212>PRT

<213>Homo sapiens

<400>273

Gln Gln Tyr Gly Ser Ser Leu Thr

1 5

<210>274

<211>5

<212>PRT

<213>Homo sapiens

<400>274

Ser Asn Ser Ile Ser

1 5

<210>275

<211>17

<212>PRT

<213>Homo sapiens

<400>275

Gly Ile Phe Ala Leu Phe Gly Thr Thr Asp Tyr Ala Gln Lys Phe Gln

1 5 10 15

Gly

<210>276

<211>12

<212>PRT

<213>Homo sapiens

<400>276

Gly Ser Gly Tyr Thr Thr Arg Asn Tyr Phe Asp Tyr

1 5 10

<210>277

<211>12

<212>PRT

<213>Homo sapiens

<400>277

Arg Ala Ser Gln Ser Val Ser Ser Asn Tyr Leu Gly

1 5 10

<210>278

<211>7

<212>PRT

<213>Homo sapiens

<400>278

Gly Ala Ser Ser Arg Ala Ser

1 5

<210>279

<211>9

<212>PRT

<213>Homo sapiens

<400>279

Gln Gln Tyr Gly Ser Ser Pro Leu Thr

1 5

<210>280

<211>5

<212>PRT

<213>Homo sapiens

<400>280

Asn Phe Ala Ile Asn

1 5

<210>281

<211>17

<212>PRT

<213>Homo sapiens

<400>281

Gly Ile Ile Ala Val Phe Gly Thr Thr Lys Tyr Ala His Lys Phe Gln

1 5 10 15

Gly

<210>282

<211>11

<212>PRT

<213>Homo sapiens

<400>282

Gly Pro His Tyr Tyr Ser Ser Tyr Met Asp Val

1 5 10

<210>283

<211>11

<212>PRT

<213>Homo sapiens

<400>283

Arg Ala Ser Gln Gly Ile Ser Thr Tyr Leu Ala

1 5 10

<210>284

<211>7

<212>PRT

<213>Homo sapiens

<400>284

Ala Ala Ser Thr Leu Gln Ser

1 5

<210>285

<211>8

<212>PRT

<213>Homo sapiens

<400>285

Gln Lys Tyr Asn Ser Ala Pro Ser

1 5

<210>286

<211>5

<212>PRT

<213>Homo sapiens

<400>286

Ser Asn Ala Val Ser

1 5

<210>287

<211>17

<212>PRT

<213>Homo sapiens

<400>287

Gly Ile Leu Gly Val Phe Gly Ser Pro Ser Tyr Ala Gln Lys Phe Gln

1 5 10 15

Gly

<210>288

<211>11

<212>PRT

<213>Homo sapiens

<400>288

Gly Pro Thr Tyr Tyr Tyr Ser Tyr Met Asp Val

1 5 10

<210>289

<211>11

<212>PRT

<213>Homo sapiens

<400>289

Gly Gly Asn Asn Ile Gly Arg Asn Ser Val His

1 5 10

<210>290

<211>7

<212>PRT

<213>Homo sapiens

<400>290

Asp Asp Ser Asp Arg Pro Ser

1 5

<210>291

<211>11

<212>PRT

<213>Homo sapiens

<400>291

Gln Val Trp His Ser Ser Ser Asp His Tyr Val

1 5 10

<210>292

<211>5

<212>PRT

<213>Homo sapiens

<400>292

Ser Tyr Ala Ile Ser

1 5

<210>293

<211>17

<212>PRT

<213>Homo sapiens

<400>293

Gly Ile Phe Gly Met Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe Gln

1 5 10 15

Gly

<210>294

<211>11

<212>PRT

<213>Homo sapiens

<400>294

Ser Ser Gly Tyr Tyr Pro Gln Tyr Phe Gln Asp

1 5 10

<210>295

<211>12

<212>PRT

<213>Homo sapiens

<400>295

Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala

1 5 10

<210>296

<211>7

<212>PRT

<213>Homo sapiens

<400>296

Gly Ala Ser Ser Arg Ala Thr

1 5

<210>297

<211>9

<212>PRT

<213>Homo sapiens

<400>297

Gln Gln Tyr Gly Ser Ser Ser Leu Thr

1 5

<210>298

<211>5

<212>PRT

<213>Homo sapiens

<400>298

Ser Tyr Ala Ile Ser

1 5

<210>299

<211>17

<212>PRT

<213>Homo sapiens

<400>299

Gly Ile Ile Ala Ile Phe His Thr Pro Lys Tyr Ala Gln Lys Phe Gln

1 5 10 15

Gly

<210>300

<211>12

<212>PRT

<213>Homo sapiens

<400>300

Gly Ser Thr Tyr Asp Phe Ser Ser Gly Leu Asp Tyr

1 5 10

<210>301

<211>11

<212>PRT

<213>Homo sapiens

<400>301

Gly Gly Asn Asn Ile Gly Ser Lys Ser Val His

1510

<210>302

<211>7

<212>PRT

<213>Homo sapiens

<400>302

Asp Asp Ser Asp Arg Pro Ser

1 5

<210>303

<211>11

<212>PRT

<213>Homo sapiens

<400>303

Gln Val Trp Asp Ser Ser Ser Asp His Val Val

1 5 10

<210>304

<211>5

<212>PRT

<213>Homo sapiens

<400>304

Ser Tyr Ala Ile Ser

1 5

<210>305

<211>17

<212>PRT

<213>Homo sapiens

<400>305

Gly Val Ile Pro Ile Phe Arg Thr Ala Asn Tyr Ala Gln Asn Phe Gln

1 5 10 15

Gly

<210>306

<211>19

<212>PRT

<213>Homo sapiens

<400>306

Leu Asn Tyr His Asp Ser Gly Thr Tyr Tyr Asn Ala Pro Arg Gly Trp

1 5 10 15

Phe Asp Pro

<210>307

<211>17

<212>PRT

<213>Homo sapiens

<400>307

Lys Ser Ser Gln Ser Ile Leu Asn Ser Ser Asn Asn Lys Asn Tyr Leu

1 5 10 15

Ala

<210>308

<211>7

<212>PRT

<213>Homo sapiens

<400>308

Trp Ala Ser Thr Arg Glu Ser

1 5

<210>309

<211>9

<212>PRT

<213>Homo sapiens

<400>309

Gln Gln Tyr Tyr Ser Ser Pro Pro Thr

1 5

<210>310

<211>5

<212>PRT

<213>Homo sapiens

<400>310

Tyr Tyr Ala Met Ser

1 5

<210>311

<211>17

<212>PRT

<213>Homo sapiens

<400>311

Gly Ile Ser Pro Met Phe Gly Thr Thr Thr Tyr Ala Gln Lys Phe Gln

1 5 10 15

Gly

<210>312

<211>11

<212>PRT

<213>Homo sapiens

<400>312

Ser Ser Asn Tyr Tyr Asp Ser Val Tyr Asp Tyr

1 5 10

<210>313

<211>11

<212>PRT

<213>Homo sapiens

<400>313

Gly Gly His Asn Ile Gly Ser Asn Ser Val His

1 5 10

<210>314

<211>7

<212>PRT

<213>Homo sapiens

<400>314

Asp Asn Ser Asp Arg Pro Ser

1 5

<210>315

<211>11

<212>PRT

<213>Homo sapiens

<400>315

Gln Val Trp Gly Ser Ser Ser Asp His Tyr Val

1 5 10

<210>316

<211>1335

<212>DNA

<213>Artificial

<220>

<223>CR6141 Heavy chain

<220>

<221>CDS

<222>(1)..(1335)

<210>317

<211>445

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>317

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 Gly Tyr

20 25 30

Tyr Val Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Arg Ser Leu Asp Val Trp Gly Gln Gly Thr Thr Val Thr

100 105 110

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

115 120 125

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

130 135 140

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

145 150 155 160

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

165 170 175

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

180 185 190

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

195 200 205

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

210 215 220

Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu

225 230 235 240

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

245 250 255

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

260 265 270

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

275 280 285

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

290 295 300

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

305 310 315 320

Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys

325 330 335

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

340 345 350

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

355 360 365

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

370 375 380

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

385 390 395 400

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

405 410 415

Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

420 425 430

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210>318

<211>657

<212>DNA

<213>Artificial

<220>

<223>CR6141 Light chain

<220>

<221>CDS

<222>(1)..(657)

<210>319

<211>219

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>319

Asp Val Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser

20 25 30

Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln

85 90 95

Tyr Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Asp Ile

100 105 110

Lys Arg Ala Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu

115 120 125

Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe

130 135 140

Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln

145 150 155 160

Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser

165 170 175

Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu

180 185 190

Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser

195 200 205

Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215

<210>320

<211>1350

<212>DNA

<213>Artificial

<220>

<223>CR6272 Heavy chain

<220>

<221>CDS

<222>(1)..(1350)

<211>450

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>321

Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr

20 25 30

Ala Ile Thr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Gly Met Phe Gly Ser Thr Asn Tyr Ala Gln Asn Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Thr Gly Tyr Tyr Pro Ala Tyr Leu His His Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val

115 120 125

Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala

130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser

145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

165 170 175

Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

180 185 190

Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys

195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp

210 215 220

Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly

285 230 235 240

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile

245 250 255

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu

260 265 270

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg

290 295 300

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys

305 310 315 320

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu

325 330 335

Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr

340 345 350

Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu

355 360 365

Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp

370 375 380

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val

385 390 395 400

Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp

405 410 415

Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His

420 425 430

Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

435 440 445

Gly Lys

450

<210>322

<211>660

<212>DNA

<213>Artificial

<220>

<223>CR6272 Light chain

<220>

<221>CDS

<222>(1)..(660)

<210>323

<211>220

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>323

Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln

1 5 10 15

Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr

20 25 30

Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu

35 40 45

Met Ile Tyr Asp Val Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe

50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu

65 70 75 80

Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser

85 90 95

Ser Thr His Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu Gly Ala

100 105 110

Ala Ala Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro

115 120 125

Ser Ser Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile

130 135 140

Ser Asp Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser

145 150 155 160

Ser Pro Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser

165 170 175

Asn Asn Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln

180 185 190

Trp Lys Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser

195 200 205

Thr Val Glu Lys Thr Val Ala Pro Thr Glu Cys Ser

210 215 220

<210>324

<211>1353

<212>DNA

<213>Artificial

<220>

<223>CR6296 Heavy chain

<220>

<221>CDS

<222>(1)..(1353)

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

435 440 445

ccc ggc aag 1353

Pro Gly Lys

450

<210>325

<211>451

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>325

Glu Val Gln Leu Val Glu Thr 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

Tyr Met 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 Gly Thr Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Glu Gly Lys Trp Gly Pro Gln Ala Ala Phe Asp Ile Trp Gly

100 105 110

Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser

115 120 125

Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala

130 135 140

Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val

145 150 155 160

Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala

165 170 175

Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val

180 185 190

Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His

195 200 205

Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys

210 215 220

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly

225 230 235 240

Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

245 250 255

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

260 265 270

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

275 280 285

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

290 295 300

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

305 310 315 320

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

325 330 335

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

340 345 350

Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser

355 360 365

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser As Ile Ala Val Glu

370 375 380

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

385 390 395 400

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

405 410 415

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

420 425 430

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

435 440 445

Pro Gly Lys

450

<210>326

<211>642

<212>DNA

<213>Artificial

<220>

<223>CR6296 Light chain

<220>

<221>CDS

<222>(1)..(642)

<210>327

<211>214

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>327

Glu Ile Val Met 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 Asp Ala Ser Ser Arg Ala Thr Asp 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 Leu

85 90 95

Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Ala Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210>328

<211>1341

<212>DNA

<213>Artificial

<220>

<223>CR6301 Heavy chain

<220>

<221>CDS

<222>(1)..(1341)

<210>329

<211>447

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>329

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 Phe Ser Ile Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Ser Ser Gly Asp Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg 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 Ala Tyr Gly Tyr Thr Phe Asp Pro Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu

115 120 125

Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys

130 135 140

Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser

145 150 155 160

Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser

165 170 175

Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser

180 185 190

Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn

195 200 205

Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His

210 215 220

Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val

225 230 235 240

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr

245 250 255

Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu

260 265 270

Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys

275 280 285

Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser

290 295 300

Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys

305 310 315 320

Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile

325 330 335

Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro

340 345 350

Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu

355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn

370 375 380

Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser

385 390 395 400

Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg

405 410 415

Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu

420 425 430

His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210>330

<211>654

<212>DNA

<213>Artificial

<220>

<223>CR6301 Light chain

<220>

<221>CDS

<222>(1)..(654)

<210>331

<211>218

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>331

Glu Ile Val Leu Thr Gln Ser 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 Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105 110

Arg Ala Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln

115 120 125

Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr

130 135 140

Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser

145 150 155 160

Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr

165 170 175

Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys

180 185 190

His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro

195 200 205

Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215

<210>332

<211>1353

<212>DNA

<213>Artificial

<220>

<223>CR6327 Heavy chain

<220>

<221>CDS

<222>(1)..(1353)

<210>333

<211>451

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>333

Glu Val Gln Leu Val Glu Thr Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Arg Thr His

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Ala Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Ile Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys

85 90 95

Ala Arg Gly Ser Gly Tyr His Ile Ser Thr Pro Phe Asp Asn Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser

115 120 125

Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala

130 135 140

Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val

145 150 155 160

Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala

165 170 175

Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val

180 185 190

Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His

195 200 205

Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys

210 215 220

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly

225 230 235 240

Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

245 250 255

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

260 265 270

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

275 280 285

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

290 295 300

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

305 310 315 320

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

325 330 335

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

340 345 350

Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser

355 360 365

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

370 375 380

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

385 390 395 400

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

405 410 415

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

420 425 430

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

435 440 445

Pro Gly Lys

450

<210>334

<211>654

<212>DNA

<213>Artificial

<220>

<223>CR6327 Light chain

<220>

<221>CDS

<222>(1)..(654)

<210>335

<211>218

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>335

Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Gln

1 5 10 15

Thr Ala Arg Ile Thr Cys Gly Gly Asn Asn Ile Gly Ser Lys Gly Val

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Val Tyr

35 40 45

Asp Asp Ser Asp Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser

50 55 60

Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Asp His

85 90 95

Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Ala Ala Ala

100 105 110

Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser

115 120 125

Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp

130 135 140

Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro

145 150 155 160

Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn

165 170 175

Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys

180 185 190

Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val

195 200 205

Glu Lys Thr Val Ala Pro Thr Glu Cys Ser

210 215

<210>336

<211>1374

<212>DNA

<213>Artificial

<220>

<223>CR6328 Heavy chain

<220>

<221>CDS

<222>(1)..(1374)

<210>337

<211>458

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>337

Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly His Ile Phe Ser Gly Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Ile Phe Gly Thr Thr Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Gln Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Asp Leu Ser Asn Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Val Lys Asp Gly Tyr Cys Thr Leu Thr Ser Cys Pro Val Gly

100 105 110

Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser

115 120 125

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys

130 135 140

Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr

145 150 155 160

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser

165 170 175

Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser

180 185 190

Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr

195 200 205

Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys

210 215 220

Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys

225 230 235 240

Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro

245 250 255

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

260 265 270

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

275 280 285

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

290 295 300

Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

305 310 315 320

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

325 330 335

Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

340 345 350

Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu

355 360 365

Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr

370 375 380

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

385 390 395 400

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

405 410 415

Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

420 425 430

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

435 440 445

Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

450 455

<210>338

<211>639

<212>DNA

<213>Artificial

<220>

<223>CR6328 Light chain

<220>

<221>CDS

<222>(1)..(639)

<210>339

<211>213

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>339

Glu Ile Val Met 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 Phe 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 Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala Ala Ala Pro

100 105 110

Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr

115 120 125

Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys

130 135 140

Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu

145 150 155 160

Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser

165 170 175

Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala

180 185 190

Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe

195 200 205

Asn Arg Gly Glu Cys

210

<210>340

<211>1353

<212>DNA

<213>Artificial

<220>

<223>CR6329 Heavy chain

<220>

<221>CDS

<222>(1)..(1353)

<210>341

<211>451

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>341

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Ile Phe Arg Ser Asn

20 25 30

Ser Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Phe Ala Leu Phe Gly Thr Thr Asp Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Ser Thr Thr Val Tyr

65 70 75 80

Leu Glu Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Ser Gly Tyr Thr Thr Arg Asn Tyr Phe Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser

115 120 125

Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala

130 135 140

Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val

145 150 155 160

Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala

165 170 175

Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val

180 185 190

Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His

195 200 205

Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys

210 215 220

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly

225 230 235 240

Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

245 250 255

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

260 265 270

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

275 280 285

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

290 295 300

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

305 310 315 320

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

325 330 335

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

340 345 350

Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser

355 360 365

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

370 375 380

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

385 390 395 400

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

405 410 415

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

420 425 430

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

435 440 445

Pro Gly Lys

450

<210>342

<211>654

<212>DNA

<213>Artificial

<220>

<223>CR6329 Light chain

<220>

<221>CDS

<222>(1)..(654)

<210>343

<211>218

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>343

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 Asn

20 25 30

Tyr Leu Gly Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Ser Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Gly 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 Arg Ala Ala Ala

100 105 110

Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser

115 120 125

Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp

130 135 140

Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro

145 150 155 160

Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn

165 170 175

Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys

180 185 190

Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val

195 200 205

Glu Lys Thr Val Ala Pro Thr Glu Cys Ser

210 215

<210>344

<211>1350

<212>DNA

<213>Artificial

<220>

<223>CR6332 Heavy chain

<210>345

<211>450

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>345

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Pro Phe Arg Asn Phe

20 25 30

Ala Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Ala Val Phe Gly Thr Thr Lys Tyr Ala His Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Asp Ser Thr Asn Thr Ala Tyr

65 70 75 80

Met Glu Leu Gly Ser Leu Lys Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Pro His Tyr Tyr Ser Ser Tyr Met Asp Val Trp Gly Glu

100 105 110

Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val

115 120 125

Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala

130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser

145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

165 170 175

Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

180 185 190

Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys

195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp

210 215 220

Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly

225 230 235 240

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile

245 250 255

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu

260 265 270

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg

290 295 300

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys

305 310 315 320

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu

325 330 335

Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr

340 345 350

Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu

355 360 365

Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp

370 375 380

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val

385 390 395 400

Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp

405 410 415

Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His

420 425 430

Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

435 440 445

Gly Lys

450

<210>346

<211>636

<212>DNA

<213>Artificial

<220>

<223>CR6332 Light chain

<220>

<221>CDS

<222>(1)..(636)

<210>347

<211>212

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>347

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 Thr 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 Lys Tyr Asn Ser Ala Pro Ser

85 90 95

Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg Ala Ala Ala Pro Ser

100 105 110

Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala

115 120 125

Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val

130 135 140

Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser

145 150 155 160

Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr

165 170 175

Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys

180 185 190

Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn

195 200 205

Arg Gly Glu Cys

210

<210>348

<211>1350

<212>DNA

<213>Artificial

<220>

<223>CR6334 Heavy chain

<220>

<221>CDS

<222>(1)..(1350)

<210>349

<211>450

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>349

Glu Val Gln Leu Val Glu Thr Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Pro Cys Lys Ser Ser Gly Ser Pro Phe Arg Ser Asn

20 25 30

Ala Val Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Val

35 40 45

Gly Gly Ile Leu Gly Val Phe Gly Ser Pro Ser Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Asn Thr Val His

65 70 75 80

Met Glu Leu Arg Gly Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Pro Thr Tyr Tyr Tyr Ser Tyr Met Asp Val Trp Gly Lys

100 105 110

Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val

115 120 125

Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala

130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser

145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

165 170 175

Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

180 185 190

Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys

195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp

210 215 220

Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly

225 230 235

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile

245 250 255

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu

260 265 270

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg

290 295 300

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys

305 310 315 320

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu

325 330 335

Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr

340 345 350

Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu

355 360 365

Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp

370 375 380

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val

385 390 395 400

Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp

405 410 415

Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His

420 425 430

Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

435 440 445

Gly Lys

450

<210>350

<211>654

<212>DNA

<213>Artificial

<220>

<223>CR6334 Light chain

<220>

<221>CDS

<222>(1)..(654)

<210>351

<211>218

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>351

Ser Tyr Val Leu Thr Gln Pro Pro Ser Glu Ser Val Ala Pro Gly Gln

1 5 10 15

Thr Ala Arg Ile Thr Cys Gly Gly Asn Asn Ile Gly Arg Asn Ser Val

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Val Tyr

35 40 45

Asp Asp Ser Asp Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser

50 55 60

Lys Ser Gly Asn Thr Ala Thr Leu Ile Ile Ser Arg Val Glu Val Gly

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp His Ser Ser Ser Asp His

85 90 95

Tyr Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu Gly Ala Ala Ala

100 105 110

Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser

115 120 125

Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp

130 135 140

Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro

145 150 155 160

Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn

165 170 175

Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys

180 185 190

Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val

195 200 205

Glu Lys Thr Val Ala Pro Thr Glu Cys Ser

210 215

<210>352

<211>1350

<212>DNA

<213>Artificial

<220>

<223>CR6336 Heavy chain

<220>

<221>CDS

<222>(1)..(1350)

<210>353

<211>450

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>353

Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Phe Gly Met Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Phe Thr Ser Ala Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Gly Ser Glu Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg Ser Ser Gly Tyr Tyr Pro Gln Tyr Phe Gln Asp Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val

115 120 125

Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala

130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser

145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

165 170 175

Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

180 185 190

Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys

195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp

210 215 220

Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly

225 230 235 240

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile

245 250 255

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu

260 265 270

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg

290 295 300

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys

305 310 315 320

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu

325 330 335

Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr

340 345 350

Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu

355 360 365

Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp

370 375 380

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val

385 390 395 400

Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp

405 410 415

Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His

420 425 430

Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

435 440 445

Gly Lys

450

<210>354

<211>642

<212>DNA

<213>Artificial

<220>

<223>CR6336 Light chain

<220>

<221>CDS

<222>(1)..(642)

<210>355

<211>214

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>355

Glu Ile Val Met Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Gln 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

Met 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

Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210>356

<211>1353

<212>DNA

<213>Artificial

<220>

<223>CR6339 Heavy chain

<220>

<221>CDS

<222>(1)..(1353)

<400>356

<220>

<223>Synthetic Construct

<400>357

Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Ile Phe Asn Ser Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Ala Ile Phe His Thr Pro Lys Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Asn Thr Ala Tyr

65 70 75 80

Met Glu Leu Arg Ser Leu Lys Ser Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Gly Ser Thr Tyr Asp Phe Ser Ser Gly Leu Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser

115 120 125

Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala

130 135 140

Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val

145 150 155 160

Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala

165 170 175

Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val

180 185 190

Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His

195 200 205

Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys

210 215 220

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly

225 230 235 240

Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

245 250 255

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

260 265 270

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

275 280 285

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

290 295 300

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

305 310 315 320

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

325 330 335

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

340 345 350

Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser

355 360 365

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

370 375 380

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

385 390 395 400

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

405 410 415

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

420 425 430

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

435 440 445

Pro Gly Lys

450

<210>358

<211>654

<212>DNA

<213>Artificial

<220>

<223>CR6339 Light chain

<220>

<221>CDS

<222>(1)..(654)

<400>358

<210>359

<211>218

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>359

Gln Ala Gly Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Gln

1 5 10 15

Thr Ala Arg Ile Thr Cys Gly Gly Asn Asn Ile Gly Ser Lys Ser Val

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Val Tyr

35 40 45

Asp Asp Ser Asp Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser

50 55 60

Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Asp His

85 90 95

Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Ala Ala Ala

100 105 110

Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser

115 120 125

Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp

130 135 140

Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro

145 150 155 160

Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn

165 170 175

Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys

180 185 190

Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val

195 200 205

Glu Lys Thr Val Ala Pro Thr Glu Cys Ser

210 215

<210>360

<211>1368

<212>DNA

<213>Artificial

<220>

<223>CR6342 Heavy chain

<220>

<221>CDS

<222>(1)..(1368)

<400>360

Ser Leu Ser Leu Ser Pro Gly Lys

450 455

<210>361

<211>456

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>361

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Phe Phe Ser Ser Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Val Ile Pro Ile Phe Arg Thr Ala Asn Tyr Ala Gln Asn Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Phe Thr Ser Tyr Met Glu

65 70 75 80

Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg

85 90 95

Leu Asn Tyr His Asp Ser Gly Thr Tyr Tyr Asn Ala Pro Arg Gly Trp

100 105 110

Phe Asp Pro Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser

115 120 125

Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr

130 135 140

Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro

145 150 155 160

Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val

165 170 175

His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser

180 185 190

Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile

195 200 205

Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val

210 215 220

Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala

225 230 235 240

Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr

355 360 365

Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro Gly Lys

450 455

<210>362

<211>657

<212>DNA

<213>Artificial

<220>

<223>CR6342 Light chain

<220>

<221>CDS

<222>(1)..(657)

<210>363

<211>219

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>363

Asp Ile Gln Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Glu Lys Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Ile Leu Asn Ser

20 25 30

Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln

85 90 95

Tyr Tyr Ser Ser Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile

100 105 110

Lys Arg Ala Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu

115 120 125

Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe

130 135 140

Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln

145 150 155 160

Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser

165 170 175

Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu

180 185 190

Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser

195 200 205

Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215

<210>364

<211>1350

<212>DNA

<213>Artificial

<220>

<223>CR6343 Heavy chain

<220>

<221>CDS

<222>(1)..(1350)

aag agc cgg tgg cag cag ggc aac gtg ttc agc tgc agc gtg atg cac 1296

Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His

420 425 430

gag gcc ctg cac aac cac tac acc cag aag agc ctg agc ctg agc ccc 1344

Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

435 440 445

ggc aag 1350

Gly Lys

450

<210>365

<211>450

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>365

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Val Thr Phe Ser Tyr Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ser Pro Met Phe Gly Thr Thr Thr Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Asp Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Val Arg Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Ser Asn Tyr Tyr Asp Ser Val Tyr Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val

115 120 125

Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala

130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser

145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

165 170 175

Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

180 185 190

Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys

195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp

210 215 220

Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly

225 230 235 240

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile

245 250 255

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu

260 265 270

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg

290 295 300

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys

305 310 315 320

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu

325 330 335

Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr

340 345 350

Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu

355 360 365

Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp

370 375 380

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val

385 390 395 400

Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp

405 410 415

Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His

420 425 430

Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

435 440 445

Gly Lys

450

<210>366

<211>654

<212>DNA

<213>Artificial

<220>

<223>CR6343 Light chain

<220>

<221>CDS

<222>(1)..(654)

<400>366

cag tct gtc gtg acg cag ccg ccc tcg gag tca gtg gcc cca gga cag 48

<210>367

<211>218

<212>PRT

<213>Artificial

<220>

<223>Synthetic Construct

<400>367

Gln Ser Val Val Thr Gln Pro Pro Ser Glu Ser Val Ala Pro Gly Gln

1 5 10 15

Thr Ala Arg Ile Thr Cys Gly Gly His Asn Ile Gly Ser Asn Ser Val

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Val Tyr

35 40 45

Asp Asn Ser Asp Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser

50 55 60

Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Gly Ser Ser Ser Asp His

85 90 95

Tyr Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu Gly Ala Ala Ala

100 105 110

Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser

115 120 125

Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp

130 135 140

Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro

145 150 155 160

Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn

165 170 175

Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys

180 185 190

Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val

195 200 205

Glu Lys Thr Val Ala Pro Thr Glu Cys Ser

210 215

<210>368

<211>12

<212>PRT

<213>Influenza A virus

<400>368

Gly Val Thr Asn Lys Val Asn Ser Ile Ile Asp Lys

1 5 10

<210>369

<211>12

<212>PRT

<213>Influenza A virus

<400>369

Gly Val Thr Asn Lys Val Asn Ser Ile Ile Asn Lys

1 5 10

<210>370

<211>12

<212>PRT

<213>Influenza A virus

<400>370

Gly Val Thr Asn Lys Glu Asn Ser Ile Ile Asp Lys

1 5 10

<210>371

<211>12

<212>PRT

<213>Influenza A virus

<400>371

Gly Val Thr Asn Lys Val Asn Arg Ile Ile Asp Lys

1 5 10

<210>372

<211>12

<212>PRT

<213>Influenza A virus

<400>372

Gly Ile Thr Asn Lys Val Asn Ser Val Ile Glu Lys

1 5 10

<210>373

<211>12

<212>PRT

<213>Influenza A virus

<400>373

Gly Ile Thr Asn Lys Glu Asn Ser Val Ile Glu Lys

1 5 10

<210>374

<211>12

<212>PRT

<213>Influenza A virus

<400>374

Gly Ile Thr Asn Lys Val Asn Ser Ile Ile Asp Lys

1 5 10

<210>375

<211>12

<212>PRT

<213>Influenza A virus

<400>375

Lys Ile Thr Ser Lys Val Asn Asn Ile Val Asp Lys

1 5 10

<210>376

<211>12

<212>PRT

<213>Influenza A virus

<400>376

Gln Ile Asn Gly Lys Leu Asn Arg Val Ile Glu Lys

1 5 10

<210>377

<211>12

<212>PRT

<213>Influenza A virus

<400>377

Gln Ile Asn Gly Lys Leu Asn Arg Leu Ile Glu Lys

1 5 10

Claims

1. isolating binding molecule, it can be discerned and in conjunction with the epi-position in the HA2 subunit of influenza hemagglutinin protein (HA), be characterised in that described binding molecule has for the influenza virus of the HA that comprises the H5 hypotype such as the neutralization activity of H5N1, H5N2, H5N8 and H5N9.

2. the binding molecule of claim 1, wherein said binding molecule do not rely in the proteic HA1 subunit of HA epi-position and in conjunction with described HA albumen.

3. claim 1 or 2 binding molecule, wherein said binding molecule also has the neutralization activity for the influenza virus of the HA that comprises the H1 hypotype such as H1N1, and preferred described binding molecule also has the neutralization activity for the influenza virus of the HA that comprises H2, H6 and/or H9 hypotype.

4. the binding molecule of claim 1, the epi-position in the wherein said HA2 subunit is selected from one group that is made up of following aminoacid sequence:

1)GVTNKVNSIIDK(SEQ ID NO：368)，

2)GVTNKVNSIINK(SEQ ID NO：369)，

3)GVTNKENSIIDK(SEQ ID NO：370)，

4)GVTNKVNRIIDK(SEQ ID NO：371)，

5)GITNKVNSVIEK(SEQ ID NO：372)，

6)GITNKENSVIEK(SEQ ID NO：373)，

7) GITNKVNSIIDK (SEQ ID NO:374), and

8)KITSKVNNIVDK(SEQ ID NO：375)。

5. the binding molecule of claim 1, wherein said binding molecule is selected from as next group:

F) comprise heavy chain CDR1 district shown in the SEQ ID NO:45, the binding molecule in heavy chain CDR3 district shown in heavy chain CDR2 district shown in the SEQ ID NO:46 and the SEQ ID NO:47,

J) comprise the binding molecule in heavy chain CDR3 district shown in heavy chain CDR2 district shown in heavy chain CDR1 district shown in the SEQ ID NO:268, the SEQ ID NO:269 and the SEQ ID NO:270,

M) comprise the binding molecule in heavy chain CDR3 district shown in heavy chain CDR2 district shown in heavy chain CDR1 district shown in the SEQ ID NO:286, the SEQ ID NO:287 and the SEQ IDNO:288,

6. the binding molecule of claim 1, wherein said binding molecule is selected from as next group:

A) comprise the binding molecule in light chain CDR3 district shown in light chain CDR2 district shown in light chain CDR1 district, the SEQ ID NO:5 shown in heavy chain CDR3 district, the SEQ ID NO:4 shown in heavy chain CDR2 district, the SEQ ID NO:3 shown in heavy chain CDR1 district shown in the SEQ ID NO:1, the SEQ ID NO:2 and the SEQ ID NO:6

B) comprise the binding molecule in light chain CDR3 district shown in light chain CDR2 district shown in light chain CDR1 district, the SEQ ID NO:8 shown in heavy chain CDR3 district, the SEQ ID NO:7 shown in heavy chain CDR2 district, the SEQ ID NO:3 shown in heavy chain CDR1 district shown in the SEQ ID NO:1, the SEQ ID NO:2 and the SEQ ID NO:9

C) comprise the binding molecule in light chain CDR3 district shown in light chain CDR2 district shown in light chain CDR1 district, the SEQ ID NO:11 shown in heavy chain CDR3 district, the SEQ ID NO:10 shown in heavy chain CDR2 district, the SEQ ID NO:3 shown in heavy chain CDR1 district shown in the SEQ ID NO:1, the SEQ ID NO:2 and the SEQ ID NO:12

D) comprise the binding molecule in light chain CDR3 district shown in light chain CDR2 district shown in light chain CDR1 district, the SEQ ID NO:14 shown in heavy chain CDR3 district, the SEQ ID NO:13 shown in heavy chain CDR2 district, the SEQ ID NO:3 shown in heavy chain CDR1 district shown in the SEQ ID NO:1, the SEQ ID NO:2 and the SEQ ID NO:15

E) comprise the binding molecule in light chain CDR3 district shown in light chain CDR2 district shown in light chain CDR1 district, the SEQ ID NO:20 shown in heavy chain CDR3 district, the SEQ ID NO:19 shown in heavy chain CDR2 district, the SEQ ID NO:18 shown in heavy chain CDR1 district shown in the SEQ ID NO:16, the SEQ ID NO:17 and the SEQ ID NO:21

F) comprise the binding molecule in light chain CDR3 district shown in light chain CDR2 district shown in light chain CDR1 district, the SEQ ID NO:25 shown in heavy chain CDR3 district, the SEQ ID NO:24 shown in heavy chain CDR2 district, the SEQ ID NO:23 shown in heavy chain CDR1 district shown in the SEQ ID NO:1, the SEQ ID NO:22 and the SEQ ID NO:26

G) comprise the binding molecule in light chain CDR3 district shown in light chain CDR2 district shown in light chain CDR1 district, the SEQ ID NO:31 shown in heavy chain CDR3 district, the SEQ ID NO:30 shown in heavy chain CDR2 district, the SEQ ID NO:29 shown in heavy chain CDR1 district shown in the SEQ ID NO:27, the SEQ ID NO:28 and the SEQ ID NO:32

H) comprise the binding molecule in light chain CDR3 district shown in light chain CDR2 district shown in light chain CDR1 district, the SEQ ID NO:34 shown in heavy chain CDR3 district, the SEQ ID NO:33 shown in heavy chain CDR2 district, the SEQ ID NO:3 shown in heavy chain CDR1 district shown in the SEQ ID NO:1, the SEQ ID NO:2 and the SEQ ID NO:35

I) comprise the binding molecule in light chain CDR3 district shown in light chain CDR2 district shown in light chain CDR1 district, the SEQ ID NO:37 shown in heavy chain CDR3 district, the SEQ ID NO:36 shown in heavy chain CDR2 district, the SEQ ID NO:3 shown in heavy chain CDR1 district shown in the SEQ ID NO:1, the SEQ ID NO:2 and the SEQ ID NO:38

J) comprise the binding molecule in light chain CDR3 district shown in light chain CDR2 district shown in light chain CDR1 district, the SEQ ID NO:43 shown in heavy chain CDR3 district, the SEQ ID NO:42 shown in heavy chain CDR2 district, the SEQ ID NO:41 shown in heavy chain CDR1 district shown in the SEQ ID NO:39, the SEQ ID NO:40 and the SEQ ID NO:44

K) comprise the binding molecule in light chain CDR3 district shown in light chain CDR2 district shown in light chain CDR1 district, the SEQ ID NO:8 shown in heavy chain CDR3 district, the SEQ ID NO:7 shown in heavy chain CDR2 district, the SEQ ID NO:47 shown in heavy chain CDR1 district shown in the SEQ ID NO:45, the SEQ ID NO:46 and the SEQ ID NO:48

L) comprise the binding molecule in light chain CDR3 district shown in light chain CDR2 district shown in light chain CDR1 district, the SEQ ID NO:34 shown in heavy chain CDR3 district, the SEQ ID NO:33 shown in heavy chain CDR2 district, the SEQ ID NO:50 shown in heavy chain CDR1 district shown in the SEQ ID NO:1, the SEQ ID NO:49 and the SEQ ID NO:51

M) comprise the binding molecule in light chain CDR3 district shown in light chain CDR2 district shown in light chain CDR1 district, the SEQ ID NO:56 shown in heavy chain CDR3 district, the SEQ ID NO:55 shown in heavy chain CDR2 district, the SEQ ID NO:54 shown in heavy chain CDR1 district shown in the SEQ ID NO:52, the SEQ ID NO:53 and the SEQ ID NO:57

N) comprise the binding molecule in light chain CDR3 district shown in light chain CDR2 district shown in light chain CDR1 district, the SEQ ID NO:266 shown in heavy chain CDR3 district, the SEQ ID NO:265 shown in heavy chain CDR2 district, the SEQ ID NO:264 shown in heavy chain CDR1 district shown in the SEQ ID NO:262, the SEQ ID NO:263 and the SEQ ID NO:267

O) comprise the binding molecule in light chain CDR3 district shown in light chain CDR2 district shown in light chain CDR1 district, the SEQ ID NO:272 shown in heavy chain CDR3 district, the SEQ ID NO:271 shown in heavy chain CDR2 district, the SEQ ID NO:270 shown in heavy chain CDR1 district shown in the SEQ ID NO:268, the SEQ ID NO:269 and the SEQ ID NO:273

P) comprise the binding molecule in light chain CDR3 district shown in light chain CDR2 district shown in light chain CDR1 district, the SEQ ID NO:278 shown in heavy chain CDR3 district, the SEQ ID NO:277 shown in heavy chain CDR2 district, the SEQ ID NO:276 shown in heavy chain CDR1 district shown in the SEQ ID NO:274, the SEQ ID NO:275 and the SEQ ID NO:279

Q) comprise the binding molecule in light chain CDR3 district shown in light chain CDR2 district shown in light chain CDR1 district, the SEQ ID NO:284 shown in heavy chain CDR3 district, the SEQ ID NO:283 shown in heavy chain CDR2 district, the SEQ ID NO:282 shown in heavy chain CDR1 district shown in the SEQ ID NO:280, the SEQ ID NO:281 and the SEQ ID NO:285

R) comprise the binding molecule in light chain CDR3 district shown in light chain CDR2 district shown in light chain CDR1 district, the SEQ ID NO:290 shown in heavy chain CDR3 district, the SEQ ID NO:289 shown in heavy chain CDR2 district, the SEQ ID NO:288 shown in heavy chain CDR1 district shown in the SEQ ID NO:286, the SEQ ID NO:287 and the SEQ ID NO:291

S) comprise the binding molecule in light chain CDR3 district shown in light chain CDR2 district shown in light chain CDR1 district, the SEQ ID NO:296 shown in heavy chain CDR3 district, the SEQ ID NO:295 shown in heavy chain CDR2 district, the SEQ ID NO:294 shown in heavy chain CDR1 district shown in the SEQ ID NO:292, the SEQ ID NO:293 and the SEQ ID NO:297

T) comprise the binding molecule in light chain CDR3 district shown in light chain CDR2 district shown in light chain CDR1 district, the SEQ ID NO:308 shown in heavy chain CDR3 district, the SEQ ID NO:307 shown in heavy chain CDR2 district, the SEQ ID NO:306 shown in heavy chain CDR1 district shown in the SEQ ID NO:304, the SEQ ID NO:305 and the SEQ ID NO:309, and

U) comprise the binding molecule in light chain CDR3 district shown in light chain CDR2 district shown in light chain CDR1 district, the SEQ ID NO:314 shown in heavy chain CDR3 district, the SEQ ID NO:313 shown in heavy chain CDR2 district shown in heavy chain CDR1 district, the SEQ IDNO:311, the SEQ ID NO:312 shown in the SEQ ID NO:310 and the SEQ ID NO:315.

7. each binding molecule of claim 1-6, wherein said binding molecule is a human monoclonal antibodies.

8. each the nucleic acid molecule of binding molecule of coding claim 1-7.

9. each binding molecule of claim 1-7 is preferred for diagnosis, treats and/or prevents influenza infection as medicine.

10. the binding molecule of claim 9, wherein said influenza infection are because due to the influenza virus, described influenza virus is relevant with popular outburst, perhaps have the popular potentiality of being correlated with that break out.

11. the binding molecule of claim 10, the relevant influenza virus strain of wherein said and popular outburst is selected from as next group: H1N1, H5N1, H5N2, H5N8, H5N9, based on strain and the H9N2 of H2.

12. a pharmaceutical composition, it comprises each binding molecule and pharmaceutically-acceptable excipients of claim 1-7.

13. each binding molecule of claim 1-7 is used for diagnosing, prevent and/or treat the application of the medicine of influenza infection in preparation.