CN101177456A - Modified transferrin fusion proteins - Google Patents

Abstract

Modified fusion proteins of transferrin and therapeutic proteins or peptides, preferably antibody variable regions, with increased serum half-life or serum stability are disclosed. Preferred fusion proteins include those modified so that the transferrin moiety exhibits no or reduced glycosylation, binding to iron and/or binding to the transferrin receptor.

Description

Modified transferrin fusion proteins

This case be that August 30, Chinese application number in 2002 are 02821637.7 the applying date, denomination of invention divides an application for the patent application of " modified transferrin fusion proteins ".

Related application

The application requires the right of priority of U.S. Provisional Application of submitting to August 30 calendar year 2001 60/315,745 and the U.S. Provisional Application of submitting to November 30 calendar year 2001 60/334,059, and these two parts of applications are all listed this paper in as a reference in full.

Technical field

The present invention relates to the therapeutic protein or the peptide of serum stability increase or serum half life prolongation, be specifically related to merge or insert the therapeutic protein or the peptide of transferrin molecule with the transferrin molecule, described molecule is through modifying, thus reduce or suppressed glycosylation, iron in conjunction with and/or the transferrin receptor combination.

Background technology

Therapeutic protein or peptide that native state or reorganization produce generally are unsettled molecules, and it shows serum stability or the short serum half life of short period of time.In addition, when these molecules are prepared, especially be mixed with the aqueous solution for diagnosis and treatment time spent, they are often very unstable.

In the practice, there is several method can prolong or promote the interior or vitro stability of body of protein-based therapeutic molecules.Polyoxyethylene glycol (PEG) is a kind of energy and protein bound, the material that causes protein prolongation action time, activity to be continued.If prolong activity of proteins with the bound energy of PEG, the frequency of administration of protein can reduce.Yet the PEG combination is through regular meeting's reduction or destroy proteinic therapeutic activity.

With can extended treatment the heterologous protein of proteinic serum half life merge and also can make therapeutic protein or stabilized peptideization.For example, compare with the therapeutic protein of non-fusion state, the therapeutic protein that merges with albumin and antibody fragment shows the serum half life of prolongation, referring to United States Patent (USP) 5,876, and 969 and 5,766,88.

Another kind of serum protein, promptly glycosylated human transferrin (Tf) also are used to merge with therapeutic protein, thereby carry out targeted delivery in cell, perhaps carry xenobiotic and pass through blood brain barrier.By total length Tf and nerve growth factor (NGF) or ciliary neurotrophic factor (CNTF) are merged, make NGF or CNTF target pass through blood brain barrier with these fusion roteins that contain glycosylated human Tf.Referring to United States Patent (USP) 5,672,683 and 5977,307.In these fusion roteins, the Tf part of molecule combines by glycosylation and with two iron atoms, this is that Tf receptors bind on Tf and the cell is necessary, and according to described patent inventor's saying, this also is that Tf passes through blood brain barrier targeted delivery NGF or the CNTF moiety is necessary.By HIV-1 proteolytic enzyme sequence being inserted in the ring of glycosylation transferrin surface exposure, also can produce transferrin fusion proteins, take this to study the ability that produces another kind of Tf fusion rotein form, described fusion rotein is passed to cell interior (Ali etc., (1999) J.Biol.Chem.274 (34): 24066-24073) via the Tf receptor target.

Serum transferrin (Tf) is that molecular weight is 80,000 daltonian monomer glycoprotein, and it combines with iron in the circulation, and via transferrin receptor (TfR) with iron transfer to a plurality of tissues (Aisen etc., (1980) Ann.Rev.Biochem.49:357-393; MacGillivray etc., (1981) J.Biol.Chem.258:3543-3553, United States Patent (USP) 5,026,651).Tf is one of modal serum molecule, and it contains the total serum protein up to about 5-10%.In alcoholic's blood, the level of sugared damaged transferrin is compared with the glycosylation transferrin to some extent and is raise, and shows long half life (about 14-17 days).Referring to vanEiik etc., (1983) Clin.Chim.Acta 132:167-171, Stibler (1991) Clin.Chem.37:2029-2037 (1991), Arndt (2001) Clin.Chem.47 (1): 13-27 and Stibler etc., " Carbohydrate-deficient consumption ", Advances in the Biosciences, (EdNordmann etc.), Pergamon, 1988, Vol.71, pages 353-357).

The clear structure of understanding Tf, and illustrate receptors bind, iron in conjunction with release and carbanion bonded mechanism (United States Patent (USP) 5,026,651,5,986,067 and MacGillivray etc., (1983) J.Biol.Chem.258 (6): 3543-3546).

As a kind of cancer therapy, used transferrin and can or carry toxic agents in conjunction with the antibody transmission of transferrin receptor to tumour cell (Baselga and Mendelsohn, 1994), transferrin has been used as non--gene-virus therapy carrier, be used for DNA is passed to cell (Frank etc., 1994; Wagner etc., 1992).Illustrate with some protein and peptide: use transferrin receptor protein to be passed to central nervous system (CNS) as going into an energy, described protein and peptide comprise CD4 (Walus etc., 1996), derive from the neurotrophic factor (Pardridge etc. of brain, 1994), derive from gelationus neurotrophic factor (Albeck etc.), vasointestinal peptide analogs (Bickel etc., 1993), beta-amyloyd peptide (Saito etc., 1995), and antisense oligonucleotide (Pardridge etc., 1995).

Yet unmodified or transformed transferrin fusion proteins still with the serum half life of extended treatment protein or peptide, or improves biological usability by the glycosylation that reduces or suppress the Tf moiety, or reduces or prevent iron and/or Tf receptors bind.

The invention summary

Such as hereinafter detailed description, the present invention includes modified Tf fusion rotein, it contains at least a therapeutic protein, polypeptide or peptide entity, wherein Tf part has been transformed with the serum half life that prolongs molecule or has been improved its biological usability.The present invention also comprises pharmaceutical preparation and the composition that contains this fusion rotein, by merging with the serum stability that strengthens therapeutic protein, prolong the serum half life and improve the method for biological usability, the nucleic acid molecule of modified Tf fusion rotein etc. of encoding with modified transferrin.Another aspect of the present invention relates to the method with modified Tf fusion rotein treatment patient.

In preferred embodiments, modified Tf fusion rotein contains the modified human transferrin Tf moiety that reduces or prevent glycosylation and/or iron and receptors bind.

The accompanying drawing summary

Fig. 1 has shown the sequence alignment result in people (Hu) transferrin (Tf) N structural domain and C-structure territory, has given prominence to similarity and identity among the figure.

Fig. 2 A-2B has shown the comparison result of the transferrin sequence that derives from different plant species.Light color shade: similarity; Dark-shaded: identity.

Fig. 3 has shown the position in a plurality of therapeutic proteins, polypeptide or peptide insertion site that the Tf surface exposes.

Fig. 4 A-4B has shown VH and the VL zone that produces the used a plurality of preferred anti-TNF alpha antibody of modified Tf fusion rotein.

Fig. 5 has shown pREX0010.

Fig. 6 has shown pREX0011.

Fig. 7 has shown pREX0012.

Fig. 8 has shown pREX0013.

Fig. 9 has shown pREX0014.

Figure 10 has shown pREX0015.

Detailed Description Of The Invention

The general description

Find: carry out gene fusion or chemical coupling by making therapeutic protein, polypeptide or peptide and being enough to prolong modified transferrin all or part of of its serum half life, can stablize therapeutic protein (such as polypeptide, antibody or peptide, or its fragment and variant) to prolong the serum half life and/or in vivo the activity of therapeutic protein to be kept the longer time. Modified transferrin fusion proteins comprises transferrin or the transferrin domain covalently bound with therapeutic protein or peptide, wherein compare with wild type transferrin sequence, contain one or more 49-Phe ,82-Ser,115-Arg,144-Met,145-Asn ,161-Arg,169-Met Human Connective tissue growth factors, insertion or disappearance after the transferrin part is modified. In one embodiment, the Tf fusion can reduce or prevent the glycosylation in Tf or the Tf domain after transforming. In other embodiments, after Tf albumen or Tf domain are modified and the combination of iron or carbanion weaken or disappear, or weaken with the compatibility of Tf acceptor (TfR) or be not combined with this receptor.

Therefore, the present invention includes transferrin fusion proteins, contain the therapeutic composition of this fusion rotein, by using the method that this fusion rotein is treated, prevented or improve disease.Transferrin fusion proteins of the present invention comprises at least one segment of therapeutic protein or at least one segment or the variant of variant and modified transferrin, both are connected with each other, preferably (promptly produce transferrin fusion proteins by translation nucleic acid by gene fusion, in described nucleic acid, the polynucleotide of all or part of therapeutic protein of encoding with the coding all or part of modified transferrin polynucleotide in frame, be connected) or chemical coupling be connected with each other.In a single day therapeutic protein and transferrin become the part of transferrin fusion proteins, can be referred to as transferrin fusion proteins " part ", " zone " or " moiety " (for example " therapeutic protein part " or " transferrin part ").

In one embodiment, the invention provides transferrin fusion proteins, it contains therapeutic protein and modified serum transferrin, perhaps is made up of these two kinds of components.In other embodiments, the invention provides transferrin fusion proteins, it contains biological activity and/or the therapeutic activity segment and the modified transferrin of therapeutic protein, perhaps is made up of described therapeutic protein segment and modified transferrin.In other embodiments, the invention provides transferrin fusion proteins, it contains biological activity and/or the therapeutic activity variant and the modified transferrin of therapeutic protein, perhaps is made up of described therapeutic protein variant and modified transferrin.In other embodiments, the invention provides transferrin fusion proteins, it contains the biological activity and/or the therapeutic activity segment of therapeutic protein and modified transferrin.In another embodiment, the therapeutic protein of transferrin fusion proteins partly is the therapeutic protein of activity form.

Except as otherwise noted, the implication of all technology used herein and scientific terminology all with general understand equivalent in meaning of the technical field of the invention those of ordinary skill.Can use similar or the method and the material that are equal to any and described herein in practice of the present invention or the test, but this paper has been described by preferable methods and material.

Definition

Term used herein " biological activity " refers to function or a whole set of activity that therapeutic molecules, protein or peptide are exercised in coenocorrelation (being organism or its replication in vitro thing).Biological activity includes but not limited to the function of the therapeutic molecules part of the fusion rotein that requires, such as but not limited to the extracellular matrix secretion of inductive effect clone, induce hormone secretion, induce chemotaxis, induce mitotic division to take place, induce the cell fission of differentiation or retarding effect cell.If fusion rotein of the present invention or peptide show one or more biological activitys of the natural counterpart of its therapeutic protein, can think their biologically actives.

Identify used herein and transferrin sequence " corresponding amino acid " or " amino acid that is equal to " by sequence alignment, thereby make identity or similarity maximization between first transferrin sequence and at least the second the transferrin sequence.Be used for identifying that being equal to of second transferrin sequence amino acid whose numeral is based on the used numeral of identifying in first transferrin sequence of corresponding amino acid.In some cases, can use these phrases describe with the rabbit anteserum transferrin in some residue human transferrin of comparing in amino-acid residue.

Term used herein " the proteic segment of Tf " or " Tf albumen " or " the proteic part of Tf " refer to contain natural Tf albumen or its mutant at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% aminoacid sequence.

Term used herein " gene " refers to any DNA section relevant with biological function.Therefore, gene includes but not limited to encoding sequence and/or the required adjusting sequence of its expression.Gene also can comprise the DNA section of non-expression, for example forms the section of other proteinic recognition sequence.Can obtain gene by a plurality of sources, comprise from interested source clone, or synthetic by sequence information known or that infer, and gene can comprise the sequence that has desired parameters after design.

" heterologous polynucleotide " used herein or " heterologous nucleic acids " or " heterologous gene " or " heterologous sequence " or " exogenous DNA section " refer to polynucleotide, nucleic acid or the DNA section that is derived from for particular host cell to external source, or it is identical to refer to originate, but its primitive form is carried out polynucleotide, nucleic acid or the DNA section of modification.Though the heterologous gene in the host cell comprises for particular host cell for endogenic, by the gene of modified.Therefore, this term refers to pair cell and is external source or allogenic DNA section, perhaps refer to and the cell homology, but certain position in host cell nucleic acid, the general DNA section that this element can not occur.For example, be allogenic with people Tf sequence bonded yeast cell natural signals sequence.

" isolating " used herein nucleotide sequence refers to through agarose gel electrophoresis to be measured, be substantially free of the nucleotide sequence of other nucleotide sequence, for example pure at least about 20%, preferably pure at least about 40%, more preferably from about 60% is pure, even more preferably from about 80% pure, most preferably from about 90% is pure, even 95% pure nucleotide sequence most preferably from about.For example,, nucleotide sequence is transferred to the different loci place that desire produces this sequence again from its natural place, can obtains isolated nucleic acid sequences by standard cloning process used in the genetically engineered.Cloning process comprises cutting-out and separates required nucleic acid fragment, this segment contains the nucleic acid encoding sequence, described segment is inserted carrier molecule, again recombinant vectors is mixed host cell, can in described cell, duplicate multiple copied or polyclonal nucleotide sequence.Nucleotide sequence can be derived from genome, cDNA, RNA, semi-synthetic, synthetic or its arbitrary combination.

When the frame endomixis between the dna encoding sequence causes the dna encoding sequence to be translated into the polypeptide fusions, can think that two or more dna encoding sequences are " connections " or " fusion ".The term " fusion " relevant with the Tf fusions includes but not limited to: at least a therapeutic protein, polypeptide or peptide combine with the N-of Tf is terminal, combine with the C-of Tf is terminal, and/or insert between any two amino acid in Tf.

" modified transferrin " used herein refers to: compare with the wild-type transferrin, have the transferrin molecule of at least one modification in the aminoacid sequence.

" modified transferrin fusion proteins " used herein refers to: at least one modified transferrin molecule (or its segment or variant) merges the protein that forms with at least one proteinaceous therapeutic molecule (or its segment or variant).

Term used herein " nucleic acid " or " polynucleotide " refer to deoxyribonucleotide or the ribonucleotide and the polymkeric substance thereof of strand or double chain form.Unless otherwise defined, this term comprises the nucleic acid of the analogue that contains natural nucleotide, described analogue have with reference to the similar binding characteristic of nucleic acid, and in the mode that is similar to natural nucleotide by metabolism.Except as otherwise noted, specific nucleotide sequence also implies it through conservative variant of modifying (replacing as degenerate codon) and complementary sequence and the sequence that spells out.Specifically, by produce the 3rd of one or more selected (or all) codons mixed-sequence that base and/or Hypoxanthine deoxyriboside residue replace, degenerate codon be can obtain and (Batzer etc., (1991) Nucleic Acid Res.19:5081 replaced; Ohtsuka etc., (1985) J.Biol.Chem.260:2605-2608; Cassol etc., (1992); Rossolini etc., (1994) Mol.Cell.Probes8:91-98).Term nucleic acid can exchange with gene, cDNA with by the mRNA of genes encoding and use.

When making certain DNA section be in the functional relationship with another DNA section, can think that the former is " can operate continuous ".For example, when the DNA of signal sequence be expressed as participate in the fusion rotein excretory before during protein, can think that it can be operated with the DNA of code book invention fusion rotein to link to each other; If promotor or enhanser promote sequence to transcribe, can think that they can be operated with encoding sequence to link to each other.In general, can operate continuous dna sequence dna is adjacency, and for signal sequence or fusion rotein, described dna sequence dna is that also being in of adjacency read a yard phase.Yet enhanser need not and the encoding sequence adjacency of transcribing under its control.In this context, connect by the adapter that in restriction site or described site easily, inserts or joint and to finish connection.

Term used herein " promotor " refer to participation in conjunction with RNA polymerase with initial DNA zone of transcribing.

Term used herein " reorganization " refers to through recombinant DNA cell transformed, tissue or organism.

Target entity used herein, protein, polypeptide or peptide refer to particular cell types [normal (as lymphocyte) or unusual (as cancer cells)] specificity and combine, and therefore can be used for the molecule with Tf fusion rotein or selectively targeted this cell type of compound (medicine or cytotoxic agent).

" therapeutic protein " used herein refers to has one or more treatments and/or bioactive protein, polypeptide, antibody, peptide or its segment or variant.The therapeutic protein that the present invention comprises includes but not limited to protein, polypeptide, peptide, antibody and biological products.Herein term peptide, protein and polypeptide can exchange use.In addition, term " therapeutic protein " can refer to the endogenic or natural related thing of therapeutic protein.Demonstrate the polypeptide of " therapeutic activity " or have the protein of " therapeutic activity " to refer to: have one or more the known organism activity relevant and/or the polypeptide of therapeutic activity with therapeutic protein (for example, as described herein or one or more therapeutic proteins known in the art).As a nonrestrictive example, " therapeutic protein " is the protein that can be used for treating, preventing or improve disease.Described disease can be people or non-human animal's a disease, for example can be used for the animal doctor.

Term used herein " conversion " refers to nucleic acid (being nucleotide polymer) is transferred in the cell.Term used herein " gene transformation " refers to DNA, and particularly recombinant DNA shifts and is incorporated in the cell.

Term used herein " transformant " refers to through cell transformed, tissue or organism.

Term used herein " transgenosis " refers in the mode of guaranteeing its function and inserts nucleic acid in organism, host cell or the carrier.

Term used herein " genetically modified " refers to: a kind of by in the multiple method for transformation, foreign gene or modified gene have been accepted, cell, cell culture, organism, bacterium, fungi, animal, plant and the offspring thereof of gene of modified Tf fusion rotein particularly encodes, wherein for the organism species of accepting foreign gene or modified gene, foreign gene or modified gene derive from identical or different species.

" variant " refers to different with reference to nucleic acid or polypeptide, but can keep the polynucleotide or the nucleic acid of its fundamental characteristics.In general, variant is closely similar on the whole, and is in a lot of zones, identical with reference nucleic acid or polypeptide." variant " used herein refers to the therapeutic protein part of transferrin fusion proteins of the present invention, the sequence of this part and natural therapeutic protein sequence are different, but have kept as described herein or at least a functional and/or therapeutic characteristic known in the art of natural protein.

Term used herein " carrier " broadly refers to plasmid, phasmid or the virus of any encoding exogenous nucleic acid.This term also comprises to be convenient to nucleic acid is transferred to the non--plasmid in virion or the cell, non--phasmid and non--virus compound, for example polylysine compound etc.Carrier also can be suitable for to do to transmit carrier nucleic acid or its mutant are passed to the virus vector in the cell, and perhaps carrier also can be the non--virus vector that is applicable to identical purpose.It is well-known in the art being used for DNA is passed to the cell and the virus of tissue and the example of non--virus vector, for example is described in Ma etc., (1997, Proc.Natl.Acad.Sci.U.S.A.94:12744-12746).The example of virus vector includes but not limited to: vaccinia virus recombinant, and recombinant adenovirus, recombinant retrovirus, recombinant adeno-associated virus, recombinant fowlpox virus etc. (Cranage etc., 1986, EMBO is J.5:3057-3063; International patent application no WO94/17810 is disclosed on August 18th, 1994; International patent application no WO94/23744 is disclosed on October 27th, 1994).The example of non--virus vector includes but not limited to: liposome, the polyamine derivative of DNA etc.

Term used herein " wild-type " refers to natural polynucleotide or peptide sequence.

Transferrin and transferrin are modified

Can use any transferrin to prepare modified Tf fusion rotein of the present invention.As if wild-type people Tf (Tf) is 679 amino acid whose protein, is about 75kDa (disregarding glycosylation), and it has two primary structure territories that are derived from gene replication, N (about 330 amino acid) and C (about 340 amino acid).Referring to GenBank accession number NM001063, XM002793, M12530, XM039845, XM039847 and S95936 ( Www.ncbi.nlm.nih.gov/) (listing this paper in as a reference all in full) and SEQ ID NO:1,2 and 3.These two structural domains have been along with alienation has also taken place in the variation of time, but have kept high-caliber identity/similarity (Fig. 1).

N structural domain and C-structure territory further are divided into two subdomains, N1 and N2, C1 and C2.The function of Tf be with iron transfer to somatocyte.This process particularly is in Tf acceptor (TfR) mediation of expressing on the cell in the active growth by all cells.TFR discerns iron mating type TF (two iron mating type Tf and a receptors bind), endocytosis takes place then, thereby the TfR/Tf mixture is transported in the endosome, the reduction of local pH value at this moment causes the release in conjunction with iron, and the TfR/Tf mixture is circulated to cell surface again and discharges TF (being known as non--iron mating type apoTf).Receptors bind need be by the C-structure territory of Tf.Because as if with non-glycosylated iron bonded Tf energy bind receptor, so two glycosylation sites in the C-structure territory do not participate in receptors bind.

Two iron atoms of each Tf molecule portability.They are compound in the gap between C1 and the C2 subdomain at N1 and N2, cause molecular conformation to change.Tf crosses over hemato encephalic barrier (BBB) via the Tf acceptor.

In human transferrin, the iron binding site contains amino acid Asp63 (Asp82 that contains the SEQ ID NO:2 of natural Tf signal sequence) at least; Asp392 (Asp 411 of SEQ ID NO:2); Tyr95 (Tyr114 of SEQ ID NO:2); Tyr426 (Tyr445 of SEQ ID NO:2); Tyr188 (Tyr207 of SEQ IDNO:2); Tyr514 or 517 (Tyr533 or the Tyr536 of SEQ ID NO:2); His249 (His268 of SEQ ID NO:2); His585 (His604 of SEQ ID NO:2), hinge region contains N structural domain amino-acid residue 94-96 at least, 245-247 and/or 316-318, and C-structure domain amino acid residue 425-427,581-582 and/or 652-658, carbonate binding site contain amino acid Thr120 (Thr139 of SEQ ID NO:2) at least; Thr452 (Thr471 of SEQ ID NO:2); Arg124 (Arg143 of SEQ ID NO:2); Arg456 (Arg475 of SEQ ID NO:2); Ala126 (Ala145 of SEQ ID NO:2); Ala458 (Ala477 of SEQ ID NO:2); Gly127 (Gly146 of SEQ ID NO:2); Gly459 (Gly478 of SEQ ID NO:2).

In one embodiment of the invention, modified transferrin fusion proteins comprises modified human transferrin, but any animal Tf molecule all can be used for producing fusion rotein of the present invention, comprise people Tf variant, milk cow, pig, sheep, dog, rabbit, rat, mouse, hamster, echnida, duckbill platypus, chicken, frog, hornworm, monkey and other ox, dog and bird (referring to the representational Tf sequence of the cover of one among Fig. 2).All these Tf sequences can obtain from GenBank and other public database easily.People Tf nucleotide sequence can obtain (referring to SEQ ID NO:1,2 and 3 and accession number mentioned above, they can derive from Www.ncbi.nlm.nih.gov/), can use these sequences to prepare gene fusion thing between Tf or Tf structural domain and the selected therapeutic molecules.Fusions also can prepare autocorrelative molecule, as lactotransferrin (lactoferrin, GenBank accession number NM_002343).

Found that natural defensive iron-conjugated protein lactoferrin (Lf) has antibacterium, antimycotic, antiviral, antitumor and anti-inflammatory activity.This protein is present in outer secreting in the thing, describedly secretes thing and is exposed to usually in normal microflora, milk, tears, nose juice, saliva, bronchorrhea, gastrointestinal fluid, uterine neck-vaginal mucus and the seminal fluid outward.In addition, Lf is the main component of the secondary specific granule of circulation polymorph neutrophile leucocytes (PMN).In the septic zone, promptly discharge apoprotein after the PMN threshing.The major function of Lf is to remove the free iron of liquid and inflamed areas, thereby suppresses the infringement of free radical-mediation, and the operability of reduction metal is with infringement microorganism and tumour cell.Checking the adult ¹²⁵In the research of I Lf turnover rate, confirm that Lf can be by liver and spleen rapid absorption, radioactivity can be kept several weeks (Bennett etc., (1979), Clin.Sci. (Lond.) 57:453-460) in liver and spleen.

In another embodiment, the transferrin of transferrin fusion proteins of the present invention partly comprises the transferrin splice variant.In an example, the transferrin splice variant can be the human transferrin splice variant.In a specific embodiments, the human transferrin splice variant can be Genbank accession number AAA61140.In another embodiment, the transferrin of transferrin fusion proteins of the present invention partly comprises the lactoferrin splice variant.In an example, human serum lactoferrin splice variant can be the new splice variant of neutrophilic granulocyte lactoferrin.In a specific embodiments, neutrophilic granulocyte lactoferrin splice variant can be Genbank accession number AAA59479.In another embodiment, neutrophilic granulocyte lactoferrin splice variant can contain following amino acid sequences EDCIALKGEADA (SEQ ID NO:8), and it comprises new montage-variation zone.

Can prepare modified Tf fusion rotein with any Tf albumen, segment, structural domain or structural domain through transforming.For example, can use the total length Tf sequence that contains or do not contain natural Tf signal sequence to prepare fusion rotein.Also can use single Tf structural domain, prepare the Tf fusion rotein as single N or C-structure territory.In some embodiments, use single N structural domain comparatively favourable because the Tf glycosylation site is present in the C-structure territory, N structural domain itself not with iron or Tf receptors bind.In other embodiments, can prepare the fusion rotein in therapeutic protein and single C-structure territory, wherein the C-structure territory is changed, reducing, to suppress or to prevent glycosylation, iron in conjunction with and/or the Tf receptors bind.

In some embodiments, Tf or Tf partly answer sufficiently long, thereby compare with serum stability (half life), external stability of solution or the biological usability of the therapeutic protein of non-fusion state, increase serum stability, external stability of solution or the biological usability of therapeutic protein.The increase of described stability, serum half life or biological usability can be to surpass about 30%, 50%, 70%, 80%, 90% or the higher increase of not merging therapeutic protein.In some cases, modified transferrin fusion proteins shows about 10-20 or more days, the serum half life of about 12-18 days or about 14-17 days.

When the C-structure territory of Tf is fusion rotein a part of, two N-linked glycosylation sites can suddenly change, promptly corresponding to the N413 of SEQ ID NO:3 and the amino-acid residue of N611, in Yeast system, to express, thereby the glycosylation of preventing or high mannose baseization and prolong fusion rotein and/or the serum half life of therapeutic protein (generation take off sialic acid-, or producing single sialyl-Tf or two sialyl-Tf) in some cases.Except Tf amino acid, also can the contiguous residue in the N-X-S/T glycosylation site be suddenlyd change to prevent or substantially minimize glycosylation corresponding to N413 and N611.United States Patent (USP) 5,986,067 referring to Funk etc.It is reported the TfN structural domain of expressing in the Pichia pastoris at the S32 place by single hexose O-linked glycosylation, also can suddenly change or modify this site to prevent this glycosylation.

Therefore, in one embodiment of the invention, transferrin fusion proteins comprises modified transferrin molecule, and wherein transferrin shows the glycosylation of reduction, its include but not limited to take off sialic acid-, single sialyl-and the Tf of two sialyl-forms.In another embodiment, the transferrin of transferrin fusion proteins partly comprise through the sudden change after can prevent glycosylated reorganization transferrin mutant.In another embodiment, the transferrin of transferrin fusion proteins partly comprises fully by glycosylated reorganization transferrin mutant.In another embodiment, the transferrin of transferrin fusion proteins partly comprises after sudden change can prevent glycosylated recombinant human serum transferrin mutant, and wherein the Asn413 of SEQ ID NO:3 and among the Asn611 at least one are mutated into and do not allow glycosylated amino acid.In another embodiment, the transferrin of transferrin fusion proteins partly comprises after sudden change and can prevent or reduce glycosylated recombinant human serum transferrin mutant greatly, wherein can the contiguous residue in the N-X-S/T glycosylation site be suddenlyd change.

As hereinafter being gone through, can to modified Tf fusion rotein of the present invention transform so that its do not combine with iron and/or not with the Tf receptors bind.In other embodiments of the present invention, iron can be used the iron-binding capacity of Tf in two ways in conjunction with keeping, and a kind of is with therapeutic protein or peptide is passed to cell interior and/or make it pass through BBB.Often need to change these embodiments in conjunction with iron and/or Tf acceptor, reducing or to prevent glycosylation, thus the proteinic serum of extended treatment half life.When load had iron, independent N structural domain did not combine with TfR, can combine with TFR with iron bonded C-structure territory, but binding affinity was different from complete molecule.

In another embodiment, the transferrin of transferrin fusion proteins partly comprises the reorganization transferrin mutant with sudden change, and wherein mutant fails to keep the ability of bond.In alternative embodiment, the transferrin of transferrin fusion proteins partly comprises the reorganization transferrin mutant with sudden change, and wherein for wild-type serum transferrin, mutant has more weak binding affinity to metal.In alternative embodiment, the transferrin of transferrin fusion proteins partly comprises the reorganization transferrin mutant with sudden change, and wherein for wild-type serum transferrin, mutant has stronger binding affinity to metal.

In another embodiment, the transferrin of transferrin fusion proteins partly comprises the reorganization transferrin mutant with sudden change, and wherein mutant fails to keep the ability in conjunction with transferrin receptor.In alternative embodiment, the transferrin of transferrin fusion proteins partly comprises the reorganization transferrin mutant with sudden change, and wherein for wild-type serum transferrin, mutant has more weak binding affinity to transferrin receptor.In alternative embodiment, the transferrin of transferrin fusion proteins partly comprises the reorganization transferrin mutant with sudden change, and wherein for wild-type serum transferrin, mutant has stronger binding affinity to transferrin receptor.

In another embodiment, the transferrin of transferrin fusion proteins partly comprises the reorganization transferrin mutant with sudden change, and wherein mutant fails to keep the ability of combined carbon hydrochlorate.In alternative embodiment, the transferrin of transferrin fusion proteins partly comprises the reorganization transferrin mutant with sudden change, and wherein for wild-type serum transferrin, mutant has more weak binding affinity to carbonate.In alternative embodiment, the transferrin of transferrin fusion proteins partly comprises the reorganization transferrin mutant with sudden change, and wherein for wild-type serum transferrin, mutant has stronger binding affinity to carbonate.

In another embodiment, the transferrin of transferrin fusion proteins partly comprises recombinant human serum transferrin mutant, and wherein at least one is selected from the Asp63 of SEQ ID NO:3, Gly65, Tyr95, Tyr188, His249, Asp392, Tyr426, Tyr514, the amino-acid residue of Tyr517 and His585 has sudden change, and wherein mutant has kept the ability of bond.In alternative embodiment, recombinant human serum transferrin mutant is selected from the Asp63 of SEQ ID NO:3 at least one, Gly65, Tyr95, Tyr188, His249, Asp392, Tyr426, Tyr514, have sudden change in the amino-acid residue of Tyr517 and His585, wherein the ability of mutant bond reduces.In another embodiment, recombinant human serum transferrin mutant is selected from the Asp63 of SEQ ID NO:3 at least one, Gly65, Tyr95, Tyr188, His249, Asp392, Tyr426 has sudden change in the amino-acid residue of Tyr517 and His585, and wherein mutant does not keep the ability of bond.

In another embodiment, the transferrin of transferrin fusion proteins partly comprises recombinant human serum transferrin mutant, wherein has sudden change among the Lys206 of SEQ ID NO:3 or the His207, wherein compare with wild-type human serum transferrin, mutant has stronger binding affinity (referring to United States Patent (USP) 5 to metal, 986,067, it lists this paper in as a reference in full).In alternative embodiment, the transferrin of transferrin fusion proteins partly comprises recombinant human serum transferrin mutant, wherein has sudden change among the Lys206 of SEQ ID NO:3 or the His207, wherein compare with wild-type human serum transferrin, mutant has more weak binding affinity to metal.In another embodiment, the transferrin of transferrin fusion proteins partly comprises recombinant human serum transferrin mutant, wherein has sudden change among the Lys206 of SEQ ID NO:3 or the His207, wherein mutant not with melts combine.

Can use any technology that can utilize to prepare fusion rotein of the present invention, include but not limited to the molecular engineering used always, Sambrook etc. for example, Molecular Cloning:A Laboratory Manual, 2nd Ed., Cold Spring Harbor Laboratory Press, disclosed technology in 1989.When using side-directed mutagenesis well-known in the art to carry out the Nucleotide replacement, preferably the secondary characteristic to coded amino acid changes, the aminoacid replacement of promptly guarding, but, also can carry out other nonconservative replacement, especially when the modified transferrin part that produces the Tf fusion rotein, for example show reduction glycosylation, reduction iron in conjunction with etc. modified Tf fusion rotein the time, can carry out non-conservative replacement.Specifically be contemplated that aminoacid replacement, little disappearance or insertion (being generally 1) to about 30 amino acid; Insertion between the transferrin structural domain; Little amino-or carboxyl-end extends, as the methionine residues of amino-end, or between the transferrin structural domain or the little joint peptide that is less than 50,40,30,20 or 10 residues of connection transferrin and therapeutic protein or peptide; Or be convenient to the little extension of purifying, as poly--Histidine tract, epitope or binding domains.

The example that conserved amino acid replaces has: the interior replacement of amino acid on the same group mutually, as basic aminoacids (as arginine, Methionin, Histidine), acidic amino acid (as L-glutamic acid and aspartic acid), polare Aminosaeren (as glutamine and l-asparagine), hydrophobic amino acid (as leucine, Isoleucine, Xie Ansuan), the replacement that takes place in die aromatischen Aminosaeuren (as phenylalanine, tryptophane, tyrosine) and p1 amino acid (as glycine, L-Ala, Serine, Threonine, the methionine(Met)) group.

Non--conservative replacement, comprise with another group amino acid of one group of aminoacid replacement.For example, non--conservative replacement, comprise with polare Aminosaeren and replace hydrophobic amino acid.The generality that relevant Nucleotide replaces is described, can be referring to for example Ford etc., and (1991), Prot.Exp.Pur.2:95-107.Non--as conservative to replace, disappearance and insert and can be used in particular for producing TF fusion rotein of the present invention, described fusion rotein reduces with combine of iron or disappears, fusion rotein and Tf acceptor combine reduction or disappearance and/or glycosylation reduction or disappearance.

In polypeptide of the present invention and protein, according to following conventional tabulation, according to following system design amino acid:

The amino acid table

Amino acid

The single-letter code

The trigram code

Amino acid	The single-letter code	The trigram code
			L-Ala	A	Ala
Arginine	R	Arg
			L-asparagine	N	Asn
Aspartic acid	D	Asp
			Halfcystine	C	Cys
Glutamine	Q	Gln
			L-glutamic acid	E	Glu
Glycine	G	Gly
			Histidine	H	His
Isoleucine	I	Ile
			Leucine	L	Leu
Methionin	K	Lys
			Methionine(Met)	M	Met
Phenylalanine	F	Phe
			Proline(Pro)	P	Pro
Serine	S	Ser
			Threonine	T	Thr
Tryptophane	W	Trp
			Tyrosine	Y	Tyr
Xie Ansuan	V	Val

By corresponding to one or more Tf N structural domain residue A sp63, Tyr95, Tyr188, His249 and/or C-structure territory residue A sp392, Tyr426, suddenly change in the amino-acid residue of Tyr514 and/or His585, comprise disappearance, replace or insert, can reduce or destroy iron combination and/or receptors bind.By mutating acid Lys206, Hys207 or Arg632 also can influence the iron combination.By corresponding to one or more TfN structural domain residue Thr120, Arg124, Ala126, Gly127 and/or C-structure territory residue Thr452, Arg456 suddenlys change in the amino-acid residue of Ala458 and/or Gly459, comprise disappearance, replace or insert, can reduce or destroy the carbonate combination.The carbonate bonded reduces or destroys can influence iron and/or receptors bind conversely.

By suddenling change in above at the amino-acid residue of iron in conjunction with described TfN structural domain residue corresponding to one or more, comprise disappearance, replace or insert, can reduce or the combining of destruction and Tf acceptor.

As mentioned above, by to suddenling change corresponding near the pairing amino-acid residue of one or more Tf C-structure territory residue the N-X-S/T site of C-structure territory residue N413 and/or N611, comprise disappearance, replace or insert, can reduce or prevent that glycosylation is (referring to United States Patent (USP) 5,986,067).For example, N413 and/or N611 can be mutated into the Glu residue.

When unmodified Tf fusion rotein of the present invention with prevent glycosylation, iron in conjunction with, carbonate in conjunction with and/or during receptors bind, can remove or peel off glycosylation, iron and/or carbanion from fusion rotein.For example, can use obtainable deglycosylating enzyme cracking glycosylated residues from the fusion rotein, particularly with Tf part bonded saccharide residue, can use the defective yeast of glycosylase to prevent glycosylation, and/or can prevent glycosylated reagent (as tunicamycin (tunicamycin)) cultivation of recombinant cells when existing.

Can carry out the three-dimensional structure of other sudden change to Tf with change TF, folding as hinge region being modified to prevent the required Tf of iron combination and Tf acceptor identification.For example, can in following amino-acid residue or near it, suddenly change: N structural domain amino-acid residue 94-96,245-247 and/or 316-318 and C-structure domain amino acid residue 425-427,581-582 and/or 652-658.In addition, can in the flanking region in these sites or near it, suddenly change to change the Tf 26S Proteasome Structure and Function.

In one aspect of the invention, transferrin fusion proteins can be used as carrier proteins with proteinic half life of extended treatment or biological usability, and in some cases, makes therapeutic protein be passed to cell interior and/or passes through hemato encephalic barrier.In alternative embodiment, transferrin fusion proteins comprises modified transferrin molecule, and wherein transferrin does not keep the ability of passing through hemato encephalic barrier.

In another embodiment, transferrin fusion proteins comprises modified transferrin molecule, and wherein the transferrin molecule has kept the ability that combines and therapeutic peptide is transported to cell interior with transferrin receptor.In alternative embodiment, transferrin fusion proteins comprises modified transferrin molecule, and wherein the transferrin molecule does not keep the ability that combines and therapeutic peptide is transported to cell interior with transferrin receptor.

In another embodiment, transferrin fusion proteins comprises modified transferrin molecule, wherein the transferrin molecule has kept and combines with transferrin receptor and therapeutic peptide is transported to the ability of cell interior, but keeps the ability of passing through hemato encephalic barrier.In alternative embodiment, transferrin fusion proteins comprises modified transferrin molecule, wherein the transferrin molecule has kept the ability of passing through hemato encephalic barrier, but does not keep the ability that combines and therapeutic peptide is transported to cell interior with transferrin receptor.

Modified transferrin fusion proteins

The proteinic fusions of the present invention can contain one or more copies with Tf albumen N-end and/or the terminal bonded therapeutic protein of C-.In some embodiments, therapeutic protein is terminal with the proteic N-of Tf and C-is terminal combines, and fusion rotein can contain the equivalent of one or more therapeutic proteins in the one or both ends of appointing of Tf.In other embodiments, therapeutic protein or polypeptide are inserted into the proteic known structure of Tf territory, for example insert in the one or more Tf ring (referring to Ali etc., (1999) J.Biolog.Chem.274 (34): 24066-24073).In other embodiments, therapeutic protein or therapeutic peptide are inserted between the N structural domain and C-structure territory of Tf.

In general, transferrin fusion proteins of the present invention can have a modified zone that derives from transferrin and a zone that derives from therapeutic protein.Yet, can use every kind of proteinic a plurality of zone preparations transferrin fusion proteins of the present invention.Similarly, can use more than one therapeutic protein to prepare transferrin fusion proteins of the present invention, thereby produce the modified Tf fusion rotein of many-function.

In one embodiment, transferrin fusion proteins of the present invention contains therapeutic protein or its part with transferrin molecule or its meromixis.In another embodiment, transferrin fusion proteins of the present invention contains the therapeutic protein that merges with the N-terminal of transferrin molecule.In alternative embodiment, transferrin fusion proteins of the present invention contains the therapeutic protein that merges with the C-terminal of transferrin molecule.In another embodiment, transferrin fusion proteins of the present invention contains the transferrin molecule that merges with the N-terminal of therapeutic protein.In alternative embodiment, transferrin fusion proteins of the present invention contains the transferrin molecule that merges with the C-terminal of therapeutic protein.

In another embodiment, modified transferrin molecule contains the N-terminal with the transferrin molecule of the meromixis that may become the therapeutic peptide N-terminal.In alternative embodiment, modified transferrin molecule contains the N-terminal of the transferrin molecule that merges with the therapeutic peptide C-terminal.In another embodiment, modified transferrin molecule contains the C-terminal with the transferrin molecule of the meromixis that may become the therapeutic peptide C-terminal.In alternative embodiment, modified transferrin molecule contains the C-terminal of the transferrin molecule that merges with the therapeutic peptide N-terminal.

In other embodiments, transferrin fusion proteins of the present invention contains and the N-of modified transferrin is terminal and the therapeutic protein of the terminal fusion of C-.In another embodiment, be identical therapeutic protein with N-and the terminal therapeutic protein that merges of C-.In alternative embodiment, be different therapeutic proteins with N-and the terminal therapeutic protein that merges of C-.In another alternative embodiment, be different therapeutic proteins with N-and the terminal therapeutic protein that merges of C-, but these protein can be used for treating or preventing identical disease.In another embodiment, be different therapeutic proteins with N-and the terminal therapeutic protein that merges of C-, described protein can be used for treating or preventing the disease that the general while known in the art occurs in the patient.

Except modified transferrin part and the N-terminal and/or the terminal fusion of C-of therapeutic protein part can be obtained the modified transferrin fusion proteins of the present invention, by with interested therapeutic protein or peptide (therapeutic protein as described herein or peptide, perhaps, for example, with therapeutic protein or its fragment or its variant bonded single-chain antibody) insert the interior region of modified transferrin, also can produce transferrin fusion proteins of the present invention.The interior region of modified transferrin includes but not limited to: iron binding site, hinge region, supercarbonate binding site or receptors bind structural domain.

In the protein sequence of modified transferrin molecule, there are a plurality of ring or corners by the disulfide linkage stabilization.These rings can be used for inserting or the inner peptide that therapeutic activity is arranged that merges, and particularly those need secondary structure to become the peptide of functional or therapeutic protein, have the active modified transferrin molecule of particular organisms thereby produce in fact.

When therapeutic protein or peptide are inserted into or replace the ring of at least one Tf molecule, in any ring zone that exposes on the surface, inserting, also can insert in other zone of Tf.For example, can contain TF amino acid 32-33,74-75,256-257 inserts (Ali etc., document is the same) (see figure 3) in the ring of 279-280 and 288-289.As mentioned above, also can insert in other zone of Tf, for example the iron that will describe in detail hereinafter and supercarbonate binding site, hinge region and receptors bind structural domain insert.Also can use the ring that is suitable in the Tf protein sequence modifying/replacing to develop the screened library of peptide inset at random to insert protein or peptide.Before being cloned into the Tf structural domain and/or merging with Tf is terminal, can use any method to prepare the nucleic acid inset to produce peptide library, comprise available phage and bacterium display systems.

The N-end of Tf is freely, and points to the direction that deviates from the branch daughter.Therefore, protein on the N-end or peptide fusions are preferred embodiments.Described fusions comprises and divides the joint area of opening with therapeutic protein or peptide and Tf, such as but not limited to one section poly--glycine sequence.Can increase secretion to the selection of the concern of the connection between the leader sequence, leader sequence and through codon operation/optimized mRNA structure (be not main stem ring to suppress the rrna development), use the recombinant protein technology of standard can easily finish these tasks.

Since there is disulfide linkage in terminal 6 amino acid of C-, therefore, the terminal as if more hidden and safety of the C-of Tf.In people Tf, the C-end amino acid is a proline(Pro), according to its directed mode, or fusions is pointed to the direction deviate from, or with fusions director molecules body inside.In some embodiments of the present invention, can be in terminal joint or the transcribed spacer moiety used of C-.

In other embodiments, can make small molecules therapeutical agent and iron compound, and load is used for therapeutical agent is passed to cell interior and passes through BBB on modified Tf protein fusions.Add the target peptide, or the cell type that for example SCA can be specific with the useful load target, as cancer cells.

Nucleic acid

The present invention also provides nucleic acid molecule.The modified Tf fusion rotein of they codings, described fusion rotein contain covalently bound with therapeutic protein or the transferrin that is connected or the part of transferrin.As hereinafter going through, can use any therapeutic protein.Fusion rotein can further contain connector area, for example is less than the joint of about 50,40,30,20 or 10 amino-acid residues.Joint can carry out covalently bound between transferrin or its part and therapeutic protein.Nucleic acid molecule of the present invention can be a purifying, also can be non-purifying.

The present invention also provides host cell and the carrier that is used for the replicating nucleic acid molecule and expresses the fusion rotein of coding.Can use any carrier or host cell, comprise protokaryon or eukaryotic cell, special preferred yeast expression system.Multiple carrier and the host cell that is used for this purpose known in the art.At required purposes, those skilled in the art can easily select appropriate host cell and carrier.

The dna sequence dna of coding transferrin, transferrin part and required therapeutic protein can be cloned from multiple genome known in the art or cDNA library.The technology that use separates described dna sequence dna based on the method for probe is a routine techniques, and is the well-known technology of those skilled in the art.The probe that separates described dna sequence dna can be based on disclosed DNA or protein sequence (referring to for example Baldwin, G.S. (1993) Comparison of Transferrin Sequences from DifferentSpecies.Comp.Biochem.Physiol.106B/1:203-218 and all reference of wherein mentioning, these documents are listed this paper in as a reference all in full).Perhaps, also can use by reference mix this paper, by Mullis etc., (United States Patent (USP) 4,683,195) and Mullis (United States Patent (USP) 4,683,202) disclosed polymerase chain reactions (PCR) method.The selection in library and the selection that separates the used probe of described dna sequence dna are that those of ordinary skills' level can be grasped.

Known in the art: as, can to measure " similarity " between two kinds of polynucleotide or the polypeptide by the Nucleotide of a kind of polynucleotide or polypeptide or aminoacid sequence and conservative Nucleotide thereof or the sequence of aminoacid replacement thing and another kind of polynucleotide or polypeptide are compared.This area is also known: " identity " refers to the sequence degree of correlation between two peptide species or the two kinds of polynucleotide sequences, and described degree of correlation is to measure by the identity of mating between the two row sequences.Identity and similarity all are (Computational Molecular Biology, Lesk, A.M., ed., Oxford UniversityPress, New York, 1988 of calculating easily; Biocomputing:Informatics and Genome Projects, Smith, D.W., ed., Academic Press, New York, 1993; Computer Analysis of SequenceData, Part I, Griffin, A.M., and Griffin, H.G., eds., Humana Press, New Jersey, 1994; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; With Sequence Analysis Primer, Gribskov, M.and Devereux, J., eds., MStockton Press, New York, 1991).

Although there is several different methods to can be used for measuring identity and similarity between two polynucleotide or the peptide sequence, but term " identity " and " similarity " are those skilled in the art well-known (Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; Sequence Analysis Primer, Gribskov, M.and Devereux, J., eds., M StocktonPress, New York, 1991; And Carillo, H., and Lipman, D., SIAM J.Applied Math., 48:1073 (1988)).Routine be used to measure two between the sequence identity or the method for similarity include but not limited to Guide to Huge Computers, Martin J.Bishop, ed., Academic Press, SanDiego, 1994, and Carillo, H., and Lipman, D., disclosed method among the SIAM J.Applied Math.48:1073 (1988).

The preferred method of measuring identity is designed to make the maximum coupling of appearance between two tested person sequences.Computer program is put out the method for mensuration identity and similarity in order.Measuring the identity between two sequences and the preferred computer adjective law of similarity includes but not limited to: GCG routine package (Devereux etc., Nucleic Acids Research 12 (1): 387 (1984)), BLASTP, BLASTN, FASTA (Atschul etc., J.Molec.Biol.215:403 (1990)).With the above similarity or the identity level determinations of indication is two identity degree between the sequence, and it can represent the difference of first sequence and second sequence.By computer program known in the art, the GAP (Needleman and Wunsch (1970) Journal of Molecular Biology48:443-453) as providing in the GCG routine package can measure two identity degree between the nucleotide sequence.In order to measure two identity degree between the nucleotide sequence in the present invention, using the GAP:GAP with following setting to produce point penalty is 5.0, and it is 0.3 that GAP extends point penalty.

The codon optimization

The degeneracy of genetic code makes and can the nucleotide sequence of transferrin and/or required therapeutic protein be made a variation, but still can produce aminoacid sequence and the identical polypeptide of the coded amino acid sequence of polypeptide of natural DNA sequence.The method (be described in United States Patent (USP) 5,547,871, it lists this paper in as a reference in full) that is known as " codon optimization " provides the method for the dna sequence dna of a kind of design through changing for people.The design of codon optimization gene should be considered a plurality of factors, and potential, synthesis path and this gene of frequency, rna stability, formation secondary structure that comprises codon usage frequency in the organism, neighbour is with the DNA operation of adopting.Particularly, when using yeast expression system, can use available method, change the codon of the given fusion rotein of coding with the easiest codon of being discerned by yeast.

The degeneracy permission of genetic code is with multiple diverse ways coding and translate identical aminoacid sequence.For example, each is encoded leucine, Serine and arginine by 6 different codons, and Xie Ansuan, proline(Pro), Threonine, L-Ala and glycine are respectively by 4 different codons codings.Yet in eukaryote and prokaryotic organism, the synonym between the different genes group is different.For example, mammiferous synonym-preference pattern is very similar, and evolution co-relation organism far away, the obvious different (Grantham of genome codon usage frequency pattern as yeast (yeast saccharomyces cerevisiae), bacterium (as intestinal bacteria) and insect (as D.melanogaster), R etc., Nucl.Acids Res., 8,49-62 (1980); Grantham, R etc., Nucl.Acids Res., 9,43-74 (1981); Maroyama, T etc., Nucl.Acids Res., 14,151-197 (1986); Aota, S etc., Nucl.Acids Res., 16,315-402 (1988); Wada, K etc., Nucl.Acids Res., 19 Supp., 1981-1985 (1991); Kurland, C.G., FEBS Letters, 285,165-169 (1991)).As if the difference of codon-preference pattern prolongs speed by regulating peptide, comes each expression of gene level exert an influence (Kurland, C.G., FEBSLetters, 285,165-169 (1991); Pedersen, S., EMBO J., 3,2895-2898 (1984); Sorensen, M.A., J.Mol.Biol., 207,365-377 (1989); Randall, L.L etc., Eur.J.Biochem., 107,375-379 (1980); Curran, J.F., and Yarus, M., J.Mol.Biol., 209,65-77 (1989); Varenne, S etc., J.Mol, Biol., 180,549-576 (1984), Varenne, S etc., J.Mol, Biol., 180,549-576 (1984); Garel, J.-R, J.Theor.Biol., 43,211-225 (1974); Ikemura, T., J.Mol.Biol., 146,1-21 (1981); Ikemura, T., J.Mol.Biol., 151,389-409 (1981)).

The preferred codon usage frequency of synthetic gene should reflect that the codon of nuclear gene uses, and described gene derives from former state (or closely-related as far as possible) genome of cell/organism (particularly yeast) of desiring to be used for recombinant protein expression.As mentioned above, in a preferred embodiment, the therapeutic protein nucleotide sequence is carried out the modification that is suitable for expressing as herein described in yeast before or after, the codon of people Tf sequence is carried out optimization.

Carrier

Being used for ceneme of the present invention generally contains with 5 ' to 3 ' direction and can operate continuous following element: transcripting promoter; Secretory signal sequence; The encode dna sequence dna of modified Tf fusion rotein, described fusion rotein contains transferrin or the transferrin part that is connected with the dna sequence dna of required therapeutic protein of coding or peptide; And transcription terminator.As mentioned above, with the Tf meromixis or be arranged in the therapeutic protein of Tf partial interior or any arranging of peptide all can be used for carrier of the present invention.Determine the selection of suitable promotor, signal sequence and terminator by selected host cell, this point is conspicuous to those skilled in the art, hereinafter will more specifically discuss.

Can be used for suitable yeast vector of the present invention and be described in United States Patent (USP) 6,291,212, it comprises YRp7 (Struhl etc., Proc.Natl.Acad.Sci.USA 76:1035-1039,1978), YEp13 (Broach etc., Gene 8:121-133,1979), pJDB249 and pJDB219 (Beggs, Nature275:104-108,1978), pPPC0005, pSeCHSA, pScNHSA, pC4 and derivative thereof.Useful yeast plasmid carrier also comprises can derive from Stratagene Cloning Systems, La Jolla, and CA 92037, the pRS403-406 of USA, pRS413-416 and pichia carrier.Plasmid pRS403, pRS404, pRS405 and pRS406 are yeast integrated plasmid (YIp), have wherein mixed yeast selective marker HIS3,7RPI, LEU2 and URA3.Plasmid pRS413～41.6th, yeast centromeric plasmid (Ycp).

Described carrier generally comprises selective marker, and described selective marker is one of gene of the multiple dominant phenotype of showing, for described phenotype, should have the phenotypic assay that can select transformant.Preferred selective marker is can compensate the host cell auxotrophy, antibiotics resistance is provided or makes cell can utilize the mark of specific carbon source, it comprises LEU2 (Broach etc., document is the same), URA3 (Botstein etc., Gene8:17,1979), HIS3 (Struhl etc., document is the same) or POT1 (Kawasaki and Bell, EP171,142).Other appropriate selection mark comprises the CAT gene that can give the yeast cell chlorampenicol resistant.Be used for promotor (Hitzeman etc., JBiol.Chem.225:12073-12080,1980 that the zymic preferred promoter comprises Yeast sugar glycolysis gene; Alber and Kawasaki, J.Mol.Appl.Genet.1:419-434,1982; Kawasaki, United States Patent (USP) 4,599,311) or the promotor (Young etc. of alcohol dehydrogenase gene, in Genetic Engineering of Microorganisms for Chemicals, Hollaender etc., (eds.), p.355, Plenum, N.Y, 1982; Ammerer, Meth.Enzymol.101:192-201,1983).In this regard, particularly preferred promotor is that TPI1 promotor (Kawasaki, United States Patent (USP) 4,599,311) and ADH2-4.sup.C[are referring to United States Patent (USP) 6,291,212] promotor (Russell etc., Nature 304:652-654,1983).Ceneme also can comprise transcription terminator.Preferred transcription terminator is TPI1 terminator (Alber and Kawasaki, document is the same).

Except yeast, can also be filamentous fungus, as expressing modified fusion rotein of the present invention in the aspergillus fungi bacterial strain.The example of useful promotor comprises the promotor that derives from Aspergillus nidulans glycolysis-gene, as ADH3 promotor (McKnight etc., EMBO J.4:2093-2099,1985) and tpiA promotor.Suitably the example of terminator is ADH3 terminator (McKnight etc., document is the same).The ceneme that utilizes said components can be cloned in the carrier, described carrier can insert for example aspergillar chromosomal DNA.

Being used to implement mammalian expression vector of the present invention comprises and can mediate the promotor that modified Tf fusion rotein is transcribed.Preferred promotor comprises viral promotors and cell promotor.Preferred viral promotors comprises the major late promoter (Kaufman and Sharp, Mol.Cell.Biol.2:1304-13199,1982) and the SV40 promotor (Subramani etc., Mol.Cell.Biol.1:854-864,1981) of adenovirus 2.Preferred cell promotor comprises that mouse metallothionein(MT) 1 promotor (Palmiter etc., Science222:809-814,1983) and mouse V.sub..kappa.[are referring to United States Patent (USP) 6,291,212] promotor (Grant etc., Nuc.Acids Res.15:5496,1987).Particularly preferred promotor is that mouse V.sub.H[is referring to United States Patent (USP) 6,291,212] promotor (Loh etc., document is the same).Described expression vector also can contain the RNA splice site that a cover is positioned at the dna sequence dna upstream of promotor downstream and coding transferrin fusion proteins.Preferred RNA splice site can derive from adenovirus and/or immunoglobulin gene.

Also can contain the polyadenylation signal that is positioned at required encoding sequence downstream in the expression vector.Polyadenylation signal comprise the early stage of SV40 or late period polyadenylation signal (Kaufman and Sharp, document is the same), the polyadenylation signal in adenovirus 5 E1B districts and human growth hormone gene terminator (DeNoto etc., Nuc.Acids Res.9:3719-3730,1981).Particularly preferred polyadenylation signal is that V.sub.H[is referring to United States Patent (USP) 6,291,212] gene terminator (Loh etc., document is the same).Expression vector can comprise the non-coding virus leader sequence between promotor and RNA splice site, as adenovirus 2 tripartite leader[s.Preferred carrier also can comprise enhancer sequence, as SV40 enhanser and mouse .mu.[referring to United States Patent (USP) 6,291,212] enhanser (Gillies, Cell 33:717-728,1983).Expression vector also can comprise the sequence of encoding adenovirus VA RNA.

Transform

The technology that transforms fungi is open in the literature, described technical description is in for example Beggs (document is the same), Hinnen etc., (Proc.Natl.Acad.Sci.USA 75:1929-1933,1978), Yelton etc., (Proc.Natl.Acad.Sci.USA 81:1740-1747,1984) and Russell (Nature 301:167-169,1983).The genotype of host cell generally contains genetic flaw, and this defective can be by the selective marker compensation that exists in the expression vector.The selection of specific host and selective marker will be apparent to those skilled in the art.

Transfection (Wigler etc., Cell 14:725,1978 by for example calcium phosphate mediation; Corsaro andPearson, Somatic Cell Genetics 7:603,1981; Graham and Van der Eb, Virology52:456,1973.), the cloned dna sequence that contains modified Tf fusion rotein of the present invention can be imported the mammalian cell of cultivating.Also can use other dna sequence dna to import the technology of mammalian cell, for example electroporation (Neumann etc., EMBO J.1:841-845,1982) or lipofection with the clone.In order to identify the cell of having integrated cloned DNA, generally with selective marker with required gene or cDNA transfered cell.The preferred selective marker that is used for the mammalian cell through cultivating comprises the gene of giving drug resistance, as Xin Meisu, Totomycin and methotrexate resistant gene.Selective marker can be the selective marker that can increase.The selective marker that preferably can increase is the DHFR gene.Particularly preferred amplifiable marker is that DHFR.sup.r[is referring to United States Patent (USP) 6,291,212] cDNA (Simonsen andLevinson, Proc.Natl.Adac.Sci.USA 80:2495-2499,1983).Thilly to selective marker carried out commenting (Mammalian Cell Technology, Butterworth Publishers, Stoneham, Mass.), the selection of selective marker is that those skilled in the art grasp easily.

Host cell

The present invention also comprises the cell that can express modified transferrin fusion proteins of the present invention through transforming, is preferably yeast cell.Except through transformed host cells itself, the present invention also comprises the culture of these cells in nutritional medium, is preferably the culture of mono-clonal (clone's homogeneous), or derived from the culture of mono-clonal culture.If polypeptide is secreted out, can contain polypeptide and cell in the substratum, perhaps after filtration or do not contain cell after centrifugal, only contain polypeptide.

Be used for implementing host cell of the present invention and comprise and can be transformed by foreign DNA or transfection, and the eukaryotic cell that can grow at substratum, also comprise prokaryotic cell prokaryocyte in some cases, for example, Mammals, insect, fungi, plant and bacterial cell through cultivating.

The fungal cell comprises that yeast class (for example sugar yeast, fragmentation sugar yeast, pichia) can be used as host cell of the present invention.Expection can be used as the host in practice of the present invention have with the yeast belong example of expressing transferrin fusion proteins of the present invention: pichia (being classified as Hansenula anomala in the past), sugar yeast, Crewe Vickers yeast, aspergillus, candiyeast, torulopsis, the spore torula is arranged, fragmentation sugar yeast, Citeromycesbaodingensis, Pachysolen engages sugar yeast, the De Balishi yeast, wood is mould, cephalo, humicola lanuginosa, Mucor, Neurospora, Yarrowia, the strange yeast of plum, red winter spore, Leucosporidium, Botryoascus, lock is thrown yeast, Endomycopyis etc.The example of sugar yeast has: yeast saccharomyces cerevisiae, Italian sugar yeast and Lu Shi sugar yeast.Crewe Vickers zymic example has: crisp wall Crewe Vickers yeast, newborn Crewe Vickers yeast and Marx's Crewe Vickers yeast.The suitable spore torula that has is that the Kai Shi of Dell has the spore torula.The example of pichia (Hansenula anomala) is P.angusta (being called as the multiform Hansenula anomala in the past), P.anomala (being called as unusual Hansenula anomala in the past) and Pichia pastoris.

For producing the useful especially host cell of Tf fusion rotein of the present invention is methyl alcohol nutritional type Pichia pastoris (Steinlein etc., (1995) Protein Express.Purif.6:619-624).The separated and clone because of its alcohol oxidase promotor, Pichia pastoris has been developed to a superior host who is used to produce exogenous protein; Reported first in 1985 conversion of Pichia pastoris.When lacking glucose, Pichia pastoris can utilize methyl alcohol as carbon source.The Pichia pastoris expression system can use methyl alcohol-inductive alcohol oxidase (AOX1) promotor, and this promotor can be controlled the gene that the coding alcohol oxidase is expressed, but the first step in the metabolism of described enzyme catalysis methanol.Identified this promotor, and it has been mixed in a series of Pichia pastoris expression vectors.Because the protein that produces in the Pichia pastoris generally can correctly fold justacrine to substratum, therefore, fermentation can provide fabulous escherichia expression system surrogate through genetic engineering modified Pichia pastoris.Use this system to prepare multiple proteins, comprise the tetanus toxin segment, bordetella pertussis pertactin, human serum albumin and N,O-Diacetylmuramidase.

For example, can be by Malardier etc., the described conversion of carrying out fusarium oxysporum (F.Oxysporum) of (1989) Gene 78:147-156.

Wine brewing yeast strain is another kind of preferred host.In preferred embodiments, used glycoprotein with l-asparagine-required gene of associated glycosylation in contain the yeast cell of genetic flaw, or more specifically be the Saccharomyces cerevisiae host cell.The sudden change of use standard and selection technology can prepare the Saccharomyces cerevisiae host cell with described defective, still, also have the yeast strain that much can obtain to be modified, can prevent or reduce glycosylation or high mannose baseization.Ballou etc., (J.Biol.Chem.255:5986-5991,1980) have described the separation of Mannoproteins biosynthesizing mutant, and the gene defectiveness of described mutant has influence on and l-asparagine-associated glycosylation.

For the production of optimization heterologous protein, also preferred host strain carries sudden change, and as yeast saccharomyces cerevisiae pep4 sudden change (Jones, Genetics 85:23-33,1977), described sudden change causes proteolytic activity to reduce.The host strain that contains sudden change in other protease-encoding district is particularly useful for mass production Tf fusion rotein of the present invention.

In suitable growth medium, cultivate the host cell that contains DNA construct of the present invention.Term used herein " suitable growth medium " refers to the substratum that contains cell growth desired nutritional material.Cell growth desired nutritional material can comprise carbon source, nitrogenous source, indispensable amino acid, VITAMIN, mineral substance and somatomedin.Growth medium generally selects to contain the cell of DNA construct by for example medicament selection or defective that must nutritive substance, described defective is compensated by the selective marker of cotransfection by being positioned on the DNA construct or with DNA construct.For example, preferred culturing yeast cell in the substratum that compound is determined, described substratum contains non--amino acid nitrogenous source, inorganic salt, VITAMIN and indispensable amino acid tonic.Preferably the pH of substratum is maintained pH greater than 2 less than 8, be preferably pH6.5.Keep the method for stablizing pH and comprise buffering and constant pH control, preferably by adding sodium hydroxide.Preferred reducing agents comprise succsinic acid and Bis-Tris (Sigma Chemical Co., St.Louis, Mo.).Preferably in containing the substratum of permeating stablizer, cultivate with l-asparagine-required gene of associated glycosylation in have defective yeast cell.Preferred permeating stablizer is with 0.1M to 1.5M, and the concentration that is preferably 0.5M or 1.0M is added into the sorbyl alcohol in the substratum.

Generally contain serum or do not contain the mammalian cell of cultivating in the substratum of serum through cultivating commercially available.Those skilled in the art select to be applicable to the substratum of used specific cells system easily.To cultivate for some time through mammalian cells transfected, be generally 1-2 days to begin to express required dna sequence dna.Use medicament selection to select the growth of expressing the cell of selective marker with stable form then.For the selective marker cells transfected that can be increased, can progressively increase drug level selecting the cloned sequence that copy number increases to some extent, thereby improve expression level.

Also can use baculovirus/insect cell expression system to produce modified Tf fusion rotein of the present invention.BacPAKTM baculovirus expression system (BD Biosciences (Clontech)) high level expression recombinant protein in insect host cell.Target gene is inserted transfer vector, described carrier with linearizing BacPAK6 viral DNA by cotransfection to insect host cell.The genomic essential part of BacPAK6 DNA disappearance baculovirus.When DNA and carrier reorganization, can recover essential element, target gene is transferred to the baculovirus genome.After the reorganization, select several viral plaques and purifying it, confirm the reorganization phenotype.The new isolating recombinant virus that increases then, and be used for the infected insect cell culture to produce a large amount of desired proteins.

Secretory signal sequence

Term " secretory signal sequence " or " signal sequence " or " secretion leader sequence " can exchange use, and it is described in for example United States Patent (USP) 6,291,212 and United States Patent (USP) 5,547,871 (listing this paper in as a reference all in full).Secretory signal sequence or signal sequence or secretion leader sequence coding secretion peptide.The secretion peptide is can mediate mature polypeptide or protein to secrete the aminoacid sequence that comes out from cell.In general, the secretion peptide is characterised in that the hydrophobic amino acid core, and its general (also not getting rid of other situation) comes across the N-terminal of new synthetic protein.The secretion peptide in the secretion process of being everlasting from the sophisticated protein cracking get off.The secretion peptide can contain when its through the secretion by way of the time, can be from the processing site of cracking signal peptide on the mature protein.Codified processing site perhaps can will process the site by for example vitro mutagenesis and be added in the signal peptide in the signal peptide.

Can use the secretion of the peptide-mediated modified Tf fusion rotein of the present invention of secretion.A kind ofly can secrete peptide with other to unite the secretion peptide of use be proteic the 3rd structural domain of yeast barrier.Secretory signal sequence or signal sequence or secretion leader sequence are a series of complexity, cause the translation post-treatment step of protein secreting necessary.If there is complete signal sequence, entered the inner chamber of ergastoplasm by expressed protein, be transported to secretion vector by golgi body then, finally be transported to the extracellular.In general, signal sequence is right after after initiator codon, and is treating the N-terminal coded signal peptide of secretory protein.In most of the cases, by specific proteolytic enzyme, i.e. signal peptidase cracking signal sequence.The preferred signals sequence can be improved the processing and the output efficiency of the recombinant protein expression that uses virus, Mammals or Yeast expression carrier.In some cases, can use natural Tf signal sequence to express and secrete fusion rotein of the present invention.

Joint

The Tf moiety and the therapeutic protein moiety of modified transferrin fusion proteins of the present invention can directly merge, perhaps use the joint peptide of multiple length that both are merged, so that bigger physical separation to be provided, make the space flexibility between the fused protein bigger, thereby the easily close property of maximization therapeutic protein part, for example, be used for related receptors bind with it.The joint peptide can by flexible or more inflexible amino acid form.For example, joint can be such as but not limited to one section poly--glycine sequence.Joint can be less than about 50,40,30,20 or 10 amino-acid residues.Joint can be covalently bound with them between transferrin or its part and therapeutic protein.

Detect the Tf fusion rotein

The test of detection has bioactive, modified transferrin-therapeutic protein fusion rotein comprises: Western transfer, western blotting or bacterium colony filter membrane and detecting merge therapeutic protein based on active test.Use Towbin etc., (Proc.Natl.Acad.Sci.USA 76:4350-4354,1979) described method can prepare Western and shift filter membrane.Briefly, electrophoresis sample in the sodium dodecyl sulfate polyacrylamide gel.Protein electrophorese in the gel is transferred to nitrocellulose filter.By using for example Minifold (Schleicher﹠amp; Schuell, Keene, N.H.) nitrocellulose filter filtering supernatant sample or enriched material can prepare the western blotting filter membrane.By on the nitrocellulose filter of having smeared suitable growth medium, cultivating bacterium colony, can prepare the bacterium colony filter membrane.In this method, preferred solid medium.Cell was cultivated 12 hours on filter membrane at least.By removing cell with suitable damping fluid flushing from filter membrane, described damping fluid can not removed and filter membrane bonded protein.Preferred damping fluid contains 25mM Tris-base, 19mM glycine, pH 8.3,20% methyl alcohol.

Also can detect fusion rotein of the present invention by the activity of analyzing the therapeutic protein moiety.Described test is to implement easily, includes but not limited to the described test of table 1.Specifically, can use the test of mentioning in table 1 " activity test that the exemplifies " hurdle, analyze the functionally active (biological example activity or therapeutic activity) of transferrin fusion proteins of the present invention.In addition, the test that those skilled in the art mention in can use table 1 corresponding line, conventional sense is corresponding to the pulsating activity of therapeutic protein of the therapeutic protein part of fusion rotein of the present invention.In addition, those skilled in the art can use testing routine known in the art to detect the pulsating activity of modified transferrin.

For example, compete in the embodiment of the ability that combines anti--therapeutical peptide antibody and/or anti--transferrin antibody a detection transferrin fusion proteins combination of the present invention or with therapeutic protein, can use panimmunity assay method known in the art, include but not limited to competitive and non--competitive assay system, described system has used following technology: radioimmunoassay, ELISA (enzyme linked immunosorbent assay), the sandwich immunoassay method, immunoradiometric assay(IRMA), gel diffusion precipitation reaction, immunodiffusion(ID) is analyzed, the original position immunoassay (is used for example Radioactive colloidal gold, enzyme or labelled with radioisotope), the western trace, precipitin reaction, agglutination test (as gel agglutination assay), the complement fixation(CF) test, immunofluorescent test, test of A albumen and immunoelectrophoretic test etc.In one embodiment, detect antibodies by the mark that detects on the first antibody.In another embodiment, detect first antibody by detecting second antibody or reagent with combining of first antibody.In another embodiment, second antibody is carried out mark.It is known in the art detecting the bonded several different methods in immunoassay, and they also fall within the scope of the present invention.

In another embodiment, when identify therapeutic protein in conjunction with counterpart (as acceptor or part) time, can detect by method well-known in the art and to contain the transferrin fusion proteins and the described combination that combine counterpart of this therapeutic protein as the therapeutic protein of fusion rotein part, described method is as reducing and non--reductive gel chromatography, protein-affinity chromatography and affine trace.Other method is also known to those skilled in the art, and falls within the scope of the present invention.

The transferrin fusion proteins that separation/purification is modified

Cultivate host cell allowing under the bioactive fusion rotein excretory condition, from its substratum, separate by excretory, bioactive modified transferrin fusion proteins is arranged.From substratum, remove cell material, use isolation technique known in the art to isolate bioactive fusion rotein.Suitable isolation technique comprises precipitation and the fractional separation by multiple chromatography, and described chromatography comprises gel-filtration, ion exchange chromatography and affinity chromatography.

Particularly preferred purification process is the affinity chromatography that carries out on iron combination or metal-chelate zygostyle, or uses the immunoaffinity chromatography of antibody, the peptide moiety of anti-transferrin of described antibody or therapeutic protein or polypeptide fusions.Preferably make antibody fix or be incorporated into solid support or substrate.Particularly preferred substrate be CNBr-activatory Sepharose (Pharmacia LKB Technologies, Inc., Piscataway, N.J.).By this method, take place under the bonded condition substratum to be mixed with antibody/substrate in permission.The flushing mixture is unfavorable for that by use the condition that mixture forms discharges or the wash-out transferrin fusion proteins to remove unconjugated material.Useful especially elution process comprises: change pH, wherein immobilized antibody has high-affinity to part under first pH, and affinity reduces under second (higher or lower) pH; Change the concentration of certain chaotropic agent; Or use stain remover.

The modified transferrin fusion proteins that is labeled

Also can be with radio isotope or other developer mark transferrin fusion proteins of the present invention, and use it for the in-vivo diagnostic purpose.Preferred radio isotope developer comprises iodine-125 with Technetium-99, and the other You of Te selects De Shi Technetium-99.The method that produces protein-isotropic substance conjugate is well-known in the art, and it for example is described in Eckelman etc., (United States Patent (USP) 4,652,440), and Parker etc., (WO87/05030) and Wilber etc., (EP 203,764).Perhaps, transferrin fusion proteins can combine with the spin labeling toughener, and is used for mr (MR) imaging.That suitable spin labeling toughener comprises is stable, the sterically hindered that has living space, free radical compounds, as nitroxide.Tagged ligand is described in for example Coffman etc., (United States Patent (USP) 4,656,026) to carry out the MR imaging method.In order to carry out administration, transferrin fusion proteins and drug acceptable carrier or the thinner through mark can be mixed as Sterile Saline or sterilized water.Preferably, be preferably intravenous injection and carry out administration by contrast-medium injection.

The preparation fusion rotein

The present invention also provides the method for using nucleic acid molecule as herein described to prepare modified fusion rotein of the present invention.In general, the protein of preparation recombinant forms generally comprises following step.

At first need obtain the nucleic acid molecule of code book invention transferrin fusion proteins.Described nucleic acid molecule can be operated with suitable control sequence mentioned above link to each other, contain the ceneme of protein open reading frame with formation.Use described ceneme to transform suitable host, and under the condition that allows the generation recombinant protein, cultivate through host transformed.Choose separating recombinant proteins matter from substratum or cell wantonly; Under the situation that allows some impurity existence, recovery of protein and purifying are optional.

Can finish each step in the above-mentioned steps with several different methods.For example, use aforesaid suitable replicon and control sequence to finish the structure of the expression vector that can in multiple host, use.Control sequence, expression vector and method for transformation depend on the type of the used host cell of expressing gene, and this point went through hereinbefore, or known to those skilled in the art.Can add suitable restriction site (if this site generally is not ready-made) at the end of encoding sequence, insert in these carriers so that the gene that can downcut to be provided.Those skilled in the art can easily change any host/expression system known in the art, to unite use with nucleic acid molecule of the present invention, produce required recombinant protein.

As mentioned above, any expression system be can use, yeast, bacterium, animal, plant, eucaryon and prokaryotic system comprised.In some embodiments, preferred yeast, mammalian cell cultures and transgenic animal or plant production system.In other embodiments, can use the modified Yeast system that reduces unartificial yeast glycosylation, height-glycosylation or proteolytic activity.

Therapeutic molecules

In method and composition of the present invention, any therapeutic molecules all can be used as the fusion counterpart of Tf.Therapeutic molecules used herein is generally protein or the peptide that can bring into play favourable biological action in external or body, comprises protein or the peptide that can bring into play the advantageous effect relevant with normal stable state, physiology or morbid state.Therapeutic molecules does not comprise the fusion counterpart that is commonly used for mark or protein purification subsidiary, for example tilactase (referring to for example United States Patent (USP) 5,986,067 and Aldred etc., (1984) Biochem.Biophys.Res.Commun.122:960-965).For example, the advantageous effect relevant with morbid state comprises favourable any effect to the treatment experimenter, comprises disease prevention, stable diseaseization, alleviates or relaxes disease symptoms or adjusting, mitigation or cure latent defect to produce the favourable effect of experimenter to being treated.

Modified transferrin fusion proteins of the present invention comprises the segment of therapeutic protein or the segment or the variant of variant and modified serum transferrin at least, preferably by gene fusion or chemical coupling both is connected with each other.

In one embodiment, transferrin fusion proteins comprises the modified transferrin molecule that links to each other with neuropharmaceutical agent.In another embodiment, modified transferrin fusion proteins comprises the transferrin that C-terminal links to each other with the N-terminal of neuropharmaceutical agent.In alternative embodiment, modified transferrin fusion proteins comprises the transferrin that N-terminal links to each other with the C-terminal of neuropharmaceutical agent.In specific embodiments, neuropharmaceutical agent is nerve growth factor or ciliary neurotrophic factor.

In another embodiment, modified transferrin fusion proteins of the present invention contains the segment or the variant of therapeutic protein at least, and/or antibody fragment or variant.In other embodiments, transferrin fusion proteins can contain the peptide segment or the peptide variant of protein or antibody, and wherein variant or segment have kept at least a biology or therapeutic activity.Transferrin fusion proteins can contain length and be at least about 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 25, at least 30, at least 35, or at least about 40, at least about 50, at least about 55, at least about 60 or at least about 70 or more a plurality of amino acid whose, merge, insert wherein with the N of modified transferrin and/or C-terminal or insert peptide segment in its ring or peptide variant as therapeutic protein.

In another embodiment, it can be the pulsating therapeutic protein part of therapeutic protein that modified transferrin fusion molecule contains, and it comprises full length protein and the polypeptide that has lacked one or more residues from the N-terminal of aminoacid sequence.

In another embodiment, it can be the pulsating therapeutic protein part of therapeutic protein that modified transferrin fusion molecule contains, it comprise full length protein and from the carboxyl-terminal deletion of aminoacid sequence the polypeptide of one or more residues.

In another embodiment, modified transferrin fusion molecule contains can the therapeutic protein part, described part from amino and carboxyl-terminal deletion one or more amino acid.

In another embodiment, modified transferrin fusion molecule contains the therapeutic protein part, described part with as herein described with reference to therapeutic protein or its segment at least about 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% is identical.In another embodiment, the transferrin fusion molecule contains the therapeutic protein part, described part and aminoacid sequence N-mentioned above and C-end have disappearance with reference to polypeptide at least about 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% is identical.

In another embodiment, modified transferrin fusion molecule contains the therapeutic protein part, and described part and the natural of for example therapeutic protein or wild-type amino acid sequence are at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% is identical.

By closing, can modify therapeutic protein, as cell surface and secretory protein corresponding to the therapeutic protein part of modified transferrin fusion proteins of the present invention with one or more oligosaccharyl unitys.But being called as the proteinic physical property of glycosylated modification remarkably influenced, also is vital for proteinic stability, secretion and location.Glycosylation takes place at the specific position along the polypeptide main chain.Two kinds of main glycosylation forms are arranged usually: be characterised in that the glycosylation of O-connection oligosaccharides, described oligosaccharides combines with Serine or threonine residues; And the glycosylation that is characterised in that N-connection oligosaccharides, described oligosaccharides combines with asparagine residue in the Asn-X-Ser/Thr sequence, and wherein X can be the amino acid except that proline(Pro).The number and the characteristic of the carbohydrate unit in different glycosylation site in the variable effect chain of protein structure and cell type.In given cell type, the same loci place also can usually see the glycosylation isomer.For example, the human interferon of several types is by glycosylation.

Can modify therapeutic protein and analogue and variant corresponding to the therapeutic protein part of transferrin fusion proteins of the present invention, make as the result who handles its nucleotide sequence by the host cell of expressing them, or cause the glycosylation of one or more site to change to some extent because of its other expression condition.For example, by abolishing or import glycosylation site, replace or the disappearance amino-acid residue as passing through, can produce the glycosylation isomer as replacing l-asparagine with glutamine, perhaps, can as marking protein in the defective yeast of glycosylation, can produce nonglycosylated recombinant protein by not making its glycosylated host cell.These methods are known in the art.

Therapeutic protein and nucleotide sequence thereof are well-known in the art, can derive from public database, as Chemical Abstracts Services Databases (as CAS Registry), GenBank and GenSeq.Accession number of hereinafter mentioning and sequence are all listed this paper in as a reference in full.

In other embodiments, transferrin fusion proteins of the present invention has therapeutic activity and/or bioactive therapeutic activity and/or the biological activity (referring to " biological activity " and " therapeutic protein X " hurdle of for example table 1) corresponding to the corresponding hurdle of table 1 and other local described therapeutic protein of the application.In other embodiments, the therapeutic activity protein portion of transferrin fusion proteins of the present invention is the segment or the variant of canonical sequence described herein.

The invention still further relates to and contain the pulsating modified Tf fusion rotein of therapeutic protein as herein described.Even can cause from the one or more amino acid of proteinic N-terminal deletion therapeutic protein part one or more biological functions modification or lose, but still can keep other therapeutic activity and/or functionally active (as the ability of biological activity, multimerization, the ability of binding partner).For example, remove the small part residue of complete polypeptide from the N-end after, the N-end has the polypeptid induction of disappearance and/or bound energy identification is complete or mature form more than the ability of antibody of peptide generally still can remain.By ordinary method described herein and known in the art, whether the specific polypeptide that can measure the N-terminal residue that lacks complete polypeptide still can keep described immunologic competence.The N-terminal deletion mutant of a large amount of amino-acid residues also might keep some biology or immunologic competence.In fact, often can cause immunne response by few peptide of forming to 6 amino-acid residues.

As mentioned above, even can cause the modification of one or more biological functions of protein or lose from the N-end of therapeutic protein or the one or more amino acid of C-terminal deletion, but still can keep other functionally active (as the ability of biological activity, multimerization, the ability of binding partner) and/or therapeutic activity.For example, remove the small part residue of complete or mature polypeptide from the C-end after, the C-end has the polypeptid induction of disappearance and/or bound energy identification is complete or mature form more than the ability of antibody of peptide generally still can remain.By ordinary method described herein and/or known in the art, can easily measure shortage and whether still can keep therapeutic activity with reference to the N-end of polypeptide and/or the specific polypeptide of C-terminal residue.

The peptide segment of therapeutic protein can be a segment, and described segment contains that can demonstrate derives and obtain the therapeutic activity of peptide sequence more than this pulsating therapeutic protein and/or the aminoacid sequence of functionally active (as biological activity), or is made up of described sequence.

Other polypeptide fragments is the biological activity segment.The biological activity segment is to show with the active similar of the used therapeutic protein of the present invention but active segment that needn't be identical.Pulsating biological activity can comprise the desirable activity of improvement or the unnecessary activity of reduction.

In general, proteinic variant is very similar on the whole, and is all identical with aminoacid sequence corresponding to the therapeutic protein of the therapeutic protein part of transferrin fusion proteins of the present invention in a lot of zones.The present invention also comprises the nucleic acid of these variants of encoding.

Operable other therapeutical peptide of the present invention be by under tight hybridization conditions well known by persons skilled in the art can with the polypeptide of the polynucleotide encoding of the complementary sequence hybridization of the nucleic acid molecule of coding therapeutic protein aminoacid sequence.(referring to for example Ausubel, F.M. etc., eds., 1989 Currentprotocol in Molecular Biology, Green Publishing Associates, Inc., and JohnWiley﹠amp; Sons Inc., New.York).The present invention also comprises the polynucleotide of these polypeptide of encoding.

Have with problem aminoacid sequence of the present invention at least for example the polypeptide of 95% " identical " aminoacid sequence refer to: can comprise in per 100 amino acid of problem aminoacid sequence nearly that except being tried peptide sequence it is identical with sequence of question to be tried amino acid sequence of polypeptide 5 amino acid changes.In other words, in order to obtain to have the polypeptide of the aminoacid sequence identical with problem aminoacid sequence at least 95%, being tried in the sequence nearly, 5% amino-acid residue can be inserted into, lacks or use another kind of aminoacid replacement.These changes of canonical sequence can occur in reference to the amino of aminoacid sequence or C-terminal position, or occur in any position between the described terminal position, or in the single residue that intersperses among canonical sequence, or intersperse among in one or more adjacent groups in the canonical sequence.

In practice, use known computer program can any specific polypeptide of conventional determining whether with for example, the aminoacid sequence of transferrin fusion proteins of the present invention or its segment (for example transferrin part of the therapeutic protein of transferrin fusion proteins part or transferrin fusion proteins) is at least about 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% is identical.Use is based on Brufiag-etc., the FASTDB computer program of the algorithm of (Comp.App.Biosci 245-(1990)), can determine to measure sequence of question (sequence of the present invention) and be tried the preferred method that the best between the sequence is mated comprehensively, described method is also referred to as the sufficient sequence comparison.

Polynucleotide variant of the present invention can be in the coding region, non-coding region or this two place contain and change.Can use to contain the polynucleotide variant that changes and prepare modified Tf fusion rotein, described change can produce reticent replacement, interpolation or disappearance, but can not change the characteristic or the activity of coded polypeptide.Can utilize because of the silence due to the genetic code degeneracy and replace the nucleotide variants that produces.In addition, can utilize to replace, lack or added to be less than approximately 50, be less than 40, be less than 30, be less than 20, be less than 10 with arbitrary combination, or 5-50,5-25,5-10,1-5 or 1-2 amino acid whose polypeptide variants.The reason that produces the polynucleotide variant can have a plurality of, for example at the expression (codon of people mRNA being changed into by above-mentioned host, as yeast or the preferred codon of intestinal bacteria) of specific host optimization codon.

In other embodiments, compare with wild-type sequence, the therapeutic protein moiety has conservative the replacement." the conservative replacement " desire refers to organize interior exchange, as aliphatics or hydrophobic amino acid Ala, Val, the replacement of Leu and Ile; The replacement of hydroxyl residue Ser and Thr; The replacement of acidic residues Asp and Glu; The replacement of amide residues Asn and Gln; The replacement of alkaline residue Lys, Arg and His; The replacement of aromatic residue Phe, Tyr and Trp; Replacement with p1 amino acid Ala, Ser, Thr, Met and Gly.For example, Bowie etc. exist, and " Deciphering the Message in Protein Sequences:Tolerance to Amino AcidSubstitutions " provides the relevant guidance of the aminoacid replacement of phenotype silence of how carrying out among the Science 247:1306-1310 (1990).In specific embodiments, polypeptide of the present invention contains therapeutic protein described herein and/or transferrin, and/or the fragment of the aminoacid sequence of modified transferrin of the present invention or variant, or form by described fragment or variant, wherein when comparing with the reference aminoacid sequence, described fragment or variant have 1-5,5-10,5-25,5-50, interpolation, replacement and/or the disappearance of a 10-50 or 50-150 amino-acid residue.In other embodiments, aminoacid replacement is guarded.The present invention also comprises the nucleic acid of these polypeptide of encoding.

Modified fusion rotein of the present invention is by forming by peptide bond or modified peptide bond amino acid connected to one another, and it can contain the amino acid except that 20 gene-coded amino acids.Can pass through any natural method, for example translate post-treatment, or come modified polypeptide by chemical modification technology well-known in the art.Describe described modification in detail in basic material and more detailed monograph and the multireel research document.

Modification can occur in any position of polypeptide, comprises peptide main chain, amino acid side chain and amino or C-terminal.Should understand several site, have the modification of the same type of identical or different degree at given polypeptide.Given polypeptide also can contain a variety of modifications.Polypeptide also can branch occur because of for example ubiquitination, and they also can be branch or unbranched ring molecule.Annular, branch and branch's annular polypeptide can be obtained by the natural process process after the translation, also can be prepared by synthetic method.Modification comprises ethanoylization, acidylate, the ADP-ribosylation, amidation, with the flavine covalent attachment, with protoheme moiety covalent attachment, with Nucleotide or nucleotide derivative covalent attachment, with lipid or lipid derivate covalent attachment, with the phosphotidylinositol covalent attachment, crosslinked, cyclisation, disulfide linkage forms, demethylation, form covalent cross-linking, form halfcystine, glycosylation, the GPI anchor forms, hydroxylation, iodate, methylate, myristylation, oxidation, prenylation, proteolysis processing, phosphorylation, isoprenylation, racemization, sulphating, the aminoacid addition that mediates by transhipment-RNA in the protein, as arginylization and ubiquitination (referring to for example PROTEINS-STRUCTURE ANDMOLECULAR PROPERTIES, 2nd Ed., T.E.Creighton, W.H.Freeman and Company, New York (1993); POST-TRANSLATIONAL COVALENT MODIFICATION OFPROTEINS, B.C.Johnson, Ed., Academic Press, New ' York, pgs.1-12 (1983); Seifter etc. (1990) Meth.Enzymol.182:626-646; Rattan etc., Ann.N.Y.Acad.Sci.663:48-62.

The therapeutic molecules that can merge with Tf or insert among the Tf includes but not limited to: hormone, stroma protein, immunosuppressor, bronchodilator, cardiovascalar agent, enzyme, the CNS medicament, neurotransmitter, receptor protein or peptide, tethelin, somatomedin, antiviral peptide, fusion inhibitor peptides, cytokine, lymphokine, monokine, interleukin-, G CFS, differentiation factor, angiogenesis factor, receptors ligand, cancer-associated protein, antineoplastic agent, viral peptide, antibacterial peptide, hematoglobin protein, antagonist protein, transcription factor, anti--angiogenesis factor, antagonist protein or peptide, receptor antagonist, antibody, single-chain antibody and cell adhesion molecule.Different therapeutic molecules can mix with single fusion rotein to produce two or multi-functional therapeutic molecules.Also can unite and use different molecules to have the fusion rotein of treatment entity and target entity with generation.

Cytokine is the soluble protein that is discharged by immune cell, and it brings into play non-enzymolysis to regulate immunne response by specific acceptor.The similarity of cytokine and hormone is: they can work under lower concentration, combine with special receptor with high-affinity.Term " cytokine " used herein " be used for describing the protein that can cause the natural or reorganization of specific biological reaction at the cell of acceptor with this cytokine, and analogue and fragment.Cytokine preferably includes interleukin-, as interleukin II (IL-2) (GenBank accession number S77834), IL-3 (GenBank accession number M14743), IL-4 (GenBank accession number M23442), IL-5 (GenBank accession number J03478), IL-6 (GenBank accession number M14584), IL-7 (GenBank accession number NM_000880), IL-10 (GenBank accession number NM_000572), IL-12 (GenBank accession number AF180562 and GenBank accession number AF180563), IL-13 (GenBank accession number U10307), IL-14 (GenBank accession number XM_170924), IL-15 (GenBank accession number X91233), IL-16 (GenBank accession number NM_004513), IL-17 (GenBank accession number NM_002190) and IL-18 (GenBank accession number NM_001562), Hemopoietic factor, as granulocyte-macrophage colony stimutaing factor (GM-CSF) (GenBank accession number X03021), granulocyte colony-stimulating factor (G-CSF) (GenBank accession number X03656), platelet activation factor (GenBank accession number NM_000437) and erythropoietin (GenBank accession number X02158), tumour necrosis factor (TNF) is as TNF α (GenBank accession number X02910), lymphokine, as lymphotoxin-α (GenBank accession number X02911), lymphotoxin-β (GenBank accession number L11016), leucoregulin, macrophage migration inhibitory factor (GenBank accession number M25639), and neuroleukin (GenBank accession number K03515), the metabolic process conditioning agent, as leptin (GenBank accession number U43415), Interferon, rabbit, as interferon alpha (IFN α) (GenBank accession number M54886), IFN β (GenBank accession number V00534), IFN γ (GenBank accession number J00219), IFNo (GenBank accession number NM_002177), thrombospondin 1 (THBS1) (GenBank accession number NM_003246), THBS2 (GenBank accession number L12350), THBS3 (GenBank accession number L38969), THBS4 (GenBank accession number NM_003248) and chemokine.Preferred modified transferrin-cell factor fusion protein of the present invention demonstrates the cytokine biological activity.

Term used herein " hormone " is used for describing any of multiple biologically active substance, and described material is produced by certain cell or tissue, and the another kind of cell or tissue that can cause being positioned at the health other places produces, and specific biological changes or activity.Preferred hormone comprises proinsulin (GenBank accession number V00565), Regular Insulin (GenBank accession number NM_000207), growth hormone 1 (GenBank accession number V00520), tethelin 2 (GenBank accession number F006060), somatotropin releasing factor (GenBank accession number NM_021081), Regular Insulin-like growth factor I (GenBank accession number M27544), Regular Insulin-like growth factor II (GenBank accession number NM_000612), conjugated protein 1 (IGFBP-1) of Regular Insulin-like growth factor (GenBank accession number M59316), IGFBP-2 (GenBank accession number X16302), IGFBP-3 (GenBank accession number NM_000598), IGFBP-4 (GenBank accession number Y12508), IGFBP-5 (GenBank accession number M65062), IGFBP-6 (GenBank accession number NM_002178), IGFBP-7 (GenBank accession number NM_001553), chorionic gona dotropin β chain (GenBank accession number NM_033142), chorionic gona dotropin α chain (GenBank accession number NM_000735), lutropin β (GenBank accession number X00264), prolan a β (GenBank accession number NM_000510), thyrotropin β (GenBank accession number NM_000549), prolactin antagonist (GenBank accession number NM_000948), proopiomelanocortin (GenBank accession number V01510), corticotropin (ACTH), β-lipotropin, α-melanotropin (α-MSH), γ-lipotropin, β-MSH, beta-endorphin and corticotropin-like intermediate peptide (CLIP).

Term used herein " somatomedin " is used to describe any and receptors bind to promote the protein or the peptide of cell proliferation.Somatomedin preferably includes thrombocyte-derivative growth factor-α (PDGF-α) (GenBank accession number X03795), PDGF-β (GenBank accession number X02811), steroid hormone, Urogastron (EGF) (GenBank accession number NM_001963), fibroblast growth factor, as desmocyte growth factor-21 (FGF1) (GenBank accession number NM_000800), FGF2 (GenBank accession number NM_002006), FGF3 (GenBank accession number NM_005247), FGF4 (GenBank accession number NM_002007), FGF5 (GenBank accession number M37825), FGF6 (GenBank accession number X57075), FGF7 (GenBank accession number NM_002009), FGF8 (GenBank accession number AH006649), FGF9 (GenBank accession number NM_002010), FGF10 (GenBank accession number AB002097), FGF11 (GenBank accession number NM_004112), FGF12 (GenBank accession number NM_021032), FGF13 (GenBank accession number NM_004114), FGF14 (GenBank accession number NM_004115), FGF16 (GenBank accession number AB009391), FGF17 (GenBank accession number NM_003867), FGF18 (GenBank accession number AF075292), FGF19 (GenBank accession number NM_005117), FGF20 (GenBank accession number NM_019851), FGF21 (GenBank accession number NM_019113), FGF22 (GenBank accession number NM_020637) and FGF23 (GenBank accession number NM_020638), angiogenin (GenBank accession number M11567), brain-deutero-neurotrophic factor (GenBank accession number M61176), ciliary nerve nutrition somatomedin (GenBank accession number X60542), transforminggrowthfactor-(TGF-α) (GenBank accession number X70340), TGF-β (GenBank accession number X02812), nerve growth factor-α (NGF-α) (GenBank accession number NM_010915), NGF-β (GenBank accession number X52599), tissue inhibitor of metalloproteinase 1 (TIMP1) (GenBank accession number NM_003254), TIMP2 (GenBank accession number NM_003255), TIMP3 (GenBank accession number U02571), TIMP4 (GenBank accession number U76456) and macrophage stimulation factor 1 (GenBank accession number L11924).

Term used herein " stroma protein " is used for describing protein or the peptide that is present in extracellular matrix usually.These protein are most important for intensity, filtration or adhesion function.Stroma protein preferably includes collagen, as collagen I (GenBank accession number Z74615), collagen I I (GenBank accession number X16711), collagen I II (GenBank accession number X14420), collagen iv (GenBank accession number NM_001845), collagen V (GenBank accession number NM_000393), collagen VI (GenBank accession number NM_058175), collagen VII (GenBank accession number L02870), collagen VIII (GenBank accession number NM_001850), collagen I X (GenBank accession number X54412), collagen X (GenBank accession number X60382), collagen XI (GenBank accession number J04177) and collagen XII (GenBank accession number U73778), ln, as LAMA2 (GenBank accession number NM_000426), LAMA3 (GenBank accession number L34155), LAMA4 (GenBank accession number NM_002290), LAMB1 (GenBank accession number NM_002291), LAMB3 (GenBank accession number L25541), LAMC1 (GenBank accession number NM_002293), nidogen (GenBank accession number NM_002508), α-tectorin (GenBank accession number NM_005422), β-tectorin (GenBank accession number NM_058222) and fibronectin (GenBank accession number X02761).

The traditional definition of term " hematoglobin protein " is the protein that derives from blood plasma, but often produce hematoglobin protein at present by recombination method, it includes but not limited to natural sera protein, its derivative, segment and mutant or variant, thrombin, its derivative, mutant, variant and segment (comprise factor VII, VIII, IX, X), proteinase inhibitor (antithrombin 3, α-1 antitrypsin), urokinase-type plasminogen activator, immunoglobulin (Ig), the von Willebrand factor and von Willebrand mutant, fibronectin, fibrinogen, zymoplasm and oxyphorase.

Term used herein " enzyme " is used to describe any energy catalysis specific reaction, and self is changed never or destructive protein or protein substance.Enzyme preferably includes coagulation factor, as F2 (GenBank accession number XM_170688), F7 (GenBank accession number XM_027508), F8 (GenBank accession number XM_013124), F9 (GenBank accession number NM_000133), F10 (GenBank accession number AF503510) etc., matrix metalloproteinase, as matrix metalloproteinase I (GenBank accession number MMP1) (GenBank accession number NM_002421), MMP2 (GenBank accession number NM_004530), MMP3 (GenBank accession number NM_002422), MMP7 (GenBank accession number NM_002423), MMP8 (GenBank accession number NM_002424), MMP9 (GenBank accession number NM_004994), MMP10 (GenBank accession number NM_002425), MMP12 (GenBank accession number NM_002426), MMP13 (GenBank accession number X75308), MMP20 (GenBank accession number NM_004771), adenosine deaminase (GenBank accession number NM_000022), mitogen-activated protein kinase, as MAPK3 (GenBank accession number XM_055766), MAP2K2 (GenBank accession number NM_030662), MAP2K1 (GenBank accession number NM_002755), MAP2K4 (GenBank accession number NM_003010), MAP2K7 (AF013588) and MAPK12 (NM_002969), kinases, as JNKK1 (GenBank accession number U17743), JNKK2 (GenBank accession number AF014401), JAK1 (M64174), JAK2 (NM_004972) and JAK3 (NM_000215) and Phosphoric acid esterase PPM1A (GenBank accession number NM_021003) and PPM1D (GenBank accession number NM_003620).

Term used herein " transcription factor " is used to describe the protein of transcribing or the peptide of any participation protein coding gene.Transcription factor comprises Sp1, Sp2 (GenBank accession number NM_003110), Sp3 (GenBank accession number AY070137), Sp4 (GenBank accession number NM_003112), NFYB (GenBank accession number NM_006166), Hap2 (GenBank accession number M59079), GATA-1 (GenBank accession number NM_002049), GATA-2 (GenBank accession number NM_002050), GATA-3 (GenBank accession number X55122), GATA-4 (GenBank accession number L34357), GATA-5, GATA-6 (GenBank accession number NM_005257), FOG2 (NM_012082), Eryf1 (GenBank accession number X17254), TRPS1 (GenBank accession number NM_014112), NF-E2 (GenBank accession number NM_006163), NF-E3, NF-E4, TFCP2 (GenBank accession number NM_005653), Oct-1 (GenBank accession number X13403), homology frame albumen, as HOXB2 (GenBank accession number NM_002145), HOX2H (GenBank accession number X16665), there is not hair homologue (GenBank accession number NM_005144), anti-parent decapentaplegic albumen, as MADH1 (GenBank accession number NM_005900), MADH2 (GenBank accession number NM_005901), MADH3 (GenBank accession number NM_005902), MADH4 (GenBank accession number NM_005359), MADH5 (GenBank accession number AF009678), MADH6 (GenBank accession number NM_005585), MADH7 (GenBank accession number NM_005904), MADH9 (GenBank accession number NM_005905), and the signal transducer of transcription factor and activator, as STAT1 (GenBank accession number XM_010893), STAT2 (GenBank accession number NM_005419), STAT3 (GenBank accession number AJ012463), STAT4 (GenBank accession number NM_003151), STAT5 (GenBank accession number L41142) and STAT6 (GenBank accession number NM_003153).

In another embodiment of the invention, therapeutic molecules right and wrong-people or non--mammalian proteins matter.For example, preferred HIV gp120, HIV Tat, the surface protein of other virus (as hepatitis virus, simplexvirus, influenza virus, adenovirus and RSV), other HIV component, the parasite surface protein, as malaria antigen, and bacterium surface albumen.These non--human proteins can be used as for example antigen, or are used because of its useful activity.For example, therapeutic molecules can be that streptokinase, staphylokinase, urokinase or other have the protein of useful enzymolysis activity.

In alternative embodiment, therapeutic molecules is the part-conjugated protein of biologically active.The receptor-ligand binding of described part-conjugated protein for example (1) blocking-up cell surface; Or the biological activity of molecule in (2) and in the blood liquid phase, thereby prevent that it from arriving cellular targets.In some embodiments; modified transferrin fusion proteins comprises the modified transferrin molecule that merges with the part of acceptor-binding domains, and described acceptor is selected from, but is not limited to low-density lipoprotein (LDL) acceptor; the ethanoyl ldl receptor; tnf, transforming growth factor, cytokine receptor; the immunoglobulin Fc acceptor; hormone receptor, glucoreceptor, glycolipid acceptor and glycosaminoglycan acceptor.In other embodiments, part-conjugated protein the CD2 (M14362) that comprises, CD3G (NM_000073), CD3D (NM_000732), CD3E (NM_000733), CD3Z (J04132), CD28 (NM_006139), CD4 (GenBank accession number NM_000616), CD1A (GenBank accession number M28825), CD1B (GenBank accession number NM_001764), CD1C (GenBank accession number NM_001765), CD1D (GenBank accession number NM_001766), CD80 (GenBank accession number NM_005191), GNB3 (GenBank accession number AF501884), CTLA-4 (GenBank accession number NM_005214), intercellular adhesion molecule, as ICAM-1 (NM_000201), ICAM-2 (NM_000873), and ICAM-3 (NM_002162), Tumor Necrosis Factor Receptors, as TNFRSF1A (GenBank accession number X55313), TNFR1SFB (GenBank accession number NM_001066), TNFRSF9 (GenBank accession number NM_001561), TNFRSF10B (GenBank accession number NM_003842), TNFRSF11B (GenBank accession number NM_002546) and TNFRSF13B (GenBank accession number NM_006573), and interleukin-1 receptor, as IL2RA (GenBank accession number NM_000417), IL2RG (GenBank accession number NM_000206), IL4R (GenBank accession number AF421855), IL7R (GenBank accession number NM_002185), IL9R (GenBank accession number XM_015989) and IL13R (GenBank accession number X95302).Preferred Tf-part of the present invention-conjugated protein fusions demonstrates part-protein-bonded biological activity.

Term used herein " cancer-associated protein " is used to describe its expression with cancer or keep relevant protein or the polypeptide of controlled cell growth, for example by tumor suppressor gene or oncogene encoded protein matter.Cancer-associated protein can be p16 (GenBank accession number AH005371), p53 (GenBank accession number NM_000546), p63 (GenBank accession number NM_003722), p73 (GenBank accession number NM_005427), BRCA1 (GenBank accession number U14680), BRCA2 (GenBank accession number NM_000059), CTBP interaction protein (GenBank accession number U72066), DMBT1 (GenBank accession number NM_004406), HRAS (GenBank accession number NM_005343), NCYM (GenBank accession number NM_006316), FGR (GenBank accession number NM_005248), myb (GenBank accession number AF104863), raf1 (GenBank accession number NM_002880), erbB2 (GenBank accession number NM_004448), VAV (GenBank accession number X16316), c-fos (VGenBank accession number 01512), c-fes (GenBank accession number X52192), c-jun (GenBank accession number NM_002228), MAS1 (GenBank accession number M13150), pim-1 (GenBank accession number M16750), TIF1 (GenBank accession number NM_003852), c-fms (GenBank accession number X03663), EGFR (GenBank accession number NM_005228), erbA (GenBank accession number X04707), c-src Tyrosylprotein kinase (GenBank accession number XM_044659), c-ab1 (GenBank accession number M14752), N-ras (GenBank accession number X02751), K-ras (GenBank accession number M54968), jun-B (GenBank accession number M29039), c-myc (GenBank accession number AH001511), RB1 (GenBank accession number M28419), DCC (GenBank accession number X76132), APC (GenBank accession number NM_000038), NF1 (GenBank accession number M89914), NF2 (GenBank accession number Y18000) and bcl-2 (GenBank accession number M13994).

Term used herein " fusion inhibitor peptide " is used for description and demonstrates antiviral activity, and is anti--the film fusion faculty, and/or regulates the peptide of the ability of cell internal procedure (as participating in coiled coil peptide structure).Antiviral activity includes but not limited to suppress HIV-1, HIV-2, and RSV, SIV, EBV, Measles virus, influenza virus or CMV are transmitted to non-infected cell.In addition, regulate the active existence that only needs peptide in the anti-fusion faculty of peptide, antiviral activity or cell, specifically, do not need to stimulate the host immune response of anti-described peptide.Anti-fusion refers to: for the film fusion level that takes place between two or more moietys during with respect to the shortage peptide, described Toplink suppresses or reduces the level of the film fusion event between the described moiety.Moiety can be for example cytolemma or virus structure, as peplos or cilium.Term used herein " antiviral peptide " refers to the infection that described Toplink suppresses viral pair cell, maybe can suppress productivity virus infection and/or the required virus activity of viral pathology that some infect via for example cell-cytogamy or free virus.Described infection can comprise that the film that betides in the envelope virus merges, perhaps other the fusion event relevant with virus structure and cellularstructure.Fusion inhibitor peptide and antiviral peptide often have the aminoacid sequence (for example deriving from HIV-1, HIV-2, the polypeptide of RSV and SIV) that derives from more than one virus proteins.

The example of fusion inhibitor peptide and antiviral peptide sees WO 94/2820, and WO 96/19495, WO96/40191, WO 01/64013 and United States Patent (USP) 6,333,395,6,258,782,6,228,983,6,133,418,6,093,794,6,068,973,6,060,065,6,054,265,6,020,459,6,017,536,6,013,263,5,464,933,5,346,989,5,603,933,5,656,480,5,759,517,6,245,737,6,326,004 and 6,348,568 (all listing this paper in as a reference).In preferred embodiments, antifusogenic peptides is selected from HIVT-20 (FWNWLSAWKDLELLEQENKE QQNQSEEILSHILSTY, SEQ ID NO:4), HIV T-1249, RSV T786 (VYPSDEYDASISQVNEEINQALAYIRKADELL ENV, SEQ ID NO:5), RSV T1584 (AVSKVLHLEGEVNKIKSALLSTNKAVVSLSNGVSVLTSKVLDLKNYIDKQL, SEQ ID NO:6) and RSV T112 (VFPSDEFDASISQVNEKINQSLAFIRESDELLHNV, SEQ ID NO:7).

The example of the peptide of other type comprises the segment of therapeutic protein described herein, has particularly kept at least a active human protein segment of parental generation molecule.The peptide that can be used for producing modified TF fusion rotein of the present invention also comprises simulating peptide and shows the biological activity of therapeutic protein, but sequence or the three-dimensional structure peptide different with the total length therapeutic protein.As non--restrictive example, peptide comprises Johnson etc. (2000) Nephrol.Dial.Transplant 15 (9): 1274-7, Kuai etc. (2000) J.Pept.Res.56 (2): 59-62, Barbone etc. (1999) Nephrol.Dial.Transplant.14 Supp2:80-4, Middleton etc. (1999) J.Biol.Chem.274 (20): 141 63-9, Johnson etc. (1998) Biochemistry 37 (11): 3699-710, Johnson etc. (1997) Chem.Biol.12:939-50, Wrighton etc. (1997) Nat.Biotechnol.15 (12): 1261-5, Livnah etc. (1996) Science273:464-71, with Wrighton etc., disclosed erythropoietin simulating peptide among (1996) Science 273:458-64.

Therapeutic protein also comprises allergenic protein and the segment through digesting thereof.It comprises the pollen allergens of artemisiifolia, rye, June grass, orchard grass, fragrant spring (sweet vernal) grass, red top (red top) grass, thimothy grass, yellow broad-leaved weeds, wheat, corn, artemisia, annual bluegrass, the annual grass in markon's welfare Asia, amaranth, Bermuda grass, spire saltwort, mountain cdear, Oak Tree, ash-leaved maple, plane tree, maple, elm etc., the dirt mite, bee venom, food allergen, animal scurf and other insect venom.

Other therapeutic molecules comprises microorganism vaccine, and described vaccine comprises virus, bacterium and protozoon vaccine and various ingredients thereof, as surface antigen.Described vaccine comprises and contains glycoprotein, protein or derived from the vaccine of these proteinic peptides.Described vaccine production is from streptococcus aureus, streptococcus pyogenes, streptococcus pneumoniae, Neisseria meningitidis, Diplococcus gonorrhoeae, Salmonellas, Shigellae, intestinal bacteria, Klebsiella pneumoniae, mycetozoan, vibrio cholerae, Campylobacter, Pseudomonas aeruginosa, hemophilus influenzae, the Whooping cough bordetella, mycobacterium tuberculosis, legionella pneumophilia, Tyreponema pallidum, chlamydozoan, Toxoid,tetanus, diphtheria toxoid, influenza virus, adenovirus, paramyxovirus (mumps virus, Measles virus), rubella virus, poliovirus, hepatitis virus, simplexvirus, rabies virus, HIV-1, HIV-2, RSV and papilloma virus.

Preferred fusion molecule can contain the anti-HIV viral peptide, and is anti--the RSV peptide, human growth hormone, α and or interferon-, erythropoietin (EPO), EPO sample peptide, granulocyte-G CFS (GCSF), granulocyte-macrophage colony stimutaing factor (GMCSF), Regular Insulin, Regular Insulin-like growth factor (IGF), thrombopoietin, peptide corresponding to antibody CDR, islet neogenesis associated protein (INGAP), thyrocalcitonin, angiostatin, endostatin, interleukin II, somatotropin releasing factor, human parathyroid hormone, Anti-tumor necrosin (TNF) peptide, interleukin 1 (IL-1) acceptor and/or single-chain antibody.

Fusion rotein of the present invention also can be prepared to and comprise peptide or the polypeptide that derives from peptide library, to filter out the molecule with new function.Described peptide library comprises commercially availablely maybe can be the peptide library that the public obtains, American Peptide Co.Inc. for example, Cell Sciences Inc., Invitrogen Corporation, Phoenix Pharmaceuticals Inc., United States Biological, and the peptide library that produces by available technology are as using the phage and the bacterium display libraries of standard method preparation.

In other embodiments of the present invention, can use therapeutic protein moiety known in the art to prepare the Tf fusion rotein, by FDA ( Www.fda.gov/cber/efoi/approve.htm) and PCT patent publication No. WO 01/79258, WO 01/77137, and WO 01/79442, and WO 01/79443, and the peptide and the protein of the up-to-date approval of WO01/79444 and WO 01/79480 (listing this paper in as a reference all in full) they promptly are the examples of described fusion rotein.

Table 1 (reorganization is from PCT international publication number WO 01/79444) provides non exhaustive therapeutic protein tabulation, and described protein is corresponding to the therapeutic protein part of modified transferrin fusion proteins of the present invention." therapeutic protein X " hurdle discloses proteinaceous therapeutic molecule, comprises formal name used at school and trade(brand)name in the bracket of its back, and described molecule contains proteinaceous therapeutic molecule or its segment or its variant, or is made up of them." therapeutic protein X " used herein refers to each proteinaceous therapeutic molecule (being limited by the aminoacid sequence that derives from CAS and Genbank accession number), or refers to the whole group therapeutic protein relevant with the disclosed given proteinaceous therapeutic molecule in this hurdle.It (is that the webpage of the state-run biotechnology information center (NCBI) of www.ncbi.nlm.nih.gov can obtain locus ID by network address for example that " identifier that exemplifies " hurdle provides Chemical Abstracts Services (CAS) accession number (open by American Chemical Society) and/or Genbank accession number, NP-XXXXX (canonical sequence protein), and XP-XXXXX (model protein) identifier), described accession number is equivalent to the inlet of CAS Registry or Genbank database, and described database contains the aminoacid sequence of proteinaceous therapeutic molecule or its segment or variant.In addition, table 1 gives GenSeq accession number and/or periodical source to identify some amino acid sequence of polypeptide that exemplified.

With each all relevant digest page in described CAS and Genbank and GenSeq accession number and the mentioned periodical publication is (for example PubMed ID number (PMID)) that can obtain, and it lists this paper in as a reference in full.PCT/ references one hurdle provides corresponding to the patent of describing proteinaceous therapeutic molecule and/or the U.S. Patent number or the PCT international publication number of disclosed patent application, and they list this paper in as a reference all in full.The biological activity relevant with proteinaceous therapeutic molecule described on biological activity one hurdle.Activity test one hurdle that exemplifies provides the reference of describing test, and described test can be used for detecting therapeutic protein or contains the treatment and/or the biological activity of the transferrin fusion proteins of the present invention of therapeutic protein X part.These reference are also listed this paper in as a reference in full." preferred indication Y " hurdle has been described therapeutic protein X or has been contained the disease that therapeutic protein X transferrin fusion proteins of the present invention partly can treat, prevents, diagnoses or improve.

Table 1

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						BMP-1	GeneSeq accession number P80618	WO8800205	BMP1 belongs to transforming growth factor-beta (TGFB) superfamily.Delicious peptide is induced cartilage and bone forming, plays an important role in kidney takes place, and plays an important role in the growth of a plurality of organs that comprise lung, heart, tooth, intestines, skin, particularly kidney.	Can use following test determination BMP-1 activity known in the art: Nat Genet.2001 Jan; 27 (1): 84-8; Eur JBiochem 1996 Apr 1; 237 (1): 295-302; J BiolChem, Vol.274, Issue 16,10897-10902, April16,1999; And Hogan, B.L.M. (1996) GenesDev.10,1580-1594.	Induce cartilage, tissue and osteogenesis, and diabetes
BMP-2	GeneSeq accession number P80619	WO8800205	BMP-2 belongs to transforming growth factor-beta (TGFB) superfamily.Delicious peptide is induced bone forming.	Can use following test determination BMP-2 activity known in the art: Nat Genet.2001 Jan; 27 (1): 84-8; Eur JBiochem 1996 Apr 1; 237 (1): 295-302; J BiolChem, Vol.274, Issue 16,10897-10902, April16,1999; And Hogan, B.L.M. (1996) GenesDev.10,1580-1594.	Induce cartilage, tissue and osteogenesis, and diabetes
						BMP-2B	GeneSeq accession number W24850	US5631142	BMP-2b belongs to transforming growth factor-beta (TGFB) superfamily.Delicious peptide is induced bone forming.	Can use following test determination BMP-2b activity known in the art: Nat Genet.200 1 Jan; 27 (1): 84-8; Eur J Biochem 1996 Apr1; 237 (1): 295-302; I Biol Cbcre, Vol.274, Issue16,10897-10902, Aprill6,1999; And Hogan, B.L.M. (1996) Genes Dev.10,1580-1594.	Induce cartilage, tissue and osteogenesis, and diabetes

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						BMP-4	GeneSeq accession number B02796	WO0020591	BMP-4 belongs to transforming growth factor-beta (TGFB) superfamily.Delicious peptide is induced bone forming.	Can use following test determination BMP-4 activity known in the art: Nat Genet.2001 Jan; 27 (1): 84-8; Eur JBiochem 1996 Apr 1; 237 (1): 295-302; J BiolChem, Vol.274, Issue 16,10897-10902, April16,1999; And Hogan, B.L.M. (1996) GenesDev.10,1580-1594.	Induce cartilage, tissue and osteogenesis, and diabetes
BMP-5	GeneSeq accession number B02797	WO0020591	BMP-5 belongs to transforming growth factor-beta (TGFB) superfamily.Delicious peptide is induced bone forming.	Can use following test determination BMP-5 activity known in the art: Nat Genet.2001 Jan; 27 (1): 84-8; Eur JBiochem 1996 Apr 1; 237 (1): 295-302; J BiolChem, Vol.274, Issue 16,10897-10902, April16,1999; And Hogan, B.L.M. (1996) GenesDev.10,1580-1594.	Induce cartilage, tissue and osteogenesis, and diabetes
						BMP-6	GeneSeq accession number R32904	US5187076	BMP-6 belongs to transforming growth factor-beta (TGFB) superfamily.Delicious peptide is induced bone forming.	Can use following test determination BMP-6 activity known in the art: Nat Genet.2001 Jan; 27 (1): 84-8; Eur JBiochem 1996 Apr 1; 237 (1): 295-302; J BiolChem, Vol.274, Issue 16,10897-10902, April16,1999; And Hogan, B.L.M. (1996) GenesDev.10,1580-1594.	Induce cartilage, tissue and osteogenesis, and diabetes

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Osteogenic Protein-1; OP-1; BMP-7	GeneSeq accession number W34783	WO973462	OP-1 belongs to transforming growth factor-beta (TGFB) superfamily.Delicious peptide is induced bone forming.	Can use following test determination OP-1 activity known in the art: Nat Genet.2001 Jan; 27 (1): 84-8; EurJBiochem 1996 Apr 1; 237 (1): 295-302; J BiolChem, Vol.274, Issue 16,10897-10902, April16,1999; And Hogan, B.L.M. (1996) GenesDev.10,1580-1594.	Induce cartilage, tissue and osteogenesis, and diabetes
Bone morphogenic protein-2	GeneSeq accession number R57973	WO9406399	OP-2 belongs to transforming growth factor-beta (TGFB) superfamily.Delicious peptide is induced bone forming.	Can use following test determination OP-2 activity known in the art: Nat Genet.2001 Jan; 27 (1): 84-8; EurJBiochem 1996 Apr 1; 237 (1): 295-302; J BiolChem, Vol.274, Issue 16,10897-10902, April16,1999; And Hogan, B.L.M. (1996) GenesDev.10,1580-1594.	Induce cartilage, tissue and osteogenesis, and diabetes

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						GDP-1	GeneSeq accession number R60961	WO9406449	The member of TGF-beta protein family combines the conduction of initiator cell signal (to comment in Massague by the heteromeric receptor mixture with I type (TbetaRI) and II type (TbetaRII) serine/threonine kinase acceptor, J. etc., (1994) Trends Cell Biol. 4:172178; Miyazono, K. etc., (1994) Adv. Immunol.55:181-220).When TGF-β combines with TbetaRII, can activate described heteromeric receptor mixture, and then replenish and phosphorylation TbetaRI.Subsequently, activated T betaRI can transmit signals to target (Chen, F.and Weinberg, R.A. (1995) PNA892:1565-1569 in downstream; Wrana, J.L. etc., (1994) Nature 370:341-347).	Be fabricated the former generation BAEC that body p3TP-Lux shifts by processing, and the expression of mensuration luciferase gene, can measure the effect of GDF-1 to the signal conduction, wherein construct contains the TGF-β effect promoter (Wrana etc. that merge with reporter gene, 1994, Nature 370:341-347).	Grow disorder, induce cartilage, tissue and osteogenesis, and diabetes
BMP-9	GeneSeq accession number R86903	WO9533830	BMP-9 belongs to transforming growth factor-beta (TGFB) superfamily.Delicious peptide is induced bone forming.	Can use following test determination BMP-9 activity known in the art: Nat Genet.2001 Jan; 27 (1): 84-8; Eur JBiochem 1996 Apr 1; 237 (1): 295-302; J BiolChem, Vol.274, Issue 16,10897-10902, April16,1999; And Hogan, B.L.M. (1996) GenesDev.10,1580-1594.	Induce cartilage, tissue and osteogenesis, and diabetes

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						BMP-10	GeneSeq accession number R66202	WO9426893	BMP-10 belongs to transforming growth factor-beta (TGFB) superfamily.Delicious peptide is induced bone forming.	Can use following test determination BMP-10 activity known in the art: Nat Genet.2001 Jan; 27 (1): 84-8; Eur J Biochem 1996 Apr 1; 237 (1): 295-302; J Biol Chem, Vol.274, Issue16,10897-10902, April 16,1999; And Hogan, B.L.M. (1996) Genes Dev.10,1580-1594.	Induce cartilage, tissue and osteogenesis, and diabetes
BMP-12	GeneSeq accession number R78734	WO9516035	BMP-12 belongs to transforming growth factor-beta (TGFB) superfamily.Delicious peptide is induced bone forming.	Can use following test determination BMP-12 activity known in the art: Nat Genet.2001 Jan; 27 (1): 84-8; EurJ Biochem 1996 Apr 1; 237 (1): 295-302; J Biol Chem, Vol.274, Issue16,10897-10902, April 16,1999; And Hogan, B.L.M. (1996) Genes Dev.10,1580-1594.	Induce cartilage, tissue and osteogenesis, and diabetes
						BMP-15	GeneSeq accession number W11261	W09636710	BMP-15 belongs to transforming growth factor-beta (TGFB) superfamily.Delicious peptide is induced bone forming.	Can use following test determination BMP-15 activity known in the art: Nat Genet.2001 Jan; 27 (1): 84-8; EurJ Biochem 1996 Apr 1; 237 (1): 295-302; J Biol Chem, Vol.274, Issue16,10897-10902, April 16,1999; And Hogan, B.L.M. (1996) Genes Dev.10,1580-1594.	Induce cartilage, tissue and osteogenesis, and diabetes

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						BMP-17	GeneSeq accession number Y17870	WO9929718	BMP-17 belongs to transforming growth factor-beta (TGFB) superfamily.Delicious peptide is induced bone forming.	Can use following test determination BMP-17 activity known in the art: Nat Genet.2001 Jan; 27 (1): 84-8; Eur J Biochem 1996 Apr 1; 237 (1): 295-302; J Biol Chem, Vol.274, Issue16,10897-10902, A pril 16,1999; And Hogan, B.L.M. (1996) Genes Dev.10,1580-1594.	Induce cartilage, tissue and osteogenesis, and diabetes
BMP-18	GeneSeq accession number Y17871	WO9929718	BMP-18 belongs to transforming growth factor-beta (TGFB) superfamily.Delicious peptide is induced bone forming.	Can use following test determination BMP-18 activity known in the art: Nat Genet.2001 Jan; 27 (1): 84-8; EurJ Biochem 1996 Apr 1; 237 (1): 295-302; J Biol Chem, Vol.274, Issue16,10897-10902, April 16,1999; And Hogan, B.L.M. (1996) Genes Dev.10,1580-1594.	Induce cartilage, tissue and osteogenesis, and diabetes
						Statin α	GeneSeq accession number B02806	WO0020591	Statin β A subunit is connected with alpha subunit, forms hypophysis FSH secretion inhibitor.Confirmed that statin can bear modulability stroma cell propagation, and had tumour-inhibitions activity.In addition, confirmed that the serum level of statin can reflect the size of GCT, so can be used as the mark of primary and recurrent disease.	Use test known in the art can measure the tumors inhibition activity of statin: Matzuk etc., Nature 1992 Nov.26:360 (6402); 313-9.	Tumor suppression.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Statin β	GeneSeq accession number H02808	WO0020591	Statin β A subunit is connected with alpha subunit, forms hypophysis FSH secretion inhibitor.Confirmed that statin can bear modulability stroma cell propagation, and had tumour-inhibitions activity.In addition, confirmed that the serum level of statin can reflect the size of GCT, so can be used as the mark of primary and recurrent disease.	Use test known in the art can measure the tumors inhibition activity of statin: Matzuk etc., Nature 1992 Nov.26:360 (6402); 313-9.	Tumor suppression.
Cerebus albumen	GeneSeq accession number W86032	WO9849296	It is believed that Cerebus participates in suppressing the BMP activity.	Use following test known in the art can measure BMP activity when having antagonist Cerebus: Nat Genet.2001Jan; 27 (1): 84-8; Eur J Biochem 1996 Apr 1; 237 (1): 295-302; J Biol Chem, Vol.274, Issue16,10897-10902, April 16,1999; And Hogan, B.L.M. (1996) Genes Dev.10,1580-1594.	Bmp antagonist can be used for osteosarcoma, unusual osteogenesis.
						Solubility bmp receptor kinase protein-3	GeneSeq accession number R95227	WO9614579	Solubility bmp receptor kinase protein-3 participates in conjunction with BMP.Solubility bmp receptor kinase protein-3 can be used as antagonist to suppress the BMP activity.	Use following test known in the art to measure to exist the BMP activity of solubility antagonist bmp receptor kinase protein-3 o'clock: Nat Genet.2001 Jan; 27 (1): 84-8; Eur JBiochem 1996 Apr 1; 237 (1): 295-302; J BiolChem, Vol.274, Issue 16,10897-10902, April16,1999; And Hogan, B.L.M. (1996) GenesDev.10,1580-1594.	Bmp antagonist can be used for osteosarcoma, unusual osteogenesis.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						BMP processive enzyme furin	GeneSeq accession number W36099	WO9741250	BMP belongs to transforming growth factor-beta (TGFB) superfamily.Delicious peptide is induced bone forming.	Use following test known in the art can measure BMP activity when having furin: Nat Genet.2001 Jan; 27 (1): 84-8; Eur J Biochem 1996 Apr 1; 237 (1): 295-302; J Biol Chem, Vol.274, Issue16,10897-10902, April 16,1999; And Hogan, B.L.M. (1996) Genes Dev.10,1580-1594.	Bone forming or heteroplasia.
TGF-β 1	GeneSeq accession number R29657	WO9216228	The member of TGF-beta protein family combines the conduction of initiator cell signal (to comment in Massague by the heteromeric receptor mixture with I type (TbetaRI) and II type (TbetaRII) serine/threonine kinase acceptor, J. etc., (1994) Trends Cell Biol.4:172178; Miyazono, K. etc., (1994) Adv.Immunol.55:181-220).When TGF-β combines with TbetaRII, can activate described heteromeric receptor mixture, and then replenish and phosphorylation TbetaRI.Subsequently, activated T betaRI can transmit signals to target (Chen, F.andWeinberg, R.A. (1995) the PNA 892:1565-1569 in downstream; Wrana, J.L. etc., (1994) Nature 370:341-347).	Be fabricated the former generation BAEC of body p3TP-Lux transfection by processing, and the expression of mensuration luciferase gene, can measure the effect of TGF-β to the signal conduction, wherein construct contains the TGF-β effect promoter (Wrana etc. that merge with reporter gene, 1994, Nature 370:341-347).	Be used for the treatment of cancer and promote wound healing.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						TGF-β 2	GeneSeq accession number R39659	EP542679	The member of TGF-beta protein family combines the conduction of initiator cell signal (to comment in Massague by the heteromeric receptor mixture with I type (TbetaRI) and II type (TbetaRII) serine/threonine kinase acceptor, J. etc., (1994) Trends Cell Biol.4:172178; Miyazono, K. etc., (1994) Adv.Immunol.55:181-220).When TGF-β combines with TbetaRII, can activate described heteromeric receptor mixture, and then replenish and phosphorylation TbetaRI.Subsequently, activated T betaRI can transmit signals to target (Chen, F.andWeinberg, R.A. (1995) the PNA 892:1565-1569 in downstream; Wrana, J.L. etc., (1994) Nature 370:341-347).	Be fabricated the former generation BAEC of body p3TP-Lux transfection by processing, and the expression of mensuration luciferase gene, can measure the effect of TGF-β to the signal conduction, wherein construct contains the TGF-β effect promoter (Wrana etc. that merge with reporter gene, 1994, Nature 370:341-347).	Be used for the treatment of cancer and promote wound healing.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						ZTGF-β 9	GeneSeq accession number Y70654	WO0015798	The member of TGF-beta protein family combines the conduction of initiator cell signal (to comment in Massague by the heteromeric receptor mixture with I type (TbetaRI) and II type (TbetaRII) serine/threonine kinase acceptor, J. etc., (1994) Trends Cell Biol.4:172178; Miyazono, K. etc., (1994) Adv.Immunol.55:181-220).When TGF-β combines with TbetaRII, can activate described heteromeric receptor mixture, and then replenish and phosphorylation TbetaRI.Subsequently, activated T betaRI can transmit signals to target (Chen, F.andWeinberg, R.A. (1995) the PNA 892:1565-1569 in downstream; Wrana, J.L. etc., (1994) Nature 370:341-347).	Be fabricated the former generation BAEC of body p3TP-Lux transfection by processing, and the expression of mensuration luciferase gene, can measure the effect of TGF-β to the signal conduction, wherein construct contains the TGF-β effect promoter (Wrana etc. that merge with reporter gene, 1994, Nature 370:341-347).	Be used for the treatment of cancer and promote wound healing.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Anti--TGF 'beta ' family antibody		GB2305921	The member of TGF-beta protein family combines the conduction of initiator cell signal (to comment in Massague by the heteromeric receptor mixture with I type (TbetaRI) and II type (TbetaRII) serine/threonine kinase acceptor, J. etc., (1994) Trends Cell Biol.4:172178; Miyazono, K. etc., (1994) Adv.Immunol.55:181-220).When TGF-β combines with TbetaRII, can activate described heteromeric receptor mixture, and then replenish and phosphorylation TbetaRI.Subsequently, activated T betaRI can transmit signals to target (Chen, F.andWeinberg, R.A. (1995) the PNA 892:1565-1569 in downstream; Wrana, J.L. etc., (1994) Nature 370:341-347).	Be fabricated the former generation BAEC of body p3TP-Lux transfection by processing, and the expression of mensuration luciferase gene, can measure anti--when TGF β antibody exists TGF-β to the effect of signal conduction, wherein construct contains the TGF-β effect promoter (Wrana etc. that merge with reporter gene, 1994, Nature370:341-347).	Be used for the sex change of controlling fiber sample, immunity, and inflammatory diseases.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						The conjugated protein II of TGF β hides	GeneSeq accession number Y70552	WO0012551	The member of TGF-beta protein family combines the conduction of initiator cell signal (to comment in Massague by the heteromeric receptor mixture with I type (TbetaRI) and II type (TbetaRII) serine/threonine kinase acceptor, J. etc., (1994) Trends Cell Biol.4:172178; Miyazono, K. etc., (1994) Adv.Immunol.55:181-220).When TGF-β combines with TbetaRII, can activate described heteromeric receptor mixture, and then replenish and phosphorylation TbetaRI.Subsequently, activated T betaRI can transmit signals to target (Chen, F.andWeinberg, R.A. (1995) the PNA 892:1565-1569 in downstream; Wrana, J.L. etc., (1994) Nature 370:341-347).	Be fabricated the former generation BAEC of body p3TP-Lux transfection by processing, and the expression of mensuration luciferase gene, can measure the effect that TGF-β conducted signal when TGF β is conjugated protein to be existed, wherein construct contains the TGF-β effect promoter (Wrana etc. that merge with reporter gene, 1994, Nature370:341-347).	Be used for suppressing tissue or tumor growth.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						MP52	GeneSeq accession number W36100	WO9741250	The member of TGF-beta protein family combines the conduction of initiator cell signal (to comment in Massague by the heteromeric receptor mixture with I type (TbetaRI) and II type (TbetaRII) serine/threonine kinase acceptor, J. etc., (1994) Trends Cell Biol.4:172178; Miyazono, K. etc., (1994) Adv.Immunol.55:181-220).When TGF-β combines with TbetaRII, can activate described heteromeric receptor mixture, and then replenish and phosphorylation TbetaRI.Subsequently, activated T betaRI can transmit signals to target (Chen, F.andWeinberg, R.A. (1995) the PNA 892:1565-1569 in downstream; Wrana, J.L. etc., (1994) Nature 370:341-347).	Be fabricated the former generation BAEC of body p3TP-Lux transfection by processing, and the expression of mensuration luciferase gene, can measure the effect of TGF-β to the signal conduction, wherein construct contains the TGF-β effect promoter (Wrana etc. that merge with reporter gene, 1994, Nature 370:341-347).	Bone forming or heteroplasia.
B57 albumen	GeneSeq accession number W69293	WO9837195	BMP participates in inducing bone forming.Specific antagonist can be used for preventing that this activity from occurring.	BMP activity when using following test known in the art can measure b57 albumen to exist: Nat Genet.2001 Jan; 27 (1): 84-8; Eur J Biochem 1996 Apr 1; 237 (1): 295-302; J Biol Chem, Vol.274, Issue16,1089-10902, April 16,1999; And Hogan, B.L.M. (1996) Genes Deve.10,1580-1594.	Bmp antagonist is used for osteosarcoma, unusual osteogenesis.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Phylaxin	GeneSeq accession number W69293	WO0064920	This gene belongs to the family that is limited by mouse FIZZ1 and FIZZ3/ resistin gene.The feature of this family is the sequence that C-terminal has one section equally spaced 10 cysteine residues.This proteinic mouse homologue is secreted by adipocyte, and it may be to make fat and the potential hormone of getting in touch of type ii diabetes generation.	Use test known in the art can measure the phylaxin influence IIThe ability of type diabetes: Pontoglio etc., J Clin Invest1998 May 15; 101 (10): 2215-22.	Type ii diabetes and X syndrome.
Galectin-4	GeneSeq accession number W11841	WO9703190	Galectin belongs to carbohydrate-conjugated protein family, and this family is characterised in that the beta galactose glycosides to containing carbohydrate conjugates has affinity.	Use test known in the art can measure the ability of Galectin-4 polypeptide in conjunction with lactose: Wada, etc., J Biol Chem1997 Feb 28; 272 (9): 6078-86.	Lactose intolerance.
						APM-I; ACRP-30; Famoxin	GeneSeq accession number Y71035	W00026363	The ACPR30 gene is only expressed in fatty tissue.It is believed that ACRP30 energy strengthen muscle tissue is to the oxidation of fatty acids effect.	Use test known in the art can measure the ability of ACRP30 polypeptide influence obesity and fats oxidn: Fruebis etc., ProcNat ' l Acad Sci USA 2001 Feb 13; 98 (4): 2005-10.	Obesity, metabolism disorder, lipid metabolism; Hormone secretion.
The ACRP-30 homologue; Complement component Clq C	GeneSeq accession number B30234	WO0063376	The ACPR30 gene is only expressed in fatty tissue.It is believed that ACRP30 energy strengthen muscle tissue is to the oxidation of fatty acids effect.	Use test known in the art can measure the ability of ACRP30 homologue polypeptide influence obesity and fats oxidn: Fruebis etc., Proc Nat ' l Acad Sci USA 2001 Feb 13; 98 (4): 2005-10.	Obesity, metabolism disorder, lipid metabolism; Hormone secretion.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Calpain-10a	GeneSeq accession number Y79567	WO0023603	It is believed that calpain works in insulin secretion and insulin activity, therefore can be used for treating type ii diabetes.	Use test known in the art can measure the ability that calpain-10 influences type ii diabetes: Pontoglio etc., J ClinInvest 1998 May 15; 101 (10): 2215-22.	Diabetes; The reaction of adjusting insulin secretion; The glucose transport disorder of insulin-mediated.
Calpain-10b	GeneSeq accession number Y79568	WO0023603	It is believed that calpain works in insulin secretion and insulin activity, therefore can be used for treating type ii diabetes.	Use test known in the art can measure the ability that calpain-10 influences type ii diabetes: Pontoglio etc., J ClinInvest 1998 May 15; 101 (10): 2215-22.	Diabetes; The reaction of adjusting insulin secretion; The glucose transport disorder of insulin-mediated.
						Calpain-10c	GeneSeq accession number Y79569	WO0023603	It is believed that calpain works in insulin secretion and insulin activity, therefore can be used for treating type ii diabetes.	Use test known in the art can measure the ability that calpain-10 influences type ii diabetes: Pontoglio etc., J ClinInvest 1998 May 15; 101 (10): 2215-22.	Diabetes; The reaction of adjusting insulin secretion; The glucose transport disorder of insulin-mediated.
PDGF-D	GeneSeq accession number Y71130	WO0027879	Vascular endothelial growth factor.	Use the proliferation test (Rizzino1988 Cancer Res.48:4266) of NR6R-3T3 cell.	Wound healing; Atherosclermis

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						FasL	GeneSeq accession number Y28594	WO9936079	The activity relevant with apoptosis and function of immune system.	Use apoptosis test known in the art can measure activity: Walczak etc., (1996) EMBO J 16:5386-5397.	Apoptosis-relative disease; Autoimmune disease; Graft versus host disease.
Chondromodulin-sample albumen	GeneSeq accession number Y71262	W00029579	It is believed that Chondromodulin albumen is the chondroprotein that can give the vasculogenesis resistance, therefore can be used as the medicament of anti--vasculogenesis, described medicament can be treated cancer.	Use test known in the art can measure Chondromodulin-sample albumen and suppress angiopoietic ability: Hirakie etc., J Biol Chem 1997 Dec 19; 272 (51): 32419-26.	The angiogenesis inhibitor medicament; The osteoblastic proliferation stimulator; Prevent the cartilaginous tissue vascularization; Be used for the treatment of cancer.
						Patched	GeneSeq accession number W72969	US5837538	Patched is tumour-supressor acceptor of Sonic hedgehog (shh), is a kind of protein that can control development models formulation and growth.	Use test known in the art can measure solubility Patched in conjunction with and suppress the active ability of shh: Stone etc., Nature 1996 Nov 14; 384 (6605): 129-34.	The acceptor of hedgehog cell proliferation signal transduction molecule.This receptor can be used as via shh signal conduction by way of the instrument that prevents cell proliferation, therefore can be used for treating cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Patched-2	GeneSeq accession number Y43261	WO9953058	Patched is tumour-supressor acceptor of Sonic hedgehog (shh), is a kind of protein that can control development models formulation and growth.	Use test known in the art can measure solubility Patched in conjunction with and suppress the active ability of shh: Stone etc., Nature 1996 Nov 14; 384 (6605): 129-34.	The acceptor of hedgehog cell proliferation signal transduction molecule.This receptor can be used as via shh signal conduction by way of the instrument that prevents cell proliferation, therefore can be used for treating cancer.
Maspin; Proteinase inhibitor 5	GeneSeq accession number R50938	WO9405804	Maspin is the member of serpin serpin family, it is believed that it can suppress metastases.	Use methods known in the art, as protease substrate through mark, as general protease substrate (casein of resorufin-mark), can measure the restraining effect of Maspin and other proteinase inhibitor: Roche MolecularBiochemicals, Cat.No.1080733.	The tumor-inhibiting factor of in mammary cancer, being reduced.Maspin albumen has tumor suppression and infects and suppress active.
						Endostatin	GeneSeq accession number B28399	WO0064946	It is believed that Endostatin can suppress the capillary endothelial cell proliferation function.	Use Cao etc., the disclosed test of (1996) J.Biol.Chem.27129461-29467 can be measured the restraining effect of endostatin.	Anti--angiogenic activity.Be used to prevent and/or treat cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						AFGF; FGF-1	GeneSeq accession number P94037	EP298723	Fibroblast growth factor	Use the proliferation test (Rizzino1988 Cancer Res.48:4266) of NR6R-3T3 cell; Embodiment 23 disclosed herein and 39.	Promote the growth and the propagation of cell such as epithelial cell and keratinocyte.Antagonist can be used as anti--cancer medicament.
BFGF; FGF-2	GeneSeq accession number R06685	FR2642086	Fibroblast growth factor	Use the proliferation test (Rizzino1988 Cancer Res.48:4266) of NR6R-3T3 cell; Embodiment 23 disclosed herein and 39.	Promote the growth and the propagation of cell such as epithelial cell and keratinocyte.Antagonist can be used as anti--cancer medicament.
						FGF-3; INT-2	GeneSeq accession number R07824	WO9503831	Fibroblast growth factor	Use the proliferation test (Rizzino1988 Cancer Res.48:4266) of NR6R-3T3 cell; Embodiment 23 disclosed herein and 39.	Promote the growth and the propagation of cell such as epithelial cell and keratinocyte.Antagonist can be used as anti--cancer medicament.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						FGF-4; HST-1; HBGF-4	GeneSeq accession number R07825	WO9503831	Fibroblast growth factor	Use the proliferation test (Rizzino1988 Cancer Res.48:4266) of NR6R-3T3 cell; Embodiment 23 disclosed herein and 39.	Promote the growth and the propagation of cell such as epithelial cell and keratinocyte.Antagonist can be used as anti--cancer medicament.
FGF-5	GeneSeq accession number W22600	WO9730155	Fibroblast growth factor	Use the proliferation test (Rizzino1988 Cancer Res.48:4266) of NR6R-3T3 cell; Embodiment 23 disclosed herein and 39.	Promote the growth and the propagation of cell such as epithelial cell and keratinocyte.Antagonist can be used as anti--cancer medicament.
						FGF-6; Heparin is in conjunction with excretory transforming factor-2	GeneSeq accession number R58555	EP613946	Fibroblast growth factor	Use the proliferation test (Rizzino1988 Cancer Res.48:4266) of NR6R-3T3 cell; Embodiment 23 disclosed herein and 39.	Promote the growth and the propagation of cell such as epithelial cell and keratinocyte.Antagonist can be used as anti--cancer medicament.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						FGF-8	GeneSeq accession number R80783	WO9524928	Fibroblast growth factor	Proliferation test (Rizzino1988 Cancer Res.48:4266) with the NR6R-3T3 cell; Embodiment 23 disclosed herein and 39.	Promote the growth and the propagation of cell such as epithelial cell and keratinocyte.Antagonist can be used as anti--cancer medicament.
FGF-9; The Gila activation factor	GeneSeq accession number R70822	WO9503831	Fibroblast growth factor	Use the proliferation test (Rizzino1988 Cancer Res.48:4266) of NR6R-3T3 cell; Embodiment 23 disclosed herein and 39.	Promote the growth and the propagation of cell such as epithelial cell and keratinocyte.Antagonist can be used as anti--cancer medicament.
						FGF-12; Fibroblastic growth factor autofactor 1-1	GeneSeq accession number W06309	WO9635708	Fibroblast growth factor	Use the proliferation test (Rizzino1988 Cancer Res.48:4266) of NR6R-3T3 cell; Embodiment 23 disclosed herein and 39.	Promote the growth and the propagation of cell such as epithelial cell and keratinocyte.Antagonist can be used as anti--cancer medicament.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						FGF-15	GeneSeq accession number Y08582	WO9927100	Fibroblast growth factor	Use the proliferation test (Rizzino1988 Cancer Res.48:4266) of NR6R-3T3 cell; Embodiment 23 disclosed herein and 39.	Promote the growth and the propagation of cell such as epithelial cell and keratinocyte.Antagonist can be used as anti--cancer medicament.
FGF-16	GeneSeq accession number Y05474	WO9918128	Fibroblast growth factor	Use the proliferation test (Rizzino1988 Cancer Res.48:4266) of NR6R-3T3 cell; Embodiment 23 disclosed herein and 39.	Promote the growth and the propagation of cell such as epithelial cell and keratinocyte.Antagonist can be used as anti--cancer medicament.
						FGF-18	GeneSeq accession number Y08590	WO9927100	Fibroblast growth factor	Use the proliferation test (Rizzino1988 Cancer Res.48:4266) of NR6R-3T3 cell; Embodiment 23 disclosed herein and 39.	Promote the growth and the propagation of cell such as epithelial cell and keratinocyte.Antagonist can be used as anti--cancer medicament.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						The fit-3 part	GeneSeq accession number R67541	EP627487	The stem cell ancestors	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Promote immunocyte growth and/or differentiation.
VEGF-110	GeneSeq accession number Y69417	WO0013702	Promote the growth and/or the propagation of endotheliocyte.	Use test known in the art, can measure the VEGF activity as disclosed test among the international publication number WO0045835.	Promote cell, as the growth and the propagation of vascular endothelial cell.Antagonist can be used as anti--vasculogenesis medicament comes in handy to cancer.
						VEGB-121	GeneSeq accession number B50432	WO0071713	Promote the growth and/or the propagation of endotheliocyte.	Use test known in the art, can measure the VEGF activity as disclosed test among the international publication number WO0045835.	Promote cell, as the growth and the propagation of vascular endothelial cell.Antagonist can be used as anti--vasculogenesis medicament comes in handy to cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						VEGF-138	GeneSeq accession number Y43483	WO9940197	Promote the growth and/or the propagation of endotheliocyte.	Use test known in the art, can measure the VEGF activity as disclosed test among the international publication number WO0045835.	Promote cell, as the growth and the propagation of vascular endothelial cell.Antagonist can be used as anti--vasculogenesis medicament comes in handy to cancer.
VEGF-145	GeneSeq accession number Y69413	WO0013702	Promote the growth and/or the propagation of endotheliocyte.	Use test known in the art, can measure the VEGF activity as disclosed test among the international publication number WO0045835.	Promote cell, as the growth and the propagation of vascular endothelial cell.Antagonist can be used as anti--vasculogenesis medicament comes in handy to cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						VEGF-16	GeneSeq accession number Y43484	W09940197	Promote the growth and/or the propagation of endotheliocyte.	Use test known in the art, can measure the VEGF activity as disclosed test among the international publication number WO0045835.	Promote cell, as the growth and the propagation of vascular endothelial cell.Antagonist can be used as anti--vasculogenesis medicament comes in handy to cancer.
VEGF-165	GeneSeq accession number Y69414	WO0013702	Promote the growth and/or the propagation of endotheliocyte.	Use test known in the art, can measure the VEGF activity as disclosed test among the international publication number WO0045835.	Promote cell, as the growth and the propagation of vascular endothelial cell.Antagonist can be used as anti--vasculogenesis medicament comes in handy to cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						VEGF-182	GeneSeq accession number Y43483	W09940197	Promote the growth and/or the propagation of endotheliocyte.	Use test known in the art, can measure the VEGF activity as disclosed test among the international publication number WO0045835.	Promote cell, as the growth and the propagation of vascular endothelial cell.Antagonist can be used as anti--vasculogenesis medicament comes in handy to cancer.
VEGF-189	GeneSeq accession number Y69415	WO0013702	Promote the growth and/or the propagation of endotheliocyte.	Use test known in the art, can measure the VEGF activity as disclosed test among the international publication number WO0045835.	Promote cell, as the growth and the propagation of vascular endothelial cell.Antagonist can be used as anti--vasculogenesis medicament comes in handy to cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						VEGF-206	GeneSeq accession number Y69416	W00013702	Promote the growth and/or the propagation of endotheliocyte.	Use test known in the art, can measure the VEGF activity as disclosed test among the international publication number WO0045835.	Promote cell, as the growth and the propagation of vascular endothelial cell.Antagonist can be used as anti--vasculogenesis medicament comes in handy to cancer.
VEGF-D	GeneSeq accession number W53240	WO9807832	Promote the growth and/or the propagation of endotheliocyte.	Use test known in the art, can measure the VEGF activity as disclosed test among the international publication number WO0045835.	Promote cell, as the growth and the propagation of vascular endothelial cell.Antagonist can be used as anti--vasculogenesis medicament comes in handy to cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						VEGF-E; VEGF-X	GeneSeq accession number Y33679	W09947677	Promote the growth and/or the propagation of endotheliocyte.	Use test known in the art, can measure the VEGF activity as disclosed test among the international publication number WO0045835.	Promote cell, as the growth and the propagation of vascular endothelial cell.Antagonist can be used as anti--vasculogenesis medicament comes in handy to cancer.
Vegf receptor; KDR; Flk-1	GeneSeq accession number W69679	WO9831794	The acceptor of VEGF polypeptide	Use test known in the art, the VEGF activity in the time of can measuring the flk-1 polypeptide and exist as disclosed test among the international publication number WO0045835.	Vegf receptor.Can be used as anti--vasculogenesis medicament with the fusion rotein of ectodomain.Antagonist can be used for promoting vasculogenesis.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Soluble VEGF-receptor	GeneSeq accession number W47037	US5712380	The acceptor of VEGF polypeptide	Use test known in the art, the VEGF activity in the time of can measuring the vegf receptor polypeptide and exist as disclosed test among the international publication number WO0045835.	Vegf receptor.Can be used as anti--vasculogenesis medicament with the fusion rotein of ectodomain.Antagonist can be used for promoting vasculogenesis.
Flt-1	GeneSeq accession number Y70751	WO0021560	The acceptor of VEGF polypeptide	Use test known in the art, the VEGF activity in the time of can measuring the flt-1 polypeptide and exist as disclosed test among the international publication number WO0045835.	Vegf receptor.Can be used as anti--vasculogenesis medicament with the fusion rotein of ectodomain.Antagonist can be used for promoting vasculogenesis.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						VEGFR-3; Flt-4	GeneSeq accession number B29047	WO0058511	The acceptor of VEGF polypeptide	Use test known in the art, the VEGF activity in the time of can measuring the flt-4 polypeptide and exist as disclosed test among the international publication number WO0045835.	Vegf receptor.Can be used as anti--vasculogenesis medicament with the fusion rotein of ectodomain.Antagonist can be used for promoting vasculogenesis.
Neuropilin-1	GeneSeq accession number Y06319	WO9929858	Vascular endothelial growth factor	Use test known in the art, can measure the VEGF activity as disclosed test among the international publication number WO0045835.	Promote cell, as the growth and the propagation of vascular endothelial cell.Antagonist can be used as anti--vasculogenesis medicament comes in handy to cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Neuropilin-2	GeneSeq accession number Y03618	WO9929858	Vascular endothelial growth factor	Use test known in the art, can measure the VEGF activity as disclosed test among the international publication number WO0045835.	Promote cell, as the growth and the propagation of vascular endothelial cell.Antagonist can be used as anti--vasculogenesis medicament comes in handy to cancer.
The fast ballism skeletal troponin of people C	GeneSeq accession number W22597	W09730085	Troponin is contractile protein, it is believed that it can suppress vasculogenesis.High-caliber troponin to cardiovascular damage back in ischemic cardiac muscle, form blood vessel again and run into difficult helpful.	Use test known in the art can measure the ability that the solubility troponin suppresses vasculogenesis: Proc Natl Acad SciU S A 1999 Mar 16; 96 (6): 2645-50.	Anti--vasculogenesis
						The fast ballism skeletal troponin of people I	GeneSeq accession number W18054	W09730085	Troponin is contractile protein, it is believed that it can suppress vasculogenesis.High-caliber troponin to cardiovascular damage back in ischemic cardiac muscle, form blood vessel again and run into difficult helpful.	Use test known in the art can measure the ability that the solubility troponin suppresses vasculogenesis: Proc Natl Acad SciU S A 1999 Mar 16; 96 (6): 2645-50.	Anti--vasculogenesis
The fast ballism skeletal troponin of people T	GeneSeq accession number W22599	W09730085	Troponin is contractile protein, it is believed that it can suppress vasculogenesis.High-caliber troponin to cardiovascular damage back in ischemic cardiac muscle, form blood vessel again and run into difficult helpful.	Use test known in the art can measure the ability that the solubility troponin suppresses vasculogenesis: Proc Natl Acad SciU S A 1999 Mar 16; 96 (6): 2645-50.	Anti--vasculogenesis

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Segment, the fribrillin Troponin I	GeneSeq accession number W18053	W09719955	Troponin is contractile protein, it is believed that it can suppress vasculogenesis.High-caliber troponin to cardiovascular damage back in ischemic cardiac muscle, form blood vessel again and run into difficult helpful.	Use test known in the art can measure the ability that the solubility troponin suppresses vasculogenesis: ProcNatl Acad SciU S A 1999 Mar 16; 96 (6): 2645-50.	Anti--vasculogenesis
The fribrillin Troponin I	GeneSeq accession number W18054	W09719955	Troponin is contractile protein, it is believed that it can suppress vasculogenesis.High-caliber troponin to cardiovascular damage back in ischemic cardiac muscle, form blood vessel again and run into difficult helpful.	Use test known in the art can measure the ability that the solubility troponin suppresses vasculogenesis: ProcNatl Acad SciU S A 1999 Mar 16; 96 (6): 2645-50.	Anti--vasculogenesis
						The troponin peptide	GeneSeq accession number Y29581, Y29582, Y29583, Y29584, Y29585, and Y29586	WO9933874	Troponin is contractile protein, it is believed that it can suppress vasculogenesis.High-caliber troponin to cardiovascular damage back in ischemic cardiac muscle, form blood vessel again and run into difficult helpful.	Use test known in the art can measure the ability that the solubility troponin suppresses vasculogenesis: Proc Natl Acad SciU S A 1999 Mar 16; 96 (6): 2645-50.	Anti--vasculogenesis

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						The fast ballism skeletal troponin C of subunit of people	GeneSeq accession number B00134	WO0054770	Troponin is contractile protein, it is believed that it can suppress vasculogenesis.High-caliber troponin to cardiovascular damage back in ischemic cardiac muscle, form blood vessel again and run into difficult helpful.	Use test known in the art can measure the ability that the solubility troponin suppresses vasculogenesis: Proc Natl Acad SciU S A 1999 Mar 16; 96 (6): 2645-50.	Anti--vasculogenesis
The fast ballism skeletal troponin of people subunit I albumen	GeneSeq accession number B00135	WO0054770	Troponin is contractile protein, it is believed that it can suppress vasculogenesis.High-caliber troponin to cardiovascular damage back in ischemic cardiac muscle, form blood vessel again and run into difficult helpful.	Use test known in the art can measure the ability that the solubility troponin suppresses vasculogenesis: Proc Natl Acad SciU S A 1999 Mar 16; 96 (6): 2645-50.	Anti--vasculogenesis
						The fast ballism skeletal troponin T of subunit of people	GeneSeq accession number B00136	WO0054770	Troponin is contractile protein, it is believed that it can suppress vasculogenesis.High-caliber troponin to cardiovascular damage back in ischemic cardiac muscle, form blood vessel again and run into difficult helpful.	Use test known in the art can measure the ability that the solubility troponin suppresses vasculogenesis: Proc Natl Acad SciU S A 1999 Mar 16; 96 (6): 2645-50.	Anti--vasculogenesis

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Activator inhibitor-1; PAI-1	GeneSeq accession number R08411	WO9013648	It is believed that PAI works in cancer, cardiovascular diseases and coagulopathy.	It is known in the art measuring the active method of Type 1 plasminogen activator inhibitor (PAI), for example detects the ability that PAI suppresses tissue plasminogen activator (tPA) or urokinase (uPA): J Biochem Biophys Methods 2000 Sep 11; 45 (2): 127-40, Breast Cancer Res Treat1996; 41 (2): 141-6.The method of measuring anti--angiogenic activity is known in the art, for example Proc Natl Acad SciU S A 1999 Mar 16; 96 (6): 2645-50.	Anti--vasculogenesis; Coagulopathy.
Type 1 plasminogen activator inhibitor-2; PAI-2	GeneSeq accession number P94160	DE3722673	It is believed that PAI works in cancer, cardiovascular diseases and coagulopathy.	It is known in the art measuring the active method of Type 1 plasminogen activator inhibitor (PAI), for example detects the ability that PAI suppresses tissue plasminogen activator (tPA) or urokinase (uPA): J Biochem Biophys Methods 2000 Sep 11; 45 (2): 127-40, Breast Cancer Res Treat1996; 41 (2): 141-6.The method of measuring anti--angiogenic activity is known in the art, for example Proc Natl Acad SciU S A 1999 Mar 16; 96 (6): 2645-50.	Anti--vasculogenesis; Coagulopathy.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Activator inhibitor-2; PAI-2	GeneSeq accession number R10921	WO9102057	It is believed that PAI works in cancer, cardiovascular diseases and coagulopathy.	It is known in the art measuring the active method of Type 1 plasminogen activator inhibitor (PAI), for example detects the ability that PAI suppresses tissue plasminogen activator (tPA) or urokinase (uPA): J Biochem Biophys Methods 2000 Sep 11; 45 (2): 127-40, Breast Cancer Res Treat1996; 41 (2): 141-6.The method of measuring anti--angiogenic activity is known in the art, for example Proc Natl Acad SciU S A 1999 Mar 16; 96 (6): 2645-50.	Anti--vasculogenesis; Coagulopathy.
People PAI-1 mutant	GeneSeq accession number R11755, R11756, R11757, R11758, R11759, R11760, R11761, R11762 and R11763	WO9105048	It is believed that PAI works in cancer, cardiovascular diseases and coagulopathy.	It is known in the art measuring the active method of Type 1 plasminogen activator inhibitor (PAI), for example detects the ability that PAI suppresses tissue plasminogen activator (tPA) or urokinase (uPA): J Biochem Biophys Methods 2000 Sep 11; 45 (2): 127-40, Breast Cancer Res Treat1996; 41 (2): 141-6.The method of measuring anti--angiogenic activity is known in the art, for example Proc Natl Acad SciU S A 1999 Mar 16; 96 (6): 2645-50.	Anti--vasculogenesis; Coagulopathy.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						CXCR3; CXC	GeneSeq accession number Y79372	WO0018431	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Solubility CXCR3 polypeptide can be used for chemokine inhibiting activity and virus infection.
Modified Rantes	GeneSeq accession number W38129	WO9737005	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						RANTES	GeneSeq accession number Y05299	EP905240	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease
MCI-1a	GeneSeq accession number R73914	WO9509232	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						MCP-1b	GeneSeq accession number Y26176	WO9929728	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease
The MCP-1 acceptor	GeneSeq accession number R79165	WO9519436	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Soluble M CP-1 receptor polypeptides can be used for chemokine inhibiting activity and virus infection.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						MCP-3	GeneSeq accession number R73915	W09509232	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease
The MCP-4 acceptor	GeneSeq accession number W56689	W09809171	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Soluble M CP-4 receptor polypeptides can be used for chemokine inhibiting activity and virus infection.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						The RANTES acceptor	GeneSeq accession number W29588	US5652133	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Solubility RANTES receptor polypeptides can be used for chemokine inhibiting activity and virus infection.
The CCR5 variant	GeneSeq accession number W88238	WO9854317	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Solubility CCR5 polypeptide can be used for chemokine inhibiting activity and virus infection.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						CCR7	GeneSeq accession number B50859	US6153441	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Solubility CCR7 polypeptide can be used for chemokine inhibiting activity and virus infection.
CXC3	GeneSeq accession number W23345	WO9727299	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Eotaxin	GeneSeq accession number W10099	WO9700960	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease
Neurotactin	GeneSeq accession number Y77537, W34307Y53259, and Y77539	US6013257 WO9742224	Neurotactin works in chemotaxis leucocyte migration and encephalitis disease process.	The chemotaxis leukocyte migration test is known in the art, and for example: J.Immunol.Methods 33, ((1980)); Nature1997 Jun 5; 387 (6633): 611-7.	Immunological disease

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						People CK β-9	GeneSeq accession number B50860	US6153441	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease
Lymphotactm	GeneSeq accession number B50052	WO0073320	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G family to 7.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease
						MIP-3 α	GeneSeq accession number W44398	WO9801557	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G family to 7.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						MIP-3 β	GeneSeq accession number W44399	WO9801557	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G family to 7.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease
MIP-γ	GeneSeq accession number R70798	WO9504158	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G family to 7.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease
						The stem cell supressor	GeneSeq accession number R11553	WO9104274	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G family to 7.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Hemopoieticgrowth factor

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Thrombopoietin	GeneSeq accession number R79905	WO9521920	Thrombopoietin participates in regulating growth and the differentiation of megalokaryocyte and preceptor thereof.	Can detect thrombopoietin (TPO) to measure regulating effect to megakaryocyte growth and differentiation.Mol Cell Biol2001 Apr; 21 (8): 2659-70; Exp Hematol 2001Jan; 29 (1): 51-8 and the document of wherein mentioning.	Hemopoieticgrowth factor
The c-kit part; SCF; Mast cell growth factor; MGF; Fibrosarcoma deutero-STEM CELL FACTOR	GeneSeq accession number Y53284, R83978 and R83977	EP992579 and EP676470	It is believed that the C-kit part can stimulate mastocyte propagation, and can strengthen the propagation of marrow sample and lymph sample hemopoietic progenitor cell in the marrow culture.The C-kit part can also act synergistically with other cytokine.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Hemopoieticgrowth factor

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Platelet-derived somatomedin	GeneSeq accession number B48653	WO0066736	Vascular endothelial growth factor	Use test known in the art, can measure the VEGF activity as disclosed test among the international publication number WO0045835.	Promote cell, as the growth and the propagation of vascular endothelial cell.Antagonist can be used as anti--vasculogenesis medicament comes in handy to cancer.
The melanoma arrestin	GeneSeq accession number R69811	WO9503328	The melanoma arrestin has melanoma-inhibition activity and can be used for treating cancer (melanoma, glioblastoma, neuroblastoma, small cell lung cancer, neuroectodermal tumor) or be used as immunosuppressor (suppressing IL-2 or phytohemagglutinin inductive peripheral blood lymphocyte propagation).	Use test known in the art can measure the tumor-inhibiting factor activity of melanoma arrestin: Matzuk etc., Nature1992 Nov 26; 360 (6402): 313-9.	Cancer, melanoma.
						Neurospongioma deutero-somatomedin	GeneSeq accession number R08120	EP399816	Vascular endothelial growth factor	Use test known in the art, can measure the VEGF activity as disclosed test among the international publication number WO0045835.	Promote cell, as the growth and the propagation of vascular endothelial cell.Antagonist can be used as anti--vasculogenesis medicament comes in handy to cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Platelet-derived somatomedin precursor A	GeneSeq accession number R84759	EP682110	Vascular endothelial growth factor	Use test known in the art, can measure the VEGF activity as disclosed test among the international publication number WO0045835.	Promote cell, as the growth and the propagation of vascular endothelial cell.Antagonist can be used as anti--vasculogenesis medicament comes in handy to cancer.
Platelet-derived somatomedin precursor B	GeneSeq accession number R84760	EP682110	Vascular endothelial growth factor	Use test known in the art, can measure the VEGF activity as disclosed test among the international publication number WO0045835.	Promote cell, as the growth and the propagation of vascular endothelial cell.Antagonist can be used as anti--vasculogenesis medicament comes in handy to cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Platelet-derived growth factor B v-sis	GeneSeq accession number P80595 and P80596	EP282317	Vascular endothelial growth factor	Use test known in the art, can measure the VEGF activity as disclosed test among the international publication number WO0045835.	Promote cell, as the growth and the propagation of vascular endothelial cell.Antagonist can be used as anti--vasculogenesis medicament comes in handy to cancer.
Placenta growth factor	GeneSeq accession number R23059 and R23060	WO9206194	Vascular endothelial growth factor	Use test known in the art, can measure the VEGF activity as disclosed test among the international publication number WO0045835.	Promote cell, as the growth and the propagation of vascular endothelial cell.Antagonist can be used as anti--vasculogenesis medicament comes in handy to cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Placenta growth factor-2	GeneSeq accession number Y08289	DE19748734	Vascular endothelial growth factor	Use test known in the art, can measure the VEGF activity as disclosed test among the international publication number WO0045835.	Promote cell, as the growth and the propagation of vascular endothelial cell.Antagonist can be used as anti--vasculogenesis medicament comes in handy to cancer.
Thrombopoietin derivative 1	GeneSeq accession number Y77244	WO0000612	Thrombopoietin participates in regulating growth and the differentiation of megalokaryocyte and preceptor thereof.	Can detect thrombopoietin (TPO) to measure regulating effect to megakaryocyte growth and differentiation.Mol Cell Biol2001 Apr; 21 (8): 2659-70; Exp Hematol 2001Jan; 29 (1): 51-8 and the document of wherein mentioning.	Thrombocytopenia, cancer.
						Thrombopoietin derivative 2	GeneSeq accession number Y77255	WO0000612	Thrombopoietin participates in regulating growth and the differentiation of megalokaryocyte and preceptor thereof.	Can detect thrombopoietin (TPO) to measure regulating effect to megakaryocyte growth and differentiation.Mol Cell Biol2001 Apr; 21 (8): 2659-70; Exp Hematol 2001Jan; 29 (1): 51-8 and the document of wherein mentioning.	Thrombocytopenia, cancer.
Thrombopoietin derivative 3	GeneSeq accession number Y77262	WO0000612	Thrombopoietin participates in regulating growth and the differentiation of megalokaryocyte and preceptor thereof.	Can detect thrombopoietin (TPO) to measure regulating effect to megakaryocyte growth and differentiation.Mol Cell Biol2001 Apr; 21 (8): 2659-70; Exp Hematol 2001Jan; 29 (1): 51-8 and the document of wherein mentioning.	Thrombocytopenia, cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Thrombopoietin derivative 4	GeneSeq accession number Y77267	WO0000612	Thrombopoietin participates in regulating growth and the differentiation of megalokaryocyte and preceptor thereof.	Can detect thrombopoietin (TPO) to measure regulating effect to megakaryocyte growth and differentiation.Mol Cell Biol2001 Apr; 21 (8): 2659-70; Exp Hematol 2001Jan; 29 (1): 51-8 and the document of wherein mentioning.	Thrombocytopenia, cancer.
Thrombopoietin derivative 5	GeneSeq accession number Y77246	WO0000612	Thrombopoietin participates in regulating growth and the differentiation of megalokaryocyte and preceptor thereof.	Can detect thrombopoietin (TPO) to measure regulating effect to megakaryocyte growth and differentiation.Mol Gell Biol2001 Apr; 21 (8): 2659-70; Exp Hematol 2001Jan; 29 (1): 51-8 and the document of wherein mentioning.	Thrombocytopenia, cancer.
						Thrombopoietin derivative 6	GeneSeq accession number Y77253	WO0000612	Thrombopoietin participates in regulating growth and the differentiation of megalokaryocyte and preceptor thereof.	Can detect thrombopoietin (TPO) to measure regulating effect to megakaryocyte growth and differentiation.Mol Cell Biol2001 Apr; 21 (8): 2659-70; Exp Hematol 2001Jan; 29 (1): 51-8 and the document of wherein mentioning.	Thrombocytopenia, cancer.
Thrombopoietin derivative 7	GeneSeq accession number Y77256	WO0000612	Thrombopoietin participates in regulating growth and the differentiation of megalokaryocyte and preceptor thereof.	Can detect thrombopoietin (TPO) to measure regulating effect to megakaryocyte growth and differentiation.Mol Cell Biol2001 Apr; 21 (8): 2659-70; Exp Hematol 2001Jan; 29 (1): 51-8 and the document of wherein mentioning.	Thrombocytopenia, cancer.
						Fractalkine	GeneSeq accession number Y53255	US6043086	It is believed that Fractalkine works in chemotactic leucocyte migration and neuropathy.	Use chemotactic leukocyte migration test known in the art can measure Fractalkine activity: J.Immunol.Methods 33, ((1980)); Nature 1997 Jun 5; 387 (6633): 611-7.	Immunological disease.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						CXC3	GeneSeq accession number W23345	WO9757599	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular B iology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease
CCR7	GeneSeq accession number B50859	US6153441	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Solubility CCR7 polypeptide can be used for chemokine inhibiting activity and virus infection.
						Nerve growth factor-β	GeneSeq accession number R11474	EP414151	Nerve growth factor	Use the proliferation test (Rizzino1988 Cancer Res.48:4266) of NR6R-3T3 cell.	Neuropathy, cancer

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Nerve growth factor-β 2	GeneSeq accession number W69725	EP859056	Nerve growth factor	Use the proliferation test (Rizzino1988 Cancer Res.48:4266) of NR6R-3T3 cell.	Neuropathy, cancer
Neurotrophin-3	GeneSeq accession number W8889	WO9821234	Neurotrophin is regulated neuronal cell survival and synaptic plasticity.	Can use Trk tyrosine-kinase enzyme activation known in the art to test and detect the neurotrophin activity, as Proc NatlAcad Sci U S A 2001 Mar 13; 98 (6): 3555-3560.	Neuropathy, cancer
						Neurotrophin-3	GeneSeq accession number R47100	WO9325684	Neurotrophin is regulated neuronal cell survival and synaptic plasticity.	Can use Trk tyrosine-kinase enzyme activation known in the art to test and detect the neurotrophin activity, as Proc NatlAcad Sci U S A 2001 Mar 13; 98 (6): 3555-3560.	Neuropathy, cancer
Neurotrophin-4a	GeneSeq accession number R47101	WO9325684	Neurotrophin is regulated neuronal cell survival and synaptic plasticity.	Can use Trk tyrosine-kinase enzyme activation known in the art to test and detect the neurotrophin activity, as Proc NatlAcad Sci U S A 2001 Mar 13; 98 (6): 3555-3560.	Neuropathy, cancer
						Neurotrophin-4b	GeneSeq accession number R47102	WO9325684	Neurotrophin is regulated neuronal cell survival and synaptic plasticity.	Can use Trk tyrosine-kinase enzyme activation known in the art to test and detect the neurotrophin activity, as Proc NatlAcad Sci U S A 2001 Mar 13; 98 (6): 3555-3560.	Neuropathy, cancer

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Neurotrophin-4c	GeneSeq accession number R47103	WO9325684	Neurotrophin is regulated neuronal cell survival and synaptic plasticity.	Can use Trk tyrosine-kinase enzyme activation known in the art to test and detect the neurotrophin activity, as Proc NatlAcad Sci U S A 2001 Mar 13; 98 (6): 3555-3560.	Neuropathy, cancer
Neurotrophin-4d	GeneSeq accession number R47102	WO9325684	Neurotrophin is regulated neuronal cell survival and synaptic plasticity.	Can use Trk tyrosine-kinase enzyme activation known in the art to test and detect the neurotrophin activity, as Proc NatlAcad Sci U S A 2001 Mar 13; 98 (6): 3555-3560.	Neuropathy, cancer
						Platelet-derived somatomedin A chain	GeneSeq accession number R38918	US5219739	Vascular endothelial growth factor	Use test known in the art, can measure the VEGF activity as disclosed test among the international publication number WO0045835.	Promote cell, as the growth and the propagation of vascular endothelial cell.Hematopoiesis and immunological disease.Antagonist can be used as anti--vasculogenesis medicament comes in handy to cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Platelet-derived growth factor B chain	GeneSeq accession number R38919	US5219739	Vascular endothelial growth factor	Use test known in the art, can measure the VEGF activity as disclosed test among the international publication number WO0045835.	Promote cell, as the growth and the propagation of vascular endothelial cell.Hematopoiesis and immunological disease.Antagonist can be used as anti--vasculogenesis medicament comes in handy to cancer.
The matrix deutero-factor-1 α	GeneSeq accession number Y39995	WO9948528	The matrix somatomedin	Use the proliferation test (Rizzino1988 Cancer Res.48:4266) of NR6R-3T3 cell.	Hematopoiesis and immunological disease, cancer.
						The matrix deutero-factor-1 β	GeneSeq accession number R75420	CA2117953	The matrix somatomedin	Use the proliferation test (Rizzino1988 Cancer Res.48:4266) of NR6R-3T3 cell.	Hematopoiesis and immunological disease, cancer.
Tarc	GeneSeq accession number W14917	WO9711969	The T lymphocyte there is chemotaxis.May in the T-cell development, work.It is believed that and to combine with CCR8 and CCR4.	The chemotactic leukocyte migration test is known in the art, for example: J.Immunol.Methods 33 ((1980)).	Anti-inflammatory, immunological disease, cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Prolactin antagonist	GeneSeq accession number R78691	WO9521625	Prolactin antagonist participates in immune cell propagation and apoptosis.	By method well-known in the art, as Buckley, AR and Buckley DJ, Ann N Y Acad Sci 2000; 917:522-33 and the document of wherein mentioning can be measured the effect of prolactin antagonist in immune cell propagation and apoptosis inhibition.	The reproductive system disease, cancer.
Prolactin antagonist 2	GeneSeq accession number Y31764	US5955346	Prolactin antagonist participates in immune cell propagation and apoptosis.	By method well-known in the art, as Buckley, AR and Buckley DJ, Ann N Y Acad Sci 2000; 917:522-33 and the document of wherein mentioning can be measured the effect of prolactin antagonist in immune cell propagation and apoptosis inhibition.	The reproductive system disease, cancer.
						The follicle stimulating hormone alpha subunit	GeneSeq accession number Y54160	EP974359	FSH impels the women's who is in follicular phase emiocytosis il-1.	Use test known in the art can measure the FSH activity: JGend SpecifMed 1999 Nov-Dec; 2 (6): 30-4; Mol Cell Endocrinol.1997 Nov 15; 134 (2): 109-18.	The reproductive system disease, cancer.
Follicle stimulating hormone β subunit	GeneSeq accession number Y54161	EP974359	FSH impels the women's who is in follicular phase emiocytosis il-1.	Use test known in the art can measure the FSH activity: JGend Specif Med 1999 Nov-Dec; 2 (6): 30-4; Mol Cell Endocrinol.1997 Nov 15; 134 (2): 109-18.	The reproductive system disease, cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						P material (tachykinin)	GeneSeq accession number B23027	WO0054053	The P material is relevant with immunomodulatory.	By method well-known in the art, as Lai etc., ProcNatl Acad Sci USA 2001 Mar 27; 98 (7): 3970-5; Jal.at-Daloz etc., Allergy AsthmaProc 2001 Jan-Feb; 22 (1): 17-23; Kahler etc., Exp Lung Res 2001 Jan-Feb; 27 (1): 25-46; And Adamus MA and Dabrowski ZJ.J CellBiochem 2001; 81 (3) 499-506 can measure the P material to immunomodulatory and marrow, the effect of cell proliferation.	Diabetes, hypertension, cancer.
Pitocin (neurophysin 1)	GeneSeq accession number B24085 and B24086	WO0053755	The calcium that the pitocin participation induces prostaglandin(PG) (E2) to discharge and discharged increasing amount by smooth muscle cell.	By method well-known in the art, as Pavan etc., AM J Obset Gynecol 2000 Jul; 183 (1): 76-82and Holda etc., Cell Calcium 1996 Jul; 20 (1): 4351, can measure pitocin and PGE (2) release and pitocin (Ca2+) and discharge.	Inflammatory diseases, immunological disease, cancer.
						Vassopressin (neurophysin II)	GeneSeq accession number B24085 and B24086	WO0053755	It is believed that vassopressin has direct antidiuretic activity to kidney, it is believed that it can cause peripheral vascular contraction.	Use test known in the art can measure the vassopressin activity: Endocr Regul 1996 Mar; 30 (1): 13-17.	Inflammatory diseases, immunological disease, cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						IL-1	GeneSeq accession number P60326	EP165654	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; And Orencole﹠amp; Dinarclio (1989) Cytokine 1,14-20.	Inflammatory diseases, immunological disease, cancer.
Sophisticated IL-1	GeneSeq accession number R14855	EP456332	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; And Orencole﹠amp; Dinarclio (1989) Cytokine 1,14-20.	Inflammatory diseases, immunological disease, cancer.
						IL-1 β	GeneSeq accession number Y08322	WO9922763	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; And Orencole﹠amp; Dinarclio (1989) Cytokine 1,14-20.	Inflammatory diseases, immunological disease, cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						The IL-3 variant	GeneSeq accession number P80382, P80383, P80384, and P80381	WO8806161	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Kitamura et al (1989) J CellPhysiol.140 323-334.	Inflammatory diseases, immunological disease, cancer.
IL-4	GeneSeq accession number P70615	WO8702990	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; And Siegel﹠amp; Mostowski (1990) JImmunol Methods 132,287-295.	Inflammatory diseases, immunological disease, cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						The IL-4 mutain	GeneSeq accession number W52151 W52152 W52153 W52154 W52155 W52156 W52157 W52158 W52159 W52160 W52161 W52162 W52163 W52164 and W52165	WO9747744	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; And Siegel﹠amp; Mostowski (1990) JImmunol Methods 132,287-295.	Inflammatory diseases, immunological disease, cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						IL-1 α	GeneSeq accession number P90108	EP324447	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; And Orencole﹠amp; Dinarello (1989) Cytokine 1,14-20.	Inflammatory diseases, immunological disease, cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						The IL-3 variant	GeneSeq accession number R38561, R38562, R38563, R38564, R38565, R38566, R38567, R38568, R38569, R38570, R38571, and R38572	WO9307171	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Aarden et al (1987) Eur.J.Immunol 17,1411-16.	Inflammatory diseases, immunological disease, cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						IL-6	GeneSeq accession number R45717 and R45718	WO9402512	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Aarden et al (1987) Eur.J.Immunol 17,1411-16.	Inflammatory diseases, immunological disease, cancer.
IL-13	GeneSeq accession number R48624	WO9404680	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Boutelier et al (1995) J.Immunol.Methods 181,29.	Inflammatory diseases, immunological disease, cancer.
						The IL-4 mutain	GeneSeq accession number R47182	DE4137333	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Manhews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; And Siegel﹠amp; Mostowski (1990) JImmunol Methods 132,287-295.	Inflammatory diseases, immunological disease, cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						IL-4 mutain Y124X	GeneSeq accession number R47183	DE4137333	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; And Siegel﹠amp; Mostowski (1990) JImmunol Methods 132,287-295.	Inflammatory diseases, immunological disease, cancer.
IL-4 mutain Y124G	GeneSeq accession number R47184	DE4137333	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; And Siegel﹠amp; Mostowski (1990) JImmunol Methods 132,287-295.	Inflammatory diseases, immunological disease, cancer.
						Human interleukin-10 (precursor)	GeneSeq accession number R41664	WO9317698	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Thompson-Snipes et al (1991) J.Exp.Med.173,507-510.	Inflammatory diseases, immunological disease, cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Human interleukin-10	GeneSeq accession number R42642	WO9318783-A	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Thompson-Snipes et al (1991) J.Exp.Med.173,507-510.	Inflammatory diseases, immunological disease, cancer.
Ro 24-7472/000-1 β precursor	GeneSeq accession number R42447	EP569042	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Ptess, Washington, D.C.1987, pp.221-225; And Orencole﹠amp; Dinarello (1989) Cytokine 1,14-20.	Inflammatory diseases, immunological disease, cancer.
						Interleukin 1 α	GeneSeq accession number R45364	EP578278	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Manhews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225.	Inflammatory diseases, immunological disease, cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Ro 24-7472/000-3 variant	GeneSeq accession number R22814	JP04063595	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Kitamura et al (1989) J CellPhysiol.140 323-334.	Inflammatory diseases, immunological disease, cancer.
The IL-li segment	GeneSeq accession number R35484 and R35485	EP541920	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; And Orencole﹠amp; Dinarclio (1989) Cytokine 1,14-20.	Inflammatory diseases, immunological disease, cancer.
						IL-1 inhibitor (IL-li)	GeneSeq accession number R35486 and R35484	EPS541920	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; And Orencole﹠amp; Dinarclio (1989) Cytokine 1,14-20.	Inflammatory diseases, immunological disease, cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						ICE22kD subunit	GeneSeq accession number R33780	EP533350	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225.	Inflammatory diseases, immunological disease, cancer.
ICE20kD subunit	GeneSeq accession number R33781	EP533350	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225.	Inflammatory diseases, immunological disease, cancer.
						ICE10kD subunit	GeneSeq accession number R33782	EP533350	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lynmphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225.	Inflammatory diseases, immunological disease, cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Human interleukin-10 (precursor)	GeneSeq accession number R41664	WO9317698	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Thompson-Snipes et al (1991) J.Exp.Med.173,507-510.	Inflammatory diseases, immunological disease, cancer.
Human interleukin-10	GeneSeq accession number R42642	WO9318783	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Thompson-Snipes et al (1991) J.Exp.Med.173,507-510.	Inflammatory diseases, immunological disease, cancer.
						Ro 24-7472/000-1 β precursor	GeneSeq accession number R42447	EP569042	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Kitamura et al (1989) J CellPhysiol.140 323-334.	Inflammatory diseases, immunological disease, cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Human interleukin-6	GeneSeq accession number R49041	WO9403492	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Aarden et al (1987) Eur.J.Immunol 17,1411-16.	Inflammatory diseases, immunological disease, cancer.
The interleukin 6 S176R of sudden change	GeneSeq accession number R54990	WO9411402	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Aarden et al (1987) Eur.J.Immunol 17,1411-16.	Inflammatory diseases, immunological disease, cancer.
						Interleukin 6	GeneSeq accession number R55256	JP06145063	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Manhews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Aarden et al (1987) Eur.J.Immunol 17,1411-16.	Inflammatory diseases, immunological disease, cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Interleukin 8 (IL-8) acceptor	GeneSeq accession number R53932	JP06100595	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Holmes et al (1991) Science 253,1278-80.	Solubility IL-8 receptor polypeptides can be used for suppressing the interleukin-activity.
Ro 24-7472/000-7	GeneSeq accession number R59919	US5328988	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Park et al (1990) J.Exp.Med.171,1073-79.	Inflammatory diseases, immunological disease, cancer.
						The fusion rotein that contains IL-3	GeneSeq accession number R79342 and R79344	WO9521254	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Kitamura et al (1989) J CellPhysiol.140 323-334.	Inflammatory diseases, immunological disease, cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						The IL-3 mutain	GeneSeq accession number R79254, R79255, R79256, R79257, R79258, R79259, R79260, R79261, R79262, R79263, R79264, R79265, R79266, R79267, R79268, R79269, R79270, R79271, R79272, R79273, R79274, R79275, R79276, R79277, R79278, R79279, R79280, R79281, R79282, R79283, R79284, and R79285	ZA9402636	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Giri et al (1994) EMBO J.132822-2830.	Inflammatory diseases, immunological disease, cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						IL-12 p40 subunit	GeneSeq accession number R63018	AU9466072	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225.	Inflammatory diseases, immunological disease, cancer.
AGF	GeneSeq accession number R64240	WO9429344	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225.	Inflammatory diseases, immunological disease, cancer.
						Ro 24-7472/000-1240kD subunit	GeneSeq accession number R79187	WO9519786	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Hori et al (1987), Blood 70,1069-1078.	Inflammatory diseases, immunological disease, cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Derive from Ro 24-7472/000-15 acceptor of clone P1	GeneSeq accession number R90843	WO9530695	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Giri et al (1994) EMBO J.132822-2830.	Solubility IL-8 receptor polypeptides can be used for suppressing the interleukin-activity.
Ro 24-7472/000-7	GeneSeq accession number R92796	WO9604306	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokiines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Park et al (1990) J.Exp.Med.171,1073-79.	Inflammatory diseases, immunological disease, cancer.
						Interleukin 9	GeneSeq accession number R92797	WO9604306	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Yang et al (1989) Blood 74,1880-84.	Inflammatory diseases, immunological disease, cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Interleukin
3	GeneSeq accession number R92801	WO9604306	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Kitamura et al (1989) J CellPhysiol.140 323-334.	Inflammatory diseases, immunological disease, cancer.
						Ro 24-7472/000-5	GeneSeq accession number R92802	WO9604306	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Kitamura et al (1989) J CellPhysiol.140 323-334.	Inflammatory diseases, immunological disease, cancer.
Recombinant interleukin-1 6	GeneSeq accession number W33373	DE19617202	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Lim et al (1996) J.Immunol.156,2566-70.	Inflammatory diseases, immunological disease, cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						People IL-16 albumen	GeneSeq accession number W33234	DE19617202	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Lim et al (1996) J.Immunol.156,2566-70.	Inflammatory diseases, immunological disease, cancer.
Thrl17 Ro 24-7472/000 9	GeneSeq accession number W27521	WO9708321	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225.	Inflammatory diseases, immunological disease, cancer.
						Metl17 Ro 24-7472/000 9	GeneSeq accession number W27522	WO9708321	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Yanget al (1989) Blood 74,1880-84.	Inflammatory diseases, immunological disease, cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						IL-1 receptor antagonist in people's cell	GeneSeq accession number W77158	EP86-4585	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; And Orencole﹠amp; Dinarello (1989) Cytokine 1,14-20.	Inflammatory diseases, immunological disease, cancer.
Ro 24-7472/000-18 albumen (IL-18)	GeneSeq accession number W77158	EP864585	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With USHIO et al (1996) J.Immunol.156,4274-79.	Inflammatory diseases, immunological disease, cancer.
						Ro 24-7472/000-18	GeneSeq accession number W77077	EP861663	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferens:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With USHIO et al (1996) J.Immunol.156,4274-79.	Inflammatory diseases, immunological disease, cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						The human interleukin-18 derivative	GeneSeq accession number W77083 W77084 W77085 W77086 W77087 W77088, and W77089	EP861663	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Ushio et al (1996) J.Immunol, 156,4274-79.	Inflammatory diseases, immunological disease, cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Interleukin 9 (IL-9) maturation protein (Thrl17 form)	GeneSeq accession number W68158	WO9827997	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Yang et al (1989) Blood 74,1880-84.	Inflammatory diseases, immunological disease, cancer.
IL-9 maturation protein variant (Metl17 form)	GenSeq accession number W68157	WO9827997	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Yang et al (1989) Blood 74,1880-84.	Inflammatory diseases, immunological disease, cancer.
						People IL-9 receptor protein variant #3	GeneSeq accession number W64058	WO9824904	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Yang et al (1989) Blood 74,1880-84.	Inflammatory diseases, immunological disease, cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						People IL-9 receptor protein variant segment	GenSeq accession number W64060	WO9824904	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Ptess, Washington, D.C.1987, pp.221-225; With Yang et al (1989) Blood 74,1880-84.	Solubility IL-9 receptor polypeptides can be used for suppressing the interleukin-activity.
People IL-9 receptor protein variant #3	GeneSeq accession number W64061	WO9824904	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Yang et al (1989) Blood 74,1880-84.	Solubility IL-9 receptor polypeptides can be used for suppressing the interleukin-activity.
						Human interleukin 12-p40 albumen	GeneSeq accession number W51311	WO9817689	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Hori et al (1987), Blood 70,1069-1078.	Inflammatory diseases, immunological disease, cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Ro 24-7472/000-12p35 albumen	GeneSeq accession number W51312	WO9817689	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Ho ri et al (1987), Blood 70,1069-1078.	Inflammatory diseases, immunological disease, cancer.
Has the active human protein of IL-16	GeneSeq accession number W63753	DE19649233-	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Manhews etc., in Lymphokines andInterferonns:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Lim et al (1996) J.Immunol.156,2566-70.	Inflammatory diseases, immunological disease, cancer.
						Has the active human protein of IL-16	GeneSeq accession number W59425	DE19649233-	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Lim et al (1996) J.Immunol.156,2566-70.	Inflammatory diseases, immunological disease, cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Ro 24-7472/000-15	GeneSeq accession number W53878	US5747024	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Giri et al (1994) EMBO J.132822-2830.	Inflammatory diseases, immunological disease, cancer.
People's wild-type interleukin 4 (hIL-4) albumen	GeneSeq accession number W52149	WO9747744	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; And Siegel﹠amp; Mostowski (1990) JImmunol Methods 132,287-295.	Inflammatory diseases, immunological disease, cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						The interleukin 4 mutain	GeneSeq accession number W52151, W52153, W52154, W52155, W52156, W52157, W52158, W52159, W52160, W52161, W52162, W52163, W52164, W52165, W52166, and W52167	WO9747744	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; And Siegel﹠amp; Mostowski (1990) JImmunol Methods 132,287-295.	Inflammatory diseases, immunological disease, cancer.

Therapeutic protein X human leukocyte	The identifier GeneSeq that exemplifies	The PCT/ references	The biological activity interleukin-is by lymphocyte, monocyte and huge biting carefully	The activity test that exemplifies is used test known in the art can measure interleukin-and is lived	Preferred indication Y
						Plain
1 δ human leukocyte is situated between	Accession number Y28408GeneSeq	WO9935268	One group of multifunctional cytokine of born of the same parents' synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.Interleukin-is by lymphocyte, monocyte and huge biting carefully	The property: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; And Orencole﹠amp; Dinarello (1989) Cytokine 1,14-20.Using test known in the art can measure interleukin-lives	Inflammatory diseases, immunological disease, cancer.
						Plain-1 receptor antagonist β people EDIRF is situated between	Accession number Y24395GeneSeq	WO9935268	One group of multifunctional cytokine of born of the same parents' synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.Interleukin-is by lymphocyte, monocyte and huge biting carefully	The property: Matthews etc., in Lymphokirnes andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; And Orencole﹠amp; Dinarello (1989) Cytokine 1,14-20.Using test known in the art can measure interleukin-lives	Inflammatory diseases, immunological disease, cancer.
The II protein sequence	Accession number Y22199	WO9932632	One group of multifunctional cytokine of born of the same parents' synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	The property: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225.	Inflammatory diseases, immunological disease, cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						People EDIRFI protein sequence	GeneSeq accession number Y22197	WO9932632	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225.	Inflammatory diseases, immunological disease, cancer.
People IL-IRD10 protein sequence	GeneSeq accession number Y14131	WO9919480	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; And Orencole﹠amp; Dinarello (1989) Cytokine 1,14-20.	Solubility IL-IRD10 receptor polypeptides can be used for suppressing the interleukin-activity.
						People IL-IRD9	GeneSeq accession number Y14122	WO9919480	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1 987, pp.221-225; And Orencole﹠amp; Diharello (1989) Cytokine 1,14-20.	Solubility IL-1RD10 receptor polypeptides can be used for suppressing the interleukin-activity.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						People DNAX interleukin 40	GeneSeq accession number Y09196	WO9919491	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225.	Inflammatory diseases, immunological disease, cancer.
(DIL-40) replaceable sequence	GeneSeq accession number Y09197	WO9919491	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225.	Inflammatory diseases, immunological disease, cancer.
						IL-11	GeneSeq accession number R50176	WO9405318	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Lu et al (1994) J immunol.Methods 173,19.	Inflammatory diseases, immunological disease, cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						People's steatogenesis supressor	GeneSeq accession number R43260	EP566410	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225.	Inflammatory diseases, immunological disease, cancer.
IL-11	GeneSeq accession number W02202	JP08127539	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Lu et al (1 994) J immunol.Methods 173,19.	Inflammatory diseases, immunological disease, cancer.
						IL-14	GeneSeq accession number R55800	WO9416074	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Ambrus et al (1993) PNAS 90,63330-34.	Inflammatory diseases, immunological disease, cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						The IL-17 acceptor	GeneSeq accession number B03807	US6072033	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Yao et al (1995) J.Immunol.155,5483-86.	Solubility IL-17 receptor polypeptides can be used for suppressing the interleukin-activity.
IL-17	GeneSeq accession number R76573	WO9518826	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Yao et al (1995) J.Immunol.155,5483-86.	Inflammatory diseases, immunological disease, cancer.
						CTLA-8	GeneSeq accession number W13651	WO9704097	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Ptess, Washington, D.C.1987, pp.22l-225.	Inflammatory diseases, immunological disease, cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						IL-19	GeneSeq accession number W37935	WO9808870	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Gallagher et al (2000) GenesImmun.1,442-50.	Inflammatory diseases, immunological disease, cancer.
IL-21 (TIF)	GeneSeq accession number Y92879	WO0024758	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises and promotes immunocyte (as t helper cell, B cell, have a liking for acid, property granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress Interferon, rabbit and produce.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225: and Paltish-Novak et al (2000) Nature408,57-63.	Inflammatory diseases, immunological disease, cancer.
						The IL-8 acceptor	GeneSeq accession number R33420	WO9306229	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Ptess, Washington, D.C.1987, pp.221-225; With Holmes et al (1991) Science 253,1278-80.	Solubility IL-8 receptor polypeptides can be used for suppressing the interleukin-activity.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						People II type interleukin 1 receptor	GeneSeq accession number R85480	US5464937	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; And Orencole﹠amp; Dinarello (1989) Cytokine 1,14-20.	Solubility II type interleukin 1 receptor polypeptide can be used for suppressing the interleukin-activity.
Ro 24-7472/000-12 acceptor	GeneSeq accession number R69632	EP638644	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Hori et al (1987), B1ood 70,1069-1078.	Solubility IL-12 receptor polypeptides can be used for suppressing the interleukin-activity.
						Interleukin 8 acceptor B	GeneSeq accession number R80758	US5440021	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Holmes et al (1991) Science 253,1278-80.	Solubility IL-8 acceptor B polypeptide can be used for suppressing the interleukin-activity.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						People IL-8 receptor protein hIL8RA	GeneSeq accession number B09989	JP08103276	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphkiones andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Holmes et al (1991) Science 253,1278-80.	Solubility IL-8 acceptor A polypeptide can be used for suppressing the interleukin-activity.
People IL-8 receptor protein hIL8R	GeneSeq accession number B09990	JP08103276	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Holmes et al (1991) Science 253,1278-80.	Solubility IL-8 receptor polypeptides can be used for suppressing the interleukin-activity.
						Interleukin 2 receptor associated protein p43	GeneSeq accession number R97569	WO9621732-	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Gillis et al (1978) J.Immunol.120,2027.	Solubility IL-2 receptor polypeptides can be used for suppressing the interleukin-activity.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Human Interleukin-17 receptor	GeneSeq accession number W04185	WO9629408	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Yao et al (1995) J.Immunol.155,5483-86.	Solubility IL-17 receptor polypeptides can be used for suppressing the interleukin-activity.
The human interleukin-11 acceptor	GeneSeq accession number R99090	WO9619574	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Lu et a1 (1994) J immunol.Methods 173,19.	Solubility IL-11 receptor polypeptides can be used for suppressing the interleukin-activity.
						Ro 24-7472/000-1 acceptor accessory protein	GeneSeq accession number W01911	WO9623067	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; And Orencole﹠amp; Dinarello (1989) Cytokine 1,14-20.	Inflammatory diseases, immunological disease, cancer.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						AGF albumen	GeneSeq accession number R92749	US5488032	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225.	Inflammatory diseases, immunological disease, cancer.
3 receptors of Ro 24-7472/000-1	GeneSeq accession number R91064	W09607739	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; And Orencole﹠amp; Dinarello (1989) Cytokine 1,14-20.	Solubility IL-type-3 receptor polypeptides can be used for suppressing the interleukin-activity.
						Ro 24-7472/000-13 beta receptor	GeneSeq accession number W24972	WO9720926	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practica, Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Boutelier et al (1995) J.Immunol.Methods 181,29.	Solubility IL-13 beta receptor polypeptide can be used for suppressing the interleukin-activity.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Ro 24-7472/000-13 α acceptor	GeneSeq accession number W24973	WO9720926	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practica lApproach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Boutelier et al (1995) J.Immunol.Methods 181,29.	Solubility IL-13 α receptor polypeptides can be used for suppressing the interleukin-activity.
The human interleukin-4 acceptor	GeneSeq accession number W13499	US5599905	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokinies andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; And Siegel﹠amp; Mostowski (1990) JImmunol Methods 132,287-295.	Solubility IL-4 receptor polypeptides can be used for suppressing the interleukin-activity.
						Ro 24-7472/000-12 β-2 acceptor	GeneSeq accession number W12771	EP759466	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Hori et al (1987), Blood 70,1069-1078.	Solubility IL-12 β-2 receptor polypeptides can be used for suppressing the interleukin-activity.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Ro 24-7472/000-12 β-1 acceptor	GeneSeq accession number W12772	EP759466	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Hori et al (1987), Blood 70,1069-1078.	Solubility IL-12 β-1 receptor polypeptides can be used for suppressing the interleukin-activity.
People IL-9 receptor protein	GeneSeq accession number W64055W64056, and W64057	WO9824904	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Yang et al (1989), Blood 74,1880-84.	Solubility IL-9 receptor polypeptides can be used for suppressing the interleukin-activity.
						The IL-10 acceptor	GeneSeq accession number W41804	US5716804	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokiines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Thompson-Snipes et al (1991) J.Exp.Med.173,507-510.	Solubility IL-10 receptor polypeptides can be used for suppressing the interleukin-activity.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Human il-6 receptor	GeneSeq accession number Y30938	JP11196867	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Aarden et al (1987) Eur.J.Immunol 17,1411-16.	Solubility IL-6 receptor polypeptides can be used for suppressing the interleukin-activity.
The I1-17 acceptor	GeneSeq accession number Y97181	US6096305	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Yao et al (1995) J.Immunol.155,5483-86.	Solubility IL-17 receptor polypeptides can be used for suppressing the interleukin-activity.
						The I1-17 acceptor	GeneSeq accession number Y97131	US6100235	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Yao et al (1995) J.Immunol.155,5483-86.	Solubility IL-17 receptor polypeptides can be used for suppressing the interleukin-activity.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Ro 24-7472/000-3 acceptor	GeneSeq accession number K25300	EP509826	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Kitamura et al (1989) J CellPhysiol.140 323-334.	Solubility IL-3 receptor polypeptides can be used for suppressing the interleukin-activity.
The human GM-CSF acceptor	GeneSeq accession number R10919	WO9102063	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Ptess, WashingtOn, D.C.1987, pp.221-225.	Soluble g M-CSF receptor polypeptides can be used for suppressing the interleukin-activity.
						People IL-5 receptor alpha chain	GeneSeq accession number R25064	EP492214	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Kitamura et al (1989) J CellPhysiol.140,323-334.	Solubility IL-5 acceptor α polypeptide can be used for suppressing the interleukin-activity.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						The I1-5 acceptor	GeneSeq accession number W82842	WO9847923	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Kitamura et al (1989) J Cell Physiol.140,323-334.	Solubility IL-5 receptor polypeptides can be used for suppressing the interleukin-activity.
The I1-6 acceptor	GeneSeq accession number R37215	JP05091892	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Aarden et al (1987) Eur.J.Immunol 17,1411-16.	Solubility IL-6 receptor polypeptides can be used for suppressing the interleukin-activity.
						Human B cell stimulating factor-2 acceptor	GeneSeq accession number P90525	AU8928720	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225.	Solubility B-cell stimulating factor-2 receptor polypeptides can be used for suppressing the interleukin-activity.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						The IL-7 receptor cloning	GeneSeq accession number R08330	EP403114	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Park et al (1990) J.Exp.Med.171,1073-79.	Solubility IL-7 receptor polypeptides can be used for suppressing the interleukin-activity.
The EPO acceptor; POR	GeneSeq accession number R06512	WO9008822	The EPO acceptor participates in erythroblastic propagation and differentiation.	Use test known in the art can measure the EPO receptor active: J Biol Chem 2001 Mar23; 276 (12:8995-9002; JAK2 protein tyrosinekinase activity:Blood 1994 Sep 1; 84 (5): 1501-7and Mol Cell Biol.1994 Oct; 14 (10:6506-14.	Inflammatory diseases, immunological disease, cancer, erythroblastic propagation and differentiation.
						The IL-15 acceptor	GeneSeq accession number R90843	WO9530695	Interleukin-is by lymphocyte, monocyte and one group of multifunctional cytokine of scavenger cell synthetic.Known function comprises promotion immunocyte (as t helper cell, B cell, eosinophilic granulocyte and lymphocyte) propagation, the lymphocytic chemotaxis of neutrophilic granulocyte and T, and/or suppress the Interferon, rabbit generation.	Use test known in the art can measure interleukin-activity: Matthews etc., in Lymphokines andInterferons:A Practical Approach, Clemens etc., eds, IRL Press, Washington, D.C.1987, pp.221-225; With Giri et al (1994) EMBO J.132822-2830.	Solubility IL-15 receptor polypeptides can be used for suppressing the interleukin-activity.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						CD137; The 4-1BB receptor protein	GeneSeq accession number R70977	WO9507984	The activity relevant with apoptosis, NF-kB activates and immunocyte (as T and B cell) stimulates altogether.	Use test known in the art can measure the apoptosis activity, NF-kB activation and B and T cell co-stimulatory: Moore etc., 1999, Science, 285 (5425): 260-3; Song HY etc., 1997 Proc Natl Acad Sci U S A94 (18): 9792-6; Epsevik and Nissen-Meyer, 1986, J.Immunol.Methods.	Solubility 4-1BB receptor polypeptides can be used for suppressing apoptosis, and NF-kB activates, and/or immunocyte (as B and T cell) stimulates altogether.
BCMA	GeneSeq accession number Y71979	WO0068378	The activity relevant with apoptosis, NF-kB activates and immunocyte (as T and B cell) stimulates altogether.	Use test known in the art can measure the apoptosis activity, NF-kB activation and B and T cell co-stimulatory: Moore etc., 1999, Science, 285 (5425): 260-3; Song HY etc., 1997 Proc Natl Acad Sci U S A94 (18): 9792-6; Epsevik and Nissen-Meyer, 1986, J.Immunol.Methods.	Solubility BCMA receptor polypeptides can be used for suppressing apoptosis, and NF-kB activates, and/or immunocyte (as B and T cell) stimulates altogether.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						CD27	GeneSeq accession number R20814	WO9201049	The activity relevant with apoptosis, NF-kB activates and immunocyte (as T and B cell) stimulates altogether.	Use test known in the art can measure the apoptosis activity, NF-kB activation and B and T cell co-stimulatory: Moore etc., 1999, Science, 285 (5425): 260-3; Song HY etc., 1997 Proc Natl Acad Sci U S A94 (18): 9792-6; Epsevik and Nissen-Meyer, 1986, J.Immunol.Methods.	Solubility CD27 polypeptide can be used for suppressing apoptosis, and NF-kB activates, and/or immunocyte (as B and T cell) stimulates altogether.
CD30	GeneSeq accession number R35478	DE4200043	The activity relevant with apoptosis, NF-kB activates and immunocyte (as T and B cell) stimulates altogether.	Use test known in the art can measure the apoptosis activity, NF-kB activation and B and T cell co-stimulatory: Moore etc., 1999, Science, 285 (5425): 260-3; Song HY etc., 1997 Proc Natl Acad Sci U S A94 (18): 9792-6; Epsevik and Nissen-Meyer, 1986, J.Immunol.Methods.	Solubility CD30 polypeptide can be used for suppressing apoptosis, and NF-kB activates, and/or immunocyte (as B and T cell) stimulates altogether.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						CD40	GeneSeq accession number Y33499	WO9945944	The activity relevant with apoptosis, NF-kB activates and immunocyte (as T and B cell) stimulates altogether.	Use test known in the art can measure the apoptosis activity, NF-kB activation and B and T cell co-stimulatory: Moore etc., 1999, Science, 285 (5425): 260-3; Song HY etc., 1997 Proc Natl Acad Sci U S A94 (18): 9792-6; Epsevik and Nissen-Meyer, 1986, J.Immunol.Methods.	Solubility CD40 polypeptide can be used for suppressing apoptosis, and NF-kB activates, and/or immunocyte (as B and T cell) stimulates altogether.
EDAR	Genbank accession number AAD50077		The activity relevant with apoptosis, NF-kB activates and immunocyte (as T and B cell) stimulates altogether.	Use test known in the art can measure the apoptosis activity, NF-kB activation and B and T cell co-stimulatory: Moore etc., 1999, Science, 285 (5425): 260-3; Song HY etc., 1997 Proc Natl Acad Sci U S A94 (18): 9792-6; Epsevik and Nissen-Meyer, 1986, J.Immunol.Methods.	Immunological disease, lymphoma, the hypohidrosis ectodermal dysplasia that X-is chain.
						OX40; ACT-4	GeneSeq accession number R74737	WO9512673	The activity relevant with apoptosis, NF-kB activates and immunocyte (as T and B cell) stimulates altogether.	Use test known in the art can measure the apoptosis activity, NF-kB activation and B and T cell co-stimulatory: Moore etc., 1999, Science, 285 (5425): 260-3; Song HY etc., 1997 Proc Natl Acad Sci U S A94 (18): 9792-6; Epsevik and Nissen-Meyer, 1986, J.Immunol.Methods.	Immunological disease, lymphoma, T cytopathy.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						TACI	GeneSeq accession number W75783	WO9839361	The activity relevant with apoptosis, NF-kB activates and immunocyte (as T and B cell) stimulates altogether.	Use test known in the art can measure the apoptosis activity, NF-kB activation and B and T cell co-stimulatory: Moore etc., 1999, Science, 285 (5425): 260-3; Song HY etc., 1997 Proc Natl Acad Sci U S A94 (18): 9792-6; Epsevik and Nissen-Meyer, 1986, J.Immunol.Methods.	Soluble T ACI receptor polypeptides can be used for suppressing apoptosis, and NF-kB activates, and/or immunocyte (as B and T cell) stimulates altogether.
TNF-R	GeneSeq accession number R10986	AU9058976	The activity relevant with apoptosis, NF-kB activates and immunocyte (as T and B cell) stimulates altogether.	Use test known in the art can measure the apoptosis activity, NF-kB activation and B and T cell co-stimulatory: Moore etc., 1999, Science, 285 (5425): 260-3; Song HY etc., 1997 Proc Natl Acad Sci U S A94 (18): 9792-6; Epsevik and Nissen-Meyer, 1986, J.Immunol.Methods.	Soluble TNF-R receptor polypeptides can be used for suppressing apoptosis, and NF-kB activates, and/or immunocyte (as B and T cell) stimulates altogether.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						TNF-RII; The TNFp75 acceptor; The Death acceptor	GeneSeq accession number R11141	EP418014	The activity relevant with apoptosis, NF-kB activates and immunocyte (as T and B cell) stimulates altogether.	Use test known in the art can measure the apoptosis activity, NF-kB activation and B and T cell co-stimulatory: Moore etc., 1999, Science, 285 (5425): 260-3; Song HY etc., 1997 Proc Natl Acad Sci U S A94 (18): 9792-6; Epsevik and Nissen-Meyer, 1986, J.Immunol.Methods.	Soluble TNF R-II receptor polypeptides can be used for suppressing apoptosis, and NF-kB activates, and/or immunocyte (as B and T cell) stimulates altogether.
HAPO-4; TROY	GeneSeq accession number W93581	WO9911791	The activity relevant with apoptosis, NF-kB activates and immunocyte (as T and B cell) stimulates altogether.	Use test known in the art can measure the apoptosis activity, NF-kB activation and B and T cell co-stimulatory: Moore etc., 1999, Science, 285 (5425): 260-3; Song HY etc., 1997 Proc Natl Acad Sci U S A94 (18): 9792-6; Epsevik and Nissen-Meyer, 1986, J.Immunol.Methods.	Immunological disease, cancer
						TNF-α precursor	GeneSeq accession number P60074	EP205038	The activity relevant with apoptosis, NF-kB activates and immunocyte (as T and B cell) stimulates altogether.	Use test known in the art can measure the apoptosis activity, NF-kB activation and B and T cell co-stimulatory: Moore etc., 1999, Science, 285 (5425): 260-3; Song HY etc., 1997 Proc Natl Acad Sci U S A94 (18): 9792-6; Epsevik and Nissen-Meyer, 1986, J.Immunol.Methods.	Inflammatory diseases, immunological disease, cancer

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						The humanTNF-	GeneSeq accession number R62463	EP619372	The activity relevant with apoptosis, NF-kB activates and immunocyte (as T and B cell) stimulates altogether.	Use test known in the art can measure the apoptosis activity, NF-kB activation and B and T cell co-stimulatory: Moore etc., 1999, Science, 285 (5425): 260-3; Song HY etc., 1997 Proc Natl Acad Sci U S A94 (18): 9792-6; Epsevik and Nissen-Meyer, 1986, J.Immunol.Methods.	Inflammatory diseases, immunological disease, cancer
The humanTNF-	GeneSeq accession number R42679	EP563714	The activity relevant with apoptosis, NF-kB activates and immunocyte (as T and B cell) stimulates altogether.	Use test known in the art can measure the apoptosis activity, NF-kB activation and B and T cell co-stimulatory: Moore etc., 1999, Science, 285 (5425): 260-3; Song HY etc., 1997 Proc Natl Acad Sci U S A94 (18): 9792-6; Epsevik and Nissen-Meyer, 1986, J.Immunol.Methods.	Inflammatory diseases, immunological disease, cancer
						People TNF-β (LT-α)	GeneSeq accession number B37799	WO0064479	The activity relevant with apoptosis, NF-kB activates and immunocyte (as T and B cell) stimulates altogether.	Use test known in the art can measure the apoptosis activity, NF-kB activation and B and T cell co-stimulatory: Moore etc., 1999, Science, 285 (5425): 260-3; Song HY etc., 1997 Proc Natl Acad Sci U S A94 (18): 9792-6; Epsevik and Nissen-Meyer, 1986, J.Immunol.Methods.	Inflammatory diseases, immunological disease, cancer

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						LT-α	GeneSeq accession number P70107	EP250000	The activity relevant with apoptosis, NF-kB activates and immunocyte (as T and B cell) stimulates altogether.	Use test known in the art can measure the apoptosis activity, NF-kB activation and B and T cell co-stimulatory: Moore etc., 1999, Science, 285 (5425): 260-3; Song HY etc., 1997 Proc Natl Acad Sci U S A94 (18): 9792-6; Epsevik andNissen-Meyer, 1986, J.Immuno1.Methods.	Inflammatory diseases, immunological disease, cancer
LT-β	GeneSeq accession number R56869	WO9413808	The activity relevant with apoptosis, NF-kB activates and immunocyte (as T and B cell) stimulates altogether.	Use test known in the art can measure the apoptosis activity, NF-kB activation and B and T cell co-stimulatory: Moore etc., 1999, Science, 285 (5425): 260-3; Song HY etc., 1997 Proc Natl Acad Sci U S A94 (18): 9792-6; Epsevik and Nissen-Meyer, 1986, J.Immunol.Methods.	Inflammatory diseases, immunological disease, cancer
						OPGL	GeneSeq accession number W83195	WO9846751	The activity relevant with apoptosis, NF-kB activates and immunocyte (as T and B cell) stimulates altogether.	Use test known in the art can measure the apoptosis activity, NF-kB activation and B and T cell co-stimulatory: Moore etc., 1999, Science, 285 (5425): 260-3; Song HY etc., 1997 Proc Natl Acad Sci U S A94 (18): 9792-6; Epsevik and Nissen-Meyer, 1986, J.Immunol.Methods.	Inflammatory diseases, immunological disease, cancer, bone mass loss

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						FasL	GeneSeq accession number W98071	WO9903999	The activity relevant with apoptosis, NF-kB activates and immunocyte (as T and B cell) stimulates altogether.	Use test known in the art can measure the apoptosis activity, NF-kB activation and B and T cell co-stimulatory: Moore etc., 1999, Science, 285 (5425): 260-3; Song HY etc., 1997 Proc Natl Acad Sci U S A94 (18): 9792-6; Epsevik and Nissen-Meyer, 1986, J.Immunol.Methods.	Inflammatory diseases, immunological disease, cancer
FasL	GeneSeq accession number W95041	WO9903998	The activity relevant with apoptosis, NF-kB activates and immunocyte (as T and B cell) stimulates altogether.	Use test known in the art can measure the apoptosis activity, NF-kB activation and B and T cell co-stimulatory: Moore etc., 1999, Science, 285 (5425): 260-3; Song HY etc., 1997 Proc Natl Acad Sci U S A94 (18): 9792-6; Epsevik and Nissen-Meyer, 1986, J.Immunol.Methods.	Inflammatory diseases, immunological disease, cancer
						CD27L	GeneSeq accession number R50121	WO9405691	The activity relevant with apoptosis, NF-kB activates and immunocyte (as T and B cell) stimulates altogether.	Use test known in the art can measure the apoptosis activity, NF-kB activation and B and T cell co-stimulatory: Moore etc., 1999, Science, 285 (5425): 260-3; Song HY etc., 1997 Proc Natl Acad Sci U S A94 (18): 9792-6; Epsevik and Nissen-Meyer, 1986, J.Immunol.Methods.	Inflammatory diseases, immunological disease, cancer

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						The CD30 part	GeneSeq accession number R45007	WO9324135	The activity relevant with apoptosis, NF-kB activates and immunocyte (as T and B cell) stimulates altogether.	Use test known in the art can measure the apoptosis activity, NF-kB activation and B and T cell co-stimulatory: Moore etc., 1999, Science, 285 (5425): 260-3; Song HY etc., 1997 Proc Natl Acad Sci U S A94 (18): 9792-6; Epsevik and Nissen-Meyer, 1986, J.Immunol.Methods.	Inflammatory diseases, immunological disease, cancer
CD40L	GeneSeq accession number R85486	WO9529935	The activity relevant with apoptosis, NF-kB activates and immunocyte (as T and B cell) stimulates altogether.	Use test known in the art can measure the apoptosis activity, NF-kB activation and B and T cell co-stimulatory: Moore etc., 1999, Science, 285 (5425): 260-3; Song HY etc., 1997 Proc Natl Acad Sci U S A94 (18): 9792-6; Epsevik and Nissen-Meyer, 1986, J.Immurnol.Methods.	Inflammatory diseases, immunological disease, cancer
						The 4-1BB part	GeneSeq accession number W26657	US5674704	The activity relevant with apoptosis, NF-kB activates and immunocyte (as T and B cell) stimulates altogether.	Use test known in the art can measure the apoptosis activity, NF-kB activation and B and T cell co-stimulatory: Moore etc., 1999, Science, 285 (5425): 260-3; Song HY etc., 1997 Proc Natl Acad Sci U S A94 (18): 9792-6; Epsevik and Nissen-Meyer, 1986, J.Immunol.Methods.	Inflammatory diseases, immunological disease, cancer

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						FAS part arrestin (DcR3)	GeneSeq accession number B19335	WO0058465	The activity relevant with apoptosis, NF-kB activates and immunocyte (as T and B cell) stimulates altogether.	Use test known in the art can measure the apoptosis activity, NF-kB activation and B and T cell co-stimulatory: Moore etc., 1999, Science, 285 (5425): 260-3; Song HY etc., 1997 Proc Natl Acad Sci U S A94 (18): 9792-6; Epsevik and Nissen-Meyer, 1986, J.Immunol.Methods.	Solubility DcR3 polypeptide can be used for suppressing apoptosis, and NF-kB activates, and/or immunocyte (as B and T cell) stimulates altogether.
OX40L	GeneSeq accession number R79903	WO9521915	The activity relevant with apoptosis, NF-kB activates and immunocyte (as T and B cell) stimulates altogether.	Use test known in the art can measure the apoptosis activity, NF-kB activation and B and T cell co-stimulatory: Moore etc., 1999, Science, 285 (5425): 260-3; Song HY etc., 1997 Proc Natl Acad Sci U S A94 (18): 9792-6; Epsevik and Nissen-Meyer, 1986, J.Immunol.Methods.	Inflammatory diseases, immunological disease, cancer

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						The proteinase inhibitor peptide	GeneSeq accession number R12435, R12436, R12437, R12438, R12439, R12440, and R1244	WO9106561	Suppress HIV function/bonded peptide.	The hiv protease activity is known in the art: hiv protease test: EP0387231.Can change to use any disclosed proteinase inhibitor polypeptide to seek restraining effect this test.	HIV, inflammatory diseases, immunological disease, cancer, virus infection

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Retroviral Protease inhibitors	GeneSeq accession number R06660, R06661, R06662, R06663, R06664, R06665, R06666, R06667, R06668, R06669, R06670, R06671, R06672, R06673, R06674, R06675, and R06676	EP387231	Suppress HIV function/bonded peptide.	The hiv protease activity is known in the art: hiv protease test: EP0387231.Can change to use any disclosed proteinase inhibitor polypeptide to seek restraining effect this test.	HIV, inflammatory diseases, immunological disease, cancer, virus infection

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						The hiv protease inhibiting peptide	GeneSeq accession number R59293, R59294, R59295, R59296, R59297, R59298, R59299, R592300, R59301, R59302, R59301, R59302, R59303, R59304, R59305, R59306, R59307, R59308, R59309, R59310, R59311, R59312, R59313, R59314, R59315, R59316, R59317, R59318, R59319, R59320, R59321, R59322, R59323, R59324, R59325, R59326, R59327, R59328, R59329, R59330, R59331, R59332, R59333, R59334, R59335, R59336, R59337, R59338, R59339, R59340, R59341, R59342, R59343, R59344, R59345, R59346, R59347, R59348, R59349, and R59350	WO9301828	Suppress HIV function/bonded peptide.	The hiv protease activity is known in the art: hiv protease test: EP0387231.Can change to use any disclosed proteinase inhibitor polypeptide to seek restraining effect this test.	HIV, inflammatory diseases, immunological disease, cancer, virus infection

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						The HIV-1 proteinase inhibitor	GeneSeq accession number R86326, R86327R86328, R86329, RR6330, R86331, RR6332, R86333, R86334, R86335, R86336, R86337, R86338, R86339, RR6340, R86341, R86342, R86343R86344, R86345, R86346, R86347, R86348, R86349, R86350, R86351, R86352, R86353, R86354, R86355, R86356, R86357, R86358, R86359, R86360, R86361, R86362, R86363, R86364, R86365, R86366, R86367, R86368, R86369, R86370, and R86371	DE4412174	Suppress HIV function/bonded peptide.	The hiv protease activity is known in the art: hiv protease test: EP0387231.Can change to use any disclosed proteinase inhibitor polypeptide to seek restraining effect this test.	HIV, inflammatory diseases, immunological disease, cancer, virus infection

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						The hiv inhibitor peptide	GeneSeq accession number Y89687	WO9959615	Suppress HIV function/bonded peptide.	The hiv protease activity is known in the art: hiv protease test: EP0387231.Can change to use any disclosed proteinase inhibitor polypeptide to seek restraining effect this test.	HIV, inflammatory diseases, immunological disease, cancer, virus infection
The hiv inhibitor peptide	GenSeq accession number Y31955	WO9948513	Suppress HIV function/bonded peptide.	The hiv protease activity is known in the art: hiv protease test: EP0387231.Can change to use any disclosed proteinase inhibitor polypeptide to seek restraining effect this test.	HIV, inflammatory diseases, immunological disease, cancer, virus infection
						The hiv inhibitor peptide	Www.sci Encexpre Ss.org;Published online12January2001:10.1126/science.1057453		Suppress HIV function/bonded peptide.	The hiv protease activity is known in the art: hiv protease test: EP0387231.Can change to use any disclosed proteinase inhibitor polypeptide to seek restraining effect this test.	HIV, inflammatory diseases, immunological disease, cancer, virus infection

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Person monocytic cell's chemoattractant factor hMCP-3	GeneSeq accession number R73915	WO9509232	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease particularly can be used for treating bacterium and/or viral meningitis.
Person monocytic cell's chemoattractant factor hMCP-1	GeneSeq accession number R73914	WO9509232	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.l.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease particularly can be used for treating bacterium and/or viral meningitis.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						People gro-β chemokine	GeneSeq accession number R66699 and W17671	WO9429341	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease, inflammatory diseases, blood-relative disease, stem cell transplantation, cancer
People gro-γ chemokine	GeneSeq accession number R66700 and W17672	WO9429341	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease, inflammatory diseases, blood-relative disease, stem cell transplantation, cancer

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						People gro-α chemokine	GeneSeq accession number R66698 and W18024	WO9429341	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease, inflammatory diseases, blood-relative disease, stem cell transplantation, cancer
The chemokine (EEC) that people's eosinophilic granulocyte is expressed	GeneSeq accession number W05186	WO9632481	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease particularly can be used for treating eosinophilia, inflammation, transformation reactions, asthma, leukemia and lymphoma.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Total length and sophisticated chemokine-sample albumen PF4-414	GeneSeq accession number R92318 and R99809	WO9613587	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Cancer and blood-relative disease, particularly bone marrow depression.
Chemokine-sample protein I L-8M3	GeneSeq accession number R99812	WO9613587	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ; With Holmes etal (1991) Science 253,1278-80.	Cancer and blood-relative disease, particularly bone marrow depression.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Ro 24-7472/000-8 (IL-8)	GeneSeq accession number R99814	WO9613587	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ; With Holmes etal (1991) Science 253,1278-80.	Cancer and blood-relative disease, particularly bone marrow depression.
Total length and sophisticated chemokine-sample protein I L-8M1	GeneSeq accession number R99815 and R99803	WO9613587	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ; With Holmes etal (1991) Science 253,1278-80.	Cancer and blood-relative disease, particularly bone marrow depression.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Total length and sophisticated chemokine-sample protein I L-8M8	GeneSeq accession number R99816 and R99805	WO9613587	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ; With Holmes etal (1991) Science 253,1278-80.	Cancer and blood-relative disease, particularly bone marrow depression.
Total length and sophisticated chemokine-sample protein I L-8M8	GeneSeq accession number R99817 and R99806	WO9613587	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ; With Holmes etal (1991) Science 253,1278-80.	Cancer and blood-relative disease, particularly bone marrow depression.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Total length and sophisticated chemokine-sample protein I L-8M8	GeneSeq accession number R99818 and R99804	WO9613587	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ; With Holmes etal (1991) Science 253,1278-80.	Cancer and blood-relative disease, particularly bone marrow depression.
Total length and sophisticated chemokine-sample protein I L-8M8	GeneSeq accession number R99819 and R99807	WO9613587	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Cancer and blood-relative disease, particularly bone marrow depression.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Total length and sophisticated chemokine-sample protein I L-8M8	GeneSeq accession number R99822 and R9807	WO9613587	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Cancer and blood-relative disease, particularly bone marrow depression.
The chemokine that people's tire spleen is expressed, FSEC	GeneSeq accession number R98499	WO9622374	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						The chemokine of liver expression-1 (LVEC-1)	GeneSeq accession number R95689	WO9616979	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Hepatitis
The chemokine of liver expression-2 (LVEC-2)	GeneSeq accession number R95690	WO9616979	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Hepatitis

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						The chemokine (PGEC) that hypophysis is expressed	GeneSeq accession number R95691	WO9616979	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Inflammation, particularly hepatitis.
The chemokine of body of gland-expression (ADEC)	GeneSeq accession number R97664	WO9617868	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Inflammation, blood vessel takes place, and tumour takes place, the flesh bone disease

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Human chemokine CC-	GeneSeq accession number W38170	WO9741230	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease, cell migration, propagation and differentiation disease
Human chemokine HCC-1	GeneSeq accession number W38171	WO9741230	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease, cell migration, propagation and differentiation disease

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Human chemokine CC-3	GeneSeq accession number W38172	WO9741230	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease, cell migration, propagation and differentiation disease
The new β chemokine that is called as PTEC	GeneSeq accession number W27271	WO9739126	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease, vascular disease, cancer

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						People CX3C111-amino acid chemokine	GeneSeq accession number W23344	WO9727299	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease, inflammatory diseases, abnormality proliferation, regeneration, degeneration and atrophy
People CCF18 chemokine	GeneSeq accession number W25942	WO9721812	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Abnormal physiology is learned and disorder of development, also can be used as anti--viral agent

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						People β chemokine-H1305 (MCP-2)	GeneSeq accession number W26655	WO9725427	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Chemotaxis, blood-relative disease, virus infection, HIV, wound healing, cancer
People's eosinophilic granulocyte CC type chemokine eotaxin	GeneSeq accession number W14990	WO9712914	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Inflammatory diseases and immunological disease

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						The cytokine (TARC) that people's thymus gland and activation are regulated	GeneSeq accession number W14018	WO9711969	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Inflammatory diseases and immunological disease
Short type human chemokine beta-8	GeneSeq accession number W16315	WO9712041	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Cancer, wound healing, immunological disease

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Microphage deutero-chemokine, MDC	GeneSeq accession number W20058	WO9640923	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Inflammatory diseases, wound healing, blood vessel takes place
Human chemokine ZSIG-35	GeneSeq accession number W30565	WO9844117	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Inflammatory diseases and immunological disease

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Primates CC chemokine " ILINCK	GeneSeq accession number W69990	WO98328658	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease, inflammatory diseases, abnormality proliferation, regeneration, reproduction and wilt disease
Primates CXC chemokine " IBICK "	GeneSeq accession number W69989	WO9832858	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease, inflammatory diseases, abnormality proliferation, regeneration, reproduction and wilt disease

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						The people CC-type chemokine protein that is called as SLC (secondary lymphoid tissue chemokine)	GeneSeq accession number W69163	WO9831809	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease, inflammatory diseases and transmissible disease, cancer
People CC chemokine ELC albumen	GeneSeq accession number W62542	WO9826071	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Cancer and transmissible disease, particularly simplexvirus

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						People DVic-1C-C chemokine	GeneSeq accession number W60649	WO9823750	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Abnormality proliferation, regeneration, degeneration and wilt disease comprise cancer
People C-C chemokine DGWCC	GeneSeq accession number W60650	WO9823750	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease, cell proliferation disease, cancer

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						People STCP-1	GeneSeq accession number W62783	WO9824907	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease, particularly T cell related diseases, virus infection and inflammation, particularly sacroiliitis
Exodua albumen	GeneSeq accession number W61279	WO9821330	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease and inflammatory diseases, blood vessel takes place, and cancer and propagation are sick, particularly the bone marrow proliferation disease

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						People Chr19Kine albumen	GeneSeq accession number W50887	WO9814581	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Cancer and Degenerative disease
The chemokine (TMEC) that human T-cell's mixed lymphocyte reacion is expressed	GeneSeq accession number W58703	US5780268	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease, inflammatory diseases and transmissible disease, cancer

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						People 6CKine albumen	GeneSeq accession number W50885	W09814581	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Cancer and Degenerative disease
The chemokine (LARC) that people's liver and activation are regulated	GeneSeq accession number W57475	WO9817800	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular B iology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease, inflammatory diseases and transmissible disease, cancer

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						The RANTES peptide	GeneSeq accession number W29538	WO9744462	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Transmissible disease, particularly HIV
RANTES8-68	GeneSeq accession number W29529	WO9744462	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, voL138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Transmissible disease, particularly HIV

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						RANTES9-68	GeneSeq accession number W29528	WO9744462	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot.T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Transmissible disease, particularly HIV
Human chemokine albumen 331D5	GeneSeq accession number W59433	WO9811226	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Abnormality proliferation, regeneration, degeneration and wilt disease comprise cancer

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Human chemokine albumen 61164	GeneSeq accession number W59430	WO9811226	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Abnormality proliferation, regeneration, degeneration and wilt disease comprise cancer
Chemokine MCP-4	GeneSeq accession number W56690	WO9809171	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease, inflammatory diseases and transmissible disease

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						The chemokine of people's stroma cell derivative, SDF-1	GeneSeq accession number W50766	FR2751658	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	HIV infects
The chemokine (TECK) that thymus gland is expressed	GeneSeq accession number W44397	WO9801557	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease and inflammatory diseases

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Human chemokine MIP-3 α	GeneSeq accession number W44398	WO9801557	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease and inflammatory diseases
Human chemokine MIP-3 β	GeneSeq accession number W44399	WO9801557	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease and inflammatory diseases

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Protein (MCPP) sequence before person monocytic cell's chemotactic	GeneSeq accession number W42072	WO9802459	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular B iology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease, respiratory disease, cancer
Scavenger cell-deutero-chemokine (MDC)	GeneSeq accession number W40811 and Y24414	US5688927/ US5932703	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease and inflammatory diseases, cancer

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Scavenger cell deutero-chemokine analogue MDC-eyfy	GeneSeq accession number Y24416	US5932703	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease and inflammatory diseases
Scavenger cell deutero-chemokine analogue MDC (n+1)	GeneSeq accession number Y24413	US5932703	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease and inflammatory diseases

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Scavenger cell deutero-chemokine analogue MDC-yl	GeneSeq accession number Y24415	US5932703	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease and inflammatory diseases
People CC type chemokine eotaxin 3 protein sequences	GeneSeq accession number Y43178	JP11243960	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Allergic disease and HIV infect

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						People MCP-3 and people Muc-1 core epi-position (VNT) fusion rotein	GeneSeq accession number Y29893	WO9946392	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Cancer and immunological disease, particularly HIV infect
People IP-10 and people Muc-1 core epi-position (VNT) fusion rotein	GeneSeq accession number Y29894	WO9946392	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Cancer and immunological disease, particularly HIV infect

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						People IP-10 and HIV-1gp 120 hypervariable region fusion roteins	GeneSeq accession number Y29897	W09946392	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Cancer and immunological disease, particularly HIV infect
Total length and the relevant chemokine of sophisticated people's mammary gland (MACK) albumen	GeneSeq accession number Y29092 and Y29093	WO9936540	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Mastopathy comprises cancer

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Tim-1 albumen	GeneSeq accession number Y28290	WO9933990	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Because of the inflammation that stimulator causes, described stimulator such as heart trouble outbreak and apoplexy infect, somatic damage, UV or ionizing rays, burn, frostbite or corrosive compound
Total length and sophisticated people Lkn-1 albumen	GeneSeq accession number Y17280, Y17274, Y17281, and Y17275	WO9928473 and WO9928472	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	HIV infects and cancer, particularly leukemia

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						The chemokine met-hSDF-1 α that N-is end modified	GeneSeq accession number Y05818	WO9920759	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methodsin Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Suppress or impel vasculogenesis, suppress the HIV combination
The chemokine met-hSDF-1 β that N-is end modified	GeneSeq accession number Y05819	WO9920759	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Suppress or impel vasculogenesis, suppress the HIV combination, anti-inflammatory; Immunosuppressor

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						The chemokine GroHEK/hSDF-1 α that N-is end modified	GeneSeq accession number Y05820	WO9920759	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Suppress or impel vasculogenesis, suppress the HIV combination, anti-inflammatory; Immunosuppressor
The chemokine GroHEK/hSDF-1 β that N-is end modified	GeneSeq accession number Y05821	WO9920759	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Suppress or impel vasculogenesis, suppress the HIV combination, anti-inflammatory; Immunosuppressor

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Chemokine Eotaxin	GeneSeq accession number Y14230	WO9912968	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Increase or strengthen inflammatory reaction, immunne response or hematopoietic cell-related activity; The treatment vascular disorder; Cancer; Strengthen wound healing; Prevention or treatment asthma, organ-graft refection, rheumatoid arthritis or transformation reactions
Chemokine hMCPla	GeneSeq accession number Y14225	WO9912968	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press inc., Totowa, NJ.	Immunological disease, vascular disease, wound healing, cancer, prevention of organ transplant rejection increases or strengthens inflammatory reaction

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Chemokine hMCP1b	GeneSeq accession number Y14226	WO9912968	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease, vascular disease, wound healing, cancer, prevention of organ transplant rejection increases or strengthens inflammatory reaction
Chemokine hSDF1b	GeneSeq accession number Y14228	WO9912968	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease, vascular disease, wound healing, cancer, prevention of organ transplant rejection increases or strengthens inflammatory reaction

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Chemokine hIL-8	GeneSeq accession number Y14229	WO9912968	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ; With Holmes etal (1991) Science 253,1278-80.	Immunological disease, vascular disease, wound healing, cancer, prevention of organ transplant rejection increases or strengthens inflammatory reaction
Chemokine hMCP1	GeneSeq accession number Y14222	WO9912968	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease, vascular disease, wound healing, cancer, prevention of organ transplant rejection increases or strengthens inflammatory reaction

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Chemokine hMCP2	GeneSeq accession number Y14223	WO9912968	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease, vascular disease, wound healing, cancer, prevention of organ transplant rejection increases or strengthens inflammatory reaction
Chemokine hMCP3	GeneSeq accession number Y14224	WO9912968	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease, vascular disease, wound healing, cancer, prevention of organ transplant rejection increases or strengthens inflammatory reaction

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						The C-C chemokine, MCP2	GeneSeq accession number Y05300	EP905240	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Inflammatory diseases, immunological disease and transmissible disease; Tuberculosis and tetter; Tumour, and vasculogenesis-and hemopoietic-relative disease
The wild-type monocyte chemotactic protein-2	GeneSeq accession number Y07233	EP906954	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Inflammatory diseases, immunological disease and transmissible disease; Tuberculosis and tetter; Tumour, and vasculogenesis-and hemopoietic-relative disease

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						The monocyte chemotactic protein-2 of brachymemma (6-76)	GeneSeq accession number Y07234	EP906954	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Inflammatory diseases, immunological disease and transmissible disease; Tuberculosis and tetter; Tumour, and vasculogenesis-and hemopoietic-relative disease
The RANTES albumen (3-68) of brachymemma	GeneSeq accession number Y07236 and Y07232	EP905241; EP906954	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Inflammatory diseases, immunological disease and transmissible disease; Tuberculosis and tetter; Tumour, and vasculogenesis-and hemopoietic-relative disease

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						The wild-type monocyte chemotactic protein-2	GeneSeq accession number Y07237	EP905241	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Inflammatory diseases, immunological disease and transmissible disease; Tuberculosis and tetter; Tumour, and vasculogenesis-and hemopoietic-relative disease
The monocyte chemotactic protein-2 of brachymemma (6-76)	GeneSeq accession number Y07238	EP905241	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Inflammatory diseases, immunological disease and transmissible disease; Tuberculosis and tetter; Tumour, and vasculogenesis-and hemopoietic-relative disease

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Portion C XCR4B albumen	GeneSeq accession number W97363	EP897980	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Solubility CXCR4B receptor polypeptides can be used for chemokine inhibiting activity and virus infection
Interferon-gamma-inducible protein (IP-10)	GeneSeq accession number W96709	US5871723	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Vasculogenesis, cancer, inflammatory diseases and immunological disease, cardiovascular diseases, flesh-bone disease

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Gamma-interferon inductive monokine (MIG)	GeneSeq accession number W96710	US5871723	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Vasculogenesis, cancer, inflammatory diseases and immunological disease, cardiovascular diseases, flesh-bone disease
Interleukin 8 (IL-8) albumen	GeneSeq accession number W96711	US5871723	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ; With Holmes etal (1991) Science 253,1278-80.	Vasculogenesis, cancer, inflammatory diseases and immunological disease, cardiovascular diseases, flesh-bone disease

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Epithelium neutrophil activation protein-7 8 (ENA-78)	GeneSeq accession number W96712	US5871723	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Vasculogenesis, cancer, inflammatory diseases and immunological disease, cardiovascular diseases, flesh-bone disease
Relevant oncogene-the α (GRO-α) of growth	GeneSeq accession number W96713	US5871723	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Vasculogenesis, cancer, inflammatory diseases and immunological disease, cardiovascular diseases, flesh-bone disease

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Relevant oncogene-the β (GRO-β) of growth	GeneSeq accession number W96714	US5871723	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Vasculogenesis, cancer, inflammatory diseases and immunological disease, cardiovascular diseases, flesh-bone disease
Relevant oncogene-the γ (GRO-γ) of growth	GeneSeq accession number W96715	US5871723	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Vasculogenesis, cancer, inflammatory diseases and immunological disease, cardiovascular diseases, flesh-bone disease

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Platelet basic protein (PBP)	GeneSeq accession number W96716	US5871723	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Vasculogenesis, cancer, inflammatory diseases and immunological disease, cardiovascular diseases, flesh-bone disease
Reticular tissue activated protein-III (CTAP-II1)	GeneSeq accession number S96717	US5871723	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Vasculogenesis, cancer, inflammatory diseases and immunological disease, cardiovascular diseases, flesh-bone disease

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						β-thromboglobulin (β-TG)	GeneSeq accession number W96718	US5871723	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Vasculogenesis, cancer, inflammatory diseases and immunological disease, cardiovascular diseases, flesh-bone disease
Neutrophil activation peptide-2 (NAP-2)	GeneSeq accession number W96719	US5871723	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Vasculogenesis, cancer, inflammatory diseases and immunological disease, cardiovascular diseases, flesh-bone disease

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Granulocyte chemoattractant protein-2 (GCP-2)	GeneSeq accession number W96720	US5871723	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Vasculogenesis, cancer, inflammatory diseases and immunological disease, cardiovascular diseases, flesh-bone disease
Human chemokine MIG-β albumen	GeneSeq accession number W90124	EP887409	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease, virus, parasite, fungi or infectation of bacteria, cancer; Autoimmune disease or transplant rejection

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						People ZCHEMO-8	GeneSeq accession number W82716	WO9854326	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease, cancer, myelocyte generates disease, autoimmune disease and immunodeficiency, inflammatory diseases and transmissible disease, vascular disease, wound healing
People Act-2 albumen	GeneSeq accession number W82717	WO9854326	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease, cancer, myelocyte generates disease, autoimmune disease and immunodeficiency, inflammatory diseases and transmissible disease, vascular disease, wound healing

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						People SISD albumen	GeneSeq accession number W82720	WO9854326	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease, cancer, myelocyte generates disease, autoimmune disease and immunodeficiency, inflammatory diseases and transmissible disease, vascular disease, wound healing
People M110 albumen	GeneSeq accession number W82721	WO9854326	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease, cancer, myelocyte generates disease, autoimmune disease and immunodeficiency, inflammatory diseases and transmissible disease, vascular disease, wound healing

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						People M11A albumen	GeneSeq accession number W82722	W09854326	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease, cancer, myelocyte generates disease, autoimmune disease and immunodeficiency, inflammatory diseases and transmissible disease, vascular disease, wound healing
People CCC3 albumen	GeneSeq accession number W82723	WO9854326	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease, cancer, myelocyte generates disease, autoimmune disease and immunodeficiency, inflammatory diseases and transmissible disease, vascular disease, wound healing

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						The people L105 chemokine that is called as huL105_3	GeneSeq accession number W87588	WO9856818	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Cancer, wound healing
The people L105 chemokine that is called as huL105_7	GeneSeq accession number W87589	WO9856818	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Cancer, wound healing

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						The ripe gro-α of the people polypeptide that is used for the treatment of sepsis	GeneSeq accession number W81498	WO9848828	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Transmissible disease, sepsis
The ripe gro-γ of the people polypeptide that is used for the treatment of sepsis	GeneSeq accession number W81500	WO9848828	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Transmissible disease, sepsis

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Chemokine TECK and TECK variant that people's thymus gland is expressed	GeneSeq accession number B19607 and B19608	WO0053635	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Inflammatory diseases, cancer, immunological disease and vascular disease
People's chemotactic is because of SDF1 α	GeneSeq accession number B15791	WO0042071	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Autoimmune disease, immunological disease, vascular disease and inflammatory diseases

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Human chemokine GRO α	GeneSeq accession number B15793	WO0042071	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Autoimmune disease, immunological disease, vascular disease and inflammatory diseases
People's chemotactic is because of eotaxin	GeneSeq accession number B15794	WO0042071	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Autoimmune disease, immunological disease, vascular disease and inflammatory diseases

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Human chemokine MIG	GeneSeq accession number B15803	WO0042071	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Autoimmune disease, immunological disease, vascular disease and inflammatory diseases
Human chemokine PF4	GeneSeq accession number B15804	WO0042071	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Autoimmune disease, immunological disease, vascular disease and inflammatory diseases

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Human chemokine I-309	GeneSeq accession number B15805	WO0042071	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Autoimmune disease, immunological disease, vascular disease and inflammatory diseases
Human chemokine HCC-1	GeneSeq accession number B15806	WO0042071	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Autoimmune disease, immunological disease, vascular disease and inflammatory diseases

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Human chemokine C10	GeneSeq accession number B15807	WO0042071	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Autoimmune disease, immunological disease, vascular disease and inflammatory diseases
Human chemokine CCR-2	GeneSeq accession number B15808	WO0042071	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Autoimmune disease, immunological disease, vascular disease and inflammatory diseases

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Human chemokine ENA-78	GeneSeq accession number B15809	WO0042071	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Autoimmune disease, immunological disease, vascular disease and inflammatory diseases
Human chemokine GRO β	GeneSeq accession number B15810	WO0042071	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Autoimmune disease, immunological disease, vascular disease and inflammatory diseases

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Human chemokine IP-10	GeneSeq accession number B15811	WO0042071	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Autoimmune disease, immunological disease, vascular disease and inflammatory diseases
Human chemokine SDF1 β	GeneSeq accession number B15812	WO0042071	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Autoimmune disease, immunological disease, vascular disease and inflammatory diseases

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Human chemokine GRO α	GeneSeq accession number B15813	WO0042071	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Autoimmune disease, immunological disease, vascular disease and inflammatory diseases
Human chemokine MIP1 β	GeneSeq accession number B15831	WO0042071	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Autoimmune disease, immunological disease, vascular disease and inflammatory diseases

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						The people C-C chemokine that is called as exodus	GeneSeq accession number B07939	US6096300	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Cancer
People's chemotactic is because of L105_7	GeneSeq accession number Y96922	US6084071	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Chemotaxis, gene therapy, wound healing

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Human chemokine L105_3	GeneSeq accession number Y96923	US6084071	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Chemotaxis, gene therapy, wound healing
People's secondary lymphoid tissue chemokine (SLC)	GeneSeq accession number B01434	WO0038706	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Cancer, vascular disease and immunological disease

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						People non--ELRCXC chemokine H174	GeneSeq accession number Y96310	WO0029439	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease and inflammatory diseases, cancer, hemostasis and thrombolysis activity
People non--ELRCXC chemokine IP10	GeneSeq accession number Y96311	WO0029439	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease and inflammatory diseases, cancer, hemostasis and thrombolysis activity

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						People non--ELRCXC chemokine Mig	GeneSeq accession number Y96313	WO0029439	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Immunological disease and inflammatory diseases, cancer, hemostasis and thrombolysis activity
Human chemokine Ck β-7	GeneSeq accession number Y96280	WO0028035	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Cancer, wound healing, inflammatory diseases and immunomodulatory disease

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Human chemokine MIP-1 α	GeneSeq accession number Y96281	WO0028035	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Cancer, wound healing, inflammatory diseases and immunomodulatory disease
The ripe chemokine Ck of people β-7 (optional for brachymemma)	GenSeq accession number Y96282	WO0028035	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Cancer, wound healing, inflammatory diseases and immunomodulatory disease

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Human chemokine receptor CXCR3	GeneSeq accession number Y79372	WO0018431	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Solubility CXCR3 polypeptide can be used for chemokine inhibiting activity and virus infection
People neurotactin chemokine-like structural domain	GeneSeq accession number Y53259	US6043086	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Neuropathy, immunological disease and respiratory disease

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						People CC type chemokine interleukin-C	GeneSeq accession number Y57771	JP11302298	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Cancer and transmissible disease
People CK β-9	GeneSeq accession number B50860	US6153441	Chemokine is the little secretory protein family that is correlated with, and its participates in hemopoietic, vasculogenesis and white corpuscle and transports this series of biologic process.The member of this family is relevant with the similar pathology of diversity, and described pathology comprise inflammation, transformation reactions, tissue rejection, virus infection and oncobiology.Chemokine works and brings into play its effect by striding film G-protein linked receptor family to 7.40 various human chemokines have been described, they can with about 17 receptors bind of having identified so far.	Use test known in the art can measure the chemokine activity: Methods in Molecular Biology, 2000, vol.138:Chemokine Protocols.Edited by:A.E.I.Proudfoot, T.N.C.Wells, and C.A.Power.  Humana Press Inc., Totowa, NJ.	Cancer, autoimmune disease and inflammatory diseases, cardiovascular diseases
						Preapoprotein former " paris " variant	GeneSeq accession number W08602	WO9637608	Apoa-1 is by impelling cholesterol and discharge from tissue and participate in cholesterol from organizing the antiport to liver by the cofactor that is used as Lecithin-cholesterol acyltransferase (lcat), thereby cholesterol is secreted outward.	Use test known in the art, as Takahaski etc., P.N.A.S., Vol.96, Issue 20,11358-11363, the cholesterol of September 28,1999 is discharged test can measure lipid in conjunction with activity.	Be used for cardiovascular diseases, cholesterin disease and hyperlipidaemia

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Preapoprotein former " milano " variant		5,721,114	Apoa-1 is by impelling cholesterol and discharge from tissue and participate in cholesterol from organizing the antiport to liver by the cofactor that is used as Lecithin-cholesterol acyltransferase (lcat), thereby cholesterol is secreted outward.	Use test known in the art, as Takahaski etc., P.N.A.S., Vol.96, Issue 20,11358-11363, the cholesterol of September 28,1999 is discharged test can measure lipid in conjunction with activity.	Be used for cardiovascular diseases, cholesterin disease and hyperlipidaemia
Glycodelin-A; Progesterone-correlator is membranin in utero	GeneSeq accession number W00289	WO9628169	The native female contraceptive bian that takes out fast in the human female in 2-3 days postpartum.Its purposes comprises contraception.	Use Oehninger, S., Coddington, C.C., Hodgen, G.D., and Seppala, M (1995) Fertil.Ste ril.63, the described hemizona test of 377-383 can be measured the Glycodelin-A activity.	Be used to prevent conceived natural contraceptive bian

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						NOGO-A	Genbank accession number CAB99248		The NOGO polypeptide is strong neurite outgrowth inhibitor.	Suppress spinous process and grow, the antagonist of NOGO polypeptide can impel spinous process to grow, and therefore can cause neuron regeneration.	The NOGO-A polypeptide antagonist can be used for promoting nerve growth, thereby can be used for treating neuropathy and the dysfunction that causes because of Degenerative disease or wound; The tumorigenic disease that is used for the treatment of CNS; Lure the structure plasticity-of neuron regeneration or promotion CNS into.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						NOGO-B	Genbank accession number CAB99249		The NOGO polypeptide is strong neurite outgrowth inhibitor.	Suppress spinous process and grow, the antagonist of NOGO polypeptide can impel spinous process to grow, and therefore can cause neuron regeneration.	The NOGO-B polypeptide antagonist can be used for promoting nerve growth, thereby can be used for treating neuropathy and the dysfunction that causes because of Degenerative disease or wound; The tumorigenic disease that is used for the treatment of CNS; Lure the structure plasticity-of neuron regeneration or promotion CNS into.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						NOGO-C	Genbank accession number CAB99250		The NOGO polypeptide is strong neurite outgrowth inhibitor.	Suppress spinous process and grow, the antagonist of NOGO polypeptide can impel spinous process to grow, and therefore can cause neuron regeneration.	The NOGO-C polypeptide antagonist can be used for promoting nerve growth, thereby can be used for treating neuropathy and the dysfunction that causes because of Degenerative disease or wound; The tumorigenic disease that is used for the treatment of CNS; Lure the structure plasticity-of neuron regeneration or promotion CNS into.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						The NOGO-66 acceptor	Genbank accession number AAG53612		The NOGO polypeptide is strong neurite outgrowth inhibitor, it is believed that it can pass through receptor-mediated its effect of NOGO-66.	Suppressing spinous process by the biological action that mediates the NOGO polypeptide grows.Solubility NOGO-66 receptor polypeptides can promote growing of spinous process, therefore can cause neuron regeneration.	The NOGO-66 receptor polypeptides can be used for promoting nerve growth, thereby can be used for treating neuropathy and the dysfunction that causes because of Degenerative disease or wound; The tumorigenic disease that is used for the treatment of CNS; Lure the structure plasticity-of neuron regeneration or promotion CNS into.
The collapsin specific antibody		US5416197	These antibody can be used for promoting that spinous process grows.	Use test known in the art, as Luo etc., Cell 1993Oct 22; 75 (2): the disclosed collapse of 217-27 test, can when the collapse specific antibody exists, measure and it is believed that the activity that can suppress the collapsin that spinous process grows.	Be used to promote nerve growth, thereby can be used for treating neuropathy and the dysfunction that causes because of Degenerative disease or wound

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Humanization anti-VEGF antibodies and segment thereof		WO9845331	These medicaments have anti-inflammatory and antitumous effect.	Use test known in the art, can measure the VEGF activity as disclosed test among the international publication number WO0045835.	Promote cell, as the growth and the propagation of vascular endothelial cell.Antagonist can be used as anti--vasculogenesis medicament comes in handy to cancer.
Humanization anti-VEGF antibodies and segment thereof		WO0029584	These medicaments have anti-inflammatory and antitumous effect.	Use test known in the art, can measure the VEGF activity as disclosed test among the international publication number WO0045835.	Promote cell, as the growth and the propagation of vascular endothelial cell.Antagonist can be used as anti--vasculogenesis medicament comes in handy to cancer.
						Embrane-associated protein	GeneSeq accession number Y66631-Y66765	WO9963088	Cancer, immunological disease	Use selectively targeted polypeptide, these protein can be connected bioactive molecules with cell, and are used to regulate the biological activity of cell.Polypeptide target for example can be used for treating cancer to can be used for killing target cell.These protein can be used for treating disease of immune system.	Use test known in the art, for example disclosed test can be measured activity among the international publication number WO0121658.

Therapeutic protein X	The identifier that exemplifies	The PCT/ references	Biological activity	The activity test that exemplifies	Preferred indication Y
						Secretion and stride membrane polypeptides	GenSeq accession number B44241-B44334	WO0053756	Cancer, immunological disease	Use selectively targeted polypeptide, these protein can be connected bioactive molecules with cell, and are used to regulate the biological activity of cell.Polypeptide target for example can be used for treating cancer to can be used for killing target cell.These protein can be used for treating disease of immune system.	Use test known in the art, for example disclosed test can be measured activity among the international publication number WO0121658.
Secretion and stride membrane polypeptides	GeneSeq accession number Y41685-Y41774	WO9946281	Cancer, immunological disease	Use selectively targeted polypeptide, these protein can be connected bioactive molecules with cell, and are used to regulate the biological activity of cell.Polypeptide target for example can be used for treating cancer to can be used for killing target cell.These protein can be used for treating disease of immune system.	Use test known in the art, for example disclosed test can be measured activity among the international publication number WO0121658.

With medicine or therapeutic protein is passed to cell interior and/or make it pass through hemato encephalic barrier (BBB)

Within the scope of the invention, modified transferrin fusion proteins can be used as carrier, is used for ferric ion compound molecule or small molecules therapeutical agent with transferrin are passed to cell interior, or makes it pass through hemato encephalic barrier.In these embodiments, generally need the Tf fusion rotein is transformed or modified with inhibition, prevents or eliminate glycosylation, thereby prolong the serum half life of fusion rotein and/or therapeutic protein part.Special wish to add the target peptide or for example single-chain antibody with further with Tf fusion rotein target to specific cell type, for example cancer cells.

In one embodiment, ferruginous anti-anemic thing iron-sorbyl alcohol-citrate complex is carried on the modified Tf fusion rotein of the present invention.Confirmed that iron-sorbyl alcohol-Citrate trianion (FSC) can be in the propagation of the multiple mouse cancer cells of vitro inhibition, and can cause tumor regression in vivo, but to the propagation of the non--malignant cell (Poljak-Blazi etc. that have no effect, (June 2000) Cancer Biotherapy andRadiopharmaceuticals (U.S.), 15/3:285-293).

In another embodiment, antitumor drug Zorubicin (Doxorubicin) and/or chemotherapeutics bleomycin (known these two kinds of medicines can form mixture with iron ion) are carried on the Tf fusion rotein of the present invention.In other embodiments, can prepare the salt of medicine, as Citrate trianion or carbonate that described salt and iron ion is compound, combine with Tf then.Because tumour cell often demonstrates higher iron turnover rate; The transferrin that carries at least a Anti-tumor agent after modified can make medicament be exposed to tumour cell more, perhaps makes the medicament load of tumour cell increase (Demant, E.J., (1983) Eur.J.of Biochem.137/ (1-2): 113-118; Padbury etc., (1985) J.Biol.Chem.260/13:7820-7823).

Pharmaceutical formulation and methods of treatment

Can use the medication of standard to use modified fusion rotein of the present invention for the patient that need treat.For example, modified Tf fusion rotein of the present invention can be used separately, also can or have sequentially co-administered with other medicament associating of regulating particular physiological process.In this article, when using simultaneously or so that during two kinds of medicaments of the mode individual application that medicament simultaneously or almost simultaneously plays a role, promptly being called co-administered two kinds of medicaments.

Can via non-enteron aisle, subcutaneous, intravenously, intramuscular, intraperitoneal, through skin and oral cavity by way of using medicament of the present invention.For example, can medicament be locally applied to injury site via microperfusion.Perhaps, or simultaneously by oral, suction, nose or lung by way of carrying out the noninvasive administration.Dosage depends on experimenter's age, healthy state and body weight, and Zhi Liao type simultaneously also depends on the characteristic of therapeutic frequency and required curative effect in case of necessity.

The present invention also provides the composition that contains one or more fusion roteins of the present invention.Although individual need is variant, those skilled in the art determine the optimum range of each composition significant quantity easily.Typical dosage contains the 1pg/kg that has an appointment to about 100mg/kg body weight.The preferred dose of general administration contains the 100ng/kg that has an appointment to about 100mg/kg body weight or about 100-200mg protein/dosage.Via microperfusion the preferred dose of certain direct administration in site is contained the 1ng/kg that has an appointment to about 1mg/kg body weight.When via direct injection or microperfusion administration, can transform so that it reduces or debond with combining of iron modified fusion rotein of the present invention, thereby part prevents partial iron toxicity.

Except the fusion rotein that pharmacologic activity is arranged, composition of the present invention can contain suitable drug acceptable carrier, and described carrier contains to be convenient to active compound is processed into the vehicle and the assistant agent that activeconstituents can be passed to the medicinal products of action site.The suitable preparation of parenterai administration comprises the active compound aqueous solution of water-soluble form (as the water-soluble salt form).In addition, can use the active compound suspension of suitable oily injection suspensions form.Suitably lipophilic solvent or carrier comprise fatty oils, for example, and sesame oil or synthetic fatty acid ester, for example ethyl oleic acid ester or triglyceride level.Moisture injectable suspensions can contain the material that can increase suspension viscosity, comprises for example Xylo-Mucine, sorbyl alcohol and dextran.Optional suspension also contains stablizer.Also can use the liposome medicament to be passed in the cell.

The pharmaceutical preparation that can prepare general administrable of the present invention is to carry out intestines, non-enteron aisle or topical.In fact, can use this preparation of three types to obtain the general administration of activeconstituents simultaneously.Oral used suitable preparation comprises hard or soft gelatin capsule, pill, and tablet comprises coated tablet, elixir, suspension agent, syrup or inhalation and controlled release forms thereof.

When implementing method of the present invention, medicament of the present invention can be separately or drug combination, or unite use with other therapeutical agent or diagnostic reagent.In some preferred embodiment, other compound that can use compound of the present invention simultaneously and advise for these diseases according to general received medical practice.Compound of the present invention can use in vivo, generally Mammals, and as using in people, sheep, horse, ox, pig, dog, cat, rat and the mouse body, also can be in external use.

Modified fusion rotein of the present invention can be used for diagnosing, predict, preventing and/or treating and endocrine system, neural system, immunity system, respiratory system, cardiovascular systems, reproductive system, the disease of Digestive tract and lack of proper care diseases associated and/or imbalance, with cell proliferation diseases associated and/or imbalance, and/or disease relevant with blood or imbalance.

In other embodiments of the present invention, modified Tf fusion rotein can be used for diagnosing, predicts, prevents and/or treats disease and/or imbalance, described disease and/or imbalance are with known relevant with the therapeutic protein moiety or can be relevant by the disease and the imbalance of the treatment of these moietys, described moiety is well known in the art, PCT patent publication No. WO 01/79258, WO 01/77137, WO 01/79442, WO 01/79443, exemplified these moietys among WO 01/79444 and the WO 01/79480 (listing this paper in as a reference all in full).Therefore, the present invention includes the method for listed disease in treatment table 1 " the preferred indication Y " hurdle or imbalance, described method comprises that the patient to this treatment of needs, prevention or improvement uses modified transferrin fusion proteins of the present invention, wherein contain the therapeutic protein part corresponding to disclosed therapeutic protein in table 1 " therapeutic protein X " hurdle, its content is enough to effective treatment, prevents or improves disease or imbalance.

In certain embodiments, transferrin fusion proteins of the present invention can be used for diagnosis and/or prediction disease and/or imbalance.

The polynucleotide of modified transferrin fusion proteins of the present invention and code book invention transferrin fusion proteins can be used for treatment, prevention, diagnosis and/or prediction disease of immune system.In addition, the polynucleotide of fusion rotein of the present invention and/or code book invention transferrin fusion proteins can be used as the mark or the detection agent of specific disease of immune system or imbalance.

In preferred embodiments, the polynucleotide of the fusion rotein of the present invention and/or the modified transferrin fusion proteins of the present invention of encoding can be used as the immunoreactive medicament of booster immunization defective individuality.In specific embodiments, the polynucleotide of fusion rotein of the present invention and/or code book invention transferrin fusion proteins can be used as the immunoreactive medicament of strengthening B cell and/or T cellular immunity deficiency individuality.

The polynucleotide of modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can be used for treatment, prevention, diagnosis and/or prediction autoimmune disease.A lot of autoimmune diseases are identified as foreign matter by immunocyte irrelevantly with self and cause.This inappropriate identification causes destroying the immunne response of host tissue.Therefore, use and can suppress to reply, the polynucleotide that particularly can suppress T-cell proliferation, differentiation or chemotactic fusion rotein of the present invention and/or code book invention transferrin fusion proteins are effective therapies of prevention autoimmune disease.

The polynucleotide of modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can be used for treatment, prevention, prediction and/or diagnosis hematopoietic cell disease.The polynucleotide of transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can be used for increasing hematopoietic cell, the differentiation and the propagation that comprise multipotential stem cell, the hematopoietic cell that is intended to treatment or prevention and some (or multiple) type reduces diseases associated, and described disease includes but not limited to that leukopenia, neutrophilic granulocyte reduce disease, anaemia and thrombocytopenia.

Perhaps, the polynucleotide of modified fusion rotein of the present invention and/or code book invention transferrin fusion proteins can be used for increasing hematopoietic cell, the differentiation and the propagation that comprise multipotential stem cell, the hematopoietic cell that is intended to treatment or prevention and some (or multiple) type increases diseases associated, and described disease includes but not limited to histiocytosis.

Use the polynucleotide of modified fusion rotein of the present invention and/or code book invention transferrin fusion proteins can also treat, prevent, diagnose and/or predict anaphylaxis and disease, as asthma (particularly allergic asthma) or other breathing problem.In addition, can use these molecular therapies, prevention, prediction and/or diagnosis supersensitivity, the uncompatibility of allergy or blood group to antigen molecule.

In addition, the polynucleotide of modified fusion rotein of the present invention and/or code book invention transferrin fusion proteins can be used for treating, prevent, diagnosing and/or predict the anaphylaxis of IgE-mediation.Described anaphylaxis includes but not limited to asthma, rhinitis and eczema.In specific embodiments, the polynucleotide of fusion rotein of the present invention and/or code book invention transferrin fusion proteins are used in external or the interior IgE of adjusting of body concentration.

In addition, the polynucleotide of modified fusion rotein of the present invention and/or code book invention transferrin fusion proteins can be used for diagnosing, predict, prevent and/or treat inflammation.For example, because the polynucleotide of fusion rotein of the present invention and/or code book invention transferrin fusion proteins can suppress to participate in activation, propagation and/or the differentiation of the cell of inflammatory reaction, therefore, these molecules can be used for preventing and/or treating chronic and acute inflammation.Described inflammation includes but not limited to for example relevant with following factor inflammation: infect (as septic shock, sepsis or systemic inflammatory response syndrome), ischemia-reperfusion injury, the intracellular toxin lethality rate, the hyperacute rejection of complement-mediation, ephritis, cytokine or chemokine inductive injury of lung, inflammatory bowel, Crohn disease, the excessive generation of cytokine (as TNF or IL-1), respiratory disease (as asthma and allergy); Gastrointestinal illness (as inflammatory bowel); Cancer (as cancer of the stomach, ovarian cancer, lung cancer, bladder cancer, liver cancer and mammary cancer); CNS disease (as multiple sclerosis); Ischemic brain injury and/or apoplexy, traumatic brain injury, neurodegenerative disease (as Parkinson's disease and Alzheimer disease); The dementia relevant with AIDS-; And prion disease; Cardiovascular diseases (as atherosclerosis, myocarditis, cardiovascular diseases and cardiopulmonary bypass complication); And various features is other disease (for example hepatitis, rheumatoid arthritis, gout, wound, pancreatitis, sarcoidosis, dermatitis, kidney ischemic reperfusion injury, Exophthalmus goiter, systemic lupus erythematous, diabetes and allotype transplant rejection) of inflammation.

Because inflammation is basic defense mechanism, so inflammation in fact can influence any tissue of health.Therefore, the polynucleotide of modified fusion rotein of the present invention and/or code book invention transferrin fusion proteins can be used for treated tissue-specificity inflammation, include but not limited to: paranephritis, dentoalveolitis, angiocholecystitis, ecphyaditis, balanitis, blepharitis, bronchitis, bursitis, carditis, phlegmon, trachelitis, cholecystitis, chorditis, cochleitis, colitis, conjunctivitis, urocystitis, dermatitis, diverticulitis, encephalitis, endocarditis, esophagitis, syringitis, fibrositis, folliculitis, gastritis, gastroenteritis, gingivitis, glossitis, hepatosplenitis, keratitis, labyrinthitis, laryngitis, lymphangitis, mazoitis, otitis media, meningitis, metritis, mucositis, myocarditis, myositis, myringitis, ephritis, neuritis, testitis, osteochondritis, otitis, pericarditis, tenosynovitis, peritonitis, pharyngitis, phlebitis, poliomyelitis, prostatitis, pulpitis, the retinitis, rhinitis, salpingitis, scleritis, sclerochoroiditis, scrotitis, sinusitis, spondylitis, pimelitis, stomatitis, synovitis, syringitis, tendonitis, tonsillitis, urethritis and vaginitis.

In specific embodiments, the polynucleotide of modified fusion rotein of the present invention and/or code book invention transferrin fusion proteins can be used for diagnosing, predict, prevent and/or treat organ-graft refection and graft-vs.-host disease.The organ rejection can take place when destroying transplanted tissue by immunne response in the host immune cell.Similarly, immunne response also relates to GVHD, but this moment, external transplantation immunity cell can destroy host tissue.Can suppress immunne response, particularly can suppress T-cell activation, propagation, differentiation or chemotactic polypeptide of the present invention, antibody or polynucleotide and/or its agonist or antagonist is effective therapy of prevention organ rejection or GVHD.

In another embodiment, the polynucleotide of modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can be used as adjuvant, and-virus immunity anti-to strengthen replied.Use composition of the present invention as adjuvant can enhanced anti--virus immunity reply and comprise virus described herein or known in the art and viral relative disease or symptom.In specific embodiments, composition of the present invention is strengthened immunne response to virus, disease or the symptom that is selected from AIDS, meningitis, singapore hemorrhagic fever, EBV and hepatitis (as hepatitis B) as adjuvant.In another embodiment, composition of the present invention is strengthened the immunne response that is selected from HIV/AIDS, respiratory syncytial virus, singapore hemorrhagic fever, rotavirus, B-mode Japanese encephalitis, first type and second type influenza virus, parainfluenza virus, measles, cytomegalovirus, rabies, Junin, cuts elder brother Gong Yare, thunder is paid virus, disease or the symptom of shelling heat, hsv and yellow jack as adjuvant.

In another embodiment, the polynucleotide of modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can be used as adjuvant-bacterium anti-or anti--fungi immunne response to strengthen.Use composition of the present invention as adjuvant can enhanced anti--bacterium or anti--fungi immunne response comprise bacterium described herein or known in the art or fungi and bacterium or fungi relative disease or symptom.In specific embodiments, composition of the present invention is strengthened the bacterium that is selected from tetanus, diphtheria, sausage poisoning and epidemic cerebrospinal meningitis B or the immunne response of fungi, disease or symptom as adjuvant.

In another embodiment, composition of the present invention can be used as adjuvant to strengthen the bacterium that is selected from vibrio cholerae, Mycobacterium leprae, salmonella typhi, salmonella paratyphi, Neisseria meningitidis, streptococcus pneumoniae, Type B suis, Shigellae, enterotoxigenic E.Coli, enterohemorrhagic Escherichia coli and B. burgdorferi or the immunne response of fungi, disease or symptom.

In another embodiment ,-parasitic immunne response anti-that the polynucleotide of modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can be used as adjuvant to strengthen.Use composition of the present invention can the enhanced antiparasitic immunity to reply and comprise parasite described herein or known in the art and parasite relative disease or symptom as adjuvant.In specific embodiments, composition of the present invention is strengthened parasitic immunne response as adjuvant.In another embodiment, composition of the present invention is strengthened plasmodium (malaria) or leishmanial immunne response as adjuvant.

In another embodiment, the polynucleotide of modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins also can be used for by preventing that additional the treatment with the activated mononuclear phagocytic cell from catching, and described disease comprises silicosis, sarcoidosis and spontaneous pulmonary fibrosis.

In another embodiment, the polynucleotide of modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can be used as antigen, are used to produce antibody to suppress or to strengthen the immune-mediated reaction of anti-polypeptide of the present invention.

In one embodiment, give animal (mouse for example, rat, rabbit, hamster, cavy, pig, miniature pig, chicken, camel, goat, horse, milk cow, sheep, dog, non-human primate and people such as cat, optimum is chosen) use the polynucleotide of modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins, to promote immunity system to produce one or more antibody of increasing amount (IgG for example, IgA, IgM and IaE), impel than the generation of high-affinity antibody and the conversion of immunoglobulin class (IgG for example, IgA, IgM and IaE), and/or enhancing immunity is replied.

In another embodiment, the polynucleotide of modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can be used for one or more application as herein described, for example can be used for veterinary drug.

In another embodiment, the polynucleotide of modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can be used for blocking the many aspects at the immunne response of exotic or self material.Need the disease of some aspect that blocking immunity replys for example to comprise: autoimmune disease, as lupus and sacroiliitis and to the immunne response of allergic, inflammation, enteropathy, damage and pathogenic agent relative disease/imbalance.

In another embodiment, the polynucleotide of modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can be used as prevention B cell proliferation and the Ig excretory therapy relevant with autoimmune disease, and described autoimmune disease comprises for example idiopathic thrombocytopenic purpure, systemic lupus erythematous and multiple sclerosis.

In another embodiment, the polynucleotide of modified transferrin fusion proteins of the present invention or code book invention transferrin fusion proteins can be used as the inhibitor of B in the endotheliocyte and/or T cell migration.This activity energy disorganize structure or correlated response can be used for for example destroying immunne response and blocking-up sepsis.

In another embodiment, the polynucleotide of modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can be used as the therapy of the chronic hypergammaglobulinemia incident in the disease, and described disease comprises the uncertain MG of meaning (MGUS) for example, waldenstrom's disease, relevant spontaneous MG and plasmoma.

In another embodiment, the polynucleotide of modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins for example can be used in some autoimmune diseases, chronic inflammatory diseases and suppress scavenger cell and precursor, neutrophilic granulocyte, basophilic granulocyte, bone-marrow-derived lymphocyte and some T-cell subsets in catching, as the polypeptide chemotaxis and the activation of the T cell and the natural killer cell of activatory and cd8 cell poison.This paper has described the example of autoimmune disease, and it comprises multiple sclerosis and insulin-dependent diabetes mellitus.

In another embodiment, the polynucleotide of modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can be used for by for example preventing that monocyte infiltration from treating atherosclerosis to arterial wall.

In another embodiment, the polynucleotide of modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can be used for treating adult respiratory distress syndrome (ARDS).

In another embodiment, the polynucleotide of modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can be used for promoting wound and tissue repair, promote vasculogenesis, and/or promote the reparation of blood vessel or lymphatic disease or imbalance.In addition, can use the regeneration of the polynucleotide promotion mucomembranous surface of fusion rotein of the present invention and/or code book invention transferrin fusion proteins.

In specific embodiments, the polynucleotide of modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can be used for diagnosing, predict, treat and/or prevent and be characterised in that primary or acquired immunodeficiency, damaged serum immune globulin generation, recurrent infection and/or the parafunctional disease of immunity system.In addition, the polynucleotide of modified fusion rotein of the present invention and/or code book invention transferrin fusion proteins can be used for treatment or prevention joint, bone, the skin and/or the parotid gland infect, the infection that blood carries is (as sepsis, meningitis, septic arthritis and/or osteomyelitis), autoimmune disease (as disclosed herein those), inflammatory diseases and malignant tumour, and/or any and these infection, disease, the disease that imbalance and/or malignant tumour are relevant includes but not limited to: CVID, other primary immunodeficiency, the HIV disease, CLL, the recurrence bronchitis, sinusitis, otitis media, conjunctivitis, pneumonia, hepatitis, meningitis, zoster (as the severe zoster) and/or Pneumocystis carinii.Can include but not limited to polynucleotide prevention, diagnosis, the prediction of fusion rotein of the present invention and/or code book invention transferrin fusion proteins and/or other disease and the imbalance for the treatment of: HIV infection, HTLV-BLV infection, lymphopenia, phagocyte bactericidal parafunction anemia, thrombocytopenia and hemoglobinuria.

In specific embodiments, the polynucleotide of modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can be used for diagnosing, predicting, prevent and/or treat cancer or tumour, comprise immunocyte or immuning tissue-associated cancer or tumour.Can prevent with the polynucleotide of fusion rotein of the present invention and/or code book invention transferrin fusion proteins, the cancer of diagnosis or treatment or the example of tumour include but not limited to: acute myelogenous leukemia, chronic lymphocytic leukemia, Hokdkin disease, non--He Jiejin lymphomas, acute lymphoblastic anaemia (ALL), chronic lymphocytic leukemia, plasmoma, multiple myeloma, burkitt's lymphoma, described disease of chapters and sections and imbalance that EBV transforms disease and/or is proposed as " excess proliferative disease " herein.

In another embodiment, the polynucleotide of modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can be used as the therapy of the cell proliferation that reduces big B-cell lymphoma.

In specific embodiments, composition of the present invention can be used as the immunoreactive medicament of strengthening the damaged individuality of B cellular immunization, and described individuality comprises and for example suffered the partially or completely individuality of splenectomy.

The polynucleotide of modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can be used for regulating hemostasis (stopping hemorrhage) or thrombolysis (thrombus) activity.For example, by increasing hemostasis or thrombolysis activity, the polynucleotide of fusion rotein of the present invention and/or code book invention transferrin fusion proteins can be used for treatment or preclude blood aggegation disease (as afibrinogenemia, factor shortage, hemophilia), blood platelet disorder (as thrombocytopenia), or the wound that causes by wound, operation or other reason.Perhaps, can use the polynucleotide that can reduce hemostasis or the fusion rotein of the present invention of thrombolysis activity and/or code book invention transferrin fusion proteins to suppress or dissolve blood coagulation.When treatment or preventing heart disease outbreak (infarct), apoplexy or cicatrization, these molecules may be vital.

In specific embodiments, the polynucleotide of modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can be used for prevention, diagnosis, prediction and/or treatment thrombosis, artery thrombosis, venous thrombosis, thromboembolism, pulmonary infarction, atherosclerosis, myocardial infarction, the outbreak of instantaneous local asphyxia, unsettled angina.In specific embodiments, the polynucleotide of transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can be used for preventing the saphenous vein graft obturation; The omnidistance thrombotic risk that reduction may be accompanied with the angioplasty process; Reduce the auricular fibrillation patient, comprise the risk of non-rheumatic auricular fibrillation patient apoplexy; The embolism risk that reduction is relevant with heart valve prosthesis and/or mitral valve disease.Other purposes of the polynucleotide of modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins includes but not limited to: prevent outer body device (as tubule, the intravital angioaccess splitter of hemodialysis patients, haemodialysis control unit and cardiopulmonary bypass instrument in the blood vessel) obturation.

In another embodiment, the polynucleotide of modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can be used for preventing, diagnose, predicting and/or treat the disease of hemopathy relevant with the tissue of expressing polypeptide of the present invention and/or blood formation organ.

The polynucleotide of modified fusion rotein of the present invention and/or code book invention transferrin fusion proteins can be used for regulating hematopoiesis activity (formation hemocyte).For example, the polynucleotide of transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can be used for increasing the quantity of whole hemocytes or hemocyte hypotype, and described hemocyte comprises for example red corpuscle, lymphocyte (B or T cell), myelocyte (as basophilic granulocyte, eosinophilic granulocyte, neutrophilic granulocyte, mastocyte, scavenger cell) and thrombocyte.The ability that reduces hemocyte or hemocyte hypotype quantity can be used for preventing, detect, diagnose and/or treats hereinafter described anaemia and oligoleukocythemia.Perhaps, the polynucleotide of modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can be used for reducing the quantity of whole hemocytes or hemocyte hypotype, and described hemocyte comprises for example red corpuscle, lymphocyte (B or T cell), myelocyte (as basophilic granulocyte, eosinophilic granulocyte, neutrophilic granulocyte, mastocyte, scavenger cell) and thrombocyte.The ability that reduces hemocyte or hemocyte hypotype quantity can be used for prevention, detects, diagnoses and/or treatment leukocytosis, for example eosinophilia.The polynucleotide of modified fusion rotein of the present invention and/or code book invention transferrin fusion proteins can be used for prevention, treatment or diagnosis blood dyscrasia.

Anaemia is the disease that the amount of red corpuscle number or oxyphorase wherein is lower than normal level.Bleed profusely, red corpuscle output reduces or the hematoclasis amount increases (as haemolysis) and can cause anaemia.The polynucleotide of modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can be used for treatment, prevention and/or diagnosis anaemia.Can be by the polynucleotide treatment of transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins, the anaemia of prevention or diagnosis comprises: hypoferric anemia, hypochromic anaemia, the microcyte anaemia, chlorotic anemia, heredity becomes abrasive grit red corpuscle anaemia, spontaneous acquired one-tenth abrasive grit red corpuscle anaemia, red blood cell development is incomplete, megalblastic anemia (as pernicious anemia (vitamin B12 deficiency) and folic acid deficiency anemia), the oligergastic anaemia, hemolytic anemia is (as autoimmune hemolytic anemia, the hemoglobinuria of microangiopathic hemolytic anemia and night-time attack).The polynucleotide of modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can be used for treating, prevent and/or the anaemia of diagnosis and following disease-related, and described disease includes but not limited to the anaemia relevant with systemic lupus erythematous, cancer, lymphoma, chronic nephropathy and splenomegaly.The polynucleotide of transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can be used for treating, preventing and/or diagnose the anaemia that is caused by pharmacological agent, for example relevant with methyldopa, dapsone and/or sulfonamide anaemia.In addition, the polynucleotide of modified fusion rotein of the present invention and/or code book invention transferrin fusion proteins can be used for treating, preventing and/or diagnosis and the unusual relevant anaemia of red blood cell structure, include but not limited to hereditary spherocytosis, heredity elliptocytosis, glucose-6-phosphate dehydrogenase (G6PD) defective and sicklemia.

The polynucleotide of modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can be used for treatment, prevention and/or diagnosis haemoglobin anomaly (for example relevant with sicklemia, Hemoglobin C disease, Hemoglobin S-C disease and Hemoglobin E disease is unusual).In addition, the polynucleotide of transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can be used for diagnosis, prevention, prediction and/or treatment thalassemia, include but not limited to the α-Di Zhonghaipinxue and the β-thalassemia of main and less important form.

In another embodiment, the polynucleotide of modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can be used for diagnosis, prediction, prevent and/or treat hemorrhagic disease, include but not limited to thrombopenia (as idiopathic thrombocytopenic purpure and thrombosed thrombopenic purpura), von Willebrand, the heredity thrombopathy is (as the storage vault disease, as Chediak-Higashi and Hermansky-Pudlak syndrome, the thromboxane A2 parafunction, thrombasthenia and Bernard-Soulier syndrome), hemolytic uremic syndrome, hemophilia (as haemophilia A or V-11 factor shortage and haemophilia B or IX factor shortage), hereditary hemorrbagic telangiectasia (also claiming Rendu-Osler-Webe syndrome), anaphylactoid purpura (Henoch Schonlein purpura) and disseminated intravascular coagulation.

In other embodiments, the polynucleotide of modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can be used as the medicament that increases cytokine production.

In certain embodiments, the polynucleotide of fusion rotein of the present invention and/or code book invention transferrin fusion proteins can be used for treatment or detect excess proliferative disease, comprise tumour.The polynucleotide of transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can suppress the propagation of disease by direct or indirect interaction.Perhaps, the polynucleotide of fusion rotein of the present invention and/or code book invention transferrin fusion proteins can be bred the cell that other can suppress excess proliferative disease.

For example, reply, particularly increase the antigen amount of excess proliferative disease, or, can treat excess proliferative disease by propagation, differentiation or transfer T-cell by enhancing immunity.By strengthening existing immunne response, or, can enhancing immunity reply by initial new immunne response.Perhaps, weaken immunne response also can yet be regarded as a kind of method for the treatment of excess proliferative disease, for example chemotherapeutic agents.

The example of the excess proliferative disease that can treat or detect by the polynucleotide of modified fusion rotein of the present invention and/or code book invention transferrin fusion proteins includes but not limited to the tumour at following position: colon, belly, bone, mammary gland, Digestive tract, liver, pancreas, peritonaeum, incretory gland (suprarenal gland, parathyroid gland, pituitary gland, testis, ovary, thymus gland, Tiroidina), eye, head and neck, neural (maincenter and on every side), lymphsystem, pelvis, skin, soft tissue, spleen, chest and urogenital tract.

Similarly, also can treat or detect other excess proliferative disease by the polynucleotide of modified fusion rotein of the present invention and/or code book invention transferrin fusion proteins.The example of described excess proliferative disease includes but not limited to: children acute lymphocytoblast leukemia, acute lymphocytoblast leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, adrenocortical carcinoma, adult's (primary) hepatocellular carcinoma, adult's (primary) liver cancer, adult's acute lymphoblastic leukemia, adult's acute myelogenous leukemia, adult's Hokdkin disease, adult He Jiejin lymphomas, the adult lymphoid chronic myeloid leukemia, adult's non--He Jiejin lymphomas, become the human primary liver cancer, adult soft tissue sarcoma, the lymphoma relevant with AIDS, the malignant tumour relevant with AIDS, anus cancer, astrocytoma, cholangiocarcinoma, bladder cancer, osteocarcinoma, the brain stem neurospongioma, brain tumor, mammary cancer, renal plevis and carcinoma of ureter, central nervous system (primary) lymphoma, central nervous system lymphoma, cerebellar astrocytoma, big cerebral astrocytoma, the neck cancer, children's (primary) hepatocellular carcinoma, children's (primary) liver cancer, children acute lymphocytoblast leukemia, the children acute myelomatosis, children's brain stem neurospongioma, children's cerebellar astrocytoma, the big cerebral astrocytoma of children, children's extracranial germ cell knurl, children's Hokdkin disease, children He Jiejin lymphomas, children's hypothalamus and visual pathway neurospongioma, children lymphocytoblast leukemia, children's medulloblastoma, children non--He Jiejin lymphomas, children's pineal gland and curtain are gone up elementary neuroectodermal tumor, children's primary hepatocarcinoma, children's rhabdosarcoma, children soft tissue sarcoma, children's vision path and hypothalamus neurospongioma, chronic lymphocytic leukemia, chronic granulocytic leukemia, colorectal carcinoma, skin T-cell lymphoma, the internal secretion islet-cell carcinoma, carcinoma of endometrium, ependymoma, epithelial cancer, the esophageal carcinoma, Ewing's sarcoma and related neoplasms, the exocrine pancreas cancer, the Extraeranial gonioma, extragonadal gonioma, the cholangiocarcinoma that liver is outer, cancer eye, women with breast cancer, familial splenic anemia, carcinoma of gallbladder, cancer of the stomach, the stomach and intestine carcinoid tumor, the stomach and intestine knurl, gonioma, the gestation trophoblastic tumor, hairy cell leukemia, head and neck cancer, hepatocellular carcinoma, Hokdkin disease, the He Jiejin lymphomas, gamma-globulin is too much, the hypopharynx cancer, intestinal cancer, intraocular melanoma, the islet cell cancer, islet-cell carcinoma, Kaposi, kidney, laryngocarcinoma, lip and oral carcinoma, liver cancer, lung cancer, the lymphocytic hyperplasia disease, macroglobulinemia, male breast carcinoma, malignant mesothe, malignant thymoma, medulloblastoma, melanoma, mesothelioma, former squamous neck of the hiding property cancer that shifts, former the squamous neck cancer that shifts, the squamous neck cancer that shifts, multiple myeloma, multiple myeloma/plasmoma, myelodysplastic syndrome, myelocytic leukemia, myelomatosis, myeloproliferative diseases, nasal cavity and nasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non--He Jiejin lymphomas in the gestation process, non--the melanoma skin cancer, non--small cell lung cancer, the squamous neck cancer that the primary of hiding shifts, the oropharynx cancer, bone/malignant fibrous sarcoma, osteosarcoma/malignant fibrous histiocytoma, osteosarcoma/bone malignant fibrous histiocytoma, epithelial ovarian cancer, the ovarian germ cell knurl, ovary hangs down pernicious potential tumor, carcinoma of the pancreas, paraproteinemia, purpura, parathyroid carcinoma, penile cancer, pheochromocytoma, the pituitary gland knurl, plasmoma/multiple myeloma, primary central nervous system lymphoma, primary hepatocarcinoma, prostate cancer, the rectum cancer, renal cell carcinoma, renal plevis and carcinoma of ureter, retinoblastoma, rhabdosarcoma, salivary-gland carcinoma, the sarcoidosis sarcoma, Sezary syndrome, skin carcinoma, small cell lung cancer, carcinoma of small intestine, soft tissue sarcoma, squamous neck cancer, cancer of the stomach, elementary neuroderm and pinealoma on the curtain, the T-cell lymphoma, carcinoma of testis, thymoma, thyroid carcinoma, renal plevis and ureteral transitional cell carcinoma, divide a word with a hyphen at the end of a line renal plevis and carcinoma of ureter, trophoblastic tumor, ureter and renal plevis cell carcinoma, urethral carcinoma, uterus carcinoma, sarcoma of uterus, carcinoma of vagina, visual pathway and hypothalamus neurospongioma, carcinoma vulvae, the WaldenstroinShi macroglobulinemia, nephroblastoma, with except that tumour, be arranged in any other excess proliferative disease of above-mentioned tract.

In a further preferred embodiment, the polynucleotide of modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can be used for diagnosing, predict, prevent and/or treat disease and prevent that them from developing into tumour or malignant tumour state in pernicious early stage, and described disease includes but not limited to above-mentioned disease.The indication of described purposes is known or suspects the disease that just past tumour or cancer direction develop, be that non--growth of tumour cell is made up of hyperplasia, metaplasia especially, or (summary of relevant misgrowth disease can be referring to Robbins.and Angell to occur dysplastic disease the most in particular, 1976, Basic Pathology, 2d Ed.W.B.Saunders Co., Philadelphia, pp.68-79).

Hyperplasia is a kind of in check cell proliferation form, comprise that the cell number in tissue or the organ increases, but structure or function does not have remarkable change.The polynucleotide of fusion rotein of the present invention and/or code book invention transferrin fusion proteins are diagnosable, the proliferative disease of prediction and/or treatment includes but not limited to: blood vessel folliculus mediastinal lymph nodes hyperplasia, blood vessel lymphocytic hyperplasia with the eosinophilia, atypical melanocytic hyperplasia, basal cell hyperplasia, optimum giant lymph node hyperplasia, hypercementosis, adrenal,congenital hyperplasia, congenital sebaceous hyperplasia, the capsule hyperplasia, mammary gland capsule hyperplasia, the denture hyperplasia, the pipe hyperplasia, endometrial hyperplasia, fibromuscular hyperplasia, the kitchen range epithelial proliferation, gingival hyperplasia, inflammatory fibering hyperplasia, the inflammatory papillary hyperplasia, intravascular papillary endothelial hyperplasia, prostate gland brief summary shape hyperplasia, brief summary shape regeneration hyperplasia, false epithelioma hyperplasia, old sebaceous hyperplasia and wart hyperplasia.

In another embodiment, the polynucleotide of as described herein and toxin or radio isotope link coupled, modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can be used for treatment and include but not limited to those cancers as herein described and tumour.In a further preferred embodiment, the polynucleotide with toxin or radio isotope link coupled, transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins as described herein can be used for treating acute myelocytic leukemia.

In addition, the polynucleotide of modified fusion rotein of the present invention and/or code book invention transferrin fusion proteins can influence apoptosis, therefore can be used for treating multiple cell survival or apoptosis with increase and suppress diseases associated.For example, can be by polynucleotide of the present invention, polypeptide and/or agonist or antagonist diagnosis, prediction, prevent and/or treat, suppress diseases associated with cell survival that increases or apoptosis and comprise that cancer is (as folliculus-lymphoma, cancer and hormone-dependent form tumour with the p53 sudden change include but not limited to colorectal carcinoma, cardiac tumor, carcinoma of the pancreas, melanoma, retinoblastoma, glioblastoma, lung cancer, intestinal cancer, carcinoma of testis, cancer of the stomach, neuroblastoma, myxoma, myomata, lymphoma, endothelioma, osteoblastoma, osteoclastoma, osteosarcoma, chondrosarcoma, adenoma, mammary cancer, prostate cancer, Kaposi and ovarian cancer); Autoimmune disease is as multiple sclerosis, siogren's syndrome, struma lymphomatosa, biliary cirrhosis, Behcet, Crohn disease, polymyositis, systemic lupus erythematous and immunity-relevant glomerulonephritis and rheumatoid arthritis) and virus infection (as simplexvirus, poxvirus and adenovirus), inflammation, graft versus host disease, acute transplant rejection and chronic transplant rejection.

In preferred embodiments, the polynucleotide of modified fusion rotein of the present invention and/or code book invention transferrin fusion proteins can be used for suppressing cancer, particularly above-mentioned cancer growth, carry out and/or shift.

Other can be by the polynucleotide diagnosis of modified fusion rotein of the present invention and/or code book invention transferrin fusion proteins, prediction, prevent and/or treat, include but not limited to the carrying out of malignant tumour and relative disease with the cell survival diseases associated that increases and/or shift, described disease such as leukemia (comprise that acute leukemia is (as acute lymphoblastic leukemia, acute myelocytic leukemia (comprises myeloblast, promyelocyte, myelomonocyte, monocyte and erythroleukemia)) and chronic leukemia (as chronic myelocytic (granulocyte) leukemia and chronic lymphocytic leukemia)), polycythemia vera lymphoma (how outstanding king's evil and non--Hokdkin disease), multiple myeloma, the WaldenstromShi macroglobulinemia, heavy chain disease, and solid tumor, include but not limited to sarcoma and cancer, as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdosarcoma, colorectal carcinoma, carcinoma of the pancreas, mammary cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, rodent cancer, gland cancer, syringocarcinoma, sebaceous carcinoma, papillary carcinoma, papillary carcinoma, cystadenocarcinoma, medullary carcinoma, bronchiogenic cancer, renal cell carcinoma, hepatoma, cholangiocarcinoma, choriocarcinoma, spermocytoma, embryonal carcinoma, nephroblastoma, cervical cancer, carcinoma of testis, lung cancer, small cell lung cancer, bladder cancer, epithelial cancer, neurospongioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic tumor, Oligodendroglioma, menangioma, melanoma, neuroblastoma and retinoblastoma.

Can diagnose, predict, prevent and/or treat by the polynucleotide of modified fusion rotein of the present invention and/or code book invention transferrin fusion proteins, comprise AIDS with the apoptosis-related disease that increases; Neurodegenerative disease (as Alzheimer disease, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, big cerebral degeneration and brain tumor or relative disease before this); Autoimmune disease is (as multiple sclerosis, siogren's syndrome, struma lymphomatosa, biliary cirrhosis, Behcet, Crohn disease, polymyositis, systemic lupus erythematous and immunity-relevant glomerulonephritis and rheumatoid arthritis) myelodysplastic syndrome (as aplastic anemia), graft versus host disease, ischemic injury is (as by myocardial infarction, the damage that apoplexy and detumescence damage cause), liver injury is (as the liver injury relevant with hepatitis, local asphyxia/reperfusion injury, cholestasis (bile duct injury) and liver cancer); Toxin-inductive hepatopathy (as the hepatopathy that causes by ethanol), septic shock, emaciation and apositia.

The encode polynucleotide of modified transferrin fusion proteins of the present invention of another preferred embodiment utilization, the gene therapy of the application of the invention and/or its protein blend compound or fragment suppress abnormal division.

Therefore, the invention provides the method for the treatment of cell proliferation disorders by the polynucleotide that insert coding modified transferrin fusion proteins of the present invention in the cell of abnormality proliferation, wherein said polynucleotide can suppress described expression.

Another embodiment of the invention provides the method for the individual cell proliferation disorders of treatment, and described method comprises to one or more abnormality proliferation cells uses one or more active gene copies of the present invention.

Be used for the direct display in the ill site of guiding of injection needles can directly be passed to polynucleotide of the present invention the ill site of cell proliferation disorders of internal, body cavity etc. by use.Also can when carrying out surgical intervention, polynucleotide of the present invention be applied to ill site.

Cell proliferation disorders refers to any meeting and has influence on any one or the human or animal's disease or the imbalance of its arbitrary combination in the part of organ, body cavity or health, the abnormality proliferation that it is characterized in that local cells, cell mass or the tissue of single-shot or pilosity, described propagation can be benign, also can be virulent.

Can use the polynucleotide of the present invention of any amount, as long as the propagation that it treats cell to desire has biological restraining effect.

In addition, use more than one polynucleotide of the present invention simultaneously can for same loci." the biological inhibition " refers to the part or all of growth-inhibiting effect and the reduction of cell proliferation or growth velocity.

The polynucleotide of modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can be used for suppressing the transfer of proliferative cell or tissue.Restraining effect can be used as the direct result of using these transferrin fusion proteins and/or polynucleotide and takes place, and also can be used as the indirect consequence of the expression that for example activates the known protein that suppresses to shift (as alpha-6 integrin) and takes place (referring to for example Curr Top Mirobiol Immunol 1998; 231:141 lists this paper in as a reference).This curative effect of the present invention can independently obtain, and also can unite acquisition with small-molecule drug or adjuvant.

In another embodiment, the invention provides the method that composition is passed to the targeted cells of express polypeptide, described composition contains the polynucleotide of the transferrin fusion proteins of the present invention and/or the transferrin fusion proteins of the present invention of encoding, and described polypeptide combines with modified transferrin fusion proteins of the present invention.Transferrin fusion proteins of the present invention can combine with heterologous polypeptide, heterologous nucleic acids, toxin or prodrug via hydrophobic, hydrophilic, ion and/or covalent effect.

Composition of the present invention can be diagnosed, prediction, the ephrosis that prevents and/or treats includes but not limited to: acute renal failure, chronic renal failure, arterial thrombosis renal failure, late period renal failure, the inflammatory diseases of kidney is (as acute glomerulonephritis, metainfective glomerulonephritis, the glomerulonephritis that carries out fast, nephritic syndrome, the film glomerulonephritis, familial nephritis syndrome, membranoprolifer ative glomerulonephritis and mesentery proliferative glomerulonephritis, chronic glomerulonephritis, matter ephritis between acute tubulose, matter ephritis between chronic tubulose, acute streptococcal glomerulo nephritis (PSGN), pyelitis, systemic lupus erythematosus, chronic nephritis, between matter ephritis and suis property glomerulonephritis), renal vascular disease is (as renal infarction, the arterial thrombosis ephrosis, cortical necrosis, malignant nephrosclerosis, renal venous thrombosis, accept dabbling kidney, the kidney retinopathy, the kidney ischemic pours into again, thrombosis of renal artery and renal artery stenosis), the per urethram sick ephrosis that causes is (as pyelitis, nephrohydrosis, urolithiasis (urinary stone disease, nephrolithiasis), the backflow ephrosis, urinary tract infection, uroschesis and acute or chronic one-sided infraction urosis).In addition, can use composition diagnosis of the present invention, prediction, prevent and/or treat the metabolism of kidney and congenital disorders (as uremia, amyloidosis, renal osteodystrophy, renal tubule acidosis, the kidney glycosuria, nephrogenic diabetes insipidus, cystinuria, fanconi's syndrome, kidney fiber cryptomere osteogenesis (rachitis renalis), how Hart pounces on disease, the Bartter Cotard, Liddle syndrome, multicystic kidney disease, the marrow cystic disease, medullary sponge kidney, Alport syndrome, nailpatella syndrome, congenital nephritis syndrome, CRUSH syndrome, horseshoe kidney, diabetic nephropathy, nephrogenic diabetes insipidus, analgesic nephropathy, urinary stone disease and membranous nephropathy) and the autoimmune disease of kidney (as systemic lupus erythematous (SLE), Goodpasture syndrome, IgA nephropathy and ICFM mesangial proliferative glomerulonephritis).

Composition of the present invention also can be used for diagnosis, prediction, prevent and/or treat the sclerosis of kidney or lecrotic disease (as glomerular sclerosis, diabetic nephropathy, faca Fsegmental glomerular sclerosis (FSGS), glomerulonephritis and necrosis of renal papillae that anesthesia causes), the cancer of kidney is (as kidney, hypernephroid carcinoma, nephroblastoma, renal cell carcinoma, transitional cell carcinoma, renal adenocarcinoma, squamous cell carcinoma and nephroblastoma) and electrolyte disturbance (as nephrocalcinosis, pyuria, oedema, nephrohydrosis, proteinuria, hyponatremia, hypernitremia, kaliopenia, blood potassium is too high, hypocalcemia, blood calcium is too high, hypophosphatemia and hyperphosphatemia).

Can use any method known in the art to use composition of the present invention, described method includes but not limited to: directly with needle injection to transmitting pouring into or topical application, aerosol transmission in site, intravenous injection, topical, conduit infusion, biolistic syringe, particle accelerator, the long-acting medicament of gel foam sponge, other commercially available stored material, osmotic pump, oral or suppository solid pharmaceutical preparation, the surgical procedure.Described method is known in the art.The part that composition of the present invention also can be used as therapeutical agent is applied, and this point will be described in more detail below.

Can use the polynucleotide of modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins to treat, prevent, diagnosis and/or predicting cardiovascular disease, include but not limited to peripheral arterial disease, as the limbs local asphyxia.

Cardiovascular diseases includes but not limited to: Cardiovascular abnormality, and as fistula of artery, arterio venous fistula, big arteriovenous malformation of brain, congenital heart defect, pulmonary atresia and scimitar syndrome.

Congenital heart defect includes but not limited to: aortic coaractation, cor triatriatum, coronary vasodilator are unusual, cruciform heart, dextrocardia, patent ductus arteriosus, Ebstein are unusual, Eisenmenger complex, hypoplastic left heart syndrome, sinistrocardia, tetralogy of Fallot, transposition of great vessels, double outlet of right ventricle, tricuspid atresia, persistent truncus arteriosus and heart septal defect, and is damaged as aorticopulmonary septal defect, endocardial cushion defect, Lu Tebaoasheer syndrome, trilogy of Fallot, chamber cardiac septum.

Cardiovascular diseases also includes but not limited to: heart trouble is not normal as the rhythm of the heart, carcinoid heart disease, high cardiac output, low cardiac output, cardiac tamponade, endocarditis (comprising bacterium), cardiac aneurysm, cardiac arrest, congestive heart failure, congestive cardiomyopathy, paroxysmal dyspnea, cardiac edema, cardiac hypertrophy, congestive cardiomyopathy, left ventricular hypertrophy, right ventricular hypertrophy, cardiac rupture behind the infarction, interventricular septum breaks, lular heart disease, cardiomyopathy, myocardial ischaemia, pericardial effusion, pericarditis (comprise constriction with tubercular), pneumopericardium, the syndrome of pericardial incision postoperative, the lung heart trouble, rheumatic heart disease, chamber kakergasia, congested, cardiovascular pregnancy complications, scimitar syndrome, cardiovascular syphilis and cardiovascular tuberculosis disease.

Irregular pulse includes but not limited to: sinus arrhythmia, atrial fibrillation, atrial flutter, heartbeat are low, premature beat, Adams Stokes syndrome, bundle branch block, sinoatrial block, QT prolong syndrome, parasystole, LGL syndrome, Mahaim-type preexcitation syndrome, Wo-Pei-Huai syndrome, sick sinus syndrome, tachycardia and ventricular fibrillation.Tachycardia comprises on paroxysmal tachycardia, the chamber that turn back tachycardia, dystopy atrial tachycardia, dystopy of tachycardia, accelerated idioventricular rhythm, atrioventricular node engages tachycardia, antrum tubercle turn back tachycardia, sinus tachycardia, torsades de pointes and ventricular tachycardia.

Lular heart disease includes but not limited to: aortic incompetence, aortic stenosis, heart murmur, aortic valve are deviate from, neutral lobe is deviate from, tricuspidal valve is deviate from, mitral incompetence, mitral stenosis, pulmonary atresia, pulmonic insufficiency, pulmonary stenosis, tricuspid atresia, tricuspid insufficiency and tricuspid stenosis.

Myocardosis includes but not limited to: narrow under alcoholic cardiomyopathy, congestive cardiomyopathy, hypertrophic cardiomyopathy, the aortic valve, lung subaortic stenosis, limited myocardosis, just add Si Shi myocardosis, endocardial fibroelastosis, endomyocardial fibrosis, Kearns syndrome, reperfusion injury of cardiac muscle and myocarditis.

Myocardial ischaemia includes but not limited to: coronary disease, and as stenocardia, coronary aneurysm, coronary sclerosis, Coronary thrombosis, coronary artery spasm, myocardial infarction and cardiac muscle stunning (stuning).

Cardiovascular diseases also comprises vascular disease, as aneurysma, angiodysplasia, angiomatosis, BA, the Hippel-Lindau disease, Klippel Trenaunay Weber syndrome, Sturge Weber syndrome, the vasoneurosis oedema, aortopathy, TakayasuShi sacroiliitis, aortitis, Leriche syndrome, arterial occlusive disease, sacroiliitis, enarthritis, polyarteritis nodosa, cerebro-vascular diseases, diabetic angiopathy, diabetic retinopathy, embolism, thrombosis, erythromelalgia, hemorrhoid, hepatic veno-occulusive disease, hypertension, ypotension, local asphyxia, peripheral vascular disease, phlebitis, pulmonary veno-occlusive disease, Raynaud disease, CREST syndrome, retinal vein occlusion, scimitar syndrome, superior vena cava syndrome, telangiectasis, ataxia telangiectasis, Osler Weber Rendu, the vein plethora, varix, varicose ulcer, vasculitis and vein deficiency.

Cerebrovascular disease includes but not limited to: heart-artery disease and respiratory disease.Can use the disease and/or the imbalance of polynucleotide treatment, prevention, diagnosis and/or the prediction respiratory system of transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins.

The disease and the imbalance of respiratory system include but not limited to: nasal vestibulitis, non-allergic rhinitis is (as acute rhinitis, chronic rhinitis, atrophic rhinitis, the vasoconstriction rhinitis), nasal polyp and sinusitis, juvenile angiofibroma, rhinocarcinoma and property childhood papilloma, polyp of vocal cord, joint knot (singer's node), contact ulcer, paralysis vocal cord, the larynx bulging, pharyngitis (as virus and bacterium), tonsillitis, the tonsilla phlegmon, secondary abscess of pharynx, laryngitis, larynx bulging and laryngocarcinoma are (as nasopharyngeal carcinoma, carcinoma of tonsil, laryngocarcinoma), lung cancer is (as squamous cell carcinoma, minicell (oat cells) cancer, large cell carcinoma and gland cancer), anaphylactic disease (eosinophilic granulocyte pneumonia, hypersensitivity pneumonitis is (as extrinsic allergic alveolitis, matter pneumonia between supersensitivity, the organic dust Pneumonoconiosis, allergic bronchopulmonary aspergillosis, asthma, Wegener granuloma (granulomatous angiitis), Goodpasture syndrome)), pneumonia is (as bacterial pneumonia (as streptococcus pneumoniae (lung coccus property pneumonia), streptococcus aureus (staphylococcus pneumonia), gram negative bacterium pneumonia (pneumonia that causes by for example klebsiella and pseudomonas), mycoplasma pneumoniae pneumonia, hemophilus influenza pneumonia, legionella pneumophilia (legionnaires disease) and chlamydia psittaci (psittacosis)) and virus pneumonia (as influenza virus, bird pox virus (varicella)).

Other disease and the imbalance of respiratory system include but not limited to: bronchiolitis, poliomyelitis (poliomyelitis), croup, respiratory syncytial virus infection, mumps, erythema infectiosum (erythema infectiosum), roserash, progressive rubella panencephalitis), rubella and subacute sclerosing panencephalitis, fungal pneumonia is (as histoplasmosis, coccidioidomycosis, blastomycosis, fungi infestation among the serious downtrod patient of immunity system is (as the torulosis that is caused by cryptococcus neoformans; The aspergillosis that causes by aspergillus); The moniliosis that causes by candidiasis; And mucormycosis)), Pneumocystis carinii (pneumocystis pneumoniae), severe acute respiratory syndrome (as mycoplasma and chlamydozoan), the opportunistic infection pneumonia, nosocomial pneumonia, chemical pneumonitis and aspiration pneumonitis, the pleura disease is (as pleuritis, leural effusion and pneumothorax are (as simple spontaneous pneumothorax, concurrent spontaneous pneumothorax, tension pneumothorax)), obstructive airway disease is (as asthma, chronic obstructive pulmonary disease (COPID), pulmonary emphysema, chronic or acute bronchitis), occupational tuberculosis is (as silicosis, black lung (coal miner's Pneumonoconiosis), asbestosis, berylliosis, occupational asthma, byssinosis and optimum Pneumonoconiosis), perviousness tuberculosis is (as pulmonary fibrosis (as FA, common interstitial pneumonia), the spontaneous lung fibrosis, desquamative interstitial pneumonia, LIP, histiocytosis is (as Letterer-Siwe disease, Hand-Sch ü iller-Christian disease, the eosinophilic granulocyte granuloma), the spontaneous lung hemosiderosis, sarcoidosis and lung pulmonary alveolar proteinosis), adult respiratory distress syndrome (being also referred to as adult respiratory distress syndrome), oedema, pulmonary infarction, bronchitis is (as virus, bacterium), bronchiectasis, atelectasis, pulmonary abscess (causing) and cystic fibrosis by streptococcus aureus or legionella pneumophilia.

The cancer of the polynucleotide treatment of available modified fusion rotein of the present invention and/or code book invention transferrin fusion proteins includes but not limited to: solid tumor comprises prostate gland, lung, mammary gland, ovary, stomach, pancreas, larynx, esophagus, lesteg, liver, parotid gland, biliary tract, colon, rectum, uterine cervix, uterus, uterine endometrium, kidney, bladder, thyroid carcinoma; Primary tumor and transfer; Melanoma; Glioblastoma; Kaposi; Leiomyosarcoma; Non--small cell lung cancer; Colorectal carcinoma; Late malignant tumour; And neoplastic hematologic disorder, as leukemia.For example, can localized delivery fusion rotein of the present invention and/or the polynucleotide of code book invention transferrin fusion proteins, with the cancer of treatment such as skin carcinoma, head and neck cancer, mammary cancer and Kaposi.

The polynucleotide of modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can be used for treating other disease except that cancer, described disease and associated angiogenesis.Described disease includes but not limited to: innocent tumour, as vascular tumor, acoustic tumor, neurofibroma, trachoma and granuloma pyogenicum; The atherosclerotic patch; Eye vasculogenesis disease is as the pteryium abnormal vascular growth of diabetic retinopathy, retinopathy of prematurity, macula degeneration, corneal graft repulsion, neovascular glaucoma, retinopathy of prematurity syndrome, flush, retinoblastoma, uveitis and eye; Rheumatoid arthritis; Psoriasis; Wound healing postpones; Endometriosis; Blood vessel takes place; Granulation takes place; Hypertrophic cicatrix (keloid); Disunited fracture; Scleroderma; Trachoma; Blood vessel adhesion; Angiogenesis of cardiac muscle; Crown pleurapophysis; The brain pleurapophysis; Arteriovenous malformotion; The ischemic extremity vascular generates; Osier-Webber syndrome; The patch tumor vessel forms; Telangiectasis; The hemophilia joint; Hemangiofibroma; Fibromuscular dysplasia; The wound granulation forms; Crohn disease; And atherosclerosis.

Therefore, on the one hand, method of the present invention provides the method for treatment ocular neovascular disease.

In addition, the disease of the polynucleotide of available modified fusion rotein of the present invention and/or code book invention transferrin fusion proteins treatment includes but not limited to: vascular tumor, sacroiliitis, psoriasis, hemangiofibroma, atherosclerotic patch, wound healing delay, granulation generation, hemophilia joint, hypertrophic cicatrix, disunited fracture, Osier-Webber syndrome, granuloma pyogenicum, scleroderma, trachoma and blood vessel adhesion.

In addition, the illness and/or the state of the polynucleotide treatment of available modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins include but not limited to: solid tumor, blood tumor, as leukemia, metastases, Kaposi, innocent tumour, vascular tumor for example, acoustic tumor, neurofibroma, trachoma and granuloma pyogenicum, rheumatoid arthritis, psoriasis, eye vasculogenesis disease, as diabetic retinopathy, retinopathy of prematurity, macula degeneration, corneal graft repels, neovascular glaucoma, retinopathy of prematurity syndrome, flush, retinoblastoma and uveitis, wound healing postpones, endometriosis, blood vessel takes place, granulation takes place, hypertrophic cicatrix (keloid), disunited fracture, scleroderma, trachoma, blood vessel adhesion, angiogenesis of cardiac muscle, crown pleurapophysis, the brain pleurapophysis, arteriovenous malformotion, the ischemic extremity vascular generates, Osier-Webber syndrome, the patch tumor vessel forms, telangiectasis, the hemophilia joint, hemangiofibroma, fibromuscular dysplasia, the wound granulation forms, Crohn disease, atherosclerosis, prevent the required angiopoietic birth control medicament of embryo, the implantation of control menstruation, with the vasculogenesis is the disease of pathological examination, as cat scratch disease (Rochele nunalia quintosa), ulcer (helicobacter pylori), bartonellosis and bacillary angiomatosis.

Aspect of method of birth control, before or after sexual intercourse and fertilization take place, use the composition of q.s, described amount should be able to be blocked the embryo and implant, thereby effective method of birth control is provided, and might " carry out " method after the sexual intercourse.The polynucleotide of modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins also can be used for controlling menstruation, perhaps use as peritoneal lavage or peritonaeum implant when the treatment endometriosis.

The polynucleotide of modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can be used for multiple surgical method.

Use the polynucleotide of modified fusion rotein of the present invention and/or code book invention transferrin fusion proteins to treat, prevention, diagnosis and/or prediction, suppress diseases associated with cell survival that increases or apoptosis and comprise that cancer is (as follicular lymphoma, cancer and hormone-dependent form tumour with sudden change include but not limited to colorectal carcinoma, cardiac tumor, carcinoma of the pancreas, melanoma, retinoblastoma, glioblastoma, lung cancer, intestinal cancer, carcinoma of testis, cancer of the stomach, neuroblastoma, myxoma, myomata, lymphoma, endothelioma, osteoblastoma, osteoclastoma, osteosarcoma, chondrosarcoma, adenoma, mammary cancer, prostate cancer, Kaposi and ovarian cancer); Autoimmune disease is as multiple sclerosis, siogren's syndrome, struma lymphomatosa, biliary cirrhosis, Behcet, Crohn disease, polymyositis, systemic lupus erythematous and immunity-relevant glomerulonephritis and rheumatoid arthritis) and virus infection (as simplexvirus, poxvirus and adenovirus), inflammation, graft versus host disease, acute transplant rejection and chronic transplant rejection.

In preferred embodiments, the polynucleotide of modified fusion rotein of the present invention and/or code book invention transferrin fusion proteins can be used for suppressing cancer, particularly above-mentioned cancer growth, carry out and/or shift.

Other can treat or detect by the polynucleotide of modified fusion rotein of the present invention and/or code book invention transferrin fusion proteins, include but not limited to the carrying out of malignant tumour and relative disease with the cell survival diseases associated that increases and/or shift, described disease such as leukemia (comprise that acute leukemia is (as acute lymphoblastic leukemia, acute myelocytic leukemia (comprises myeloblast, promyelocyte, myelomonocyte, monocyte and erythroleukemia)) and chronic leukemia (as chronic myelocytic (granulocyte) leukemia and chronic lymphocytic leukemia)), polycythemia vera lymphoma (how outstanding king's evil and non--Hokdkin disease), multiple myeloma, the WaldenstromShi macroglobulinemia, heavy chain disease, and solid tumor, include but not limited to sarcoma and cancer, as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdosarcoma, colorectal carcinoma, carcinoma of the pancreas, mammary cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, rodent cancer, gland cancer, syringocarcinoma, sebaceous carcinoma, papillary carcinoma, papillary carcinoma, cystadenocarcinoma, medullary carcinoma, bronchiogenic cancer, renal cell carcinoma, hepatoma, cholangiocarcinoma, choriocarcinoma, spermocytoma, embryonal carcinoma, nephroblastoma, the neck cancer, carcinoma of testis, lung cancer, small cell lung cancer, bladder cancer, epithelial cancer, neurospongioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic tumor, Oligodendroglioma, menangioma, melanoma, neuroblastoma and retinoblastoma.

Polynucleotide treatment, prevention, diagnosis and/or prediction that can be by modified fusion rotein of the present invention and/or code book invention transferrin fusion proteins, include but not limited to AIDS with the apoptosis-related disease that increases; Neurodegenerative disease (as Alzheimer disease, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, cerebellar degeneration and brain tumor or relative disease before this); Autoimmune disease is (as multiple sclerosis, siogren's syndrome, struma lymphomatosa, biliary cirrhosis, Behcet, Crohn disease, polymyositis, systemic lupus erythematous and immunity-relevant glomerulonephritis and rheumatoid arthritis) myelodysplastic syndrome (as aplastic anemia), graft versus host disease, ischemic injury is (as by myocardial infarction, the damage that apoplexy and reperfusion injury cause), liver injury is (as the liver injury relevant with hepatitis, local asphyxia/reperfusion injury, cholestasis (bile duct injury) and liver cancer); Toxin-inductive hepatopathy (as the hepatopathy that causes by ethanol), septic shock, emaciation and apositia.

In addition, the polynucleotide of modified fusion rotein of the present invention and/or code book invention transferrin fusion proteins can be used for treating or the generation of prevent diabetes.Just be diagnosed as I and type ii diabetes, still remain with among the patient of some islet cell functions, the polynucleotide of fusion rotein of the present invention and/or code book invention transferrin fusion proteins can be used for keeping islet function, thereby alleviate, postpone or prevent the long-term clinical manifestation of this disease.In addition, the polynucleotide of fusion rotein of the present invention and/or code book invention transferrin fusion proteins can be used as auxiliary to improve or to promote the function of islet cells in islet cell transplantation.

The polynucleotide of modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can be used for diagnosis and/or treatment brain and/or neural disease, imbalance, infringement or damage.Can with composition of the present invention (polynucleotide of fusion rotein for example of the present invention and/or code book invention transferrin fusion proteins) treatment, be confined to neural nervous system disorder and include but not limited to: can cause that aixs cylinder disconnects, damage and the disease or the imbalance of neurone minimizing or sex change or demyelinization.But the method according to this invention nervous system damage treatment, patient's (comprising people and non-human mammal patient) includes but not limited to the infringement of following maincenter (comprising spinal cord, brain) or peripheral nervous system: the infringement of (1) ischemic, wherein partial nerve system anoxic causes neuronal damage or death, comprise cerebral infarction or local asphyxia, or infarction of spinal cord or local asphyxia; (2) traumatic lesion comprises the infringement that caused by physical injury or the infringement relevant with operation, for example, and neural infringement of breaking part or compression injury; (3) malignant lesions, wherein the partial nerve system is destroyed or injures by malignant tissue, and described malignant tissue is the malignant tumour relevant with neural system, or derived from the malignant tumour of neural system tissue; (4) infectious infringement, the consequence of partial nerve system wherein, for example abscess and destroyed or injury is perhaps relevant with the infection of human immunodeficiency virus, varicella zoster virus or hsv or Lyme disease, tuberculosis or syphilis because of infecting; (5) degenerative lesion, wherein partial nerve system destroyed or injury because of the result of degeneration process, described degeneration process includes but not limited to and Parkinson's disease, Alzheimer disease, Huntington Chorea or the relevant degeneration of amyotrophic lateral sclerosis (ALS); (6) with the trophopathy or the relevant infringement of lacking of proper care, wherein partial nerve system destroyed or injury because of the result of metabolic trophopathy or imbalance, described disease or imbalance include but not limited to: vitamin B12 deficiency disease, folic acid deficiency, acute hemorrhagic polioencephalitis, tobacco-alcoholic amblyopia, Marchiafava-Blanami disease (primary degeneration of corpus callosum) and alcohol cerebral degeneration; (7) nervous lesion relevant with systemic disease, described disease includes but not limited to: diabetes (diabetic neuropathy, bell's palsy), systemic lupus erythematous, cancer or sarcoidosis; (8) infringement that causes by the toxicant that comprises alcohol, lead or particularly neurotoxin; (9) demyelination infringement, wherein the partial nerve system is destroyed or injures by demyelination, and described disease includes but not limited to: multiple sclerosis, human immunodeficiency virus-relevant myelopathy, transverse myelopathy or Different types of etiopathogenises, progressive multifocal leukoencephalopathy and central pontine myelinolysis.

In one embodiment, the polynucleotide of modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can be used for the neuroprotective cell and avoid the anoxybiotic detrimental effect.In a further preferred embodiment, the polynucleotide of modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can be used for the detrimental effect that the neuroprotective cell is avoided cerebral anoxia.

In specific embodiments, the treatable motor neurone disease of the present invention includes but not limited to: such as infraction, infect, be exposed to toxin, wound, the operation infringement, degenerative disease maybe can influence the disease of the malignant tumour of motor neuron and other component of neural system, and selectivity affect the nerves the unit disease, as amyotrophic lateral sclerosis, include but not limited to progressive spinal muscular atrophy, PBP, primary lateral sclerosis, infant's amyotrophy, children's PBP (Fazio-Londe syndrome), poliomyelitis and post poliomyelitis syndrome, and hereditary motor and sensory neuropathy (charcot-Marie-Tooth disease).

In addition, the polynucleotide of modified fusion rotein of the present invention and/or code book invention transferrin fusion proteins can be at neuronal survival; Cynapse forms; Conduction; Work in the Neural Differentiation etc.Therefore, composition of the present invention (polynucleotide that comprise fusion rotein of the present invention and/or code book invention transferrin fusion proteins) can be used for diagnosis and/or treatment or prevention and these effect diseases associated or imbalance, includes but not limited to study and/or cognitive illnesses.Composition of the present invention also can be used for treatment or prevention neurodegenerative disease state and/or conduct disorder.Described neurodegenerative disease state and/or conduct disorder include but not limited to: Alzheimer disease, Parkinson's disease, Huntington's disease, tourette's syndrome, schizophrenia, mania, dementia, paranoia, obsessive compulsive disorder, HA, deficiency of learning ability, ALS, psychosis, autism and behavior change comprise diet, sleep pattern, balance and sensation disease.

The neuropathic example that the polynucleotide of modified fusion rotein of the present invention and/or code book invention transferrin fusion proteins can treat or detect comprises encephalopathic, and as metabolic encephalopathy, it comprises pku, as maternal phenylketonuria disease, pyruvate carboxylase deficiency, the pyruvate salt dehydrogenase complex lacks, Wernicke ' s encephalopathic, cerebral edema, cerebral tumor is as cerebellar tumor, comprise an act following tumour, tumor of ventricle, as tumor of choroid plexus, hypothalamic tumors, tumour on the curtain, the continuous sex change of brain, little encephalopathic is as cerebellar ataxia, comprise spinocerebellar degeneration, as louis bar, cerebellum dyssynergia, Friederich ataxia, Ma-Yue disease, olivopontocerebellar atrophy, cerebellar tumor is as tumour under the curtain, diffuse cerebrosclerosis, as encephalitis periaxialis, spheroid cell leukodystrophy, metachromatic leukodystrophy and subacute sclerosing panencephalitis.

Other neuropathy that the polynucleotide of modified fusion rotein of the present invention and/or code book invention transferrin fusion proteins can treat or detect comprises that cerebrovascular disease is (as the carotid artery disease, comprise the carotid artery thrombosis, carotid artery stenosis and moyamoya), cerebral amyloid angiopathy, the brain internal carotid artery posterior communicating artery aneurysm, cerebral anoxia, cerebralarteriosclerosis, big arteriovenous malformation of brain, the arteriae cerebri disease, cerebral embolism and thrombosis, as the carotid artery thrombosis, hole thrombosis and Wallenberg syndrome, hematencephalon, as the epidermis hemotoncus, subdural hematoma and subarachnoid hemorrhage, cerebral infarction, cerebral ischemia, as instantaneous cerebral ischemia, subclavian steal syndrome and vertebro-basilar artery insufficiency, vascular dementia, as multi-infarct dementia, chamber week alba is softening, vascular headache is as cluster headache and migraine.

Other neuropathy that the polynucleotide of modified fusion rotein of the present invention and/or code book invention transferrin fusion proteins can treat or detect comprises dementia, as the dull-witted complex of AIDS, presenile dementia, sick and the Creutzf é ldt-Jakob syndrome as Alzheimer, senile dementia, as Alzheimer disease and stein-leventhal syndrome, vascular dementia, as multi-infarct dementia, encephalitis comprises encephalitis periaxialis, viral encephalitis, as epidemic encephalitis, Japanese encephalitis, the St.Louis encephalitis, tick encephalitis and west Nile fever, acute disseminated encephalomyelitis, meningoencephalitis, as uvea meningoencephalitis syndrome, Parkinson's disease and subacute sclerosing panencephalitis after the meningitis, encephalomalacia, softening as chamber week alba, epilepsy as generalized epilepsy, comprises infantile spasm, inattentive epilepsy, lafora's disease comprises MERRF syndrome, and is tetanic-clonic epilepsy, the part epilepsy, as the part epilepsy of complexity, frontal lobe epilepsy and temporal epilepsy, post-traumatic epilepsy, continuous epilepsy is as epilepsia partialis continua and Ha-Shi syndrome.

Other neuropathy that the polynucleotide of modified fusion rotein of the present invention and/or code book invention transferrin fusion proteins can treat or detect comprises hydrocephalus, as Dandy-Walker syndrome and normal pressure hydrocephalus, hypothalamic disorder is as hypothalamic tumors, cerebral malaria, narcolepsy comprises cataplexy, bulbar poliomyelitis, pseudotumor cerebri, Rett syndrome, Reye syndrome, thalamus disease, big brain toxoplasmosis, encephalic tuberculoma and Ze Weige syndrome, central nervous system infection is as AIDS, dull-witted complex, cerebral abscess, subdural empyema, encephalomyelitis, as equine encephalomyelitis, Venezuelan equine encephalomyelitis causes downright bad hemorrhagic encephalomyelitis, visna and cerebral malaria.

Other neuropathy that the polynucleotide of modified fusion rotein of the present invention and/or code book invention transferrin fusion proteins can treat or detect comprises meningitis, as arachnoiditis, aseptic meningitis as viral meningitis, comprises the lymphocyte chronic meningitis, bacterial meningitis, comprise Haemophilus meningitis, Listeria meningitis, meningococcal meningitis, as Waterhouse-Fridericlisen syndrome, pneumococcal meningitis and meningeal tuberculosis disease, fungal meningitis is as cryptococcal meningitis, subdural effusion, meningoencephalitis is as uvea meningoencephalitis syndrome, myelitis, as transverse myelitis, neurosyphilis, as myelophthisis, poliomyelitis, comprise bulbar poliomyelitis and post poliomyelitis syndrome, prion disease (as Creutzfeldt-Jakob syndrome, mad cow disease, Gerstmann-Straussler syndrome, Kuru disease, the itch disease) and big brain toxoplasmosis.

Other neuropathy that the polynucleotide of modified fusion rotein of the present invention and/or code book invention transferrin fusion proteins can treat or detect comprises central nerve neuroma, as cerebral tumor, comprise cerebellar tumor, as tumour under the curtain, tumor of ventricle, as tumor of choroid plexus, hypothalamic tumors and curtain are gone up tumour, the meninges tumour, tumor of spinal cord, comprise epidural neoplasm, demyelinating disease, as the continuous sex change of brain, dispersivity brain sculleries, comprise the sadreno leukodystrophy, encephalitis periaxialis, spheroid cell leukodystrophy, the generalization cerebral sclerosis, as metachromatic leukodystrophy, allergic encephalomyelitis causes downright bad hemorrhagic encephalomyelitis, progressive multifocal leukoencephalopathy, multiple sclerosis, central pontine myelinolysis, transverse myelitis, optic neuromyelitis, the itch disease, Swayback, chronic fatigue syndrome, visna, high pressure nervous syndrome, meningism, myelopathy, as congenital amyotonia, amyotrophic lateral sclerosis, Duchenne-Arandisease is as Werdnig-Hoffmann disease, compression of spinal cord, tumor of spinal cord, as epidural neoplasm, syringomyelia, myelophthisis, the stiff-man syndrome, mental retardation is as Angelman syndrome, cat's cry syndrome, de Lange syndrome, mongolism, Gangliosidosis, as G type Gangliosidosis (MI), sandhoff disease, Tay Sachs disease, how Hart pounces on disease, homocystinuria, Laurence-Moon-Bied syndrome, Lesch-Nylian syndrome, maple syrup urine disease, Mucolipidosis, as Fucosidosis, the cured sample matter of neurone fipofuscinosis, oculo cerebro renal syndrome, pku, as maternal phenylketonuria disease, Pu-Wei syndrome, Rett syndrome, Rubinstein-Taybi syndrome, tuberous sclerosis, WAGR syndrome, nervous system abnormality, as holoprosencephaly, neural tube defect as anencephalus, comprises hydroanencephalus, the Arnold-Chairi deformity, the brain bulging, meninx bulging, the bulging of spinal meninges spinal cord, spinal dysraphism is as spina bifida cystica and hemirachischisis.

Endocrine system and/or hormonal imbalance and/or disease comprise uterus motility disease, include but not limited to gestation and childbirth complication (as childbirth in advance, post term pregnancy, spontaneous abortion and secretion slowly and stop); With menstrual cycle imbalance and/or disease (as dysmenorrhoea and endometriosis).

Endocrine system and/or hormonal imbalance and/or disease comprise pancreas imbalance and/or disease, for example, and diabetes, diabetes insipidus, congenital pancreas underdevelopment, pheochromocytoma islet cell tumor syndrome; Suprarenal gland imbalance and/or disease, for example, the Addison disease, the class Kendall compound lacks, manlike disease, hirsutism, hypercortisolism, hyperaldosteronism, pheochromocytoma; Pituitary gland imbalance and/or disease, for example, hyperpituitarism, hypopituitarism, growth hormone deficiency dwarfism, pituitary adenoma, panhypopituitarism, acromegaly, gigantosoma; Tiroidina imbalance and/or disease, include but not limited to hyperthyroidism, hypothyroidism, the Plummer, Christopher disease, Exophthalmus goiter (graves disease), toxic nodular goiter, thyroiditis (struma lymphomatosa, subacute granulomatous thyroiditis and the lymphocytic thyroiditis of stopping), PendreWs syndrome, myxedema, cretinism, thyrotoxicosis, thyroid hormone coupling defect, thymic aplasia, thyroid Hurthle cell tumor, thyroid carcinoma, thyroid carcinoma, medullary thyroid carcinoma; Parathyroid gland imbalance and/or disease, hyperparathyroidism for example, hypoparathyroidism; Hypothalamus imbalance and/or disease.

In addition, endocrine system and/or hormonal imbalance and/or disease also comprise testis or ovary imbalance and/or disease, comprise cancer.Other testis or ovary imbalance and/or disease also comprise for example ovarian cancer, polycystic ovarian syndrome, klinefelter syndrome, vanishing testes syndrome (bilateral anorchia), congenital Leydig cell deficiency disease, cryptorchidism, Noonan syndrome, myotonic dystrophy, testis capillary blood tuberculation (optimum), testis and newborn testicular tumor form.

In addition, endocrine system and/or hormonal imbalance and/or disease also comprise following imbalance and/or disease: polyadenous lacks syndrome, pheochromocytoma, neuroblastoma, multiple endocrine neoplasia and endocrine tissue's imbalance and/or cancer.

The polynucleotide of modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can be used for diagnosis, treatment or prevention reproductive system disease and/or imbalance.The treatable reproductive system disease of composition of the present invention includes but not limited to: reproductive system damage, infect, tumor disease, congenital defect, that described disease or imbalance can cause is sterile, gestation or childbirth complication and postpartum difficulty.

Reproductive system imbalance and/or disease comprise testis disease and/or imbalance, comprise testicular atrophy, testicular feminization, cryptorchism (one-sided and bilateral), anorchia, ectopic testis, epididymitis and testitis (are generally caused by following infection: gonorrhoea, parotitis, tuberculosis and syphilis), testicular torsion, the vasitis tubercle, germinoma (as spermocytoma, embryonal cell lipoma, teratoma, choriocarcinoma, yolk sac tumor and teratoma), stromal tumors (as leydig cell tumor), hydrocele, vaginal hematocele, essence is a phlebangioma, spermatocele, and the disease that inguinal hernia and sperm produce is (as immotile-cilia syndrome, sperm, the sperm debility, azoospermia, oligospermia and teratozoospermia).

Reproductive system disease also comprises prostatosis, for example acute non--bacterial prostatitis, chronic non--bacterial prostatitis, the acute bacterial prostatitis, chronic bacterial prostatitis, prostate gland dystonia, prostatosis, granulomatous prostatitis, malakoplakia, benign prostatauxe or hyperplasia, with the tumor of prostate disease, comprise gland cancer, transitional cell carcinoma, duct carcinoma and squamous cell carcinoma.

In addition, composition of the present invention can be used for diagnosis, treat and/or prevent penis and urethral disease, comprise inflammatory diseases, balanoposthitis for example, balanitis xeroticaobliterans, phimosis, paraphimosis, syphilis, hsv, gonorrhoea, non--gonococcal urethritis, chlamydozoan, mycoplasma, trichomonas, HIV, AIDS, Reiter syndrome, pointed condyloma, condyloma latum and pearly penile papules, urethra is unusual, as hypospadia, epispadia and phimosis, the preceding infringement of cancerating comprises EQ, Bowen disease, the Bowen disease bowenoid papulosis, criant condyloma and the verrucous carcinoma of Buscke-Lowenstein; Penile cancer comprises squamous cell carcinoma, carcinoma in situ, verrucous carcinoma and dispersivity penile cancer; The tumor of urethra disease comprises the penis urethral carcinoma, bulb urethrae film cancer and prostate-urethra cancer; With the erection disease, as priapism, Peyronie disease, erectile dysfunction and impotence.

In addition, disease of the vas deferens and/or illness comprise vasitis and CBAVD (congenital bilateral vas deferens disappearance); In addition, the polynucleotide of transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can be used for diagnosis, treat and/or prevent seminal vesicle disease and/or illness, comprise echinococcosis, congenital chioride diarrhoea and multicystic kidney disease.

Other male reproductive system imbalance and/or disease for example comprise: Klinefelter syndrome, Young syndrome, premature ejaculation, diabetes, cystic fibrosis, Kartagener syndrome, high heat, multiple sclerosis and gynecomastia.

In addition, polynucleotide of the present invention, the polynucleotide of modified fusion rotein and/or code book invention transferrin fusion proteins can be used for diagnosis, treat and/or prevent vagina and vulva disease and/or illness, comprise bacterial vaginitis, monilial vaginitis, hsv, venereal ulcer, granuloma inguinale, lymphogranuloma venereum, scabies, human papillomavirus, the vagina wound, trauma of vulva, adenopathy, the chlamydozoan vaginitis, gonorrhoea, trichomonal vaginitis, pointed condyloma, syphilis, molluscum contagiosum, atrophic vaginitis, the Paaet disease, the lichen scleroma, lichen planus, vulvodynia, toxic shock syndrome, vulvismus, vulvovaginitis, vulvar vestibulitis and tumor disease, for example squamous cell hyperplasia, clear cell carcinoma, rodent cancer, melanoma, Bartholin gland cancer and vulva intraepaelial tumorigenesis.

Uterine disorder and/or disease comprise: dysmenorrhoea, retroversion, endometriosis, fibroma, endometriosis, anovulatory bleeding, menolipsis, Cushiner syndrome, hydatidiform mole, Asherman syndrome, menopause praecox, puberty precocity, metropolypus, anovulatory dysfunctional uterine hemorrhage (for example uterine hemorrhage that is caused by unusual hormone signal) and tumor disease, for example gland cancer, leiomyosarcoma and sarcoma.In addition, the polynucleotide of transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can be used for diagnosing, treating and/or preventing congenital abnormal uterus as described below, and can be used as the mark or the detection agent of these diseases, described disease for example comprises: bicornute uterus, uterus septus, simple uterus unicornis, have non--sex immature angle, chamber uterus unicornis, have the non--uterus unicornis at cavity sex immature angle, uterus unicornis, uterus arcuatus, duplex uterus and T-shape uterus with cavity angle.

Disease of ovary and/or illness comprise ovulation, polycystic ovarian syndrome (Stein-Leventhal syndrome), ovarian cysts, hypo-ovaria, ovary is insensitive to gonadotrophins, the excessive generation male sex hormone of ovary, right ovarian vein syndrome, menolipsis, hirsutism and ovarian cancer (include but not limited to the growth of primary and secondary carcinoma, the Sertoli-Leydig tumour, the ovary endometrioid carcinoma, the ovary papillary serous adenocarcinoma, ovary mucinous adenocarcinoma and ovary krukenberg's tumor).

Cervix diseases and/or illness comprise cervicitis, chronic cervicitis, mucus purulence cervicitis and dysplasia of cervix, cervical polyp, Naboth tumour, cervical erosion, cervical incompetence and cervix neoplasms (comprising that for example cervical cancer, squamous metaplasia, squamous cell carcinoma, glandular scale shape glucagonoma form and mast cell's tumorigenesis).

The polynucleotide of modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can be used for treatment or detect infectant.For example, reply, particularly strengthen the propagation and the differentiation of B and/or T cell, can treat infectious diseases by enhancing immunity.By strengthening existing immunne response, or, can enhancing immunity reply by fusion rotein of the present invention and/or initial new immunne response.Perhaps, the polynucleotide of code book invention transferrin fusion proteins also can directly suppress infectant, and needn't cause immunne response.

Virus is an example that can cause the infectant of disease or symptom, and described disease or symptom can be treated or detect to the polynucleotide of transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins.The example of virus includes but not limited to following DNA and RNA viruses and Viraceae: arboviruses, Adenoviridae, Arenaviridae, Arterivirus, Bimaviridae, Bunyaviridae, the embedding Caliciviridae, Circoviridae, coronaviridae, dengue virus, EBV, HIV, flaviviridae, Hepadnaviridae, hepatitis virus, herpetoviridae (cytomegalovirus for example, hsv, zoster), Mononegavirus is (as Paramyxoviridae, Measles virus, Rhabdoviridae), orthomyxoviridae family is (as influenza A virus, Influenza B virus and parainfluenza virus), papillomavirus, papovaviridae, Parvoviridae, Picornaviridae, Poxviridae (as variola minor virus or vaccinia virus), Reoviridae (as rotavirus), Retroviridae (HTLV-I, HTLV-11, slow virus) and Togaviridae (as rubella virus).

Similarly, can cause and to be included but not limited to following Gram-negative and gram positive bacterium by the polynucleotide of transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins treatments or the disease that detects or the bacterium and the fungi factor of symptom, bacterium section and fungi: actinomycetes (as Norcard í a), acinetobacter calcoaceticus, cryptococcus neoformans, aspergillus, Bacillaceae (as Bacillus anthracis), bacterioide (as bacteroides fragilis), blastomycete, Bordetella, burgdorferi (as B. burgdorferi), brucella, candidiasis, Campylobacter, chlamydozoan, clostridium is (as Clostridium botulinum, clostridium difficile, clostridium perfringens, clostridium tetani), coccidioides immitis, coryneform bacteria (as diphtheria corynebacterium), cryptococcus, dermatophytes, intestinal bacteria (as enterotoxigenic E.Coli and enterohemorrhagic Escherichia coli), enterobacteria (as enteroaerogen), enterobacteriaceae (klebsiella, Salmonellas is (as salmonella typhi, Salmonella enteritidis, salmonella typhi), Serratia, Yersinia, Shigellae), Erysipelothrix, influenzae (as the second type influenza virus influenzae), Helicobacter pylori, legionella (as legionella pneumophilia), Leptospira, listeria spp (as the monocyte hyperplasia listeria spp), mycoplasma, mycobacterium (as hansen's bacillus and Mycobacterium tuberculosis), vibrios (as vibrio cholerae), Neisseria gonorrhoeae is (as Diplococcus gonorrhoeae, Neisseria meningitidis), Pasteurellaceae, mycetozoan, pseudomonas (as pseudomonas aeruginosa), Rickettsiaceae, spirochete is (as treponema, Leptospira, burgdorferi), Shigellae, staphylococcus (as streptococcus aureus), meningococcus, streptococcus pneumoniae and suis are (as streptococcus pneumoniae and A, B and C group B streptococcus B) and the urea substance.

In addition, can cause and to be included but not limited to following section or guiding principle by the treatment of the polynucleotide of fusion rotein of the present invention and/or code book invention transferrin fusion proteins, prevention and/or the disease of diagnosis or the parasite factor of symptom: amoeba worm, babesia, coccidia, Cryptosporidium, double-core amoeba worm, horse class vertebra worm, epizoa, giardia lamblia, worm, leishmania, schistosomicide, theileria, toxoplasma, trypanosome and trichomonad and sporozoite (as Plasmodium vivax, Piasmodium falciparum quotidianum, malariae and Plasmodium ovale).

The polynucleotide of modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can be used for differentiation, propagation and attract cell, cause tissue regeneration (referring to Science276:59-87 (1997)).Tissue regeneration can be used for repairing, substitutes or protection is damaged and the tissue of infringement by congenital defect, wound (wound, burn, otch or ulcer), age, disease (as osteoporosis, osteoarthritis, periodontal disease, liver failure), operation (comprising the beauty and shaping surgical operation), cystic fibrosis, reperfusion injury or general cytokine.

Use the present invention to comprise organ (as pancreas, liver, intestines, kidney, skin, endothelium), muscle (unstriated muscle, skeletal muscle or cardiac muscle), vascular system (comprising blood vessel and lymphatic vessel), nerve, hematopoiesis and bone (bone, cartilage, heel string and ligament) tissue by the regenerated tissue.Preferred not epulosis or few epulosis when regeneration takes place.Regeneration also can comprise vasculogenesis.

The polynucleotide of modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can be used for treatment, prevention, diagnosis and/or prediction disorder of gastrointestinal tract, comprise inflammatory diseases and/or state, infection, cancer (as intestinal cancer (enteric carcinoid knurl, small intestine non--He Jiejin lymphomas, enteric lymphoma)) and ulcer, as peptide ulceration.

Gastrointestinal disorder comprises: dysphagia, odynophagia, the oesophagus inflammation, peptic esophagitis, the stomach adverse current, submucosal fibrosis and structure, the Mallory-Weiss infringement, leiomyoma, lipoma, epithelial cancer, gland cancer, the gastric retention disease, gastroenteritis, gastratrophy, cancer of the stomach, polyp of stomach, autoimmune disease (as pernicious anemia), pyloristenosis, gastritis is (bacillary, viral, eosinophilic granulocyte, nervous-bring out, chronic aggressiveness, atrophic, plasmocyte and Menetrier gastritis) and peritoneopathy (as chyloperitoneum, hemoperitoneum, mesenteric cyst, mesenteric lymphadenitis, the mesentery angiemphraxis, pimelitis, tumour, peritonitis, pneumoperitoneum, the bubphrenic abscess.

Gastrointestinal disorder also comprises the illness relevant with small intestine, as malabsorption syndrome, expand, irritable bowel syndrome, sugar does not tolerate, celiac disease, duodenal ulcer, duodenitis, ceylon sore mouth, Whipple disease, intestinal lymphangiectasia, Crohn disease, ecphyaditis, ileocleisis, meckel's diverticulum, many diverticulums, the complete spinning obstacle of small intestine and large intestine, lymphoma and bacterium and parasitic disease are (as traveler's diarrhea, typhoid fever and paratyphoid, and cholera, roundworm (AscariasisItimbricoides), hookworm (Anclostoma duodenale), nematode (Enterobius vermicularis), tapeworm jaenia saginata, Echinococcus granulosus, the infection of Taenia lata and T.SOHUM).

Hepatic diseases and/or illness comprise: intrahepatic cholestasis (Alagille syndrome, cholehepatocirrhosis), fatty liver (alcoholic fatty liver, Lay syndrome), hepatic vein thrombosis forms, hepatolenticular degeneration, hepatomegaly, hepatopulmonary syndrome, hepatorenal syndrome, portal hypertension (oesophagus and gastric varices), liver abscess (amebic liver abscess), liver cirrhosis (alcohol, courage and experimental liver cirrhosis), alcoholic liver disease (fatty liver, hepatitis, liver cirrhosis), parasitic hepatopathy (echinococciasis of liver, fascioliasis, amebic liver abscess), jaundice (haemolysis, liver cell and cholestasis type jaundice), cholestasis, portal hypertension, hepatomegaly, ascites, hepatitis (alcoholic hepatitis, aniffial hepatitis, chronic hepatitis (autoimmune hepatitis, hepatitis B, hepatitis C, hepatitis D, the hepatitis of medicine-bring out), toxic hepatitis, viral human hepatitis (hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E), the Wilson disease, granulomatous hepatitis, the Secondary cases cholehepatocirrhosis, hepatogenic encephalopathy, portal hypertension, varix, hepatogenic encephalopathy, primary courage vascular tumor, cholehepatocirrhosis, primary sclerosing cholangitis, adenoma, hepatolithiasis, liver failure (hepatogenic encephalopathy, acute hepatic failure) and liver tumor (angiomyoliopma, the calcification hepatic metastases, the capsule hepatic metastases, epithelial tumor, layer of fibers liver cancer, focal nodular hyperplasia, adenoma of liver, hepatobiliary cystadenoma, hepatoblastoma, hepatocellular carcinoma, hepatocellular carcinoma, liver cancer, angioendothelioma of liver, mesenchymal hamartoma, the liver mesenchymoma, nodular regenerative hyperplasia, optimum liver tumor (hepatic cyst, simple cyst, the polycystic liver disease, hepatobiliary cystadenoma, choledochal cyst, mesenchymal neoplasm, mesenchymal hamartoma, baby's hemangioendothelioma, vascular tumor, the purpura hepatitis, lipoma, the false tumour of inflammatory, various epithelial tumors, epithelial duct (bile duct progonoma, cholangioadenoma), liver cell (adenoma, focal nodular hyperplasia, nodular regenerative hyperplasia), malignancy hepatic tumor (liver cell, hepatoblastoma, hepatoma, bile duct cell, cholangiocarcinoma, cystadenocarcinoma, vascular tumor, angiosarcoma, Kaposi, hemangioendothelioma, other tumour, embryo's sarcoma, fibrosarcoma, leiomyosarcoma, rhabdosarcoma, sarcocarcinoma, teratoma, carcinoid tumor, squamous cell carcinoma, the primary lymphoma)), hepatic peliosis, red hepatic porphyria, hepatic porphyria (acute intemittent porphyria, porphyria cutanea tarda), Zelli Neger syndrome).

Pancreatic disease and/or illness comprise: acute pancreatitis, chronic pancreatitis (acute necrotizing pancreatitis, alcoholic pancreatitis), tumour (pancreas adenocarcinoma, cystadenocarcinoma, nesidioblastoma, gastrinoma and glucacronoma, cysticcitmeoplasms, islet cell tumor, Pancreatoblastoma) and other pancreatic disease (as cystic fibrosis, tumour (pancreatic pseudocyst, pancreatic fistula, pancreas deficiency)).

Cholecystopathy comprises postoperative syndrome, diverticulum of gallbladder disease, acute cholecystitis, chronic cholecystitis, tumor of bile duct and the mucous cyst of gallbladdergallstonecholetithiasis (chololithiasis and choledocholithiasis), cholecystectomy.

Large intestine disease and/or illness comprise: the colitis relevant with microbiotic, diverticulitis, ulcerative colitis, acquired megacolon, abscess, fungi and infectation of bacteria, anorectal disease is (as anal fissure, hemorrhoid), colon disease (colitis, colon tumor, colorectal carcinoma, adenoma polyp of colon (as villous adenoma), colorectal carcinoma, colorectal carcinoma, diverticulitis of colon, diverticulosis of colon, megacolon, Hirschsprung disease, toxic megacolon, the sigmoid colon disease, rectocolitis, the sigmoid colon tumour, constipation, Crohn disease, diarrhoea (infantile diarrhea, dysentery), dodecadactylon disease (duodenum tumour, duodenal obstruction, duodenal ulcer, duodenitis), enteritis (enterocolitis), the HIV disorder of the small intestine, ileum disease (ileal neoplasm, ileitis), the immunoproliferation disorder of the small intestine, inflammatory bowel (ulcerative colitis, Crohn disease), intestinal occlusion, parasitosis (anisakiasis, balantidiasis, yeast infection, cryptosporidiosis, double-core amoeba parasitosis, amebic dysentery, giardiasis), intestinal fistula (rectal fistula), intestinal tumor (cecal neoplasma, colon tumor, the duodenum tumour, ileal neoplasm, polyp intestinal, the jejunum tumour, rectal neoplasm), intestinal obstruction (afferent loop syndrome, duodenal obstruction, fecal impaction, the intestines pseudo-obstruction, volvulus of cecum, intussusception), intestinal perforation, polyp intestinal (polyp of colon, Gardner syndrome, Peutz-jeghers syndrome), the jejunum disease, the jejunum tumour), nutriment malabsorption syndrome (blind loop syndrome, celiac disease, lactose intolerance, short bowel syndrome, ceylon sore mouth, Whipple disease), the mesentery angiemphraxis, pneumatosis cystoides intestinalis, lose proteinic disorder of the small intestine (intestinal lymphangiectasia), rectum disease (anal disease, scoracratia, hemorrhoid, rectitis, rectal fistula, proctoptosis, proctoptosis), peptide ulceration (duodenal ulcer, peptic esophagitis, hemorrhage, perforation, stomach ulcer, Zuo-Ai syndrome), dumping syndrome (dumping syndrome), stomach trouble is (as no hydrochloric acid in gastric juice, duodenogastric reflux (bile regurgitation), the vasodilation of stomach hole, gastric fistula, the stomach outlet is blocked, gastritis (atrophic or menetrier's disease), gastroparesis, gastric distension, gastric diverticulum, gastric tumor (cancer of the stomach, polyp of stomach, adenocarcinoma of stomach, the hyperplasia polyp of stomach), gastric rupture, stomach ulcer, gastric volvulus), tuberculosis, visceroptosis, vomiting is (as spitting blood, the Gestation period vomits strongly, postoperative nausea and vomiting) and the hemorrhagic colitis.

Other gastrointestinal system disorder and/or illness comprise biliary tract, as Gastroschisis, fistula is (as the bile duct fistula, esophageal fistula, gastric fistula, intestinal fistula, pancreatic fistula), tumour is (as tumor of biliary tract, esophageal neoplasm, as adenocarcinoma of esophagus, esophageal squamous cell carcinoma, gastrointestinal tumor, pancreatic neoplasm is as pancreas adenocarcinoma, pancreas mucous bursa tumour, the pancreatic cyst knurl, Pancreatoblastoma and peritoneal tumor), esophagopathy is (as the bleb disease, moniliosis, the glycoaenie acanthosis, ulcer, Barrett esophagus varix, locking, tumour, diverticulum (as the Zenker diverticulum), fistula (as tracheo esophageal fistula), the power disease is (as CREST syndrome, swallow disease, achalasia, spasm, gastroesophageal reflux), tumour, perforation is (as Boerhaave syndrome, Ma-Wei syndrome), narrow, esophagitis, diaphragmatocele (as the ceasma hernia); Gastrointestinal disorder is as gastro-enteritis (infecting as cholera disease, norwalk virus), hemorrhage (as spitting blood, melaena, digestive ulcerative bleeding), gastric tumor (cancer of the stomach, polyp of stomach, adenocarcinoma of stomach, cancer of the stomach)), hernia (as congenital diaphragmatic hernia, femoral hernia, inguinal hernia, oodeocele, umbilical hernia, laparacele) and enteropathy (as caecum disease (ecphyaditis, cecal neoplasma)).

The polynucleotide of modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can have chemotactic activity.Chemotactic molecule attracts cell (as monocyte, inoblast, neutrophilic granulocyte, T-cell, mastocyte, eosinophilic granulocyte, epithelial cell and/or endotheliocyte) or moves to the intravital specific site of body, as the site of inflammation, infection or hyper-proliferative.Then, the cell that the is moved specific wound or unusual of to defeat and/or to fully recover.

The polynucleotide of modified transferrin fusion proteins of the present invention and/or code book invention transferrin fusion proteins can increase the chemotactic activity of specific cells.The number of the cell by making target health specific position increases then, and these chemotactic molecules are used for the treatment of inflammation, infection, excess proliferative disease, or any disease of immune system.

Transgenic animal

One embodiment of the invention wish to produce transgenosis non--people animal, described animal contains modified transferrin fusion constructs of the present invention, and it has the serum half life of increase, the serum stability of increase or the biological usability of increase.In some embodiments, lactoferrin can be used as the Tf part of fusion rotein, thereby make fusion rotein produce justacrine to milk.

A lot of patents and publication, as United States Patent (USP) 6,291,740 (September 18 calendar year 2001 is open), United States Patent (USP) 6,281, the successful generation of transgenic nonhuman animal has been described in 408 (August 28 calendar year 2001 is open) and the United States Patent (USP) 6,271,436 (August 7 calendar year 2001 is open) (its content is all listed this paper in as a reference).

Change animal, have various commercial purposes as the ability of the genomic constitution of livestock Mammals (comprising milk cow, pig, goat, horse, ox and sheep).These purposes comprise: generation can be expressed the animal of a large amount of exogenous protein in the mode (as expressing to milk or blood) that is easy to obtain, generation has that the body weight of increase, the efficient of feeding, body are formed, the animal of milk generation or content, disease resistance and resistance that specified microorganisms is infected, and produces growth velocity and improve or reproductive characteristic enhanced animal.The animal that contains exogenous dna sequence dna in the genome is called as transgenic animal.

Method most popular, that produce transgenic animal is to the embryo's that is fertilized pronucleus (Wall etc., J.Cell.Biochem.49:113[1992]) with DNA micro-injection.Other method that produces transgenic animal comprises with retrovirus or retroviral vector embryonal vaccination.Existing people reported with wild-type or recombinant retrovirus infect implant before and implant the back mice embryonic (Janenich, Proc.Natl.Acad.Sci.USA 73:1260[1976]; Janenich etc., Cell 24:519[1981]; Stuhlmann etc., Proc.Natl.Acad.Sci.USA 81:7151[1984]; Jahner etc., Proc.Natl.Acad Sci.USA82:6927[1985]; Van der Putten etc., Proc.Natl.Acad Sci.USA 82:6148-6152[1985]; Stewart etc., EMBO are J.6:383-388[1987]).

Another kind of method with the retroviral infection embryo is to the segmentation cavity of mice embryonic (Jahner, D. etc., Nature 298:623[1982]) with viral or virus-production injection cell.Someone reported that the intrauterine retroviral infection that uses the microhabitat mice embryonic imported mouse kind system (Jahner etc., document the same [1982]) with transgenosis.Also the someone reported with retrovirus or retroviral vector infected cattle and sheep embryo to produce transgenic animal.These methods comprise cessation of growth cessation cell (i.e. the cell of handling through mitomycin C-) micro-injection that retroviral particle maybe can be discharged retroviral particle to the ovum week crack of zygote or body early embryo (PCT International Application No. WO 90/08832[1990]; Haskell andBowen, Mol.Reprod.Dev., 40:386[1995]).PCT International Application No. WO 90/08832 has been described the ovum week crack that wild-type feline leukemia virus B is injected to 2 to 8 cell stage sheep embryos.Confirmed to such an extent that the fetus of the embryonal vaccination of hanging oneself contains a plurality of integration sites.

United States Patent (USP) 6,291,740 (September 18 calendar year 2001 openly) were described the retroviral vector (as the carrier derived from murine leukemia virus [MLV]) that passes through to use the transduction somatoblast, and ovocyte that exogenous DNA importing maturation is preceding and sophisticated unfertilized egg parent cell (being progamous ovocyte) are to produce transgenic animal.This patent has also been described the cytomegalovirus promoter driving and mouse mammary tumor LTR expresses the used method and composition of multiple recombinant protein.

United States Patent (USP) 6,281,408 (August 28 calendar year 2001 is open) have been described and have been used embryonic stem cell to produce the method for transgenic animal.Briefly, with morular cell mixing altogether-use embryonic stem cell to produce transgenic animal in the culture.Before cultivating altogether, exogenous genetic material is imported embryonic stem cell by for example electroporation, micro-injection or retrovirus transmission.Via selective marker, select the ES cell of transfection in this manner to be used for integrator gene as Xin Meisu.

United States Patent (USP) 6,271,436 (August 7 calendar year 2001 is open) have been described and have been used following method to produce transgenic animal, described method comprises: separate primordial germ cells, cultivate these cells to produce derived from genitaloid clone, transform primordial germ cells and, use these to produce transgenic animal through cell transformed and clone through cultured cells system.The efficient that produces transgenic animal improves greatly, take this to use homologous recombination produce genetically modified non--rodent.

Gene therapy

One embodiment of the invention wish to use modified transferrin fusion constructs to carry out gene therapy, and wherein modified transferrin or transferrin structural domain are connected with therapeutic protein or peptide.Have the serum half life of increase or the of the present invention modified transferrin fusion constructs of serum stability and be fit to very much gene therapy.

Existing people described and successfully uses gene therapy to give expression to soluble fusion protein.Briefly, recently, Ijima etc., (June 10,2001) Human Gene Therapy (U.S.) 12/9:1063-77 has disclosed the gene therapy of carrying out via the injection adenovirus carrier, described carrier contains the gene of the soluble fusion protein of encoding, and described fusion rotein partly is made up of the Fc of cellulotoxic lymphocyte antigen 4 (CTLA4) and immunoglobulin G while 1.In this gene therapy is used, successfully treated the sacroiliitis mouse model that causes by the II Collagen Type VI by the intra-articular injection carrier.

Gene therapy also is described in many pieces of United States Patent (USP)s, comprises United States Patent (USP) 6,225,290 (May 1 calendar year 2001 is open); United States Patent (USP) 6,187,305 (February 13 calendar year 2001 is open); With United States Patent (USP) 6,140,111 (on October 31st, 2000 is open).

United States Patent (USP) 6,225,290 provide method and construct, take this to carry out gene alteration to the intestinal epithelial cells of mammalian subject, can give expression to the proteinic gene with required curative effect thereby operationally mix.Can finish the intestinal cells conversion by using the preparation of mainly forming by naked DNA, also can oral DNA.The interior route of administration of oral or other stomach and intestine provides simple medication, and uses naked nucleic acid can avoid and use virus vector to finish the gene therapy complications associated with arterial system.To obtain proteinic therapeutic blood level, take this treatment needs described proteinic patient to the protein direct secretion that gives expression to gi tract and/or the blood flow.By overexpression protein, the intestinal epithelial cells through transforming provides short-term or secular therapy for lacking the relevant disease that maybe can adapt to this treatment with specified protein.

United States Patent (USP) 6,187,305 provide vertebrates, particularly carry out the method for gene or DNA target in the cell in Mammals source.Briefly, by homologous recombination or make the IDNA target that is directed into former generation or secondary cell genomic dna, DNA is imported the former generation or the secondary cell in vertebrates source to the site of selecting in advance.

United States Patent (USP) 6,140,111 (on October 31st, 2000 is open) have been described reverse transcription virus gene treatment carrier.Disclosed retroviral vector comprises the insertion site of required gene, and can be in multiple transfectional cell type high level expression derived from the protein of required gene.This patent also discloses a class retroviral vector, and described carrier lacks selective marker, therefore is suitable for the human gene therapy, need not altogether-the presentation markup product, can treat various disease states as microbiotic.These retroviral vectors are particularly useful for some package cell line.Retroviral vector inserts the genomic ability of mammalian cell makes them become the drug candidate of human and animal's inherited disease likely especially gene therapy.Gene therapy generally comprises: (1) is added into new genetic material in the parental cell in vivo, or (2) remove parental cell in body, adds new genetic material and they are imported in the body again i.e. outer-gene treatment in cell.Relevantly how to use retroviral vector carries out gene therapy in various kinds of cell the discussion can be referring to laid-open U.S. Patents 4 on September 19th, 1989 for example, 868,116 and December 25 nineteen ninety laid-open U.S. Patents 4,980,286 (epithelial cells), disclosed WO89/07136 on August 10 (liver cell) in 1989, July 25 nineteen ninety disclosed EP378,576 (inoblasts) and on June 15th, 1989 disclosed WO89/05345 and nineteen ninety disclosed WO/90/06997 on June 28 (endotheliocyte), the content of described patent is all listed this paper in as a reference.

Need not continue to describe, just can believe that those skilled in the art can use description above and the embodiment that hereinafter exemplifies prepares and utilize the present invention, and put into practice desired method.For example, those skilled in the art can easily measure the interior biological activity of external and body that fusion protein construct of the present invention is compared with its similar activity of therapeutic moiety that is in non-fusion state.Similarly, those skilled in the art can easily measure the serum half life and the serum stability of construct of the present invention.Therefore, work embodiment has hereinafter specifically noted the preferred embodiments of the invention, but these embodiment can not be interpreted as the restriction to all the other contents.

Embodiment

Embodiment 1

By the anti-nucleotide sequence of HIV-1 peptide (T-20) and the nucleotide sequence of TF of merging of the coding that merges one or more copies, prepare the modified Tf that contains this sequence and the fusion rotein of described peptide, the fusion rotein that is produced has and N-or the terminal peptide that merges of C-of Tf.

In one embodiment, the Tf of fusion rotein part is transformed, and making can glycosylation when producing in yeast.As mentioned above, human transferrin has two N-linked glycosylation sites at about N413 and about N611 place.Sequence N-X-S/T is contained in N-linked glycosylation site.In one embodiment, N (Asn) becomes Q (Gln); Also can carry out other change, for example Asn becomes Ala or Ser becomes any other amino acid.

Specifically, carry out oligonucleotide-directed mutagenesis, change N413 and N611 codon into GAT and GAC by using dut-and ung-method.Referring to Kunkel etc., (1985) Proc.Natl.Acad.Sci.82:488-492.Synthetic mutagenic oligonucleotide 5 '-GCAGAAAACTACGATAAGAGCGATAAT-3 ' (SEQ ID NO:9) and 5 '-CTATTTGGAAGCGACGTAACTGACTGC-3 ' (SEQ ID NO:10), use these oligonucleotide, according to (United States Patent (USP)s 5 such as Funk, 986,067) method mutagenesis N413 and N611 codon.

Destroy receptors bind and/or iron or carbonate combination by suddenly change following iron and/or carbanion in conjunction with residue then:

The iron combination

The N structural domain The C-structure territory

Asp 63 (Asp 82 of SEQ ID NO:2) Asp 392 (Asp 411 of SEQ ID NO:2)

Tyr 95 (Tyr 114 of SEQ ID NO:2) Tyr 426 (Tyr 445 of SEQ ID NO:2)

Tyr 188 (Tyr 207 of SEQ ID NO:2) Tyr 514 or 517 (Tyr 533 of SEQ ID NO:2 or Tyr 536)

His 249 (His 268 of SEQ ID NO:2) His 585 (His 604 of SEQ ID NO:2)

The carbanion combination

The N structural domain The C-structure territory

Thr 120 (Thr 139 of SEQ ID NO:2) Thr 452 (Thr 471 of SEQ ID NO:2)

Arg 124 (Arg 143 of SEQ ID NO:2) Arg 456 (Arg 475 of SEQ ID NO:2)

Ala 126 (Ala 145 of SEQ ID NO:2) Ala 458 (Ala 477 of SEQ ID NO:2)

Gly 127 (Gly 146 of SEQ ID NO:2) Gly 459 (Gly 478 of SEQ ID NO:2)

Can finish the preparation of iron by multiple technologies in conjunction with defective mutant.Referring to United States Patent (USP) 5,986,067.Use Nelson, R.M.and Long, the method for G.L. (1989) Analyt.Biochem.180:147-151 prepares D63S and replaces.Briefly, the HpaII/BamHI fragment subclone that hTF/2N encoding sequence 5 ' is terminal is to pUC18, then as template to carry out mutagenesis program based on two-step pcr.From the sequencing vector of double chain form, discharge fragment by XbaI and BamHI digestion, described fragment is connected with the BamHI/HindIII fragment of original people Tf construct, produce the D63S-encoding sequence of total length, confirm the fidelity of montage by the restrictive diges-tion analysis.

In order in pichia, to express, can use the system of RCT/Invitrogen.Can obtain three kinds and be suitable for carrier pPIC9K, pPIC3.5K and the pAO815 that multiple copied is expressed.For example, can use the pPIC9K carrier that allows to secrete to the growth medium.

Change the end of transferrin cDNA by overlapping PCR mutagenesis, thus with modified transferrin sequence clone to the pPIC9K carrier, produce carrier pREX0010.Remove in carrier and the encoding sequence or add a plurality of restriction sites therein to help clone's step (Fig. 5) of back.

HIV is anti--and the sequence of fusogenic peptide DP-178 also is known as T-20.The N-of self and transferrin is provided this peptide or C-is terminal merges, because this peptide need move freely to satisfy its function.

DP-178 sequence: YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF (SEQ ID NO:4)

When reverse translation becomes DNA (use and be suitable for the zymic codon most), obtain following sequence (SEQID NO:13 and 14):

tacacaagcttaatacactccttaattgaagaatcgcaaaaccagcaagaaaagaatgaacaagaatta

y t s l i h s l i e e s q n q q e k n e q e l

ttggaattagataaatgggcaagtttgtggaattggttt

l e l d k w a s l w n w f

In order to insert above-mentioned sequence, the carrier pREX0010 that has modified transferrin cDNA with Restriction Enzyme Xba I/Kpn I digestion digests described carrier to insert at 3 ' end with 5 ' the terminal insertion with Sal I/Hind III.

In order to insert synthetic two 5 ' terminal overlapping oligonucleotide that form the XbaI overhang and form Kpn I overhang at 3 ' end of described sequence at 5 ' end in DP-178 sequence mentioned above.These oligonucleotide are annealed (seeing below) together, be connected to pREX0010 carrier through Xba I/Kpn I digestion.

----

1 ctagagaaaa ggtacactag cttaatacac tccttaattg aagaatcgca aaaccagcaa gaaaagaatg aacaagaatt

tctttt ccatgtgatc gaattatgtg aggaattaac ttcttagcgt tttggtcgtt cttttcttac ttgttcttaa

l e k r y t s l i h s l i e e s q r q q e k n e q e

>>.................................T-20..................................>

>>.........>>

KpnI

----

81 attggaatta gataaatggg caagtttgtg gaattggttt gtac

SEQ ID NOS:15 and 16

taaccttaat ctatttaccc gttcaaacac cttaaccaaa

l l e l d k w a s l w n w f v

>>>>

>..................T-20..................>>

Insert and lost Kpn I site after the annealed oligonucleotide causes inserting.Cause producing carrier pREX0011 (Fig. 6).

For in the terminal insertion of C-,, add the HindIII site and take similar method (Fig. 7) at 3 ' end by in 5 ' the terminal SalI site of adding.

Then, transform, select and express according to Invitrogen Pichia Expression test kit operational manual is described.

Embodiment 2

Use the people INGAP aminoacid sequence of reverse translation to prepare the INGAP fusions.Protein sequence is as follows: sp|Q92778|PBCG_HUMAN Human INGAP

MMLPMTLCRMSWMLLSCLMFLSWVEGEESQKKLPSSRITCPQGSVAYGS

YCYSLILIPQTWSNAELSCQMHFSGHLAFLLSTGEITFVSSLVKNSLTAYQY

IW[IGLHDPSHGTLPNG]GWKWSSSNVLTFYNWERNPSIAADRGYCAVLS

QKSGFQKWRDFNCENELPYICKFKV(SEQ ID NO：17)

Reverse translation becomes DNA (being suitable for the zymic codon most) to provide following sequence (SEQ ID NO:18 and 19).

1 atgatgttgc caatgacttt gtgtagaatg tcttggatgt tgttgtcttg tttgatgttt

m m l p m t l c r m s w m l l s c l m f

61 ttgtcttggg ttgaaggtga agaatctcaa aaaaaattgc catcttctag aattacttgt

l s w v e q e e s q k k l p s s r i t c

121 ccacaaggtt ctgttgctta tggttcttat tgttattctt tgattttgat tccacaaact

p q g s v a y g s y c y s l i l i p g t

181 tggtctaatg ctgaattgtc ttgtcaaatg catttttctg gtcatttggc ttttttgttg

w s n a e l s c q m h f s g h l a f l l

241 tctactggtg aaattacttt tgtttcttct ttggttaaaa attctttgac tgcttatcaa

s t g e i t f v s s l v k n s l t a y q

301 tat[atttgga ttggtttgca tgatccatct catggtactt tgccaaatgg ttct]ggttgg

y i w i g l h d p s h g t l p n g s g w

361 aaatggtctt cttctaatgt tttgactttt tataattggg aaagaaatcc atctattgct

k w s s s n v l t f y n w e r n p s i a

421 gctgatagag gttattgtgc tgttttgtct caaaaatctg gttttcaaaa atggagagat

a d r g y c a v l s g k s g f q k w r d

481 tttaattgtg aaaatgaatt gccatatatt tgtaaattta aagtt

f n c e n e l p y i c k f k v

Most probable leader sequence cracking site is the KK of above-mentioned underscore sequence end.

A methodology that can be used for producing the construct of expressing the INGAP that merges with transferrin N-or C-end is the overlapping oligonucleotide of synthetic a series of designs from above-mentioned sequence (deducting the leader sequence of underscore).These primers of annealing can produce INGAP cDNA.Use be 5 ' with the different oligonucleotide of 3 ' tip designs, annealed cDNA can be connected to 5 ' or 3 ' end of transferrin among the pREX0010.

Sequence in the bracket is to be used to induce the active peptide of INGAP.Therefore, some site between complete sequence and this shortest essential sequence, sequence can be matched.

N-is terminal to be merged

For N-was terminal, it should have can be at the overhang in 5 ' the terminal XbaI of formation site and can be compatible with 3 ' terminal KpnI site, but can cause the ruined overhang in KpnI site.

XbaI

---

1 ctagagaaaa ggttgccatc ttccagaatt acttgtccac aaggttctgt tgcttatggt

tctttt ccaacggtag aaggtcttaa tgaacaggtg ttccaagaca acgaatacca

l e k r l p s s r i t c p q g s v a y g

61 tcttattgtt attctttgat tttgattcca caaacttggt ctaatgctga attgtcttgt

agaataacaa taagaaacta aaactaaggt gtttgaacca gattacgact taacagaaca

s y c y s l i l i p q t w s n a e l s c

21 caaatgcatt tttctggtca tttggctttt ttgttgtcta ctggtgaaat tacttttgtt

gtttacgtaa aaagaccagt aaaccgaaaa aacaacagat gaccacttta atgaaaacaa

q m h f s g h l a f l l s t g e i t f v

81 tcttctttgg ttaaaaattc tttgactgct tatcaatata tttggattgg tttgcatgat

agaagaaacc aatttttaag aaactgacga atagttatat aaacctaacc aaacgtacta

s s l v k n s l t a y q y i w i g l h d

241 ccatctcatg gtactttgcc aaatggttct ggttggaaat ggtcttcttc taatgttttg

ggtagagtac catgaaacgg tttaccaaga ccaaccttta ccagaagaag attacaaaac

p s h g t l p n g s g w k w s s s n v l

301 actttttaca attgggaaag aaatccatct attgctgctg atagaggtta ttgtgctgtt

tgaaaaatgt taaccctttc tttaggtaga taacgacgac tatctccaat aacacgacaa

t f y n w e r n p s i a a d r g y c a v

361 ttgtctcaaa aatctggttt tcaaaaatgg agagatttta attgtgaaaa tgaattgcca

aacagagttt ttagaccaaa agtttttacc tctctaaaat taacactttt acttaacggt

l s q k s g f q k w r d f n c e n e l p

KpnI

----

421 tatatttgta aatttaaagt tgtac

Atataaacat ttaaatttca a SEQ ID NOS:20 and 21

y i c k f k v v

With XbaI and KpnI digestion pREX0010, connect above-mentioned sequence and produce carrier pREX0013 (Fig. 8).

C-is terminal to be merged

For C-was terminal, 5 ' terminally can form the SalI site, and 3 ' end has terminator codon and adds the HindIII site.

SalI

---

1 tcgacctttg ccatcttcca gaattacttg tccacaaggt tctgttgctt atggttctta

ggaaac ggtagaaggt cttaatgaac aggtgttcca agacaacgaa taccaagaat

r p l p s s r i t c p q g s v a y g s

61 ttgttattct ttgattttga ttccacaaac ttggtctaat gctgaattgt cttgtcaaat

aacaataaga aactaaaact aaggtgtttg aaccagatta cgacttaaca gaacagttta

y c y s l i l i p q t w s n a e l s c q

121 gcatttttct ggtcatttgg cttttttgtt gtctactggt gaaattactt ttgtttcttc

cgtaaaaaga ccagtaaacc gaaaaaacaa cagatgacca ctttaatgaa aacaaagaag

m h f s g h l a f l l s t g e i t f v s

181 tttggttaaa aattctttga ctgcttatca atatatttgg attggtttgc atgatccatc

aaaccaattt ttaagaaact gacgaatagt tatataaacc taaccaaacg tactaggtag

s l v k n s l t a y q y i w i g l h d p

241 tcatggtact ttgccaaatg gttctggttg gaaatggtct tcttctaatg ttttgacttt

agtaccatga aacggtttac caagaccaac ctttaccaga agaagattac aaaactgaaa

s h g t l p n g s g w k w s s s n v l t

301 ttacaattgg gaaagaaatc catctattgc tgctgataga ggttattgtg ctgttttgtc

aatgttaacc ctttctttag gtagataacg acgactatct ccaataacac gacaaaacag

f y n w e r n p s i a a d r g y c a v l

361 tcaaaaatct ggttttcaaa aatggagaga ttttaattgt gaaaatgaat tgccatatat

agtttttaga ccaaaagttt ttacctctct aaaattaaca cttttactta acggtatata

s q k s g f q k w r d f n c e n e l p y

HindIII

421 ttgtaaattt aaagtttaat a

Aacatttaaa tttcaaatta ttcga SEQ ID NOS 22 and 23

j c k f k v -

With SalI and HindIII digestion pREX0010, connect above-mentioned sequence and produce carrier pREX0014 (Fig. 9).

Then, transform, select and express according to Invitiogen Pichia Expression test kit operational manual is described.

Embodiment 3

Confirmed that the peptide that hereinafter provides can be by causing the Dimerized EPO of the simulation activity of EPO acceptor.Described peptide of annular and EPO do not have homology.For activity, described peptide is had to and another kind of peptide (promptly as dimer) together works, and makes the acceptor of two copies lean on enough closely to form activated complex.Concerning a variety of peptides, peptide dimer only has of short duration half life, it can from the fusion of transferrin the half life of making a profit and obtaining prolonging.In this embodiment, two peptides are added in the transferrin skeleton.

1 ggtggtactt actcttgtca ttttggtcca ttgacttggg tttgtaagcc acaaggtggt

g g t y s c h f g p l t w v c k p q g g

SEQ ID NO:24 and 25.

As people's such as Ali detailed description, can between the His289 of transferrin and Gly290, successfully add peptide.Transferrin molecule inherent repetition (two structural domains reflect mutually) means and peptide can be inserted between the Glu625 and Thr626 of C-structure territory repeat region.

N 277 D-KSKE--FQ LFSSP

KDL LFKDSAHGFL KVPPRMDAKM YLGYEYVTAI

C 611 NVTDCSGNFC LFRS

KDL LFRDDTVCLA KLHDRNTYEK YLGEEYVKAV

SEQ ID NO:26 and 27.

Each inserts needs synthetic two eclipsed mutagenesis primers (seeing below).Use pREX0010 as template, react with each mutagenesis primer and the outside primer that derives from Tf cDNA 5 ' or 3 ' end.The product that mixes these two reactions then further reacts so that two products are linked together with outside primer.Digest His289-Gly290 inset PCR product to be connected to pKBX0010 with XbaI and HpaI through XbaI/HpaI digestion.Digest the gained carrier to be connected to Glu625-Thr626 inset PCR product with HpaI and SalI then through HpaI/SalI digestion.

His289-Gly290 inset (SEQ ID NO:28).

←------------

2031 agacaaatca[aaagaatttc aactattcag ctctcctcat ggtggtactt actcttgtca ttttggtcca

tctgtttagt tttcttaaag ttgataagtc gagaggagta ccaccatgaa[tgagaacagt aaaaccaggt

>>.............EMOm..............>

>....................................Tf....................................>

>.................................N domain.................................>

2101 ttgacttggg tttgtaagcc]acaaggtggt gggaaggacc tgctgtttaa ggactctgcc cacgggtttt

aactgaaccc aaacattcgg tgttccacca cccttcctgg acgacaaatt cctgagacgg]gtgcccaaaa

-----------→

>...........EMOm.............>>

>....................................Tf....................................>

>...............................N domain.................................>

Glu625-Thr626 inset (SEQ ID NO:29).

←-------------

3081 cctatttgga agcaacgtaa ctgactgctc[gggcaacttt tgtttgttcc ggtcggaagg tggtacttac

ggataaacct tcgttgcatt gactgacgag cccgttgaaa acaaacaagg ccagccttcc accatgaat[g

>>...EPOm...>

>.................................C domain.................................>

>....................................Tf....................................>

KpnI

-------

3151 tcttgtcatt ttggtccatt gacttgggtt tgtaagccac]aaggtggtac caaggacctt ctgttcagag

agaacagtaa aaccaggtaa ctgaacccaa acattcggtg ttccaccatg gttcctggaa gacaagtctc

-----------→

>......................EPOm.......................>>

>.................................cdomain..................................>

>....................................Tf....................................>

3221 atgacacagt atgtttggcc aaacttcatg acagaaacac atatgaaaaa tacttaggag aagaatatgt

tactgtgtca]tacaaaccgg tttgaagtac tgtctttgtg tatacttttt atgaatcctc ttcttataca

>.................................C domain.................................>

>....................................Tf....................................>

So obtain plasmid pREX0015 (Figure 10).Transform, select and express according to InVitrogen Pichia Expression test kit operational manual is described.

Other the alternative site that can insert EPO simulating peptide or any other peptide is two glycosylation site N413 and the N611 on the transferrin C-structure territory.The advantage in this site is: one with identical incident in can obtain to insert, can prevent glycosylation by destroying the N-X-S/T sequence simultaneously.

Embodiment 4

By N-or the C-end that merges anti-RSV fusion inhibitor peptide sequence and Tf, or by described sequence being inserted in the Tf ring, can prepare the fusion rotein between Tf and the described peptide, wherein Tf carried out modifying and to prevent glycosylation after making it can not be in conjunction with iron and/or Tf modified.The RSV peptide can comprise: T786:VYPSDEYDASISQVNEEINQALAYIRKADELLENV (SEQ IDNO:5) and/or T1584:AVSKVLHLEGEVNKIKSALLSTNKAVVSLSNGVSVLTSKVLDL KNYIDKQL (SEQ ID NO:6).

The T786 peptide has the RK dipeptides, and it can be used as the cracking site of endotrypsin Kex2p.This can cause producing the peptide of brachymemma.Therefore, this peptide can be modified into RE by RK.There is solubility problem in the non-fusion form of the T786 peptide T112 of the another kind of form stronger than T786 (VFPSDEFDASISQVNEKINQSLAFIRESDELLHNV, SEQ ID NO:7).Therefore, also need prepare the T112 form that is modified to RE by RK, to produce the peptide form that merges with Tf.

In order to produce gene construct, but the codon preference of end user, yeast or any other organism becomes DNA with the peptide sequence reverse translation suitably the time.

Embodiment 5

The various kinds of cell factor can with N-, the C-of Tf or N-and C-is terminal merges.Use the different piece or the structural domain of modified transferrin,, also can make up these fusions as N structural domain or C-structure territory.The joint peptide fusion protein matter of directly fused protein, or use different lengths.Also can be in all or part of active cells factor of transferrin skeleton endomixis.

Can pass through several different methods, for example separate required cytokine by mRNA, from the cDNA library by RT-PCR, cDNA as EPO, by by the described cDNA of the synthetic structure of overlapping oligonucleotide, obtain described cDNA (all methods are all used standard method) by PCR or the separation of other methods known in the art.All these proteinic nucleotides sequences are listed in for example United States Patent (USP) 4,703,008,4,810,643 and 5,908,763 and public database, as all being known among the GenBank and can obtaining.Can modify to produce restriction site, to make 5 ' and the 3 ' end of cDNA to use oligonucleotide joint that this cDNA is cloned in the carrier that contains transferrin cDNA.Cell factor cDNA can be positioned at transferrin sequence of N-or C-end, can use or not use intervening sequence, perhaps the cDNA of cytokine can be inserted among the cDNA of transferrin.With cytokine, be cloned in the carrier as EPO and TfcDNA, from carrier, downcut complete expression cassette then, insert expression vector with expressed fusion protein in yeast (or any other suitable expression system).From substratum, collect then and purifying yeast excretory fusion rotein and detect its biological activity.

In order in mammal cell line, to express, can adopt similar method, what difference was used expression cassette use is mammalian promoter, leader sequence and terminator.Downcut expression cassette then, insert in the plasmid that is suitable for transfection mammalian cell system.

Embodiment 6

Multiple Interferon, rabbit can with N-, the C-of modified transferrin or N-and C-is terminal merges.Use the different piece or the structural domain of transferrin,, also can make up these fusions as N structural domain or C-structure territory.The joint peptide fusion protein matter of directly fused protein, or use different lengths.Also can be at all or part of Interferon, rabbit of transferrin skeleton endomixis.

The object lesson of the Interferon, rabbit that can merge with Tf is an interferon-beta.Can pass through several different methods, for example separate required Interferon, rabbit by mRNA or cDNA, from the cDNA library by RT-PCR, cDNA as interferon beta, by by the described cDNA of the synthetic structure of overlapping oligonucleotide, obtain described cDNA (all methods are all used standard method) by PCR or the separation of other methods known in the art.Interferon, rabbit, as IFN α, the nucleotides sequence of IFN β and IFN γ is listed in for example United States Patent (USP) 5,326,859,4,588,585 and EP 32 134 and public database, as all being known among the GenBank and can obtaining.Can modify to produce restriction site, to make 5 ' and the 3 ' end of cDNA to use oligonucleotide joint that this cDNA is cloned in the carrier that contains modified transferrin cDNA.Interferon, rabbit cDNA can be positioned at the transferrin sequence of N-, C-or N-and C-end, can use or not use intervening sequence.IFN β (or other Interferon, rabbit) cDNA is cloned in the carrier, from carrier, downcuts complete expression cassette then, insert expression vector with expressed fusion protein in yeast.From substratum, collect then and purifying yeast excretory fusion rotein and detect its biological activity.

In order in mammal cell line, to express, can adopt similar method, what difference was used expression cassette use is mammalian promoter, leader sequence and terminator.Downcut expression cassette then, insert in the plasmid that is suitable for transfection mammalian cell system.The IFN that merges with transferrin has longer half life, and therefore, the therapeutic dose of fusion rotein is than IFN much less.Therefore, fused interferon better effects and if toxicity is lower.

Embodiment 7

Originally inventing multiple single-chain antibody (SCA) is that antibody is selected and production in order to simplify.Yet, confirmed too little and body weak point of interior half life owing to their, so the limited or basic inefficacy of curative effect.Half life in the body of interpolation transferrin energy significant prolongation SCA in SCA.

SCA can with N-, the C-of modified transferrin or N-and C-is terminal merges.Use the different piece or the structural domain of transferrin,, also can carry out described fusion as N structural domain or C-structure territory.The joint peptide fusion protein matter of directly fused protein, or use different lengths.Also can be at all or part of active SCA of transferrin skeleton endomixis.In this case, by preparing fusion rotein among the cDNA that the cDNA of SCA is inserted transferrin, thereby in cell, produce protein.The object lesson of the SCA that can merge with transferrin is anti-TNF (tumour necrosis factor).Multiple inflammation of anti-tnf treatment and autoimmune disease have been used.TNF-SCA can merge with the N-or the C-end of modified transferrin, amalgamation mode can be that the coding N-end of TNF-SCA directly combines with transferrin C-end amino acid, or the C-end amino acid of TNF-SCA directly combines with the transferrin-terminal amino acid.Perhaps, can between transferrin and TNF-SCA, insert peptide linker so that bigger spacing to be provided, and make the spatial mobility of two fused proteins bigger.The several examples that shown TNF-SCA among Fig. 4 A-4B.

Can produce single-chain antibody by several method, described method includes but not limited to: select from phage library, cDNA by clonal antibody also uses the flank constant region to clone the variable region as primer, or clones the variable region of specific antibodies by the oligonucleotide of synthetic variable region corresponding to any specific antibodies.Can modify to produce restriction site, to make 5 ' and the 3 ' end of cDNA to use oligonucleotide joint that this cDNA is cloned in the carrier that contains transferrin cDNA.SCAcDNA can be positioned at transferrin sequence of N-or C-end or N-and C-end, can use or not use intervening sequence.CDNA is cloned in the carrier with the SCA molecule, downcuts complete expression cassette then from carrier, inserts expression vector with expressed fusion protein in yeast.From substratum, collect then and purifying yeast excretory fusion rotein and detect its biological activity.In order in mammal cell line, to express, can adopt similar method, what difference was used expression cassette use is mammalian promoter, leader sequence and terminator.Downcut expression cassette then, insert in the plasmid that is suitable for transfection mammalian cell system.The antibody that purifying produces in this manner from substratum uses the immuno-chemical method of standard to detect itself and its antigen bonded ability.

Embodiment 8

CDR is the antibody variable region with AI.It is made up of one section relatively short peptide sequence usually.Heavy chain of antibody and light chain generally respectively have 3 CDR.One or more can the fusion to give transferrin molecule and antigen bonded activity with modified transferrin with the antibody CDR of AI.CDR can with the N-of transferrin, C-, N-and C-are terminal to be merged, or is inserted in the inner skeleton of transferrin.The example of the CDR sequence of anti-TNF antibody is shown in TNF-SCA (Fig. 4 A-4B).CDNA corresponding to one or more CDR can merge to give transferrin and TNF bonded activity with modified transferrin.

Embodiment 9

Also can use the transferrin integration technology to improve, as the treatment characteristic of the peptide found in phage display library and the peptide library in a plurality of systems.A lot of biologically actives are arranged in these peptides, but do not have any homology with natural protein or peptide.Because therefore the body of these peptides weak point of interior half life is the good candidate that merges with modified transferrin.Because they are very little, therefore can merge with a plurality of zones of transferrin molecule.Except N-and C-end, they can be inserted a plurality of zones in the transferrin, include but not limited to the Gelucystine ring.In this manner, the peptide three-dimensional structure in the transferrin show relative rigidity.Various peptides that 1 copy is above and more than one peptide can merge with modified transferrin.In addition, can use peptide sequence to substitute the transferrin part to give the transferrin therapeutic activity.Because most of peptides are shorter, the cDNA with suitable restriction site that can synthesize described peptide is to insert modified transferrin cDNA.CDNA can be inserted then and contain in the carrier of transferrin cDNA, make peptide be expressed as the part of transferrin or the fusion rotein that merges with the transferrin molecule.Perhaps, synthetic pcr primer thing, described primer contain required peptide and suitable transferrin segment.Use these primer amplification transferrins cDNA, cause the selected site on peptide and the transferrin to be merged.The example of described peptide is EPO simulating peptide: GGTYSCHFGPLTWVCKPQGG (SEQ ID NO:11); DREGCRRGWVGQCKAWFN (SEQ ID NO:12); And QRVEILEGRTECVLSNLRGRTRY (SEQ ID NO:30), they and natural EPO do not have homology, but have similar biological activity, because they can activate the EPO acceptor as agonist.These peptides also need to have special conformation and satisfy its optimum activity.The EPO simulating peptide can be inserted in one or more Gelucystine rings of (or substituting) transferrin.In this manner, transferrin can obtain the EPO activity.Can be to have and combine active peptide like the antibody class with other peptide that transferrin merges.These peptides can be high relatively affinity and protein bound, and provide the biological function identical with antibody, but in their body half life very short.Can give these peptides longer half life these peptides and transferrin fusion, and can not destroy their combination activity.These peptides can with the N-of transferrin molecule or C-end or two ends or inner the fusion.Described peptide also can replace the part transferrin.In addition, above peptide or several different peptide of 1 copy can combine with single transferrin molecule.The example of described molecule is can be in conjunction with the peptide of TNF.This peptide and combining of transferrin are given transferrin in conjunction with TNF and the ability that works according to the mode that is similar to anti-TNF antibody.In this manner, can prepare antibody molecule with more simple and economical preparation method.

Embodiment 10

Target Tf fusion rotein has protein that two or more and modified transferrin merge or peptide simultaneously with as bifunctional molecule.At this moment, modified transferrin and a kind of protein or peptide merge to have new biological activity, merge to carry out target with another kind of protein or peptide.Described proteinic example is to contain repressible protein matter such as endostatin and target peptide, maybe can discern the transferrin of the binding peptide of tumour as SCA.In this manner, the inhibition molecule is needed the tumour of this molecule by target.The cDNA of desired protein is separable from the cDNA library, maybe can use the molecular biology method of standard, with the described cDNA of the synthetic preparation of several overlapping Oligonucleolide primers.Can in cDNA, import suitable Nucleotide forming restriction site easily, and can according to form the similar method of other fusion rotein, proteinic cDNA is combined with the cDNA of transferrin.In addition, targeting proteins matter or peptide cDNA, as single-chain antibody or can mediating protein enter the peptide of cell interior, as nuclear localization signal can with the other end or its inner fusion of transferrin.Desired protein and target peptide are cloned in the carrier that allows to merge with transferrin cDNA.In this manner, proteins/peptides can merge with modified transferrin.Downcut the cDNA that merges then, insert expression vector with expressed fusion protein in yeast.

Can use molecular biological standard method to implement above-mentioned all methods.From substratum, collect and the oozy fusion rotein of purifying yeast, and use suitable biological chemistry and biological test to detect its biologic activity and target activity thereof.Also can prepare these protein as using suitable carrier and transfection method in the mammalian tissues culture in other system.

Embodiment 11

Can pass through several different methods, the cDNA that for example separates required enzyme by mRNA, from the cDNA library by RT-PCR, by by the described cDNA of the synthetic structure of overlapping oligonucleotide, obtain described cDNA (all methods are all used standard method) by PCR or the separation of other methods known in the art.Can modify to produce restriction site, to make 5 ' and the 3 ' end of cDNA to use oligonucleotide joint that this cDNA is cloned in the carrier that contains modified transferrin cDNA.Enzyme cDNA can be positioned at transferrin sequence of N-or C-end, can use or not use intervening sequence.Enzyme cDNA is cloned in the carrier, from carrier, downcuts complete expression cassette then, insert expression vector with expressed fusion protein in yeast.From substratum, collect then and purifying yeast excretory fusion rotein and detect its biological activity.In order in mammal cell line, to express, can adopt similar method, what difference was used expression cassette use is mammalian promoter, leader sequence and terminator.Downcut expression cassette then, insert in the plasmid that is suitable for transfection mammalian cell system.

Embodiment 12

Use phage display, isolate the peptide that for example is specific to tumor cell surface specific cells mark.Then with the N-of described peptide and modified transferrin, C-or N-and C-be terminal merge with the fusion rotein target to specific cell type.Then, make transferrin fusion proteins load metal ion, described ionic transferrin binding characteristic is similar to iron, but has cytotoxicity, for example gallium or isotopic ion.By this mechanism, gallium or isotopic ion are by this cell type of target.

Although describe the present invention in detail, should understand and to carry out multiple modification to the present invention without departing from the spirit of the invention with reference to the foregoing description.Therefore, the present invention only is subjected to the restriction of following claims.All patents, patent application and the publication of mentioning among the application all listed this paper in as a reference in full.

Sequence table

＜110〉Shenyang XinSong robot automation Co., Ltd (BIOREXIS PHARMACEUTICAL CORPORATION)

＜120〉modified transferrin fusion proteins

<130>MLB Ref.54710-5001-CN

＜140〉Chinese application number

<141>2002-08-30

<150>US 60/315,745

<151>2001-08-30

<150>US 60/334,059

<151>2001-11-30

<150>PCT/US02/27637

<151>2002-08-30

<160>30

<170>PatentIn Ver.2.1

<210>1

<211>2318

<212>DNA

＜213〉people (Homo sapiens)

<220>

<221>CDS

<222>(51)..(2147)

＜223〉GenBank numbering NM_001063, transferrin gene and albumen

<220>

<221>sig_peptide

<222>(51)..(107)

<400>1

gcacagaagc gagtccgact gtgctcgctg ctcagcgccg cacccggaag atg agg 56

Met Arg

1

ctc gcc gtg gga gcc ctg ctg gtc tgc gcc gtc ctg ggg ctg tgt ctg 104

Leu Ala Val Gly Ala Leu Leu Val Cys Ala Val Leu Gly Leu Cys Leu

5 10 15

gct gtc cct gat aaa act gtg aga tgg tgt gca gtg tcg gag cat gag 152

Ala Val Pro Asp Lys Thr Val Arg Trp Cys Ala Val Ser Glu His Glu

20 25 30

gcc act aag tgc cag agt ttc cgc gac cat atg aaa agc gtc att cca 200

Ala Thr Lys Cys Gln Ser Phe Arg Asp His Met Lys Ser Val Ile Pro

35 40 45 50

tcc gat ggt ccc agt gtt gct tgt gtg aag aaa gcc tcc tac ctt gat 248

Ser Asp Gly Pro Ser Val Ala Cys Val Lys Lys Ala Ser Tyr Leu Asp

55 60 65

tgc atc agg gcc att gcg gca aac gaa gcg gat gct gtg aca ctg gat 296

Cys Ile Arg Ala Ile Ala Ala Asn Glu Ala Asp Ala Val Thr Leu Asp

70 75 80

gca ggt ttg gtg tat gat gct tac ctg gct ccc aat aac ctg aag cct 344

Ala Gly Leu Val Tyr Asp Ala Tyr Leu Ala Pro Asn Asn Leu Lys Pro

85 90 95

gtg gtg gca gag ttc tat ggg tca aaa gag gat cca cag act ttc tat 392

Val Val Ala Glu Phe Tyr Gly Ser Lys Glu Asp Pro Gln Thr Phe Tyr

100 105 110

tat gct gtt gct gtg gtg aag aag gat agt ggc ttc cag atg aac cag 440

Tyr Ala Val Ala Val Val Lys Lys Asp Ser Gly Phe Gln Met Asn Gln

115 120 125 130

ctt cga ggc aag aag tcc tgc cac acg ggt cta ggc agg tcc gct ggg 488

Leu Arg Gly Lys Lys Ser Cys His Thr Gly Leu Gly Arg Ser Ala Gly

135 140 145

tgg aac atc ccc ata ggc tta ctt tac tgt gac tta cct gag cca cgt 536

Trp Asn Ile Pro Ile Gly Leu Leu Tyr Cys Asp Leu Pro Glu Pro Arg

150 155 160

aaa cct ctt gag aaa gca gtg gcc aat ttc ttc tcg ggc agc tgt gcc 584

Lys Pro Leu Glu Lys Ala Val Ala Asn Phe Phe Ser Gly Ser Cys Ala

165 170 175

cct tgt gcg gat ggg acg gac ttc ccc cag ctg tgt caa ctg tgt cca 632

Pro Cys Ala Asp Gly Thr Asp Phe Pro Gln Leu Cys Gln Leu Cys Pro

180 185 190

ggg tgt ggc tgc tcc acc ctt aac caa tac ttc ggc tac tcg gga gcc 680

Gly Cys Gly Cys Ser Thr Leu Asn Gln Tyr Phe Gly Tyr Ser Gly Ala

195 200 205 210

ttc aag tgt ctg aag gat ggt gct ggg gat gtg gcc ttt gtc aag cac 728

Phe Lys Cys Leu Lys Asp Gly Ala Gly Asp Val Ala Phe Val Lys His

215 220 225

tcg act ata ttt gag aac ttg gca aac aag gct gac agg gac cag tat 776

Ser Thr Ile Phe Glu Asn Leu Ala Asn Lys Ala Asp Arg Asp Gln Tyr

230 235 240

gag ctg ctt tgc ctg gac aac acc cgg aag ccg gta gat gaa tac aag 824

Glu Leu Leu Cys Leu Asp Asn Thr Arg Lys Pro Val Asp Glu Tyr Lys

245 250 255

gac tgc cac ttg gcc cag gtc cct tct cat acc gtc gtg gcc cga agt 872

Asp Cys His Leu Ala Gln Val Pro Ser His Thr Val Val Ala Arg Ser

260 265 270

atg ggc ggc aag gag gac ttg atc tgg gag ctt ctc aac cag gcc cag 920

Met Gly Gly Lys Glu Asp Leu Ile Trp Glu Leu Leu Asn Gln Ala Gln

275 280 285 290

gaa cat ttt ggc aaa gac aaa tca aaa gaa ttc caa cta ttc agc tct 968

Glu His Phe Gly Lys Asp Lys Ser Lys Glu Phe Gln Leu Phe Ser Ser

295 300 305

cct cat ggg aag gac ctg ctg ttt aag gac tct gcc cac ggg ttt tta 1016

Pro His Gly Lys Asp Leu Leu Phe Lys Asp Ser Ala His Gly Phe Leu

310 315 320

aaa gtc ccc ccc agg atg gat gcc aag atg tac ctg ggc tat gag tat 1064

Lys Val Pro Pro Arg Met Asp Ala Lys Met Tyr Leu Gly Tyr Glu Tyr

325 330 335

gtc act gcc atc cgg aat cta cgg gaa ggc aca tgc cca gaa gcc cca 1112

Val Thr Ala Ile Arg Asn Leu Arg Glu Gly Thr Cys Pro Glu Ala Pro

340 345 350

aca gat gaa tgc aag cct gtg aag tgg tgt gcg ctg agc cac cac gag 1160

Thr Asp Glu Cys Lys Pro Val Lys Trp Cys Ala Leu Ser His His Glu

355 360 365 370

agg ctc aag tgt gat gag tgg agt gtt aac agt gta ggg aaa ata gag 1208

Arg Leu Lys Cys Asp Glu Trp Ser Val Asn Ser Val Gly Lys Ile Glu

375 380 385

tgt gta tca gca gag acc acc gaa gac tgc atc gcc aag atc atg aat 1256

Cys Val Ser Ala Glu Thr Thr Glu Asp Cys Ile Ala Lys Ile Met Asn

390 395 400

gga gaa gct gat gcc atg agc ttg gat gga ggg ttt gtc tac ata gcg 1304

Gly Glu Ala Asp Ala Met Ser Leu Asp Gly Gly Phe Val Tyr Ile Ala

405 410 415

ggc aag tgt ggt ctg gtg cct gtc ttg gca gaa aac tac aat aag agc 1352

Gly Lys Cys Gly Leu Val Pro Val Leu Ala Glu Asn Tyr Asn Lys Ser

420 425 430

gat aat tgt gag gat aca cca gag gca ggg tat ttt gct gta gca gtg 1400

Asp Asn Cys Glu Asp Thr Pro Glu Ala Gly Tyr Phe Ala Val Ala Val

435 440 445 450

gtg aag aaa tca gct tct gac ctc acc tgg gac aat ctg aaa ggc aag 1448

Val Lys Lys Ser Ala Ser Asp Leu Thr Trp Asp Asn Leu Lys Gly Lys

455 460 465

aag tcc tgc cat acg gca gtt ggc aga acc gct ggc tgg aac atc ccc 1496

Lys Ser Cys His Thr Ala Val Gly Arg Thr Ala Gly Trp Asn Ile Pro

470 475 480

atg ggc ctg ctc tac aat aag atc aac cac tgc aga ttt gat gaa ttt 1544

Met Gly Leu Leu Tyr Asn Lys Ile Asn His Cys Arg Phe Asp Glu Phe

485 490 495

ttc agt gaa ggt tgt gcc cct ggg tct aag aaa gac tcc agt ctc tgt 1592

Phe Ser Glu Gly Cys Ala Pro Gly Ser Lys Lys Asp Ser Ser Leu Cys

500 505 510

aag ctg tgt atg ggc tca ggc cta aac ctg tgt gaa ccc aac aac aaa 1640

Lys Leu Cys Met Gly Ser Gly Leu Asn Leu Cys Glu Pro Asn Asn Lys

515 520 525 530

gag gga tac tac ggc tac aca ggc gct ttc agg tgt ctg gtt gag aag 1688

Glu Gly Tyr Tyr Gly Tyr Thr Gly Ala Phe Arg Cys Leu Val Glu Lys

535 540 545

gga gat gtg gcc ttt gtg aaa cac cag act gtc cca cag aac act ggg 1736

Gly Asp Val Ala Phe Val Lys His Gln Thr Val Pro Gln Asn Thr Gly

550 555 560

gga aaa aac cct gat cca tgg gct aag aat ctg aat gaa aaa gac tat 1784

Gly Lys Asn Pro Asp Pro Trp Ala Lys Asn Leu Asn Glu Lys Asp Tyr

565 570 575

gag ttg ctg tgc ctt gat ggt acc agg aaa cct gtg gag gag tat gcg 1832

Glu Leu Leu Cys Leu Asp Gly Thr Arg Lys Pro Val Glu Glu Tyr Ala

580 585 590

aac tgc cac ctg gcc aga gcc ccg aat cac gct gtg gtc aca cgg aaa 1880

Asn Cys His Leu Ala Arg Ala Pro Asn His Ala Val Val Thr Arg Lys

595 600 605 610

gat aag gaa gct tgc gtc cac aag ata tta cgt caa cag cag cac cta 1928

Asp Lys Glu Ala Cys Val His Lys Ile Leu Arg Gln Gln Gln His Leu

615 620 625

ttt gga agc aac gta act gac tgc tcg ggc aac ttt tgt ttg ttc cgg 1976

Phe Gly Ser Asn Val Thr Asp Cys Ser Gly Asn Phe Cys Leu Phe Arg

630 635 640

tcg gaa acc aag gac ctt ctg ttc aga gat gac aca gta tgt ttg gcc 2024

Ser Glu Thr Lys Asp Leu Leu Phe Arg Asp Asp Thr Val Cys Leu Ala

645 650 655

aaa ctt cat gac aga aac aca tat gaa aaa tac tta gga gaa gaa tat 2072

Lys Leu His Asp Arg Asn Thr Tyr Glu Lys Tyr Leu Gly Glu Glu Tyr

660 665 670

gtc aag gct gtt ggt aac ctg aga aaa tgc tcc acc tca tca ctc ctg 2120

Val Lys Ala Val Gly Asn Leu Arg Lys Cys Ser Thr Ser Ser Leu Leu

675 680 685 690

gaa gcc tgc act ttc cgt aga cct taa aatctcagag gtagggctgc 2167

Glu Ala Cys Thr Phe Arg Arg Pro

695

caccaaggtg aagatgggaa cgcagatgat ccatgagttt gccctggttt cactggccca 2227

agtggtttgt gctaaccacg tctgtcttca cagctctgtg ttgccatgtg tgctgaacaa 2287

aaaataaaaa ttattattga ttttatattt c 2318

<210>2

<211>698

<212>PRT

＜213〉people (Homo sapiens)

<400>2

Met Arg Leu Ala Val Gly Ala Leu Leu Val Cys Ala Val Leu Gly Leu

1 5 10 15

Cys Leu Ala Val Pro Asp Lys Thr Val Arg Trp Cys Ala Val Ser Glu

20 25 30

His Glu Ala Thr Lys Cys Gln Ser Phe Arg Asp His Met Lys Ser Val

35 40 45

Ile Pro Ser Asp Gly Pro Ser Val Ala Cys Val Lys Lys Ala Ser Tyr

50 55 60

Leu Asp Cys Ile Arg Ala Ile Ala Ala Asn Glu Ala Asp Ala Val Thr

65 70 75 80

Leu Asp Ala Gly Leu Val Tyr Asp Ala Tyr Leu Ala Pro Asn Asn Leu

85 90 95

Lys Pro Val Val Ala Glu Phe Tyr Gly Ser Lys Glu Asp Pro Gln Thr

100 105 110

Phe Tyr Tyr Ala Val Ala Val Val Lys Lys Asp Ser Gly Phe Gln Met

115 120 125

Asn Gln Leu Arg Gly Lys Lys Ser Cys His Thr Gly Leu Gly Arg Ser

130 135 140

Ala Gly Trp Asn Ile Pro Ile Gly Leu Leu Tyr Cys Asp Leu Pro Glu

145 150 155 160

Pro Arg Lys Pro Leu Glu Lys Ala Val Ala Asn Phe Phe Ser Gly Ser

165 170 175

Cys Ala Pro Cys Ala Asp Gly Thr Asp Phe Pro Gln Leu Cys Gln Leu

180 185 190

Cys Pro Gly Cys Gly Cys Ser Thr Leu Asn Gln Tyr Phe Gly Tyr Ser

195 200 205

Gly Ala Phe Lys Cys Leu Lys Asp Gly Ala Gly Asp Val Ala Phe Val

210 215 220

Lys His Ser Thr Ile Phe Glu Asn Leu Ala Asn Lys Ala Asp Arg Asp

225 230 235 240

Gln Tyr Glu Leu Leu Cys Leu Asp Asn Thr Arg Lys Pro Val Asp Glu

245 250 255

Tyr Lys Asp Cys His Leu Ala Gln Val Pro Ser His Thr Val Val Ala

260 265 270

Arg Ser Met Gly Gly Lys Glu Asp Leu Ile Trp Glu Leu Leu Asn Gln

275 280 285

Ala Gln Glu His Phe Gly Lys Asp Lys Ser Lys Glu Phe Gln Leu Phe

290 295 300

Ser Ser Pro His Gly Lys Asp Leu Leu Phe Lys Asp Ser Ala His Gly

305 310 315 320

Phe Leu Lys Val Pro Pro Arg Met Asp Ala Lys Met Tyr Leu Gly Tyr

325 330 335

Glu Tyr Val Thr Ala Ile Arg Asn Leu Arg Glu Gly Thr Cys Pro Glu

340 345 350

Ala Pro Thr Asp Glu Cys Lys Pro Val Lys Trp Cys Ala Leu Ser His

355 360 365

His Glu Arg Leu Lys Cys Asp Glu Trp Ser Val Asn Ser Val Gly Lys

370 375 380

Ile Glu Cys Val Ser Ala Glu Thr Thr Glu Asp Cys Ile Ala Lys Ile

385 390 395 400

Met Asn Gly Glu Ala Asp Ala Met Ser Leu Asp Gly Gly Phe Val Tyr

405 410 415

Ile Ala Gly Lys Cys Gly Leu Val Pro Val Leu Ala Glu Asn Tyr Asn

420 425 430

Lys Ser Asp Asn Cys Glu Asp Thr Pro Glu Ala Gly Tyr Phe Ala Val

435 440 445

Ala Val Val Lys Lys Ser Ala Ser Asp Leu Thr Trp Asp Asn Leu Lys

450 455 460

Gly Lys Lys Ser Cys His Thr Ala Val Gly Arg Thr Ala Gly Trp Asn

465 470 475 480

Ile Pro Met Gly Leu Leu Tyr Asn Lys Ile Asn His Cys Arg Phe Asp

485 490 495

Glu Phe Phe Ser Glu Gly Cys Ala Pro Gly Ser Lys Lys Asp Ser Ser

500 505 510

Leu Cys Lys Leu Cys Met Gly Ser Gly Leu Asn Leu Cys Glu Pro Asn

515 520 525

Asn Lys Glu Gly Tyr Tyr Gly Tyr Thr Gly Ala Phe Arg Cys Leu Val

530 535 540

Glu Lys Gly Asp Val Ala Phe Val Lys His Gln Thr Val Pro Gln Asn

545 550 555 560

Thr Gly Gly Lys Asn Pro Asp Pro Trp Ala Lys Asn Leu Asn Glu Lys

565 570 575

Asp Tyr Glu Leu Leu Cys Leu Asp Gly Thr Arg Lys Pro Val Glu Glu

580 585 590

Tyr Ala Asn Cys His Leu Ala Arg Ala Pro Asn His Ala Val Val Thr

595 600 605

Arg Lys Asp Lys Glu Ala Cys Val His Lys Ile Leu Arg Gln Gln Gln

610 615 620

His Leu Phe Gly Ser Asn Val Thr Asp Cys Ser Gly Asn Phe Cys Leu

625 630 635 640

Phe Arg Ser Glu Thr Lys Asp Leu Leu Phe Arg Asp Asp Thr Val Cys

645 650 655

Leu Ala Lys Leu His Asp Arg Asn Thr Tyr Glu Lys Tyr Leu Gly Glu

660 665 670

Glu Tyr Val Lys Ala Val Gly Asn Leu Arg Lys Cys Ser Thr Ser Ser

675 680 685

Leu Leu Glu Ala Cys Thr Phe Arg Arg Pro

690 695

<210>3

<211>679

<212>PRT

＜213〉people (Homo sapiens)

<220>

＜223〉ripe transferrin

<400>3

Val Pro Asp Lys Thr Val Arg Trp Cys Ala Val Ser Glu His Glu Ala

1 5 10 15

Thr Lys Cys Gln Ser Phe Arg Asp His Met Lys Ser Val Ile Pro Ser

20 25 30

Asp Gly Pro Ser Val Ala Cys Val Lys Lys Ala Ser Tyr Leu Asp Cys

35 40 45

Ile Arg Ala Ile Ala Ala Asn Glu Ala Asp Ala Val Thr Leu Asp Ala

50 55 60

Gly Leu Val Tyr Asp Ala Tyr Leu Ala Pro Asn Asn Leu Lys Pro Val

65 70 75 80

Val Ala Glu Phe Tyr Gly Ser Lys Glu Asp Pro Gln Thr Phe Tyr Tyr

85 90 95

Ala Val Ala Val Val Lys Lys Asp Ser Gly Phe Gln Met Asn Gln Leu

100 105 110

Arg Gly Lys Lys Ser Cys His Thr Gly Leu Gly Arg Ser Ala Gly Trp

115 120 125

Asn Ile Pro Ile Gly Leu Leu Tyr Cys Asp Leu Pro Glu Pro Arg Lys

130 135 140

Pro Leu Glu Lys Ala Val Ala Asn Phe Phe Ser Gly Ser Cys Ala Pro

145 150 155 160

Cys Ala Asp Gly Thr Asp Phe Pro Gln Leu Cys Gln Leu Cys Pro Gly

165 170 175

Cys Gly Cys Ser Thr Leu Asn Gln Tyr Phe Gly Tyr Ser Gly Ala Phe

180 185 190

Lys Cys Leu Lys Asp Gly Ala Gly Asp Val Ala Phe Val Lys His Ser

195 200 205

Thr Ile Phe Glu Asn Leu Ala Asn Lys Ala Asp Arg Asp Gln Tyr Glu

210 215 220

Leu Leu Cys Leu Asp Asn Thr Arg Lys Pro Val Asp Glu Tyr Lys Asp

225 230 235 240

Cys His Leu Ala Gln Val Pro Ser His Thr Val Val Ala Arg Ser Met

245 250 255

Gly Gly Lys Glu Asp Leu Ile Trp Glu Leu Leu Asn Gln Ala Gln Glu

260 265 270

His Phe Gly Lys Asp Lys Ser Lys Glu Phe Gln Leu Phe Ser Ser Pro

275 280 285

His Gly Lys Asp Leu Leu Phe Lys Asp Ser Ala His Gly Phe Leu Lys

290 295 300

Val Pro Pro Arg Met Asp Ala Lys Met Tyr Leu Gly Tyr Glu Tyr Val

305 310 315 320

Thr Ala Ile Arg Asn Leu Arg Glu Gly Thr Cys Pro Glu Ala Pro Thr

325 330 335

Asp Glu Cys Lys Pro Val Lys Trp Cys Ala Leu Ser His His Glu Arg

340 345 350

Leu Lys Cys Asp Glu Trp Ser Val Asn Ser Val Gly Lys Ile Glu Cys

355 360 365

Val Ser Ala Glu Thr Thr Glu Asp Cys Ile Ala Lys Ile Met Asn Gly

370 375 380

Glu Ala Asp Ala Met Ser Leu Asp Gly Gly Phe Val Tyr Ile Ala Gly

385 390 395 400

Lys Cys Gly Leu Val Pro Val Leu Ala Glu Asn Tyr Asn Lys Ser Asp

405 410 415

Asn Cys Glu Asp Thr Pro Glu Ala Gly Tyr Phe Ala Val Ala Val Val

420 425 430

Lys Lys Ser Ala Ser Asp Leu Thr Trp Asp Asn Leu Lys Gly Lys Lys

435 440 445

Ser Cys His Thr Ala Val Gly Arg Thr Ala Gly Trp Asn Ile Pro Met

450 455 460

Gly Leu Leu Tyr Asn Lys Ile Asn His Cys Arg Phe Asp Glu Phe Phe

465 470 475 480

Ser Glu Gly Cys Ala Pro Gly Ser Lys Lys Asp Ser Ser Leu Cys Lys

485 490 495

Leu Cys Met Gly Ser Gly Leu Asn Leu Cys Glu Pro Asn Asn Lys Glu

500 505 510

Gly Tyr Tyr Gly Tyr Thr Gly Ala Phe Arg Cys Leu Val Glu Lys Gly

515 520 525

Asp Val Ala Phe Val Lys His Gln Thr Val Pro Gln Asn Thr Gly Gly

530 535 540

Lys Asn Pro Asp Pro Trp Ala Lys Asn Leu Asn Glu Lys Asp Tyr Glu

545 550 555 560

Leu Leu Cys Leu Asp Gly Thr Arg Lys Pro Val Glu Glu Tyr Ala Asn

565 570 575

Cys His Leu Ala Arg Ala Pro Asn His Ala Val Val Thr Arg Lys Asp

580 585 590

Lys Glu Ala Cys Val His Lys Ile Leu Arg Gln Gln Gln His Leu Phe

595 600 605

Gly Ser Asn Val Thr Asp Cys Ser Gly Asn Phe Cys Leu Phe Arg Ser

610 615 620

Glu Thr Lys Asp Leu Leu Phe Arg Asp Asp Thr Val Cys Leu Ala Lys

625 630 635 640

Leu His Asp Arg Asn Thr Tyr Glu Lys Tyr Leu Gly Glu Glu Tyr Val

645 650 655

Lys Ala Val Gly Asn Leu Arg Lys Cys Ser Thr Ser Ser Leu Leu Glu

660 665 670

Ala Cys Thr Phe Arg Arg Pro

675

<210>4

<211>36

<212>PRT

＜213〉human immunodeficiency virus

<220>

＜223〉antifusogenic peptides

<400>4

Phe Trp Asn Trp Leu Ser Ala Trp Lys Asp Leu Glu Leu Leu Glu Gln

1 5 10 15

Glu Asn Lys Glu Gln Gln Asn Gln Ser Glu Glu Ile Leu Ser His Ile

20 25 30

Leu Ser Thr Tyr

35

<210>5

<211>35

<212>PRT

＜213〉human respiratory syncytial virus

<220>

＜223〉antifusogenic peptides

<400>5

Val Tyr Pro Ser Asp Glu Tyr Asp Ala Ser Ile Ser Gln Val Asn Glu

1 5 10 15

Glu Ile Asn Gln Ala Leu Ala Tyr Ile Arg Lys Ala Asp Glu Leu Leu

20 25 30

Glu Asn Val

35

<210>6

<211>51

<212>PRT

＜213〉human respiratory syncytial virus

<220>

＜223〉antifusogenic peptides

<400>6

Ala Val Ser Lys Val Leu His Leu Glu Gly Glu Val Asn Lys Ile Lys

1 5 10 15

Ser Ala Leu Leu Ser Thr Asn Lys Ala Val Val Ser Leu Ser Asn Gly

20 25 30

Val Ser Val Leu Thr Ser Lys Val Leu Asp Leu Lys Asn Tyr Ile Asp

35 40 45

Lys Gln Leu

50

<210>7

<211>35

<212>PRT

＜213〉human respiratory syncytial virus

<220>

＜223〉antifusogenic peptides

<400>7

Val Phe Pro Ser Asp Glu Phe Asp Ala Ser Ile Ser Gln Val Asn Glu

1 5 10 15

Lys Ile Asn Gln Ser Leu Ala Phe Ile Arg Glu Ser Asp Glu Leu Leu

20 25 30

His Asn Val

35

<210>8

<211>12

<212>PRT

＜213〉people (Homo sapiens)

<220>

＜223〉lactoferrin splice variant sequence

<400>8

Glu Asp Cys Ile Ala Leu Lys Gly Glu Ala Asp Ala

1 5 10

<210>9

<211>27

<212>DNA

＜213〉artificial sequence

<220>

＜223〉description of artificial sequence: the oligonucleotide that is used for mutagenesis

<400>9

gcagaaaact acgataagag cgataat 27

<210>10

<211>27

<212>DNA

＜213〉artificial sequence

<220>

＜223〉description of artificial sequence: the oligonucleotide that is used for mutagenesis

<400>10

ctatttggaa gcgacgtaac tgactgc 27

<210>11

<211>20

<212>PRT

＜213〉artificial sequence

<220>

＜223〉description of artificial sequence: EPO simulating peptide

<400>11

Gly Gly Thr Tyr Ser Cys His Phe Gly Pro Leu Thr Trp Val Cys Lys

1 5 10 15

Pro Gln Gly Gly

20

<210>12

<211>18

<212>PRT

＜213〉artificial sequence

<220>

＜223〉description of artificial sequence: EPO simulating peptide

<400>12

Asp Arg Glu Gly Cys Arg Arg Gly Trp Val Gly Gln Cys Lys Ala Trp

1 5 10 15

Phe Asn

<210>13

<211>108

<212>DNA

＜213〉artificial sequence

<220>

＜223〉the anti-fusion sequence of the description of artificial sequence: HIV

<220>

<221>CDS

<222>(1)..(108)

<400>13

tac aca agc tta ata cac tcc tta att gaa gaa tcg caa aac cag caa 48

Tyr Thr Ser Leu Ile His Ser Leu Ile Glu Glu Ser Gln Asn Gln Gln

1 5 10 15

gaa aag aat gaa caa gaa tta ttg gaa tta gat aaa tgg gca agt ttg 96

Glu Lys Asn Glu Gln Glu Leu Leu Glu Leu Asp Lys Trp Ala Ser Leu

20 25 30

tgg aat tgg ttt 108

Trp Asn Trp Phe

35

<210>14

<211>36

<212>PRT

＜213〉artificial sequence

<220>

＜223〉the anti-fusion sequence of the description of artificial sequence: HIV

<400>14

Tyr Thr Ser Leu Ile His Ser Leu Ile Glu Glu Ser Gln Asn Gln Gln

1 5 10 15

Glu Lys Asn Glu Gln Glu Leu Leu Glu Leu Asp Lys Trp Ala Ser Leu

20 25 30

Trp Asn Trp Phe

35

<210>15

<211>124

<212>DNA

＜213〉artificial sequence

<220>

＜223〉description of artificial sequence: the anti-fusion sequence of HIV fusion rotein

<220>

<221>CDS

<222>(1)..(123)

<400>15

cta gag aaa agg tac act agc tta ata cac tcc tta att gaa gaa tcg 48

Leu Glu Lys Arg Tyr Thr Ser Leu Ile His Ser Leu Ile Glu Glu Ser

1 5 10 15

caa aac cag caa gaa aag aat gaa caa gaa tta ttg gaa tta gat aaa 96

Gln Asn Gln Gln Glu Lys Asn Glu Gln Glu Leu Leu Glu Leu Asp Lys

20 25 30

tgg gca agt ttg tgg aat tgg ttt gta c 124

Trp Ala Ser Leu Trp Asn Trp Phe Val

35 40

<210>16

<211>41

<212>PRT

＜213〉artificial sequence

<220>

＜223〉description of artificial sequence: the anti-fusion sequence of HIV fusion rotein

<400>16

Leu Glu Lys Arg Tyr Thr Ser Leu Ile His Ser Leu Ile Glu Glu Ser

1 5 10 15

Gln Asn Gln Gln Glu Lys Asn Glu Gln Glu Leu Leu Glu Leu Asp Lys

20 25 30

Trp Ala Ser Leu Trp Asn Trp Phe Val

35 40

<210>17

<211>174

<212>PRT

＜213〉people (Homo sapiens)

<220>

＜223〉INGAP albumen

<400>17

Met Met Leu Pro Met Thr Leu Cys Arg Met Ser Trp Met Leu Leu Ser

1 5 10 15

Cys Leu Met Phe Leu Ser Trp Val Glu Gly Glu Glu Ser Gln Lys Lys

20 25 30

Leu Pro Ser Ser Arg Ile Thr Cys Pro Gln Gly Ser Val Ala Tyr Gly

35 40 45

Ser Tyr Cys Tyr Ser Leu Ile Leu Ile Pro Gln Thr Trp Ser Asn Ala

50 55 60

Glu Leu Ser Cys Gln Met His Phe Ser Gly His Leu Ala Phe Leu Leu

65 70 75 80

Ser Thr Gly Glu Ile Thr Phe Val Ser Ser Leu Val Lys Asn Ser Leu

85 90 95

Thr Ala Tyr Gln Tyr Ile Trp Ile Gly Leu His Asp Pro Ser His Gly

100 105 110

Thr Leu Pro Asn Gly Gly Trp Lys Trp Ser Ser Ser Asn Val Leu Thr

115 120 125

Phe Tyr Asn Trp Glu Arg Asn Pro Ser Ile Ala Ala Asp Arg Gly Tyr

130 135 140

Cys Ala Val Leu Ser Gln Lys Ser Gly Phe Gln Lys Trp Arg Asp Phe

145 150 155 160

Asn Cys Glu Asn Glu Leu Pro Tyr lle Cys Lys Phe Lys Val

165 170

<210>18

<211>525

<212>DNA

＜213〉artificial sequence

<220>

＜223〉description of artificial sequence: INGAP sequence

<220>

<221>CDS

<222>(1)..(525)

<400>18

atg atg ttg cca atg act ttg tgt aga atg tct tgg atg ttg ttg tct 48

Met Met Leu Pro Met Thr Leu Cys Arg Met Ser Trp Met Leu Leu Ser

1 5 10 15

tgt ttg atg ttt ttg tct tgg gtt gaa ggt gaa gaa tct caa aaa aaa 96

Cys Leu Met Phe Leu Ser Trp Val Glu Gly Glu Glu Ser Gln Lys Lys

20 25 30

ttg cca tct tct aga att act tgt cca caa ggt tct gtt gct tat ggt 144

Leu Pro Ser Ser Arg Ile Thr Cys Pro Gln Gly Ser Val Ala Tyr Gly

35 40 45

tct tat tgt tat tct ttg att ttg att cca caa act tgg tct aat gct 192

Ser Tyr Cys Tyr Ser Leu Ile Leu Ile Pro Gln Thr Trp Ser Asn Ala

50 55 60

gaa ttg tct tgt caa atg cat ttt tct ggt cat ttg gct ttt ttg ttg 240

Glu Leu Ser Cys Gln Met His Phe Ser Gly His Leu Ala Phe Leu Leu

65 70 75 80

tct act ggt gaa att act ttt gtt tct tct ttg gtt aaa aat tct ttg 288

Ser Thr Gly Glu Ile Thr Phe Val Ser Ser Leu Val Lys Asn Ser Leu

85 90 95

act gct tat caa tat att tgg att ggt ttg cat gat cca tct cat ggt 336

Thr Ala Tyr Gln Tyr Ile Trp Ile Gly Leu His Asp Pro Ser His Gly

100 105 110

act ttg cca aat ggt tct ggt tgg aaa tgg tct tct tct aat gtt ttg 384

Thr Leu Pro Asn Gly Ser Gly Trp Lys Trp Ser Ser Ser Asn Val Leu

115 120 125

act ttt tat aat tgg gaa aga aat cca tct att gct gct gat aga ggt 432

Thr Phe Tyr Asn Trp Glu Arg Asn Pro Ser Ile Ala Ala Asp Arg Gly

130 135 140

tat tgt gct gtt ttg tct caa aaa tct ggt ttt caa aaa tgg aga gat 480

Tyr Cys Ala Val Leu Ser Gln Lys Ser Gly Phe Gln Lys Trp Arg Asp

145 150 155 160

ttt aat tgt gaa aat gaa ttg cca tat att tgt aaa ttt aaa gtt 525

Phe Asn Cys Glu Asn Glu Leu Pro Tyr Ile Cys Lys Phe Lys Val

165 170 175

<210>19

<211>175

<212>PRT

＜213〉artificial sequence

<220>

＜223〉description of artificial sequence: INGAP sequence

<400>19

Met Met Leu Pro Met Thr Leu Cys Arg Met Ser Trp Met Leu Leu Ser

1 5 10 15

Cys Leu Met Phe Leu Ser Trp Val Glu Gly Glu Glu Ser Gln Lys Lys

20 25 30

Leu Pro Ser Ser Arg Ile Thr Cys Pro Gln Gly Ser Val Ala Tyr Gly

35 40 45

Ser Tyr Cys Tyr Ser Leu Ile Leu Ile Pro Gln Thr Trp Ser Asn Ala

50 55 60

Glu Leu Ser Cys Gln Met His Phe Ser Gly His Leu Ala Phe Leu Leu

65 70 75 80

Ser Thr Gly Glu Ile Thr Phe Val Ser Ser Leu Val Lys Asn Ser Leu

85 90 95

Thr Ala Tyr Gln Tyr Ile Trp Ile Gly Leu His Asp Pro Ser His Gly

100 105 110

Thr Leu Pro Asn Gly Ser Gly Trp Lys Trp Ser Ser Ser Asn Val Leu

115 120 125

Thr Phe Tyr Asn Trp Glu Arg Asn Pro Ser Ile Ala Ala Asp Arg Gly

130 135 140

Tyr Cys Ala Val Leu Ser Gln Lys Ser Gly Phe Gln Lys Trp Arg Asp

145 150 155 160

Phe Asn Cys Glu Asn Glu Leu Pro Tyr Ile Cys Lys Phe Lys Val

165 170 175

<210>20

<211>445

<212>DNA

＜213〉artificial sequence

<220>

＜223〉description of artificial sequence: the INGAP sequence of fusion rotein

<220>

<221>CDS

<222>(1)..(444)

<400>20

cra gag aaa agg ttg cca tct tcc aga att act tgt cca caa ggt tct 48

Leu Glu Lys Arg Leu Pro Ser Ser Arg Ile Thr Cys Pro Gln Gly Ser

1 5 10 15

gtt gct tat ggt tct tat tgt tat tct ttg att ttg att cca caa act 96

Val Ala Tyr Gly Ser Tyr Cys Tyr Ser Leu Ile Leu Ile Pro Gln Thr

20 25 30

tgg tct aat gct gaa ttg tct tgt caa atg cat ttt tct ggt cat ttg 144

Trp Ser Asn Ala Glu Leu Ser Cys Gln Met His Phe Ser Gly His Leu

35 40 45

gct ttt ttg ttg tct act ggt gaa att act ttt gtt tct tct ttg gtt 192

Ala Phe Leu Leu Ser Thr Gly Glu Ile Thr Phe Val Ser Ser Leu Val

50 55 60

aaa aat tct ttg act gct tat caa tat att tgg att ggt ttg cat gat 240

Lys Asn Ser Leu Thr Ala Tyr Gln Tyr Ile Trp Ile Gly Leu His Asp

65 70 75 80

cca tct cat ggt act ttg cca aat ggt tct ggt tgg aaa tgg tct tct 288

Pro Ser His Gly Thr Leu Pro Asn Gly Ser Gly Trp Lys Trp Ser Ser

85 90 95

tct aat gtt ttg act ttt tac aat tgg gaa aga aat cca tct att gct 336

Ser Asn Val Leu Thr Phe Tyr Asn Trp Glu Arg Asn Pro Ser Ile Ala

100 105 110

gct gat aga ggt tat tgt gct gtt ttg tct caa aaa tct ggt ttt caa 384

Ala Asp Arg Gly Tyr Cys Ala Val Leu Ser Gln Lys Ser Gly Phe Gln

115 120 125

aaa tgg aga gat ttt aat tgt gaa aat gaa ttg cca tat att tgt aaa 432

Lys Trp Arg Asp Phe Asn Cys Glu Asn Glu Leu Pro Tyr Ile Cys Lys

130 135 140

ttt aaa gtt gta c 445

Phe Lys Val Val

145

<210>21

<211>148

<212>PRT

＜213〉artificial sequence

<220>

＜223〉description of artificial sequence: the INGAP sequence of fusion rotein

<400>21

Leu Glu Lys Arg Leu Pro Ser Ser Arg Ile Thr Cys Pro Gln Gly Ser

1 5 10 15

Val Ala Tyr Gly Ser Tyr Cys Tyr Ser Leu Ile Leu Ile Pro Gln Thr

20 25 30

Trp Ser Asn Ala Glu Leu Ser Cys Gln Met His Phe Ser Gly His Leu

35 40 45

Ala Phe Leu Leu Ser Thr Gly Glu Ile Thr Phe Val Ser Ser Leu Val

50 55 60

Lys Asn Ser Leu Thr Ala Tyr Gln Tyr Ile Trp Ile Gly Leu His Asp

65 70 75 80

Pro Ser His Gly Thr Leu Pro Asn Gly Ser Gly Trp Lys Trp Ser Ser

85 90 95

Ser Asn Val Leu Thr Phe Tyr Asn Trp Glu Arg Asn Pro Ser Ile Ala

100 105 110

Ala Asp Arg Gly Tyr Cys Ala Val Leu Ser Gln Lys Ser Gly Phe Gln

115 120 125

Lys Trp Arg Asp Phe Asn Cys Glu Asn Glu Leu Pro Tyr Ile Cys Lys

130 135 140

Phe Lys Val Val

145

<210>22

<211>441

<212>DNA

＜213〉artificial sequence

<220>

＜223〉description of artificial sequence: the INGAP sequence of fusion rotein

<220>

<221>CDS

<222>(2)..(436)

<400>22

t cga cct ttg cca tct tcc aga att act tgt cca caa ggt tct gtt gct 49

Arg Pro Leu Pro Ser Ser Arg Ile Thr Cys Pro Gln Gly Ser Val Ala

1 5 10 15

tat ggt tct tat tgt tat tct ttg att ttg att cca caa act tgg tct 97

Tyr Gly Ser Tyr Cys Tyr Ser Leu Ile Leu Ile Pro Gln Thr Trp Ser

20 25 30

aat gct gaa ttg tct tgt caa atg cat ttt tct ggt cat ttg gct ttt 145

Asn Ala Glu Leu Ser Cys Gln Met His Phe Ser Gly His Leu Ala Phe

35 40 45

ttg ttg tct act ggt gaa att act ttt gtt tct tct ttg gtt aaa aat 193

Leu Leu Ser Thr Gly Glu Ile Thr Phe Val Ser Ser Leu Val Lys Asn

50 55 60

tct ttg act gct tat caa tat att tgg att ggt ttg cat gat cca tct 241

Ser Leu Thr Ala Tyr Gln Tyr Ile Trp Ile Gly Leu His Asp Pro Ser

65 70 75 80

cat ggt act ttg cca aat ggt tct ggt tgg aaa tgg tct tct tct aat 289

His Gly Thr Leu Pro Asn Gly Ser Gly Trp Lys Trp Ser Ser Ser Asn

85 90 95

gtt ttg act ttt tac aat tgg gaa aga aat cca tct att gct gct gat 337

Val Leu Thr Phe Tyr Asn Trp Glu Arg Asn Pro Ser Ile Ala Ala Asp

100 105 110

aga ggt tat tgt gct gtt ttg tct caa aaa tct ggt ttt caa aaa tgg 385

Arg Gly Tyr Cys Ala Val Leu Ser Gln Lys Ser Gly Phe Gln Lys Trp

115 120 125

aga gat ttt aat tgt gaa aat gaa ttg cca tat att tgt aaa ttt aaa 433

Arg Asp Phe Asn Cys Glu Asn Glu Leu Pro Tyr Ile Cys Lys Phe Lys

130 135 140

gtt taata 441

Val

145

<210>23

<211>145

<212>PRT

＜213〉artificial sequence

<220>

＜223〉description of artificial sequence: the INGAP sequence of fusion rotein

<400>23

Arg Pro Leu Pro Ser Ser Arg Ile Thr Cys Pro Gln Gly Ser Val Ala

1 5 10 15

Tyr Gly Ser Tyr Cys Tyr Ser Leu Ile Leu Ile Pro Gln Thr Trp Ser

20 25 30

Asn Ala Glu Leu Ser Cys Gln Met His Phe Ser Gly His Leu Ala Phe

35 40 45

Leu Leu Ser Thr Gly Glu Ile Thr Phe Val Ser Ser Leu Val Lys Asn

50 55 60

Ser Leu Thr Ala Tyr Gln Tyr Ile Trp Ile Gly Leu His Asp Pro Ser

65 70 75 80

His Gly Thr Leu Pro Asn Gly Ser Gly Trp Lys Trp Ser Ser Ser Asn

85 90 95

Val Leu Thr Phe Tyr Asn Trp Glu Arg Asn Pro Ser Ile Ala Ala Asp

100 105 110

Arg Gly Tyr Cys Ala Val Leu Ser Gln Lys Ser Gly Phe Gln Lys Trp

115 120 125

Arg Asp Phe Asn Cys Glu Asn Glu Leu Pro Tyr Ile Cys Lys Phe Lys

130 135 140

Val

145

<210>24

<211>60

<212>DNA

＜213〉artificial sequence

<220>

＜223〉description of artificial sequence: EPO simulated series

<220>

<221>CDS

<222>(1)..(60)

<400>24

ggt ggt act tac tct tgt cat ttt ggt cca ttg act tgg gtt tgt aag 48

Gly Gly Thr Tyr Ser Cys His Phe Gly Pro Leu Thr Trp Val Cys Lys

1 5 10 15

cca caa ggt ggt 60

Pro Gln Gly Gly

20

<210>25

<211>20

<212>PRT

＜213〉artificial sequence

<220>

＜223〉description of artificial sequence: EP0 simulated series

<400>25

Gly Gly Thr Tyr Ser Cys His Phe Gly Pro Leu Thr Trp Val Cys Lys

1 5 10 15

Pro Gln Gly Gly

20

<210>26

<211>47

<212>PRT

＜213〉artificial sequence

<220>

＜223〉description of artificial sequence: the transferrin peptide inserts the district

<400>26

Asp Lys Ser Lys Glu Phe Gln Leu Phe Ser Ser Pro His Gly Lys Asp

1 5 10 15

Leu Leu Phe Lys Asp Ser Ala His Gly Phe Leu Lys Val Pro Pro Arg

20 25 30

Met Asp Ala Lys Met Tyr Leu Gly Tyr Glu Tyr Val Thr Ala Ile

35 40 45

<210>27

<211>49

<212>PRT

＜213〉artificial sequence

<220>

＜223〉description of artificial sequence: the transferrin peptide inserts the district

<400>27

Asn Val Thr Asp Cys Ser Gly Asn Phe Cys Leu Phe Arg Ser Glu Thr

1 5 10 15

Lys Asp Leu Leu Phe Arg Asp Asp Thr Val Cys Leu Ala Lys Leu His

20 25 30

Asp Arg Asn Thr Tyr Glu Lys Tyr Leu Gly Glu Glu Tyr Val Lys Ala

35 40 45

Val

<210>28

<211>140

<212>DNA

＜213〉artificial sequence

<220>

＜223〉description of artificial sequence: the transferrin peptide inserts the dna sequence dna in district

<400>28

agacaaatca aaagaatttc aactattcag ctctcctcat ggtggtactt actcttgtca 60

ttttggtcca ttgacttggg tttgtaagcc acaaggtggt gggaaggacc tgctgtttaa 120

ggactctgcc cacgggtttt 140

<210>29

<211>210

<212>DNA

＜213〉artificial sequence

<220>

＜223〉description of artificial sequence: the transferrin peptide inserts the dna sequence dna in district

<400>29

cctatttgga agcaacgtaa ctgactgctc gggcaacttt tgtttgttcc ggtcggaagg 60

tggtacttac tcttgtcatt ttggtccatt gacttgggtt tgtaagccac aaggtggtac 120

caaggacctt ctgttcagag atgacacagt atgtttggcc aaacttcatg acagaaacac 180

atatgaaaaa tacttaggag aagaatatgt 210

<210>30

<211>23

<212>PRT

＜213〉artificial sequence

<220>

＜223〉description of artificial sequence: EP0 simulating peptide

<400>30

Gln Arg Val Glu Ile Leu Glu Gly Arg Thr Glu Cys Val Leu Ser Asn

1 5 10 15

Leu Arg Gly Arg Thr Arg Tyr

20

Claims (56)

1. contain the proteinic fusion rotein of transferrin (Tf) that merges with at least a therapeutic protein or peptide, described transferrin shows the glycosylation of reduction.

2. the fusion rotein of claim 1, wherein the serum half life of therapeutic protein or peptide, be higher than therapeutic protein or the peptide serum half life at non-fusion state.

3. the fusion rotein of claim 1, the wherein fusion of the C-of therapeutic protein or peptide and Tf end.

4. the fusion rotein of claim 1, the wherein fusion of the N-of therapeutic protein or peptide and Tf end.

5. the fusion rotein of claim 1, wherein therapeutic protein or peptide are inserted at least one ring of Tf.

6. the fusion rotein of claim 1, wherein Tf albumen reduces the affinity of TfR.

7. each fusion rotein among the claim 1-5, wherein Tf albumen is lactotransferrin (lactoferrin).

8. the fusion rotein of claim 6, wherein TF albumen does not combine with TfR.

9. the fusion rotein of claim 1, wherein Tf albumen reduces the affinity of iron.

10. the fusion rotein of claim 9, wherein Tf albumen does not combine with iron.

11. the fusion rotein of claim 1, wherein said Tf albumen contains at least one can prevent glycosylated sudden change.

12. the fusion rotein of claim 11, wherein Tf albumen is lactotransferrin (lactoferrin).

13. the fusion rotein of claim 1, it is expressed in the presence of tunicamycin.

14. the fusion rotein of claim 1, wherein said Tf albumen contain the part of a part, bridging peptide and the Tf PROTEIN C structural domain of Tf albumen N structural domain.

15. the fusion rotein of claim 14, wherein the bridging peptide links up therapeutic protein or peptide and Tf.

16. the fusion rotein of claim 14, wherein said therapeutic protein, peptide or polypeptide are inserted between proteic N structural domain of Tf and the C-structure territory.

17. the fusion rotein of claim 1, wherein Tf albumen has at least one aminoacid replacement, disappearance or interpolation at hinge region.

18. the fusion rotein of claim 17, wherein said hinge region is selected from about residue 94 to about residue 96, approximately residue 245 is to about residue 247, approximately residue 316 is to about residue 318, approximately residue 425 is to about residue 427, approximately residue 581 to about residue 582 and approximately residue 652 to about residue 658.

19. the fusion rotein of claim 1, wherein said Tf albumen have at least one aminoacid replacement, disappearance or interpolation: Asp 63 being selected from following position, Gly 65, and Tyr 95, Tyr188, Lys 206, and His 207, His 249, and Asp 392, and Tyr 426, Tyr 514, and Tyr 517, and His 585, Thr 120, Arg 124Ala 126, and Gly 127, Thr 452, and Arg 456, Ala 458 and Gly 459.

20. the fusion rotein of claim 5, wherein therapeutic protein or peptide replace at least one ring.

21. the fusion rotein of claim 11, wherein glycosylation site is selected from corresponding to amino acid N 413, the amino-acid residue of N611.

22. the fusion rotein of claim 6 or 8, wherein Tf is containing at least one aminoacid replacement, disappearance or interpolation: Asp 63 corresponding to being selected from following amino acid whose amino-acid residue place, and Gly 65, and Tyr 95, Tyr 188, and Lys 206, and His 207, and His 249, Asp 392, and Tyr 426, and Tyr 514, Tyr 517, and His 585, and Thr 120, Arg 124, and Ala 126, and Gly 127, Thr 452, and Arg 456, Ala 458 and Gly 459.

23. contain the proteinic fusion rotein of transferrin (Tf) that merges with at least a therapeutic protein or peptide, described transferrin shows the affinity to transferrin receptor (TfR) of reduction.

24. the fusion rotein of claim 1, wherein the serum half life of therapeutic protein or peptide, be higher than therapeutic protein or the peptide serum half life at non-fusion state.

25. the fusion rotein of claim 1, wherein the C-of therapeutic protein or peptide and Tf is terminal merges.

26. the fusion rotein of claim 1, wherein the N-of therapeutic protein or peptide and Tf is terminal merges.

27. the fusion rotein of claim 1, wherein therapeutic protein or peptide are inserted at least one ring of Tf.

28. the fusion rotein of claim 23, wherein TF albumen does not combine with TfR.

29. the fusion rotein of claim 23, wherein Tf albumen reduces the affinity of iron.

30. the fusion rotein of claim 9, wherein Tf albumen does not combine with iron.

31. the fusion rotein of claim 23, wherein said Tf albumen shows the glycosylation of reduction, or does not show glycosylation.

32. the fusion rotein of claim 31 contains at least one and can prevent glycosylated sudden change.

33. the fusion rotein of claim 23, wherein said Tf albumen contain the part of a part, bridging peptide and the Tf PROTEIN C structural domain of Tf albumen N structural domain.

34. the fusion rotein of claim 33, wherein the bridging peptide links up therapeutic protein or peptide and Tf.

35. the fusion rotein of claim 33, wherein said therapeutic protein, peptide or polypeptide are inserted between proteic N structural domain of Tf and the C-structure territory.

36. the fusion rotein of claim 23, wherein Tf albumen has at least one aminoacid replacement, disappearance or interpolation at the Tf hinge region.

37. the fusion rotein of claim 36, wherein said hinge region is selected from about residue 94 to about residue 96, approximately residue 245 is to about residue 247, approximately residue 316 is to about residue 318, approximately residue 425 is to about residue 427, approximately residue 581 to about residue 582 and approximately residue 652 to about residue 658.

38. the fusion rotein of claim 23, wherein said Tf albumen have at least one aminoacid replacement, disappearance or interpolation: Asp 63 being selected from following position, Gly 65, and Tyr 95, Tyr 188, and Lys 206, and His 207, and His 249, Asp 392, and Tyr 426, and Tyr 514, Tyr 517, and His 585, and Thr 120, Arg 124, and Ala 126, and Gly 127, Thr 452, and Arg 456, Ala 458 and Gly 459.

39. the fusion rotein of claim 25, wherein therapeutic protein or peptide replace at least one ring.

40. the fusion rotein of claim 31, wherein glycosylation site is selected from corresponding to amino acid N 413, the amino-acid residue of N611.

41. the nucleic acid molecule of each fusion rotein in the coding claim 1 or 23.

42. contain the carrier of the nucleic acid molecule of claim 41.

43. contain the host cell of the carrier of claim 42.

44. contain the host cell of the nucleic acid molecule of claim 41.

45. express the method for Tf fusion rotein, be included in the host cell of cultivating claim 43 under the condition that to express coded fusion rotein.

46. express the method for Tf fusion rotein, be included in the host cell of cultivating claim 44 under the condition that to express coded fusion rotein.

47. the host cell of claim 43, wherein cell is protokaryon or eukaryotic cell.

48. the host cell of claim 44, wherein cell is protokaryon or eukaryotic cell.

49. the host cell of claim 47, wherein cell is a yeast cell.

50. the host cell of claim 48, wherein cell is a yeast cell.

51. contain the transgenic animal of the nucleic acid molecule of claim 41.

52. produce the method for Tf fusion rotein, comprise in the transgenic animal of Accessory Right requirement 51 and divide isolated fusion protein.

53. the method for claim 52, wherein the Tf fusion rotein contains lactoferrin.

54. the method for claim 53, wherein fusion rotein separates from the biological liquid of transgenic animal.

55. the method for claim 53, wherein liquid is serum or milk.

56. treat the method for patient disease or disease symptoms, comprise the step of the fusion rotein of using claim 1 or claim 23.

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