CN101541832B - Human binding molecules capable of neutralizing influenza virus H5N1 and uses thereof - Google Patents

Human binding molecules capable of neutralizing influenza virus H5N1 and uses thereof Download PDF

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CN101541832B
CN101541832B CN200780041285.1A CN200780041285A CN101541832B CN 101541832 B CN101541832 B CN 101541832B CN 200780041285 A CN200780041285 A CN 200780041285A CN 101541832 B CN101541832 B CN 101541832B
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CN101541832A (en
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E·N·范登布林克
C·A·德克吕夫
M·思罗斯比
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Janssen Vaccines and Prevention BV
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Crucell Holand BV
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
    • C07K16/1018—Orthomyxoviridae, e.g. influenza virus

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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 energy and 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 influenza virus H 5 N 1 infect diagnosis, 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.But highly pathogenic influenza A strain causes poultry systemic infection as H5N1, mortality ratio can reach 100%.The animal that has infected influenza virus A has illustrated and has crossed species barrier and infect people usually used as influenza virus storehouse (reservoir) and some hypotypes.
Allelic variation in the antigenicity region of two genes of influenza virus A based on coded surface glycoprotein and can be divided into hypotype, 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 current 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).But, report that in recent years the pathogenic H5N1 hypotype of avian influenza virus A is crossed species barrier and infects people, cause some patients' death, as 1997 and 2003 in the Documentary Records in Hong Kong.
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 that heating, expiratory dyspnea (comprise and breathe hard and cough), lymphopenia, diarrhoea and glucose level regulate difficulty.Contrary with seasonal influenza, the crowd in risk is the health adult of formation crowd main body.Due to the particularly highly pathogenic and attested ability that it crosses species barrier infection human body of H5N1 of some avian influenza virus A hypotype, therefore there is great economy and the public health risk relevant to these virus strain, comprise serious popularity and explosive threat.The scale of this threat, as the influenza great outburst of 1918, causes exceeding 50,000,000 people's death.
The effective vaccine that does not also have at present H5N1 to infect, the passive immunotherapy therefore carrying out with immunoglobulin (Ig) may be a kind of alternative strategy.It is reported that the application of passive immunization reduces by half mortality ratio during 1918.In view of they are for the treatment benefit of human body, therefore need in energy and the preferred human binding molecules of binding molecule of H5N1.The invention provides these binding molecules and disclosed them and can be used in 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) to carry out different hemagglutinin (HA).Restructuring HA is carried out to reductibility SDS-PAGE analysis and immunoblotting assay.Swimming lane 1 illustrates the sHA of H5N1TV, swimming lane 2 illustrates restructuring HA, hypotype H5 (A/Vietnam/1203/2004 (H5N1)), swimming lane 3 illustrates restructuring HA, hypotype H3 (A/Wyoming/3/2003 (H3N2)), and swimming lane 4 illustrates restructuring HA, hypotype H1 (A/New Caledonia/20/99 (H1N1)).In figure, also mark the position that can find HA0, HA1 and HA2.
Fig. 2 illustrates the average clinical score of (embodiment 12) every group of mouse in a research, wherein infecting the day before yesterday with influenza virus H 5 N 1, with three-type-person H5N1 monoclonal antibody CR6261, CR6323, and CR6325 is with various dose prophylactic treatment mouse.
Fig. 3 is illustrated in and infects during latter 21 days by the body weight change (embodiment 12) during anti-H5N1 antibody prophylactic treatment mouse.
Fig. 4 be illustrated in the research (embodiment 12) of Fig. 2 and 3 not on the same group in the number of survival mice.
Fig. 5 be illustrated in mortality ratio in the research (embodiment 12) of Fig. 2-4 and the anti-H5N1 antibody dosage that gives between relation.
Fig. 6 is illustrated in the average clinical score of (embodiment 13) every group of mouse in a research, wherein uses the influenza virus H 5 N 1 infecting mouse of lethal dose and treats in metainfective different time points (4 hours, 1 day, 2 days and 3 days) the anti-H5N1 monoclonal antibody of CR6261 or incoherent antibody CR2006 (giving for the 1st day after infection).
Fig. 7 illustrates described in Fig. 6 the survival number of every group of mouse in research.All animals (1 animal in the 1st group) of 1-4 group all survive until infect latter the 21st day during whole research.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 research described in Fig. 6.Stopped measuring the 5th group of Mouse Weight at the 9th day, because all mouse of this group are now dead.Although the speed of every treated animal rehabilitation depends on treatment time, the mouse surviving in 1-4 group all reaches normal type level for the 21st day after infection.
Fig. 9 illustrates the per-cent of surviving animals in every treated animal of a research, wherein use the H1N1 influenza infection mouse of lethal dose and treat with the anti-H5N1 monoclonal antibody of CR6261 or incoherent antibody CR57 (giving for the 1st day after infection) in different time points (infect first 1 day, infect latter 1,2 and 3 day).
Figure 10 illustrates described in Fig. 9 the mean body weight of every group of mouse during research.Stopped measuring the 5th group of Mouse Weight at the 9th day, because all mouse of this group are now dead.Although the speed of every treated animal rehabilitation depends on treatment time, the mouse surviving in 1-4 group all reaches normal type level for the 21st day after infection.
Invention is described
Below set forth the definition of some terms of the present invention's use.
As used herein, term " binding molecule " refers to complete immunoglobulin (Ig), comprise monoclonal antibody, as chimeric antibody, humanized antibody or human monoclonal antibodies, or refer to antigen in conjunction with and/or variable domains, it comprises the immunoglobulin fragment with for example H5N1 of binding partners of immunoglobulin (Ig) described in described complete immunoglobulin (Ig) competition specific binding.Regardless of structure, described Fab is in conjunction with the same antigen by described complete immunoglobulin (Ig) identification.Fab can comprise peptide or the polypeptide with such aminoacid sequence, 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 that described aminoacid sequence is described binding molecule.
As used herein, term " binding molecule " comprises all immunoglobulin classes known in the art and subclass.According to the aminoacid sequence of 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 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-chain antibody (diabody), three chain antibodies (triabody), four chain antibodies (tetrabody), contain and be at least enough to (many) peptides of giving the immunoglobulin fragment of being combined with (many) peptide specifics antigen etc.Above-mentioned fragment can synthesize produce or by enzyme or the complete immunoglobulin (Ig) of chemical cracking produce or can by recombinant DNA technology genetically engineered.Described production method is known in the art, for example be incorporated to for referencial use by E.Harlow and D herein, 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, described binding site can be same to each other or different to each other.
Binding molecule can be naked or unconjugated binding molecule, but can be also a part for immunoconjugates.Naked or unconjugated binding molecule refers to such binding molecule, it is not puted together with effect part or mark, operably connects or other physics or functional associated, and described effect part or mark are for example toxicant, radioactive substance, liposome, enzyme.That naked or unconjugated binding molecule is not got rid of is stabilized, polymer, humanization or (except the adhering to of effect components or the mark) binding molecule with any alternate manner operation.Therefore, naked being all included in wherein with unconjugated binding molecule of all posttranslational modifications, comprise be wherein the cell that produces the binding molecule of recombinate by generations in the cellular environment of natural binding molecule produce modify and after initial binding molecule preparation by artificial importing modification.Certainly, term naked or unconjugated binding molecule be not precluded within the ability that gives described binding molecule and effector cell after body and/or molecule and form functional cohesion because some such interactions are performance, biological action is necessary.Lacking therefore for being defined in naked or unconjugated binding molecule external instead of in vivo of the effect group being associated or mark.
As used herein, several samples type contained in term " biological sample ", comprises blood and other humoral sample of biological origin, and solid tissue sample is as biopsy sample or tissue culture, or derived from cell or its offspring wherein.This term is also included in after acquisition by the sample of any mode processing, for example, use some composition of agent treated, dissolving or enrichment 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) " refers to that binding molecule is as the sequence in the variable region of immunoglobulin (Ig), it forms antigen binding site conventionally to a great extent, aspect form and charge distribution with the epi-position complementation identified on antigen.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 protein with its native conformation, or are present on protein with denatured form (for example, by dissolving in SDS) in some cases.Epi-position also can be made up of the posttranslational modification thing of protein.
As used herein, term " disappearance " refers to compared with the parental generation molecule with normally natural generation, lacks respectively the change of one or more amino acid or nucleotide residue in aminoacid sequence or nucleotide sequence.
As used herein, term " regulate express nucleotide sequence " refers to that the encoding sequence operably connecting expresses necessary and/or affect the polynucleotide sequence that described encoding sequence is expressed in specific host organism.Regulate the nucleotide sequence of expressing can be in the host organisms of selecting the activated any nucleotide sequence of tool and can be derived from coding the gene with the protein of host organisms homology or allos, described sequence is for example suitable transcriptional initiation sequence, terminator sequence, promoter sequence, enhancer sequence; Repressor or activator sequence; Effectively RNA processing signal is as montage and polyadenylation signal; The sequence of stabilized cell matter mRNA; Strengthen the sequence (for example ribosome bind site) of translation efficiency; The sequence of Enhancin matter stability; And the sequence that Enhancin matter is secreted when needed.Regulate the discriminating of the sequence of expressing to know with the those skilled in the art that base on practicality.
As used herein, term " functional variant " refers to such binding molecule, it comprises one or more Nucleotide and/or the reformed Nucleotide of amino acid and/or aminoacid sequence compared with the nucleotide sequence of parental generation binding molecule and/or aminoacid sequence, and still can compete in conjunction with such as H5N1 of described binding partners compared with parental generation binding molecule.In other words, not remarkably influenced of modification in amino acid and/or the nucleotide sequence of parental generation binding molecule or change the binding characteristic by described described binding molecule nucleotide sequence coded or that contain described aminoacid sequence, described binding molecule still can be identified 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, the mutagenesis of for example directed mutagenesis and random PCR mediation, and can comprise natural and non-natural nucleotide and amino acid.
Conserved amino acid replaces and comprises that amino-acid residue is wherein by the replacement of another radical amino acid replacement with analog structure or chemical property.The family with the amino-acid residue of similar side chain limits in the art.These families comprise amino acid (for example Methionin with basic side chain, arginine, Histidine), acid side-chain amino acid (for example aspartic acid, L-glutamic acid), for example, without charge polarity side chain amino acid (l-asparagine, glutamine, Serine, Threonine, tyrosine, halfcystine, tryptophane), non-polar sidechain amino acid (for example glycine, L-Ala, α-amino-isovaleric acid, leucine, Isoleucine, proline(Pro), phenylalanine, methionine(Met)), β-branched building block amino acid (for example Threonine, α-amino-isovaleric acid, Isoleucine) and aromatic side chain amino acid (for example tyrosine, phenylalanine, tryptophane).Those skilled in the art understand other amino-acid residue family classification mode 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, or 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 nucleotide sequence can be the single change (point mutation) at a locus, for example conversion or transversional mutation, or can insert, lack or change multiple Nucleotide at a locus.In the locus of any number that in addition, can be in nucleotide sequence, produce one or more change.Described sudden change can be undertaken by any appropriate method known in the art.
As used herein, term " host " refers to the organism or the cell that have wherein imported carrier, and described carrier is for example cloning vector or expression vector.Described organism or cell can be protokaryon or most eukaryotes or cell.Should understand this term and not only refer to special object organism or cell, and can be the offspring of this organism or cell.Because sudden change or environmental influence cause some modification to occur in the generation subsequently, therefore in fact this offspring is perhaps not identical with described parental generation organism or cell, but it is still included in term as used herein " host's " scope.
Term " people " is when referring to direct derived from human or the molecule based on human sequence when describing binding molecule described herein.When binding molecule derived from or based on human sequence and subsequently by modify time, still think that in this manual it is people's molecule.In other words, term " people " is when comprising having such variable region and the binding molecule of constant region when describing binding molecule, described variable region and constant region derived from human racial immunity sphaeroprotein sequence or variable region or constant region based on occurring in people or human lymphocyte and modify with some forms.Therefore, human binding molecules can comprise the amino-acid residue not being by people's germline immunoglobulin sequences coding, comprises and replaces and/or disappearance (for example, by external random or site-specific mutagenesis method or by the sudden change of somatic mutation method importing in body).As used herein, " based on " refer to such situation, nucleotide sequence can accurately copy from template, or for example has micromutation by fallibility PCR method, or through synthetic preparation and with described template exact matching or there is little modification.Semi-synthetic molecule based on human sequence is also considered to people's molecule in this article.
Term " insertion " is also known as " interpolation ", refers to the variation in amino acid or the nucleotide sequence that causes respectively adding one or more amino acid or nucleotide residue compared with parental generation sequence.
Term " separation " is when referring to such binding molecule when describing binding molecule described herein, it does not basically contain other oroteins or polypeptide, does not particularly contain and have other binding molecule of different antigen-specifiies, and does not basically contain other cell material and/or chemicals.For example, in the time that described binding molecule is restructuring generation, it does not preferably basically contain substratum; When described binding molecule is while producing by chemical synthesis process, it does not preferably basically contain chemicals precursor or other chemicals, and it is what to separate with the chemicals precursor or other chemicals that participate in protein synthesis.The nucleotide sequence that term " separation " refers to the described binding molecule of wherein encoding in the time of nucleic acid molecule for description encoding binding molecule described herein containing 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 " separation " refers to the nucleic acid molecule substantially separating with other cellular constituent, described other cellular constituent is and natural acid molecule natural cellular constituent accompanying in its natural host, for example rrna, polysaccharase or with its natural genome sequence being associated.In addition, " separation " nucleic acid molecule, as cDNA molecule can not basically contain other cell material or substratum in the time producing by recombinant technology, does not basically contain chemicals precursor or other chemicals when by chemosynthesis.
As used herein, term " monoclonal antibody " refers to the prepared product of single molecular antibody molecule.Monoclonal antibody is shown single binding specificity and affinity for defined epitope.Therefore, term " human monoclonal antibodies " refers to shows the antibody of single binding specificity, its have derived from or based on people's germline immunoglobulin sequences or derived from variable region and the constant region of completely synthetic sequence.The method of preparing monoclonal antibody has nothing to do.
As used herein, term " natural generation " when describing an object, refers to the fact that can find at occurring in nature this object.For example, be present in separable from natural source and be natural generation without polypeptide or polynucleotide sequence in artificial organism of having a mind to modify in laboratory.
As used herein, term " nucleic acid molecule " refers to the polymerized form of Nucleotide, comprises sense and antisense chain and the synthesized form of above-mentioned molecule and the polymkeric substance of mixing of RNA, cDNA, genomic dna.Nucleotide refers to 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 natural generation linking together by nucleotide bond natural generation and/or that non-natural occurs and the Nucleotide of modification is arbitrary or these two.Described nucleic acid molecule can be modified or can contain non-natural or derivative nucleotide base through chemistry or biochemical method, 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, between Nucleotide modify as such as, such as, without electric charge key (methylphosphonate, phosphotriester, phosphoramidate, carbamate etc.), electrically charged key (thiophosphatephosphorothioate, phosphorodithioate etc.), overhang (pendent moiety) (for example polypeptide), intercalator (such as acridine, psoralene etc.), sequestrant, alkylating agent, and the key (different nucleic acid of such as α etc.) of modifying.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 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 molecular backbone chain with peptide bond.Unless otherwise indicated, while mentioning nucleotide sequence, comprise its complement.Therefore the nucleic acid molecule that, there is 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 " refers to normally physical connection of two or more nucleotide sequence element, and function is associated each other.For example, if promotor energy is initial or regulate transcribing or expressing of encoding sequence, this promotor is operably connected with described encoding sequence, should understand in this case described encoding sequence in described promotor " under control ".
" the acceptable vehicle of medicine " refers to any inert substance, and itself and bioactive molecule combine to prepare suitable or conventional formulation as medicine, medicament or binding molecule." the acceptable vehicle of medicine " be in dosage used and concentration for the avirulent vehicle of acceptor, and compatible with other composition of the preparation that comprises described medicine, medicament or binding molecule.The widespread use in the art of the acceptable vehicle of medicine.
As used herein, term " specific binding " is when for example meaning that for describing for example antibody of binding molecule and its binding partners this interaction depends on the existence of for example antigenic determinant of ad hoc structure on described binding partners or epi-position when the interaction between antigen.In other words, antibody preferential in conjunction with or identification binding partners, even also like this in the time that 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 the combination of these two mediates.Again in other words, term " specific binding " refers to the immunologic opsonin of antigen or its fragment and is combined, and is not that immunologic opsonin is combined with other antigen.Can lower affinity be combined with other peptide or polypeptide with the binding molecule of antigen immune specific binding, for example, determine by radioimmunoassay (RIA), enzyme-linked immunosorbent assay (ELISA), BIACORE or other measuring method known in the art.With the binding molecule of antigen immune specific binding or its fragment can with related antigen cross reaction.Preferably, with binding molecule or its fragment and other not cross reaction of antigen of antigen immune specific binding.
As used herein, " replacement " refers to that one or more amino acid or Nucleotide are respectively by different amino acid or nucleotide subsitution.
Term " treatment significant quantity " refers to that binding molecule described herein effectively prevents, improves and/or treat the amount of the illness that derives from H5N1 infection.
Term " treatment " refers to therapeutic treatment and prevention (prophylactic) or protection (preventative) measure with cure diseases or makes disease stop progress or at least postpone progression of disease.Need those objects for the treatment of comprise the object of illness due to suffering from H5N1 infects and wherein H5N1 infect and wait those objects of being prevented.The object partly or completely restoring in H5N1 infects perhaps also needs treatment.Generation, development or the progress of one or more symptom that the H5N1 propagation that prevention comprises inhibition or reduction or inhibition or reduction are relevant to H5N1 infection.
Term " carrier " refers to such nucleic acid molecule, can insert wherein another kind of nucleic acid molecule to import in host, and in host, it will be replicated, 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 the carrier derived from phage or plant or animal (comprising people) virus.Carrier comprises the replication orgin by host's identification of proposing, other regulatory region that also comprises promotor and identified by described host in the situation of expression vector.The carrier that contains another nucleic acid molecule is by conversion, transfection or by using cell entry mechanism to be imported in cell.Self-replicating in the host that some carrier can be imported at it (carrier for example with bacterium replication orgin can copy in bacterium).Other carrier can be integrated in host genome in the time importing in host, thereby copies together with host genome.
Summary of the invention
The invention provides can specific binding influenza virus H 5 N 1 and present in H5N1 and active human binding molecules.The present invention also provides and finishes the binding molecule that closes the epi-position in hemagglutinin total between influenza virus sub-strain, and therefore relates in the hypotype based on H5-, H1-, H2-, H6-and H9-influenza virus as H5N1, H1N1 and the binding molecule of cross reaction between other influenza virus strain that contains the HA albumen with these defined epitopes.The invention still further relates to the nucleic acid molecule of the land of at least described human binding molecules of coding.The present invention further provides human binding molecules of the present invention and prevented and/or treated the application of suffering from H5N1 infection or the object in 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 can specific binding influenza virus A, the particularly binding molecule of influenza virus A hypotype H5N1.Preferably, described binding molecule is human binding molecules.Preferably, binding molecule of the present invention presents the neutralization activity for influenza virus A hypotype H5N1.On the other hand, the different influenza virus H 5 N 1 strain of binding molecule energy specific binding of the present invention and/or that it is had to neutralization is active.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 that the HA gene of H5N1 from 2004 and 2005 outburst is carried out has disclosed two different pedigrees (lineage) of HA gene, is 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 from clade 1 isolate from the H5N1 strain isolated of some circumjacent states, belongs to the clade 2 of more dispersing.Clade 1 H5N1 virus separates people and the bird from Vietnam, Thailand and Cambodia, but only separates from bird with Malaysia in Laos.Clade 2 viruses are found in the virus just separating from the bird of China, Indonesia, Japan and Korea S.Within 2003, respectively formed clade 1 ' (be also classified as in clade 1) and clade 3 (see WHOGlobal Influenza Program Surveillance Network, 2005) in Hong Kong from bird and the virus separating people with 1997.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/recom mendation vaccine.pdf.Preferably, binding molecule energy specific binding clade 1 of the present invention, clade 2 and clade 3 strains and that it is had to neutralization is active.Influenza virus H 5 N 1 binding molecule energy specific binding survival of the present invention, 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 by formaldehyde, β-propionic acid lactone (BPL), Thiomersalate and/or UV treatment.
Binding molecule of the present invention also can specific binding influenza virus H 5 N 1 one or more fragment, the H5N1 protein producing as one or more protein derived from hypotype H5N1 and/or (many) peptides or one or more restructuring and/or the prepared product of polypeptide.For treating and/or preventing the method that H5N1 infects, the surface that described binding molecule preferably can specific binding H5N1 can and protein discharge necessary surface glycoprotein hemagglutinin (HA) and neuraminidase (NA) or membranin (M1 and M2) as adhered to for virus with cell.In specific embodiment, the HA molecule of binding molecule energy specific binding H5N1 strain of the present invention.They perhaps can specific binding HA molecule HA1 and/or HA2 subunit.Their linearity or structure and/or conformational epitopes on perhaps can HA1 and/or the HA2 subunit of specific binding HA molecule.Described HA molecule can produce and optionally separate from virus or restructuring by purifying before using.Or HA can express on the surface of cell.
For diagnostic purpose, binding molecule also can specific binding H5N1 surface on non-existent protein, 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 the aminoacid sequence of protein 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, the fragment of the above-mentioned protein of binding molecule energy specific binding of the present invention and/or polypeptide, wherein said fragment at least comprises the antigenic determinant being identified by binding molecule of the present invention.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 specific binding HA the outer part of born of the same parents (herein also referred to as solvable HA (sHA)).
Binding molecule of the present invention can be that complete for example polyclone of immunoglobulin molecules or monoclonal antibody or described binding molecule can be Fabs, includes 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-chain antibody, three chain antibodies, four chain antibodies and at least contain and be enough to (many) peptides of the fragment of giving the immunoglobulin (Ig) of being combined with the specific antigens of influenza virus H 5 N 1 strain or its fragment.In preferred embodiments, binding molecule of the present invention is human monoclonal antibodies.
Binding molecule of the present invention can use with form unsegregated or that separate.In addition, binding molecule of the present invention can be applied separately or apply in the mixture that comprises at least one 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 the pharmaceutical composition of more kinds of binding molecule of the present invention, its variant or fragment.For example, there is difference but the binding molecule of complementary activity can be combined in a treatment plan to reach prevention, treatment or the diagnostic effect of hope, but or also the binding molecule with identical activity can be combined in a treatment plan to reach prevention, treatment or the diagnostic effect of hope.Optionally, described mixture further comprises at least one other therapeutical agent.Preferably, described therapeutical agent for example, for example, infects as M2 inhibitor (amantidine, Rimantadine (rimantadine)) and/or neuraminidase inhibitor (zanamivir (zanamivir), Oseltamivir (oseltamivir)) can be used for preventing and/or treating influenza virus H 5 N 1.
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) 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, more preferably less than 1.0 × 10 -9m, more preferably less than 1.0 × 10 -10m, even more preferably less than 1.0 × 10 -11m, particularly preferably lower than 1.0 × 10 -12m.Described affinity costant is according to Antibody types and can be different.For example, the affinity of IgM isotype is in conjunction with referring at least about 1.0 × 10 -7the binding affinity of M.Affinity constant can for example by using surface plasma resonance technology to measure, for example, use BIACORE system (Pharmacia Biosensor AB, Uppsala, Sweden).
Binding molecule of the present invention can be in conjunction with for example influenza virus H 5 N 1 in sample or in suspension of soluble form or its fragment or can be in conjunction with being combined with carrier or base material or adhering to influenza virus H 5 N 1 or its fragment of being for example combined with microtitre flat board, film and pearl or adhering to.Carrier or base material can such as, be made up of glass, plastics (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-unpack format.
It is active that binding molecule of the present invention presents neutralization.The for example measurement as described herein of neutralization activity.The another kind of active measuring method of neutralization of measuring is for example at WHO Manual on Animal InfluenzaDiagnosis and Surveillance, and Geneva:World Health Organisation, describes in 2005, version2002.5.The present invention relates to the human binding molecules separating, it can be identified 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 for the influenza virus of the HA that comprises H5 hypotype.The HA that contains this H5 hypotype and be that the example with the influenza virus strain of the popular important strain threatening is H5N1, H5N2, H5N8 and H5N9.In particularly preferably being at least and the binding molecule of H5N1 influenza virus strain.Preferably, the combination of described binding molecule of the present invention and described HA albumen does not rely on the epi-position in the HA1 subunit of HA albumen.In prior art field, describe also in conjunction with the known murine antibody (C179) of identical epi-position in HA2 structural domain also depend on the HA1 structural domain of HA albumen in the combination 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, much antibody of the present invention (as CR6307 and CR6323) does not rely on conformational epitope, even can identify the HA2 epi-position (when for western blotting) of reduction form.This is better than the antibody of prior art, because when the no matter sudden change of what sample and import conformational change in HA albumen time, this conformational change unlikely hinders the combination of antibody of the present invention and HA2 epi-position in the another part due at protein; And in the time that this sudden change occurs, conformation-dependent antibody very may not be in conjunction with.
In another preferred embodiment, it is active that binding molecule of the present invention also has neutralization for the influenza virus of the HA that comprises H1 hypotype, and it is active that preferred wherein said binding molecule also has neutralization for the influenza virus of the HA that comprises H2, H6 and/or H9 hypotype.Disclose the epi-position existing in the HA2 epi-position existing in binding molecule of the present invention and H5, H1, H2, H6 and H9 hypotype herein and interacted, and disclosed binding molecule of the present invention because this epi-position is shared and have a cross neutralization between influenza virus sub-strain.Infer that depending on specific part in HA2 structural domain be combined the binding molecule of the present invention of (and not and have another epi-position that sudden change is inclined in HA1 be combined) and between influenza virus sub-strain, have cross neutralization because seem its do not rely on HA1 in the combination of the structural domain obviously being changed due 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 HA2 subunit, described epi-position is selected from a group of following aminoacid sequence composition: 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).From the data shown in table 13, can infer that GVTNKVNSIIDK (the SEQ ID NO:368) epi-position existing in some binding molecule CR6261, CR6325 of the present invention and CR6329 and H5N1 interacts, and be not subject to the obstruction suddenling change in the TGLRN epi-position in HA1, this sudden change affects the combination of C179.In addition, some binding molecules, as the obstruction that CR6307 and CR6323 are not even subject to escape mutant, sport L-glutamic acid (GVTNKENSIIDK (SEQ ID NO:370)) at the 6th α-amino-isovaleric acid as described in Okuno et al. (1993).A part for the α spiral extending in this epi-position ShiHA2 district.Predict that this infers the residue that is exposed to solvent in epi-position is most the residue at runic underscore place: GV tnKE nsI idK (SEQ ID NO:370).The most accessible binding molecule of these amino acid, and therefore form the most important region of epi-position.Identical of views with this, highlighted amino acid is being definitely conservative aspect homogeny and position in all sequences that present.The knowledge of this respect can be used for predicting the combination epi-position (being H3, H7 and B strain) in influenza virus sub-strain without above-mentioned identical sequence.
Preferred binding molecule of the present invention is selected from as next group:
A) binding molecule that comprises heavy chain CDR3 district shown in heavy chain CDR2 district shown in heavy chain CDR1 district shown in SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3,
B) binding molecule that comprises heavy chain CDR3 district shown in heavy chain CDR2 district shown in heavy chain CDR1 district shown in SEQ ID NO:16, SEQ ID NO:17 and SEQ ID NO:18,
C) binding molecule that comprises heavy chain CDR3 district shown in heavy chain CDR2 district shown in heavy chain CDR1 district shown in SEQ ID NO:1, SEQ ID NO:22 and SEQ ID NO:23,
D) binding molecule that comprises heavy chain CDR3 district shown in heavy chain CDR2 district shown in heavy chain CDR1 district shown in SEQ ID NO:27, SEQ ID NO:28 and SEQ ID NO:29,
E) binding molecule that comprises heavy chain CDR3 district shown in heavy chain CDR2 district shown in heavy chain CDR1 district shown in SEQ ID NO:39, SEQ ID NO:40 and SEQ ID NO:41,
F) binding molecule that comprises heavy chain CDR3 district shown in heavy chain CDR2 district shown in heavy chain CDR1 district shown in SEQ ID NO:45, SEQ ID NO:46 and SEQ ID NO:47,
G) binding molecule that comprises heavy chain CDR3 district shown in heavy chain CDR2 district shown in heavy chain CDR1 district shown in SEQ ID NO:1, SEQ ID NO:49 and SEQ ID NO:50,
H) binding molecule that comprises heavy chain CDR3 district shown in heavy chain CDR2 district shown in heavy chain CDR1 district shown in SEQ ID NO:52, SEQ ID NO:53 and SEQ ID NO:54,
I) binding molecule that comprises heavy chain CDR3 district shown in heavy chain CDR2 district shown in heavy chain CDR1 district shown in SEQ ID NO:262, SEQ ID NO:263 and SEQ ID NO:264,
J) binding molecule that comprises heavy chain CDR3 district shown in heavy chain CDR269 district shown in heavy chain CDR1 district shown in SEQ ID NO:268, SEQ ID NO:2 and SEQ ID NO:270,
K) binding molecule that comprises heavy chain CDR3 district shown in heavy chain CDR2 district shown in heavy chain CDR1 district shown in SEQ ID NO:274, SEQ ID NO:275 and SEQ ID NO:276,
1) binding molecule that comprises heavy chain CDR3 district shown in heavy chain CDR2 district shown in heavy chain CDR1 district shown in SEQ ID NO:280, SEQ ID NO:281 and SEQ ID NO:282,
M) binding molecule that comprises heavy chain CDR3 district shown in heavy chain CDR2 district shown in heavy chain CDR1 district shown in SEQ ID NO:286, SEQ ID NO:287 and SEQ ID NO:288,
N) binding molecule that comprises heavy chain CDR3 district shown in heavy chain CDR2 district shown in heavy chain CDR1 district shown in SEQ ID NO:292, SEQ ID NO:293 and SEQ ID NO:294,
O) binding molecule that comprises heavy chain CDR3 district shown in heavy chain CDR2 district shown in heavy chain CDR1 district shown in SEQ ID NO:304, SEQ ID NO:305 and SEQ ID NO:306, and
P) binding molecule that comprises heavy chain CDR3 district shown in heavy chain CDR2 district shown in heavy chain CDR1 district shown in SEQ ID NO:310, SEQ ID NO:311 and SEQ ID NO:312.
In a preferred embodiment, binding molecule of the present invention, as medicine, is preferred for diagnosis, treats and/or prevents influenza infection.In aspect of this application, described influenza infection is due to relevant to popularity outburst or have with popularity and break out (seeing WO 2007/045674 and table wherein) due to the influenza virus of relevant potentiality.Preferably, a group of selecting free H1N1, H5N1, H5N2, H5N8, H5N9, virus based on H2 and H9N2 to form of the described influenza virus strain that disease relevant to popularity outburst and that caused by these strains can be treated by binding molecule of the present invention.
The invention still further relates to the pharmaceutical composition that comprises binding molecule of the present invention and the acceptable vehicle of medicine.
In another embodiment, the present invention relates to binding molecule of the present invention and diagnose, prevent and/or treat the application in the medicine of influenza infection in preparation.This infection can occur in microcommunity, but also can propagate at world wide in prevailing disease mode in season, or more seriously at global spread, millions of individualities are in danger.The invention provides to neutralize and cause prevailing disease and the binding molecule of the infection of potential global epiphytotics influenza virus strain 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 due to and the combination of shared epi-position between the HA albumen of various flows Influenza Virus strain, therefore can use at present binding molecule of the present invention between these strains, to carry out cross-neutralization.This is particularly advantageous; because before infecting or give afterwards described binding molecule and can protect Mammals (as embodiment discloses), therefore not clear described infection whether during by the causing of the strain based on H1, H2, H5, H6 or H9 (at the commitment of morbidity) also play effect like this.When can using binding molecule prophylactic treatment of the present invention or infecting, treat healthy workers, soldier and general population.Potentially, binding molecule of the present invention can huge stocks form be prepared and storage, because it provides the provide protection for different popular strains, and is favourable for preparing for contingent flu outbreak in the future.
In a preferred embodiment, human binding molecules of the present invention is characterised in that described human binding molecules is selected from as next group: a) comprise the heavy chain CDR1 district with amino acid sequence as shown in SEQ ID NO:1, there is the heavy chain CDR2 district of the shown amino acid sequence of SEQ ID NO:2, there is the heavy chain CDR3 district of the shown amino acid sequence of SEQ ID NO:3, there is the light chain CDR1 district of the shown amino acid sequence of SEQ ID NO:4, the human binding molecules in the light chain CDR2 district with the shown amino acid sequence of SEQ ID NO:5 and the light chain CDR3 district with the shown amino acid sequence of SEQ ID NO:6, b) the heavy chain CDR1 district with the shown amino acid sequence of SEQ ID NO:1 is comprised, there is the heavy chain CDR2 district of the shown amino acid sequence of SEQ ID NO:2, there is the heavy chain CDR3 district of the shown amino acid sequence of SEQ ID NO:3, there is the light chain CDR1 district of the shown amino acid sequence of SEQ ID NO:7, the human binding molecules in the light chain CDR2 district with the shown amino acid sequence of SEQ ID NO:8 and the light chain CDR3 district with the shown amino acid sequence of SEQ ID NO:9, c) the heavy chain CDR1 district with the shown amino acid sequence of SEQ ID NO:1 is comprised, there is the heavy chain CDR2 district of the shown amino acid sequence of SEQ ID NO:2, there is the heavy chain CDR3 district of the shown amino acid sequence of SEQ ID NO:3, there is the light chain CDR1 district of the shown amino acid sequence of SEQ ID NO:10, the human binding molecules in the light chain CDR2 district with the shown amino acid sequence of SEQ ID NO:11 and the light chain CDR3 district with the shown amino acid sequence of SEQ ID NO:12, d) the heavy chain CDR1 district with the shown amino acid sequence of SEQ ID NO:1 is comprised, there is the heavy chain CDR2 district of the shown amino acid sequence of SEQ IDNO:2, there is the heavy chain CDR3 district of the shown amino acid sequence of SEQ ID NO:3, there is the light chain CDR1 district of the shown amino acid sequence of SEQ ID NO:13, the human binding molecules in the light chain CDR2 district with the shown amino acid sequence of SEQ ID NO:14 and the light chain CDR3 district with the shown amino acid sequence of SEQ ID NO:15, e) the heavy chain CDR1 district with the shown amino acid sequence of SEQ ID NO:16 is comprised, there is the heavy chain CDR2 district of the shown amino acid sequence of SEQ ID NO:17, there is the heavy chain CDR3 district of the shown amino acid sequence of SEQ ID NO:18, there is the light chain CDR1 district of the shown amino acid sequence of SEQ ID NO:19, the human binding molecules in the light chain CDR2 district with the shown amino acid sequence of SEQ ID NO:20 and the light chain CDR3 district with the shown amino acid sequence of SEQ ID NO:21, f) comprise and there is SEQ ID NO:The heavy chain CDR1 district of 1 shown amino acid sequence, there is the heavy chain CDR2 district of the shown amino acid sequence of SEQ ID NO:22, there is the heavy chain CDR3 district of the shown amino acid sequence of SEQID NO:23, there is the light chain CDR1 district of the shown amino acid sequence of SEQ ID NO:24, the human binding molecules in the light chain CDR2 district with the shown amino acid sequence of SEQ ID NO:25 and the light chain CDR3 district with the shown amino acid sequence of SEQ ID NO:26, g) the heavy chain CDR1 district with the shown amino acid sequence of SEQ ID NO:27 is comprised, there is the heavy chain CDR2 district of the shown amino acid sequence of SEQ IDNO:28, there is the heavy chain CDR3 district of the shown amino acid sequence of SEQ ID NO:29, there is the light chain CDR1 district of the shown amino acid sequence of SEQ ID NO:30, the human binding molecules in the light chain CDR2 district with the shown amino acid sequence of SEQ ID NO:31 and the light chain CDR3 district with the shown amino acid sequence of SEQ IDNO:32, h) the heavy chain CDR1 district with the shown amino acid sequence of SEQ IDNO:1 is comprised, there is the heavy chain CDR2 district of the shown amino acid sequence of SEQ ID NO:2, there is the heavy chain CDR3 district of the shown amino acid sequence of SEQ ID NO:3, there is the light chain CDR1 district of the shown amino acid sequence of SEQ ID NO:33, the human binding molecules in the light chain CDR2 district with the shown amino acid sequence of SEQ ID NO:34 and the light chain CDR3 district with the shown amino acid sequence of SEQ ID NO:35, i) the heavy chain CDR1 district with the shown amino acid sequence of SEQ ID NO:1 is comprised, there is the heavy chain CDR2 district of the shown amino acid sequence of SEQ ID NO:2, there is the heavy chain CDR3 district of the shown amino acid sequence of SEQ IDNO:3, there is the light chain CDR1 district of the shown amino acid sequence of SEQ ID NO:36, the human binding molecules in the light chain CDR2 district with the shown amino acid sequence of SEQ ID NO:37 and the light chain CDR3 district with the shown amino acid sequence of SEQ ID NO:38, j) the heavy chain CDR1 district with the shown amino acid sequence of SEQ ID NO:39 is comprised, there is the heavy chain CDR2 district of the shown amino acid sequence of SEQ ID NO:40, there is the heavy chain CDR3 district of the shown amino acid sequence of SEQ ID NO:41, there is the light chain CDR1 district of the shown amino acid sequence of SEQ ID NO:42, the human binding molecules in the light chain CDR2 district with the shown amino acid sequence of SEQ ID NO:43 and the light chain CDR3 district with the shown amino acid sequence of SEQ ID NO:44, k) the heavy chain CDR1 district with the shown amino acid sequence of SEQ ID NO:45 is comprised, there is the heavy chain CDR2 district of the shown amino acid sequence of SEQ ID NO:46,There is the heavy chain CDR3 district of the shown amino acid sequence of SEQ ID NO:47, there is the light chain CDR1 district of the shown amino acid sequence of SEQID NO:7, the human binding molecules in the light chain CDR2 district with the shown amino acid sequence of SEQ ID NO:8 and the light chain CDR3 district with the shown amino acid sequence of SEQ ID NO:48, 1) the heavy chain CDR1 district with the shown amino acid sequence of SEQ ID NO:1 is comprised, there is the heavy chain CDR2 district of the shown amino acid sequence of SEQ ID NO:49, there is the heavy chain CDR3 district of the shown amino acid sequence of SEQ IDNO:50, there is the light chain CDR1 district of the shown amino acid sequence of SEQ ID NO:33, the human binding molecules in the light chain CDR2 district with the shown amino acid sequence of SEQ ID NO:34 and the light chain CDR3 district with the shown amino acid sequence of SEQ ID NO:51, m) the heavy chain CDR1 district with the shown amino acid sequence of SEQ ID NO:52 is comprised, there is the heavy chain CDR2 district of the shown amino acid sequence of SEQ IDNO:53, there is the heavy chain CDR3 district of the shown amino acid sequence of SEQ ID NO:54, there is the light chain CDR1 district of the shown amino acid sequence of SEQ ID NO:55, the human binding molecules in the light chain CDR2 district with the shown amino acid sequence of SEQ ID NO:56 and the light chain CDR3 district with the shown amino acid sequence of SEQ IDNO:57, n) the heavy chain CDR1 district with the shown amino acid sequence of SEQ IDNO:262 is comprised, there is the heavy chain CDR2 district of the shown amino acid sequence of SEQ ID NO:263, there is the heavy chain CDR3 district of the shown amino acid sequence of SEQ ID NO:264, there is the light chain CDR1 district of the shown amino acid sequence of SEQ ID NO:265, the human binding molecules in the light chain CDR2 district with the shown amino acid sequence of SEQ IDNO:266 and the light chain CDR3 district with the shown amino acid sequence of SEQ ID NO:267, o) the heavy chain CDR1 district with the shown amino acid sequence of SEQ ID NO:268 is comprised, there is the heavy chain CDR2 district of the shown amino acid sequence of SEQ ID NO:269, there is the heavy chain CDR3 district of the shown amino acid sequence of SEQ ID NO:270, there is the light chain CDR1 district of the shown amino acid sequence of SEQID NO:271, the human binding molecules in the light chain CDR2 district with the shown amino acid sequence of SEQ ID NO:272 and the light chain CDR3 district with the shown amino acid sequence of SEQ ID NO:273, p) the heavy chain CDR1 district with the shown amino acid sequence of SEQ ID NO:274 is comprised, there is the heavy chain CDR2 district of the shown amino acid sequence of SEQ ID NO:275, there is the heavy chain CDR3 district of the shown amino acid sequence of SEQID NO:276, there is SEQ ID NO:The light chain CDR1 district of 277 shown amino acid sequences, the human binding molecules in the light chain CDR2 district with the shown amino acid sequence of SEQ ID NO:278 and the light chain CDR3 district with the shown amino acid sequence of SEQ ID NO:279, q) the heavy chain CDR1 district with the shown amino acid sequence of SEQ ID NO:280 is comprised, there is the heavy chain CDR2 district of the shown amino acid sequence of SEQ ID NO:281, there is the heavy chain CDR3 district of the shown amino acid sequence of SEQ ID NO:282, there is the light chain CDR1 district of the shown amino acid sequence of SEQ ID NO:283, the human binding molecules in the light chain CDR2 district with the shown amino acid sequence of SEQ ID NO:284 and the light chain CDR3 district with the shown amino acid sequence of SEQ ID NO:285, r) the heavy chain CDR1 district with the shown amino acid sequence of SEQ ID NO:286 is comprised, there is the heavy chain CDR2 district of the shown amino acid sequence of SEQ ID NO:287, there is the heavy chain CDR3 district of the shown amino acid sequence of SEQ ID NO:288, there is the light chain CDR1 district of the shown amino acid sequence of SEQ ID NO:289, the human binding molecules in the light chain CDR2 district with the shown amino acid sequence of SEQ ID NO:290 and the light chain CDR3 district with the shown amino acid sequence of SEQ IDNO:291, s) the heavy chain CDR1 district with the shown amino acid sequence of SEQ IDNO:292 is comprised, there is the heavy chain CDR2 district of the shown amino acid sequence of SEQ ID NO:293, there is the heavy chain CDR3 district of the shown amino acid sequence of SEQ ID NO:294, there is the light chain CDR1 district of the shown amino acid sequence of SEQ ID NO:295, the human binding molecules in the light chain CDR2 district with the shown amino acid sequence of SEQ IDNO:296 and the light chain CDR3 district with the shown amino acid sequence of SEQ ID NO:297, t) the heavy chain CDR1 district with the shown amino acid sequence of SEQ ID NO:304 is comprised, there is the heavy chain CDR2 district of the shown amino acid sequence of SEQ ID NO:305, there is the heavy chain CDR3 district of the shown amino acid sequence of SEQ ID NO:306, there is the light chain CDR1 district of the shown amino acid sequence of SEQ IDNO:307, the human binding molecules in the light chain CDR2 district with the shown amino acid sequence of SEQ ID NO:308 and the light chain CDR3 district with the shown amino acid sequence of SEQ ID NO:309, u) the heavy chain CDR1 district with the shown amino acid sequence of SEQ ID NO:310 is comprised, there is the heavy chain CDR2 district of the shown amino acid sequence of SEQ ID NO:311, there is the heavy chain CDR3 district of the shown amino acid sequence of SEQID NO:312, there is the light chain CDR1 district of the shown amino acid sequence of SEQ ID NO:313,The human binding molecules in the light chain CDR2 district with the shown amino acid sequence of SEQ ID NO:314 and the light chain CDR3 district with the shown amino acid sequence of SEQ ID NO:315, v) the heavy chain CDR1 district with the shown amino acid sequence of SEQ ID NO:238 is comprised, there is the heavy chain CDR2 district of the shown amino acid sequence of SEQ ID NO:239, there is the heavy chain CDR3 district of the shown amino acid sequence of SEQ ID NO:240, there is the light chain CDR1 district of the shown amino acid sequence of SEQ ID NO:241, the human binding molecules in the light chain CDR2 district with the shown amino acid sequence of SEQ ID NO:242 and the light chain CDR3 district with the shown amino acid sequence of SEQ ID NO:243, w) the heavy chain CDR1 district with the shown amino acid sequence of SEQ ID NO:244 is comprised, there is the heavy chain CDR2 district of the shown amino acid sequence of SEQ IDNO:245, there is the heavy chain CDR3 district of the shown amino acid sequence of SEQ ID NO:246, there is the light chain CDR1 district of the shown amino acid sequence of SEQ ID NO:247, the human binding molecules in the light chain CDR2 district with the shown amino acid sequence of SEQ ID NO:248 and the light chain CDR3 district with the shown amino acid sequence of SEQ IDNO:249, x) the heavy chain CDR1 district with the shown amino acid sequence of SEQ IDNO:250 is comprised, there is the heavy chain CDR2 district of the shown amino acid sequence of SEQ ID NO:251, there is the heavy chain CDR3 district of the shown amino acid sequence of SEQ ID NO:252, there is the light chain CDR1 district of the shown amino acid sequence of SEQ ID NO:253, the human binding molecules in the light chain CDR2 district with the shown amino acid sequence of SEQ IDNO:254 and the light chain CDR3 district with the shown amino acid sequence of SEQ ID NO:255, y) the heavy chain CDR1 district with the shown amino acid sequence of SEQ ID NO:256 is comprised, there is the heavy chain CDR2 district of the shown amino acid sequence of SEQ ID NO:257, there is the heavy chain CDR3 district of the shown amino acid sequence of SEQ ID NO:258, there is the light chain CDR1 district of the shown amino acid sequence of SEQID NO:259, the human binding molecules in the light chain CDR2 district with the shown amino acid sequence of SEQ ID NO:260 and the light chain CDR3 district with the shown amino acid sequence of SEQ ID NO:261, and z) comprise the heavy chain CDR1 district with the shown amino acid sequence of SEQ ID NO:298, there is the heavy chain CDR2 district of the shown amino acid sequence of SEQ ID NO:299, there is the heavy chain CDR3 district of the shown amino acid sequence of SEQ ID NO:300, there is the light chain CDR1 district of the shown amino acid sequence of SEQ ID NO:301, there is SEQ ID NO:The light chain CDR2 district of 302 shown amino acid sequences and there is the human binding molecules in light chain CDR3 district of the shown amino acid sequence of SEQ ID NO:303.
In specific embodiment, binding molecule of the present invention comprise have aminoacid sequence shown in SEQ ID NO:1 heavy chain CDR1 district, there is the heavy chain CDR2 district of aminoacid sequence shown in SEQ ID NO:2 and there is the heavy chain CDR3 district of aminoacid sequence shown in SEQ ID NO:3.Binding molecule CDR of the present invention district is shown in table 7.Described in Kabat et al. (1991), CDR district is the sequence of the interested protein of immunology.In embodiments of the invention, binding molecule can comprise two, three, four, five or all Liu Ge CDR district that disclose herein.Preferably, binding molecule of the present invention comprises at least two CDR that disclose herein.
In one embodiment, binding molecule of the present invention comprises VH germline VH1-69 and (sees Tomlinson IM, 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, described heavy chain comprises and has the variable heavy chain being selected from as the aminoacid sequence 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, described light chain comprises and has the variable light chain being selected from as the aminoacid sequence 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 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 with parental generation binding molecule competition specific binding influenza virus H 5 N 1 or its fragment, think the functional variant that this variant molecule is 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 specific binding of described functional variant energy is by the different influenza virus H 5 N 1 strain of at least two (or more) of parental generation binding molecule specific binding or its fragment.In addition, if certain molecule has the active influenza virus H 5 N 1 of neutralization, preferably has neutralization activity at least two (or multiple) influenza virus H 5 N 1 strain it for parental generation binding molecule, think that this molecule is the functional variant of binding molecule of the present invention.Functional variant include but not limited to primary structure sequence substantially similar, but for example contain in parental generation binding molecule the derivative of chemistry in undiscovered external or body and/or biochemical modification.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.
Or, functional variant can be binding molecule of the present invention, it comprises such aminoacid sequence, the combination that contains one or more amino acid whose replacement, insertion, disappearance or this modification compared with the aminoacid sequence of described aminoacid sequence and 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 can have identical or different, higher or lower binding affinity compared with parental generation binding molecule, but still can be in conjunction with influenza virus H 5 N 1 or its fragment.For example, functional variant of the present invention can have for influenza virus H 5 N 1 or its fragment the binding affinity that increases or reduce compared with parental generation binding molecule.Preferably, variable region includes but not limited to that the aminoacid sequence in framework region, hypervariable region, particularly CDR3 district is modified.Conventionally, light chain and variable region of heavy chain comprise three hypervariable regions, comprise three CDR, and more conservative region, i.e. so-called framework region (FR).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 at least about 50% to about 99%, preferably at least about 60% to about 99%, more preferably at least about 70% to about 99%, even more preferably at least about 80% to about 99%, most preferably at least about 90% to about 99%, particularly at least about 95% to about 99%, and at least about 97% to about 99% amino acid sequence homology particularly.Computerized algorithm well known by persons skilled in the art can be used for best arranged amido acid sequence to contrast and precisely similar or identical amino-acid residue as Gap or Bestfit.Functional variant can be by using common molecular biology method known in the art to change parental generation binding molecule or its a part of acquisition, 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 neutralization activity for influenza virus H 5 N 1.Active the comparing with parental generation binding molecule of described neutralization can be identical or higher or lower.After this,, in the time 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, comprise at least one binding molecule described herein and further comprise at least one mark as the molecule of detectable part/material.The invention still further relates to the mixture of immunoconjugates of the present invention or the mixture of at least one immunoconjugates of the present invention and another molecule, described another molecule is 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 noncovalently be combined/put together with binding molecule.Described mark also can by covalent linkage and human binding molecules directly in conjunction with/put together.Or described mark can connect compound by one or more and be combined/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 therapeutical agent, but they can be also 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 that comprises detectable substance for for example evaluating the object generation whether influenza virus infection H5N1 strain or the part monitoring influenza virus H 5 N 1 as clinical experiment program infect or progress for example to determine effect of TA scheme.But they also can be 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.Such as, in order to detect and/or analysis and/or diagnostic purpose depend on the particular detection/analysis/diagnostic techniques of use and/or such as immunohistochemical staining of method (tissue) sample, flow cytometry, the detection of laser scanning cytometry, fluorescence immunoassay, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), biological assay (phagolysis mensuration), western blotting application etc. for the mark of mark binding molecule.Be well known to those skilled in the art for detection/analysis/diagnostic techniques known in the art and/or the suitable mark of method.
In addition, human binding molecules of the present invention or immunoconjugates also can be attached on solid support, and it is used in particular in vitroimmunoassay or the purifying of influenza virus H 5 N 1 or its fragment.This solid support can be porous or atresia, plane or nonplanar.Binding molecule of the present invention can merge so that purifying as peptide with flag sequence.The example of described flag sequence includes but not limited to six histidine marks, hemagglutinin (HA) mark, myc mark or flag mark.Or a kind of antibody can be puted together and form antibody allos conjugate (heteroconjugate) with another kind of antibody.On the other hand, binding molecule of the present invention can be puted together/adhere to one or more antigen.Preferably, these antigens are by the antigen of immune system recognition of object that has given binding molecule-antigen conjugate.Described antigen can be mutually the same, but can be also different.The conjugation methods that makes to adhere to antigen and binding molecule is known in the art, includes but not limited to use linking agent.Binding molecule of the present invention is attacked in conjunction with influenza virus H 5 N 1 and the antigen that is attached to binding molecule the strong T cell causing for described conjugate, the destruction that finally causes influenza virus H 5 N 1.
Except for example, puting together by direct or indirect (passing through joint), chemistry produces immunoconjugates, 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 building nucleic acid molecule and expressing subsequently generations of recombinating of described nucleic acid molecule, the nucleotide sequence of the nucleotide sequence that described nucleic acid molecule comprises in-frame coding binding molecule and the appropriate flags of encoding.
The present invention provides the nucleic acid molecule of encode at least one binding molecule of the present invention, its functional variant or immunoconjugates on the other hand.This nucleic acid molecule can be as intermediate to clone, for example, for affinity maturation method described above.In a preferred embodiment, described nucleic acid molecule is isolated or purified.
Technician is also a part of the present invention by the functional variant of recognizing these nucleic acid molecule.Functional variant is such nucleotide sequence, by using standard genetic code it directly can be translated so that the aminoacid sequence identical with the sequence of translating from parental generation nucleic acid molecule to be provided.
Preferably, the binding molecule that described nucleic acid molecule encoding comprises above-mentioned CDR district.The binding molecule in 2,3,4,5 or even all 6 GeCDR districts that in another embodiment, described nucleic acid molecule encoding comprises binding molecule of the present invention.
In another embodiment, the binding molecule that described nucleic acid molecule encoding comprises heavy chain, described heavy chain comprises above-mentioned variable heavy chain sequence.In another embodiment, the binding molecule that described nucleic acid molecule encoding comprises light chain, described light chain comprises above-mentioned variable sequence of light chain.The nucleotides sequence of binding molecule of the present invention is listed in 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 as F, R1, RP1, Co1, pBR322, TOL, Ti etc.; Clay; Phage is 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 clone and/or expresses binding molecule of the present invention, even can be used for gene therapy object.The present invention also comprises the carrier that comprises one or more nucleic acid molecule of the present invention that regulates nucleic acid molecule to be operably connected with one or more expression.The selective dependency of carrier is in restructuring program subsequently and the host of use.Carrier is imported in host cell and can be realized 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 copied together with it is integrated into karyomit(e) wherein.Preferably, described carrier contains one or more selective marker.The selective dependency of mark is in the host cell of selecting, 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, Liu Suanyan NEOMYCIN SULPHATE, 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 encoding human binding molecule that the protein of separation human binding molecules or one or more nucleic acid molecule of peptide be operably connected with coding.These protein or peptide include but not limited to glutathione-S-transferase, maltose binding protein, polyhistidine, green fluorescent protein, luciferase and beta-galactosidase enzymes in conjunction with metal.
The host of the carrier of one or more copy that contains above-mentioned carrier is another aspect of the present invention.Preferably, described host is 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, and some bacterial classifications of for example enterobacter are as intestinal bacteria (E.coli) and Rhodopseudomonas.In fungal cell, preferably use yeast cell.Expression in yeast can be by being used yeast strain to realize, and described yeast strain is as pichia pastoris phaff (Pichia pastoris), yeast saccharomyces cerevisiae (Saccharomyces cerevisiae) and multiple-shaped nuohan inferior yeast (Hansenula polymorpha).In addition, insect cell can be used as host cell as fruit bat and Sf9 cell.In addition, host cell can be vegetable cell, for example farm crop are as the cell of forest plants, or provide food and raw-material vegetable cell, as cereal grass or medicinal plant, or the cell of ornamental plant, or the cell of bouquet root farm crop (flower bulb crop).(transgenosis) plant or the vegetable cell that transform produce by currently known methods, and the DNA that for example agriculture bacillus mediated transgenosis, leaf dish transform, induce by polyoxyethylene glycol shifts the protoplast transformation of carrying out, electroporation, ultrasonic, microinjection or bolistic gene transfer method.In addition, suitable expression system can be 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 protein of the expression with posttranslational modification, the most similar to the natural molecule in Mammals source.Owing to the present invention relates to give people's molecule, therefore complete people's expression system particularly preferably.Therefore, preferred host cell is people's cell.The example of people's cell is HeLa, 911, AT1080, A549,293 and HEK293T cell.In preferred embodiments, people produces at least funtion part of the nucleotide sequence that cell comprises encoding adenovirus E 1 district that can expression-form.In a more preferred embodiment, described host cell derived from human retina and with the nucleic acid immortalization that comprises adenovirus E 1 sequence, for example 911 cells or be deposited in and be positioned at CAMR on February 29th, 1996, Salisbury, Wiltshire SP4 OJG, clone in the European cell culture center (European Collection of Cell Cultures (ECACC)) of GreatBritain, preserving number is 96022940, with (PER.C6 is the registered trademark of Crucell Holland B.V.) trade mark is sold.For the application's object, " PER.C6 cell " refers to 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.In host cell, the generation of recombinant protein can be carried out according to method well known in the art.With the cell that trade mark is sold is described as being applied in WO 00/63403 of production platform of interested protein, and described document is incorporated to for referencial use herein with 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) under the condition that is of value to binding molecule expression, to cultivate host of the present invention, b) optionally reclaims the binding molecule of expressing.The binding molecule of expressing can reclaim from cell-free extract, but preferably from substratum, reclaims.Above-mentioned production method also can be used for producing the functional variant of binding molecule of the present invention and/or immunoconjugates.From cell-free extract or substratum, reclaiming protein is well known to those skilled in the art as the method for binding molecule.Also be a part of the present invention by the obtainable binding molecule of aforesaid method, its functional variant and/or immunoconjugates.
Or after host expresses in as host cell, binding molecule of the present invention and immunoconjugates can produce or use in cell free translation system synthetic generation of RNA nucleic acid derived from DNA molecular of the present invention by conventional peptide synthesizer is synthetic.Also be a part of the present invention by above-mentioned synthetic production method or the obtainable binding molecule of cell free translation system and immunoconjugates.
In another embodiment, binding molecule of the present invention also can produce in as rabbit, goat or ox at transgenic nonhuman mammal, and is secreted into for example its Ruzhong.
In another embodiment, the human binding molecules of binding molecule of the present invention, preferably specific binding influenza virus H 5 N 1 or its fragment can be produced as transgenic mice or rabbit by the transgenic nonhuman mammal of expressing human immunoglobulin gene.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 the prepared product immunization of influenza virus H 5 N 1 purifying or enrichment or its fragment.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 & Sons Inc., New York, described document is all incorporated to for referencial use herein.Immunization scheme generally includes or without the repeatedly immunization of adjuvant, described adjuvant, as Freund's complete adjuvant and Freund's incomplete adjuvant, also can comprise 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 prepared by B cell and the immortalized cells fusion by deriving from above-mentioned transgenic nonhuman mammal.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 is also a part of the present invention.
On the other hand, the invention provides the method for differentiating the binding molecule of specific binding influenza virus H 5 N 1 or the nucleic acid molecule of this binding molecule of encoding, described binding molecule is for example that human binding molecules is 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 packaging under the condition that is of value to combination with influenza virus H 5 N 1 or its fragment, (b) the reproducible heredity packaging that at least selection is once combined with influenza virus H 5 N 1 or its fragment, (c) pack from the reproducible heredity that separation recovery are combined with influenza virus H 5 N 1 or its fragment with influenza virus H 5 N 1 or the uncombined reproducible heredity packaging of its fragment.As used herein, reproducible hereditary packaging can be protokaryon or eukaryote, comprises cell, spore, yeast, bacterium, virus, (bacterium) phage, rrna and polysome.Preferred reproducible heredity packaging is phage.It is upper that for example scFv of described binding molecule is illustrated in reproducible heredity packaging, and they are attached to the group or the molecule that are positioned at reproducible heredity packaging outside surface.Described reproducible heredity packaging is the unit that can screen, and it comprises the screened binding molecule for the treatment of being connected with the nucleic acid molecule of coding binding molecule.Described nucleic acid molecule in vivo (for example, as carrier) or external (for example by PCR, transcribe and translate) copies.In body, copying can be self-replicating (with regard to cell), copies (with regard to virus) or the two copies (with regard to phagemid) by means of host and helper virus by means of host's factor.Reproducible hereditary packaging of showing binding molecule set is to form like this, and the nucleic acid molecule that is about to the external source binding molecule of encoding to be demonstrated imports in the reproducible hereditary genome of packing to form fusion rotein with the intrinsic protein of the outside surface normal expression from reproducible heredity packaging.The expression of described fusion rotein, be transported to outside surface and assembling causes external source binding molecule to be shown from the outside surface of reproducible heredity packaging.
Selection step in the inventive method can be carried out with influenza virus H 5 N 1, described virus be live and still there is infectivity or 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, use 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 using in aforesaid method can be unsegregated, for example, be present in the serum and/or blood of infected individuality.The influenza virus H 5 N 1 using also can separate from the cell culture in suitable culture medium.
In one embodiment, influenza virus H 5 N 1 is in suspension in the time contacting with reproducible heredity packaging.Or, in the time coming in contact, they also can with carrier coupling.In one embodiment, can carry out for the influenza virus H 5 N 1 strain of same clade with further selection for the first time.Or, can carry out for the influenza virus H 5 N 1 strain of Different Evolutionary branch (for example select for the first time to carry out for clade 1 strain, select for the second time to carry out for clade 2 or 3 strains) with further selection for the first time.
Or, select step under the condition that has fragment such as cell membrane preparations, restructuring H5N1 albumen or the polypeptide of influenza virus H 5 N 1, the fusion rotein that comprises H5N1 albumen or polypeptide, the expression restructuring protein of H5N1 or the cell of polypeptide etc., to carry out.The outer expose portion of born of the same parents of these protein or polypeptide also can be used as selection material.The fragment of influenza virus H 5 N 1 can be fixed on suitable material or can use by suspension before using.In one embodiment, described selection can be carried out for the fragment of the different fragments of influenza virus H 5 N 1 or different influenza virus H 5 N 1 strains.Find that suitable Selection and Constitute 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 that obtains specific binding influenza virus H 5 N 1 strain or the binding molecule of its fragment or the nucleic acid molecule of this binding molecule of encoding, wherein said method comprises the steps: a) to carry out the method for above-mentioned discriminating binding molecule, b) from the reproducible heredity packaging reclaiming, separates the nucleic acid molecule of described binding molecule and/or the described binding molecule of encoding.The set of the binding molecule on reproducible hereditary surface of package can be the set of scFv or Fab.For example, once determine or differentiated new scFv or Fab by the method for the nucleic acid molecule of above-mentioned discriminating binding molecule or the described binding molecule of encoding, can separate the DNA of the described scFv of coding or Fab and wish the construct of specific scFv, divalence scFv, Fab or complete human normal immunoglobulin (IgG, IgA or IgM) with standard molecular biological technique combination results coding from bacterium or phage.These construct transfections can be entered in clone, finally can produce complete human monoclonal antibodies and (see Huls et al., 1999; Boel et al., 2000).
As previously mentioned, preferred reproducible heredity packaging is phage.Differentiate and obtain for example phage display method of (people) monoclonal antibody of (people) binding molecule and be 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 Laboratoty Press, ColdSpring Harbor, describes in New York.All these reference are all incorporated to for referencial use herein with its full content.In order to build phage display library, make to express (seeing de Kruif et al., 1995b) with for example scFv (scFv) or Fab form on the surface that is integrated into the preferred filobactivirus of phage, particle of human monoclonal antibodies heavy chain and chain variable region gene.The large library typical case of the phage of expression antibody fragment is contained and is exceeded 1.0 × 10 9plant antibodies specific, and can be from the immunoglobulin (Ig) V district assembling of expressing the bone-marrow-derived lymphocyte of immunity or non-immune individuality.In a particular of the present invention, the phage library of binding molecule, preferably scFv phage library is to prepare from the RNA of cell from separating, and described cell derives from and inoculates influenza virus (for example H5N1), inoculates incoherent pathogenic agent recently, experiences the cell of the object that influenza virus H 5 N 1 infects or derive from the cell of healthy individuals recently.RNA can separate from marrow or peripheral blood, preferable separation from the B of peripheral blood lymphocyte or separation cell or even the subgroup of B cell as memory B cell.Described object can be animal, preferably people.In a preferred embodiment, described library can be assembled from the immunoglobulin (Ig) V district of being expressed by IgM memory B cell.
Or phage display library can be from building to import other antibody diversity in library (semi-synthetic library) the immune globulin variable region of part assembling in vitro.For example, the DNA sequence dna of synthetic that produce, randomization or incomplete randomization for example, is contained in the variable region of assembling in those molecular domains important for antibodies specific (CDR district) in vitro.The phage antibody that is specific to influenza virus H 5 N 1 can be selected from library, is specific to the phage of the antibody fragment of described virus or its fragment by viral or its fragment are exposed to phage library so that associative list is reached.Unconjugated phage is removed by washing, and the phage of elution of bound also breeds subsequently with ehec infection.Conventionally need to repeatedly select and breed circulation to be enough to the phage of virus described in enrichment specific binding or its fragment.If needed, before phage library is exposed to described virus or its fragment, can be first by phage library is exposed to non-target material as the virus of different strains or its fragment (being non-H5N1 influenza virus) subdue as described in phage library.These subdue (subtractor) virus or its fragment can be combined with solid phase or can be in suspension.Also can be for selecting phage with the combination of complex antigen, described complex antigen is for example optionally to have added the H5N1 albumen of other material or the compounding mixture of (many) peptides.Expression of influenza virus one or more protein of H5N1 or the host cell of (many) peptides also can be for selecting object.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 from target molecule between screening, thereby strongly increases the chance of finding relevant binding molecule.Certainly,, subduing 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 be incorporated to United States Patent (USP) 6,265,150 for referencial use herein).
Again on the one hand, the invention provides to obtain and potentially have for influenza virus H 5 N 1, the preferred method of the binding molecule of the neutralization activity of the influenza virus H 5 N 1 strain of clade 1,2 and 3 at least, described method comprises the steps: that (a) carries out as the method for the nucleic acid molecule of the binding molecule of above-mentioned acquisition specific binding influenza virus H 5 N 1 or its fragment or this binding molecule of encoding, the binding molecule that (b) inspection separates for described virus, preferably whether to have neutralization for the influenza virus H 5 N 1 strain of clade 1 and 2 at least active.Whether inspection 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, 2005 version 2002.5).
On the other hand, the present invention relates to there is the active binding molecule of neutralization by aforesaid method is obtainable.
Again on the one hand, the invention provides and comprise the preferred human monoclonal antibodies of binding molecule at least of the present invention, the composition of its functional variant, immunoconjugates at least of the present invention or its combination at least.In addition, described composition can comprise stable molecule as albumin or polyoxyethylene glycol or salt.Preferably, salt used be retain binding molecule hope biologic activity and do not cause the salt of any undesirable toxic action.If needed, human binding molecules of the present invention can be coated among a kind of material or on to protect it to avoid sour effect and maybe can make other impact natural or non-natural condition of described binding molecule inactivation.
On the one hand, the invention provides the composition that comprises at least one nucleic acid molecule of the present invention again.Described composition for example can comprise the aqueous solution, for example, as contained the aqueous solution of salt (NaCl or as above-mentioned salt), stain remover (SDS) and/or other suitable component.
In addition, the present invention relates to pharmaceutical composition, it comprises at least one binding molecule as human monoclonal antibodies of the present invention (or its function fragment or variant), at least one immunoconjugates of the present invention, at least one composition of the present invention or its combination.Pharmaceutical composition of the present invention further comprises the acceptable vehicle of at least one medicine.The acceptable vehicle of medicine is well known to those skilled in the art.Pharmaceutical composition of the present invention can further comprise at least one other therapeutical agent.Suitable medicament is also well known to those skilled in the art.
In one embodiment, described pharmaceutical composition can comprise two or more and has the active binding molecule of neutralization for influenza virus H 5 N 1.In one embodiment, in the time of applied in any combination, it is active that described binding molecule presents collaborative neutralization.In other words, described composition comprises at least two kinds and has the active binding molecule of neutralization, be characterised in that described binding molecule in and in influenza virus H 5 N 1, play synergy.As used herein, term " is worked in coordination with " and is referred in the time of applied in any combination, the adduction of the compound action of binding molecule during higher than independent application.Described synergistic binding molecule can be in conjunction with the different structure in the identical or different fragment of influenza virus H 5 N 1.Calculating synergistic mode is to calculate by combinatorial index.The concept of combinatorial index (CI) is described by Chou and Talalay (1984).Described composition also can comprise and has active a kind of binding molecule and a kind of non-neutral H5N1 specific binding molecules of neutralization.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 one other therapeutical agent, preventive and/or diagnostic reagent.Preferably, described pharmaceutical composition comprises at least one other preventive and/or therapeutical agent.Preferably, described further therapeutical agent and/or preventive are the medicaments that can prevent and/or treat influenza virus H 5 N 1 infection 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 at present influenza virus infection H5N1 patient 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 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 (reconstitution) before carrying or in the time carrying in the acceptable vehicle of suitable medicine.In the situation of the sterilized powder for the preparation of sterile injectable solution, preferred preparation method is vacuum-drying and lyophilize (freeze-drying), and generation activeconstituents powder adds from any other of previous filtration sterilization solution wishes composition.
Or, binding molecule of the present invention, immunoconjugates, nucleic acid molecule or composition can be in solution and before carrying or while conveying, can add or with the suitable acceptable mixed with excipients of medicine so that the unitary dose of injectable forms to be provided.Preferably, the acceptable vehicle of medicine using in the present invention is suitable for high drug level, can keep adequate liquidity, and if can postpone while needing to absorb.
The selection that the best of pharmaceutical composition gives approach is subject to the impact of some factors, and described factor comprises the relation of the therapeutic action of physical-chemical property, the emergency of clinical condition and the plasma concentration of bioactive molecule and the hope of bioactive molecule in composition.For example, if needed, binding molecule of the present invention can be prepared together with carrier, to protect it to avoid quick release, for example, controls release formulations, 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 be with preventing material or the coated described binding molecule of compound of described human binding molecules inactivation or give described binding molecule together with these materials or compound.For example, described binding molecule can give object in suitable carrier, and described carrier is for example 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 formulas can contain drug excipient, include but not limited to inert diluent, granulating agent and decomposition agent, bonding 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 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 dosage used 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 can be used as medicine as human monoclonal antibodies (its function fragment and variant), immunoconjugates, composition or pharmaceutical composition.Therefore the method that, uses 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 diagnosis, prevention, treatment or its combination of influenza virus H 5 N 1 infection.Their are applicable 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, such as relatives, (bird) raiser etc. of health care practitioner, infection object.
Above-mentioned molecule or composition can with can be used for diagnosis, other molecule combined utilization of preventing and/or treating.They can be in vitro, (ex vivo) or use in vivo in vitro.For example, binding molecule of the present invention can give with the vaccine of influenza virus H 5 N 1 (if can obtain) jointly as human monoclonal antibodies (or its functional variant), immunoconjugates, composition or pharmaceutical composition.Or vaccine also can give before or after 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 pharmaceutical composition with treatment or diagnosis significant quantity.Or they can be prepared separately and give.For example, other molecule as antiviral agent can general application, and binding molecule of the present invention can give by intravenously.
For example can adjust dosage regimen, so that best required replying (treatment is replied) to be provided.Suitable dosage range can be for example 0.1-100mg/kg body weight, preferably 0.5-15mg/kg body weight.In addition, for example can give once to inject, give in time repeatedly separate doses or can reduce in proportion or increase dosage according to the emergency for the treatment of situation.Molecule of the present invention and composition are preferably aseptic.The method that makes these molecules and composition sterile is known in the art.Can give with the dosage regimen similar to binding molecule of the present invention for other molecule of diagnosing, preventing and/or treating.If give separately other molecule, 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 patient.Accurate dosage regimen for people patient is picked out conventionally during clinical experiment.
In the time that as interior therapeutic, agent gives people; 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 the antibody giving conventionally substantially lower than 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 as the application in the medicine for the preparation of diagnosis, prevention, the infection for the treatment of influenza virus H 5 N 1 or its combination of neutrality human monoclonal antibodies (its function fragment and variant), immunoconjugates, nucleic acid molecule, composition or pharmaceutical composition.
Next, test kit is also a part of the present invention, and described test kit comprises at least one binding molecule of the present invention as neutrality human monoclonal antibodies (its function fragment and variant), at least one immunoconjugates, at least one nucleic acid molecule, at least one composition, at least one pharmaceutical composition, at least one carrier, at least one host or its combination.Optionally, the mentioned component of test kit of the present invention is packaged in suitable container, and indicates diagnosis, prevents and/or treats appointment illness.Mentioned component can be stored in unitary dose or multi-dose container, using the preferred aseptic aqueous solution form of the aqueous solution or as the preferred sterile freeze-drying preparation form storage of freeze-drying to be reconstructed.Described container can be made up of various materials, for example glass or plastics, and can there is the aseptic hole (for example container can be the bottle of intravenous injection solution bag or the stopper that can be pierced through by hypodermic needle) that enters.Described test kit can further comprise multiple containers, wherein comprises the acceptable damping fluid of medicine.Described test kit can further be included as business and other required material of user, comprise the substratum of other damping fluid, thinner, strainer, syringe needle, syringe, one or more suitable host, even may comprise at least one other therapeutical agent, preventive or diagnostic reagent.The subsidiary specification sheets conventionally comprising in the commercial package for the treatment of, prevention or diagnostic products of this test kit, this specification sheets contains the information about 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 that detects influenza virus H 5 N 1 in sample, wherein said method comprises the steps: that (a) contacts sample with binding molecule of the present invention (its function fragment and variant) or the immunoconjugates of diagnosis significant quantity, (b) determine the whether molecule of specific binding sample of described binding molecule or immunoconjugates.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, or abiology sample is as water, beverage etc.Described (potential) infects object can be people, and the animal that still also can carry to suspecting influenza virus H 5 N 1 detects the situation that exists of described virus, uses human binding molecules of the present invention or immunoconjugates to carry out.First can process so that it is more suitable for detection method sample.Processing means that this virus resolves into antigenicity composition as protein, (many) peptides or other antigenicity fragment thus to suspecting that the sample that contains and/or contain described virus processes.Preferably, human binding molecules of the present invention or immunoconjugates are formed between the virus that makes perhaps to exist in human binding molecules and sample or its antigenicity composition with sample under the condition of immunocomplex and contact.Then detected and measured the formation of described immunocomplex by suitable method, the formation of described immunocomplex represents to exist in sample described virus.This method comprises homogeneous and heterogeneous combination 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 screening patients serum and blood and blood derived product is ELISA and western blotting technology.Particularly preferably ELISA test.In order to be used as reagent at these measuring methods, binding molecule of the present invention or immunoconjugates are combined on the internal surface in microtitre hole expediently.Binding molecule of the present invention or immunoconjugates can be directly combined on microtitre hole.But the maximum combined in binding molecule of the present invention or immunoconjugates and hole can be by adding binding molecule of the present invention or immunoconjugates to realize with after PL200 pre-treatment hole.In addition, binding molecule of the present invention or immunoconjugates can be by known way and hole covalent attachment.Conventionally, use the binding molecule of 0.01-100 μ g/ml or immunoconjugates to be used for being coated with, but also can use greater concn and lower amount.Then sample is added with in binding molecule of the present invention or the coated hole of immunoconjugates.
In addition, binding molecule of the present invention can be used for differentiating the specific binding structure of influenza virus H 5 N 1.Described integrated structure can be the epi-position on protein and/or polypeptide.They can be linear, but can be also structure and/or conformation.In one embodiment, described integrated structure can be analyzed by PEPSCAN analytical procedure (seeing WO 84/03564, WO 93/09872, Slootstra et al., 1996).Or, can be for comprising the random peptide library from the peptide of influenza virus H 5 N 1 protein in conjunction with the peptide screening of binding molecule of the present invention.Integrated structure/peptide/epi-position of finding can be as vaccine and for diagnosing influenza virus H 5 N 1 to infect.In situation in the fragment except protein and/or polypeptide by described binding molecule combination, integrated structure can pass through mass spectroscopy, high performance liquid chromatography and magnetic nuclear resonance method and differentiate.
On the other hand, the invention provides the method for the binding molecule (or its function fragment or variant) of the epi-position of the influenza virus H 5 N 1 that screening specific binding is identical with epi-position by human binding molecules combination 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 compete specific binding influenza virus H 5 N 1 or its fragment with binding molecule of the present invention.In further step, can determine whether the screened binding molecule that can compete specific binding influenza virus H 5 N 1 or its fragment has neutralization activity.Can be another part of the present invention with the binding molecule of binding molecule competition specific binding influenza virus H 5 N 1 of the present invention or its fragment.In above-mentioned screening method, " the identical epi-position of specific binding " also comprises specific binding and the epi-position basic (substantially) of binding molecule combination of the present invention or the epi-position that (essentially) is identical substantially.Blocking-up or compete ability typical case that binding molecule of the present invention is combined with influenza virus H 5 N 1 refer to treat screened binding molecule in conjunction with and the influenza virus H 5 N 1 identified of binding molecule immunologic opsonin of the present invention on the influenza virus H 5 N 1 of binding site Structural superposition on epi-position or binding site.Or, this refer to treat screened binding molecule in conjunction with binding site by binding molecule immunologic opsonin identification of the present invention very approaching epi-position or binding site or suppress the combination of binding molecule of the present invention and influenza virus H 5 N 1 in spatial disposition.
Conventionally, competitive inhibition is measured by such measuring method, wherein antigen composition is comprised to the composition of influenza virus H 5 N 1 or its fragment and is binding molecule of the present invention with reference to binding molecule and treats that screened binding molecule mixes.Conventionally, 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 the reference binding molecule of combination, and its combination is because the existence for the treatment of screened binding molecule of substantially identifying identical epi-position reduces.In the binding molecule competitiveness research of carrying out with reference to binding molecule and treat to carry out between screened any binding molecule (no matter species or isotype), those skilled in the art can be first with detectable mark to reference to binding molecule in addition mark to carry out discriminating subsequently, described mark is for example vitamin H, enzyme labelling, radio-labeling or other mark, the binding molecule (competitive binding molecule or cross reaction binding molecules) of differentiating by these competitive assay method includes but not limited to that combination is by with reference to binding molecule being the epi-position of binding molecule combination of the present invention or the antibody of binding site, antibody fragment and other bonding agents, and in conjunction with the epi-position very approaching with described epi-position of being combined with reference to binding molecule or the antibody of binding site, antibody fragment and other bonding agents, described treat screened binding molecule and with reference to binding molecule between there is competitive binding.Preferably, in the time of excessive existence of competitive binding molecule of the present invention, by the specific binding suppressing with reference to the target of binding molecule and selection, 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 the epi-position of binding molecule combination 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.Due to the discriminating of competitive binding molecule be that binding molecule of the present invention contrasts and determines with reference to binding molecule, therefore should understand and in fact not need to determine by any way that the described epi-position with reference to binding molecule and the combination of competitive binding molecule is to differentiate the competitive binding molecule in conjunction with or essentially identical epi-position identical with epi-position with reference to binding molecule combination.
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
Use the RNA extracting from memory B cell to build scFv phage display library
Collect peripheral blood by venipuncture from normal health donor and be placed in EDTA anti-freezing sample hose.By PBS dilution twice for blood sample (45ml), get 30ml etc. and be placed in 10ml Ficoll-Hypaque (Pharmacia) on, at 900 × g room temperature uninterruptedly centrifugal 20 minutes.Carefully take out the supernatant on the white layer that contains lymphocytes and platelets fraction.Then, by careful this layer take out (～10ml), move in 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 obtaining 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 fluorocyte sorting to separate 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.By 1 × 10 5individual cell harvesting in DMEM/50%FBS, after sorting completes by its at 400 × g centrifugal 10 minutes, and cracking in the total RNA of 500 μ lTRIZOL extracts solution.Use 200 μ l chloroforms and isopropanol precipitating method from cracked solution, to extract RNA, as TRIZOL solution scheme is described in detail.Then, application 1 μ l PelletPaint (Novogen) strengthens and manifests precipitation process.Whole RNA prepared products are dissolved in the ultrapure water (Invitrogen) that 23 μ l DEPC process, and carry out cDNA conversion with SuperScript III reversed transcriptive enzyme (Invitrogen).By 1 μ l Random Hexamers, (500ng/ μ l) (Promega) adds in RNA sample, mixes, and unwinds 5 minutes at 65 DEG C in heat lid PCR instrument.Sample is cold in the upper speed of wet ice (wet-ice), add following composition: 8 μ l 5X RT damping fluid (250mM Tris-HCl pH8.3,375mMKCl, 15mM MgCl 2), 2 μ l dNTP (every kind of 10mM) (Invitrogen), 2 μ l DTT (100mM), (40U/ μ is (Promega) l), and (200U/ μ is (Invitrogen) l) for 2 μ l SuperScript III for 2 μ l RNAse inhibitor.First the mixture obtaining is incubated to 5 minutes in room temperature, then moves in heat lid PCR instrument 50 DEG C of operations 1 hour.By heating until 75 DEG C carry out 15 minutes and termination reaction.The cDNA obtaining is diluted to 200 μ l with ultrapure water, stores until further use at-20 DEG C.
Application two-wheeled pcr amplification method, is used as shown in Table 1 and Table 2 primer sets with separating immune globulin VHHe VL district from donor reservoir (repertoire) separately.The amplification composition using in 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 fluid (200mM Tris-HCl pH8.4,500mM KCl), 1.5 μ l MgCl 2(50mM), 0.5 μ l dNTP (every kind of 25mM), (5U/ μ is (Invitrogen) l) for 0.25 μ l Taq polysaccharase.Primer sets shown in use table 1 produces respectively 7,6 and 9 products of about 650 base pairs for VH, V κ and V λ district to the first round amplification that cDNA carries out separately.For the amplification of IgM memory B cell VH district, use the constant combination of primers OH1-OH7 of OCM.The thermal cycling program of first round amplification is: 2 minutes 96 DEG C (denaturing step), 30 circulations are as follows: 30 seconds 96 DEG C/30 seconds 55 DEG C/60 seconds 72 DEG C, 72 DEG C of finally extensions in 10 minutes, and cooling at 4 DEG C.Product application of sample on 1% sepharose and use gel-extraction column (Qiagen) therefrom to separate, is eluted in 50 μ l 1mM Tris-HCl pH8.0.By 10% first round amplified production, (5 μ l) carry out second and take turns amplification, the primer shown in use table 2.These primers extend with restriction site, and VLHe VH district directed cloning is separately entered in Vector for Phage Display PDV-C06.Second to take turns pcr amplification program as follows: 2 minutes 96 DEG C (denaturing step), 30 following circulations: 30 seconds 96 DEG C/30 seconds 60 DEG C/60 seconds 72 DEG C, 10 minutes 72 DEG C of final extensions, and cooling at 4 DEG C.First gather second according to the natural appearance of the J sections of finding and take turns amplified production (～350 base pair) in immunoglobulin gene product, produce respectively 7,6 and 9 set (in table 3 and table 4) for VH, V κ and V λ variable region.For the stdn of immunoglobulin sequences in adaptive immune library distributes, 6 V κ of percentage mix and the set of 9 V lambda light chains mentioned according to table 3.By this single final VL set, (3 μ g) spend 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, be connected to as follows in the PDV-C06 carrier (～5000 base pair) of SalI-NotI cutting: (50ng/ μ l) for 10 μ l PDV-C06 carriers, (10ng/ μ l) for 7 μ l VL insertosomes, 5 μ l 10X connect damping fluid (NEB), (400U/ μ is (NEB) l) for 2.5T4 DNA ligase, 25.5 μ l ultrapure waters (carrier and insertosome ratio are 1: 2).In 16 DEG C of water-baths, connect and spend the night.Then, water doubles sample volume, (Invitrogen) extract with isopyknic benzene phenol-chloroform-primary isoamyl alcohol (75: 24: 1), use subsequently chloroform (Merck) extract, and with 1 μ l Pellet Paint (Novogen), 10 μ l sodium acetates (3M pH5.0) and 100 μ l Virahols-20 DEG C precipitate 2 hours.Subsequently by centrifugal 30 minutes at 4 DEG C at 20.000 × g the sample obtaining.Precipitation 70% washing with alcohol obtaining, 20.000 × g in room temperature centrifugal 10 minutes.Remove ethanol by vacuum take-off, will be deposited in air drying several minutes, be then dissolved in the 50 μ l damping fluids that contain 10mM Tris-HCl (pH8.0).1 μ l connects mixture and uses and be set as 1.7kV, 200Ohm for the 0.1cm electroporation pipe (Biorad) cooling, the Genepulser II equipment (Biorad) of 25 μ F (time constant～4,5msec) transforms 40 μ l TG-1 electroreception state cells (Stratagene).After pulse, from electroporation pipe, rinse bacterium with the SOC substratum (Invitrogen) that the 1000 μ l of 37 DEG C contain 5% (w/v) glucose (Sigma) immediately, be transferred in 15ml round bottom culture test tube.500 μ l SOC/ glucose are in addition used for rinsing remaining bacterium from electroporation pipe, and are added in culture test tube.By cultivating and just in time within 1 hour, reclaim bacterium at 220rpm in shaking table incubator at 37 DEG C.The bacterium of conversion is plated in the square culture dish of large 240mm (NUNC), in described culture dish, contain 200ml 2TY agar (16g/l bacto-tryptone, 10g/l bacterium yeast extract, 5g/l NaCl, 15g/l agar, pH7.0) supplemented with 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 to grow overnight in 37 DEG C of culturing room (culture stove) totally.Typically, use such scheme to obtain about 1 × 10 7cfu.Be placed in 10ml 2TY substratum by the each dull and stereotyped bacterium of scraping gently and gather in the crops intermediate VL light chain library from flat board.Cell quality is measured and is determined by OD600, and the bacterium of 2 times of 500OD is prepared in a large number for plasmid DNA, uses two P500maxiprep posts (Qiagen) to instruct and carry out according to manufacturer.
Similar with VL variable region, first take turns VH-JH product by second and mix to obtain normal J sections use distribution (in table 4), produce the sub-set of 7 VH that is called PH1-PH7.This gathers to obtain standardized sequence distribution percentage mix shown in use table 4, obtains a VH fraction, is used SfiI and the digestion of XhoI restriction enzyme and is connected to as in the PDV-VL intermediate library of the SfiI-XhoI cutting of above-mentioned acquisition.The setting, purification process connecting, TG1 subsequently transform and the results of bacterium with for consistent (seeing above) described in VL intermediate library.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.Exceed 95% bacterium colony correct length insertosome (in table 5) is shown.Bacterium colony PCR product illustrates the bacterium colony per-cent of complete ORF to detect sequence variation and evaluation for DNA sequence analysis subsequently.This per-cent typical case exceedes 70% (in table 5).Also analyzed the mutation frequency in V gene.In 50 sequences, having 47 sequences (94%) is not germline configuration, represents ripening process consistent with the memory phenotype of the B cell in the RNA source as library.Finally, use CT helper phage (seeing WO 02/103012) save and increase described library for carrying out phage antibody selection by hereinafter described elutriation method.
embodiment 2
Carry the selection for the phage of the Single-Chain Fv Fragment of Murine of H5N1
Use antibody phage display libraries and the common display technique of bacteriophage and basic as United States Patent (USP) 6,265 of basic as above-mentioned structure, 150 and WO 98/15833 (these two sections of documents are all incorporated to for referencial use herein) described in choice of technology antibody fragment.In addition, described method and the helper phage of WO 02/103012 (being incorporated to for referencial use herein) is used for the present invention.
For restructuring hemagglutinin (HA) hypotype H5 (A/Vietnam/1203/2004 that uses baculovirus vector to produce in insect cell; See SEQ ID NO:110) select (Protein Sciences, CT, USA).Be shown in SEQ ID NO:111 and SEQ ID NO:112 from the aminoacid sequence of HA of isolate A/Vietnam/1194/2004 (H5N1TV) and the consensus amino acid sequences of the representative HA of the strain (H5N1IC) that next comfortable Indonesia separates with China.Also select for the solvable restructuring HA (sHA) from H5N1.Use standard DNA clone technology in the expression vector that contains myc-and his-mark, to clone following sequence: (solvable) partly sequence of (sHA) outside the HA born of the same parents of coding from isolate A/Vietnam/1194/2004 (H5N1), this sequence represents the HA (sHA of H5N1TV differentiating in the influenza virus strain (clade 1) separating with Vietnam in Thailand for 2004, SEQ ID NO:113), and represent 2003/2004 year consensus sequence (sHA of H5N1IC at the HA soluble part of Indonesia and the China H5N1 strain (clade 2) that separates, SEQ ID NO:114).H5N1TV is different at 9 amino acid positions from the HA of H5N1IC, is all arranged in the HA1 subunit of described molecule.Use standard technique in PER.C6 cell, to carry out 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 (restructuring HA and the sHA of H5N1TV) is diluted in PBS (5.0 μ g/ml), add MaxiSorp tMin Nunc-Immuno Tubes (Nunc), on runner 4 DEG C 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 sealing damping fluid, at room temperature insulation 1-2 hour.In addition, by immune test tube with anti-myc antibody coated spend the night and with the sealing damping fluid insulation of the sHA of the H5N1TV that contains 5 μ g/ml myc-marks.By equal portions (500-1000 μ l, 0.5 × 10 of the phage display library of set 13-1 × 10 13cfu, uses CT helper phage amplification (seeing WO 02/103012)) having added in the foetal calf serum of 10% non-heated and inactivated and the sealing damping fluid of 2% mice serum at room temperature sealing 1-2 hour.The phage library of sealing is added in immune test tube, room temperature insulation 2 hours, wash to remove unconjugated phage with lavation buffer solution (0.05% (v/v) Tween-20 in PBS).In conjunction with 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 (pH7.5) of 0.5ml with in and pH.This mixture grows to for infecting at 37 DEG C the XL1-Blue culture of Escherichia coli that OD600nm is about 0.3 5ml.Make phage infect XL1-Blue bacterium 30 minutes at 37 DEG C.Then by this mixture room temperature with 3000 × g centrifugal 10 minutes, bacterial precipitation is resuspended in to 0.5ml 2-Tryptones yeast extract (in 2TY substratum.The bacterial suspension of acquisition is assigned in two 2TY agar plates adding tsiklomitsin, penbritin and glucose.By flat board, after 37 DEG C of incubated overnight, the phage library from dull and stereotyped scraping bacterium colony for the preparation of enrichment carries out substantially as described in DeKruif et al. (1995a) and WO 02/103012.In brief, by the bacterium of scraping, for inoculating the 2TY substratum that contains penbritin, tsiklomitsin and glucose, growing to OD 600nm at 37 DEG C is～0.3.Add 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 DEG C.Second day, remove and degerm from 2TY substratum by centrifugal, use afterwards the phage in polyoxyethylene glycol (PEG) 6000/NaCl precipitation substratum.Finally, phage is dissolved in the 2ml PBS with 1% bovine serum albumin (BSA), filtration sterilization is also selected for next round.
Or use total length HA express cell system to carry out phage selection.For this reason, use the expression vector transfection PER.C6 cell containing from the complete encoding sequence of total length HA of isolate A/Vietnam/1194/2004 (H5N1TV) and the consensus sequence of the total length HA of the H5N1 strain (H5N1IC) that representative separates with China in Indonesia.Use anti-HA antibody and each phage to select the parallel flow cytometry that carries out to express (data are not shown) with the HA of the PER.C6 cell of guarantee H5N1TV-and H5N1IC-transfection.By 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, in rolling type rotor (end-over-endrotor), is incubated 1 hour with 5rpm at 4 DEG C.To the PER.C6 cell mixture of phage library/untransfected at 4 DEG C with 300 × g after centrifugal 5 minutes, the supernatant that contains phage is with 10 × 10 6the PER.C6 cell of untransfected is subdued for the second time.Subsequently by the phage prepared product and 1 × 10 of subduing 6the PER.C6 cytomixis of individual expression HA is incubated 2 hours with 5rpm at 4 DEG C in rolling type rotor.Subsequently cell is rotated 2 minutes at 3000 × g, cell precipitation is resuspended in 1ml PBS/0.05%Tween-20 to wash away unconjugated phage.By cell at 3000 × g centrifugal 2 minutes, then repeated washing 5 times.After each washing, cell is moved in new test tube.In conjunction with phage by with the 100mM TEA of 1ml in rolling type rotor with 5rpm room temperature insulation 10 minutes and from 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 (pH7.5).As the above-mentioned phage to wash-out is saved and breeds.Before separating each single chain variable fragment phage antibody, carry out two-wheeled selection.After second takes turns selection, each intestinal bacteria bacterium colony is for the preparation of mono-clonal phage antibody.Substantially make each bacterium colony grow to logarithmic phase in 96 hole flat boards, and with the infection of VCS-M13 helper phage, make afterwards phage antibody produce and spend the night.The supernatant that contains phage antibody is directly used in ELISA with in conjunction with HA antigen.Or phage antibody is carried out to PEG/NaCl-precipitation and filtration sterilization to carry out fluidic cell quantitative analysis.
embodiment 3
The confirmation of HA specific single-chain phage antibody
In ELISA, confirm the specificity of the single chain variable fragment phage antibody of the selection that obtains in above-mentioned screening method, with the combination of HA antigen.For this reason, by coated the sHA of the purifying of the restructuring HA (ProteinSciences, CT, USA) of baculovirus expression and H5N1TV and H5N1IC Maxisorp tMeLISA flat board.Anti-myc mA 9E10 (Roche) is fixed on to Maxisorp tMon ELISA flat board as negative control antigen.In the PBS washing 3 times in the PBS that after coated, flat board is being contained to 0.1%v/v Tween-20 and containing 3%BSA or 2%ELK, seal 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 the equal-volume PBS that contains 4%ELK.Turned letter is dull and stereotyped, with PBS/0.1%Tween-20 washing 3 times, the single chain variable fragment phage antibody of sealing is added in hand-hole.Be incubated 1 hour, dull and stereotyped with PBS/0.1%Tween-20 washing, use the phage antibody (using OD492nm to measure) of being combined with the anti-M13 antibody test of 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.From the selection of carrying out at different HA antigen with IgM memory B cell library, obtain 92 unique single chain variable fragment phage antibodies that are specific to restructuring HA or sHA.
Or, use fluidic cell quantitative analysis to detect for the reactivity of the single-chain antibody selected with expressing the combination of PER.C6 cell of HA.The phage of PEG/NaCl precipitation is mixed with isopyknic PBS/2%ELK, seal on ice 30 minutes.The phage of sealing is added in the cell of precipitation to (the PER.C6 cell of untransfected and express the PER.C6 cell of HA), be incubated 1 hour on ice.By PBS/1%BSA washing 3 times for cell; at 300 × g centrifugal 1 minute subsequently, use biotinylated anti-M13 antibody (Fitzgerald) and use subsequently streptavidin-phycoerythrin conjugate (Caltag) to observe the combination of described single chain variable fragment phage antibody and cell.The selection that uses the PER.C6 cell of expressing HA to carry out provides 24 unique single chain variable fragment phage antibodies, between the different restructuring HA albumen selecting period of use, does not identify these antibody.
embodiment 4
The qualification 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 Directory.Cambridge United Kingdom:MRC Centre for Protein Engineering (1997)) are shown in table 6.Described HA specific immunoglobulin CDR district is shown in table 7.
embodiment 5
From the scFv of selecting, build complete human normal immunoglobulin molecule (human monoclonal antibodies)
Digest the heavy chain of scFv described in Direct Cloning and variable region of light chain to express by restriction in 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 encoding human IgG1 heavy chain and light chain is combined to transient expression in 293T cell, use standard purification method to obtain and produce the supernatant that contains human IgG1's antibody.By described human IgG1's antibody in 10-0.003 μ g/ml concentration range for H5 titration (data are not shown).SARS-CoV specific antibody antibody in contrast.IgG1 molecule illustrates the pattern of reactivity identical with single chain variable fragment phage antibody.
In table 8, illustrated the heavy chain of antibody of following title and the Nucleotide of 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.Analyze anti-HA IgG and express the combination of the PER.C6 cell of HA by flow cytometry subsequently.Analyze the antibody flow cytometry of being combined with HA show antibody CR6255, CR6257, CR6260, CR6261, CR6262, CR6268, CR6307, CR6310, CR6314, CR6323, CR6325, CR6331 and CR6344 in conjunction with expression HA (H5N1TV)-PER.C6 cell (in table 9).Antibody CR6261 and CR6344 also demonstrate with the control cells of untransfected and are combined, but obtain signal than with express HA (H5N1TV) PER.C6 cell combination obtain signal low about 10 times (in table 9).Do not observe control antibodies CR3014 and express the cell of HA and the combination of untransfected control cells.
embodiment 6
H5N1 specific IgG is for the external neutralizing effect (virus neutralization's mensuration) of H5N1 influenza virus
In order to determine whether the IgG selecting can block H5N1 and infect, and carries out external virus neutralization mensuration (VNA).Mdck cell (ATCC CCL-34) is carried out to VNA.By mdck cell at mdck cell substratum (MEM substratum, add microbiotic, 20mM Hepes and 0.15% (w/v) sodium bicarbonate (MEM substratum completely), added 10% (v/v) foetal calf serum) middle cultivation.Be 4 × 10 by the H5N1 permutatation strain NIBRG-14 dilution using in this mensuration 3tCID50/ml (the every ml of 50% tissue culture infective dose) tires, and calculates and tires according to the method for Spearman and Karber.By IgG prepared product (200 μ g/ml) in bipartite hole in complete MEM substratum 2 times (1: 2-1: 16) of serial dilutions.By 25 μ l IgG diluent separately, (100TCID50/25 μ l) mixed, 37 DEG C of insulations 1 hour with 25 μ l viral suspensions.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 converging.Before using, mdck cell is seeded in mdck cell substratum, density is 3 × 10 4the every hole of individual cell, growth, until cell reaches converges, with 300-350 μ l PBS (pH7.4) washing, and adds the complete MEM substratum of 50 μ l in the most backward each hole.The cell of inoculation is cultivated 3-4 days at 33 DEG C, 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.In each cell culture, do not exist CPF to be restricted to provide protection completely.The anti-A/Vietnam/1194/04 H5N1 of sheep influenza virus HA (04/214, NIBSC) is used as positive control in this mensuration.
In addition, use immunohistochemical method to detect the situation that exists of virus in culture.For this reason, discard culture supernatant, cell is fixed to 15 minutes with 40% (v/v) acetone and 60% (v/v) methyl alcohol.Fixing cell is being added the sealing damping fluid (200mMNaCl of 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, pH7.45) in 37 DEG C sealing 30 minutes.Subsequently, cell and 50 μ l mouse resisiting influenza virus A monoclonal antibody mixtures (Chemicon) of dilution in 1: 1000 in lavation buffer solution are incubated to 1 hour at 37 DEG C.With after 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 lavation buffer solution, 37 DEG C of insulations 1 hour.With after lavation buffer solution washing 3 times, be added in 50 μ l streptavidin-peroxidase conjugated things (Calbiochem) of dilution in 1: 3000 in lavation buffer solution, 37 DEG C of insulations 30 minutes.With after lavation buffer solution washing 3 times, use and contain 1 μ l H 2o 2aEC solution (0.12% (w/v) AEC, 30% (v/v) N-N-dimethyl formamide and 70% (v/v) acetate buffer) the observation dyeing situation of/1ml AEC solution.With after lavation buffer solution washing 3 times, analyze under the microscope dyeing situation again.
The anti-HA antibody of people that is called CR6255, CR6257, CR6260, CR6261, CR6262, CR6268, CR6307, CR6310, CR6314, CR6323, CR6325, CR6331 and CR6344 is carried out to 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 table 10.In the hole that observes CPE, confirm exist (data are not shown) of virus by Cell immunohistochemical staining method.
For determine more accurately H5N1 specific IgG in and effect, the external virus neutralization that repeats to carry out with NIBRG-14 measures, but specifically IgG prepared product is further diluted.By 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 detect.In VNA determine following title the anti-H5N1 antibody of people in and effect: 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/ml exists under the condition of 100TCID50 virus) of these antibody protections MDCK culture antagonism CPE is shown in table 11.In the hole that observes CPE, confirm exist (data are not shown) of virus by Cell immunohistochemical staining method.
embodiment 7
The immunoblotting assay of H5N1 specific IgG
For the specificity of further Effect of Anti HA antibody, different restructuring hemagglutinin influenza virus A antigen is carried out to SDS-PAGE under reductive condition, carry out subsequently anti-HA immunoblotting assay.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 restructuring HA, described restructuring HA is the hypotype H5 (A/Vietnam/1203/2004 (H5N1) that uses baculovirus vector to produce in insect cell, see SEQ ID NO:110) (Protein Sciences, CT, USA) (Fig. 1, right side, swimming lane 2).Uncracked HA0 polypeptide does not detect in this HA prepared product.In swimming lane 1 and swimming lane 2, between HA subunit, the difference of size can be explained by the different glycosylation effect of the HA of insect cell and PER.C6 cells.CR5111 nonrecognition is that hypotype H1 (A/New Caledonia/20/99 (H1N1)) (is shown in Fig. 1, right side, swimming lane 4) or hypotype H3 (A/Wyoming/3/2003 (H3N2)) (Fig. 1, right side, swimming lane 3) HA1 and/or the HA0 polypeptide of restructuring HA.
The sHA of antibody CR6307 and CR6323 identification H5N1TV (is shown in Fig. 1, left side and middle portion, swimming lane 1) and restructuring HA (the HA2 subunit of A/Vietnam/1203/2004 (H5N1) (seeing Fig. 1, left side and middle portion, swimming lane 2) of hypotype H5.Interestingly,, when HA2 subunit is complete while existing, uncracked HA0 polypeptide is not identified.Obviously the epi-position of being identified by CR6307 and CR6323 becomes and can approach in the time of HA0 cracking.In addition, the HA2 subunit of the restructuring HA of antibody CR6307 and CR6323 identification hypotype H1 (A/New Caledonia/20/99 (H1N1)) (is shown in Fig. 1, left side and middle portion, swimming lane 4), but the HA2 subunit of the restructuring HA of nonrecognition hypotype H3 (A/Wyoming/3/2003 (H3N2)) (is shown in Fig. 1, left side and middle portion, swimming lane 3), these two restructuring HA all use baculovirus vector to produce (Protein Sciences in insect cell, 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 the vaccine (part) that can induce extensive cross reactivity antibodies against influenza virus to reply.
After antibody CR6307 and CR6323, be called the antibody of CR6141, CR6296 and CR6301 for immunoblotting assay.Each antibody in these three antibody all can be in conjunction with the sHA of H5N1TV and hypotype H5 (A/Vietnam/1203/2004; H5N1) the HA2 subunit (data are not shown) of restructuring HA.
embodiment 8
Determine the specific facs analysis of subunit of H5N1 specific IgG
In order to assess the contribution of HA1 subunit for anti-H5N1 antibodies, measure, wherein HA1 subunit discharges from the PER.C6 cell of expressing HA.To express the PER.C6 of HA PBS (pH7.4) washing 3 times cell for, and be incubated 10 minutes in acidifying PBS (pH4.9).Subsequently, by PBS for cell (pH7.4) washing, be used in 10 μ g/ml trypsin treatment in PBS (pH7.4) 10 minutes to make HA0 molecule be cracked into HA1 and HA2 subunit that disulfide linkage connects.Finally, cell is in the 20mM DTT in PBS (pH7.4), be incubated 20 minutes to discharge HA1 subunit from the HA2 subunit of film grappling.The PBS washed twice that contains 1%w/vBSA for the cell that untreated and sour/trypsinase/DTT processes.In order to carry out fluidic cell quantitative analysis, each dyeing is used 2.5 × 10 5individual cell.Observe with negative control antibody CR3014 processing and untreated cell dye-free.Antibody CR5111 is in conjunction with HA1 subunit in immunoblotting assay, and it makes the PER.C6 cell dyeing of untreated expression HA, and the cell unrecognized (data are not shown) of processing.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 are not shown).The release of HA1 subunit does not obviously affect the combination of these antibody, further confirms the result of the immunoblotting assay that derives from described antibodies HA2 subunit.Antibody CR6325 and CR6331 be in conjunction with untreated cell, and with compared with untreated cell, obviously reduce (data are not shown) with the combination of the cell of processing.This results suggest antibody obviously reduces due to conformational change for the affinity of its epi-position, and described conformational change is to induce by acid treatment or by the disulfide linkage that reduction connects HA1 and HA2 subunit.
embodiment 9
Utilize phage antibody and IgG to carry out hemagglutinin competitive ELISA
In order to differentiate the antibody in conjunction with non-overlapped noncompetitive epi-position, carry out hemagglutinin competitive ELISA.By Nunc-Immuno tMmaxisorp F96 flat board is used in 0.5 μ g/ml hypotype H5 in PBS, and (the restructuring HA of A/Vietnam/1203/2004 (H5N1) (Protein Sciences) is 4 DEG C of coated spending the night.Wash away not coated protein, afterwards hole is sealed 1 hour in room temperature with the 300 μ l PBS (lock solution) that contain 2%w/v skim-milk.Discard lock solution, in each hole, be incorporated in the anti-H5N1IgG of 10 μ g/ml of 50 μ l in lock solution, room temperature insulation 1 hour.With being incorporated in the 50l phage antibody in lock solution in backward each hole, concentration is the twice of the concentration that causes 50% maximum combined (determining in measuring formerly), is incubated 1 hour in room temperature again.With the PBS washing hole that contains 0.1%v/v Tween-20 3 times.Use the phage antibody of the anti-M13 antibody test combination of peroxidase conjugated.As above-mentioned washing hole again and by adding the OPD reagent (Sigma) of the 100 μ l ELISA that further develops the color.Reaction is by adding 50 μ l 1M H 2sO 4and stop the OD then measuring at 492nm.Under the condition that has IgG, the combination of phage antibody with condition not there is not IgG under the per-cent of combination represent, do not exist the combination under IgG condition to be set as 100%.In the HA1 subunit of identification H5 hemagglutinin, the phage antibody SC05-111 of epi-position and corresponding IgG CR5111 are with comparing.
Result shows that most of phage antibodies and IgG are in conjunction with the overlapping epi-position (data are not shown) on the restructuring HA of hypotype H5 (A/Vietnam/1203/2004 (H5N1)).The combination of SC05-111 phage antibody is blocked by CR5111 IgG, but can't help any other IgG blocking-up, points out other IgG identification the epi-position different from the land of CR5111.5 IgG CR6262, CR6272, CR6307, CR6339 and CR6343 and remaining IgG compared with low degree compete in conjunction with (more than 25% residue in conjunction with).For IgG CR6262, CR6272, CR6339 and CR6343, this can be explained by the lower affinity for HA.This is supported by such observed result, is more effectively competed by other IgG corresponding to the phage antibody of these antibody.The combination of phage antibody SC06-307 is blocked by IgG CR6307, but other IgG is lower on its impact.Unique epi-position that this prompting SC06-307 is different from the epi-position of other IgG identification with CR6307 identification.
embodiment 10
Use the cross reactivity ELISA of anti-H5N1 IgG
Whether guard in the HA except hypotype H5 for the epi-position that detects anti-H5N1 antibody, carry out hemagglutinin cross reactivity ELISA.By Nunc-Immuno tMmaxisorp F96 flat board (Nunc) is coated with and spends the night at 4 DEG C with following material: 0.5 μ g/ml hypotype H1 (A/NewCaledonia/20/99 (H1N1)) in PBS, hypotype H3 (A/Wyoming/3/03 (H3N2)), hypotype H5 (A/Vietnam/1203/04 (H5N1)), the restructuring HA of hypotype H7 (A/Netherlands/219/03 (H7N7)) and hypotype H9 (A/Hong Kong/1073/99 (H9N2)) (Protein Sciences Corp.).In addition, the viral prepared product of the BPL-inactivation of the HA of the A/New Caledonia/20/99 (H1N1) that contains 0.5 μ g/ml and permutatation strain NIBRG-14 (A/Vietnam/1194/04 (H5N1)) is coated with and is spent the night in PBS on flat board.With the PBS washing hole that contains 0.1%v/v Tween-20 3 times to remove not coated protein, subsequently with the 300 μ l PBS (lock solution) that contain 2%w/v skim-milk room temperature sealing 1 hour.Discard lock solution, every hole was incorporated in the anti-H5N1 antibody of 5 μ g/ml of 100 μ l in lock solution, 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 the antibody of combination.Develop the color as aforementioned and measure.Table 12 illustrates that all anti-H5N1 IgG are all in conjunction with the restructuring HA of the NIBRG-14 virus prepared product of hypotype H5 (A/Vietnam/1203/2004 (H5N1)) and BPL-inactivation, and the latter is containing the HA of toxic strain A/Vietnam/1194/2004 (H5N1).The restructuring HA of hypotype H3 and H7 is not identified by the anti-H5N1 IgG of any detection.Interestingly, except CR5111 and CR6307 all anti-H5N1 IgG all in conjunction with the restructuring HA of the viral prepared product of the strain A/New Caledonia/20/99 (H1N1) of hypotype H1 and H9 and BPL-inactivation.This epi-position that shows most of anti-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 Smirnov 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 the neutralizing effect to these hypotypes for the mouse monoclonal antibody C179 of this epi-position.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 HA molecule Gan district.Whether identify this epi-position in order to assess aforementioned anti-HA antibody, be created in the HA molecule that contains aminoacid replacement in this region.
Be attributed to the region (amino acid is numbered as described in Okuno et al.1999) of the 47-58 residue of the 318-322 position residue that comprises HA1 subunit and HA2 subunit by the epi-position of antibody C179 (Takara Bio Inc.) identification.The escape virus that contains such HA is no longer identified and is neutralized by C179, and described HA has the replacement of Thr to Lys or has the replacement of Val to Glu the 52nd of HA2 subunit the 318th of HA1 subunit.These suddenly change (the 318th Thr to Lys, mutant I, the 52nd Val to Glu, mutant II), the Leu to Met that HA1 subunit is the 320th replaces (mutant III, Met320 is present in the region, 318-322 position of HA1 of hypotype H3 and H7), the Ser to Arg that HA2 subunit is the 54th replaces (mutant IV, Arg54 is present in the region, 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 region, 47-58 position of HA2 of strain A/Hong Kong/156/97 (H5N1)) import in the total length HA of isolate A/Vietnam/1194/2004 (H5N1TV), and dye at PER.C6 transit cell.If the combination of the PER.C6 cell of aforementioned C179 and the anti-HA antibody of people and these mutant of expression is by FACA analysis and evaluation.In anti-HA1 subunit, the antibody CR5111 of epi-position and Anti-TNF-α H5 sheep serum confirm PER.C6 cell expressing H5N1TV and the HA mutant (data are not shown) of transfection.Observe with negative control antibody CR3014 or under the condition that does not have antibody dye-free (data are not shown).As desired, antibody C179 nonrecognition mutant I and II, it has the aminoacid replacement identical with HA in C179 escape virus (seeing Okuno et al., 1993).In addition, C179 is not in conjunction with mutant IV, and the combination of C179 and mutant III and V is unaffected.Observe similar pattern of reactivity for antibody CR6342, this prompting antibody C179 identifies similar epi-position with CR6342.Antibody CR6261, CR6325 and CR6329 identify all mutant except mutant II.This prompting antibody CR6261, CR6325 are different with the epi-position of C179 with the epi-position of CR6329.Because the combination of these antibody is not eliminated in the replacement in HA1 subunit, therefore its epi-position is probably arranged in HA2 subunit.Antibody CR6307 and CR6323 identify all mutant, point out the epi-position of these antibody also different from the epi-position of C179.About the sequence of mutant and the overview of antibodies shown in table 13.In a word, result shows that antibody CR6261, CR6325, CR6329, CR6307 and CR6323 are the ideal candidate of combination neutralized stream Influenza Virus, and it has sudden change and is therefore no longer neutralized by this antibody in the epi-position of being identified by mouse monoclonal antibody C179.
embodiment 12
The human IgG monoclonal antibody prophylactic activity that anti-lethal H5N1 attacks in vivo
Give the influenza virus H 5 N 1 strain A/HongKong/156/97 of mouse lethal dose with the prophylactic effect of research human monoclonal IgG antibody CR6261, CR6323 and CR6325.Be the antibody of every mouse through 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 infect latter 21 days.Carrying out this research is in order to evaluate the anti-H5N1 IgG of described monoclonal human antibody prophylactic effect in vivo.
H5N1 strain derives from the 3 years old children who suffers from respiratory system disease at first.This virus is gone down to posterity twice on mdck cell.For infecting mouse batch [8.1log TCID tires 50/ ml] in chicken embryo, breed once.
By 80 female 7 week age Balb/c mouse be divided into 8 groups, 10 every group, with H5N1 virus attack before carry out as hemostasis for every mouse:
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
The anti-H5N3 immune serum of 7.500 μ l rabbit (100 × dilution)
8.15mg/kg CR3014.
All animals conformed and raise 6 days, beginning one's study afterwards.Infect the day before yesterday with H5N1 virus, giving 500 μ l antibody by peritoneal injection.Used 25LD at the 0th day 50(about 50 μ are l) through intranasal vaccination animal, and proceed 21 days for virus.The viral actual dose giving has derived from the several same sample of remaining inoculum after animal inoculation pvaccination and assessment by titration.The virus titer (TCID50/mL) of inoculum is determined on mdck cell.The results are shown in preparation or give not to be not intended to occur viral inactivation during 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.For the rabbit polyclonal serum antibody of the anti-H5N3 influenza virus generation of this group injected in mice.
From virus inoculation the-1 day until monitor clinical symptom and body weight the 21st day every day.Clinical symptom is marked with points-scoring system and is recorded that (0=is without clinical symptom; 1=is by hair coarse (rough coat); 2=is coarse by hair, 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 in the time 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 rear serum in order producing, within the 21st day, from the animal of survival, to collect blood.Serum is stored in to-20 DEG C ± 2 DEG C until analyze the existence of special viral antibody.Use the H5N1 HK/97 substrate of 4HAU to detect in duplicate serum.Dilution reciprocal expression of highest serum of tiring to illustrate HI, start at 1/10 extent of dilution.
During conforming, all mouse be all 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 the group (the 8th group) with negative control Ab CR3014 inoculation, observe negative clinical symptom and occur.Respiratory distress, at the 6th day first record, continues 1-4 days.In the mouse (the 6th group) of processing at the CR6325 with 15mg/kg, 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 more late generation clinical symptom and lower average clinical score are relevant.In lowest dose level (0.7mg/kg) group, observe respiratory distress, but do not observe in higher dosage (2,5 and 15mg/kg) group.All mouse are all illustrated in 9-13 days (the 2nd, 3 and 5 groups) or be improved since the 17th day (the 4th group) its clinical condition.There is serious disease and dead subsequently in the mouse (the 7th group) of injection rabbit polyclonal antibody, show that rabbit antibody can not bring into play anti-infectious provide protection in vivo in 3 days.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 animal that H5N1 infects illustrates weight loss (Fig. 3) in various degree.Proportional weight loss is relevant to antibody dosage with the outbreak moment.In the group by maximum dose level antibody treatment, As time goes on body weight is stable increases, and the body weight of age-dependent increases consistent.The animal groups of inoculation lowest dose level CR6261 is than the more fast reducing of animal groups body weight of accepting higher dosage antibody.In compared with low dose group, the total amount of weight loss is larger, and in the group of inoculation 2 and 0.7mg/kg CR6261, mean body weight reduces respectively about 15% and 40% compared with starting weight.In compared with low dose group, illustrate that animal in some clinical symptom are improved, showing mean body weight increases.
Fig. 4 illustrates the number of mice of every group of survival every day.Dose response relationship clearly between the antibody amount that existence gives and mean survival time.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.In the time giving the CR6261 antibody of 0.7mg/kg, protected and avoided death lower than 50% animal.But in the time giving the antibody of maximum dose level, 9-10 mouse survival.In negative control group (CR3014), without mouse survival, what show to use in this research is 100% lethal challenge dose really.
Whether can present anti-infectious complete provide protection in order to evaluate IgG antibody, carry out HI mensuration, use the 21st day from accept 15mg/kg CR6261 (the 1st group) mouse collect serum measure.Although these data should show that mouse, without clinical manifestation, has experienced H5N1 infection.
These results illustrate that the anti-H5N1 antibody of at least three-type-person of discriminating as described herein and exploitation (CR6261, CR6323 and CR6325) all can provide the provide protection that resists in vivo lethal dose influenza virus H 5 N 1 independently.Observe the clear dose response relationship between the CR6261 antibody amount giving and mean survival time.Result shows when in the time that infection gives every kind of monoclonal anti-H5N1IgG antibody of detection of mouse 15mg/kg dosage the day before yesterday, the clinical manifestation that described antibody all can prevent H5N1 to infect in mouse.
embodiment 13
After infecting, the influenza virus H 5 N 1 of lethal dose gives endogenous protective and the therapeutic action of the anti-H5N1 antibody of human monoclonal
The interior therapeutic effect of studying to detect for example CR6261 of monoclonal antibody as herein described in model resist lethal H5N1 A/HK/97 influenza viruse attack after infection.Described virus batch and type and Mouse Age are used identical with embodiment 12.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 infect latter the 21st day.
By 58 female 7 week age Balb/c mouse be divided into 5 groups, as described below after infection different steps accept antibody:
1.10 mouse, give 15mg/kg CR6261 for latter 4 hours in infection
2.14 mouse, give 15mg/kg CR6261 for latter 1 day in infection
3.10 mouse, give 15mg/kg CR6261 for latter 2 days in infection
4.10 mouse, give 15mg/kg CR6261 for latter 3 days in infection
5.14 mouse, give 15mg/kg CR2006 for latter 1 day in infection.
All animals conformed and raise 6 days, beginning one's study afterwards.Be animal via intranasal vaccination 25LD at the 0th day 50h5N1 influenza virus (about 50 μ l) and monitor 21 days.The several same sample of remaining inoculum after the viral actual dose giving is derived from inoculation animal and completed by titration and assessment.The virus titer (TCID50/mL) of inoculum is determined on mdck cell.Result shows in preparation or during giving inoculum, is not intended to occur virally inactivated.Give 500 μ l antibody at postvaccinal particular point in time by peritoneal injection.The 5th group as negative control.In this group, animal is injected incoherent monoclonal antibody (CR2006) for the 1st day after infection.
From the-1 day until evaluate clinical symptom and body weight the 21st day every day.Clinical symptom is marked as described in embodiment 12, and score scope is 0-4.The animal of survival at the 21st day by row euthanasia and get blood.In order to evaluate pathological change, within the 6th day after attack, put to death 4 animals of the 2nd group and the 5th group.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, remains 10 animals after selection in the time starting.After virus inoculation the-1 day until evaluate clinical symptom and body weight the 21st day every day.
During conforming all animals be all enliven and look like healthy, 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 are all included in the rear mouse that clinical symptom is shown on the 1st day of infection.According to the time that gives antibody, described clinical symptom is eliminated, and all or else exists the 15th day clinical symptom in all groups.In control group 5, all occur that the 9th day all animal serious clinical symptom and all animals are all dead or by row euthanasia, because these animals reach clinical score 4.What this showed to give animal is the influenza virus of lethal dose.In the 1st group, animal is accepted antibody in latter 4 hours in infection, and clinical symptom does not appear in some animals, and clinical symptom appears in other animal.The number that occurs the animal of the clinical symptom that can mark is provided in table 16.Because influenza virus can have remarkable effect for respiratory organs, therefore also measure respiratory distress situation and provide in table 17.Fig. 7 and table 18 illustrate respectively surviving animals number and the mortality ratio of all groups.Due to unknown cause, within latter 4 hours, accept in the 1st group of antibody an animal death in the 10th day in infection.After influenza infection, accept all residue animals all survivals and healthy at the 21st day in the animal groups of antibody.This is high-visible the weight data obtaining 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 in the time infecting, after giving antibody, the weight recovery of mouse is to normal level.Obviously, return to normal type level and depend on the selection of time of Antybody therapy, in the rapid rehabilitation of animal of exposure treatment in latter 4 hours and reached normal level at the 7th day; Animal in infection treatment in latter 3 days reached its normal type at the 17th day.All animals all reach similar and healthy body weight in the time that research finishes the 21st day.Obviously, the animal of accepting negative control antibody does not recover body weight, stops measuring death in the 9th day.
These results show using after lethal dose H5N1 influenza viruse attack, and for example CR6261 of monoclonal antibody of the anti-H5N1 influenza virus of disclosing with the present invention after infection treats and can save mammalian object, if this paper is as shown in mouse.Stage even late, infect latter 3 days, described antibody still can make the clinical symptom level that no longer can monitor to clinical symptom that falls back.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 Monoclonal Antibody Against for the HA of H5N1 by cross-protection in the body of the lethal attack of allos influenza virus sub-strain
(embodiment 11) as previously mentioned, antibody more of the present invention are obviously identified the single epi-position in the HA2 structural domain of H5 hemagglutinin.Embodiment 7 illustrate some binding molecule of the present invention can non-conformation mode and HA2 epi-position interact, in other words, the folded form of hemagglutinin seems not hinder neutralization activity and the provide protection of these antibody that the present invention discloses.
The sequence (change of immune determining area in the HA1 region of antigenic drift=described protein causes the annual influenza virus vaccine that upgrades of needs) of the part of the no antigen drift tendency of influenza virus hemagglutinin albumen known in the art.Be contained in aminoacid sequence GVTNKVN4IIDK (SEQ ID NO:368, in table 13) by the epi-position in the HA2 of CR6261, CR6325 and CR6329 identification, be also present in the hemagglutinin of H1 and H9 hypotype, in 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 identify the HA (in table 12) of H1 and H9.Therefore, binding molecule of the present invention is identified the epi-position in the multiple HA albumen that are present in various flows Influenza Virus serotype.
In order to study the cross-application of these antibody for interior therapeutic, in mouse, test, consistent with the dosage regimen of the experiment of describing in 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 for example CR6261 treatment mouse of antibody of the present invention, monitor afterwards clinical symptom, respiratory distress and the body weight totally 3 weeks of mouse in infection.As mentioned below, these binding molecules can be saved the mouse that H5N1 infects, and also can save the mammalian object that H1N1 infects.
The interior therapeutic effect of studying to detect for example CR6261 of monoclonal antibody in model resist lethal H1N1 A/WSN/33 influenza viruse attack after infection.This virus batch derives from ATCC (VR-219) and breeds once in chicken embryo.Tire as 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 infect latter 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 mouse, give 15mg/kg CR6261 for first 1 day in infection
2.10 mouse, give 15mg/kg CR6261 for latter 1 day in infection
3.10 mouse, give 15mg/kg CR6261 for latter 2 days in infection
4.10 mouse, give 15mg/kg CR6261 for latter 3 days in infection
5.10 mouse, give 15mg/kg negative control CR57 for latter 1 day in infection
All animals conformed and raise at least 4 days, beginning one's study afterwards.Be lethal dose H1N1 virus (the 6.6log TCID of the about 50 μ l of animal inoculation pvaccination at the 0th day 50; 25 × LD 50equivalent) and monitoring.Fixed time point before/after inoculation gives 500 μ l antibody by peritoneal injection.During studying, monitor the general health situation of mouse.From the-1 day until evaluate clinical symptom and body weight the 21st day every day.Utilize grading system described in embodiment 12 and 13 to symptom scores, score scope is 0-4.The animal of survival at the 21st day by row euthanasia and get blood.
Table 19 provides the mortality ratio of every group, is illustrated in the mouse number of living in each study group during research.Two mouse after inoculation dead (at the 1st day, the 2nd group one, the 3rd group one) soon get rid of it as specified in advance in research project from analyze.All mouse in control group 5 are all dead at the 9th day, with the research the same (in table 18) of previously carrying out with H5N1.The per-cent of the animal surviving under this lethal challenge dose H1N1 is drawn in Fig. 9.Shown in every group, the number of the mouse of relevant clinical symptom provides in table 20.In the 1st group, do not observe clinical symptom, and clinical symptom appears in some mouse in the 2nd, 3 and 4 groups, these symptoms are completely dissolve in the 14th day after inoculation.All mouse of the 5th group started to occur clinical symptom at the 2nd day.This group is without mouse rehabilitation.The number that occurs the mouse of the respiratory distress symptom of score 2 or 3 provides in table 21.In 1-4 group, after the 13rd day, do not observe clinical symptom, and in control group 5 all there is serious respiratory distress in all remaining mouse.
Figure 10 illustrates the mean body weight of each study group small mouse.Obviously, in the 5th group, after the 8th day, can provide without take off data.Can find out from this figure, 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, showing, when described antibody is when high-titer exists in lung, provides very strong antiviral provide protection.This is clinical relevant, because highly pathogenic virus is as relevant in H5N1 copies as in the human body of high-titer and these high viral loads and infection the frequent serious consequence occurring after infection.In addition, all protected mouse are along with the time all returns to one's perfect health from this lethal infection.Therefore infer in conjunction with the of the present invention anti-H5N1 antibody (as CR6261, CR6325 and CR6329) without (single) epi-position in antigenic drift tendency HA2 district cross-protection in the body that resists multiple influenza virus serotype is provided, no longer need to be for the suddenly change antibody in susceptibility HA1 district of height.The epi-position that should understand in the HA that is not subject to exist only in H5 influenza virus serotype limits, and all influenza virus serotypes that binding molecule of the present invention also can contain identical epi-position for prevention or treatment in the stable region of HA2 are as H1N1 and comprise H2, H6 and the influenza virus of H9 hemagglutinin.
embodiment 15
Affinity research
Use surface plasma resonance analysis to carry out affinity research, use BIAcore3000 analytical system to use HBS-EP (Biacore AB, Sweden) to carry out with 75 μ l/ minute flow velocitys as running buffer at 25 DEG C and 37 DEG C.Use amine coupling method that IgG is fixed on research grade CM5 4-flow channel (Fc) sensor chip (Biacore AB, Sweden).The HA of the H5N1 viruss (A/Vietnam/1203/2004) of the different amounts of injection is to analyze the binding interactions between described HA albumen and fixing IgG.Use 20mM NaOH to regenerate to remove the HA of combination each measurement while finishing, make to remain on chip fixing IgG simultaneously.
Determine the affinity constant of CR6261, CR6323 and CR6325 antibody.(per injection 100 μ's HA of 4 times of dilutions of five kinds of concentration of injection subsequently l), dissociate 3600 seconds, use 10 μ l 20mMNaOH regeneration.Use 1: 1 (Langmuir) model-fitting the data obtained.But, can not calculate accurate dissociation constant (KD).This is due in 25 DEG C of low-down dissociation rates (even measuring by the measuring method of expansion) cause calculating due to unacceptable error.When in the time repeating to test for 37 DEG C, the recognizable generation of dissociating, but be still not enough to accurately measure KD.Test to determine the accurate KD of antibody.These are at least the affinities in single digit nM scope according to estimates, are likely the affinity in pM scope.These experiments illustrate that binding molecule of the present invention has high affinity for its epi-position existing in influenza virus HA albumen.
Below provide and be called SEQ ID NO:58-143, SEQ ID NO:212-237 and the nucleic acid of SEQID NO:316-367 and the detailed description of aminoacid sequence herein.
SEQ ID NO：58
SEQ ID NO：59
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SEQ ID N0：79
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SEQ ID NO：143
SEQ ID NO：212
SEQ ID NO：213
SEQ ID NO：214
1
SEQ ID NO：215
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>
SEQ ID NO：217
E
SEQ ID NO：218
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SEQ ID NO：316
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SEQ ID N0：322
SEQ ID NO：323
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SEQ ID NO：329
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SEQ ID N0：332
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SEQ ID NO：354
SEQ ID NO：355
SEQ ID NO：356
SEQ ID NO：357
SEQ ID NO：358
SEQ ID NO：359
SEQ ID NO：360
SEQ ID NO：361
SEQ ID NO：362
SEQ ID NO：363
SEQ ID NO：364
SEQ ID NO：365
SEQ ID NO：366
SEQ ID NO：367
Table 1: first round V κ, V λ and VH amplification
*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
*mix with 1: 1: 1 ratio
# mixes with 1: 1 ratio
+ mix with 1: 1 ratio
Table 3. the second LunVL district amplification is summarized
Table 4. the second LunVH district amplification is summarized
Table 5: the feature in individual IgM memory B cell library
The data of table 6:HA specific single-chain Fv
*shown in bracket, form the amino acid of variable region of heavy chain (VH) and variable region of light chain (VL)
The data in table 7:HA specific immunoglobulin CDR district.SEQ ID NO provides in bracket
The data of table 8.HA specific IgG
* shown in bracket, form the amino acid of variable region of heavy chain (VH) and variable region of light chain (VL)
The combination of the PER.C6 cell of table 9.IgG to expression HA (H5N1TV)
*be illustrated in the facs analysis carrying out in an independent experiment
The effect of the anti-HA antibody of table 10. in NAT is measured
*do not observe neutralization at 50 μ g/ml
The effect of the anti-HA antibody of table 11. in NAT is measured
-refer at 100 μ g/ml and do not observe neutralization
The cross reactivity .ND of the HA molecule of the anti-H5N1 IgG that table 12. is measured by ELISA (OD 492nm) to different HA hypotypes: do not determine
The epitope mapping of the anti-HA antibody of table 13. people.
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) in α-amino-isovaleric acid (V) → L-glutamic acid (E) replace
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，H5 and H6 subtypes 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
In <120> energy and human binding molecules and the application thereof of influenza virus H 5 N 1
<130>0145WO 00ORD
<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
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<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
<212>DNA
<213>Homo sapiens
<220>
<221>CDS
<222>(1)..(1353)
<400>58
gag gtg cag ctg gtg gag tct ggg gct gag gtg aag aag cct ggg tcc 48
Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aaa gtc tct tgc aag gct tct gga ggc ccc ttc cgc agc tat 96
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Pro Phe Arg Ser Tyr
20 25 30
gct atc agc tgg gtg cga cag gcc cct gga caa ggg cct gag tgg atg 144
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Pro Glu Trp Met
3 540 45
gga ggg atc atc cct att ttt ggt aca aca aaa tac gca ccg aag ttc 192
Gly Gly Ile Ile Pro Ile Phe Gly Thr Thr Lys Tyr Ala Pro Lys Phe
50 55 60
cag ggc aga gtc acg att acc gcg gac gat ttc gcg ggc aca gtt tac 240
Gln Gly Arg Val Thr Ile Thr Ala Asp Asp Phe Ala Gly Thr Val Tyr
65 70 75 80
atg gag ctg agc agc ctg cga tct gag gac acg gcc atg tac tac tgt 288
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
gcg aaa cat atg ggg tac cag gtg cgc gaa act atg gac gtc tgg ggc 336
Ala Lys His Met Gly Tyr Gln yal Arg Glu Thr Met Asp Val Trp Gly
100 105 110
aaa ggg acc acg gtc acc gtc tcg agt gct agc acc aag ggc ccc agc 384
Lys Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
gtg ttc ccc ctg gcc ccc agc agc aag agc acc agc ggc ggc aca gcc 432
Vel Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
gcc ctg ggc tgc ctg gtg aag gac tacttc ccc gag ccc gtg acc gtg 480
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
agc tgg aac agc ggc gcc ttg acc agc ggc gtg cac acc ttc ccc gcc 528
Ser Trp Asp Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
gtg ctg cag agc agc ggc ctg tac agc ctg agc agc gtg gtg acc gtg 576
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
ccc agc agc agc ctg ggc acc cag acc tec atc tgc aac gtg aac cac 624
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Vel Asn His
195 200 205
aag ccc agc aac acc aag gtg gac aaa cgc gtg gag ccc aag agc tgc 672
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys
210 215 220
gac aag acc cac acc tgc ccc ccc tgc cct gcc ccc gag ctg ctg ggc 720
Asp Lys Thr Gis Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Lgu Gly
225 230 235 240
gga ccc tcc gtg ttc ctg ttc ccc ccc aag ccc aag gac acc ctc atg 768
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
atc agc cgg acc ccc gag gtg acc tgc gtg gtg gtg gac gtg agc cac 816
Lle Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
gag gac ccc gag gtg aag ttc aac tgg tac gtg gac ggc gtg gag gtg 864
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp GlyVal Glu Val
275 280 285
cac aac gcc aag acc aag ccc cgg gag gag cag tac aac agc acc tac 912
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
cgg gtg gtg agc gtg ctc acc gtg ctg cac cag gac tgg ctg aac ggc 960
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
aag gag tac aag tgc aag gtg agc aac aag gcc ctg cct gcc ccc atc 1008
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
gag aag acc arc agc aag gcc aag ggc cag ccc cgg gag ccc cag gtg 1056
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
tac acc ctg ccc ccc agc cgg gag gag atg acc aag aac cag gtg tcc 1104
Tyr Thr Leu Pro Pro Ser Arb Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
ctc acc tgt ctg gtg aag ggc ttc tac ccc agc gac atc gcc gtg gag 1152
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
tgg gag agc aac ggc cag ccc gag aac aac tac aag acc acc ccc cct 1200
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
gtg ctg gac agc gac ggc agc ttc ttc ctg tac agc aag ctc acc gtg 1248
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
gac aag agc cgg tgg cag cag ggc aac gtg ttc agc tgc agc gtg atg 1296
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
cac gag gcc ctg cac aac cac tac acc cag aag agc ctg agc ctg agc 1344
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>59
<211>451
<212>PRT
<213>Homo sapiens
<400>59
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 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>60
<211>1353
<212>DNA
<213>Homo sapiens
<220>
<221>CDS
<222>(1)..(1353)
<400>60
cag gtc cag ctg gtg cag tct ggg gct gag gtg aag aag cct ggg tcc 48
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aaa gtc tct tgc aag gct tct gga ggc ccc ttc cgc agc tat
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Pro Phe Arg Ser Tyr 96
20 25 30
gct atc agc tgg gtg cga cag gcc cct gga caa ggg cct gag tgg atg 144
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Pro Glu Trp Met
35 40 45
gga ggg atc atc cct att ttt ggt aca aca aaa tac gca ccg aag ttc 192
Gly Gly Ile Ile Pro Ile Phe Gly Thr Thr Lys Tyr Ala Pro Lys Phe
50 55 60
cag ggc aga gtc acg att acc gcg gac gat ttc gcg ggc aca gtt tac 240
Gln Gly Arg Val Thr Ile Thr Ala Asp Asp Phe Ala Gly Thr Val Tyr
65 70 75 80
atg gag ctg agc agc ctg cga tct gag gac acg gcc atg tac tac tgt 288
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
gcg aaa cat atg ggg tac cag gtg cgc gaa act atg gac gtc tgg ggc 336
Ala Lys His Met Gly Tyr Gln Val Arg Glu Thr Met Asp Val Trp Gly
100 105 110
aaa ggg acc acg gtc acc gtc tcg agt gct agc acc aag ggc ccc agc 384
Lys Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
gtg ttc ccc ctg gcc ccc agc agc aag agc acc agc ggc ggc aca gcc 432
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
gcc ctg ggc tgc ctg gtg aag gac tac ttc ccc gag ccc gtg acc gtg 480
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
agc tgg aac agc ggc gcc ttg acc agc ggc gtg cac acc ttc ccc gcc 528
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
gtg ctg cag agc agc ggc ctg tac agc ctg agc agc gtg gtg acc gtg 576
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
ccc agc agc agc ctg ggc acc cag acc tac atc tgc aac gtg aac cac 624
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
aag ccc agc aac acc aag gtg gac aaa cgc gtg gag ccc aag agc tgc 672
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys
210 215 220
gac aag acc cac acc tgc ccc ccc tgc cct gcc ccc gag ctg ctg ggc 720
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
gga ccc tcc gtg ttc ctg ttc ccc ccc aag ccc aag gac acc ctc atg 768
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro LysAsp Thr Leu Met
245 250 255
atc agc cgg acc ccc ag gt acc tgc gtg gtg gtg gac gtg agc cac 816
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
gag gac ccc gag gtg aag ttc aac tgg tac gtg gac ggc gtg gag gtg 864
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280
cac aac gcc aag acc aag ccc cgg gag gag cag tac aac agc acc tac 912
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
cgg gtg gtg agc gtg ctc acc gtg ctg cac cag gac tgg ctg aac ggc
Arg Val Val Ser Val Leu Thr Val Leu Gis Gln Asp Trp Leu Asn Gly
305 310 315 320
aag Gag tac aag tgc aag gtg agc aac aag gcc ctg cct gcc ccc atc
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 1008
325 330 335
gag aag acc atc agc aag gcc aag ggc cag ccc cgg gag ccc cag gtg 1056
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
tac acc ctg ccc ccc agc cgg gag gag atg acc aag aac cag gtg tcc 1104
Tyr Thr Leu Pro Pro Ser Arg Gluu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
ctc acc tgt ctg gtg aag ggc ttc tac ccc agc gac atc gcc gtg gag 1152
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lle Ala Val Glu
370 375 380
tgg gag agc aac ggc cag ccc gag aac aac tac aag acc acc ccc cct 1200
Trp Gluu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
gtg ctg gac agc gac ggc agc ttc ttc ctg tac agc aag ctc acc gtg 1248
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
gac aag agc cgg tgg cag cag ggc aac gtg ttc agc tgc agc gtg atg 1296
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
cac gag gcc ctg cac aac cac tac acc cag aag agc ctg agc ctg agc 1344
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>61
<211>451
<212>PRT
<213>Homo sapiens
<400>61
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 Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu hla 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
260265270
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 Ash 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
420 430 425
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210>62
<21l>1353
<212>DNA
<213>Homo sapiens
<220>
<221>CDS
<222>(1)..(1353)
<400>62
gag gtg cag ctg gtg gag tct ggg gct gag gtg aag aag cct ggg tcc 48
Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aaa gtc tct tgc aag gct tct gga ggc ccc ttc cgc agc tat 96
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Pro Phe Arg Ser Tyr
20 25 30
gct atc agc tgg gtg cga cag gcc cct gga caa ggg cct gag tgg atg 144
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Pro Glu Trp Met
35 40 45
gga ggg atc atc cct att ttt ggt aca aca aaa tac gca ccg aag ttc 192
Gly Gly Ile Ile Pro Ile Phe Gly Thr Thr Lys Tyr Ala Pro Lys Phe
50 55 60
cag ggc aga gtc acg att acc gcg gac gat ttc gcg ggc aca gtt tac 240
Gln Gly Arg Val Thr Ile Thr Ala Asp Asp Phe Ala Gly Thr Val Tyr
65 70 75 80
atg gag ctg agc agc ctg cga tct gag gac acg gcc atg tac tac tgt 288
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
gcg aaa cat atg ggg tac cag gtg cgc gaa act atg gac gtc tgg ggc 336
Ala Lys His Met Gly Tyr Gln Val Arg Glu Thr Met Asp Val Trp Gly
100 105 110
aaa ggg acc acg gtc acc gtc tcg agt gct agc acc aag ggc ccc agc 384
Lys Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
gtg ttc ccc ctg gcc ccc agc agc aag agc acc agc ggc ggc aca gcc 432
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
gcc ctg ggc tgc ctg gtg aag gac tac ttc ccc gag ccc gtg acc gtg 480
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
agc tgg aac agc ggc gcc ttg acc agc ggc gtg cac acc ttc ccc gcc 528
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
gtg ctg cag agc agc ggc ctg tac agc ctg agc agc gtg gtg acc gtg 576
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
ccc agc agc agc ctg ggc acc cag acc tac atc tgc aac gtg aac cac 624
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
aag ccc agc aac acc aag gtg gac aaa cgc gtg gag ccc aag agc tgc 672
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys
210 215 220
gac aag acc cac acc tgc ccc ccc tgc cct gcc ccc gag ctg ctg ggc 720
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
gga ccc tcc gtg ttc ctg ttc ccc ccc aag ccc aag gac acc ctc atg 768
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
atc agc cgg acc ccc gag gtg acc tgc gtg gtg gtg gac gtg agc cac 816
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
gag gac ccc gag gtg aag ttc aac tgg tac gtg gac ggc gtg gag gtg 864
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
cac aac gcc aag acc aag ccc cgg gag gag cag tac aac agc acc tac 912
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
cgg gtg gtg agc gtg ctc acc gtg ctg cac cag gac tgg ctg aac ggc 960
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
aag gag tac aag tgc aag gtg agc aac aag gcc ctg cct gcc ccc atc 1008
Lys Glu Tyr Lys Cys Lys Val Leu Ser Lys Ala Leu Pro Ala Pro Ile
325 330 335
gag aag acc atc agc aag gcc aag ggc cag ccc cgg gag ccc cag gtg 1056
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
tac acc ctg ccc ccc agc cgg gag gag atg acc aag aac cag gtg tcc 1104
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
ctc acc tgt ctg gtg aag ggc ttc tac ccc agc gac atc gcc gtg gag 1152
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
tgg gag agc aac ggc cag ccc gag aac aac tac aag acc acc ccc cct 1200
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
gtg ctg gac agc gac ggc agc ttc ttc ctg tac agc aag ctc acc gtg 1248
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
gac aag agc cgg tgg cag cag ggc aac gtg ttc agc tgc agc gtg atg 1296
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
cac gag gcc ctg cac aac cac tac acc cag aag agc ctg agc ctg agc 1344
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>63
<211>451
<212>PRT
<213>Homo sapiens
<400>63
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 lle 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 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 Ash 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 ValGlu 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 GlyGln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln ValSer
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 ValPhe 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>64
<211>1353
<212>DNA
<213>Homo sapiens
<220>
<221>CDS
<222>(1)..(1353)
<400>64
gag gtg cag ctg gtg gag tct ggg gct gag gtg aag aag cct ggg tcc 48
Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aaa gte tct tgc aag gct tct gga ggc ccc ttc cgc agc tat 96
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Pro Phe Arg Ser Tyr
20 25 30
gcg atc agc tgg gtg cga cag gcc cct gga caa ggg cct gag tgg atg 144
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Pro Glu Trp Met
35 40 45
gga ggg atc atc cct att ttt ggt aca aca aaa tac gca ccg aag ttc 192
Gly Gly Ile Ile Pro Ile Phe Gly Thr Thr Lys Tyr Ala Pro Lys Phe
50 55 60
cag ggc aga gtc acg att acc gcg gac gat ttc gcg ggc aca gtt tac 240
Gln Gly Arg Val Thr Ile Thr Ala Asp Asp Phe Ala Gly Thr Val Tyr
65 70 75 80
atg gag ctg agc agc ctg cga tct gag gac acg gcc atg tac tac tgt 288
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
gcg aaa cat atg ggg tac cag gtg cgc gaa act atg gac gtc tgg ggc 336
Ala Lys His Met Gly Tyr Gln Val Arg Glu Thr Met Asp Val Trp Gly
100 105 110
aaa ggg acc acg gtc acc gtc tcg agt gct agc acc aag ggc ccc agc 384
Lys Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
gtg ttc ccc ctg gcc ccc agc agc aag agc acc agc ggc ggc aca gcc 432
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
gcc ctg ggc tgc ctg gtg aag gac tac ttc ccc gag ccc gtg acc gtg 480
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
agc tgg aac agc ggc gcc ttg acc agc ggc gtg cac acc ttc ccc gcc 528
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Acc
165 170 175
gtg ctg cag agc agc ggc ctg tac agc ctg agc agc gtg gtg acc gtg 576
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
ccc agc agc agc ctg ggc acc cag acc tac atc tgc aac gtg aac cac 624
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
aag ccc agc aac acc aag gtg gac aaa cgc gtg gag ccc aag agc tgc 672
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg ValGlu Pro Lys Ser Cys
210 215 220
gac aag acc cac acc tgc ccc ccc tgc cct gcc ccc gag ctg ctg ggc 720
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
gga ccc tcc gtg ttc ctg ttc ccc ccc aag ccc aag gac acc ctc atg 768
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
atc agc cgg acc ccc gag gtg acc tgc gtg gtg gtg gac gtg agc cac 816
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
gag gac ccc gag gtg aag ttc aac tgg tac gtg gac ggc gtg gag gtg 864
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
cac aac gcc aag acc aag ccc cgg gag gag cag tac aac agc acc tac 912
His Asn Ala Lys Thr Lys Pro Arg GluGlu Gln Tyr Asn Ser Thr Tyr
290 295 300
cgg gtg gtg agc gtg ctc acc gtg ctg cac cag gac tgg ctg aac ggc 960
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
aag gag tac aag tgc aag gtg agc aac aag gcc ctg cct gcc ccc atc 1008
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
gag aag acc atc agc aag gcc aag ggc cag ccc cgg gag ccc cag gtg 1056
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
tac acc ctg ccc ccc agc cgg gag gag atg acc aag aac cag gtg tcc 1104
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
ctc acc tgt ctg gtg aag ggc ttc tac ccc agc gac atc gcc gtg gag 1152
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
tgg gag agc aac ggc cag ccc gag aac aac tac aag acc acc ccc cct 1200
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
gtg ctg gac agc gac ggc agc ttc ttc ctg tac agc aag ctc acc gtg 1248
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
gac aag agc cgg tgg cag cag ggc aac gtg ttc agc tgc agc gtg atg 1296
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
cac gag gcc ctg cac aac cac tac acc cag aag agc ctg agc ctg agc 1344
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>65
<211>451
<212>PRT
<213>Homo sapiens
<400>65
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 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 Sar 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 SerArg Glu Glu Mer 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>66
<211>1350
<212>DNA
<213>Homo sapiens
<220>
<221>CDS
<222>(1)..(1350)
<400>66
cag gta cag ctg cag cag tca ggg gct gag gtg aag aag cct ggg tcc 48
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aag gtc tcc tgc aag gtt tcc ga gtc att ttc agc ggc agt 96
Ser Val Lys Val Ser Cys Lys Val Ser Gly Val Ile Phe Ser Gly Ser
20 25 30
gcg atc agc tgg gtg cga cag gcc cct gga caa ggc ctt gag tgg atg
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
gga ggg atc agc cct ctc ttt ggc aca aca aat tac gca caa aag ttc 192
Gly Gly Ile Ser Pro Leu Phe Gly Thr Thr Asn Tyr Ala Gln Lys Phe
50 55 60
cag ggc aga gtc acg att acc gcg gac caa tcc acg aac aca acc tac 240
Gln Gly Arg Val Thr Ile Thr Ala Asp Gln Ser Thr Asn Thr Thr Tyr
65 70 75 80
atg gag gtg aac agc ctg aga tat gag gac acg gcc gtg tat ttc tgt 288
Met Glu Val Asn Ser Leu Arg Tyr Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
gcg cga ggt cca aaa tat tac agt gag tac atg gac gtc tgg ggc aaa 336
Ala Arg Gly Pro Lys Tyr Tyr Ser Glu Tyr Met Asp Val Trp Gly Lys
100 105 110
ggg acc acg gtc acc gtc tcg agt gct agc acc aag ggc ccc agc gtg 384
Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
ttc ccc ctg gcc ccc agc agc aag agc acc agc ggc ggc aca gcc gcc 432
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly ThrAla Ala
130 135 140
ctg ggc tgc ctg gtg aag gac tac ttc ccc gag ccc gtg acc gtg agc 480
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
tgg aac agc ggc gcc ttg acc agc ggc gtg cac acc ttc ccc gcc gtg 528
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
ctg cag agc agc ggc ctg tac agc ctg agc agc gtg gtg acc gtg ccc 576
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
agc agc agc ctg ggc acc cag acc tac atc tgc aac gtg aac cac aag 624
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
ccc agc aac acc aag gtg gac aaa cgc gtg gag ccc aag agc tgc gac 672
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp
210 215 220
aag acc cac acc tgc ccc ccc tgc cct gcc ccc gag ctg ctg ggc gga 720
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
ccc tcc gtg ttc ctg ttc ccc ccc aag ccc aag gac acc ctc atg atc 768
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
agc cgg acc ccc gag gtg acc tgc gtg gtg gtg gac gtg agc cac gag 816
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
gac ccc gag gtg aag ttc aac tgg tac gtg gac ggc gtg gag gtg cac 864
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
aac gcc aag acc aag ccc cgg gag gag cag tac aac agc acc tac cgg 912
Asn Ala Lys Thr Lys Pro ArgGluGlu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
gtg gtg agc gtg ctc acc gtg ctg cac caggac tgg ctg aac ggc aag 960
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
gag tac aag tgc aag gtg agc aac aag gcc ctg cct gcc ccc atc gag 1008
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
aag acc atc agc aag gcc aag ggc cag ccc cgg gag ccc cag gtg tac 1056
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
acc ctg ccc ccc agc cgg gag gag atg acc aag aac cag gtg tcc ctc 1104
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
acc tgt ctg gtg aag ggc ttc tac ccc agc gac atc gcc gtg gag tgg 1152
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
gag agc aac ggc cag ccc gag aac aac tac aag acc acc ccc cct gtg 1200
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
ctg gac agc gac ggc agc ttc ttc ctg tac agc aag ctc acc gtg gac 1248
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
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>67
<211>450
<212>PRT
<213>Homo sapiens
<400>67
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 Mer
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 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 Ash Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Ash Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ash 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>68
<211>1350
<212>DNA
<213>Homo sapiens
<220>
<221>CDS
<222>(1)..(1350)
<400>68
cag gtc cag ctg gta cag tct ggg gct gag gtg aag aag cct ggg tcc 48
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aag gtc tcc tgc aag gct tct gga ggc acc ttc agt agt tat 96
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
gct atc agc tgg gtg cga cag gcc cct gga caa ggg ctt gag tgg atg 144
Ala Ile Ser Trp Val Arg GlnAla Pro Gly Gln Gly LeuGlu Trp Met
35 40 45
gga gga atc atg ggt atg ttt ggc aca act aac tac gca cag aag ttc 192
Gly Gly Ile Met Gly Met Phe Gly Thr Thr Asn Tyr Ala Gln Lys Phe
50 55 60
cag ggc aga gtc acg att acc gcg gac gaa ttc acg agc gca gcc tac
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Phe Thr Ser Ala Ala Tyr 240
65 70 75 80
atg gag ctg agg agc ctg aga tct gag gac acg gcc gtc tac tac tgt 288
Met Glu Leu Arg Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
gcg agg tct agt ggt tat tac ccc gaa tac ttc cag gac tgg ggc cag 336
Ala Arg Ser Ser Gly Tyr Tyr Pro Glu Tyr Phe Gln Asp Trp Gly Gln
100 105 110
ggc acc ctg gtc acc gtc tcg agt gct agc acc aag ggc ccc agc gtg 384
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
ttc ccc ctg gcc ccc agc agc aag agc acc agc ggc ggc aca gcc gcc 432
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
ctg ggc tgc ctg gtg aag gac tac ttc ccc gag ccc gtg acc gtg agc 480
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
tgg aac agc ggc gcc ttg acc agc ggc gtg cac acc ttc ccc gcc gtg 528
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
ctg cag agc agc ggc ctg tac agc ctg agc agc gtg gtg acc gtg ccc 576
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
agc agc agc ctg ggc acc cag acc tac atc tgc aac gtg aac cac aag 624
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
ccc agc aac acc aag gtg gac aaa cgc gtg gag ccc aag agc tgc gac 672
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp
210 215 220
aag acc cac acc tgc ccc ccc tgc cct gcc ccc gag ctg ctg ggc gga 720
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
ccc tcc gtg ttc ctg ttc ccc ccc aag ccc aag gac acc ctc atg atc 768
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
agc cgg acc ccc gag gtg acc tgc gtg gtg gtg gac gtg agc cac gag
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 816
260 265 270
gac ccc gag gtg aag ttc aac tgg tac gtg gac ggc gtg gag gtg cac 864
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
aac gcc aag acc aag ccc cgg gag gag cag tac aac agc acc tac cgg 912
Ash Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
gtg gtg agc gtg ctc acc gtg ctg cac cag gac tgg ctg aac ggc aag 960
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
gag tac aag tgc aag gtg agc aac aag gcc ctg cct cc ccc atc gag 1008
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
aag acc atc agc aag gcc aag ggc cag ccc cgg gag ccc cag gtg tac 1056
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
acc ctg ccc ccc agc cgg gag gag atg acc aag aac cag gtg tcc ctc 1104
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
acc tgt ctg gtg aag ggc ttc tac ccc agc gac atc gcc gtg gag tgg 1152
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
gag agc aac ggc cag ccc gag aac aac tac aag acc acc ccc cct gtg 1200
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
ctg gac agc gac ggc agc ttc ttc ctg tac agc aag ctc acc gtg gac 1248
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
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>69
<211>450
<212>PRT
<213>Homo sapiens
<400>69
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 ValArg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Met Gly Met Phe Gly Thr Thr Ash 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 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 Set 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>70
<211>1356
<212>DNA
<213>Homo sapiens
<220>
<221>CDS
<222>(1)..(1356)
<400>70
cag gtc cag ctg gtg cag tct ggg gga ggc ctg gtc aag cct ggg ggg 48
Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
tcc ctg aga ctc tcc tgt gca gcc tct gga ttc acc ttc agt agc tat 96
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
agc atg aac tgg gtc cgc cag gct cca ggg aag ggg ctg gag tgg gtc 144
Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
tca tcc att agt agt agt agt agt tac ata tac tac gta gac tca gtg 192
Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Val Asp Ser Val
50 55 60
aag ggc cga ttc acc atc tcc aga gac aac gcc aag aac tca ctg tat 240
Lys Gly Arg Phe Thr Ile Ser ArgAsp AsnAla Lys Asn Ser Leu Tyr
65 70 75 80
ctg caa atg aac agc ctg aga gcc gag gac acg gct gtg tat tac tgt
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 288
85 90 95
gcg aga ggt ggt ggg agc tac ggg gcc tac gaa ggc ttt gac tac tgg 336
Ala Arg Gly Gly Gly Ser Tyr Gly Ala Tyr Glu Gly Phe Asp Tyr Trp
100 105 110
ggc cag ggc acc ctg gtc acc gtc tcg agt gct agc acc aag ggc ccc 384
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120 125
agc gtg ttc ccc ctg gcc ccc agc agc aag agc acc agc ggc ggc aca
Ser Vag Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 432
130 135 140
gcc gcc ctg ggc tgc ctg gtg aag gac tac ttc ccc gag ccc gtg acc 480
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
gtg agc tgg aac agc ggc gcc ttg acc agc ggc gtg cac acc ttc ccc 528
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
165 170 175
gcc gtg ctg cag agc agc ggc ctg tac agc ctg agc agc gtg gtg acc 576
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
180 185 190
gtg ccc agc agc agc ctg ggc acc cag acc tac atc tgc aac gtg aac 624
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
195 200 205
cac aag ccc agc aac acc aag gtg gac aaa cgc gtg gag ccc aag agc 672
His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser
210 215 220
tgc gac aag acc cac acc tgc ccc ccc tgc cct gcc ccc gag ctg ctg 720
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
225 230 235 240
ggc gga ccc tcc gtg ttc ctg ttc ccc ccc aag ccc aag gac acc ctc 768
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
245 250 255
atg atc agc cgg acc ccc gag gtg acc tgc gtg gtg gtg gac gtg agc 816
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
260 265 270
cac gag gac ccc gag gtg aag ttc aac tgg tac gtg gac ggc gtg gag 864
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
275 280 285
gtg cac aac gcc aag acc aag ccc cgg gag gag cag tac aac agc acc 912
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
290 295 300
tac cgg gtg gtg agc gtg ctc acc gtg ctg cac cag gac tgg ctg aac 960
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
305 310 315 320
ggc aag gag tac aag tgc aag gtg agc aac aag gcc ctg cct gcc ccc 1008
Gly Lys Glu Tyr Lys Cys Lys Val Set Asn Lys Ala Leu Pro Ala Pro
325 330 335
atc gag aag acc atc agc aag gcc aag ggc cag ccc cgg gag ccc cag 1056
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
340 345 350
gtg tac acc ctg ccc ccc agc cgg gag gag atg acc aag aac cag gtg 1104
Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
355 360 365
tcc ctc acc tgt ctg gtg aag ggc ttc tac ccc agc gac atc gcc gtg 1152
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
370 375 380
gag tgg gag agc aac ggc cag ccc gag aac aac tac aag acc acc ccc 1200
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
385 390 395 400
cct gtg ctg gac agc gac ggc agc ttc ttc ctg tac agc aag ctc acc 1248
Pro Val Leu Asp Set Asp Gly Ser Phe Phe Leu Tyr Set Lys Leu Thr
405 410 415
gtg gac aag agc cgg tgg cag cag ggc aac gtg ttc agc tgc agc gtg 1296
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
420 425 430
atg cac gag gcc ctg cac aac cac tac acc cag aag agc ctg agc ctg 1344
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
435 440 445
agc ccc ggc aag 1356
Ser Pro Gly Lys
450
<210>71
<211>452
<212>PRT
<213>Homo sapiens
<400>71
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 Ala Ser Thr Lys Gly Pro
115 120 125
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
165 170 175
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser
210 215 220
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
225 230 235 240
Cly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
245 250 255
Met Ile Set Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
260 265 270
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
275 280 285
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
290 295 300
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Ash
305 310 315 320
Gly Lys Glu Tyr Lys Cys Lys Val Ser Ash Lys Ala Leu Pro Ala Pro
325 330 335
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
340 345 350
Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
355 360 365
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
370 375 380
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
385 390 395 400
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
405 410 415
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
420 425 430
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
435 440 445
Ser Pro Gly Lys
450
<210>72
<211>1353
<212>DNA
<213>Homo sapiens
<220>
<221>CDS
<222>(1)..(1353)
<400>72
gag gtg cag ctg gtg gag tct ggg gct gag gtg aag aag cct ggg tcc 48
Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aaa gtc tct tgc aag gct tct gga ggc ccc ttc cgc agc tat 96
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Pro Phe Arg Ser Tyr
20 25 30
gct atc agc tgg gtg cga cag gcc cct gga caa ggg cct gag tgg atg 144
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Pro Glu Trp Met
35 40 45
gga ggg atc atc cct att ttt ggt aca aca aaa tac gca ccg aag ttc 192
Gly Gly Ile Ile Pro Ile Phe Gly Thr Thr Lys Tyr Ala Pro Lys Phe
50 55 60
cag ggc aga gtc acg att acc gcg gac gat ttc gcg ggc aca gtt tac 240
Gln Gly Arg Val Thr Ile Thr Ala Asp Asp Phe Ala Gly Thr Val Tyr
65 70 75 80
atg gag ctg agc agc ctg cga tct gag gac acg gcc atg tac tac tgt 288
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
gcg aaa cat atg ggg tac cag gtg cgc gaa act atg gac gtc tgg ggc 336
Ala Lys His Met Gly Tyr Gln Val Arg Glu Thr Met Asp Val Trp Gly
100 105 110
aaa ggg acc acg gtc acc gtc tcg agt gct agc acc aag ggc ccc agc 384
Lys Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
gtg ttc ccc ctg gcc ccc agc agc aag agc acc agc ggc ggc aca gcc 432
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
gcc ctg ggc tgc ctg gtg aag gac tac ttc ccc gag ccc gtg acc gtg 480
Ala Leu Gly Cys Leu Val Lys AspTyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
agc tgg aac agc ggc gcc ttg acc agc ggc gtg cac acc ttc ccc gcc 528
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
gtg ctg cag agc agc ggc ctg tac agc ctg agc agc gtg gtg acc gtg 576
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
ccc agc agc agc ctg ggc acc cag acc tac atc tgc aac gtg aac cac 624
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asp His
195 200 205
aag ccc agc aac acc aag gtg gac aaa cgc gtg gag ccc aag agc tgc 672
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys
210 215 220
gac aag acc cac acc tgc ccc ccc tgc cct gcc ccc gag ctg ctg ggc 720
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
gga ccc tcc gtg ttc ctg ttc ccc ccc aag ccc aag gac acc ctc atg 768
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
atc agc cgg acc ccc gag gtg acc tgc gtg gtg gtg gac gtg agc cac 816
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
gag gac ccc gag gtg aag ttc aac tgg tac gtg gac ggc gtg gag gtg 864
Glu Asp Pro Glu Val Lys Phe Asp Trp Tyr Val Asp Gly Val Glu Val
275 280 285
cac aac gcc aag acc aag ccc cgg gag gag cag tac aac agc acc tac 912
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
cgg gtg gtg agc gtg ctc acc gtg ctg cac cag gac tgg ctg aac ggc 960
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
aag gag tac aag tgc aag gtg agc aac aag gcc ctg cct gcc ccc atc 1008
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
gag aag acc atc agc aag gcc aag ggc cag ccc cgg gag ccc cag gtg 1056
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
tac acc ctg ccc ccc agc cgg gag gag atg acc aag aac cag gtg tcc 1104
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
ctc acc tgt ctg gtg aag ggc ttc tac ccc agc gac atc gcc gtg gag 1152
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
tgg gag agc aac ggc cag ccc gag aac aac tac aag acc acc ccc cct 1200
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
gtg ctg gac agc gac ggc agc ttc ttc ctg tac agc aag ctc acc gtg 1248
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
gac aag agc cgg tgg cag cag ggc aac gtg ttc agc tgc agc gtg atg 1296
Asn Lys Ser Arg Trn Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
cac gag gcc ctg cac aac cac tac acc cag aag agc ctg agc ctg agc 1344
His Glu Ala Leu His Asp His Tyr Thr Glp Lys Ser Leu Ser Leu Ser
435 440 445
ccc ggc aag 1353
Pro Gly Lys
450
<210>73
<211>451
<212>PRT
<213>Homo sapiens
<400>73
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 Aso 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 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 Glp Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210>74
<211>1353
<212>DNA
<213>Homo sapiens
<220>
<221>CDS
<222>(1)..(1353)
<400>74
gag gtg cag ctg gtg gag tct ggg gct gag gtg aag aag cct ggg tcc 48
Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aaa gtc tct tgc aag gct tct gga ggc ccc ttc cgc agc tat 96
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Pro Phe Arg Ser Tyr
20 25 30
gct atc agc tgg gtg cga cag gcc cct gga caa ggg cct gag tgg atg 144
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Pro Glu Trp Met
35 40 45
gga ggg atc atc cct att ttt ggt aca aca aaa tac gca ccg aag ttc 192
Gly Gly Ile Ile Pro Ile Phe Gly Thr Thr Lys Tyr Ala Pro Lys Phe
50 55 60
cag ggc aga gtc acg att acc gcg gac gat ttc gcg ggc aca gtt tac 240
Glp Gly Arg Val Thr Ile Thr Ala Asp Asp Phe Ala Gly Thr Val Tyr
65 70 75 80
atg gag ctg agc agc ctg cga tct gag gac acg gcc atg tac tac tgt 288
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
gcg aaa cat atg ggg tac cag gtg cgc gaa act atg gac gtc tgg ggc 336
Ala Lys His Met Gly Tyr Gln Val Arg Glu Tnr Met Asp Val Trp Gly
100 105 110
aaa ggg acc acg gtc acc gtc tcg agt gct agc acc aag ggc ccc agc 384
Lys Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
gtg ttc ccc ctg gcc ccc agc agc aag agc acc agc ggc ggc aca gcc 432
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
gcc ctg ggc tgc ctg gtg aag gac tac ttc ccc gag ccc gtg acc gtg 480
Ala Leu Gly Cys Leu Va lLys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
agc tgg aac agc ggc gcc ttg acc agc ggc gtg cac acc ttc ccc gcc 528
Ser Trp Asp Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
gtg ctg cag agc agc ggc ctg tac agc ctg agc agc gtg gtg acc gtg 576
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
ccc agc agc agc ctg ggc acc cag acc tac atc tgc aac gtg aac cac 624
Pro Ser Ser Ser Leu Gly Thr Glp Thr Tyr Ile Cys Asp Val Asp His
195 200 205
aag ccc agc aac acc aag gtg gac aaa cgc gtg gag ccc aag agc tgc 672
Lys Pro Ser Asp Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys
210 215 220
gac aag acc cac acc tgc ccc ccc tgc cct gcc ccc gag ctg ctg ggc 720
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
gga ccc tcc gtg ttc ctg ttc ccc ccc aag ccc aag gac acc ctc atg 768
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
atc agc cgg acc ccc gag gtg acc tgc gtg gtg gtg gac gtg agc cac 816
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Va lVal Asp Val Ser His
260 265 270
gag gac ccc gag gtg aag ttc aac tgg tac gtg gac ggc gtg gag gtg 864
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
cac aac gcc aag acc aag ccc cgg gag gag cag tac aac agc acc tac 912
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
cgg gtg gtg agc gtg ctc acc gtg ctg cac cag gac tgg ctg aac ggc 960
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
aag gag tac aag tgc aag gtg agc aac aag gcc ctg cct gcc ccc atc 1008
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
gag aag acc atc agc aag gcc aag ggc cag ccc cgg gag ccc cag gtg 1056
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
tac acc ctg ccc ccc agc cgg gag gag atg acc aag aac cag gtg tcc 1104
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
ctc acc tgt ctg gtg aag ggc ttc tac ccc agc gac atc gcc gtg gag 1152
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
tgg gag agc aac ggc cag ccc gag aac aac tac aag acc acc ccc cct 1200
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
gtg ctg gac agc gac ggc agc ttc ttc ctg tac agc aag ctc acc gtg 1248
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
gac aag agc cgg tgg cag cag ggc aac gtg ttc agc tgc agc gtg atg 1296
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
cac gag gcc ctg cac aac cac tac acc cag aag agc ctg agc ctg agc 1344
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>75
<211>451
<212>PRT
<213>Homo sapiens
<400>75
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 ArgSer 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 LysPhe
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 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 Hi s Thr PhePro 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 AlaVal 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>76
<211>1350
<212>DNA
<213>Homo sapiens
<220>
<221>CDS
<222>(1)..(1350)
<400>76
gag gtg cag ctg gtg gag tct ggg gct gag gtg aag aag cca ggg tcc 48
Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aag gtc tcc tgt aag gcc tct gga ggc acc ttc tcc agc tat 96
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
ggt atc agc tgg gtg cga cag gcc cct gga caa ggg ctt gag tgg atg 144
Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
gga gac atc atc ggt atg ttt ggt tca aca aac tac gca cag aac ttc 192
Gly Asp Ile Ile Gly Met Phe Gly Ser Thr Asn Tyr Ala Gln Asn Phe
50 55 60
cag ggc aga ctc acg att acc gcg gac gaa tcc acg agc aca gcc tac 240
Gln Gly Arg Leu Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
atg gag ctg agc agc ctg aga tct gag gac acg gcc gtg tat tac tgt 288
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
gcg aga agt agt ggt tat tac cct gca tac ctc ccc cac tgg ggc cag 336
Ala Arg Ser Ser Gly Tyr Tyr Pro Ala Tyr Leu Pro His Trp Gly Gln
100 105 110
ggc acc ttg gtc acc gtc tcg agt gct agc acc aag ggc ccc agc gtg 384
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
ttc ccc ctg gcc ccc agc agc aag agc acc agc ggc ggc aca gcc gcc 432
rhe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
ctg ggc tgc ctg gtg aag gac tac ttc ccc gag ccc gtg acc gtg agc 480
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
tgg aac agc ggc gcc ttg acc agc ggc gtg cac acc ttc ccc gcc gtg 528
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
ctg cag agc agc ggc ctg tac agc ctg agc agc gtg gtg acc gtg ccc 576
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
agc agc agc ctg ggc acc cag acc tac atc tgc aac gtg aac cac aag 624
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn Gis Lys
195 200 205
ccc agc aac acc aag gtg gac aaa cgc gtg gag ccc aag agc tgc gac 672
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp
210 215 220
aag acc cac acc tgc ccc ccc tgc cct gcc ccc gag ctg ctg ggc gga 720
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
ccc tcc gtg ttc ctg ttc ccc ccc aag ccc aag gac acc ctc atg atc 768
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro lys Asp Thr Leu Met Ile
245 250 255
agc cgg acc ccc gag gtg acc tgc gtg gtg gtg gac gtg agc cac gag 816
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
gac ccc gag gtg aag ttc aac tgg tac gtg gac ggc gtg gag gtg cac 864
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val Gis
275 280 285
aac gcc aag acc aag ccc cgg gag gag cag tac aac agc acc tac cgg 912
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
gtg gtg agc gtg ctc acc gtg ctg cac cag gac tgg ctg aac ggc aag 960
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
gag tac aag tgc aag gtg agc aac aag gcc ctg cct gcc ccc atc gag 1008
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
aag acc atc agc aag gcc aag ggc cag ccc cgg gag ccc cag gtg tac 1056
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
acc ctg ccc ccc agc cgg gag gag atg acc aag aac cag gtg tcc ctc 1104
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
acc tgt ctg gtg aag ggc ttc tac ccc agc gac atc gcc gtg gag tgg 1152
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
gag agc aac ggc cag ccc gag aac aac tac aag acc acc ccc cct gtg 1200
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
ctg gac agc gac ggc agc ttc ttc ctg tac agc aag ctc acc gtg gac 1248
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
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 Asp His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Prg
435 440 445
ggc aag 1350
Gly Lys
450
<210>77
<211>450
<212>PRT
<213>Homo sapiens
<400>77
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 Trn 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 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 ArgVal 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>78
<211>1353
<212>DNA
<213>Homo sapiens
<220>
<221>CDS
<222>(1)..(1353)
<400>78
gag gtg cag ctg gtg gag tct ggg gct gag gtg aag aag ccg ggg tcc 48
Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aag gtc tcc tgc aag gct tct gga ggc acc ttc agc ttc tat 96
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Phe Tyr
20 25 30
tct atg agc tgg gtg cga cag gcc cct gga caa gga ctt gag tgg atg 144
Ser Met Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
gga ggg atc atc cct atg ttt ggt aca aca aac tac gca cag aag ttc 192
Gly Gly Ile Ile Pro Met Phe Gly Thr Thr Asn Tyr Ala Gln Lys Phe
50 55 60
cag ggc aga gtc acg att acc gcg gtc gaa tcc acg agc aca gcc tac 240
Gln Gly Arg Val Thr Ile Thr Ala Val Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
atg gag gtg agc agc ctg aga tct gag gac acg gcc gtt tat tac tgt 288
Met Glu Val Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
gcg aga ggt gat aag ggt atc tac tac tac tac atg gac gtc tgg ggc 336
Ala Arg Gly Asp Lys Gly Ile Tyr Tyr Tyr Tyr Met Asp Val Trp Gly
100 105 110
aaa ggg acc acg gtc acc gtc tcg agt gct agc acc aag ggc ccc agc 384
Lys Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
gtg ttc ccc ctg gcc ccc agc agc aag agc acc agc ggc ggc aca gcc 432
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
gcc ctg ggc tgc ctg gtg aag gac tac ttc ccc gag ccc gtg acc gtg 480
Ala Leu Gly Cys Leu Val Lys Asp Tyr Pne Pro Glu Pro Val Tnr Val
145 150 155 160
agc tgg aac agc ggc gcc ttg acc agc ggc gtg cac acc ttc ccc gcc 528
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
gtg ctg cag agc agc ggc ctg tac agc ctg agc agc gtg gtg acc gtg 576
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
ccc agc agc agc ctg ggc acc cag acc tac atc tgc aac gtg aac cac 624
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
aag ccc agc aac acc aag gtg gac aaa cgc gtg gag ccc aag agc tgc 672
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys
210 215 220
gac aag acc cac acc tgc ccc ccc tgc cct gcc ccc gag ctg ctg ggc 720
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
gga ccc tcc gtg ttc ctg ttc ccc ccc aag ccc aag gac acc ctc atg 768
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
atc agc cgg acc ccc gag gtg acc tgc gtg gtg gtg gac gtg agc cac 816
Tle Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
gag gac ccc gag gtg aag ttc aac tgg tac gtg gac ggc gtg gag gtg 864
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
cac aac gcc aag acc aag ccc cgg gag gag cag tac aac agc acc tac 912
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
cgg gtg gtg agc gtg ctc acc gtg ctg cac cag gac tgg ctg aac ggc 960
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
aag gag tac aag tgc aag gtg agc aac aag gcc ctg cct gcc ccc atc 1008
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
gag aag acc atc agc aag gcc aag ggc cag ccc cgg gag ccc cag gtg 1056
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
tac acc ctg ccc ccc agc cgg gag gag atg acc aag aac cag gtg tcc 1104
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
ctc acc tgt ctg gtg aag ggc ttc tac ccc agc gac atc gcc gtg gag 1152
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
tgg gag agc aac ggc cag ccc gag aac aac tac aag acc acc ccc cct 1200
Trn Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
gtg ctg gac agc gac ggc agc ttc ttc ctg tac agc aag ctc acc gtg 1248
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
gac aag agc cgg tgg cag cag ggc aac gtg ttc agc tgc agc gtg atg 1296
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
cac gag gcc ctg cac aac cac tac acc cag aag agc ctg agc ctg agc 1344
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>79
<211>451
<212>PRT
<213>Homo sapiens
<400>79
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 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>80
<211>1350
<212>DNA
<213>Homo sapiens
<220>
<221>CDS
<222>(1)..(1350)
<400>80
gag gtg cag ctg gtg gag tct ggg gct gag gtg aag aag cct ggg tcc 48
Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aag gtc tcc tgc aag gct tct gga ggc acc ttc agc agc tat 96
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
gct atc agc tgg gtg cga cag gcc cct gga caa ggg ctt gag tgg atg 144
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
gga ggg atc atc ggt atg ttc ggt aca gca aac tac gca cag aag ttc 192
Gly Gly Ile Ile Gly Met Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
cag ggc aga gtc acg att acc gcg gac gaa ttt acg agc aca gcc tac 240
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Phe Thr Ser Thr Ala Tyr
65 70 75 80
atg gag ctg agc agc ctg aga tct gag gac acg gcc gtg tat tac tgt 288
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
gcg aga gga aat tat tac tat gag agt agt ctc gac tac tgg ggc cag 336
Ala Arg Gly Asn Tyr Tyr Tyr Glu Ser Ser Leu Asp Tyr Trp Gly Gln
100 105 110
gga acc ctg gtc acc gtc tcg agt gct agc acc aag ggc ccc agc gtg 384
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
ttc ccc ctg gcc ccc agc agc aag agc acc agc ggc ggc aca gcc gcc 432
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
ctg ggc tgc ctg gtg aag gac tac ttc ccc gag ccc gtg acc gtg agc 480
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
tgg aac agc ggc gcc ttg acc agc ggc gtg cac acc ttc ccc gcc gtg 528
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
ctg cag agc agc ggc ctg tac agc ctg agc agc gtg gtg acc gtg ccc 576
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
agc agc agc ctg ggc acc cag acc tac atc tgc aac gtg aac cac aag 624
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
ccc agc aac acc aag gtg gac aaa cgc gtg gag ccc aag agc tgc gac 672
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp
210 215 220
aag acc cac acc tgc ccc ccc tgc cct gcc ccc gag ctg ctg ggc gga 720
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
ccc tcc gtg ttc ctg ttc ccc ccc aag ccc aag gac acc ctc atg atc 768
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
agc cgg acc ccc gag gtg acc tgc gtg gtg gtg gac gtg agc cac gag 816
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
gac ccc gag gtg aag ttc aac tgg tac gtg gac ggc gtg gag gtg cac 864
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
aac gcc aag acc aag ccc cgg gag gag cag tac aac agc acc tac cgg 912
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
gtg gtg agc gtg ctc acc gtg ctg cac cag gac tgg ctg aac ggc aag 960
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
gag tac aag tgc aag gtg agc aac aag gcc ctg cct gcc ccc atc gag 1008
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
aag acc atc agc aag gcc aag ggc cag ccc cgg gag ccc cag gtg tac 1056
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
acc ctg ccc ccc agc cgg gag gag atg acc aag aac cag gtg tcc ctc 1104
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
acc tgt ctg gtg aag ggc ttc tac ccc agc gac atc gcc gtg gag tgg 1152
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
gag agc aac ggc cag ccc gag aac aac tac aag acc acc ccc cct gtg 1200
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
ctg gac agc gac ggc agc ttc ttc ctg tac agc aag ctc acc gtg gac 1248
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
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>81
<211>450
<212>PRT
<213>Homo sapiens
<400>81
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 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 Aso 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>82
<211>1359
<212>DNA
<213>Homo sapiens
<220>
<221>CDS
<222>(1)..(1359)
<400>82
cag gtg cag ctg gtg cag tct ggg gct gag gtg aag aag cct ggg tcc 48
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aga gtc tcc tgc aag gct tct gga agc atc ttc aga aac tat 96
Ser Val Arg Val Ser Cys Lys Ala Ser Gly Ser Ile Phe Arg Asn Tyr
20 25 30
gct atg agc tgg gtg cga cag gcc cct gga caa ggg ctt gag tgg atg 144
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
gga ggg atc atc gct att ttt ggg aca cca aag tac gca cag aag ttc 192
Gly Gly Ile Ile Ala Ile Phe Gly Thr Pro Lys Tyr Ala Gln Lys Phe
50 55 60
cag ggc aga gtc acg att acc gcg gac gaa tcg acg agc act gtc tac 240
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Val Tyr
65 70 75 80
atg gaa ctg agc gga ctg aga tct gag gac acg gcc atg tat tac tgt 288
Met Glu Leu Ser Gly Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
gcg agg att ccc cac tat aat ttt ggt tcg ggg agt tat ttc gac tac 336
Ala Arg Ile Pro His Tyr Asn Phe Gly Ser Gly Ser Tyr Phe Asp Tyr
100 105 110
tgg ggc cag gga acc ctg gtc acc gtc tcg agt gct agc acc aag ggc 384
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
ccc agc gtg ttc ccc ctg gcc ccc agc agc aag agc acc agc ggc ggc 432
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
aca gcc gcc ctg ggc tgc ctg gtg aag gac tac ttc ccc gag ccc gtg 480
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
acc gtg agc tgg aac agc ggc gcc ttg acc agc ggc gtg cac acc ttc 528
Thr Val Ser Trn Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
ccc gcc gtg ctg cag agc agc ggc ctg tac agc ctg agc agc gtg gtg 576
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
acc gtg ccc agc agc agc ctg ggc acc cag acc tac atc tgc aac gtg 624
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Lle Cys Asn Val
195 200 205
aac cac aag ccc agc aac acc aag gtg gac aaa cgc gtg gag ccc aag 672
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
agc tgc gac aag acc cac acc tgc ccc ccc tgc cct gcc ccc gag ctg 720
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
225 230 235 240
ctg ggc gga ccc tcc gtg ttc ctg ttc ccc ccc aag ccc aag gac acc 768
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
ctc atg atc agc cgg acc ccc gag gtg acc tgc gtg gtg gtg gac gtg 816
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
agc cac gag gac ccc gag gtg aag ttc aac tgg tac gtg gac ggc gtg 864
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
gag gtg cac aac gcc aag acc aag ccc cgg gag gag cag tac aac agc 912
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
acc tac cgg gtg gtg agc gtg ctc acc gtg ctg cac cag gac tgg ctg 960
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
aac ggc aag gag tac aag tgc aag gtg agc aac aag gcc ctg cct gcc 1008
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
ccc atc gag aag acc atc agc aag gcc aag ggc cag ccc cgg gag ccc 1056
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
cag gtg tac acc ctg ccc ccc agc cgg gag gag atg acc aag aac cag 1104
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
gtg tcc ctc acc tgt ctg gtg aag ggc ttc tac ccc agc gac atc gcc 1152
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
gtg gag tgg gag agc aac ggc cag ccc gag aac aac tac aag acc acc 1200
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
ccc cct gtg ctg gac agc gac ggc agc ttc ttc ctg tac agc aag ctc 1248
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
acc gtg gac aag agc cgg tgg cag cag ggc aac gtg ttc agc tgc agc 1296
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
gtg atg cac gag gcc ctg cac aac cac tac acc cag aag agc ctg agc 1344
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
ctg agc ccc ggc aag 1359
Leu Ser Pro Gly Lys
450
<210>83
<211>453
<212>PRT
<213>Homo sapiens
<400>83
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 Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
225 230 235 240
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asn Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asn Trn Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Lys
450
<210>84
<211>660
<212>DNA
<213>Homo sapiens
<220>
<221>CDS
<222>(1)..(660)
<400>84
tcc tat gtg ctg act cag cca ccc tca gcg tct ggg acc ccc ggg cag 48
Ser Tyr Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
agg gtc acc atc tct tgt tct gga agc acg ttc aac atc gga agt aat 96
Arg yal Thr Ile Ser Cys Ser Gly Ser Thr Phe Asn Ile Gly Ser Asn
20 25 30
gct gta gac tgg tac cgg cag ctc cca gga acg gcc ccc aaa ctc ctc 144
Ala Val Asp Trp Tyr Arg Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
atc tat agt aat aat cag cgg ccc tca ggg gtc cct gac cga ttc tct 192
Ile Tyr Ser Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
ggc tcc agg tct ggc acc tca gcc tcc ctg gcc atc agt ggg ctc cag 240
Gly Ser Arg Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln
65 70 75 80
tct gag gat gag gct gat tat tac tgt gca gca tgg gat gac atc ctg 288
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ile Leu
85 90 95
aat gtt ccg gta ttc ggc gga ggg acc aag ctg acc gtc cta ggt gcg 336
Asn Val Pro Val Pne Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Ala
100 105 110
gcc gca ggc cag ccc aag gcc gct ccc agc gtg acc ctg ttc ccc ccc 384
Ala Ala Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro
115 120 125
tcc tcc gag gag ctg cag gcc aac aag gcc acc ctg gtg tgc ctc atc 432
Ser Ser Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile
130 135 140
agc gac ttc tac cct ggc gcc gtg acc gtg gcc tgg aag gcc gac agc 480
Ser Asn Phe Tyr Pro Gly Ala Val Thr Val Ala Trn Lys Ala Asn Ser
145 150 155 160
agc ccc gtg aag gcc ggc gtg gag acc acc acc ccc agc aag cag agc 528
Ser Pro Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser
165 170 175
aac aac aag tac gcc gcc agc agc tac ctg agc ctc acc ccc gag cag 576
Asn Asn Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln
180 18 5190
tgg aag agc cac cgg agc tac agc tgc cag gtg acc cac gag ggc agc 624
Trp Lys Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser
195 200 205
acc gtg gag aag acc gtg gcc ccc acc gag tgc agc 660
Thr Val Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
210 215 220
<210>85
<211>220
<212>PRT
<213>Homo sapiens
<400>85
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 Thr Phe Asn Ile Gly Ser Asn
20 25 30
Ala Val Asp Trp Tyr Arg Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ser Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Arg Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ile Leu
85 90 95
Asn Val 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>86
<211>660
<212>DNA
<213>Homo sapiens
<220>
<221>CDS
<222>(1)..(660)
<400>86
cag tct gcc ctg act cag cct gcc gcc gtg tct ggg tct cct gga cag 48
Gln Ser Ala Leu Thr Gln Pro Ala Ala Val Ser Gly Ser Pro Gly Gln
1 5 10 15
tcg atc acc atc tcc tgc act gga acc agc agt gac gtt ggt ggt tat 96
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asn Val Gly Gly Tyr
20 25 30
aac tat gtc tcc tgg tac caa cag cac cca ggc aaa gcc ccc aaa ctc 144
Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
atg att tat gag gtc agt aat cgg ccc tca ggg gtt tct aat cgc ttc 192
Met Ile Tyr Glu Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe
50 55 60
tct ggc tcc aag tct ggc aac acg gcc tcc ctg acc atc tct ggg ctc 240
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
cag gct gag gac gag gct gat tat tac tgc agc tca tat aca agc agc 288
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser
85 90 95
agc act tat gtc ttc gga act ggg acc aag gtc acc gtc cta ggt gcg 336
Ser Thr Tyr Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu Gly Ala
100 105 110
gcc gca ggc cag ccc aag gcc gct ccc agc gtg acc ctg ttc ccc ccc 384
Ala Ala Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro
115 120 125
tcc tcc gag gag ctg cag gcc aac aag gcc acc ctg gtg tgc ctc atc 432
Ser Ser Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile
130 135 140
agc gac ttc tac cct ggc gcc gtg acc gtg gcc tgg aag gcc gac agc 480
Ser Asp Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser
145 150 155 160
agc ccc gtg aag gcc ggc gtg gag acc acc acc ccc agc aag cag agc 528
Ser Pro Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser
165 170 175
aac aac aag tac gcc gcc agc agc tac ctg agc ctc acc ccc gag cag 576
Asn Asn Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln
180 185 190
tgg aag agc cac cgg agc tac agc tgc cag gtg acc cac gag ggc agc 624
Trp Lys Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser
195 200 205
acc gtg gag aag acc gtg gcc ccc acc gag tgc agc 660
Thr Val Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
210 215 220
<210>87
<211>220
<212>PRT
<213>Homo sapiens
<400>87
Gln Ser Ala Leu Thr Gln Pro Ala Ala Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asn 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 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>88
<211>660
<212>DNA
<213>Homo sapiens
<220>
<221>CDS
<222>(1)..(660)
<400>88
tcc tat gtg ctg act cag cca ccc tca gtc tct ggg acc ccc ggg cag 48
Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Gly Thr Pro Gly Gln
1 5 10 15
agg gtc acc atc tct tgc tct gga agc cgc tcc aac gtc gga gat aat 96
Arg Val Thr Ile Ser Cys Ser Gly Ser Arg Ser Asn Val Gly Asp Asn
20 25 30
tct gta tat tgg tat caa cac gtc cca gaa atg gcc ccc aaa ctc ctc 144
Ser Val Tyr Trp Tyr Gln His Val Pro Glu Met Ala Pro Lys Leu Leu
35 40 45
gtc tat aag aat act caa cgg ccc tca gga gtc cct gcc cgg ttt tcc 192
Val Tyr Lys Asn Thr Gln Arg Pro Ser Gly Val Pro Ala Arg Phe Ser
50 55 60
ggc tcc aag tct ggc act tca gcc tcc ctg gcc atc att ggc ctc cag 240
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ile Gly Leu Gln
65 70 75 80
tcc ggc gat gag gct gat tat tat tgt gtg gca tgg gat gac agc gta 288
Ser Gly Asp Glu Ala Asp Tyr Tyr Cys Val Ala Trp Asp Asp Ser Val
85 90 95
gat ggc tat gtc ttc gga tct ggg acc aag gtc acc gtc cta ggt gcg 336
Asp Gly Tyr Val Phe Gly Ser Gly Thr Lys Val Thr Val Leu Gly Ala
100 105 110
gcc gca ggc cag ccc aag gcc gct ccc agc gtg acc ctg ttc ccc ccc 384
Ala Ala Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro
115 120 125
tcc tcc gag gag ctg cag gcc aac aag gcc acc ctg gtg tgc ctc atc 432
Ser Ser Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile
130 135 140
agc gac ttc tac cct ggc gcc gtg acc gtg gcc tgg aag gcc gac agc 480
Ser Asp Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser
145 150 155 160
agc ccc gtg aag gcc ggc gtg gag acc acc acc ccc agc aag cag agc 528
Ser Pro Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser
165 170 175
aac aac aag tac gcc gcc agc agc tac ctg agc ctc acc ccc gag cag 576
Asn Asn Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln
180 185 190
tgg aag agc cac cgg agc tac agc tgc cag gtg acc cac gag ggc agc 624
Trp Lys Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser
195 200 205
acc gtg gag aag acc gtg gcc ccc acc gag tgc agc 660
Thr Val Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
210 215 220
<210>89
<211>220
<212>PRT
<213>Homo sapiens
<400>89
Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Arg Ser Asn Val Gly Asp Asn
20 25 30
Ser Val Tyr Trp Tyr Gln His Val Pro Glu Met Ala Pro Lys Leu Leu
35 40 45
Val Tyr Lys Asn Thr Gln Arg Pro Ser Gly Val Pro Ala Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ile Gly Leu Gln
65 70 75 80
Ser Gly Asp Glu Ala Asp Tyr Tyr Cys Val Ala Trp Asp Asp Ser Val
85 90 95
Asp Gly Tyr Val Phe Gly Ser 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
Trn 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>90
<211>663
<212>DNA
<213>Homo sapiens
<220>
<221>CDS
<222>(1)..(663)
<400>90
cag tct gtg ttg acg cag ccg ccc tca gtg tct gcg gcc cca gga cag 48
Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln
1 5 10 15
aag gtc acc atc tcc tgc tct gga agc agc tcc aac att ggg aat gat 96
Lys Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asp
20 25 30
tat gta tcc tgg tac cag cag ctc cca gga aca gcc ccc aaa ctc ctc 144
Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
att tat gac aat aat aag cga ccc tca ggg att cct gac cga ttc tct 192
Ile Tyr Asp Asn Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser
50 55 60
ggc tcc aag tct ggc acg tca gcc acc ctg ggc atc acc gga ctc cag 240
Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln
65 70 75 80
act ggg gac gag gcc aac tat tac tgc gca aca tgg gat cgc cgc ccg 288
thr Gly Asp Glu Ala Asn Tyr Tyr Cys Ala Tnr Trp Asp Arg Arg Pro
85 90 95
act gct tat gtt gtc ttc ggc gga ggg acc aag ctg acc gtc cta ggt 336
Tnr Ala Tyr Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
gcg gcc gca ggc cag ccc aag gcc gct ccc agc gtg acc ctg ttc ccc 384
Ala Ala Ala Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro
115 120 125
ccc tcc tcc gag gag ctg cag gcc aac aag gcc acc ctg gtg tgc ctc 432
Pro Ser Ser Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu
130 135 140
atc agc gac ttc tac cct ggc gcc gtg acc gtg gcc tgg aag gcc gac 480
Ile Ser Asp Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp
145 150 155 160
agc agc ccc gtg aag gcc ggc gtg gag acc acc acc ccc agc aag cag 528
Ser Ser Pro Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln
165 170 175
agc aac aac aag tac gcc gcc agc agc tac ctg agc ctc acc ccc gag 576
Ser Asn Asn Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu
180 185 190
cag tgg aag agc cac cgg agc tac agc tgc cag gtg acc cac gag ggc 624
Gln Trp Lys Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly
195 200 205
agc acc gtg gag aag acc gtg gcc ccc acc gag tgc agc 663
Ser Thr Val Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
210 215 220
<210>91
<211>221
<212>PRT
<213>Homo sapiens
<400>91
Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln
1 5 10 15
Lys Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asp
20 25 30
Tyr Val Ser Trn Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Asp Asn Asn Lys Arg Pro Ser Gly Ile 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 Asn Tyr Tyr Cys Ala Thr Trp Asp Arg Arg Pro
85 90 95
Thr Ala Tyr Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
Ala Ala Ala Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro
115 120 125
Pro Ser Ser Glu Glu Leu G1n Ala Asn Lys Ala Thr Leu Val Cys Leu
130 135 140
Ile Ser Asp Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp
145 150 155 160
Ser Ser Pro Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln
165 170 175
Ser Asn Asn Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu
180 185 190
Gln Trp Lys Ser His ArgSer 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)
<400>92
gac atc cag atg acc cag tct cca tcc tcc ctg tct gca tct gta gga 48
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
gac aga gtc acc atc act tgc cgg gcg agt cag ggc att agc agt tat 96
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Tyr
20 25 30
tta gcc tgg tat cag cag aag cca ggg aaa gtt cct aca ctc ctg atc 144
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Thr Leu Leu Ile
35 40 45
tat gat gca tcc act ttg cga tca ggg gtc cca tct cgc ttc agt ggc 192
Tyr Asn Ala Ser Tnr Leu Arg Ser Gly Val rro Ser Arg Phe Ser Gly
50 55 60
agt gga tct gcg aca gat ttc act ctc acc atc agc agc ctg cag cct 240
Ser Gly Ser Ala Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
gaa gat gtt gca act tat tac tgt caa agg tat aac agt gcc ccc ccg 288
Glu Asp Val Ala Thr Tyr Tyr Cys Gln Arg Tyr Asn Ser Ala Pro Pro
85 90 95
atc acc ttc ggc caa ggg aca cga ctg gag att aaa cgt gcg gcc gca 336
Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Arg Ala Ala Ala
100 105 110
ccc agc gtg ttc atc ttc ccc ccc tcc gac gag cag ctg aag agc ggc 384
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
acc gcc agc gtg gtg tgc ctg ctg aac aac ttc tac ccc cgg gag gcc 432
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
aag gtg cag tgg aag gtg gac aac gcc ctg cag agc ggc aac agc cag 480
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
gag agc gtg acc gag cag gac agc aag gac tcc acc tac agc ctg agc 528
Glu Ser Val Thr Glu Gln Asn Ser Lys Asn Ser Thr Tyr Ser Leu Ser
165 170 175
agc acc ctc acc ctg agc aag gcc gac tac gag aag cac aag gtg tac 576
Ser Thr Leu Thr Leu Ser Lys Ala Asn Tyr Glu Lys His Lys Val Tyr
180 185 190
gcc tgc gag gtg acc cac cag ggc ctg agc agc ccc gtg acc aag agc 624
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
ttc aac cgg ggc gag tgt 642
Phe Asn Arg Gly Glu Cys
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>(1)..(648)
<400>94
cag tct gtg ctg act cag cca ccc tca gag tcc gtg tcc cca gga cag 48
Gln Ser Val Leu Thr Gln Pro Pro Ser Glu Ser Val Ser Pro Gly Gln
1 5 10 15
aca gcc agc gtc acc tgc tct gga cat aaa ttg ggg gat aaa tat gtt 96
Thr Ala Ser Val Thr Cys Ser Gly His Lys Leu Gly Asp Lys Tyr Val
20 25 30
tcg tgg tat cag cag aag cca ggc cag tcc cct gta tta ctc atc tat 144
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Val Leu Leu Ile Tyr
35 40 45
caa gat aac agg cgg ccc tca ggg atc cct gag cga ttc ata ggc tcc 192
Gln Asp Asn Arg Arg Pro Ser Gly Ile Pro Glu Arg Phe Ile Gly Ser
50 55 60
aac tct ggg aac aca gcc act ctg acc atc agc ggg acc cag gct ctg 240
Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Leu
65 70 75 80
gat gag gct gac tat tac tgt cag gcg tgg gac agc agc act gcg gtt 288
Asp Glu Ala Asp Tyr Tyr Cys Gln Ala Trp Asp Ser Ser Thr Ala Val
85 90 95
ttc ggc gga ggg acc aag ctg acc gtc cta ggt gcg gcc gca ggc cag 336
Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Ala Ala Ala Gly Gln
100 105 110
ccc aag gcc gct ccc agc gtg acc ctg ttc ccc ccc tcc tcc gag gag 384
Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu
115 120 125
ctg cag gcc aac aag gcc acc ctg gtg tgc ctc atc agc gac ttc tac 432
Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Pne Tyr
130 135 140
cct ggc gcc gtg acc gtg gcc tgg aag gcc gac agc agc ccc gtg aag 480
Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys
145 150 155 160
gcc ggc gtg gag acc acc acc ccc agc aag cag agc aac aac aag tac 528
Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr
165 170 175
gcc gcc agc agc tac ctg agc ctc acc ccc gag cag tgg aag agc cac 576
Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His
180 185 190
cgg agc tac agc tgc cag gtg acc cac gag ggc agc acc gtg gag aag 624
Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly SerThr Val Glu Lys
195 200 205
acc gtg gcc ccc acc gag tgc agc 648
Thr Val Ala Pro Thr Glu Cys Ser
210 215
<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)
<400>96
gaa att gtg ctg act cag tct cca ggc acc ctg tct ttg tct cca ggg 48
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
gaa aga gcc acc ctc tcc tgc agg gcc agt cag cgt gtt agc agc tac 96
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Arg Val Ser Ser Tyr
20 25 30
tta gcc tgg tac caa cag aaa cct ggc cag gct ccc agg ctc ctc atc 144
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
tat ggt gca tcc acc agg gcc gct ggc atc cca gac agg ttc agt ggc 192
Tyr Gly Ala Ser Thr Arg Ala Ala Gly Ile Pro Asp Arg Phe Ser Gly
50 55 60
agt ggg tct ggg aca gac ttc act ctc acc atc agc aga ctg gag cct 240
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro
65 70 75 80
gaa gat tct gca gtg tat tac tgt cag cag tat ggt agg aca ccg ctc 288
Glu Asn Ser Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Arg Thr Pro Leu
85 90 95
act ttc ggc gga ggg acc aag gtg gag atc aaa cgt gcg gcc gca ccc 336
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Ala Ala Ala Pro
100 105 110
agc gtg ttc atc ttc ccc ccc tcc gac gag cag ctg aag agc ggc acc 384
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
gcc agc gtg gtg tgc ctg ctg aac aac ttc tac ccc cgg gag gcc aag 432
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
gtg cag tgg aag gtg gac aac gcc ctg cag agc ggc aac agc cag gag 480
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
agc gtg acc gag cag gac agc aag gac tcc acc tac agc ctg agc agc 528
Ser Val Thr Glu Gln Asn Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
acc ctc acc ctg agc aag gcc gac tac gag aag cac aag gtg tac gcc 576
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
tgc gag gtg acc cac cag ggc ctg agc agc ccc gtg acc aag agc ttc 624
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
aac cgg ggc gag tgt 639
Asn Arg Gly Glu Cys
210
<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)
<400>98
tcc tat gtg ctg act cag cca ccc tcg gtg tca gtg gcc cca gga cag 48
Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Gln
1 5 10 15
acg gcc agg att acc tgt ggg gga aac aac att gga agt aaa agt gtg 96
Thr Ala Arg Ile Thr Cys Gly Gly Asn Asn Ile Gly Ser Lys Ser Val
20 25 30
cac tgg tac cag cag aag cca ggc cag gcc cct gtg ctg gtc gtc tat 144
His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Val Tyr
35 40 45
gat gat agc gac cgg ccc tca ggg atc cct gag cga ttc tct ggc tcc 192
Asp Asp Ser Asp Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser
50 55 60
aac tct ggg aac acg gcc acc ctg acc atc agc agg gtc gaa gcc ggg 240
Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly
65 70 75 80
gat gag gcc gac tat tac tgt cag gtg tgg gat agt agt agt gat cat 288
Asp Glu Ala Asp Tyr Tyr Cys Glp Val Trp Asp Ser Ser Ser Asp His
85 90 95
gct gtg ttc gga gga ggc acc cag ctg acc gtc ctc ggt gcg gcc gca 336
Ala Val Phe Gly Gly Gly Thr Gln Leu Thr Val Leu Gly Ala Ala Ala
100 105 110
ggc cag ccc aag gcc gct ccc agc gtg acc ctg ttc ccc ccc tcc tcc 384
Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser
115 120 125
gag gag ctg cag gcc aac aag gcc acc ctg gtg tgc ctc atc agc gac 432
Glu Glu Leu Gln Ala Asn Lys Ala Tnr Leu Val Cys Leu Ile Ser Asp
130 135 140
ttc tac cct ggc gcc gtg acc gtg gcc tgg aag gcc gac agc agc ccc 480
Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro
145 150 155 160
gtg aag gcc ggc gtg gag acc acc acc ccc agc aag cag agc aac aac 528
Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn
165 170 175
aag tac gcc gcc agc agc tac ctg agc ctc acc ccc gag cag tgg aag 576
Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys
180 185 190
agc cac cgg agc tac agc tgc cag gtg acc cac gag ggc agc acc gtg 624
Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val
195 200 205
gag aag acc gtg gcc ccc acc gag tgc agc 654
Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
210 215
<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)
<400>100
tcc tat gtg ctg act cag cca ccc tca gcg tct ggg acc ccc ggg cag 48
Ser Tyr Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Tnr Pro Gly Gln
1 5 10 15
agg gtc acc atc tct tgt tct gga agc agc tcc aac atc gga agt aat 96
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
tat gta tac tgg tac cag cag ctc cca ggc acg gcc ccc aaa ctc ctc 144
Tyr Val Tyr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
atc tat agg gat ggt cag cgg ccc tca ggg gtc cct gac cga ttc tct 192
Ile Tyr Arg Asp Gly Gln Arg Pro Ser Gly Val Pro Asp Arg Pne Ser
50 55 60
ggc tcc aag tct ggc acc tca gcc tcc ctg gcc atc agt gga ctc cgg 240
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
tcc gat gat gag gct gat tat tac tgt gca aca tgg gat gac aac ctg 288
Ser Asp Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Asp Asn Leu
85 90 95
agt ggt cca gta ttc ggc gga ggg acc aag ctg acc gtc cta ggt gcg 336
Ser Gly Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Ala
100 105 110
gcc gca ggc cag ccc aag gcc gct ccc agc gtg acc ctg ttc ccc ccc 384
Ala Ala Gly Gln Pro Lys Ala Ala Pro Ser Val Tnr Leu Pne Pro Pro
115 120 125
tcc tcc gag gag ctg cag gcc aac aag gcc acc ctg gtg tgc ctc atc 432
Ser Ser Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile
130 135 140
agc gac ttc tac cct ggc gcc gtg acc gtg gcc tgg aag gcc gac agc 480
Ser Asp Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser
145 150 155 160
agc ccc gtg aag gcc ggc gtg gag acc acc acc ccc agc aag cag agc 528
Ser Pro Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser
165 170 175
aac aac aag tac gcc gcc agc agc tac ctg agc ctc acc ccc gag cag 576
Asp Asp Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln
180 185 190
tgg aag agc cac cgg agc tac agc tgc cag gtg acc cac gag ggc agc 624
Trp Lys Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser
195 200 205
acc gtg gag aag acc gtg gcc ccc acc gag tgc agc 660
Thr Val Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
210 215 220
<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 Aso 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 Ash 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>Gomo sapiens
<220>
<221>CDS
<222>(1)..(642)
<400>102
gaa att gtg ttg acc cag tct cca ggc acc ctg tct ttg tct cca ggg 48
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
gaa aga gcc acc ctc tcc tgc agg gcc agt cag agt gtt agc agc agc 96
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
tac tta gcc tgg tac cag cag aaa cct ggc cag gct ccc agg ctc ctc 144
Tyr Leu Ala Trp Tyr 5ln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
atc tat ggt gca tcc agc agg gcc act ggc atc cca gac agg ttc agt 192
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
ggc agt ggg tct ggg aca gac ttc act ctc acc atc agc aga ctg gag 240
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
cct gaa gat ttt gca gtg tat tac tgt cag cag tat ggt agc tca ccc 288
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
aga act ttc ggc gga ggg acc aag gtg gag atc aaa cgt gcg gcc gca 336
Arg Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Ala Ala Ala
100 105 110
ccc agc gtg ttc atc ttc ccc ccc tcc gac gag cag ctg aag agc ggc 384
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
acc gcc agc gtg gtg tgc ctg ctg aac aac ttc tac ccc cgg gag gcc 432
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Pne Tyr Pro Arg Glu Ala
130 135 140
aag gtg cag tgg aag gtg gac aac gcc ctg cag agc ggc aac agc cag 480
Lys Val Gln Trn Lys Val Asn Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
gag agc gtg acc gag cag gac agc aag gac tcc acc tac agc ctg agc 528
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
agc acc ctc acc ctg agc aag gcc gac tac gag aag cac aag gtg tac 576
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
gcc tgc gag gtg acc cac cag ggc ctg agc agc ccc gtg acc aag agc 624
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Tnr Lys Ser
195 200 205
ttc aac cgg ggc gag tgt 642
Phe Asn Arg Gly Glu Cys
210
<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
Tle 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 Vel 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 Gis 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)
<400>104
cag tct gcc ctg act cag cct gcc tcc gtg tct ggg tct cct gga cag 48
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
tcg atc acc atc tcc tgc act gga acc agc agt gac gtt ggt ggt tat 96
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30
aac tat gtc tcc tgg tac caa cag cac cca ggc aaa gcc ccc aaa ctc 144
Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
atg att tat gag gtc agt aat cgg ccc tca ggg gtt tct aat cgc ttc 192
Met Ile Tyr Gln Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe
50 55 60
tct ggc tcc aag tct ggc aac acg gcc tcc ctg acc atc tct ggg ctc 240
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
cag gct gag gac gag gct gat tat tac tgc agc tca tat aca agc agc 288
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser
85 90 95
agc act ctt gtc ttc gga act ggg acc aag gtc acc gtc cta ggt gcg 336
Ser Thr Leu Val Phe Gly Thr Gly Thr Lys Val lhr yal Leu Gly Ala
100 105 110
gcc gca ggc cag ccc aag gcc gct ccc agc gtg acc ctg ttc ccc ccc 384
Ala Ala Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro
115 120 125
tcc tcc gag gag ctg cag gcc aac aag gcc acc ctg gtg tgc ctc atc 432
Ser Ser Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile
130 135 140
agc gac ttc tac cct ggc gcc gtg acc gtg gcc tgg aag gcc gac agc 480
Ser Asp Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser
145 150 155 160
agc ccc gtg aag gcc ggc gtg gag acc acc acc ccc agc aag cag agc 528
Ser Pro Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser
165 170 175
aac aac aag tac gcc gcc agc agc tac ctg agc ctc acc ccc gag cag 576
Asp Asp Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln
180 185 190
tgg aag agc cac cgg agc tac agc tgc cag gtg acc cac gag ggc agc 624
Trp Lys Ser His Arg Ser Tyr Ser Cys Gln Val Thr Gis Glu Gly Ser
195 200 205
acc gtg gag aag acc gtg gcc ccc acc gag tgc agc 660
Thr Val Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
210 215 220
<210>105
<211>220
<212>PRT
<213>Gomo 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 Ash 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)
<400>106
cag tct gtc gtg acg cag ccg ccc tcg gtg tca gtg gcc cca gga cag 48
Gln Ser Val Val Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Gln
1 5 10 15
acg gcc agg att acc tgt ggg gga aac aac att gga agt aaa agt gtg 96
Thr Ala Arg Ile Thr Cys Gly Gly Asn Asn Ile Gly Ser Lys Ser Val
20 25 30
cac tgg tac cag cag aag cca ggc cag gcc cct gtg ctg gtc gtc tat 144
Gis Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Val Tyr
35 40 45
gat gat agc gac cgg ccc tca ggg atc cct gag cga ttc tct ggc tcc 192
Asp Asp Ser Asp Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser
50 55 60
aac tct ggg aac acg gcc acc ctg acc atc agc agg gtc gaa gcc ggg 240
Asn Ser Gly Asp Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly
65 70 75 80
gat gag gcc gac tat tac tgt cag gtg tgg gat agt agt agt gat cat 288
Asp Glu Ala Asp Tyr Tyr Lys Glp Val Trp Asp Ser Ser Ser Asp His
85 90 95
tat gtc ttc gga act ggg acc aag gtc acc gtc cta ggt gcg gcc gca 336
Tyr Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu Gly Ala Ala Ala
100 105 110
ggc cag ccc aag gcc gct ccc agc gtg acc ctg ttc ccc ccc tcc tcc 384
Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser
115 120 125
gag gag ctg cag gcc aac aag gcc acc ctg gtg tgc ctc atc agc gac 432
Glu Glu Leu Glp Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp
130 135 140
ttc tac cct ggc gcc gtg acc gtg gcc tgg aag gcc gac agc agc ccc 480
Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro
145 150 155 160
gtg aag gcc ggc gtg gag acc acc acc ccc agc aag cag acc aac aac 528
Val Lys Ala Gly Val Glu Thr Thr Thr Prp Ser Lys Gln Ser Asn Asn
165 170 175
aag tac gcc gcc agc agc tac ctg agc ctc acc ccc gag cag tgg aag 576
Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys
180 185 190
agc cac cgg agc tac agc tgc cag gtg acc cac gag ggc agc acc gtg 624
Ser His Arg Ser Tyr Ser Cys Glp Val Thr His Glu Gly Ser Thr Val
195 200 205
gag aag acc gtg gcc ccc acc gag tgc agc 654
Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
210 215
<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 Trn Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Val Tyr
35 40 45
Asn Asp Ser Asn 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
Asn Glu Ala Asp Tyr Tyr Cys Gln Val Trn 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)
<400>108
act gtg ttg aca cag ccg ccc tca gtg tct ggg gcc cca ggg cag agg 48
Thr Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln Arg
1 5 10 15
gtc acc atc tcc tgc act ggg agc agc tcc aac atc ggg gca ggt tat 96
Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly Tyr
20 25 30
gat gta cac tgg tac cag cag ctt cca gga aca gcc ccc aaa ctc ctc 144
Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
atc tat ggt aac agc aat cgg ccc tca ggg gtc cct gac cga ttc tct 192
Ile Tyr Gly Asn Ser Asn Arg Pro Ser Gly Val Pro Asn Arg Phe Ser
50 55 60
ggc tcc aag tct ggc acg tca gcc acc ctg ggc atc acc gga ctc cag 240
Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln
65 70 75 80
act ggg gac gag gcc gat tat tac tgc gga aca tgg gat agc agc ctg 288
Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ser Ser Leu
85 90 95
agt gct tat gtc ttc gga act ggg acc aag gtc acc gtc cta ggt gcg 336
Ser Ala Tyg Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu Gly Ala
100 105 110
gcc gca ggc cag ccc aag gcc gct ccc agc gtg acc ctg ttc ccc ccc 384
Ala Ala Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro
115 120 125
tcc tcc gag gag ctg cag gcc aac aag gcc acc ctg gtg tgc ctc atc 432
Ser Ser Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile
130 135 140
agc gac ttc tac cct ggc gcc gtg acc gtg gcc tgg aag gcc gac agc 480
Ser Asp Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser
145 150 155 160
agc ccc gtg aag gcc ggc gtg gag acc acc acc ccc agc aag cag agc 528
Ser Pro Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser
165 170 175
aac aac aag tac gcc gcc agc agc tac ctg agc ctc acc ccc gag cag 576
Asn Asn Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln
180 185 190
tgg aag agc cac cgg agc tac agc tgc cag gtg acc cac gag ggc agc 624
Trn Lys Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser
195 200 205
acc gtg gag aag acc gtg gcc ccc acc gag tgc agc 660
Thr Val Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
210 215 220
<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 Asn 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>GA protein of influenza virus H5N1isolate 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 Gis Leu Leu Ser Arg Ile Asn His Phe Glu
115 120 125
Lys Ile Gln Ile Ile Pro Lys Ser Ser Trp Ser Ser Gis 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 Gis Gis 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 GIy 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 Gis 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 prootein of influenza virus H5N1isolate 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 Asp 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 Mer 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 G1y 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 lle 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 Hlu 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 lle 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 yirus
<220>
<221>MISC_FEATURE
<223>Solublle 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
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 ValGly 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 ValTrp 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 ValLys 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 yirus
<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 lle 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 3603 65
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 GIy
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 Gis 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)
<400>115
gag gtg cag ctg gtg gag tct ggg gct gag gtg aag aag cct ggg tcc 48
Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aaa gtc tct tgc aag gct tct gga ggc ccc ttc cgc agc tat 96
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Pro Phe Arg Ser Tyr
20 25 30
gct atc agc tgg gtg cga cag gcc cct gga caa ggg cct gag tgg atg 144
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Pro Glu Trp Met
35 40 45
gga ggg atc atc cct att ttt ggt aca aca aaa tac gca ccg aag ttc 192
Gly Gly Ile Ile Pro Ile Phe Gly Thr Thr Lys Tyr Ala Pro Lys Phe
50 55 60
cag ggc aga gtc acg att acc gcg gac gat ttc gcg ggc aca gtt tac 240
Gln Gly Arg Val Thr Ile Thr Ala Asp Asp Phe Ala Gly Thr Val Tyr
65 70 75 80
atg gag ctg agc agc ctg cga tct gag gac acg gcc atg tac tac tgt 288
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
gcg aaa cat atg ggg tac cag gtg cgc gaa act atg gac gtc tgg ggc 336
Ala Lys His Met Gly Tyr Gln Val Arg Glu Thr Met Asp Val Trp Gly
100 105 110
aaa ggg acc acg gtc acc gtc tcg agc ggt acg ggc ggt tca ggc gga 384
Lys Gly Thr Thr Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly
115 120 125
acc ggc agc ggc act ggc ggg tcg acg tcc tat gtg ctg act cag cca 432
Thr Gly Ser Gly Thr Gly Gly Ser Thr Ser Tyr Val Leu Thr Gln Pro
130 135 140
ccc tca gcg tct ggg acc ccc ggg cag agg gtc acc atc tct tgt tct 480
Pro Ser Ala Ser Gly Thr Pro Gly Gln Arg Val Thr Ile Ser Cys Ser
145 150 155 160
gga agc acg ttc aac atc gga agt aat gct gta gac tgg tac cgg cag 528
Gly Ser Tnr Phe Asn Ile Gly Ser Asn Ala Val Asp Trp Tyr Arg Gln
16 5170 175
ctc cca gga acg gcc ccc aaa ctc ctc atc tat agt aat aat cag cgg 576
Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr Ser Asn Asn Gln Arg
180 185 190
ccc tca ggg gtc cct gac cga ttc tct ggc tcc agg tct ggc acc tca 624
Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Arg Ser Gly Thr Ser
195 200 205
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 yal 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)
<400>117
cag gtc cag ctg gtg cag tct ggg gct gag gtg aag aag cct ggg tcc 48
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aaa gtc tct tgc aag gct tct gga ggc ccc ttc cgc agc tat 96
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Pro Phe Arg Ser Tyr
20 25 30
gct atc agc tgg gtg cga cag gcc cct gga caa ggg cct gag tgg atg 144
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Pro Glu Trp Met
35 40 45
gga ggg atc atc cct att ttt ggt aca aca aaa tac gca ccg aag ttc 192
Gly Gly Ile Ile Pro Ile Phe Gly Thr Thr Lys Tyr Ala Pro Lys Phe
50 55 60
cag ggc aga gtc acg att acc gcg gac gat ttc gcg ggc aca gtt tac 240
Gln Gly Arg Val Thr lle Thr Ala Asp Asp Phe Ala Gly Thr Val Tyr
65 70 75 80
atg gag ctg agc agc ctg cga tct gag gac acg gcc atg tac tac tgt 288
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
gcg aaa cat atg ggg tac cag gtg cgc gaa act atg gac gtc tgg ggc 336
Ala Lys Gis Met Gly Tyr Gln Val Arg Glu Thr Met Asp Val Trp Gly
100 105 110
aaa ggg acc acg gtc acc gtc tcg agc ggt acg ggc ggt tca ggc gga 384
Lys Gly Thr Thr Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly
115 120 125
acc ggc agc ggc act ggc ggg tcg acg cag tct gcc ctg act cag cct 432
Thr Gly Ser Gly Thr Gly Gly Ser Thr Gln Ser Ala Leu Thr Gln Pro
130 135 140
gcc gcc gtg tct ggg tct cct gga cag tcg atc acc atc tcc tgc act 480
Ala Ala Val Ser Gly Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr
145 150 155 160
gga acc agc agt gac gtt ggt ggt tat aac tat gtc tcc tgg tac caa 528
Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln
165 170 175
cag cac cca ggc aaa gcc ccc aaa ctc atg att tat gag gtc agt aat 576
Gln His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr Glu Val Ser Asn
180 185 190
cgg ccc tca ggg gtt tct aat cgc ttc tct ggc tcc aag tct ggc aac 624
Arg Pro Ser Gly Val Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn
195 200 205
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 Gis 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)
<400>119
gag gtg cag ctg gtg gag tct ggg gct gag gtg aag aag cct ggg tcc 48
Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aaa gtc tct tgc aag gct tct gga ggc ccc ttc cgc agc tat 96
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Pro Phe Arg Ser Tyr
20 25 30
gct atc agc tgg gtg cga cag gcc cct gga caa ggg cct gag tgg atg 144
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Pro Glu Trp Met
35 40 45
gga ggg atc atc cct att ttt ggt aca aca aaa tac gca ccg aag ttc 192
Gly Gly Ile Ile Pro Ile Phe Gly lhr lhr Lys Tyr Ala Pro Lys Phe
50 55 60
cag ggc aga gtc acg att acc gcg gac gat ttc gcg ggc aca gtt tac 240
Gln Gly Arg Val Thr Ile Thr Ala Asp Asp Phe Ala Gly Thr Val Tyr
65 70 75 80
atg gag ctg agc agc ctg cga tct gag gac acg gcc atg tac tac tgt 288
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
gcg aaa cat atg ggg tac cag gtg cgc gaa act atg gac gtc tgg ggc 336
Ala Lys His Met Gly Tyr Gln Val Arg Glu Thr Met Asp Val Trp Gly
100 105 110
aaa ggg acc acg gtc acc gtc tcg agc ggt acg ggc ggt tca ggc gga 384
Lys Gly Thr Thr Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly
115 120 125
acc ggc agc ggc act ggc ggg tcg acg tcc tat gtg ctg act cag cca 432
Thr Gly Ser Gly Thr Gly Gly Ser Thr Ser Tyr Val Leu Thr Gln Pro
130 135 140
ccc tca gtc tct ggg acc ccc ggg cag agg gtc acc atc tct tgc tct 480
Pro Ser Val Ser Gly Thr Pro Gly Gln Arg Val Thr Ile Ser Cys Ser
145 150 155 160
gga agc cgc tcc aac gtc gga gat aat tct gta tat tgg tat caa cac 528
Gly Ser Arg Ser Ash Val Gly Asp Asn Ser Val Tyr Trp Tyr Gln Gis
165 170 175
gtc cca gaa atg gcc ccc aaa ctc ctc gtc tat aag aat act caa cgg 576
Val Pro Glu Met Ala Pro Lys Leu Leu Val Tyr Lys Asn Thr Gln Arg
180 185 190
ccc tca gga gtc cct gcc cgg ttt tcc ggc tcc aag tct ggc act tca 624
Pro Ser Gly Val Pro Ala Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser
195 200 205
gcc tcc ctg gcc atc att ggc ctc cag tcc ggc gat gag gct gat tat 672
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)
<400>121
gag gtg cag ctg gtg gag tct ggg gct gag gtg aag aag cct ggg tcc 48
Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aaa gtc tct tgc aag gct tct gga ggc ccc ttc cgc agc tat 96
Ser Val Lys Val Ser Cys Lys Ala Ser Gly G1y Pro Phe Arg Ser Tyr
20 25 30
gct atc agc tgg gtg cga cag gcc cct gga caa ggg cct gag tgg atg 144
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Pro Glu Trp Met
35 40 45
gga ggg atc atc cct att ttt ggt aca aca aaa tac gca ccg aag ttc 192
Gly Gly Ile Ile Pro Ile Phe Gly Thr Thr Lys Tyr Ala Pro Lys Phe
50 55 60
cag ggc aga gtc acg att acc gcg gac gat ttc gcg ggc aca gtt tac 240
Gln Gly Arg Val Thr Ile Thr Ala Asp Asp Phe Ala Gly Thr Val Tyr
65 70 75 80
atg gag ctg agc agc ctg cga tct gag gac acg gcc atg tac tac tgt 288
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
gcg aaa cat atg ggg tac cag gtg cgc gaa act atg gac gtc tgg ggc 336
Ala Lys His Met Gly Tyr Gln Val Arg Glu Thr Met Asp yal Trp Gly
100 105 110
aaa ggg acc acg gtc acc gtc tcg agc ggt acg ggc ggt tca ggc gga 384
Lys Gly Thr Thr Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly
115 120 125
acc ggc agc ggc act ggc ggg tcg acg cag tct gtg ttg acg cag ccg 432
Thr G1y Ser Gly Thr Gly Gly Ser Thr Gln Ser Val Leu Thr Gln Pro
130 135 140
ccc tca gtg tct gcg gcc cca gga cag aag gtc acc atc tcc tgc tct 480
Pro Ser Val Ser Ala Ala Pro Gly Gln Lys Val Thr Ile Ser Cys Ser
145 150 155 160
gga agc agc tcc aac att ggg aat gat tat gta tcc tgg tac cag cag 528
Gly Ser Ser Ser Asn Ile Gly Asn Asp Tyr Val Ser Trp Tyr Gln Gln
165 170 175
ctc cca gga aca gcc ccc aaa ctc ctc att tat gac aat aat aag cga 576
Leu Pro Gly Thr Ala Pro Lys Leu Leu lle Tyr Asp Asn Asn Lys Arg
180 185 190
ccc tca ggg att cct gac cga ttc tct ggc tcc aag tct ggc acg tca 624
Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser
195 200 205
gcc acc ctg ggc atc acc gga ctc cag act ggg gac gag gcc aac tat 672
Ala Thr Leu Gly Ile Thr Gly Leu Gln Thr Gly Asp Glu Ala Asn Tyr
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 gga 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
165 170 175
Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr Asp Ash 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)
<400>123
cag gta cag ctg cag cag tca ggg gct gag gtg aag aag cct ggg tcc 48
Gln Val Gln Leu Gln Gln Ser G1y Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aag gtc tcc tgc aag gtt tcc gga gtc att ttc agc ggc agt 96
Ser Val Lys Val Ser Cys Lys Val Ser Gly Val Ile Phe Ser Gly Ser
20 25 30
gcg atc agc tgg gtg cga cag gcc cct gga caa ggc ctt gag tgg atg 144
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu GlG Trp Met
35 40 45
gga ggg atc agc cct ctc ttt ggc aca aca aat tac gca caa aag ttc 192
Gly Gly Ile Ser Pro Leu Phe Gly Thr Thr Asn Tyr Ala Gln Lys Pne
50 55 60
cag ggc aga gtc acg att acc gcg gac caa tcc acg aac aca acc tac 240
Gln Gly Arg Val Thr Ile Thr Ala Asp Gln Ser Thr Asn Thr Thr Tyr
65 70 75 80
atg gag gtg aac agc ctg aga tat gag gac acg gcc gtg tat ttc tgt 288
Met Glu Val Asn Ser Leu Arg Tyr Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
gcg cga ggt cca aaa tat tac agt gag tac atg gac gtc tgg ggc aaa 336
Ala Arg Gly Pro Lys Tyr Tyr Ser Glu Tyr Met Asp Val Trp Gly Lys
100 105 110
ggg acc acg gtc acc gtc tcg agc ggt acg ggc ggt tca ggc gga acc 384
Gly Thr Thr Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly Thr
115 120 125
ggc agc ggc act ggc ggg tcg acg gac atc cag atg acc cag tct cca 432
Gly Ser Gly Thr Gly Gly Ser Thr Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
tcc tcc ctg tct gca tct gta gga gac aga gtc acc atc act tgc cgg 480
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
145 150 155 160
gcg agt cag ggc att agc agt tat tta gcc tgg tat cag cag aag cca 528
Ala Ser Gln Gly Ile Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro
165 170 175
ggg aaa gtt cct aca ctc ctg atc tat gat gca tcc act ttg cga tca 576
Gly Lys Val Pro Thr Leu Leu Ile Tyr Asp Ala Ser Thr Leu Arg Ser
180 185 190
ggg gtc cca tct cgc ttc agt ggc agt gga tct gcg aca gat ttc act 624
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Ala Thr Asp Phe Thr
195 200 205
ctc acc atc agc agc ctg cag cct gaa gat gtt gca act tat tac tgt 672
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys
210 215 220
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 cst 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)
<400>125
cag gtc cag ctg gta cag tct ggg gct gag gtg aag aag cct ggg tcc 48
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aag gtc tcc tgc aag gct tct gga ggc acc ttc agt agt tat 96
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
gct atc agc tgg gtg cga cag gcc cct gga caa ggg ctt gag tgg atg 144
Ala Ile Ser Trn Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
gga gga atc atg ggt atg ttt ggc aca act aac tac gca cag aag ttc 192
Gly Gly Ile Met Gly Met Phe Gly Thr Thr Asn Tyr Ala Gln Lys Phe
50 55 60
cag ggc aga gtc acg att acc gcg gac gaa ttc acg agc gca gcc tac 240
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Phe Thr Ser Ala Ala Tyr
65 70 75 80
atg gag ctg agg agc ctg aga tct gag gac acg gcc gtc tac tac tgt 288
Met Glu Leu Arg Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
gcg agg tct agt ggt tat tac ccc gaa tac ttc cag gac tgg ggc cag 336
Ala Arg Ser Ser Gly Tyr Tyr Pro Glu Tyr Phe Gln Asp Trp Gly Gln
100 105 110
ggc acc ctg gtc acc gtc tcg agc ggt acg ggc ggt tca ggc gga acc 384
Gly Thr Leu Val Thr Val Ser Ser Gly Tnr Gly Gly Ser Gly Gly Thr
115 120 125
ggc agc ggc act ggc ggg tcg acg cag tct gtg ctg act cag cca ccc 432
Gly Ser Gly Thr Gly Gly Ser Thr Gln Ser Val Leu Thr Gln Pro Pro
130 135 140
tca gag tcc gtg tcc cca gga cag aca gcc agc gtc acc tgc tct gga 480
Ser Glu Ser Val Ser Pro Gly Gln Thr Ala Ser Val Thr Cys Ser Gly
145 150 155 160
cat aaa ttg ggg gat aaa tat gtt tcg tgg tat cag cag aag cca ggc 528
His Lys Leu Gly Asp Lys Tyr Val Ser Trp Tyr Gln Gln Lys Pro Gly
165 170 175
cag tcc cct gta tta ctc atc tat caa gat aac agg cgg ccc tca ggg 576
Gln Ser Pro Val Leu Leu Ile Tyr Gln Asp Asn Arg Arg Pro Ser Gly
180 185 190
arc cct gag cga ttc ata ggc tcc aac tct ggg aac aca gcc act ctg 624
Ile Pro Glu Arg Phe Ile Gly Ser Asn Ser Gly Asn Thr Ala Thr Leu
195 200 205
acc atc agc ggg acc cag gct ctg gat gag gct gac tat tac tgt cag 672
Thr Ile Ser Gly Thr Gln Ala Leu Asp Glu Ala Asp Tyr Tyr Cys Gln
210 215 220
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 Ash 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)
<400>127
cag gtc cag ctg gtg cag tct ggg gga ggc ctg gtc aag cct ggg ggg 48
Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
tcc ctg aga ctc tcc tgt gca gcc tct gga ttc acc ttc agt agc tat 96
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
agc atg aac tgg gtc cgc cag gct cca ggg aag ggg ctg gag tgg gtc 144
Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
tca tcc att agt agt agt agt agt tac ata tac tac gta gac tca gtg 192
Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Val Asp Ser Val
50 55 60
aag ggc cga ttc acc atc tcc aga gac aac gcc aag aac tca ctg tat 240
Lys Gly Arg Phe Thr Ile Set Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
ctg caa atg aac agc ctg aga gcc gag gac acg gct gtg tat tac tgt 288
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
gcg aga ggt ggt ggg agc tac ggg gcc tac gaa ggc ttt gac tac tgg 336
Ala Arg Gly Gly Gly Ser Tyr Gly Ala Tyr Glu Gly Phe Asp Tyr Trp
100 105 110
ggc cag ggc acc ctg gtc acc gtc tcg agc ggt acg ggc ggt tca ggc 384
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly
115 120 125
gga acc ggc agc ggc act ggc ggg tcg acg gaa att gtg ctg act cag 432
Gly Thr Gly Ser Gly Thr Gly Gly Ser Thr Glu Ile Val Leu Tnr Gln
130 135 140
tct cca ggc acc ctg tct ttg tct cca ggg gaa aga gcc acc ctc tcc 480
Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Tnr Leu Ser
145 150 155 160
tgc agg gcc agt cag cgt gtt agc agc tac tta gcc tgg tac caa cag 528
Cys Arg Ala Ser Gln Arg Val Ser Ser Tyr Leu Ala Trp Tyr Gln Gln
165 170 175
aaa cct ggc cag gct ccc agg ctc ctc atc tat ggt gca tcc acc agg 576
Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Thr Arg
180 185 190
gcc gct ggc atc cca gac agg ttc agt ggc agt ggg tct ggg aca gac 624
Ala Ala Gly Ile Pro Asp Arg Pne Ser Gly Ser Gly Ser Gly Tnr Asp
195 200 205
ttc act ctc acc atc agc aga ctg gag cct gaa gat tct gca gtg tat 672
Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Ser Ala Val Tyl
210 215 220
tac tgt cag cag tat ggt agg aca ccg ctc act ttc ggc gga ggg acc 720
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
<212>Artificial
<220>
<223>SC06-310
<220>
<221>CDS
<222>(1)..(738)
<400>129
gag gtg cag ctg gtg gag tct ggg gct gag gtg aag aag cct ggg tcc 48
Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aaa gtc tct tgc aag gct tct gga ggc ccc ttc cgc agc tat 96
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Pro Phe Arg Ser Tyr
20 25 30
gct atc agc tgg gtg cga cag gcc cct gga caa ggg cct gag tgg atg 144
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Pro Glu Trp Met
35 40 45
gga ggg atc atc cct att ttt ggt aca aca aaa tac gca ccg aag ttc 192
Gly Gly Ile Ile Pro Ile Phe Gly Thr lhr Lys Tyr Ala Pro Lys Phe
50 55 60
cag ggc aga gtc acg att acc gcg gac gat ttc gcg ggc aca gtt tac 240
Gln Gly Arg Val Thr Ile Thr Ala Asp Asp Phe Ala Gly Thr Val Tyr
65 70 75 80
atg gag ctg agc agc ctg cga tct gag gac acg gcc atg tac tac tgt 288
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
gcg aaa cat atg ggg tac cag gtg cgc gaa act atg gac gtc tgg ggc 336
Ala Lys His Met Gly Tyr Gln Val Arg Glu Thr Met Asp Val Trp Gly
100 105 110
aaa ggg acc acg gtc acc gtc tcg agc ggt acg ggc ggt tca ggc gga 384
Lys Gly Thr Thr Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly
115 120 125
acc ggc agc ggc act ggc ggg tcg acg tcc tat gtg ctg act cag cca 432
Thr Gly Ser Gly Thr Gly Gly Ser Thr Ser Tyr Val Leu Thr Gln Pro
130 135 140
ccc tcg gtg tca gtg gcc cca gga cag acg gcc agg att acc tgt ggg 480
Pro Ser Val Ser Val Ala Pro Gly Gln Thr Ala Arg Ile Thr Cys Gly
145 150 155 160
gga aac aac att gga agt aaa agt gtg cac tgg tac cag cag aag cca 528
Gly Asn Asn Ile Gly Ser Lys Ser Val Gis Trp Tyr Gln Gln Lys Pro
165 170 175
ggc cag gcc cct gtg ctg gtc gtc tat gat gat agc gac cgg ccc tca 576
Gly Gln Ala Pro Val Leu Val yal Tyr Asp Asp Ser Asp Arg Pro Ser
180 185 190
ggg atc cct gag cga ttc tct ggc tcc aac tct ggg aac acg gcc acc 624
Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn Thr Ala Thr
195 200 205
ctg acc atc agc agg gtc gaa gcc ggg gat gag gcc gac tat tac tgt 672
Leu Thr lle Ser Arg ValGlu Ala Gly Asp Glu Ala Asp Tyr Tyr Cys
2l0 215 220
cag gtg tgg gat agt agt agt gat cat gct gtg ttc gga gga ggc acc 720
Gln Val Trp Asp Ser Ser Ser Asp Gis Ala Val Phe Gly Gly Gly Thr
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 Gis 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)
<400>131
gag gtg cag ctg gtg gag tct ggg gct gag gtg aag aag cct ggg tcc 48
Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aaa gtc tct tgc aag gct tct gga ggc ccc ttc cgc agc tat 96
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Pro Phe Arg Ser Tyr
20 25 30
gct atc agc tgg gtg cga cag gcc cct gga caa ggg cct gag tgg atg 144
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Pro Glu Trp Met
35 40 45
gga ggg atc atc cct att ttt ggt aca aca aaa tac gca ccg aag ttc 192
Gly Gly Ile Ile Pro Ile Phe Gly Thr Thr Lys Tyr Ala Pro Lys Phe
50 55 60
cag ggc aga gtc acg att acc gcg gac gat ttc gcg ggc aca gtt tac 240
Gln Gly Arg Val Thr Ile Thr Ala Asp Asp Phe Ala Gly Thr Val Tyr
65 70 75 80
atg gag ctg agc agc ctg cga tct gag gac acg gcc atg tac tac tgt 288
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
gcg aaa cat atg ggg tac cag gtg cgc gaa act atg gac gtc tgg ggc 336
Ala Lys His Met Gly Tyr Gln Val Arg Glu Thr Met Asp Val Trp Gly
100 105 110
aaa ggg acc acg gtc acc gtc tcg agc ggt acg ggc ggt tca ggc gga 384
Lys Gly Thr Thr Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly
115 120 125
acc ggc agc ggc act ggc ggg tcg acg tcc tat gtg ctg act cag cca 432
Thr Gly Ser Gly Thr Gly Gly Ser Thr Ser Tyr Val Leu Thr Gln Pro
130 135 140
ccc tca gcg tct ggg acc ccc ggg cag agg gtc acc atc tct tgt tct 480
Pro Ser Ala Ser Gly Thr Pro Gly Gln Arg Val Thr Ile Ser Cys Ser
145 150 155 160
gga agc agc tcc aac atc gga agt aat tat gta tac tgg tac cag cag 528
Gly Ser Ser Ser Asn Ile Gly Ser Asn Tyr Val Tyr Trp Tyr Gln Gln
165 170 175
ctc cca ggc acg gcc ccc aaa ctc ctc atc tat agg gat ggt cag cgg 576
Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr Arg Asp Gly Gln Arg
180 185 190
ccc tca ggg gtc cct gac cga ttc tct ggc tcc aag tct ggc acc tca 624
Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser
195 200 205
gcc tcc ctg gcc atc agt gga ctc cgg tcc gat gat gag gct gat tat 672
Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Asp Asp Glu Ala Asp Tyr
210 215 220
tac tgt gca aca tgg gat gac aac ctg agt ggt cca gta ttc ggc gga 720
Tyr Cys Ala Thr Trp Asp Asp Asn Leu Ser Gly 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 GIy
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 Ash 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 GIy 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)
<400>133
gag gtg cag ctg gtg gag tct ggg gct gag gtg aag aag cca ggg tcc 48
Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aag gtc tcc tgt aag gcc tct gga ggc acc ttc tcc agc tat 96
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
ggt atc agc tgg gtg cga cag gcc cct gga caa ggg ctt gag tgg atg 144
Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
gga gac atc atc ggt atg ttt ggt tca aca aac tac gca cag aac ttc 192
Gly Asp Ile lle Gly Met Phe Gly Ser Thr Asn Tyr Ala Gln Asn Phe
50 55 60
cag ggc aga ctc acg att acc gcg gac gaa tcc acg agc aca gcc tac 240
Gln Gly Arg Leu Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
atg gag ctg agc agc ctg aga tct gag gac acg gcc gtg tat tac tgt 288
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
gcg aga agt agt ggt tat tac cct gca tac crc ccc cac tgg ggc cag 336
Ala Arg Ser Ser Gly Tyr Tyr Pro Ala Tyr Leu Pro Gis Trp Gly Gln
100 105 110
ggc acc ttg gtc acc gtc tcg agc ggt acg ggc ggt tca ggc gga acc 384
Gly Thr Leu Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly Thr
115 120 125
ggc agc ggc act ggc ggg tcg acg gaa att gtg ttg acc cag tct cca 432
Gly Ser Gly Thr Gly Gly Ser Thr Glu Ile Val Leu Thr Gln Ser Pro
130 135 140
ggc acc ctg tct ttg tct cca ggg gaa aga gcc acc ctc tcc tgc agg 480
Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg
145 150 155 160
gcc agt cag agt gtt agc agc agc tac tta gcc tgg tac cag cag aaa 528
Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys
165 170 175
cct ggc cag gct ccc agg ctc ctc atc tat ggt gca tcc agc agg gcc 576
Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala
180 185 190
act ggc atc cca gac agg ttc agt ggc agt ggg tct ggg aca gac ttc 624
Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
195 200 205
act ctc acc atc agc aga ctg gag cct gaa gat ttt gca gtg tat tac 672
Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr
210 215 220
tgt cag cag tat ggt agc tca ccc aga act ttc ggc gga ggg acc aag 720
Cys Gln Gln Tyr Gly Ser Ser Pro Arg Thr Phe Gly Gly Gly Thr Lys
225 230 235 240
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)
<400>135
gag gtg cag ctg gtg gag tct ggg gct gag gtg aag aag ccg ggg tcc 48
Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aag gtc tcc tgc aag gct tct gga ggc acc ttc agc ttc tat 96
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Phe Tyr
20 25 30
tct atg agc tgg gtg cga cag gcc cct ggg caa gga ctt gag tgg atg 144
Ser Met Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
gga ggg atc atc cct atg ttt ggt aca aca aac tac gca cag aag ttc 192
Gly Gly lle Ile Pro Met Phe Gly Thr Thr Asn Tyr Ala Gln Lys Phe
50 55 60
cag ggc aga gtc acg att acc gcg gtc gaa tcc acg agc aca gcc tac 240
Gln Gly Arg Val Thr Ile Thr Ala Val Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
atg gag gtg agc agc ctg aga tct gag gac acg gcc gtt tat tac tgt 288
Met Glu Val Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
gcg aga ggt gat aag ggt atc tac tac tac tac atg gac gtc tgg ggc 336
Ala Arg Gly Asp Lys Gly Ile Tyr Tyr Tyr Tyr Met Asp Val Trp Gly
100 105 110
aaa ggg acc acg gtc acc gtc tcg agc ggt acg ggc ggt tca ggc gga 384
Lys Gly Thr Thr Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly
115 120 125
acc ggc agc ggc act ggc ggg tcg acg cag tct gcc ctg act cag cct 432
Thr Gly Ser Gly Thr Gly Gly Ser Thr Gln Ser Ala Leu Thr Gln Pro
130 135 140
gcc tcc gtg tct ggg tct cct gga cag tcg atc acc atc tcc tgc act 480
Ala Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr
145 150 155 160
gga acc agc agt gac gtt ggt ggt tat aac tat gtc tcc tgg tac caa 528
Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln
165 170 175
cag cac cca ggc aaa gcc ccc aaa ctc atg att tat gag gtc agt aat 576
Gln His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr Glu Val Ser Asn
180 185 190
cgg ccc tca ggg gtt tct agt cgc ttc tct ggc tcc aag tct ggc aac 624
Arg Pro Ser Gly Val Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn
195 200 205
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 ctt gtc ttc gga act 720
Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser Ser Thr Leu Val Pne Gly Tnr
225 230 235 240
ggg acc aag gtc acc gtc cta ggt 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 GIy 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)
<400>137
gag gtg cag ctg gtg gag tct ggg gct gag gtg aag aag cct ggg tcc 48
Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aag gtc tcc tgc aag gct tct gga ggc acc ttc agc agc tat 96
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
gct atc agc tgg gtg cga cag gcc cct gga caa ggg ctt gag tgg atg 144
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
gga ggg atc atc ggt atg ttc ggt aca gca aac tac gca cag aag ttc 192
Gly Gly Ile Ile Gly Met Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
cag ggc aga gtc acg att acc gcg gac gaa ttt acg agc aca gcc tac 240
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Phe Thr Ser Thr Ala Tyr
65 70 75 80
atg gag ctg agc agc ctg aga tct gag gac acg gcc gtg tat tac tgt 288
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
gcg aga gga aat tat tac tat gag agt agt ctc gac tac tgg ggc cag 336
Ala Arg Gly Asn Tyr Tyr Tyr Glu Ser Ser Leu Asp Tyr Trp Gly Gln
100 105 110
gga acc ctg gtc acc gtc tcg agc ggt acg ggc ggt rca ggc gga acc 384
Gly Thr Leu Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly Thr
115 120 125
ggc agc ggc act ggc ggg tcg acg cag tct gtc gtg acg cag ccg ccc 432
Gly Ser Gly Thr Gly Gly Ser Thr Gln Ser Val Val Thr Gln Pro Pro
130 135 140
tcg gtg tca gtg gcc cca gga cag acg gcc agg att acc tgt ggg gga 480
Ser Val Ser Val Ala Pro Gly Gln Thr Ala Arg Ile Thr Cys Gly Gly
145 150 155 160
aac aac att gga agt aaa agt gtg cac tgg tac cag cag aag cca ggc 528
Asn Asn Ile Gly Ser Lys Ser Val His Trp Tyr Gln Gln Lys Pro Gly
165 170 175
cag gcc cct gtg ctg gtc gtc tat gat gat agc gac cgg ccc tca ggg 576
Gln Ala Pro Val Leu Val Val Tyr Asp Asp Ser Asp Arg Pro Ser Gly
180 185 190
atc cct gag cga ttc tct ggc tcc aac tct ggg aac acg gcc acc ctg 624
Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Ash Thr Ala Thr Leu
195 200 205
acc atc agc agg gtc gaa gcc ggg gat gag gcc gac tat tac tgt cag 672
Thr Ile Ser Arg Val Glu Ala Gly Asp Glu Ala Asp Tyr Tyr Cys Gln
210 215 220
gtg tgg gat agt agt agt gat cat tat gtc ttc gga act ggg acc aag 720
Val Trp Asp Ser Ser Ser Asp His Tyr Val Phe Gly Thr Gly Thr Lys
225 230 235 240
gtc acc gtc cta ggt 735
Val Thr Val Leu Gly
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 Ash 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 GIy 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 Ash 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)
<400>139
cag gtg cag ctg gtg cag tct ggg gct gag gtg aag aag cct ggg tcc 48
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aga gtc tcc tgc aag gct tct gga agc atc ttc aga aac tat 96
Ser Val Arg Val Ser Cys Lys Ala Ser Gly Ser Ile Phe Arg Asn Tyr
20 25 30
gct atg agc tgg gtg cga cag gcc cct gga caa ggg ctt gag tgg atg 144
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
gga ggg atc atc gct att ttt ggg aca cca aag tac gca cag aag ttc 192
Gly Gly Ile Ile Ala Ile Phe Gly lhr Pro Lys Tyr Ala Gln Lys Phe
50 55 60
cag ggc aga gtc acg att acc gcg gac gaa tcg acg agc act gtc tac 240
Gln Gly Arg Val Thr lle Thr Ala Asp Glu Ser Thr Ser Thr Val Tyr
65 70 75 80
atg gaa ctg agc gga ctg aga tct gag gac acg gcc atg tat tac tgt 288
Met Glu Leu Ser Gly Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
gcg agg att ccc cac tat aat ttt ggt tcg ggg agt tat ttc gac tac 336
Ala Arg Ile Pro His Tyr Asn Phe Gly Ser Gly Ser Tyr Phe Asp Tyr
100 105 110
tgg ggc cag gga acc ctg gtc acc gtc tcg agc ggt acg ggc ggt tca 384
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Thr Gly Gly Ser
115 120 125
ggc gga acc ggc agc ggc act ggc ggg tcg acg act gtg ttg aca cag 432
Gly Gly Thr Gly Ser Gly Thr Gly Gly Ser Thr Thr Val Leu Thr Gln
130 135 140
ccg ccc tca gtg tct ggg gcc cca ggg cag agg gtc acc atc tcc tgc 480
Pro Pro Ser Val Ser Gly Ala Pro Gly Gln Arg Val Thr Ile Ser Cys
145 150 155 160
act ggg agc agc tcc aac atc ggg gca ggt tat gat gta cac tgg tac 528
Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly Tyr Asp Val His Trp Tyr
165 170 175
cag cag ctt cca gga aca gcc ccc aaa ctc ctc atc tat ggt aac agc 576
Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr Gly Asn Ser
180 185 190
aat cgg ccc tca ggg gtc cct gac cga ttc tct ggc tcc aag tct ggc 624
Asn Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly
195 200 205
acg tca gcc acc ctg ggc atc acc gga ctc cag act ggg gac gag gcc 672
Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln Thr Gly Asp Glu Ala
210 215 220
gat tat tac tgc gga aca tgg gat agc agc ctg agt gct tat gtc ttc 720
Asp Tyr Tyr Cys Gly Thr Trp Asp Ser Ser Leu Ser Ala Tyr Val Phe
225 230 235 240
gga act ggg acc aag gtc acc gtc cta ggt 750
Gly Thr Gly Thr Lys Val Thr Val Leu Gly
245 250
<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 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 acatcttett 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 23
cagtctgtgc tgactcagcc acc
<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>15823
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>0JK3(HuJK3-NOT)
<400>182
gagtcattct cgacttgcgg ccgcacgttt gatatccact ttggtccc 48
<210>183
<211>48
<212>DNA
<213>Artificial
<220>
<223>0JK4(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>OLSS(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(HuLH1/2-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)
<400>212
gag gtc cag ctg gtg cag tct ggg gct gag gtg aag aag cct ggg gcc 48
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
tca gtg aag gtc tcc tgc aag gct tct ggg tac acc ttc acc ggc tac 96
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
tat gtg tac tgg gtg cga cag gcc cct gga caa ggg ctt gag tgg atg 144
Tyr Val Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
30 40 45
gga tgg atc agc gct tac aat ggt aac aca aac tat gca cag aag ttc 192
Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Phe
50 55 60
cag ggc aga gtc acg att acc gcg gac aaa tcc acg agc aca gcc tac 240
Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
atg gag ctg agc agc ctg aga tct gaa gac acg gct gtg tat tac tgt 288
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
gcg aga agt aga tcc ctg gac gtc tgg ggc caa ggg acc acg gtc acc 336
Ala Arg Ser Arg Ser Leu Asp Val Trp Gly Glp Gly Thr Thr Val Thr
100 105 110
gtc tcg agc ggt acg ggc ggt tca ggc gga acc ggc agc ggc act ggc 384
Val Ser Ser Gly Thr Gly Gly Ser Gly Gly Thr Gly Ser Gly Thr Gly
115 120 125
ggg tcg acg gat gtt gtg atg act cag tct cca gac tcc ctg gct gtg 432
Gly Ser Thr Asp Val Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val
130 135 140
tct ctg ggc gag agg gcc acc atc aac tgc aag tcc agc cag agt gtt 480
Ser Leu Gly Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val
145 150 155 160
tta tac agc tcc aac aat aag aac tac tta gct tgg tac cag cag aaa 528
Leu Tyr Ser Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys
165 170 175
cca gga cag cct cct aag ctg ctc att tac tgg gca tct acc cgg gaa 576
Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu
180 185 190
tcc ggg gtc cct gac cga ttc agt ggc agc ggg tct ggg aca gat ttc 624
Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
195 200 205
act ctc acc atc agc agc ctg cag gct gaa gat gtg gca gtt tat tac 672
Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr
210 215 220
tgt cag caa tat tat agt act cct ctc act ttc ggc gga ggg acc aaa 720
Cys Gln Gln Tyr Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys
225 230 235 240
gtg gat atc aaa cgt 735
Val Asp Ile Lys Arg
245
<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)
<400>214
cag atg cag ctg gtg cag tct ggg gct gag gtg aag aag cct ggg tcc 48
Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aag gtc tcc tgc aag gct tct gga ggc acc ttc tcc agt tat 96
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
gct atc acc tgg gtg cga cag gcc cct gga caa ggg ctt gag tgg atg 144
Ala Ile Thr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
gga ggg atc atc ggt atg ttt ggt tca aca aac tac gca cag aac ttc 192
Gly Gly Ile Ile Gly Met Phe Gly Ser Thr Asn Tyr Ala Gln Asn Phe
50 55 60
cag ggc aga gtc acg att acc gcg gac gaa tcc acg agc aca gcc tac 240
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
atg gag ctg agc agc ctc aga tct gag gac acg gcc gtg tat tac tgt 288
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
gcg aga agt act ggt tat tac cct gca tac ctc cac cac tgg ggc cag 336
Ala Arg Ser Thr Gly Tyr Tyr Pro Ala Tyr Leu His His Trp Gly Gln
100 105 110
ggc acc ctg gtc acc gtc tcg agc ggt acg ggc ggt tca ggc gga acc 384
Gly Thr Leu Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly Thr
115 120 125
ggc agc ggc act ggc ggg tcg acg cag tct gcc ctg act cag cct cgc 432
Gly Ser Gly Thr Gly Gly Ser Thr Gln Ser Ala Leu Thr Gln Pro Arg
130 135 140
tca gtg tcc ggg tct cct gga cag tca gtc acc atc tcc tgc act gga 480
Ser Val Ser Gly Ser Pro Gly Gln Ser Val Thr Ile Ser Cys Thr Gly
145 150 155 160
acc agc agt gat gtt ggt ggt tat aac tat gtc tcc tgg tac caa cag 528
Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln
165 170 175
cac cca ggc aaa gcc ccc aaa ctc atg att tat gat gtc agt aag cgg 576
His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr Asp Val Ser Lys Arg
180 185 190
ccc tca ggg gtc cct gat cgc ttc tct ggc tcc aag tct ggc aac acg 624
Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr
195 200 205
gcc tcc ctg acc atc tct ggg ctc cag gct gag gat gag gct gat tat 672
Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr
210 215 220
tac tgc agc tca tat aca agc agc agc act cat gtc ttc gga act ggg 720
Tyr Cys Ser Ser Tyr Thr Ser Ser Ser Thr Gis Val Phe Gly Thr Gly
225 230 235 240
acc aag gtc acc gtc cta ggt 741
Thr Lys Val Thr Val Leu Gly
245
<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 Gis 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)
<400>216
gag gtg cag ctg gtg gag acc ggg gct gag gtg aag aag cct ggg gcc 48
Glu Val Gln Leu Val Glu Thr Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
tca gtg aag gtt tcc tgc aag gca tct gga tac acc ttc acc agc tac 96
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
tat atg cac tgg gtg cga cag gcc cct gga caa ggg ctt gag tgg atg 144
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
gga tgg atc aac cct aac agt ggt ggc aca aac tat gca cag aag ttt 192
Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe
50 55 60
cag ggc agg gtc acc atg acc agg gac acg tcc ate agc aca gcc tac 240
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser lle Ser Thr Ala Tyr
65 70 75 80
atg gag ctg agc agg ctg aga tct gac gac acg gcc gtg tat tac tgt 288
Met Glu Leu Ser Arg Leu Arg Set Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
gcg aga gag ggg aaa tgg gga cct caa gcg gct ttt gat atc tgg ggc 336
Ala Arg Glu Gly Lys Trp Gly Pro Gln Ala Ala Phe Asp lle Trp Gly
100 105 110
caa ggg aca atg gtc acc gtc tcg agc ggt acg ggc ggt tca ggc gga 384
Gln Gly Thr Met Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly
115 120 125
acc ggc agc ggc act ggc ggg tcg acg gaa att gtg atg acg cag tct 432
Thr Gly Ser Gly Thr Gly Gly Ser Thr Glu Ile Val Met Thr Gln Ser
130 135 140
cca ggc acc ctg tct ttg tct cca ggg gaa aga gcc acc ctc tcc tgc 480
Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys
145 150 155 160
agg gcc agt cag agt gtt agc agc agc tac tta gcc tgg tac cag cag 528
Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln
165 170 175
aaa cct ggc cag gct ccc agg ctc ctc atc tat gat gca tcc agc agg 576
Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Asp Ala Ser Ser Arg
180 185 190
gcc act gac atc cca gac agg ttc agt ggc agt ggg tct ggg aca gac 624
Ala Thr Asp Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
195 200 205
ttc act ctc acc atc agc aga ctg gag cct gaa gat ttt gca gtg tat 672
Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr
210 215 220
tac tgt cag cag tat ggt agc tca ctt tgg acg ttc ggc caa ggg acc 720
Tyr Cys Gln Gln Tyr Gly Ser Ser Leu Trp Thr Phe Gly Gln Gly Thr
225 230 235 240
aag gtg gag atc aaa cgt 738
Lys Val Glu Ile Lys Arg
245
<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 Ash 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>
<22l>CDS
<222>(1)..(738)
<400>218
gag gtg cag ctg gta gag tct ggg gga ggc ttg gta cag cct ggg ggg 48
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
tcc ctg aga ctc tcc tgt gca gcc tct gga ttc acc ttt agc atc tat 96
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ile Tyr
20 25 30
gcc atg agc tgg gtc cgc cag gca cca ggg aag ggg ctg gag tgg gtc 144
Ala Met Ser Trn Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
tca gct att agt agt agt ggt gat agc aca tac tac gca gac tcc gtg 192
Ser Ala Ile Ser Ser Ser GIy Asp Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
aag ggc cgg ttc acc atc tcc aga gac aac gcc agg aac acg ctg tat 240
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Thr Leu Tyr
65 70 75 80
ctg caa atg aac agt ctg aga gcc gag gac acg gct gtg tat tac tgt 288
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
gcg aga gcg tat ggc tac acg ttc gac ccc tgg ggc cag gga acc ctg 336
Ala Arg Ala Tyr Gly Tyr Thr Phe Asp Pro Trp Gly Gln Gly Thr Leu
100 105 110
gtc acc gtc tcg agc ggt acg ggc ggt tca ggc gga acc ggc agc ggc 384
Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly Thr Gly Ser Gly
115 120 125
act ggc ggg tcg acg gaa att gtg ctg act cag tct cca ctc tcc ctg 432
Thr Gly Gly Ser Thr Glu Ile Val Leu Thr Gln Ser Pro Leu Ser Leu
130 135 140
ccc gtc acc cct gga gag ccg gcc tcc atc tcc tgc agg tct agt cag 480
Pro Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln
145 150 155 160
agc ctc ctg cat agt aat gga tac aac tat ttg gat tgg tac ctg cag 528
Ser Leu Leu Gis Ser Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln
165 170 175
aag cca ggg cag tct cca cag ctc ctg atc tat ttg ggt tct aat cgg 576
Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg
180 185 190
gcc tcc ggg gtc cct gac agg ttc agt ggc agt gga tca ggc aca gat 624
Ala Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
195 200 205
ttt aca ctg aaa atc agc aga gtg gag gct gag gat gtt ggg gtt tat 672
Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr
210 215 220
tac tgc atg caa gct cta caa act ccc ctc act ttc ggc gga ggg acc 720
Tyr Cys Met Gln Ala Leu Gln Thr Pro Leu Thr Phe Gly Gly Gly Thr
225 230 235 240
aag gtg gag atc aaa cgt 738
Lys yal Glu Ile Lys Arg
245
<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 Gis 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)
<400>220
gag gtg cag ctg gtg gag acc ggg gct gag gtg aag agg cct ggg tcc 48
Glu Val Gln Leu Val Glu Thr Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 13
tcg gtg aag gtc tcc tgc aag gcc tct gga ggc acc ttc agg acc cat 96
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Arg Thr Gis
20 25 30
gct atc agt tgg gtg cga cag gcc cct gga caa ggg ctt gag tgg atg 144
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
gga ggg atc atc gct atc ttc gga aca gca aac tac gca cag aag ttc 192
Gly Gly Ile Ile Ala Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
cag ggc aga atc acg att acc gcg gac gaa tcc acg agt aca gcc tac 240
Gln Gly Arg Ile Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
atg gag ctg agc agc ctg aga tct gag gac acg gcc gtg tat ttc tgt 288
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
gcg aga ggc agt ggt tat cat ata tcg aca ccc ttt gac aac tgg ggc 336
Ala Arg Gly Ser Gly Tyr His Ile Ser Thr Pro Phe Asp Asn Trp Gly
100 105 110
cag gga acc ctg gtc acc gtc tcg agc ggt acg ggc ggt tca ggc gga 384
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly
115 120 125
acc ggc agc ggc act ggc ggg tcg acg tcc tat gtg ctg act cag cca 432
Vhr Gly Ser Gly Thr Gly Gly Ser Thr Ser Tyr Val Leu Thr Gln Pro
130 135 140
ccc tcg gtg tca gtg gcc cca gga cag acg gcc agg att acc tgt ggg 480
Pro Ser Val Ser Val Ala Pro Gly Gln Thr Ala Arg Ile Thr Cys Gly
145 150 155 160
gga aac aac att gga agt aaa ggt gtg cac tgg tac cag cag aag cct 528
Gly Asn Asn Ile Gly Ser Lys Gly Val Gis Trp Tyr Gln Gln Lys Pro
165 170 175
ggc cag gcc cct gtg ctg gtc gtc tat gat gat agc gac cgg ccc tca 576
Gly Gln Ala Pro Val Leu Val Val Tyr Asp Asp Ser Asp Arg Pro Ser
180 185 190
ggg atc cct gag cga ttc tct ggc tcc aac tct ggg aac acg gcc acc 624
Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn Thr Ala Thr
195 200 205
ctg acc atc agc agg gtc gaa gcc ggg gat gag gcc gac tat tac tgt 672
Leu Thr Ile Ser Arg Val Glu Ala Gly Asp Glu Ala Asp lyr Tyr Cys
210 215 220
cag gtg tgg gat agt agt agt gat cat gtg gta ttc ggc gga ggg acc 720
Gln Val Trp Asp Ser Ser Ser Asp Gis Val Val Phe Gly Gly Gly Thr
225 230 235 240
aag ctg acc gtc cta ggt 738
Lys Leu Thr Val Leu Gly
245
<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)
<400>222
gag grg cag ctg gtg gag tct ggg gct gag gtg aag aag cct ggg tcc 48
Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aag gtc tcc tgc aag gct tct gga cae atc ttc agc ggc tat 96
Ser Val Lys Val Ser Cys Lys Ala Ser Gly His Ile Phe Ser Gly Tyr
20 25 30
gca atc agt tgg gtg cga cag gcc cct gga caa ggg ctt gag tgg atg 144
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
gga ggg atc atc cct atc ttt ggt aca aca aac tac gca cag aag ttc 192
Gly Gly Ile Ile Pro Ile Phe Gly Thr Thr Ash Tyr Ala Gln Lys Phe
50 55 60
cag ggc aga gtc acg att acc gcg gac caa tcc acg agc aca gcc tac 240
Gln Gly Arg Val Thr Ile Thr Ala Asp Gln Ser Thr Ser Thr Ala Tyr
65 70 75 80
atg gac ctg agc aac ttg aga tct gag gac acg gcc gtc tat tac tgt 288
Met Asp Leu Ser Asn Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
gcg aga gtg aaa gat gga tat tgt act ctt acc agc tgc cct gtc ggc 336
Ala Arg Val Lys Asp Gly Tyr Cys Thr Leu Thr Ser Cys Pro Val Gly
100 105 110
tgg tac ttc gat ctc tgg ggc cgt ggc acc ctg gtc act gtc tcg agc 384
Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser
115 120 125
ggt acg ggc ggt tca ggc gga acc ggc agc ggc act ggc ggg tcg acg 432
Gly Thr Gly Gly Ser Gly Gly Thr Gly Ser Gly Thr Gly Gly Ser Thr
130 135 140
gaa att gtg atg acg cag tct cca ggc acc ctg tct ttg tct cca ggg 480
Glu Ile Val Met Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
145 150 155 160
gaa aga gcc acc ctc tcg tgc agg gcc agt cag agt gtt agc agc agc 528
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
165 170 175
tac tta gcc tgg tac cag cag aaa cct ggc cag gct ccc agg ctc ctc 576
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
180 185 190
atc ttt ggt gcc tcc agc agg gcc act ggc atc cca gac agg ttc agt 624
Ile Phe Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
195 200 205
ggc agt ggg tct ggg aca gac ttc act ctc acc atc agc aga ctg gag 672
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
210 215 220
cct gaa gat ttt gca gtg tat tac tgt cag cag tat ggt agc tca ctc 720
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Leu
225 230 235 240
act ttc ggc gga ggg acc aag ctg gag atc aaa cgt 756
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
245 250
<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)
<400>224
gag gtc cag ctg gta cag tct ggg gct gag gtt aag aag cct ggg tcc 48
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aag gtc tcc tgc aag gct tct gga ggc atc ttc aga agc aat 96
Ser yal Lys Val Ser Cys Lys Ala Ser Gly Gly Ile Pne Arg Ser Asn
20 25 30
tct atc agt tgg gtg cga cag gcc cct ggg caa ggg ctt gag tgg atg 144
Ser Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
gga ggg atc ttc gct ctt ttc gga aca aca gac tac gcg cag aag ttc 192
Gly Gly Ile Phe Ala Leu Phe Gly Thr Thr Asp Tyr Ala Gln Lys Phe
50 55 60
cag ggc aga gtc acg att acc gcg gac gaa tct tcg acc aca gtc tac 240
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Ser Thr Thr Val Tyr
65 70 75 80
ctg gag ctg agt agc ctg aca tct gag gac acg gcc gtt tat tac tgt 288
Leu Glu Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
gcg aga ggc agt ggc tac acc aca cgc aac tac ttt gac tac tgg ggc 336
Ala Arg Gly Ser Gly Tyr Thr Thr Arg Asn Tyr Phe Asp Tyr Trp Gly
100 105 110
cag ggc acc ctg gtc acc gtc tcg agc ggt acg ggc ggt tca ggc gga 384
Gln Gly Thr Leu Val Tnr Val Ser Ser Gly Tnr Gly Gly Ser Gly Gly
115 120 125
acc ggc agc ggc act ggc ggg tcg acg gaa att gtg ctg act cag tct 432
Thr Gly Ser Gly Thr Gly Gly Ser Thr Glu Ile Val Leu Thr Gln Ser
130 135 140
cca ggc acc ctg tct ttg tct cca ggg gaa aga gcc aca ctc tcc tgc 480
Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys
145 150 155 160
agg gcc agt cag agt gtt agc agc aac tac tta ggc tgg tac cag cag 528
Arg Ala Ser Gln Ser Val Ser Ser Asn Tyr Leu Gly Trp Tyr Gln Gln
165 170 175
aaa cct ggc cag gct ccc agg ctc ctg atc tat ggt gca tcc agc agg 576
Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg
180 185 190
gcc agt ggc arc cca gac agg ttc agt ggc ggt ggg tct ggg aca gac 624
Ala Ser Gly Ile Pro Asp Arg Phe Ser Gly Gly Gly Ser Gly Thr Asp
195 200 205
ttc act ctc acc arc agc aga ctg gag cct gaa gat ttt gca gtg tat 672
Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr
210 215 220
tac tgt cag cag tat ggt agc tca ccc ctc act ttc ggc gga ggg acc 720
Tyr Cys Gln Gln Tyr Gly Ser Ser Pro Leu Thr Phe Gly Gly Gly Thr
225 230 235 240
aag gtg gag arc aaa cgt 738
Lys Val Glu Ile Lys Arg
245
<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 Asn
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)
<400>226
cag gtg cag ctg gtg cag tct ggg gct gag gtg aag aag cct ggg tcc 48
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gta aag gtc tcc tgc aag gct tct gga ggc ccc ttc cgc aat ttt 96
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Pro Phe Arg Asn Phe
20 25 30
gct atc aac tgg gtg cga cag gcc cct gga caa ggg ctt gag tgg atg 144
Ala Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
gga ggg atc atc gct gtc ttt ggg acg aca aag tac gca cat aag ttc 192
Gly Gly Ile Ile Ala Val Phe Gly Thr Thr Lys Tyr Ala His Lys Phe
50 55 60
cag ggc aga gtc acc atc acc gcg gac gac tcc aca aat aca gct tac 240
Gln Gly Arg Val Thr Ile T hr Ala Asp Asp Ser Thr Asn Thr Ala Tyr
65 70 75 80
atg gag ctg ggc agc ctg aaa tct gag gac acg gcc gtg tat tac tgt 288
Met Glu Leu Gly Ser Leu Lys Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
gcg aga ggt ccc cac tac tac tcc tcc tac atg gac gtc tgg ggc gaa 336
Ala Arg Gly Pro Gis Tyr Tyr Ser Ser Tyr Met Asp Val Trp Gly Glu
100 105 110
ggg acc acg gtc acc gtc tcg agc ggt acg ggc ggt tca ggc gga acc 384
Gly Thr Thr Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly Thr
1l5 120 125
ggc agc ggc act ggc ggg tcg acg gac atc cag ttg acc cag tct cca 432
Gly Ser Gly Thr Gly Gly Ser Thr Asp Ile Gln Leu Thr Gln Ser Pro
130 135 140
tcc tcc ctg tct gca tct gta gga gac aga gtc acc atc act tgc cgg 480
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
145 150 155 160
gcg agt cag ggc att agc act tat tta gcc tgg tat cag cag aaa ccc 528
Ala Ser Gln Gly Ile Ser Thr Tyr Leu Ala Trp Tyr Gln Gln Lys Pro
165 170 175
ggg aaa gtt cct aaa ctc ctg atc tat gct gca tcc act ttg caa tca 576
Gly Lys Val Pro Lys Leu Leu Ile Tyr Ala Ala Ser Thr Leu Gln Ser
180 185 190
ggg gtc cca tct cgg ttc agt ggc agt gga tct ggg aca gat ttc act 624
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
195 200 205
ctc acc atc agc agc ctg cag cct gaa gat gtt gca act tat tac tgt 672
Leu Thr Ile Ser Ser Leu Glnn Pro Glu Asp ValAla Thr Tyr Tyr Cys
210 215 220
caa aag tat aac agt gcc cct tct ttc ggc cct ggg acc aaa gtg gat 720
Gln Lys Tyr Asn Ser Ala Pro Ser Phe Gly Pro Gly Thr Lys Val Asp
225 230 235 240
atc aaa cgt 729
Ile Lys Arg
<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 Ash 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 GIy Ser GIy 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)
<400>228
gag gtg cag ctg gtg gag act ggg gct gag gtg aag aag cct ggg tcc 48
Glu Val Gln Leu Val Glu Thr Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aag gtc ccc tgc aaa tct tct gga agc ccc ttc agg agt aat 96
Ser Val Lys Val Pro Cys Lys Ser Ser Gly Ser Pro Phe Arg Ser Asn
20 25 30
gct gtc agc tgg gtg cga cag gcc ccc gga caa ggg ctt gag tgg gtg 144
Ala Val Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Val
35 40 45
gga gga atc ctc ggt gtc ttt ggt tca cca agc tac gca cag aag ttc 192
Gly Gly Ile LeuGly Val Phe Gly Ser Pro Ser Tyr Ala Gln Lys PGe
50 55 60
cag ggc aga gtc acg att acc gcg gac gaa tcc acc aac aca gtc cac 240
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Asn Thr Val His
65 70 75 80
atg gag ctg aga ggt ttg aga tct gag gac acg gcc gtg tat tat tgt 288
Met Glu Leu Arg Gly Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
gcg aga ggt cct acc tac tac tac tcc tac atg gac gtc tgg ggc aaa 336
Ala Arg Gly Pro Thr Tyr Tyr Tyr Ser Tyr Met Asp Val Trp Gly Lys
100 105 110
ggg acc acg gtc acc gtc tcg agc ggt acg ggc ggt tca ggc gga acc 384
Gly Tnr Thr Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly Thr
115 120 125
ggc agc ggc act ggc ggg tcg acg tcc tat gtg ctg act cag cca ccc 432
Gly Ser Gly Tnr Gly Gly Ser Tnr Ser Tyr Val Leu Tnr Gln Pro Pro
130 135 140
tcg gag tca gtg gcc cca gga cag acg gcc agg att acc tgt ggg gga 480
Ser Glu Ser Val Ala Pro Gly Gln Thr Ala Arg Ile Thr Cys Gly Gly
145 150 155 160
aat aac att gga aga aat agt gtg cac tgg tat cag cag aag cca ggc 528
Ash Asn Ile Gly Arg Asn Ser Val His Trp Tyr Gln Gln Lys Pro Gly
165 170 175
cag gcc cct gtg ctg gtc gtg tat gat gat agc gac cgg ccc tca ggg 576
Gln Ala Pro Val Leu Val Val Tyr Asp Asp Ser Asp Arg Pro Ser Gly
180 185 190
atc cct gag cga ttt tct ggc tcc aag tct ggg aac acg gcc acc ctg 624
Ile Pro Glu Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Thr Leu
195 200 205
att atc agc agg gtc gaa gtc ggg gat gag gcc gac tac tac tgt cag 672
Ile Ile Ser Arg Val Glu Val Gly Asp Glu Ala Asp Tyr Tyr Cys Gln
210 215 220
gtg tgg cat agt agt agt gat cat tat gtc ttc gga act ggg acc aag 720
Val Trp Gis Ser Ser Ser Asp His Tyr Val Phe Gly Thr Gly Thr Lys
225 230 235 240
gtc acc gtc cta ggt 735
Val Thr Val Leu Gly
245
<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
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 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)
<400>230
cag atg cag ctg gta caa tct gga gct gag gtg aag aag cct ggg tcc 48
Gln Met Gln Leu Val Gln Ser Gly Ala Gln Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aag gtc tcc tgc aag gct tct gga ggc acc ttc agc agc tat 96
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
gct atc agc tgg gtg cga cag gcc cct gga caa ggg ctt gag tgg atg 144
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
gga ggg atc ttc ggt atg ttt ggg aca gca aac tac gcg cag aag ttc 192
Gly Gly Ile Phe Gly Met Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
cag ggc aga gtc acg att acc gcg gac gaa ttc acg agc gcg gcc tac 240
Gln Gly Argg Val Thr Ile Thr Ala Asp Glu Phe Thr Ser Ala Ala Tyr
65 70 75 80
atg gag ctg agc agc ctg gga tct gag gac acg gcc atg tat tac tgt 288
Met Glu Leu Ser Ser Leu Gly Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
gcg agg tct agt ggt tat tac ccc caa tac ttc cag gac tgg ggc cag 336
Ala Arg Ser Ser Gly Tyr Tyr Pro Gln Tyr Phe Gln Asp Trp Gly Gln
100 105 110
ggc acc ctg gtc acc gtc tcg agc ggt acg ggc ggt tca ggc gga acc 384
Gly Thr Leu Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly Thr
115 120 125
ggc agc ggc act ggc ggg tcg acg gaa att gtg atg aca cag tct cca 432
Gly Ser Gly Thr Gly Gly Ser Thr Glu Ile Val Met Thr Gln Ser Pro
130 135 140
ggc acc ctg tct ttg tct cca ggg caa aga gcc acc ctc tcc tgc agg 480
Gly Thr Leu Ser Leu Ser Pro Gly Gln Arg Ala Thr Leu Ser Cys Arg
145 150 155 160
gcc agt cag agt gtt agc agc agc tac tta gcc tgg tac cag cag aaa 528
Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys
165 170 175
cct ggc cag gct ccc aga ctc ctc atg tat ggt gca tcc agc agg gcc 576
Pro Gly Gln Ala Pro Arg Leu Leu Met Tyr Gly Ala Ser Ser Arg Ala
180 185 190
act ggc atc cca gac agg ttc agt ggc agt ggg tct ggg aca gac ttc 624
Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
195 200 205
act ctc acc atc agc aga ctg gag cct gaa gat ttt gca gtg tat tac 672
Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tvr Tvr
210 215 220
tgt cag cag tat ggt agc tca tcg ctc act ttc ggc gga ggg acc aag 720
Cys Gln Gln Tyr Gly Ser Ser Ser Leu Thr Phe Gly Gly Gly Thr Lys
225 230 235 240
ctg gag atc aaa cgt 735
Leu Glu Ile Lys Arg
245
<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 Trn 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)
<400>232
gag gtg cag ctg gtg gag tcc ggg gct gag gtg aag aag cct ggg tcc 48
Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aag gtc tcc tgc aag gct tct gga ggc atc ttc aac agt tat 96
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Ile Phe Asn Ser Tyr
20 25 30
gct atc agc tgg gtg cga cag gcc cct gga caa ggg ctt gag tgg atg 144
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
gga ggc atc atc gct atc ttt cat aca cca aag tac gca cag aag ttc 192
Gly Gly Ile Ile Ala Ile Phe His Thr Pro Lys Tyr Ala Gln Lys Phe
50 55 60
cag ggc aga gtc acg att acc gcg gac gaa tcc acg aac aca gcc tac 240
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Asn Thr Ala Tyr
65 70 75 80
atg gaa ctg aga agc ctg aaa tct gag gac acg gcc ctg tat tac tgt 288
Met Glu Leu Arg Ser Leu Lys Ser Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
gcg aga ggg tcc act tac gat ttt tcg agt ggc ctt gac tac tgg ggc 336
Ala Arg Gly Ser Thr Tyr Asp Phe Ser Ser Gly Leu Asp Tyr Trp Gly
100 105 110
cag gga acc ctg gtc acc gtc tcg agc ggt acg ggc ggt tca ggc gga 384
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly
115 120 125
acc ggc agc ggc act ggc ggg tcg acg cag gca ggg ctg act cag cca 432
Thr Gly Ser Gly Thr Gly Gly Ser Thr Gln Ala Gly Leu Thr Gln Pro
130 135 140
ccc tcg gtg tca gtg gcc cca gga cag acg gcc agg att acc tgt ggg 480
Pro Ser Val Ser Val Ala Pro Gly Gln Thr Ala Arg Ile Thr Cys Gly
145 150 155 160
gga aac aac att gga agt aaa agt gtg cac tgg tac cag cag aag cca 528
Gly Asn Asn Ile Gly Ser Lys Ser Val His Trp Tyr Gln Gln Lys Pro
165 170 175
ggc cag gcc cct gtc cta gtc gtc tat gat gat agc gac cgg ccc tca 576
Gly Gln Ala Pro Val Leu Val Val Tyr Asp Asp Ser Asp Arg Pro Ser
180 185 190
ggg atc cct gag cga ttc tct ggc tcc aac tct ggg aac acg gcc acc 624
Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn Thr Ala Thr
195 200 205
ctg acc atc agc agg gtc gaa gcc ggg gat gag gcc gac tat tac tgt 672
Leu Thr Ile Ser Arg Val Glu Ala Gly Asp Glu Ala Asp Tyr Tyr Cys
210 215 220
cag gtg tgg gat agt agt agt gat cat gtg gta ttc ggc gga ggg acc 720
Gln Val Trp Asp Ser Ser Ser Asp Gis Val Val Phe Gly Gly Gly Thr
225 230 235 240
aag ctg acc gtc cta ggt 738
Lys Leu Thr Val Leu Gly
245
<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 Gis 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 Ash 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 Gis 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)
<400>234
cag gtc cag ctg gtg cag tct ggg gct gag gtg aag aag cct ggg tcc 48
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aag gtc tcc tgc aag gct tct gga ggc ttc ttc agc agc tat 96
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Phe Phe Ser Ser Tyr
20 25 30
gct atc agc tgg gtg cgc cag gcc cct gga caa gga ctt gag tgg atg 144
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
ggg ggg gtc atc cct atc ttt cgt aca gca aac tac gca cag aac ttc 192
Gly Gly Val Ile Pro Ile Phe Arg Thr Ala Asn Tyr Ala Gln Asn Phe
50 55 60
cag ggc aga gtc acc att acc gcg gac gaa ttc aca tcg tat atg gag 240
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Phe Thr Ser Tyr Met Glu
65 70 75 80
ctg agc agc ctg aga tct gac gac acg gcc gtg tat tac tgt gcg agg 288
Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg
85 90 95
ttg aat tac cat gat tcg ggg act tat tat aac gcc ccc cgg ggc tgg 336
Leu Asn Tyr Gis Asp Ser Gly Thr Tyr Tyr Asn Ala Pro Arg Gly Trp
100 105 110
ttc gac ccc tgg ggc cag gga acc ctg gtc acc gtc tcg agc ggt acg 384
Phe Asp Pro Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Thr
115 120 125
ggc ggt tca ggc gga acc ggc agc ggc act ggc ggg tcg acg gac atc 432
Gly Gly Ser Gly Gly Thr Gly Ser Gly Thr Gly Gly Ser Thr Asp Ile
130 135 140
cag atg acc cag tct cca gac tcc ctg gct gtg tct ctg ggc gag aag 480
Gln Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly Glu Lys
145 150 155 160
gcc acc atc aac tgc aag tcc agc cag agt att tta aac agc tcc aac 528
Ala Thr lle Asn Cys Lys Ser Ser Gln Ser Ile Leu Asn Ser Ser Asn
165 170 175
aat aag aac tac tta gct tgg tac cag cag aaa cca gga cag cct cct 576
Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
180 185 190
aag ctg ctc att tac tgg gca tct acc cgg gaa tcc ggg gtc cct gac 624
Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val Pro Asp
195 200 205
cga ttc agt ggc agc ggg tct ggg aca gat ttc act ctc acc atc agc 672
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
210 215 220
agc ctg cag gct gaa gat gtg gca gtt tat tac tgt cag caa tat tat 720
Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Tyr Tyr
225 230 235 240
agt agt ccg ccg acg ttc ggc caa ggg acc aag gtg gaa atc aaa cgt 768
Ser Ser Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
245 250 255
<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
180 185 190
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 ValGlu Ile Lys Arg
245 250 255
<210>236
<211>735
<212>DNA
<213>Artificial
<220>
<223>SC06-343
<220>
<221>CDS
<222>(1)..(735)
<400>236
cag gtc cag ctg gtg cag tct gga gct gag gtg aag aag cct ggg tcc 48
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aag gtc tcc tgc aag gct tct gga gtc acc ttc agt tac tat 96
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Val Thr Phe Ser Tyr Tyr
20 25 30
gct atg agc tgg gtg cga cag gcc cct gga caa ggg ctt gag tgg atg 144
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
gga gga atc agc cct atg ttt ggg aca aca acc tac gca cag aag ttc 192
Gly Gly Ile Ser Pro Met Phe Gly Thr Thr Thr Tyr Ala Gln Lys Phe
50 55 60
cag ggc aga gtc acg att act gcg gac gac tcc acg agt aca gcc tac 240
Gln Gly Arg Val Thr Ile Thr Ala Asp Asp Ser Thr Ser Thr Ala Tyr
65 70 75 80
atg gag gtg agg agc ctg aga tct gag gac acg gcc gtg tat tac tgt 288
Met Glu Val Arg Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
gcg aga tct tcg aat tac tat gat agt gta tat gac tac tgg ggc cag 336
Ala Arg Ser Ser Asn Tyr Tyr Asp Ser Val Tyr Asp Tyr Trp Gly Gln
100 105 110
gga acc ctg gtc acc gtc tcg agc ggt acg ggc ggt tca ggc gga acc 384
Gly Thr Leu Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly Thr
115 120 125
ggc agc ggc act ggc ggg tcg acg cag tct gtc gtg acg cag ccg ccc 432
Gly Ser Gly Thr Gly Gly Ser Thr Gln Ser Val Val Thr Gln Pro Pro
130 135 140
tcg gag tca gtg gcc cca gga cag acg gcc agg att acc tgt ggg gga 480
Ser Glu Ser Val Ala Pro Gly Gln Thr Ala Arg Ile Thr Cys Gly Gly
145 150 155 160
cat aac att gga agt aat agt gtg cac tgg tac cag cag aag cca ggc 528
Gis Asn Ile Gly Ser Asn Ser Val His Trp Tyr Gln Gln Lys Pro Gly
165 170 175
cag gcc cct gtg ctg gtc gtg tat gat aat agc gac cgg ccc tca ggg 576
Gln Ala Pro Val Leu Val Val Tyr Asp Asn Ser Asp Arg Pro Ser Gly
180 185 190
atc cct gag cga ttc tct ggc tcc aac tct ggg aac acg gcc acc ctg 624
Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn Thr Ala Thr Leu
195 200 205
acc atc agc agg gtc gaa gcc ggg gat gag gcc gac tat tac tgt cag 672
Thr Ile Ser Arg Val Glu Ala Gly Asp Glu Ala Asp Tyr Tyr Cys Gln
210 215 220
gtg tgg ggt agt agt agt gac cat tat gtc ttc gga act ggg acc aag 720
Val Trp Gly Ser Ser Ser Asp His Tyr Val Phe Gly Thr Gly Thr Lys
225 230 235 240
gtc acc gtc cta ggt 735
Val Thr Val Leu Gly
245
<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>Gomo 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
Hln 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
Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala
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
GIy Ile Phe Ala Leu Phe GIy 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 l0
<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
GIy 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
1 5 10
<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>CR6141Heavy chain
<220>
<221>CDS
<222>(1)..(1335)
<400>316
gag gtc cag ctg gtg cag tct ggg gct gag gtg aag aag cct ggg gcc 48
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
tca gtg aag gtc tcc tgc aag gct tct ggg tac acc ttc acc ggc tac 96
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
tat gtg tac tgg gtg cga cag gcc cct gga caa ggg ctt gag tgg atg 144
Tyr Val Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
gga tgg atc agc gct tac aat ggt aac aca aac tat gca cag aag ttc 192
Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Phe
50 55 60
cag ggc aga gtc acg att acc gcg gac aaa tcc acg agc aca gcc tac 240
Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
atg gag ctg agc agc ctg aga tct gaa gac acg gct gtg tat tac tgt 288
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
gcg aga agt aga tcc ctg gac gtc tgg ggc caa ggg acc acg gtc acc 336
Ala Arg Ser Arg Ser Leu Asp Val Trp Gly Gln Gly Thr Thr Val Thr
100 105 110
gtc tcg agt gct agc acc aag ggc ccc agc gtg ttc ccc ctg gcc ccc 384
Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
115 120 125
agc agc aag agc acc agc ggc ggc aca gcc gcc ctg ggc tgc ctg gtg 432
Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala AlaLeu Gly Cys Leu Val
130 135 140
aag gac tacttc ccc gag ccc gtgg acc gtg agc tgg aac agc ggc gcc 480
Lys Asp Tyr Pne Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala
145 150 155 160
ttg acc agc ggc gtg cac acc ttc ccc gcc gtg ctg cag agc agc ggc 528
Leu Tnr Ser Gly Val Hls Tnr Pne Pro Ala Val Leu Gln Ser Ser Gly
165 170 175
ctg tac agc ctg agc agc gtg gtg acc gtg ccc agc agc agc ctg ggc 576
Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly
180 185 190
acc cag acc tac atc tgc aac gtg aac cac aag ccc agc aac acc aag 624
Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys
195 200 205
gtg gac aaa cgc gtg gag ccc aag agc tgc gac aag acc cac acc tgc 672
Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys
210 215 220
ccc ccc tgc cct gcc ccc gag ctg ctg ggc gga ccc tcc gtg ttc ctg 720
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
225 230 235 240
ttc ccc ccc aag ccc aag gac acc ctc atg atc agc cgg acc ccc gag 768
Phe Pro Pro Lyg Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
245 250 255
gtg acc tgc gtg gtg gtg gac gtg agc cac gag gac ccc gag gtg aag 816
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
260 265 270
ttc aac tgg tac gtg gac ggc gtg gag gtg cac aac gcc aag acc aag 864
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
275 280 285
ccc cgg gag gag cag tac aac agc acc tac cgg gtg gtg agc gtg ctc 912
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
290 295 300
acc gtg ctg cac cag gac tgg ctg aac ggc aag gag tac aag tgc aag 960
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
305 310 315 320
gtg agc aac aag gcc ctg cct gcc ccc atc gag aag acc atc agc aag 1008
Val Ser Asn Lys Ala Leu Pro AlaPro Ile Glu Lys Thr Ile Ser Lys
325 330 335
gcc aag ggc cag ccc cgg gag ccc cag gtg tac acc ctg ccc ccc agc 1056
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
340 345 350
cgg gag gag atg acc aag aac cag gtg tcc ctc acc tgt ctg gtg aag 1104
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
355 360 365
ggc ttc tac ccc agc gac atc gcc gtg gag tgg gag agc aac ggc cag 1152
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
370 375 380
ccc gag aac aac tac aag acc acc ccc cct gtg ctg gac agc gac ggc 1200
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
385 390 395 400
agc ttc ttc ctg tac agc aag ctc acc gtg gac aag agc cgg tgg cag 1248
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
405 410 415
cag ggc aac gtg ttc agc tgc agc gtg atg cac gag gcc ctg cac aac 1296
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
420 425 430
cac tac acc cag aag agc ctg agc ctg agc ccc ggc aag 1335
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<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 ValThr 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>CR6141Light chain
<220>
<221>CDS
<222>(1)..(657)
<400>318
gat gtt gtg atg act cag tct cca gac tcc ctg gct gtg tct ctg ggc 48
Asp Val Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
gag agg gcc acc atc aac tgc aag tcc agc cag agt gtt tta tac agc 96
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser
20 25 30
tcc aac aat aag aac tac tta gct tgg tac cag cag aaa cca gga cag 144
Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
cct cct aag ctg ctc att tac tgg gca tct acc cgg gaa tcc ggg gtc 192
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
cct gac cga ttc agt ggc agc ggg tct ggg aca gat ttc act ctc acc 240
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
atc agc agc ctg cag gct gaa gat gtg gca gtt tat tac tgt cag caa 288
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln
85 90 95
tat tat agt act cot ctc act ttc ggc gga ggg acc aaa gtg gat atc 336
Tyr Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Asp Ile
100 105 110
aaa cgt gcg gcc gca ccc agc gtg ttc atc ttc ccc ccc tcc gac gag 384
Lys Arg Ala Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
cag ctg aag agc ggc acc gcc agc gtg gtg tgc ctg ctg aac aac ttc 432
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
tac ccc cgg agg gcc aag gtg cag tgg aag gtg gac aac gcc ctg cag 480
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
agc ggc aac agc cag gag agc gtg acc gag cag gac agc aag gac tcc 528
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
acc tac agc ctg agc agc acc ctc acc ctg agc aag gcc gac tac gag 576
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
aag cac aag gtg tac gcc tgc gag gtg acc cac cag ggc ctg agc agc 624
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
ccc gtg acc aag agc ttc aac cgg ggc gag tgt 657
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<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 Asn 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>CR6272Heavy chain
<220>
<221>CDS
<222>(1)..(1350)
<400>320
cag atg cag ctg gtg cag tct ggg gct gag gtg aag aag cct ggg tcc 48
Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aag gtc tcc tgc aag gct tct gga ggc acc ttc tcc agt tat 96
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
gct atc acc tgg gtg cga cag gcc cct gga caa ggg ctt gag tgg atg 144
Ala Ile Thr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
gga ggg atc atc ggt atg ttt ggt tca aca aac tac gca cag aac ttc 192
Gly Gly Ile Ile Gly Met Phe Gly Ser Thr Asn Tyr Ala Gln Asn Phe
50 55 60
cag ggc aga gtc acg att acc gcg gac gaa tcc acg agc aca gcc tac 240
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
atg gag ctg agc agc ctc aga tct gag gac acg gcc gtg tat tac tgt 288
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
gcg aga agt act ggt tat tac cct gca tac ctc cac cac tgg ggc cag 336
Ala Arg Ser Thr Gly Tyr Tyr Pro Ala Tyr Leu His His Trp Gly Gln
100 105 110
ggc acc ctg gtc acc gtc tcg agt gct agc acc aag ggc ccc agc gtg 384
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
ttc ccc ctg gcc ccc agc agc aag agc acc agc ggc ggc aca gcc gcc 432
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
ctg ggc tgc ctg gtg aag gac tac ttc ccc gag ccc gtg acc gtg agc 480
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
tgg aac agc ggc gcc ttg acc agc ggc gtg cac acc ttc ccc gcc gtg 528
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
ctg cag agc agc ggc ctg tac agc ctg agc agc gtg gtg acc gtg ccc 576
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
agc agc agc ctg ggc acc cag acc tac atc tgc aac gtg aac cac aag 624
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
ccc agc aac acc aag gtg gac aaa cgc gtg gag ccc aag agc tgc gac 672
Pro Ser Asn Thr Lys Val Asn Lys Arg Val Glu Pro Lys Ser Cys Asp
210 215 220
aag acc cac acc tgc ccc ccc tgc cct gcc ccc gag ctg ctg ggc gga 720
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
ccc tcc gtg ttc ctg ttc ccc ccc aag ccc aag gac acc crc atg atc 768
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Lle
245 250 255
agc cgg acc ccc gag gtg acc tgc gtg gtg gtg gac gtg agc cac gag 816
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
gac ccc gag gtg aag ttc aac tgg tac gtg gac ggc gtg gag gtg cac 864
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
aac gcc aag acc aag ccc cgg gag gag cag tac aac agc acc tac cgg 912
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
gtg gtg agc gtg ctc acc gtg ctg cac cag gac tgg ctg aac ggc aag 960
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
gag tac aag tgc aag gtg agc aac aag gcc ctg cct gcc ccc atc gag 1008
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
aag acc atc agc aag gcc aag ggc cag ccc cgg gag ccc cag gtg tac 1056
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
acc ctg ccc ccc agc cgg gag gag atg acc aag aac cag gtg tcc ctc 1104
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
acc tgt ctg gtg aag ggc ttc tac ccc agc gac atc gcc gtg gag tgg 1152
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
gag agc aac ggc cag ccc gag aac aac tac aag acc acc ccc cct gtg 1200
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
ctg gac agc gac ggc agc ttc ttc ctg tac agc aag ctc acc gtg gac 1248
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
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 Ash His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
ggc aag 1350
Gly Lys
450
<210>321
<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
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 ValSer 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>CR6272Light chain
<220>
<221>CDS
<222>(1)..(660)
<400>322
cag tct gcc ctg act cag cct cgc tca gtg tcc ggg tct cct gga cag 48
Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
tca gtc acc atc tcc tgc act gga acc agc agt gat gtt ggt ggt tat 96
Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30
aac tat gtc tcc tgg tac caa cag cac cca ggc aaa gcc ccc aaa ctc 144
Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
atg att tat gat gtc agt aag cgg ccc tca ggg gtc cct gat cgc ttc 192
Met Ile Tyr Asp Val Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe
50 55 60
tct ggc tcc aag tct ggc aac acg gcc tcc ctg acc atc tct ggg ctc 240
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
cag gct gag gat gag gct gat tat tac tgc agc tca tat aca agc agc 288
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser
85 90 95
agc act cat gtc ttc gga act ggg acc aag gtc acc gtc cta ggt gcg 336
Ser Thr His Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu Gly Ala
100 105 110
gcc gca ggc cag ccc aag gcc gct ccc agc gtg acc ctg ttc ccc ccc 384
Ala Ala Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro
115 120 125
tcc tcc gag gag ctg cag gcc aac aag gcc acc ctg gtg tgc ctc atc 432
Ser Ser Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile
130 135 140
agc gac ttc tac cct ggc gcc gtg acc gtg gcc tgg aag gcc gac agc 480
Ser Asp Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser
145 150 155 160
agc ccc gtg aag gcc ggc gtg gag acc acc acc ccc agc aag cag agc 528
Ser Pro Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser
165 170 175
aac aac aag tac gcc gcc agc agc tac ctg agc ctc acc ccc gag cag 576
Ash Asn Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln
180 185 190
tgg aag agc cac cgg agc tac agc tgc cag gtg acc cac gag ggc agc 624
Trp Lys Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser
195 200 205
acc gtg gag aag acc gtg gcc ccc acc gag tgc agc 660
Thr Val Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
210 215 220
<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
Ash 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>CR6296Heayy chain
<220>
<221>CDS
<222>(1)..(1353)
<400>324
gag gtg cag ctg gtg gag acc ggg gct gag gtg aag aag cct ggg gcc 48
Glu Val Gln Leu Val Glu Thr Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
tca gtg aag gtt tcc tgc aag gca tct gga tac acc ttc acc agc tac 96
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
tat atg cac tgg gtg cga cag gcc cct gga caa ggg ctt gag tgg atg 144
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
gga tgg atc aac cct aac agt ggt ggc aca aac tat gca cag aag ttt 192
Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Ash Tyr Ala Gln Lys Phe
50 55 60
cag ggc agg gtc acc atg acc agg gac acg tcc atc agc aca gcc tac 240
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
atg gag ctg agc agg ctg aga tct gac gac acg gcc gtg tat tac tgt 288
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
gcg aga gag ggg aaa tgg gga cct caa gcg gct ttt gat atc tgg ggc 336
Ala Arg Glu Gly Lys Trp Gly Pro Gln Ala Ala Phe Asp Ile Trp Gly
100 105 110
caa ggg aca atg gtc acc gtc tcg agt gct agc acc aag ggc ccc agc 384
Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
gtg ttc ccc ctg gcc ccc agc agc aag agc acc agc ggc ggc aca gcc 432
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
gcc ctg ggc tgc ctg gtg aag gac tac ttc ccc gag ccc gtg acc gtg 480
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
agc tgg aac agc ggc gcc ttg acc agc ggc gtg cac acc ttc ccc gcc 528
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
gtg ctg cag agc agc ggc ctg tac agc ctg agc agc gtg gtg acc gtg 576
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
ccc agc agc agc ctg ggc acc cag acc tac atc tgc aac gtg aac cac 624
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
aag ccc agc aac acc aag gtg gac aaa cgc gtg gag ccc aag agc tgc 672
Lys Pro Ser Asp Thr Lys ValAsp Lys Arg Val Glu Pro Lys Ser Cys
210 215 220
gac aag acc cac acc tgc ccc ccc tgc cct gcc ccc gag ctg ctg ggc 720
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
gga ccc tcc gtg ttc ctg ttc ccc ccc aag ccc aag gac acc ctc atg 768
Gly pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
atc agc cgg acc ccc gag gtg acc tgc gtg gtg gtg gac gtg agc cac 816
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
gag gac ccc gag gtg aag ttc aac tgg tac gtg gac ggc gtg gag gtg 864
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
cac aac gcc aag acc aag ccc cgg gag gag cag tac aac agc acc tac 912
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
cgg gtg gtg agc gtg ctc acc gtg ctg cac cag gac tgg ctg aac ggc 960
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
aag gag tac aag tgc aag gtg agc aac aag gcc ctg cct gcc ccc atc 1008
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
gag aag acc atc agc aag gcc aag ggc cag ccc cgg gag ccc cag gtg 1056
Glu Lys Thr Ile Ser Lys Alg Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
tac acc ctg ccc ccc agc cgg gag gag atg acc aag aac cag gtg tcc 1104
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
ctc acc tgt ctg gtg aag ggc ttc tac ccc agc gac atc gcc gtg gag 1152
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
tgg gag agc aac ggc cag ccc gag aac aac tac aag acc acc ccc cct 1200
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
gtg ctg gac agc gac ggc agc ttc ttc ctg tac agc aag ctc acc gtg 1248
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
gac aag agc cgg tgg cag cag ggc aac gtg ttc agc tgc agc gtg atg 1296
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
cac gag gcc ctg cac aac cac tac acc cag aag agc ctg agc ctg agc 1344
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 Ash Pro Ash 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 Ash Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr hsn 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 4l5
Asp Lys Ser Arg Trp Gln Gln Gly Ash 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>CR6296Light chain
<220>
<221>CDS
<222>(1)..(642)
<400>326
gaa att gtg atg acg cag tct cca ggc acc ctg tct ttg tct cca ggg 48
Glu Ile Val Met Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
gaa aga gcc acc ctc tcc tgc agg gcc agt cag agt gtt agc agc agc 96
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
tac tta gcc tgg tac cag cag aaa cct ggc cag gct ccc agg ctc ctc 144
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
atc tat gat gca tcc agc agg gcc act gac atc cca gac agg ttc agt 192
Ile Tyr Asp Ala Ser Ser Arg Ala Thr Asp Ile Pro Asp Arg Phe Ser
50 55 60
ggc agt ggg tct ggg aca gac ttc act ctc acc atc agc aga ctg gag 240
Gly Ser Gly Ser Gly Thr AsP Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
cct gaa gat ttt gca gtg tat tac tgt cag cag tat ggt agc tca ctt 288
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Leu
85 90 95
tgg acg ttc ggc caa ggg acc aag gtg gag atc aaa cgt gcg gcc gca 336
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Ala Ala Ala
100 105 110
ccc agc gtg ttc atc ttc ccc ccc tcc gac gag cag ctg aag agc ggc 384
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
acc gcc agc gtg gtg tgc ctg ctg aac aac ttc tac ccc cgg gag gcc 432
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
aag gtg cag tgg aag gtg gac aac gcc ctg cag agc ggc aac agc cag 480
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
gag agc gtg acc gag cag gac agc aag gac tcc acc tac agc ctg agc 528
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Sar Thr Tyr Ser Leu Ser
165 170 175
agc acc ctc acc ctg agc aag gcc gac tac gag aag cac aag gtg tac 576
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
gcc tgc gag gtg acc cac cag ggc ctg agc agc ccc gtg acc aag agc 624
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
ttc aac cgg ggc gag tgt 642
Phe Asn Arg Gly Glu Cys
210
<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 Cvs 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>CR6301Heavy chain
<220>
<221>CDS
<222>(1)..(1341)
<400>328
gag gtg cag ctg gta gag tct ggg gga ggc ttg gta cag cct ggg ggg 48
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
tcc ctg aga ctc tcc tgt gca gcc tct gga ttc acc ttt agc atc tat 96
Ser Leu Arg Leu Sar Cys Ala Ala Ser Gly Phe Thr Phe Ser Ile Tyr
20 25 30
gcc atg agc tgg gtc cgc cag gca cca ggg aag ggg ctg gag tgg gtc 144
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
tca gct att agt agt agt ggt gat agc aca tac tac gca gac tcc gtg 192
Ser Ala Ile Ser Ser Ser Gly Asp Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
aag ggc cgg ttc acc atc tcc aga gac aac gcc agg aac acg ctg tat 240
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Thr Leu Tyr
65 70 75 80
ctg caa atg aac agt ctg aga gcc gag gac acg gct gtg tat tac tgt 288
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Tnr Ala Val Tyr Tyr Cys
85 90 95
gcg aga gcg tat ggc tac acg ttc gac ccc tgg ggc cag gga acc ctg 336
Ala Arg Ala Tyr Gly Tyr Thr Phe Asp Pro Trp Gly Gln Gly Thr Leu
100 105 110
gtc acc gtc tcg agt gct agc acc aag ggc ccc agc gtg ttc ccc ctg 384
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
gcc ccc agc agc aag agc acc agc ggc ggc aca gcc gcc ctg ggc tgc 432
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
130 135 140
ctg gtg aag gac tac ttc ccc gag ccc gtg acc gtg agc tgg aac agc 480
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
ggc gcc ttg acc agc ggc gtg cac acc ttc ccc gcc gtg ctg cag agc 528
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
agc ggc ctg tac agc ctg agc agc gtg gtg acc gtg ccc agc agc agc 576
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
ctg ggc acc cag acc tac atc tgc aac gtg aac cac aag ccc agc aac 624
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
acc aag gtg gac aaa cgc gtg gag ccc aag agc tgc gac aag acc cac 672
Tnr Lys yal Asp Lys Arg yal Glu Pro Lys Ser Cys Asp Lys Tnr His
210 215 220
acc tgc ccc ccc tgc cct gcc ccc gag ctg ctg ggc gga ccc tcc gtg 720
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
225 230 235 240
ttc ctg ttc ccc ccc aag ccc aag gac acc ctc atg atc agc cgg acc 768
Phe Lec Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
ccc gag gtg acc tgc gtg gtg gtg gac gtg agc cac gag gac ccc gag 816
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
gtg aag ttc aac tgg tac gtg gac ggc gtg gag gtg cac aac gcc aag 864
Val Lys Phe Asn Trp Tyr Val Asp Gly ValGlu Val His Asn Ala Lys
275 280 285
acc aag ccc cgg gag gag cag tac aac agc acc tac cgg gtg gtg agc 912
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
gtg ctc acc gtg ctg cac cag gac tgg ctg aac ggc aag gag tac aag 960
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
tgc aag gtg agc aac aag gcc ctg cct gcc ccc atc gag aag acc atc 1008
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
agc aag gcc aag ggc cag ccc cgg gag ccc cag gtg tac acc ctg ccc 1056
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
ccc agc cgg gag gag atg acc aag aac cag gtg tcc ctc acc tgt ctg 1104
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
gtg aag ggc ttc tac ccc agc gac atc gcc gtg gag tgg gag agc aac 1152
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
ggc cag ccc gag aac aac tac aag acc acc ccc cct gtg ctg gac agc 1200
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
gac ggc agc ttc ttc ctg tac agc aag ctc acc gtg gac aag agc cgg 1248
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
tgg cag cag ggc aac gtg ttc agc tgc agc gtg atg cac gag gcc ctg 1296
Trp Glp Glp Gly Asp Val Phe Ser Cys Ser Vel Met His Glu Ala Leu
420 425 430
cac aac cac tac acc cag aag agc ctg agc ctg agc ccc ggc aag 1341
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<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
AIa Pro Ser Ser Lys Ser Thr Ser Gly GIy 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 Aso 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>CR6301Light chain
<220>
<221>CDS
<222>(1)..(654)
<400>330
gaa att gtg ctg act cag tct cca ctc tcc ctg ccc gtc acc cct gga 48
Glu Ile Val Leu Thr Gln Ser Pro Leu Ser Leu Pro Val Tnr Pro Gly
1 5 10 15
gag ccg gcc tcc atc tcc tgc agg tct agt cag agc ctc ctg cat agt 96
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
aat gga tac aac tat ttg gat tgg tac ctg cag aag cca ggg cag tct 144
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
cca cag ctc ctg atc tat ttg ggt tct aat cgg gcc tcc ggg gtc cct 192
Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro
50 55 60
gac agg ttc agt ggc agt gga tca ggc aca gat ttt aca ctg aaa atc 240
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
agc aga gtg gag gct gag gat gtt ggg gtt tat tac tgc atg caa gct 288
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala
85 90 95
cta caa act ccc ctc act ttc ggc gga ggg acc aag gtg gag atc aaa 336
Leu Gln Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
cgt gcg gcc gca ccc agc gtg ttc atc ttc ccc ccc tcc gac gag cag 384
Arg Ala Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
ctg aag agc ggc acc gcc agc gtg gtg tgc ctg ctg aac aac ttc tac 432
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
ccc cgg gag gcc aag gtg cag tgg aag gtg gac aac gcc ctg cag agc 480
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
ggc aac agc cag gag agc gtg acc gag cag gac agc aag gac tcc acc 528
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
tac agc ctg agc agc acc ctc acc ctg agc aag gcc gac tac gag aag 576
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
cac aag gtg tac gcc tgc gag gtg acc cac cag ggc ctg agc agc ccc 624
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
gtg acc aag agc ttc aac cgg ggc gag tgt 654
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<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>CR6327Heayy chain
<220>
<221>CDS
<222>(1)..(1353)
<400>332
gag gtg cag ctg gtg gag acc ggg gct gag gtg aag aag cct ggg tcc 48
Glu Val Gln Leu Val Glu Thr Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aag gtc tcc tgc aag gcc tct gga ggc acc ttc agg acc cat 96
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Arg Thr His
20 25 30
gct atc agt tgg gtg cga cag gcc cct gga caa ggg ctt gag tgg atg 144
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
gga ggg atc atc gct atc ttc gga aca gca aac tac gca cag aag ttc 192
Gly Gly Ile Ile Ala Ile Phe Gly Tnr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
cag ggc aga atc acg att acc gcg gac gaa tcc acg agt aca gcc tac 240
Gln Gly Arg Ile Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
atg gag ctg agc agc ctg aga tct gag gac acg gcc gtg tat ttc tgt 288
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
gcg aga ggc agt ggt tat cat ata tcg aca ccc ttt gac aac tgg ggc 336
Ala Arg Gly Ser Gly Tyr His Ile Ser Thr Pro Phe Asp Asn Trp Gly
100 105 110
cag gga acc ctg gtc acc gtc tcg agt gct agc acc aag ggc ccc agc 384
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
gtg ttc ccc ctg gcc ccc agc agc aag agc acc agc ggc ggc aca gcc 432
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
gcc ctg ggc tgc ctg gtg aag gac tac ttc ccc gag ccc gtg acc gtg 480
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
agc tgg aac agc ggc gcc ttg acc agc ggc gtg cac acc ttc ccc gcc 528
Ser Trn Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
gtg ctg cag agc agc ggc ctg tac agc ctg agc agc gtg gtg acc gtg 576
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
ccc agc agc agc ctg ggc acc cag acc tac atc tgc aac gtg aac cac 624
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Ash Val Asn His
195 200 205
aag ccc agc aac acc aag gtg gac aaa cgc gtg gag ccc aag agc tgc 672
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys
210 215 220
gac aag acc cac acc tgc ccc ccc tgc cct gcc ccc gag ctg ctg ggc 720
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
gga ccc tcc gtg ttc ctg ttc ccc ccc aag ccc aag gac acc ctc atg 768
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
atc agc cgg acc ccc gag gtg acc tgc gtg gtg gtg gac gtg agc cac 816
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
gag gac ccc gag gtg aag ttc aac tgg tac gtg gac ggc gtg gag gtg 864
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
cac aac gcc aag acc aag ccc cgg gag gag cag tac aac agc acc tac 912
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
cgg gtg gtg agcgtg ctc acc gtg ctg cac cag gac tgg ctg aac ggc 960
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
aag gag tac aag tgc aag gtg agc aac aag gcc ctg cct gcc ccc atc 1008
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
gag aag acc atc agc aag gcc aag ggc cag ccc cgg gag ccc cag gtg 1056
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
tac acc ctg ccc ccc agc cgg gag gag atg acc aag aac cag gtg tcc 1104
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
ctc acc tgt ctg gtg aag ggc ttc tac ccc agc gac atc gcc gtg gag 1152
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
tgg gag agc aac ggc cag ccc gag aac aac tac aag acc acc ccc cct 1200
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
gtg ctg gac agc gac ggc agc ttc ttc ctg tac agc aag ctc acc gtg 1248
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
gac aag agc cgg tgg cag cag ggc aac gtg ttc agc tgc agc gtg atg 1296
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
cac gag gcc ctg cac aac cac tac acc cag aag agc ctg agc ctg agc 1344
His Glu Ala Leu His Asn Gis Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
ccc ggc aag 1353
Pro Gly Lys
450
<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>CR6327Light chain
<220>
<221>CDS
<222>(1)..(654)
<400>334
tcc tat gtg ctg act cag cca ccc tcg gtg tca gtg gcc cca gga cag 48
Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Gln
1 5 10 15
acg gcc agg att acc tgt ggg gga aac aac att gga agt aaa ggt gtg 96
Thr Ala Arg Ile Thr Cys Gly GIy Asn Asn Ile Gly Ser Lys Gly Val
20 25 30
cac tgg tac cag cag aag cct ggc cag gcc cct gtg ctg gtc gtc tat 144
His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Val Tyr
35 40 45
gat gat agc gac cgg ccc tca ggg atc cct gag cga ttc tct ggc tcc 192
Asp Asp Ser Asp Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser
50 55 60
aac tct ggg aac acg gcc acc ctg acc atc agc agg gtc gaa gcc ggg 240
Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly
65 70 75 80
gat gag gcc gac tat tac tgt cag gtg tgg gat agt agt agt gat cat 288
Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Asp His
85 90 95
gtg gta ttc ggc gga ggg acc aag ctg acc gtc cta ggt gcg gcc gca 336
Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Ala Ala Ala
100 105 110
ggc cag ccc aag gcc gct ccc agc gtg acc ctg ttc ccc ccc tcc tcc 384
Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser
115 120 125
gag gag ctg cag gcc aac aag gcc acc ctg gtg tgc ctc atc agc gac 432
Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp
130 135 140
ttc tac cct ggc gcc gtg acc gtg gcc tgg aag gcc gac agc agc ccc 480
Phe Tyr Pro Gly Ala Val Thr Val Ala Trn Lys Ala Asn Ser Ser Pro
145 150 155 160
gtg aag gcc ggc gtg gag acc acc acc ccc agc aag cag agc aac aac 528
Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn
165 170 175
aag tac gcc gcc agc agc tac ctg agc ctc acc ccc gag cag tgg aag 576
Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys
180 185 190
agc cac cgg agc tac agc tgc cag gtg acc cac gag ggc agc acc gtg 624
Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val
195 200 205
gag aag acc gtg gcc ccc acc gag tgc agc 654
Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
210 215
<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 ValAla 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 ValAla Pro Thr Glu Cys Ser
210 215
<210>336
<211>1374
<212>DNA
<213>Artificial
<220>
<223>CR6328Heayy chain
<220>
<221>CDS
<222>(1)..(1374)
<400>336
gag gtg cag ctg gtg gag tct ggg gct gag gtg aag aag cct ggg tcc 48
Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aag gtc tcc tgc aag gct tct gga cac atc ttc agc ggc tat 96
Ser Val Lys Val Ser Cys Lys Ala Ser Gly His Ile Phe Ser Gly Tyr
20 25 30
gca atc agt tgg gtg cga cag gcc cct gga caa ggg ctt gag tgg atg 144
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
gga ggg atc atc cct atc ttt ggt aca aca aac tac gca cag aag ttc 192
Gly Gly Ile Ile Pro Ile Phe Gly Thr Thr Asn Tyr Ala Gln Lys Phe
50 55 60
cag ggc aga gtc acg att acc gcg gac caa tcc acg agc aca gcc tac 240
Gln Gly Arg Val Thr Ile Thr Ala Asp Gln Ser Thr Ser Thr Ala Tyr
65 70 75 80
atg gac ctg agc aac ttg aga tct gag gac acg gcc gtc tat tac tgt 288
Met Asp Leu Ser Asn Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
gcg aga gtg aaa gat gga tat tgt act ctt acc agc tgc cct gtc ggc 336
Ala Arg Val Lys Asp Gly Tyr Cys Thr Leu Thr Ser Cys Pro Val Gly
100 105 110
tgg tac ttc gat ctc tgg ggc cgt ggc acc ctg gtc act gtc tcg agt 384
Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu yal Thr yal Ser Ser
115 120 125
gct agc acc aag ggc ccc agc gtg ttc ccc ctg gcc ccc agc agc aag 432
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
130 135 140
agc acc agc ggc ggc aca gcc gcc ctg ggc tgc ctg gtg aag gac tac 480
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
145 150 155 160
ttc ccc gag ccc gtg acc gtg agc tgg aac agc ggc gcc ttg acc agc 528
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
165 170 175
ggc gtg cac acc ttc ccc gcc gtg ctg cag agc agc ggc ctg tac agc 576
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
180 185 190
ctg agc agc gtg gtg acc gtg ccc agc agc agc ctg ggc acc cag acc 624
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
195 200 205
tac atc tgc aac gtg aac cac aag ccc agc aac acc aag gtg gac aaa 672
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
210 215 220
cgc gtg gag ccc aag agc tgc gac aag acc cac acc tgc ccc ccc tgc 720
Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
225 230 235 240
cct gcc ccc gag ctg ctg ggc gga ccc tcc gtg ttc ctg ttc ccc ccc 768
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser ValPhe Leu Phe Pro Pro
245 250 255
aag ccc aag gac acc ctc atg atc agc cgg acc ccc gag gtg acc tgc 816
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
260 265 270
gtg gtg gtg gac gtg agc cac gag gac ccc gag gtg aag ttc aac tgg 864
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trn
275 280 285
tac gtg gac ggc gtg gag gtg cac aac gcc aag acc aag ccc cgg gag 912
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
290 295 300
gag cag tac aac agc acc tac cgg gtg gtg agc gtg ctc acc gtg ctg 960
Glu Gln Tyr Asn Ser Thr Tyr Arg ValVal Ser Val Leu Thr Val Leu
305 310 315 320
cac cag gac tgg ctg aac ggc aag gag tac aag tgc aag gtg agc aac 1008
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
325 330 335
aag gcc ctg cct gcc ccc atc gag aag acc atc agc aag gcc aag ggc 1056
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
340 345 350
cag ccc cgg gag ccc cag gtg tac acc ctg ccc ccc agc cgg gag gag 1104
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
355 360 365
atg acc aag aac cag gtg tcc ctc acc tgt ctg gtg aag ggc ttc tac 1152
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
370 375 380
ccc agc gac atc gcc gtg gag tgg gag agc aac ggc cag ccc gag aac 1200
Pro Ser Asp Ile Ala Val Glu Trp Glu Set Asn Gly Gln Pro Glu Asn
385 390 395 400
aac tac aag acc acc ccc cct gtg ctg gac agc gac ggc agc ttc ttc 1248
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
405 410 415
ctg tac agc aag ctc acc gtg gac aag agc cgg tgg cag cag ggc aac 1296
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
420 425 430
gtg ttc agc tgc agc gtg atg cac gag gcc ctg cac aac cac tac acc 1344
yal Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
435 440 445
cag aag agc ctg agc ctg agc ccc ggc aag 1374
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
450 455
<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 Tle 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>CR6328Light chain
<220>
<221>CDS
<222>(1)..(639)
<400>338
gaa att gtg atg acg cag tct cca ggc acc ctg tct ttg tct cca ggg 48
Glu Ile Val Met Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
gaa aga gcc acc ctc tcg tgc agg gcc agt cag agt gtt agc agc agc 96
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
tac tta gcc tgg tac cag cag aaa cct ggc cag gct ccc agg ctc ctc 144
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
atc ttt ggt gcc tcc agc agg gcc act ggc atc cca gac agg ttc agt 192
Ile Phe Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
ggc agt ggg tct ggg aca gac ttc act ctc acc atc agc aga ctg gag 240
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
cct gaa gat ttt gca gtg tat tac tgt cag cag tat ggt agc tca ctc 288
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Leu
85 90 95
act ttc ggc gga ggg acc aag ctg gag atc aaa cgt gcg gcc gca ccc 336
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala Ala Ala Pro
100 105 110
agc gtg ttc atc ttc ccc ccc tcc gac gag cag ctg aag agc ggc acc 384
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
gcc agc gtg gtg tgc ctg ctg aac aac ttc tac ccc cgg gag gcc aag 432
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
gtg cag tgg aag gtg gac aac gcc ctg cag agc ggc aac agc cag gag 480
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
agc gtg acc gag cag gac agc aag gac tcc acc tac agc ctg agc agc 528
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
acc ctc acc ctg agc aag gcc gac tac gag aag cac aag gtg tac gcc 576
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
tgc gag gtg acc cac cag ggc ctg agc agc ccc gtg acc aag agc ttc 624
Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
aac cgg ggc gag tgt 639
Asn Arg Gly Glu Cys
210
<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 Trn 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>CR6329Heavy chain
<220>
<221>CDS
<222>(1)..(1353)
<400>340
gag gtc cag ctg gta cag tct ggg gct gag gtt aag aag cct ggg tcc 48
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aag gtc tcc tgc aag gct tct gga ggc atc ttc aga agc aat 96
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Ile Phe Arg Ser Asn
20 25 30
tct atc agt tgg gtg cga cag gcc cct ggg caa ggg ctt gag tgg atg 144
Ser Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
gga ggg atc ttc gct ctt ttc gga aca aca gac tac gcg cag aag ttc 192
Gly Gly Ile Phe Ala Leu Phe Gly Thr Thr Asp Tyr Ala Gln Lys Phe
50 55 60
cag ggc aga gtc acg att acc gcg gac gaa tct tcg acc aca gtc tac 240
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Ser Thr Thr Val Tyr
65 70 75 80
ctg gag ctg agt agc ctg aca tct gag gac acg gcc gtt tat tac tgt 288
Leu Glu Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
gcg aga ggc agt ggc tac acc aca cgc aac tac ttt gac tac tgg ggc 336
Ala Arg Gly Ser Gly Tyr Thr Thr Arg Asn Tyr Phe Asp Tyr Trp Gly
100 105 110
cag ggc acc ctg gtc acc gtc tcg agt gct agc acc aag ggc ccc agc 384
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
gtg ttc ccc ctg gcc ccc agc agc aag agc acc agc ggc ggc aca gcc 432
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
gcc ctg ggc tgc ctg gtg aag gac tac ttc ccc gag ccc gtg acc gtg 480
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
agc tgg aac agc ggc gcc ttg acc agc ggc gtg cac acc ttc ccc gcc 528
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
gtg ctg cag agc agc ggc ctg tac agc ctg agc agc gtg gtg acc gtg 576
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
ccc agc agc agc ctg ggc acc cag acc tac atc tgc aac gtg aac cac 624
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
aag ccc agc aac acc aag gtg gac aaa cgc gtg gag ccc aag agc tgc 672
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys
210 215 220
gac aag acc cac acc tgc ccc ccc tgc cct gcc ccc gag ctg ctg ggc 720
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
gga ccc tcc gtg ttc ctg ttc ccc ccc aag ccc aag gac acc ctc atg 768
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
atc agc cgg acc ccc gag gtg acc tgc gtg gtg gtg gac gtg agc cac 816
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
gag gac ccc gag gtg aag ttc aac tgg tac gtg gac ggc gtg gag gtg 864
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
cac aac gcc aag acc aag ccc cgg gag gag cag tac aac agc acc tac 912
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
cgg gtg gtg agc gtg ctc acc gtg ctg cac cag gac tgg ctg aac ggc 960
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
aag gag tac aag tgc aag gtg agc aac aag gcc ctg cct gcc ccc atc 1008
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
gag aag acc atc agc aag gcc aag ggc cag ccc cgg gag ccc cag gtg 1056
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
tac acc ctg ccc ccc agc cgg gag gag atg acc aag aac cag gtg tcc 1104
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
ctc acc tgt ctg gtg aag ggc ttc tac ccc agc gac atc gcc gtg gag 1152
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala ValGlu
370 375 380
tgg gag agc aac ggc cag ccc gag aac aac tac aag acc acc ccc cct 1200
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
gtg ctg gac agc gac ggc agc ttc ttc ctg tac agc aag ctc acc gtg 1248
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
gac aag agc cgg tgg cag cag ggc aac gtg ttc agc tgc agc gtg atg 1296
Asp Lys Ser Arg Trp Gln Gln Gly Ash Val Phe Ser Cys Ser Val Met
420 425 430
cac gag gcc ctg cac aac cac tac acc cag aag agc ctg agc ctg agc 1344
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>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
Gis 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>CR6329Light chain
<220>
<221>CDS
<222>(1)..(654)
<400>342
gaa att gtg ctg act cag tct cca ggc acc ctg tct ttg tct cca ggg 48
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
gaa aga gcc aca ctc tcc tgc agg gcc agt cag agt gtt agc agc aac 96
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn
20 25 30
tac tta ggc tgg tac cag cag aaa cct ggc cag gct ccc agg ctc ctg 144
Tyr Leu Gly Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro ArgLeu Leu
35 40 45
atc tat ggt gca tcc agc agg gcc agt ggc atc cca gac agg ttc agt 192
Ile Tyr Gly Ala Ser Ser Arg Ala Ser Gly Ile Pro Asp Arg Phe Ser
50 55 60
ggc ggt ggg tct ggg aca gac ttc act ctc acc atc agc aga ctg gag 240
Gly Gly Gly Ser Gly Tnr Asp Phe Tnr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
cct gaa gat ttt gca gtg tat tac tgt cag cag tat ggt agc tca ccc 288
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
ctc act ttc ggc gga ggg acc aag gtg gag atc aaa cgt gcg gcc gca 336
Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Ala Ala Ala
100 105 110
ggc cag ccc aag gcc gct ccc agc gtg acc ctg ttc ccc ccc tcc tcc 384
Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser
115 120 125
gag gag ctg cag gcc aac aag gcc acc ctg gtg tgc ctc atc agc gac 432
Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp
130 135 140
ttc tac cct ggc gcc gtg acc gtg gcc tgg aag gcc gac agc agc ccc 480
Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro
145 150 155 160
gtg aag gcc ggc gtg gag acc acc acc ccc agc aag cag agc aac aac 528
Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn
165 170 175
aag tac gcc gcc agc agc tac ctg agc ctc acc ccc gag cag tgg aag 576
Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys
180 185 190
agc cac cgg agc tac agc tgc cag gtg acc cac gag ggc agc acc gtg 624
Ser His Arg Ser Tyr Ser Cys Gln yal Thr His Glu Gly Ser Thr Val
195 200 205
gag aag acc gtg gcc ccc acc gag tgc agc 654
Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
210 215
<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 Ash 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>CR6332Heavy chain
<220>
<221>CDS
<222>(1)..(1350)
<400>344
cag gtg cag ctg gtg cag tct ggg gct gag gtg aag aag cct ggg tcc 48
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gta aag gtc tcc tgc aag gct tct gga ggc ccc ttc cgc aat ttt 96
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Pro Phe Arg Asn Phe
20 25 30
gct atc aac tgg gtg cga cag gcc cct gga caa ggg ctt gag tgg atg 144
Ala Ile Asn Tro Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
gga ggg atc atc gct gtc ttt ggg acg aca aag tac gca cat aag ttc 192
Gly Gly Ile Ile Ala Val Phe Gly Thr Thr Lys Tyr Ala His Lys Phe
50 55 60
cag ggc aga gtc acc atc acc gcg gac gac tcc aca aat aca gct tac 240
Gln Gly Arg Val Thr Ile Thr Ala Asp Asp Ser Thr Asn Thr Ala Tyr
65 70 75 80
atg gag ctg ggc agc ctg aaa tct gag gac acg gcc gtg tat tac tgt 288
Met Glu Leu Gly Ser Leu Lys Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
gcg aga ggt ccc cac tac tac tcc tcc tac atg gac gtc tgg ggc gaa 336
Ala Arg Gly Pro his Tyr Tyr Ser Ser Tyr Met Asp Val Trp Gly Glu
100 105 110
ggg acc acg gtc acc gtc tcg agt gct agc acc aag ggc ccc agc gtg 384
Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
ttc ccc ctg gcc ccc agc agc aag agc acc agc ggc ggc aca gcc gcc 432
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
ctg ggc tgc ctg gtg aag gac tac ttc ccc gag ccc gtg acc gtg agc 480
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
tgg aac agc ggc gcc ttg acc agc ggc gtg cac acc ttc ccc gcc gtg 528
Trp Asn Ser Gly Ala Leu Tnr Ser Gly Val His Tnr Pne Pro Ala Val
165 170 175
ctg cag agc agc ggc ctg tac agc ctg agc age gtg gtg acc gtg ccc 576
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
agc agc agc ctg ggc acc cag acc tac atc tgc aac gtg aac cac aag 624
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Ash Val Ash His Lys
195 200 205
ccc agc aac acc aag gtg gac aaa cgc gtg gag ccc aag agc tgc gac 672
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp
210 215 220
aag acc cac acc tgc ccc ccc tgc cct gcc ccc gag ctg ctg ggc gga 720
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
ccc tcc gtg ttc ctg ttc ccc ccc aag ccc aag gac acc ctc atg atc 768
Pro Ser Val Pne Leu Pne Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
agc cgg acc ccc gag gtg acc tgc gtg gtg gtg gac gtg agc cac gag 816
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
gac ccc gag gtg aag ttc aac tgg tac gtg gac ggc gtg gag gtg cac 864
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
aac gcc aag acc aag ccc cgg gag gag cag tac aac agc acc tac cgg 912
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
gtg gtg agc gtg ctc acc gtg ctg cac cag gac tgg ctg aac ggc aag 960
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
gag tac aag tgc aag gtg agc aac aag gcc ctg cct gcc ccc atc gag 1008
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
aag acc atc agc aag gcc aag ggc cag ccc cgg gag ccc cag gtg tac 1056
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
acc ctg ccc ccc agc cgg gag gag atg acc aag aac cag gtg tcc ctc 1104
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lsy Asn Gln Val Ser Leu
355 360 365
acc tgt ctg gtg aag ggc ttc tac ccc agc gac atc gcc gtg gag tgg 1152
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
gag agc aac ggc cag ccc gag aac aac tac aag acc acc ccc cct gtg 1200
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
ctg gac agc gac ggc agc ttc ttc ctg tac agc aag ctc acc gtg gac 1248
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
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>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 ValArg 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>CR6332Light chain
<220>
<221>CDS
<222>(1)..(636)
<400>346
gac atc cag ttg acc cag tct cca tcc tcc ctg tct gca tct gta gga 48
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
gac aga gtc acc atc act tgc cgg gcg agt cag ggc att agc act tat 96
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Thr Tyr
20 25 30
tta gcc tgg tat cag cag aaa ccc ggg aaa gtt cct aaa ctc ctg atc 144
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
35 40 45
tat gct gca tcc act ttg caa tca ggg gtc cca tct cgg ttc agt ggc 192
Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
agt gga tct ggg aca gat ttc act ctc acc atc agc agc ctg cag cct 240
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
gaa gat gtt gca act tat tac tgt caa aag tat aac agt gcc cct tct 288
Glu Asp Val Ala Thr Tyr Tyr Cys Gln Lys Tyr Asn Ser Ala Pro Ser
85 90 95
ttc ggc cct ggg acc aaa gtg gat atc aaa cgt gcg gcc gca ccc agc 336
Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg Ala Ala Ala Pro Ser
100 105 110
gtg ttc atc ttc ccc ccc tcc gac gag cag ctg aag agc ggc acc gcc 384
Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala
115 120 125
agc gtg gtg tgc ctg ctg aac aac ttc tac ccc cgg gag gcc aag gtg 432
Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val
130 135 140
cag tgg aag gtg gac aac gcc ctg cag agc ggc aac agc cag gag agc 480
Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser
145 150 155 160
gtg acc gag cag gac agc aag gac tcc acc tac agc ctg agc agc acc 528
Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr
165 170 175
ctc acc ctg agc aag gcc gac tac gag aag cac aag gtg tac gcc tgc 576
Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys Gis Lys Val Tyr Ala Cys
180 185 190
gag gtg acc cac cag ggc ctg agc agc ccc gtg acc aag agc ttc aac 624
Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn
195 200 205
cgg ggc gag tgt 636
Arg Gly Glu Cys
210
<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 Ash 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>CR6334Heavy chain
<220>
<221>CDS
<222>(1)..(1350)
<400>348
gag gtg cag ctg gtg gag act ggg gct gag gtg aag aag cct ggg tcc 48
Glu Val Gln Leu Val Glu Thr Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aag gtc ccc tgc aaa tct tct gga agc ccc ttc agg agt aat 96
Ser Val Lys Val Pro Cys Lys Ser Ser Gly Ser Pro Phe Arg Ser Asn
20 25 30
gct gtc agc tgg gtg cga cag gcc ccc gga caa ggg ctt gag tgg gtg 144
Ala Val Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Val
35 40 45
gga gga atc ctc ggt gtc ttt ggt tca cca agc tac gca cag aag ttc 192
Gly Gly Ile Leu Gly ValPhe Gly Ser Pro Ser Tyr Ala Gln Lys Phe
50 55 60
cag ggc aga gtc acg att acc gcg gac gaa tcc acc aac aca gtc cac 240
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Asn Thr Val His
65 70 75 80
atg gag ctg aga ggt ttg aga tct gag gac acg gcc gtg tat tat tgt 288
Met Glu Leu Arg Gly Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
gcg aga ggt cct acc tac tac tac tcc tac atg gac gtc tgg ggc aaa 336
Ala Arg Gly Pro Thr Tyr Tyr Tyr Ser Tyr Met Asp Val Trp Gly Lys
100 105 110
ggg acc acg gtc acc gtc tcg agt gct agc acc aag ggc ccc agc gtg 384
Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
ttc ccc ctg gcc ccc agc agc aag agc acc agc ggc ggc aca gcc gcc 432
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
ctg ggc tgc ctg gtg aag gac tac ttc ccc gag ccc gtg acc gtg agc 480
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
tgg aac agc ggc gcc ttg acc agc ggc gtg cac acc ttc ccc gcc gtg 528
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
ctg cag agc agc ggc ctg tac agc ctg agc agc gtg gtg acc gtg ccc 576
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
agc agc agc ctg ggc acc cag acc tac atc tgc aac gtg aac cac aag 624
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Ash His Lys
195 200 205
ccc agc aac acc aag gtg gac aaa cgc gtg gag ccc aag agc tgc gac 672
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp
210 215 220
aag acc cac acc tgc ccc ccc tgc cct gcc ccc gag ctg ctg ggc gga 720
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
ccc tcc gtg ttc ctg ttc ccc ccc aag ccc aag gac acc ctc atg atc 768
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
agc cgg acc ccc gag gtg acc tgc gtg gtg gtg gac gtg agc cac gag 816
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
gac ccc gag gtg aag ttc aac tgg tac gtg gac ggc gtg gag gtg cac 864
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly ValGlu Val His
275 280 285
aac gcc aag acc aag ccc cgg gag gag cag tac aac agc acc tac cgg 912
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
gtg gtg agc gtg ctc acc gtg ctg cac cag gac tgg ctg aac ggc aag 960
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
gag tac aag tgc aag gtg agc aac aag gcc ctg cct gcc ccc atc gag 1008
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
aag acc atc agc aag gcc aag ggc cag ccc cgg gag ccc cag gtg tac 1056
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
acc ctg ccc ccc agc cgg gag gag atg acc aag aac cag gtg tcc ctc 1104
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
acc tgt ctg gtg aag ggc ttc tac ccc agc gac atc gcc gtg gag tgg 1152
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
gag agc aac ggc cag ccc gag aac aac tac aag acc acc ccc cct gtg 1200
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
ctg gac agc gac ggc agc ttc ttc ctg tac agc aag ctc acc gtg gac 1248
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
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>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 ValLys 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 GIy 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 Gis 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>350
<211>654
<212>DNA
<213>Artificial
<220>
<223>CR6334Light chain
<220>
<221>CDS
<222>(1)..(654)
<400>350
tcc tat gtg ctg act cag cca ccc tcg gag tca gtg gcc cca gga cag 48
Ser Tyr Val Leu Thr Gln Pro Pro Ser Glu Ser Val Ala Pro Gly Gln
1 5 10 15
acg gcc agg att acc tgt ggg gga aat aac att gga aga aat agt gtg 96
Thr Ala Arg Ile Thr Cys Gly Gly Asn Asn Ile Gly Arg Asn Ser Val
20 25 30
cac tgg tat cag cag aag cca ggc cag gcc cct gtg ctg gtc gtg tat 144
His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Val Tyr
35 40 45
gat gat agc gac cgg ccc tca ggg atc cct gag cga ttt tct ggc tcc 192
Asp Asp Ser Asp Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser
50 55 60
aag tct ggg aac acg gcc acc ctg att atc agc agg gtc gaa gtc ggg 240
Lys Ser Gly Asn Thr Ala Thr Leu Ile Ile Ser Arg Val Glu Val Gly
65 70 75 80
gat gag gcc gac tac tac tgt cag gtg tgg cat agt agt agt gat cat 288
Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp His Ser Ser Ser Asp His
85 90 95
tat gtc ttc gga act ggg acc aag gtc acc gtc cta ggt gcg gcc gca 336
Tyr Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu Gly Ala Ala Ala
100 105 110
ggc cag ccc aag gcc gct ccc agc gtg acc ctg ttc ccc ccc tcc tcc 384
Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser
115 120 125
gag gag ctg cag gcc aac aag gcc acc ctg gtg tgc ctc atc agc gac 432
Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp
130 135 140
ttc tac cct ggc gcc gtg acc gtg gcc tgg aag gcc gac agc agc ccc 480
Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro
145 150 155 160
gtg aag gcc ggc gtg gag acc acc acc ccc agc aag cag agc aac aac 528
Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Ash
165 170 175
aag tac gcc gcc agc agc tac ctg agc ctc acc ccc gag cag tgg aag 576
Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys
180 185 190
agc cac cgg agc tac agc tgc cag gtg acc cac gag ggc agc acc gtg 624
Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val
195 200 205
gag aag acc gtg gcc ccc acc gag tgc agc 654
Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
210 215
<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>CR6336Heavy chain
<220>
<221>CDS
<222>(1)..(1350)
<400>352
cag atg cag ctg gta caa tct gga gct gag gtg aag aag cct ggg tcc 48
Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aag gtc tcc tgc aag gct tct gga ggc acc ttc agc agc tat 96
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
gct atc agc tgg gtg cga cag gcc cct gga caa ggg ctt gag tgg atg 144
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
gga ggg atc ttc ggt atg ttt ggg aca gca aac tac gcg cag aag ttc 192
Gly Gly Ile Phe Gly Met Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
cag ggc aga gtc acg att acc gcg gac gaa ttc acg agc gcg gcc tac 240
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Phe Thr Ser Ala Ala Tyr
65 70 75 80
atg gag ctg agc agc ctg gga tct gag gac acg gcc atg tat tac tgt 288
Met Glu Leu Ser Ser Leu Gly Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
gcg agg tct agt ggt tat tac ccc caa tac ttc cag gac tgg ggc cag 336
Ala Arg Ser Ser Gly Tyr Tyr Pro Gln Tyr Phe Gln Asp Trp Gly Gln
100 105 110
ggc acc ctg gtc acc gtc tcg agt gct agc acc aag ggc ccc agc gtg 384
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
ttc ccc ctg gcc ccc agc agc aag agc acc agc ggc ggc aca gcc gcc 432
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
ctg ggc tgc ctg gtg aag gac tac ttc ccc gag ccc gtg acc gtg agc 480
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
tgg aac agc ggc gcc ttg acc agc ggc gtg cac acc ttc ccc gcc gtg 528
Trp Asp Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
ctg cag agc agc ggc ctg tac agc ctg agc agc gtg gtg acc gtg ccc 576
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
agc agc agc ctg ggc acc cag acc tac atc tgc aac gtg aac cac aag 624
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Ash His Lys
195 200 205
ccc agc aac acc aag gtg gac aaa cgc gtg gag ccc aag agc tgc gac 672
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp
210 215 220
aag acc cac acc tgc ccc ccc tgc cct gcc ccc gag ctg ctg ggc gga 720
lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
ccc tcc gtg ttc ctg ttc ccc ccc aag ccc aag gac acc ctc atg atc 768
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
agc cgg acc ccc gag gtg acc tgc gtg gtg gtg gac gtg agc cac gag 816
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
gac ccc gag gtg aag ttc aac tgg tac gtg gac ggc gtg gag gtg cac 864
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
aac gcc aag acc aag ccc cgg gag gag cag tac aac agc acc tac cgg 912
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
gtg gtg agc gtg ctc acc gtg ctg cac cag gac tgg ctg aac ggc aag 960
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
gag tac aag tgc aag gtg agc aac aag gcc ctg cct gcc ccc atc gag 1008
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
aag acc atc agc aag gcc aag ggc cag ccc cgg gag ccc cag gtg tac 1056
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
acc ctg ccc ccc agc cgg gag gag atg acc aag aac cag gtg tcc ctc 1104
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
acc tgt ctg gtg aag ggc ttc tac ccc agc gac atc gcc gtg gag tgg 1152
Thr Cys Leu Val Lys Gly Pne Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
gag agc aac ggc cag ccc gag aac aac tac aag acc acc ccc cct gtg 1200
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Tnr Pro Pro Val
385 390 395 400
ctg gac agc gac ggc agc ttc ttc ctg tac agc aag ctc acc gtg gac 1248
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
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>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
l 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 Ash 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 Asp Val Asn Gis 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 Asp 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 Ash Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Ash 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 Ash 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 Ash 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>CR6336Light chain
<220>
<221>CDS
<222>(1)..(642)
<400>354
gaa att gtg atg aca cag tct cca ggc acc ctg tct ttg tct cca ggg 48
Glu Ile Val Met Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
caa aga gcc acc ctc tcc tgc agg gcc agt cag agt gtt agc agc agc 96
Gln Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
tac tta gcc tgg tac cag cag aaa cct ggc cag gct ccc aga ctc ctc 144
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
atg tat ggt gca tcc agc agg gcc act ggc atc cca gac agg ttc agt 192
Met Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
ggc agt ggg tct ggg aca gac ttc act ctc acc atc agc aga ctg gag 240
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
cct gaa gat ttt gca gtg tat tac tgt cag cag tat ggt agc tca tcg 288
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Ser
85 90 95
ctc act ttc ggc gga ggg acc aag ctg gag ate aaa cgt gcg gcc gca 336
Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala Ala Ala
100 105 110
ccc agc gtg ttc atc ttc ccc ccc tcc gac gag cag ctg aag agc ggc 384
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
acc gcc agc gtg gtg tgc ctg ctg aac aac ttc tac ccc cgg gag gcc 432
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
aag gtg cag tgg aag gtg gac aac gcc ctg cag agc ggc aac agc cag 480
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Ash Ser Gln
145 150 155 160
gag agc gtg acc gag cag gac agc aag gac tcc acc tac agc ctg agc 528
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
agc acc ctc acc ctg agc aag gcc gac tac gag aag cac aag gtg tac 576
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
gcc tgc gag gtg acc cac cag ggc ctg agc agc ccc gtg acc aag agc 624
Ala Cys Glu Val Thr Gis Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
ttc aac cgg ggc gag tgt 642
Phe Asn Arg Gly Glu Cys
210
<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 Ash 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 Gis 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>CR6339Heavy chain
<220>
<221>CDS
<222>(1)..(1353)
<400>356
gag gtg cag ctg gtg gag tcc ggg gct gag gtg aag aag cct ggg tcc 48
Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aag gtc tcc tgc aag gct tct gga ggc atc ttc aac agt tat 96
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Ile Phe Asn Ser Tyr
20 25 30
gct atc agc tgg gtg cga cag gcc cct gga caa ggg ctt gag tgg atg 144
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
gga ggc atc atc gct atc ttt cat aca cca aag tac gca cag aag ttc 192
Gly Gly Ile Ile Ala Ile Phe His Thr Pro Lys Tyr Ala Gln Lys Phe
50 55 60
cag ggc aga gtc acg att acc gcg gac gaa tcc acg aac aca gcc tac 240
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Asn Thr Ala Tyr
65 70 75 80
atg gaa ctg aga agc ctg aaa tct gag gac acg gcc ctg tat tac tgt 288
Met Glu Leu Arg Ser Leu Lys Ser Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
gcg aga ggg tcc act tac gat ttt tcg agt ggc ctt gac tac tgg ggc 336
Ala Arg Gly Ser Thr Tyr Asp Phe Ser Ser Gly Leu Asp Tyr Trp Gly
100 105 110
cag gga acc ctg gtc acc gtc tcg agt gct agc acc aag ggc ccc agc 384
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
gtg ttc ccc ctg gcc ccc agc agc aag agc acc agc ggc ggc aca gcc 432
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
gcc ctg ggc tgc ctg gtg aag gac tac ttc ccc gag ccc gtg acc gtg 480
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
agc tgg aac agc ggc gcc ttg acc agc ggc gtg cac acc ttc ccc gcc 528
Ser Trp Asp Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
gtg ctg cag agc agc ggc ctg tac agc ctg agc agc gtg gtg acc gtg 576
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
ccc agc agc agc ctg ggc acc cag acc tac atc tgc aac gtg aac cac 624
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn Gis
195 200 205
aag ccc agc aac acc aag gtg gac aaa cgc gtg gag ccc aag agc tgc 672
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys
210 215 220
gac aag acc cac acc tgc ccc ccc tgc cct gcc ccc gag ctg ctg ggc 720
Asp Lys Thr Gis Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
gga ccc tcc gtg ttc ctg ttc ccc ccc aag ccc aag gac acc ctc atg 768
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
atc agc cgg acc ccc gag gtg acc tgc gtg gtg gtg gac gtg agc cac 816
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
gag gac ccc gag gtg aag ttc aac tgg tac gtg gac ggc gtg gag gtg 864
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
cac aac gcc aag acc aag ccc cgg gag gag cag tac aac agc acc tac 912
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
cgg gtg gtg agc gtg ctc acc gtg ctg cac cag gac tgg ctg aac ggc 960
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
aag gag tac aag tgc aag gtg agc aac aag gcc ctg cct gcc ccc atc 1008
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
gag aag acc atc agc aag gcc aag ggc cag ccc cgg gag ccc cag gtg 1056
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
tac acc ctg ccc ccc agc cgg gag gag atg acc aag aac cag gtg tcc 1104
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
ctc acc tgt ctg gtg aag ggc ttc tac ccc agc gac atc gcc gtg gag 1152
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
tgg gag agc aac ggc cag ccc gag aac aac tac aag acc ecc ccc cct 1200
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
gtg ctg gac agc gac ggc agc ttc ttc ctg tac agc aag ctc acc gtg 1248
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
gac aag agc cgg tgg cag cag ggc aac gtg ttc agc tgc agc gtg atg 1296
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
cac gag gcc ctg cac aac cac tac acc cag aag agc ctg agc ctg agc 1344
Gis 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>357
<211>451
<212>PRT
<213>Artificial
<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 Ash 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 SerLeu Ser
435 440 445
Pro Gly Lys
450
<210>358
<211>654
<212>DNA
<213>Artificial
<220>
<223>CR6339Light chain
<220>
<221>CDS
<222>(1)..(654)
<400>358
cag gca ggg ctg act cag cca ccc tcg gtg tca gtg gcc cca gga cag 48
Gln Ala Gly Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Gln
1 5 10 15
acg gcc agg att acc tgt ggg gga aac aac att gga agt aaa agt gtg 96
Thr Ala Arg Ile Thr Cys Gly Gly Asn Asn Ile Gly Ser Lys Ser Val
20 25 30
cac tgg tac cag cag aag cca ggc cag gcc cct gtc cta gtc gtc tat 144
His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val ValTyr
35 40 45
gat gat agc gac cgg ccc tca ggg atc cct gag cga ttc tct ggc tcc 192
Asp Asp Ser Asp Arg Pro Ser Gly lle Pro Glu Arg Phe Ser Gly Ser
50 55 60
aac tct ggg aac acg gcc acc ctg acc atc agc agg gtc gaa gcc ggg 240
Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly
65 70 75 80
gat gag gcc gac tat tac tgt cag gtg tgg gat agt agt agt gat cat 288
Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Asp His
85 90 95
gtg gta ttc ggc gga ggg acc aag ctg acc gtc cta ggt gcg gcc gca 336
Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Ala Ala Ala
100 105 110
ggc cag ccc aag gcc gct ccc agc gtg acc ctg ttc ccc ccc tcc tcc 384
Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser
115 120 125
gag gag ctg cag gcc aac aag gcc acc ctg gtg tgc ctc atc agc gac 432
Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp
130 135 140
ttc tac cct ggc gcc gtg acc gtg gcc tgg aag gcc gac agc agc ccc 480
Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro
145 150 155 160
gtg aag gcc ggc gtg gag acc acc acc ccc agc aag cag agc aac aac 528
Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn
165 170 175
aag tac gcc gcc agc agc tac ctg agc ctc acc ccc gag cag tgg aag 576
Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys
180 185 190
agc cac cgg agc tac agc tgc cag gtg acc cac gag ggc agc acc gtg 624
Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val
195 200 205
gag aag acc gtg gcc ccc acc gag tgc agc 654
Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
210 215
<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>CR6342Heavy chain
<220>
<221>CDS
<222>(1)..(1368)
<400>360
cag gtc cag ctg gtg cag tct ggg gct gag gtg aag aag cct ggg tcc 48
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aag gtc tcc tgc aag gct tct gga ggc ttc ttc agc agc tat 96
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Phe Phe Ser Ser Tyr
20 25 30
gct atc agc tgg gtg cgc cag gcc cct gga caa gga ctt gag tgg atg 144
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
ggg ggg gtc atc cct atc ttt cgt aca gca aac tac gca cag aac ttc 192
Gly Gly Val Ile Pro Ile Phe Arg Thr Ala Asn Tyr Ala Gln Ash Phe
50 55 60
cag ggc aga gtc acc att acc gcg gac gaa ttc aca tcg tat atg gag 240
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Phe Thr Ser Tyr Met Glu
65 70 75 80
ctg agc agc ctg aga tct gac gac acg gcc gtg tat tac tgt gcg agg 288
Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg
85 90 95
ttg aat tac cat gat tcg ggg act tat tat aac gcc ccc cgg ggc tgg 336
Leu Asn Tyr His Asp Ser Gly Thr Tyr Tyr Asn Ala Pro Arg Gly Trp
100 105 110
ttc gac ccc tgg ggc cag gga acc ctg gtc acc gtc tcg agt gct agc 384
Phe Asp Pro Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser
115 120 125
acc aag ggc ccc agc gtg ttc ccc ctg gcc ccc agc agc aag agc acc 432
Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr
130 135 140
agc ggc ggc aca gcc gcc ctg ggc tgc ctg gtg aag gac tac ttc ccc 480
Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro
145 150 155 160
gag ccc gtg acc gtg agc tgg aac agc ggc gcc ttg acc agc ggc gtg 528
Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val
165 170 175
cac acc ttc ccc gcc gtg ctg cag agc agc ggc ctg tac agc ctg agc 576
His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser
180 185 190
agc gtg gtg acc gtg ccc agc agc agc ctg ggc acc cag acc tac atc 624
Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile
195 200 205
tgc aac gtg aac cac aag ccc agc aac acc aag gtg gac aaa cgc gtg 672
Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val
210 215 220
gag ccc aag agc tgc gac aag acc cac acc tgc ccc ccc tgc cct gcc 720
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
225 230 235 240
ccc gag ctg ctg ggc gga ccc tcc gtg ttc ctg ttc ccc ccc aag ccc 768
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
245 250 255
aag gac acc ctc atg atc agc cgg acc ccc gag gtg acc tgc gtg gtg 816
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
260 265 270
gtg gac gtg agc cac gag gac ccc gag gtg aag ttc aac tgg tac gtg 864
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
275 280 285
gac ggc gtg gag gtg cac aac gcc aag acc aag ccc cgg gag gag cag 912
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
290 295 300
tac aac agc acc tac cgg gtg gtg agc gtg ctc acc gtg ctg cac cag 960
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
305 310 315 320
gac tgg ctg aac ggc aag gag tac aag tgc aag gtg agc aac aag gcc 1008
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
325 330 335
ctg cct gcc ccc atc gag aag acc atc agc aag gcc aag ggc cag ccc 1056
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
340 345 350
cgg gag ccc cag gtg tac acc ctg ccc ccc agc cgg gag gag atg acc 1104
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
355 360 365
aag aac cag gtg tcc ctc acc tgt ctg gtg aag ggc ttc tac ccc agc 1152
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
370 375 380
gac atc gcc gtg gag tgg gag agc aac ggc cag ccc gag aac aac tac 1200
AsP Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
385 390 395 400
aag acc acc ccc cct gtg ctg gac agc gac ggc agc ttc ttc ctg tac 1248
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
405 410 415
agc aag ctc acc gtg gac aag agc cgg tgg cag cag ggc aac gtg ttc 1296
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Pne
420 425 430
agc tgc agc gtg atg cac gag gcc ctg cac aac cac tac acc cag aag 1344
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
435 440 445
agc ctg agc ctg agc ccc ggc aag 1368
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 Ash 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>CR6342Light chain
<220>
<221>CDS
<222>(1)..(657)
<400>362
gac atc cag atg acc cag tct cca gac tcc ctg gct gtg tct ctg ggc 48
Asp Ile Gln Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
gag aag gcc acc atc aac tgc aag tcc agc cag agt att tta aac agc 96
Glu Lys Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Ile Leu Asn Ser
20 25 30
tcc aac aat aag aac tac tta gct tgg tac cag cag aaa cca gga cag 144
Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
cct cct aag ctg ctc att tac tgg gca tct acc cgg gaa tcc ggg gtc 192
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
cct gac cga ttc agt agc agc ggg tct ggg aca gat ttc act ctc acc 240
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
atc agc agc ctg cag gct gaa gat gtg gca gtt tat tac tgt cag caa 288
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln
85 90 95
tat tat agt agt ccg ccg acg ttc ggc caa ggg acc aag gtg gaa atc 336
Tyr Tyr Ser Ser Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
100 105 110
aaa cgt gcg gcc gca ccc agc gtg ttc atc ttc ccc ccc tcc gac gag 384
Lys Arg Ala Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
cag ctg aag agc ggc acc gcc agc gtg gtg tgc ctg ctg aac aac ttc 432
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
tac ccc cgg gag gcc aag gtg cag tgg aag gtg gac aac gcc ctg cag 480
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
agc ggc aac agc cag gag agc gtg acc gag cag gac agc aag gac tcc 528
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
acc tac agc ctg agc agc acc ctc acc ctg agc aag gcc gac tac gag 576
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
aag cac aag gtg tac gcc tgc gag gtg acc cac cag ggc ctg agc agc 624
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
ccc gtg acc aag agc ttc aac cgg ggc gag tgt 657
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<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 Asn 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 Glp
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lsy 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>CR6343Heavy chain
<220>
<221>CDS
<222>(1)..(1350)
<400>364
cag gtc cag ctg gtg cag tct gga gct gag gtg aag aag cct ggg tcc 48
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
tcg gtg aag gtc tcc tgc aag gct tct gga gtc acc ttc agt tac tat 96
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Val Thr Phe Ser Tyr Tyr
20 25 30
gct atg agc tgg gtg cga cag gcc cct gga caa ggg ctt gag tgg gtg 144
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
gga gga atc agc cct atg ttt ggg aca aca acc tac gca cag aag ttc 192
Gly Gly Ile Ser Pro Met Phe Gly Thr Thr Thr Tyr Ala Gln Lys Phe
50 55 60
cag ggc aga gtc acg att act gcg gac gac tcc acg agt aca gcc tac 240
Gln Gly Arg yal Tnr lle lnr Ala Asp ASp Ser Thr Ser Thr Ala Tyr
65 70 75 80
atg gag gtg agg agc ctg aga tct gag gac acg gcc gtg tat tac tgt 288
Met Glu Val Arg Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
gcg aga tct tcg aat tac tat gat agt gta tat gac tac tgg ggc cag 336
Ala Arg Ser Ser Asn Tyr Tyr Asp Ser Val Tyr Asp Tyr Trp Gly Gln
100 105 110
gga acc ctg gtc acc gtc tcg agt gct agc acc aag ggc ccc agc gtg 384
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
ttc ccc ctg gcc ccc agc agc aag agc acc agc ggc ggc aca gcc gcc 432
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
ctg ggc tgc ctg gtg aag gac tac ttc ccc gag ccc gtg acc gtg agc 480
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
tgg aac agc ggc gcc ttg acc agc ggc gtg cac acc ttc ccc gcc gtg 528
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
ctg cag agc agc ggc ctg tac agc ctg agc agc gtg gtg acc gtg ccc 576
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
agc agc agc ctg ggc acc cag acc tac atc tgc aac gtg aac cac aag 624
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
ccc agc aac acc aag gtg gac aaa cgc gtg gag ccc aag agc tgc gac 672
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp
210 215 220
aag acc cac acc tgc ccc ccc tgc cct gcc ccc gag ctg ctg ggc gga 720
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
ccc tcc gtg ttc ctg ttc ccc ccc aag ccc aag gac acc ctc atg atc 768
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
agc cgg acc ccc gag gtg acc tgc gtg gtg gtg gac gtg agc cac gag 816
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
gac ccc gag gtg aag ttc aac tgg tac gtg gac ggc gtg gag gtg cac 864
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
aac gcc aag acc aag ccc cgg gag gag cag tac aac agc acc tac cgg 912
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
gtg gtg agc gtg ctc acc gtg ctg cac cag gac tgg ctg aac ggc aag 960
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
gag tac aag tgc aag gtg agc aac aag gcc ctg cct gcc ccc atc gag 1008
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
aag acc atc agc aag gcc aag ggc cag ccc cgg gag ccc cag gtg tac 1056
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
acc ctg ccc ccc agc cgg gag gag atg acc aag aac cag gtg tcc ctc 1104
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
acc tgt ctg gtg aag ggc ttc tac ccc agc gac atc gcc gtg gag tgg 1152
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
gag agc aac ggc cag ccc gag aac aac tac aag acc acc ccc cct gtg 1200
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
ctg gac agc gac ggc agc ttc ttc ctg tac agc aag ctc acc gtg gac 1248
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
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>CR6343Light 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
Gln Ser Val Val Thr Gln Pro Pro Ser Glu Ser Val Ala Pro Gly Gln
1 5 10 15
acg gcc agg att acc tgt ggg gga cat aac att gga agt aat agt gtg 96
Thr Ala Arg Ile Thr Cys Gly Gly His Asn Ile Gly Ser Asn Ser Val
20 25 30
cac tgg tac cag cag aag cca ggc cag gcc cct gtg ctg gtc gtg tat 144
His Trn Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Val Tyr
35 40 45
gat aat agc gac cgg ccc tca ggg atc cct gag cga ttc tct ggc tcc 192
Asp Asn Ser Asp Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser
50 55 60
aac tct ggg aac acg gcc acc ctg acc atc agc agg gtc gaa gcc ggg 240
Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly
65 70 75 80
gat gag gcc gac tat tac tgt cag gtg tgg ggt agt agt agt gac cat 288
Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Gly Ser Ser Ser Asp Gis
85 90 95
tat gtc ttc gga act ggg acc aag gtc acc gtc cta ggt gcg gcc gca 336
Tyr Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu Gly Ala Ala Ala
100 105 110
ggc cag ccc aag gcc gct ccc agc gtg acc ctg ttc ccc ccc tcc tcc 384
Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser
115 120 125
gag gag ctg cag gcc aac aag gcc acc ctg gtg tgc ctc atc agc gac 432
Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Gys Leu Ile Ser Asp
130 135 140
ttc tac cct ggc gcc gtg acc gtg gcc tgg aag gcc gac agc agc ccc 480
Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro
145 150 155 160
gtg aag gcc ggc gtg gag acc acc acc ccc agc aag cag agc aac aac 528
Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn
165 170 175
aag tac gcc gcc agc agc tac ctg agc ctc acc ccc gag cag tgg aag 576
Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys
180 185 190
agc cac cgg agc tac agc tgc cag gtg acc cac gag ggc agc acc gtg 624
Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val
195 200 205
gag gag acc gtg gcc ccc acc gag tgc agc 654
Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
210 215
<210>367
<211>218
<212>PRT
<213>Artificial
<220>
<223>Synthetic Construct
<400>367
Gln Set Val Val Thr Gln Pro Pro Set Glu Set Val Ala Pro Gly Gln
1 5 10 15
Thr Ala Arg Ile Thr Cys Gly Gly His Asn Ile Gly Set 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>269
<211>12
<212>PRT
<213>Influenza A yirus
<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 yirus
<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
G1y Ile Thr Asn Lys Val Asn Ser Val Ile Glu Lys
1 5 10
<210>373
<211>12
<212>PRT
<213>Influenza A yirus
<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 yirus
<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 yirus
<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 yirus
<400>377
Gln Ile Asn Gly Lys Leu Asn Arg Leu Ile Glu Lys
1 5 10

Claims (11)

1. the human binding molecules of a separation, it can be identified 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 for the influenza virus of the HA that comprises H5 hypotype, wherein said binding molecule comprises light chain CDR3 district shown in light chain CDR2 district shown in light chain CDR1 district, SEQ ID NO:14 shown in heavy chain CDR3 district, SEQ ID NO:13 shown in heavy chain CDR2 district, SEQ ID NO:3 shown in heavy chain CDR1 district shown in SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:15.
2. the binding molecule of claim 1, wherein said binding molecule also has the neutralization activity for the influenza virus of the HA that comprises H1 hypotype.
3. the binding molecule of claim 2, wherein said binding molecule also has the neutralization activity for the influenza virus of the HA that comprises H2, H6 and/or H9 hypotype.
4. claim 1,2 or 3 binding molecule, wherein said binding molecule comprises variable region of heavy chain, amino acid/11-121 that described variable region of heavy chain comprises SEQ ID NO:65.
5. claim 1,2 or 3 binding molecule, wherein said binding molecule comprises variable region of heavy chain and variable region of light chain, amino acid/11-121 that described variable region of heavy chain comprises SEQ ID NO:65, amino acid/11-112 that described variable region of light chain comprises SEQ ID NO:91.
6. the binding molecule of claim 1-5 any one, wherein said binding molecule is human monoclonal antibodies.
7. the nucleic acid molecule of the binding molecule of coding claim 1-6 any one.
8. a pharmaceutical composition, the binding molecule that it comprises claim 1-6 any one and the acceptable vehicle of medicine.
The binding molecule of claim 1-6 any one for the preparation of diagnosis, prevent and/or treat the application in the medicine of influenza infection.
10. the application of claim 9, wherein said influenza infection is due to due to influenza virus, described influenza virus is relevant to popular outburst, or has the popular relevant potentiality that break out.
The application of 11. claims 10, the relevant influenza virus strain of wherein said and popular outburst is selected from as next group: H1N1, H5N1, H5N2, H5N8, H5N9, strain and H9N2 based on H2.
CN200780041285.1A 2006-09-07 2007-09-06 Human binding molecules capable of neutralizing influenza virus H5N1 and uses thereof Active CN101541832B (en)

Applications Claiming Priority (11)

Application Number Priority Date Filing Date Title
US84293006P 2006-09-07 2006-09-07
EP06120316.2 2006-09-07
EP06120316 2006-09-07
US60/842,930 2006-09-07
EP06120644.7 2006-09-14
EP06120644 2006-09-14
EP06125107.0 2006-11-30
EP06125107 2006-11-30
EP07111235.3 2007-06-28
EP07111235 2007-06-28
PCT/EP2007/059356 WO2008028946A2 (en) 2006-09-07 2007-09-06 Human binding molecules capable of neutralizing influenza virus h5n1 and uses thereof

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CN102046654A (en) * 2007-03-13 2011-05-04 胡马斯有限公司 Antibodies against H5N1 strains of influenza a virus
CN102791734B (en) * 2010-03-08 2014-10-15 赛特瑞恩股份有限公司 Human monoclonal antibodies derived from human B cells and having neutralizing activity against influenza a viruses
CN102219853B (en) * 2010-04-15 2013-10-30 上海人类基因组研究中心 Anti-H5N1 type bird flue virus vicuna VHH heavy chain antibody as well as preparation method and application thereof
US20130039943A1 (en) * 2010-05-03 2013-02-14 Bruno Rene Andre Novel method
CN102279266A (en) * 2010-06-09 2011-12-14 中国科学院动物研究所 Biological chip for detecting H5 subtype avian influenza virus, and preparation method and purpose thereof
CN102041265B (en) * 2010-09-30 2012-10-17 中国科学院武汉病毒研究所 Immunoassay reagent for assaying influenza A H1N1 virus antigen
PL3418300T3 (en) * 2011-07-18 2021-05-04 Institute For Research In Biomedicine Neutralizing anti-influenza a virus antibodies and uses thereof
CN105848722B (en) * 2013-10-02 2021-09-03 免疫医疗有限责任公司 Neutralizing anti-influenza a antibodies and uses thereof
JP6731346B2 (en) * 2014-02-10 2020-07-29 メルク パテント ゲーエムベーハー Targeted TGFβ inhibition
MX2018013521A (en) * 2016-05-05 2019-06-10 Univ Pennsylvania Dna monoclonal antibodies targeting influenza virus.
CN111440228B (en) * 2020-03-09 2021-08-24 扬州大学 Common epitope, antibody, identification method and application of HA2 protein of multiple subtypes of influenza viruses
CN113121680B (en) * 2021-04-12 2022-03-29 华南农业大学 H5 subtype avian influenza resisting nano antibody protein and encoding gene and application thereof
CN113433328B (en) * 2021-08-30 2021-11-02 南京立顶医疗科技有限公司 Virus neutralizing antibody and non-neutralizing antibody combined detection method, detection card and application

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