CN1444992A - Method and combination for treating tumors based on ERBB-3 - Google Patents
Method and combination for treating tumors based on ERBB-3 Download PDFInfo
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- CN1444992A CN1444992A CN02116259A CN02116259A CN1444992A CN 1444992 A CN1444992 A CN 1444992A CN 02116259 A CN02116259 A CN 02116259A CN 02116259 A CN02116259 A CN 02116259A CN 1444992 A CN1444992 A CN 1444992A
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Abstract
A composition and method for preventing and treating the tumor of mammal or human body features use of ErbB-3 protein, nucleic acid for coding said protein, or their function fragment. The nucleic acid for coding the extracellular domain of said protein, its function fragment, or its function fragment, the basically purified said extracellular domain or its function fragment, and the antibody binding with the antigen of said domain or its function fragment are also disclosed.
Description
Technical field
The present invention relates to be used for the treatment of compositions and the method for mammal, particularly human tumor.More particularly, be to the invention provides a kind of method of preventing, treat or delay mammal tumor with ErbB-3 albumen, the coding proteic nucleic acid of ErbB-3 or its function fragment.The present invention also provides the nucleic acid that separates the proteic ectodomain of coding ErbB-3, or its function fragment, basically the proteic ectodomain of the ErbB-3 of purification, or its function fragment and can with the bonded antibody of epitope of the proteic ectodomain of ErbB-3, or its function fragment.The present invention further provides the nucleic acid that comprises the proteic ectodomain of ErbB-3 or its function fragment or this extracellular protein of encoding and with the pharmaceutical composition of bonded antibody of this extracellular protein or their function fragment or/and vaccine.
Background technology
Cancer is to cause human dead principal disease, and it is caused by physiological cell proliferation out of control.Physiological cell proliferation out of control has influenced the body normal physiological state, causes serious pathological reaction, often causes death.Though the mankind are making great effort aspect cancer research and the treatment, cancer remains human main causes of death at present.The method that has multiple treatment cancer patient now comprises operation, radiation and chemotherapy.Because preceding two kinds of methods, i.e. operation can not be eliminated the intravital cancerous cell of patient fully with radiotherapy, so the latter, and promptly chemotherapy combines or generally be used for individually the growth of control cancer cell with additive method.The anticancer compound that is used for patient normally targeting stops cancer cell multiplication or kills somatoblast.
When chemical compound was poisonous to cancerous cell, they also seriously influenced those normal somatoblasts essential for people's life usually.Therefore, cancer research main direction is exactly to seek the method that can specificity hinders cancerous cell or kill cancer cell and do not influence normal cell propagation.Currently be starved of a kind of like this Therapeutic Method that is used for cancer patient.
ErbBs belongs to the receptor of first order protein tyrosine kinase.The cell signal of ErbB mediation plays key effect to fetal development and ripe organ dysfunction.On cellular level, the signal that ErbB is receptor-mediated cell proliferation, differentiation, migration and cellularity organized again.The ErbB albumen that has four kinds of structural similarities, i.e. ErbB-1, ErbB-2, ErbB-3 and ErbB-4.Epidermal growth factor (EGF) is can discern and in conjunction with one of several parts of last ErbB-1.ErbB-3 and ErbB-4 also can combine with several parts, comprise neuregulin-1 NRG-1 Neu Differentiation Factor NDF glial growth factors GGF (NRG-1).The part of ErbB-2 is not also found so far.Yet ErbB-2 is as the composition of energy and ErbB-3, ErbB-4 or ErbB-1 formation heterodimer and plays a crucial role in the activated cellular signal transduction of neuregulin-1 NRG-1 Neu Differentiation Factor NDF glial growth factors GGF (NRG-1).
Studies show that the animal body developmental defect that the ErbB-2 gene inactivation has caused and neuregulin-1 NRG-1 Neu Differentiation Factor NDF glial growth factors GGF (NRG-1) gene inactivation is same in the body of gene mapping experiment.These two kinds of animals all show defective in cranial nerve ganglion and cardiac trabeculae growth.And the mice of ErbB-3 or ErbB-4 gene inactivation has and the similar or eclipsed Phenotype of mice that has knocked out neuregulin-1 NRG-1 Neu Differentiation Factor NDF glial growth factors GGF (NRG-1) or ErbB-2 gene.These data declarations ErbB-2, ErbB-3 and ErbB-4 all be in the activated signal chains of NRG-1.
Except working in growth, people ErbB-2 gene increases in the polytype human tumor of being everlasting and causes the ErbB-2 albumen overexpression of its coding.The oncogene point mutation that causes forming the ErbB-2 homodimer of discovering in early days of relevant ErbB-2 can cause significant phosphorylation conversely on the tyrosine residue of cell intracellular domain.Though do not find corresponding point mutation individuality in the human tumor of ErbB-2 gene overexpression, the up regulation of ErbB-2 has caused the formation of homodimer, this has also increased the tyrosine residue phosphorylation of its cell intracellular domain.This process is a starting point that triggers the signal cascade amplification of cell transformation or growth by hypothesis, thereby has started the tumor generation.Yet exist and overthrow the evidence that the ErbB-2 homodimer has started tumorigenic hypothesis: i) some transform not influence by the ErbB-2 mutant pair cell that engineered method improves dimer and autophosphorylation degree.Ii) some combines with the ectodomain of ErbB-2 and imagines the growth effect that the antibody that promotes homodimer to form causes the tumor cell of ErbB-2 expression, and other then stop the growth of tumor cell.These data show that the homodimerization of ErbB-2 is not enough to produce short cancer effect of cell growth or cell transformation, and other conditions may relate to specific dimer direction or conformation, are necessary.
The ErbB-2 conduct is worked with the part of the heterodimer part of ErbB-3 or ErbB-4 receptors bind.Part, neuregulin-1 NRG-1 Neu Differentiation Factor NDF glial growth factors GGF (NRG-1) has two independently receptor binding sites to be found: one has higher affinity with ErbB-3 or ErbB-4, and another has the low nonspecific affinity of all ErbB albumen.So the cell of expressing ErbB-3 or ErbB-4 and ErbB-2 can cause the heterodimer of ErbB-3 or ErbB-4 and ErbB-2 formation when being subjected to NRG-1 and influence.But when no part, whether ErbB-2 has affinity to other ErbB albumen is that unclear and such interaction may relate to the tumor generation.In the proteic receptor of all ErbB, ErbB-3 is unique, because: i) the easy and ErbB-3 formation heterodimer of ErbB-2; Ii) the conversion ratio that obtains when with ErbB-2 and ErbB-3 while transformant NIH3T3 transforms height separately than with ErbB-2; Iii) in the breast cancer cell relevant with the ErbB-2 overexpression, ErbB-3 also shows high expressed; Iv) ErbB-3 also obtains overexpression in the tumor cell from the ErbB-2 overexpression of ErbB-2 transgenic mice.
Many patents disclose ErbB-2 and/or the ErbB-3 relevant with tumor or treatment of cancer with patent application.For example, WO 00/78347 discloses prevention or cell growth inhibiting, especially the method for growth of cancer cells, this method comprises the conformation that stops or reduce the heterodimer of ErbB-2/ErbB-3 in the formation of heterodimer of ErbB-2/ErbB-3 or the interference cell, medicament with stoping or reduce the conformation of the heterodimer of ErbB-2/ErbB-3 in the formation of heterodimer of ErbB-2/ErbB-3 or the interference cell stops or cell growth inhibiting thereby reach.U.S. Patent No. 5,578,482 relate to ErbB-2 part and its functional derivatives, and these materials possess and the bonded characteristic of erbB-2 gene prod.U.S. Patent No. 5,820,859 relate to a kind of method of expressing the erbB-3 receptor agents that is used for the treatment of of seeking.U.S. Patent No. 5,968,511 relate to ErbB-3 antibody.
In the present technique field, there is demand to the ErbB-3 of the more effective and/or higher price-performance ratio relevant with oncotherapy.The present invention relates to these one side and other related needs in present technique field.
Before this invention, it is new anticancer target that the existing invention (Chinese patent application 00137771.X) of the inventor proposes erbB-3, and the inventor discovers that the formed heterodimer of ErbB-2/ErbB-3 is the main mechanism of tumor development.The inventor of this application has systematically studied the ErbB-3 proteantigen that using gene engineering is expressed: DE3-1 is an escherichia coli expression albumen; B3 is the proteic antigen fragment of eukaryotic cell expression to specific tumor as effect and the method for tumor vaccine in cancers such as prevention and treatment human breast cancer.
Summary of the invention
In one aspect, the present invention relates to prevent, treat and delay the method for mammalian body tumor.This method comprise to the mammal animal take reach prevention, treat or delay tumor required or suitable, the ErbB-3 albumen of effective dose, or its function fragment, the proteic nucleic acid of ErbB-3 of perhaps encoding, or its function fragment, thereby produce the immunoreation of anti-described tumor, and then described tumor is prevented, is treated or delayed.
In yet another aspect, the present invention relates to isolating nucleic acid fragment, this isolating nucleic acid fragment comprises the proteic ectodomain of coding ErbB-3, or the nucleotide sequence of its function fragment, the proteic ectodomain of this ErbB-3 or its function fragment comprise the aminoacid sequence described in SEQ ID NO:2 (Fig. 5) or the SEQID NO:3 (Figure 11).
In yet another aspect, the present invention relates to the protein or the peptide of purification basically, it comprises the proteic ectodomain of ErbB-3, or its function fragment, and the proteic ectodomain of this ErbB-3 or its function fragment comprise SEQ ID NO:2 or the described aminoacid sequence of SEQ ID NO:3.
In yet another aspect, the present invention relates to a kind of conjugate, this conjugate comprises: a) comprise the protein or the peptide of the proteic ectodomain of ErbB-3 or its function fragment, the proteic ectodomain of this ErbB-3 or its function fragment comprise SEQ ID NO:2 or the described aminoacid sequence of SEQ ID NO:3; B) with the proteic ectodomain of ErbB-3 or its function fragment directly or the promoter that is connected by joint, wherein promoter helps: i) affine isolated or purified conjugate; Ii) conjugate is adsorbed onto on the surface; Or iii) detect conjugate.
In yet another aspect, the present invention relates to a kind of antibody, the combining an of epitope of this antibody and the proteic ectodomain of ErbB-3 or its function fragment.The proteic ectodomain of this ErbB-3 or its function fragment comprise SEQ ID NO:2 or the described aminoacid sequence of SEQ ID NO:3.
The present invention also provides and has comprised the proteic ectodomain of ErbB-3 or its function fragment, or the nucleic acid of coding and with the pharmaceutical composition and/or the vaccine of bonded antibody of this ectodomain and function fragment thereof.
The accompanying drawing summary
Fig. 1 represents B3 cDNA sequence (SEQ ID NO:4).
Fig. 2 illustrates the Restriction Enzyme digestion situation of B3 plasmid.Swimming lane 1:1kb ladder (NEB). swimming lane 2-9: with BamHI/XbaI to the digestion of the DNA property identified.The clone on swimming lane 5, every other clone is correct clone.Swimming lane 10: the pCDNA3 carrier is digested separately with BamHI/XbaI.
Fig. 3 illustrates the structure of B3 plasmid.
Fig. 4 illustrates separation and/or purification and SDS-PAGE analysis B3 albumen.Swimming lane 1-4:BSA contrast, the corresponding application of sample amount of every swimming lane is 10ug, 5ug, 3ug, 1ug.Swimming lane 5: protein standard, 7708S, NEB.The inductive B3 protein expression of swimming lane 6-7:COS7.
Fig. 5 represents the aminoacid sequence (SEQ ID NO:2) of B3.
Fig. 6 represents DE3-1cDNA sequence (SEQ ID NO:5).
Fig. 7 represents the structure of DE3-1 plasmid.
Fig. 8 illustrates the digestion with restriction enzyme situation of DE3-1 plasmid.Swimming lane 1: the pGEX4T-1 that digests the DE3-1 that recombinated with BamHI/XhoI.Swimming lane 2: the pET32a that digests the DE3-1 that recombinated with BamHI/XhoI.Swimming lane 3:1kb ladder (NEB).
Fig. 9 illustrates the SDS-PAGE analysis result that DE3-1 expresses.Swimming lane 1: before inducing.Swimming lane 2: after inducing.Swimming lane 3: inclusion body.Swimming lane 4: the supernatant after the supersound process.
Figure 10 illustrates the proteic separation of DE3-1 and/or purification and SDS-PAGE analysis.Swimming lane 1: whole protein.Swimming lane 2-8: through the eluent of NTA histidine mark affinity column.
Figure 11 represents the aminoacid sequence (SEQ ID NO:3) of DE3-1
Figure 12 illustrates the influence of different vaccines to the sickness rate of FVB/N transgenic mice.
Figure 13 illustrates the influence (5 week) of different pharmaceutical to the mouse tumor growth.
Figure 14 illustrates the suppression ratio (5 week) of different pharmaceutical to tumor growth.
Figure 15 illustrates the influence (5 week) of DE3-1 to the mouse breast cancer growth.
Figure 16 illustrates the suppression ratio (5 week) of DE3-1 to tumor growth.
Figure 17 illustrates B2 and B3 cross immunity originality experiment (B3 albumen bag quilt).
Figure 18 illustrates B2 and B3 cross immunity originality experiment (B2 albumen bag quilt).
Embodiments of the present invention
In order to disclose clearly rather than, the detailed description of inventing to be divided into following trifle in order to limit.A. lexical or textual analysis
Unless other definition is arranged, technology and scientific terminology have the same implication that the common skill personnel with the technical field of the invention generally understand as used herein for all.Here all patents of reference, application, disclosed application and other publications all are incorporated herein by reference.If the definition that this section is set forth with this with reference in patent, application, disclosed application and other publications definition of setting forth when opposite or inconsistent, the definition that this section is set forth is better than the definition of other lists of references.
Used at this, the meaning of " " is " at least one " or " one or more than one ".
Used at this, " tumor " is meant abnormal new growth, so comprise optimum and malignant tumor.Be different from hypertrophy, after lacking primitive stimulus, tumor proliferation can be proceeded.
Used at this, " cancer " is meant the general name by the disease due to the malignant tumor of any kind.
At this, " virulent " is used for tumor, is meant primary tumor, and it has the ability of transfer, promptly lost Growth Control and Position Control simultaneously.
Used at this, " erb " refers to two kinds of oncogenes, and erb A and erb B are with erythroblastosis virus relevant (a kind of acute convertibility retrovirus).
Used at this, " immunoreation " is meant in response to the immune effect change of antigenic organism; In the vertebrates body, this process may relate to antibody and produce, the immunity of inducing cell mediation, the formation of complement activation or immunoglobulin toleration.
Used at this, " immunoreation reinforcing agent " is meant the material of energy enhancement antigen effect in causing immunoreation.
Used at this, " vaccine " is meant any compositions that is used for the active immunity prevention.Vaccine can be used for the treatment of disease on therapeutics, or in advance or infect the back and stop advancing of disease or reduce severity of disease.Typical vaccine include but not limited to this, the dead thalline of preparation virulent strain or the viable bacteria body of attenuated strain (mutation or mutant), perhaps microorganism, fungus, plant, protozoacide or metazoal derivant or product." vaccine " also comprises based on the proteins/peptides of vaccine and nucleic acid/oligonucleotide.
Used at this, " anti-tumor agents (using with the anticancer agent exchange) " is meant any medicament that is used for antineoplaston.This comprise any separately or with other compound use can alleviate, reduce, improve, prevent or maintain do not have clinical symptoms or with tumor the medicament of relevant diagnostic markers, and these medicaments can be used in this method that provides, unite use and compositions.Anti-tumor agents comprises, but be not limited only to this, anti-angiogenic agent, alkylating agent, antimetabolite, certain natural products, platinum coordination complex, amerantrone, substituted ureas, methylhydrazine derivant, adrenal cortex inhibitor, certain hormone and antagonist, anticancer polysaccharide and certain medicinal herbs extract be Chinese herbal medicine extract for example.
Used at this, " antineoplaston " is meant that any design is used for the treatment of tumor or treatment for cancer method by what alleviate or improve its symptom.The generation of prophylaxis of tumours or cancer or the treatment that alleviates its order of severity are also paid attention to.
Used at this, " anti-tumor agents (or anticancer agent) or antineoplaston " do not comprise ErbB-3 albumen or its function fragment or the coding proteic nucleic acid of ErbB-3 or its function fragment, perhaps they are used for the treatment of, but are included as all medicaments and the treatment modalities that certain mode that has known to those skilled in the art is improved tumor or cancer symptoms.
Used at this, " effective dose that is used for the treatment of the chemical compound of specified disease " is meant to be enough to improve, or reduces the consumption with the symptom of this disease association in some way.Such consumption can be used as single dose or according to its effective taking dose of prescription.This consumption possibility cure diseases, but typical situation is to take in order to improve disease symptoms.For reaching the doing well,improving of expectation, may need to take continuously.
Used at this, the meaning of " treatment " is the method that the symptom of any state, discomfort or disease is improved or have useful variation.Treatment comprises that also wherein any Drug therapy of compositions is used.
At this, be meant any alleviating by taking the symptom " improvement " that specific Drug therapy compositions reaches specific discomfort, persistent or of short duration no matter be permanent or temporary transient, need only this alleviate can give the credit to or with take compositions relation arranged.
Used at this, " antibody " is used with its wideest intended scope, as long as the many specificitys antibody that specifically comprises complete monoclonal antibody, polyclonal antibody, forms from least two kinds of complete antibodies is bi-specific antibody and show the antibody fragment of desired biological activity for example.For example, antibody can be IgM, IgG, for example IgG
1, IgG
2, IgG
3Or IgG
4, IgD, IgA or IgE.
Used at this, " antibody fragment " comprises the part of complete antibody, normally the antigen binding domain of complete antibody or variable region.The example of antibody fragment comprises Fab, Fab ', F (ab ')
2And Fv fragment; Binary; The single-chain antibody molecule; And the many specificitys antibody that forms by antibody fragment.
Used at this, " monoclonal antibody " is meant the antibody of the antibody population of homology in essence, and just, the single antibody of forming antibody population is identical, unless the few natural mutation of contingent quantity.Monoclonal antibody also is highly single-minded, only at an antigen site.Further, with the prepared product difference that typically comprises at traditional antibody (polyclonal antibody) of the different antibodies of different determinants (epitope), each monoclonal antibody is only at the single determinant on the antigen.Except its specificity, monoclonal antibody also has an advantage, and promptly they are synthetic by the hybridoma cultivation, can not polluted by other immunoglobulins.
Used at this, " polyclonal antibody " is meant the situation just as in animal body, the antibody that is produced by several bone-marrow-derived lymphocytes clones.Typically refer to and appear at the intravital antibody of immune animal, and monoclonal antibody is usually by the product of the monoclonal bone-marrow-derived lymphocyte of In vitro culture.
Used at this, " hybridoma " is meant hybrid cell, and wherein tumor cell constitutes one of germinal cell.Typical hybridoma is the hybrid cell by the suitable myeloma cell line of T lymphocyte or bone-marrow-derived lymphocyte and generation monoclonal antibody.
Used at this, " humanized antibody " be meant through modifying and contain the antibody of " people's " aminoacid sequence, so that do not cause immunoreation when being used in human body.The method for preparing this antibody is known.For example, changing the hybridoma of expressing monoclonal antibody with recombinant DNA technology makes it express the antibody of non-amino acid sequences based on people's antibody.Existing computer program is used to distinguish such zone.
Used at this, " recombination method production " is meant the production method of using the recombinant nucleic acid method.This method is with the well-known coded proteinic molecular biology method of expression of nucleic acid with cloning.
Used at this, when being meant two nucleic acid molecules, the meaning is that two nucleotide sequences can be hybridized " complementary ", preferably be lower than 25%, be more preferably and be lower than 15%, even to be more preferably being to be lower than 5%, most preferably is not have the mistake pairing at relative nucleotide place.Preferably under stringent condition, these two molecular hybridizations.
Used at this, the wrong pairing of decision percentile " stringency of hybridization " following regulation:
High stringency: 0.1xSSPE, 0.1%SDS, 65 ℃;
Medium stringency: 0.2xSSPE, 0.1%SDS, 50 ℃; (also referring to appropriate stringency)
Low stringency: 1.0xSSPE, 0.1%SDS, 50 ℃;
Be interpreted as using buffer, salt and the temperature of equity, can obtain suitable stringency.
Used at this, " carrier (or plasmid) " is meant and is used for discontinuous element that the foreign DNA transfered cell is expressed or duplicated.Select and use this kind carrier in this technical staff's technical scope, to be widely known by the people.Expression vector comprise can expressible dna carrier, its DNA effectively with regulating and controlling sequence, for example promoter region links together.Regulating and controlling sequence can influence the segmental expression of this segment DNA.So expression vector is meant that recombinant DNA or RNA constitute thing, for example plasmid, phage, recombinant virus or other carriers, in a single day they import in the appropriate host cell, causes the DNA that clones to express.Suitable expression vector is fully aware of to those skilled in the art, and comprises the carrier that can duplicate and keep free state or be integrated into the carrier of host cell gene group in eukaryotic cell and/or prokaryotic cell.
Used at this, " promoter region or promoter element " is meant transcription DNA or the RNA fragment of controlling with its DNA that effectively is connected or RNA.Promoter region comprises is enough to allow the particular sequence of RNA polymerase identification, combination and transcription initiation.This part of promoter region is meant promoter.And promoter region also comprises regulates RNA polymerase identification, combination and the active sequence of transcription initiation.These sequences can be the cis acting factors or trans acting factor responded.According to the character of regulating, promoter can be composing type or adjustment type.Consider that being used for procaryotic typical promoter comprises phage t7 and T3 promoter and similar promoter.
Used at this, " effectively connect and effectively in conjunction with " be meant nucleotide effect sequence and regulate sequence, for example promoter, enhancer, transcribe and translation termination site and other signal sequences and DNA between functional relationship.For example, make single-minded identification, combination and transcribe the RNA polymerase of this segment DNA can transcribing from initial this segment DNA of promoter for the effective physics and functional relationship that is meant between DNA and promoter that be connected of DNA and promoter, this relation.For ease of optimization expression and/or in vitro transcription, be necessary to remove, increase or change clone's 5 ' not translator units, no matter so that eliminate unnecessary, potential inappropriate substituting translation initiation codon or other be transcribe or translation skill on disturb or reduce the sequence of expressing.Additive method is right after 5 of start codon ' insertion with the ribosome binding site consensus sequence in addition, can strengthen expression.(reference example, Kozak, journal of biological chemistry (J.Biol.Chem.),
266: 19867-19870 (1991).The hope of this correction (or needs) can be decided by experience.
Used at this, " protein bound sequence " is meant to possess extensively at other albumen or peptide sequence the albumen of the single-minded binding ability of one histone or peptide sequence or specific protein or peptide sequence or peptide.
Used at this, " epitope label " is meant that it helps subsequently to the albumen of " epitope labelling " or the biochemistry and the immune analysis of peptide corresponding to the short sequence of the amino acid residue of epitope." epitope label " is to realize by additional " epitope label " sequence on the albumen coded sequence of suitable expression vector.The albumen of " epitope labelling " can use the narrow spectrum antibody of height that is produced by label to carry out affinity purification.
Used at this, " protein A or Protein G " be meant can with the bonded albumen in the Fc of many IgG isomorphys zone.Protein A or Protein G typically are present in the cell wall of some bacterial strain of staphylococcus.Should in protein A or Protein G, comprise and not influence its active conserved amino acid alternative sequence really.
Used at this, " nucleotide binding sequence " is meant to possess extensively at nucleotide sequence, the albumen or the peptide sequence of the single-minded binding ability of one group of nucleotide sequence or specific nucleotide sequence.
Used at this, " contaminated with lipid sequence " is meant to possess extensively at lipid, the albumen or the peptide sequence of the single-minded binding ability of one group of lipid or specific lipids material.
Used at this, " polysaccharide binding sequence " is meant to possess extensively at polysaccharide, the albumen or the peptide sequence of the single-minded binding ability of one group of polysaccharide or specific polysaccharide material.
Used at this, " melts combine sequence " is meant to possess extensively at metal ion, the albumen or the peptide sequence of one group of metal ion or the ionic single-minded binding ability of special metal.B. use ErbB-3 to prevent, treat or delay the method for tumor
From an aspect, the present invention relates to prevent, treat and delay the method for mammalian body tumor.This method comprise to animal take reach prevention, treat or delay tumor required or suitable, the ErbB-3 albumen of effective dose, or its function fragment, the proteic nucleic acid of ErbB-3 of perhaps encoding, or its function fragment, thereby produce immunoreation, and then described tumor is prevented, is treated or delayed at described tumor.
Method of the present invention can be used for any mammal tumor prevention, treat or delay, for example mice, home mouse, rabbit, cat, Canis familiaris L., pig, milch cow, cattle, sheep, goat, horse, monkey and other inhuman primates.Preferably, method of the present invention can be used for human tumor prevention, treat or delay.
Any can initiation immunoreactive suitable ErbB-3 albumen occurs at the tumor that will treat, prevent or delay, or its function fragment, and the proteic nucleic acid of ErbB-3 of perhaps encoding, or its function fragment can both be used for this method.The immunoreation that ErbB-3 causes may be a cellular level, and body fluid level or both have both at the same time.For example, U.S. Patent No. 5,820,859 disclosed ErbB-3 albumen, or its function fragment, the proteic nucleic acid of ErbB-3 of perhaps encoding, or its function fragment can be used for this method.In other example, derive from the ErbB-3 albumen of home mouse ErbB-3, or its function fragment, the proteic nucleic acid of ErbB-3 of perhaps encoding, or its function fragment (GenBank Accession No.U29339; With Hellyer etc., gene (Gene),
165 (2): 279-284 (1995)), Fugu rubripes ErbB-3 (GenBank Accession No.AF056116; With Gellner and Brenner, genome research (Genome Res.),
9 (3): 251-258 (1999)), people ErbB-3 (GenBank Accession No.M29366; With Kraus etc., institute of NAS periodical (Proc.Natl.Acad.Sci.U.S.A.),
86: 9193-9197 (1989)) can be used in this method.Preferably, from the ErbB-3 albumen of people's ErbB-3, or its function fragment, the proteic nucleic acid of ErbB-3 of perhaps encoding, or its function fragment is used for this method.Exist conservative nucleotide sequence to replace but not seriously influence its active any ErbB-3 albumen, or its function fragment can be used for this method.
In preferred embodiments, use the proteic ectodomain of ErbB-3 or its function fragment of effective dose, the nucleic acid of the proteic ectodomain of ErbB-3 of perhaps encoding or its function fragment.In another preferred embodiment, use the ErbB-3 albumen that effective dose comprises that the described aminoacid sequence of SEQ ID NO:1 is formed.Still in an other preferred embodiment, use the proteic ectodomain of ErbB-3 or its function fragment that effective dose comprises that SEQ ID NO:2 or the described aminoacid sequence of SEQ ID NO:3 are formed.
This method further comprises to administration immunoreation reinforcing agent.The immunoreation reinforcing agent can used ErbB-3 albumen, or its function fragment, the proteic nucleic acid of ErbB-3 of perhaps encoding, or before its function fragment, simultaneously or carry out subsequently.Typical immunostimulant comprise bacillus calmette-guerin vaccine (BCG) (Ratliff, Eur.Urol,
2: 17-21 (1992)), Corynebacterium (Lillehojet a1, Avian Dis,
37 (3): 731-40 (1993)), brucella abortus extract (Brucellaabortus extract), glucosan, levamisole, tilorone, enzyme, avirulent virus, polysaccharide, the medicinal herbs extract is Chinese herbal medicine extract for example.
ErbB-3 albumen, or its function fragment, the proteic nucleic acid of ErbB-3 of perhaps encoding, or use prescription, dosage and the route of administration of its function fragment during especially as pharmaceutical composition, can be determined according to the method known to the present technique field.(referring to, for example, Lei Mingdun: the pharmaceutics science with put into practice (Remington:The Science and Practice of Pharmacy), AlfonsoR.Gennaro (editor), Mack publishing house, in April, 1997; Therapeutic peptide and albumen: prescription, processing and transmission system (Therapeutic Peptides and Proteins:Formulation, Processing, and Delivery Systems), Banga, 1999; With the development (Pharmaceutical Formulation Development of Peptides andProteins) of peptide and albumen pharmaceutical formulation, Hovgaard and Frkjr (editor), Taylor﹠amp; Francis company, 2000; The medical application of liposome (Medical Applications ofLiposomes), Lasic and Papahadjopoulos (editor), Elsevier Science, 1998; Gene therapy study course (Textbookof Gene Therapy), Jain, Hogrefe﹠amp; Huber publishing house, 1998; Adenovirus: the basic biology of gene therapy (Adenoviruses:Basic Biology to Gene Therapy), 15 volumes, Seth, Landes Bioscience, 1999; The drug design of bio-pharmaceuticals and development (Biopharmaceutical Drug Design and Development), Wu-Pong and Rojanasakul (editor), Humana publishing house, 1999; Blood vessel on the therapeutics takes place: to clinical (Therapeutic Angiogenesis:From Basic Science to theClinic), 28 roll up Dole etc. (editor), Springer-Verlag New York, 1999 from basic science).ErbB-3 albumen, or its function fragment, the proteic nucleic acid of ErbB-3 of perhaps encoding, or its function fragment can be mixed be used for oral, rectally, local application, the inhalation medication, oral cavity medicine (for example Sublingual), injecting drug use is (for example, subcutaneous, intramuscular, Intradermal, venous), percutaneous dosing or other route of administration that is fit to.Under any given situation, only route of administration will depend on character and the order of severity and the used specific ErbB-3 albumen of the situation of will treating, or its function fragment, the proteic nucleic acid of ErbB-3 of perhaps encoding, or the character of its function fragment.
ErbB-3 albumen, or its function fragment, the proteic nucleic acid of ErbB-3 of perhaps encoding, or its function fragment can be used for mammiferous any suitable position.Preferably, ErbB-3 albumen, or its function fragment, the proteic nucleic acid of ErbB-3 of perhaps encoding, or its function fragment is used for the original position administration of tumor, promptly is used in tumorigenic place or its contiguous position.And preferably, this method further is included in tumorigenic original position and uses the immunoreation reinforcing agent.
ErbB-3 albumen, or its function fragment, the proteic nucleic acid of ErbB-3 of perhaps encoding, or its function fragment can use separately.Alternatively and preferred mode be ErbB-3 albumen, or its function fragment, the proteic nucleic acid of ErbB-3 of perhaps encoding, or acceptable carrier or excipient use jointly on its function fragment and the Drug therapy.Any suitable Drug therapy acceptable carrier or excipient can be used for this method.(referring to, for example, Lei Mingdun: the pharmaceutics science with put into practice (Remington:The Science and Practice of Pharmacy), Alfonso R.Gennaro (editor), Mack publishing house, in April, 1997).
This method can be used separately.Perhaps, this method can with other anti-tumor method, for example radiotherapy, chemotherapy and operative treatment are united use.This method also can be united use with other anti-tumor agents.Other antineoplaston or medicament can be used in ErbB-3 albumen, or its function fragment, the proteic nucleic acid of ErbB-3 of perhaps encoding, or before the use of its function fragment, among or afterwards.For embodiment, ErbB-3 albumen, or its function fragment, the proteic nucleic acid of ErbB-3 of perhaps encoding, or its function fragment can use jointly with anti-tumor agents.
Any suitable anti-tumor agents can be used for this method.Typical anti-tumor agents comprise anti-angiogenic agent (referring to, for example, Auerbach and Auerbach, Pharmacol.Ther,
63 (3): 265-311 (1994)), alkylating agent, antimetabolite, certain natural products, platinum coordination complex, amerantrone, substituted ureas, methylhydrazine derivant, adrenal cortex inhibitor, certain hormone, antagonist, oncogene inhibitor, tumor suppression subbase because of or albumen, antioncogene antibody, antioncogene antisense oligonucleotide, anticancer cell surface antigen antibody and other anti-tumor vaccine.
Coding ErbB-3 proteic nucleic acid, or its function fragment, or any tumor suppression subbase is because of being used with the form of naked DNA, complex DNA, cDNA, plasmid DNA, RNA or other mixture composition as gene transfer system.In another embodiment, the proteic nucleic acid of coding ErbB-3, or its function fragment, or the tumor suppression subbase is because of being contained in the viral vector.Any viral vector that is suitable for gene therapy can be united in the use at this and used.For example, adenovirus vector (U.S. Patent No. 5,869,305), monkey disease poisonous carrier (U.S. Patent No. 5,962,274), condition replication form human immune deficiency type viral vector (U.S. Patent No. 5,888,767), retrovirus retrovirus, simian virus-40, herpes simplex virus amplicon vector and vaccinia virus vector can use.And these genes can change the non-virus carrier system over to, liposome for example, and in liposome, lipid protects DNA or other biological substance not oxidated in coacervation process.
This method can be used for the treatment of, prevents or delay any suitable tumor or cancer.Preferably, this method is used for the treatment of, prevents or the interaction that delays any suitable wherein ErbB-2 and ErbB-3 is the crucial paathogenic factor or the tumor or the cancer of the factor of reinforcement.For example, this method can be used for the treatment of, prevention or delay the adrenal gland, anus, auditory nerve, biliary ductuli, bladder, bone, brain, breast, bruccal, the central nervous system, cervix uteri, colon, ear, endometrium, esophagus, eyes, eyelid, fallopian tube, gastrointestinal tract, incidence, heart, kidney, larynx, liver, lung, lower jaw, the lower jaw lateral condyle, upper jaw bone, mouth, nasopharynx, nose, the oral cavity, ovary, pancreas, the parotid gland, penis, auricle, hypophysis, prostate, rectum, retina, salivary gland, skin, small intestinal, spinal cord, stomach, testis, thyroid, tonsil, urethra, vagina, eighth cranial nerve and vaginal orifice tumor.Preferably, this method can be used for the treatment of, prevents or delay breast, ovary, stomach, prostate, colon and pulmonary's cancer.More preferably, this method is used for the treatment of, prevents or delays breast carcinoma.
According to the present invention, no matter separately or with other medicament, carrier or excipient to unite the ErbB-3 albumen of use, or its function fragment, the proteic nucleic acid of ErbB-3 of perhaps encoding, or its function fragment, can system be used for any route of administration, such as injection in the spongy body, subcutaneous injection, intravenous injection, intramuscular injection, intradermal injection, oral or local application.This method can be used the ejection preparation with the antiseptic that contains interpolation of unit dosage form, ampoule injection or multi-dose container.This prescription can adopt the suspension in oil or the water quality excipient, solution or emulsion form and can comprise prescription reagent, for example suspending agent, stabilizing agent and/or dispersant.Active component also can be a powdery, so as before use with the carrier, aseptic water or other solvent that does not contain thermal source that are fit to.Local application of the present invention can adopt foam, gelinite, frost, ointment, transdermal ointment or ointment.
May be used for Drug therapy acceptable composition of the present invention and method and be included in, but be not limited only to United States Patent(USP) Nos. 5,736,154; 6,197,801 B1; 5,741,511; 5,886,039; 5,941,868; 6,258,374 B1; With 5,686, in 102.
The big young pathbreaker of treatment or prevention Chinese medicine therapeutic dose changes with the order of severity and the route of administration of the situation of treatment.Dosage and dose frequency also will change according to patient self age, body weight, disease condition and reaction.
Please remember how and when the doctor in charge should know because drug toxicity or disadvantageous effect stop, interruption is maybe adjusted to low dosage with treatment.On the contrary, the doctor how and when should know because clinical effect deficiency (having got rid of the toxicity seondary effect) is adjusted to high level with treatment.
Any suitable route of administration can be used.Dosage form comprises tablet, lozenge, cachet, dispersion, suspension, solution, capsule, ointment and similar form.Reference, Lei Mingdunshi Drug therapy science.
In actual applications, no matter separately or with other medicament to unite the ErbB-3 albumen of use, or its function fragment, the proteic nucleic acid of ErbB-3 of perhaps encoding, or its function fragment, can according to conventional medicament treat hybrid technology as active component with form tight interpolation mixture such as the Drug therapy carrier or the excipient of beta-schardinger dextrin-and 2-hydroxyl-propyl group-beta-schardinger dextrin-.Carrier is according to the expectation occupation mode, and part or injecting drug use are taked multiple formulation forms.When preparation is used for the compositions of injection, for example intravenous injection or intravenous infusion, identical pharmacy medium can use, and water, ethylene glycol, oil, buffer, sugar, antiseptic, liposome and other have the medium known to the people of present technique field technical ability.The example of injectable composition includes, but not limited to glucose, normal physiological saline solution or other solution of 5%w/v.No matter unite use separately or with other medicament, treat the ErbB-3 albumen of administration, its function fragment, the proteic nucleic acid of ErbB-3 of perhaps encoding, or the accumulated dose of its function fragment can contain volume at a bottle and uses from 1 milliliter to 2000 milliliters intravenous fluid.According to used accumulated dose, the diluent liquid volume will change to some extent.
The present invention also provides the test kit that carries out therapeutic scheme of the present invention.This test kit comprise place one or more containers no matter separately or with other medicament unite the ErbB-3 albumen of the treatment effective dose of use, or its function fragment, the proteic nucleic acid of ErbB-3 of perhaps encoding, or its function fragment.Preferred medicament forms is and physiological saline solution that the acceptable sterile liquid is united use in glucose solution or buffer soln or other pharmacy.Compositions also can lyophilizing or drying; In this case, test kit further can optionally comprise the pharmaceutically acceptable solution that is stored in the container, and preferred sterile solution forms injection solution to reassemble into complex.Typical pharmaceutically acceptable solution is normal saline and glucose solution.
In another embodiment, test kit of the present invention further comprises the entry needle of one piece of preferred aseptic packaging that is used for injectable composition or the ethanol liner of syringe and/or packing.Being suitable for doctor or patient uses the indicative explanation of this compositions optionally to be included in above the test kit.The proteic ectodomain of C.ErbB-3 or its function fragment, the nucleic acid of the proteic ectodomain of ErbB-3 of perhaps encoding or its function fragment
From another aspect, the present invention relates to isolating nucleic acid fragment, this isolating nucleic acid fragment under low, the high stringent condition of neutralization with coding ErbB-3 proteic ectodomain, or the nucleotide sequence of its function fragment or the hybridization of its complementary strand, the proteic ectodomain of this ErbB-3, or its function fragment is included in the aminoacid sequence described in SEQ ID NO:2 or the SEQ ID NO:3.
In a preferred embodiment, isolating nucleic acid fragment under high stringent condition with coding ErbB-3 proteic ectodomain, or the nucleotide sequence of its function fragment or the hybridization of its complementary strand, the proteic ectodomain of this ErbB-3, or its function fragment is included in the aminoacid sequence described in SEQ ID NO:2 or the SEQ ID NO:3.In the another one embodiment preferred, isolating nucleic acid fragment comprises the proteic ectodomain of coding ErbB-3, or the nucleotide sequence of its function fragment or its complementary strand, the proteic ectodomain of this ErbB-3, or its function fragment is included in the aminoacid sequence described in SEQ ID NO:2 or the SEQ ID NO:3.Still in the another one embodiment preferred, isolating nucleic acid fragment is included in the pairing nucleotide sequence of aminoacid sequence or its complementary strand of expression among SEQ ID NO:4 (Fig. 1) or the SEQ ID NO:5 (Fig. 6).
Isolating nucleic acid fragment can be any suitable form.For example, isolating nucleic acid fragment can comprise DNA, RNA, PNA or derivatives thereof.In addition, isolating nucleic acid fragment can comprise DNA and RNA or derivatives thereof.Isolating nucleic acid fragment can be single stranded form and be suitable for hybridization analysis.In addition, isolating nucleic acid fragment also can be double chain form and can degeneration become single-stranded structure before hybridization analysis.
Isolating nucleic acid fragment can comprise any oligonucleotide or the nucleic acid chains that comprises hereditary information coding and/or abiogenous structure.Isolating nucleic acid fragment can comprise non-natural structure, for example non-natural base, for example hypoxanthine and xanthine, non-natural saccharide, for example 2 ,-methoxyl group nucleic acid, or non-natural phosphodiester bond, for example methyl phosphonate, phosphoro ester and peptide.
Isolating nucleic acid fragment can produce with any suitable method.For example, isolating nucleic acid fragment can by chemosynthesis (referring to, Ausubel (editor) molecular biology popular approach (CurrentProtocols in Molecular Biology), 2.11. the synthetic and purification (Svnthesisand purification of oligonucleotides) of oligonucleotide, John Wiley﹠amp; Sons company (2000)), from nature material, separate, by recombination method produce or by said method in conjunction with producing.Preferably, produce isolating nucleic acid fragment with recombination method.
Isolating nucleic acid fragment can give labelling because of various objectives, for example help to detect, purification and/or with the adhering to of surface.Label can be chemical, enzyme, immunogenicity, radioactive, fluorescigenic, luminous or FRET (fluorescence resonance energy transfer) labelling (FRET).
The present invention also provides the plasmid that comprises above-mentioned nucleic acid fragment.The cell that comprises above-mentioned plasmid further is provided.Can use any suitable cell, for example, bacterial cell, yeast cells, fungal cell, plant cell, insect cell, zooblast and people's cell.
In yet another aspect, the present invention relates to produce the proteic ectodomain of ErbB-3, or the method for its function fragment, this method is included in the proteic ectodomain of cellular expression ErbB-3, or cultivate above-mentioned cell under the condition of its function fragment and reclaim the proteic ectodomain of ErbB-3 of expressing, or its function fragment.
In yet another aspect, the present invention relates to the protein or the peptide of purification basically, it comprises the proteic ectodomain of ErbB-3, or its function fragment, comprises SEQ ID NO:2 or the described aminoacid sequence of SEQID NO:3.Can produce the proteic ectodomain of ErbB-3 with any suitable method, or its function fragment.For example, the proteic ectodomain of ErbB-3, or its function fragment can separate from nature material by chemosynthesis, with recombination method produce or by said method in conjunction with production.Preferably, produce the proteic ectodomain of ErbB-3 with recombination method, or its function fragment.
In yet another aspect, the present invention relates to a kind of conjugate, this conjugate comprises: a) protein or the peptide of the proteic ectodomain of a kind of ErbB-3 of comprising or its function fragment (comprising the aminoacid sequence described in SEQ ID NO:2 or the SEQID NO:3); B) with the proteic ectodomain of ErbB-3 or its function fragment directly or the promoter that is connected by joint, wherein promoter helps: i) affine isolated or purified conjugate; Ii) conjugate is adsorbed onto on the surface; Or iii) detect conjugate.This conjugate can be a kind of fusion rotein.When this conjugate was a kind of fusion rotein, promoter can also be i) Subcellular Localization sequence in cell after synthetic; The ii) sequence of enhance immunity originality; Or the iii) tumor antigen of other protide.In addition, ErbB-3 albumen or its function fragment can be connected by enough additive methods with promoter.When conjugate was fusion rotein, the nucleic acid of coding conjugate was also provided.
Conjugate can produce with chemical coupling, for example connects by mercaptan, but preferably produces with recombination method as fusion rotein.In fusion rotein, peptide or its fragment are aminoterminal (N-end) or the c-terminuses (C-end) that is connected to the proteic ectodomain of ErbB-3 or its function fragment.In the chemical coupling thing, peptide or its fragment can be connected Anywhere, so that coupling reaction is affected, and numerous peptides may occur or its fragment is connected to an ErbB-3 albumen, or its function fragment, or numerous on them.
Coupling reaction can be known to those skilled in the art any method affect.As described below, coupling reaction can be subjected to the chemical method influence, by covalent bond, ionic bond or other suitable keys.For example, can use the reagent and the method for disclosed coupling reaction in WO 01/02600.
In certain embodiments, conjugate is a fusion rotein, and this conjugate can give isolated or purified by the albumen of fusion rotein or the affine absorption between fragments of peptides and the affine adsorption component.Any isolated or purified fusion rotein that can be used in of affinity interaction.Affinity interaction as described herein, but is not limited only to this, is albumen/albumen, albumen/nucleotide, albumen/lipid, albumen/polysaccharide or albumen/intermetallic interaction.
In other embodiments, conjugate can be adsorbed onto on the surface.More preferably, conjugate can be adsorbed onto on the surface by the affine absorption between the affine adsorption component of promoter on the conjugate and absorption surface.Any absorption conjugate that can be used in of affinity interaction comprises albumen/albumen, albumen/nucleotide, albumen/lipid, albumen/polysaccharide or albumen/intermetallic interaction.
In yet another aspect, the present invention relates to a kind of pharmaceutical composition, this pharmaceutical composition comprises an isolating nucleic acid fragment and pharmaceutically acceptable carrier or excipient, this isolating nucleic acid fragment under low, the high stringent condition of neutralization with coding ErbB-3 proteic ectodomain, or the nucleotide sequence of its function fragment or the hybridization of its complementary strand, the proteic ectodomain of this ErbB-3, or its function fragment comprises the aminoacid sequence that SEQ ID NO:2 or SEQ ID NO:3 represent.Preferably, this isolating nucleic acid comprises the proteic ectodomain of coding ErbB-3, or its function fragment, comprises nucleotide sequence or its complementary strand of the aminoacid sequence that SEQ ID NO:2 or SEQ ID NO:3 represent.Pharmaceutical composition may further include immunoreation reinforcing agent and/or anti-tumor agents.Comprise above-mentioned isolating nucleic acid fragment separately or also provided with the blended vaccine of immunoreation reinforcing agent.
In yet another aspect, the present invention relates to a kind of pharmaceutical composition, this pharmaceutical composition comprises protein or peptide and a kind of pharmaceutically acceptable carrier or the excipient of purification basically, this protein or peptide comprise the proteic ectodomain of ErbB-3, or its function fragment, comprise the aminoacid sequence that SEQ IDNO:2 or SEQ ID NO:3 represent.Pharmaceutical composition may further include immunoreation reinforcing agent and/or anti-tumor agents.Comprise the protein of above-mentioned purification basically or peptide separately or also provided with the blended vaccine of immunoreation reinforcing agent.
In yet another aspect, the present invention relates to a kind of antibody, the proteic ectodomain of this antibody and ErbB-3 or its function fragment comprise an epitope combination of the aminoacid sequence that SEQ ID NO:2 or SEQ ID NO:3 represent.Preferably, this antibody specificity ground and the proteic ectodomain of ErbB-3 or its function fragment comprise an epitope combination of the aminoacid sequence that SEQ ID NO:2 or SEQ ID NO:3 represent.
Antibody can be any suitable form.For example, antibody can be monoclonal, polyclonal, chimeric, strand, the people's or humanized antibody (for example, referring to, U.S. Patent No. 5,968,511).Multi-form antibody can prepare according to any means known in the art (for example, referring to, Coligan etc. (editor), immunology popular approach (Current Protocols inImmunology), John Wiley﹠amp; Sons company (2000)).Comprise above-mentioned antibody separately or also provided with anti-tumor agents hybrid medicine compositions and a kind of pharmaceutically acceptable carrier or excipient.
Embodiment
Be the typical embodiment that only is used for illustration purpose below.
The present inventor finds that B3, DE3-1 are as effect and the method for tumor vaccine in cancers such as treatment human breast cancers.
The present inventor finds that B3 has significant reduction effect as tumor vaccine in the incidence rate to tumors such as human breast cancers.
The present inventor provides with B3 has the method for remarkable reduction incidence rate effect as tumor vaccine in high-risk crowds' such as prevention human breast cancer tumor.
The present inventor finds that B3, DE3-1 also have significant delay action as tumor vaccine to the time of origin of tumors such as human breast cancer.
The present inventor finds that B3, DE3-1 have significant inhibitory effect as tumor vaccine to growth of tumor such as human breast cancers.
The present inventor provides a kind of method that suppresses growth of cancer cells such as breast carcinoma.This method is to reply to form by body immunoreactive to realize.
Above-mentioned cell can be a tumor cell, more can be people's the breast cancer cell and the cancerous cell of other ErbB-2/ErbB-3 high expresseds.
Realize said method according to the present invention, be the ErbB-3 proteantigen of expressing with a kind of using gene engineering: DE3-1 is an escherichia coli expression albumen; B3 is proteic antigen of eukaryotic cell expression or the ErbB-3 antigen that produces with additive method, and ErbB-3 antigen can be ErbB-3 molecule or part fragment.
Under a kind of typical situation, be used for treatment for cancer such as breast carcinoma with the ErbB-3 vaccine that produces in every way of doses and can suppress growth of tumor.
Above-mentioned described cancer comprises breast carcinoma, ovarian cancer, gastric cancer, carcinoma of prostate, rectal cancer and pulmonary carcinoma etc.
In order more to be expressly understood aforementioned invention, below describe in detail.One. the preparation of experiment material and method (one) B3 and DE3-1 vaccine
In this research, related vaccine comprises with outer albumen of ErbB-2 cell membrane and the outer protein part fragment of film, is called B2, SD32 here.The outer proteic part fragment of ErbB-3 cell membrane outskirt protein molecular and film is a laboratory sample, is called B3, DE3-1 here; More than four kinds of vaccines prepare by Zesheng Science and Technology Development Co Ltd, Shanghai.The preparation method of B3 and DE3-1 is as follows:
1.B3 preparation:
The B3 gene is the proteic cDNA sequence of ErbB-3 cell membrane outskirt of coding, sees Fig. 1; With the PCR method amplification, primer sequence is
Wherein italicized item is the flag sequence.
Genes of interest is cloned in the pMD-18T carrier behind pcr amplification, and transformant is (see figure 2) after enzyme action and order-checking evaluation correctly, cuts out with BamHI/SalI, is connected among the pCDNA3BamHI/xhoI.
The foundation of efficient expression engineering and screening: the engineering bacteria clone that learn from else's experience PCR and enzyme action are identified, carry out 15%SDS-PAGE electrophoresis, thin slice scan analysis, Western-blotting evaluation, obtain a strain through repeated screening and stablize the high-expression target proteins engineering bacteria.The B3 protein purification, affinitive layer purification is seen Fig. 4.The B3 purifying protein is through determined amino acid sequence and destination protein, and aminoacid sequence is seen Fig. 5.
2.DE3-1 preparation
The pcr amplification genes of interest is the outer proteic segment cDNA sequence (the cDNA sequence is from Genebank) of coding ErbB-3 film, and sequence is seen Fig. 6; The structure of expression plasmid: target gene fragment is cut out with BamHI/XhoI from pGEX4T-1 carrier (Phamacia company), connect among pET32a carrier (Novagen company) BamHI/XhoI, this albumen is expressed with the T7 promoters driven, N end and Trx.Tag, HisTag and S-Tag merge, and collection of illustrative plates is seen Fig. 7.Fig. 8 is seen in the checking of plasmid construction enzyme action.
The DE3-1 protein expression: change plasmid over to the BL21 bacterial strain, inoculating strain spends the night in 5ml LB+AP; Be inoculated at 1: 100 among the warm LB+AP, 37 ℃, 2.5-3 hrs (OD=0.6); Induce 37 ℃ through IPTG, 3hrs or 30 ℃, 8hrs; 4 ℃ centrifugal, 6K, 10min; Remove supernatant, precipitation is put on ice; Suspend the back ultrasonication with PBS cold, that 1/20 bacteria liquid is long-pending; 4 ℃ centrifugal, and 12K, 10min can get the destination protein (see figure 9) of a large amount of 34KD.The DE3-1 protein purification: DE3-1 albumen appears in the inclusion body, behind the 6M guanidine hydrochloride dissolution, carries out dialysis NTA-O buffer (Histag purification solution), and renaturation is all right.With Histag affinity chromatograph column purification (available from betting office) Figure 10, purification DE3-1 albumen is through determined amino acid sequence, and is consistent with the destination protein sequence, aminoacid sequence Figure 11.(2) the anti-tumor effect study of B3 and DE3-1
1.B3 and DE3-1 is to tumorigenic preventive effect
Select the 8-10 FVB/N commentaries on classics neu dna murine (available from Jackson Lab.USA) in age in week for use, animal is divided into five groups, every group 40, be respectively matched group, B2, SD32, B3 and DE3-1 group, after using BSA, B2, SD32, B3 and DE3-1 and complete Freund's adjuvant (CFA, complete Freud ' s adjuvant is available from Sigma company) to mix respectively, per 20 days lumbar injections once, totally 7 times.BSA, B2, SD32, B3 and DE3-1 vaccine dose are respectively 10,5,10,5,10 μ g//times.Check incidence weekly one time.A situation arises to determine tumor, and carry out statistical analysis.
2.B3 to the immunotherapy of tumors effect
The transplanted tumor model is selected the FVB/N transgenic mice spontaneous tumor that detects neu albumen high expressed through SABC for use, gets about 1000mm
3Left and right sides tumor mass is worn into individual cells with nylon wire with tumor mass, and every FVB/N transgenic mice injection cell concentration is 5 * 10
6Individual, injection inoculation under the mammary gland.Inoculation back about 10-14 days, matched group can touch (＞5mm) tumor occurs, modeling i.e. success.
Experiment is grouped into matched group, does not do any processing; SD32 experimental group, B3 experimental group begin to treat with SD32 and B3 vaccine after inoculation 24 hours, respectively above-mentioned vaccine are adsorbed on the Al (OH) of 0.1mg/ml
3On, the subcutaneous multi-point injection of mice; Whenever biweekly, totally three times; Medication for the third time finishes experiment after 14 days.Check incidence weekly one time, measure the tumor size weekly, with gross tumor volume (major diameter * minor axis with vernier caliper measurement
2/ 2) represent its size, and paint tumor growth curve.
Experiment end back taking-up tumor is weighed and is calculated suppression ratio, suppression ratio=[(matched group tumor weight-experimental group tumor weight)/matched group tumor weight] * 100
3. various dose DE3-1 studies the immunotherapy of tumors effect
Animal and transplanted tumor model production method: the same (B3 and DE3-1 vaccine are to immunotherapy of tumors effect research).It is that the transplanted tumor model does not add any processing, negative control group is injection histag albumen that animal is respectively the blank group; Positive controls is with amycin (Shantou Mingzhi medicine company limited) treatment, and the DE3-1 experiment component is for being 5 μ g, 20 μ g, the processing of 80 μ g dosage.
Inoculate after 1 day positive controls mice, lumbar injection amycin, 2.2mg/Kg, continuous use 7 days; Negative control group mouse peritoneal injection histag albumen+Al (OH)
3DE3-1 experimental group, DE3-1 vaccine are adsorbed on the Al (OH) of 0.1mg/ml
3On, immunization therapy is carried out in the subcutaneous multi-point injection immunity of mice, per two all medications once, totally three times.End is tested in medication for the third time after 14 days.Check incidence weekly one time, measure the tumor size with vernier caliper measurement, with gross tumor volume (major diameter * minor axis
2/ 2) represent its size, and paint tumor growth curve, carry out statistical analysis.
Experiment end back taking-up tumor is weighed and is calculated suppression ratio, and suppression ratio=[(matched group tumor weight-experimental group tumor weight)/matched group tumor weight] * 100 carries out statistical analysis.
4.B2 and B3 cross immunity originality experiment
With B2 albumen and the immune FVB transgenic mice of B3 albumen difference, immunity was got blood after ten days, surveyed its antibody titer with the ELISA method.B2 and B3 with the 0.3ug/ hole wrap quilt respectively, measure B2 and B3 and the B2 and the B3 standard serum of dilution in 1: 1000 on each plate respectively, hatch 30 minutes at 37 ℃, the back is with 1%BSA sealing, adds with two anti-, develops the color 15 minutes with DAD, the Bio-Rad microplate reader, 450nm detects.Two. experimental result and discussion
1.B3 and DE3-1 presses down, and tumor effect study experimental result sees Table 1, Figure 12
Table 1.B3 and DE3-1 vaccine tumor suppression effect study experimental result number of packet (only) treatment dosage (μ g//time) tumour time of origin (week) Tumor incidence (%) negative control group 40 BSA+CFA 10 19 37.5B2 experimental group 40 B2+CFA 5 21 12.5SD32 experimental group 40 SD32+CFA 10 22 10B3 experimental group 40 B3+CFA 5 20 12.5DE3-1 experimental group 40 DE3-1+CFA 10 23 35
This experiment purpose is whether to understand B3 and DE3-1 vaccine to the preventive effect that has to tumor.Selecting the FVB/N transgenic mice for use is that this transgenic mice changes in the mice body at the rat wild type neu cDNA of mice breast disease virus promoter control, makes neu albumen high expressed, spontaneous generation breast carcinoma in 5-8 month, and incidence rate is about 50%.This transgenic mice pathogenic process and histological type are similar to the human breast cancer pathogenic process.Therefore, be applied to when clinical, may be more effective.Sample is 40 every group, selects so big sample size for use, and purpose is to guarantee that every group is sent out rate number＞10, makes it have statistical significance.The selection of dosage is according to the preliminary experiment result and fixed.
With BSA, B2, B3, SD32, DE3-1 difference immune transgenic mice, from chart, since negative control group be 37.5% tumor generation tumor incidence rate was arranged in 19 weeks; And use SD32, and B3, the time that B2 group tumor begins to take place was respectively for the 21st, 22 and 20 weeks, and the incidence rate of tumor is respectively 10%, 12.5%, 12.5%, and SD32 is described, and B3, B2 vaccine have significant inhibitory effect (P＜0.025 to tumor; x
2Check), simultaneously, they make the time of origin of tumor that delay also be arranged.DE3-1 group is more late than matched group tumor time of origin, but the tumor incidence rate is 35% to compare (P＞0.05 that do not have significant difference with matched group; x
2Check).
2.B3 and DE3-1 vaccine Graft Versus Tumor research experiment result
B3 vaccine Graft Versus Tumor research experiment the results are shown in Table two and Figure 13-14
Table 2.B3 and DE3-1 vaccine Graft Versus Tumor research experiment result packet are handled gross tumor volume (mm
3) tumor weight (g) suppression ratio (%) negative control group histag albumen+Al (OH)
37849.8 ± 849.8 5.76 ± 0.55SD32 experimental group SD32+Al (OH)
34246.5 ± 540.6 3.28 ± 0.36 46B3 experimental group B3+Al (OH)
35271.8 ± 658.9 3.13 ± 0.33 33
The artificial effect of determining the B3 vaccine at oncotherapy of invention is used for the transplanted tumor model with the B3 vaccine and carries out immunization therapy research.
Table 2 and Figure 13-14 is the influences of different vaccines to the mouse tumor growth, shows that SD32, B3 are respectively the suppression ratio of tumor growth: 46%, 33%, show that they all have remarkable inhibitory action (P＜0.01 to growth of tumor; The t check).
3.DE3-1 vaccine Graft Versus Tumor research experiment result
For the DE3-1 that further determines various dose to the immunization therapy effect of tumor growth and be to use clinically to seek suitable therapeutic dose, experimental group is with 5 μ g, 20 μ g, 80 μ g//time immune mouse, experimental result sees Table 3 and Figure 15-16.
Table 3.DE3-1 vaccine Graft Versus Tumor experimental result number of packet is handled gross tumor volume (mm
3) tumor weight (g) suppression ratio % blank group 8 6742.9 ± 657.8 4.769 ± 0.56 negative control group 8 histag albumen+Al (OH)
36476.9 ± 567.9 4.461 ± 0.52 positive controls 8 ADR 2.2mg/kg 4603.1 ± 478.3 3.564 ± 0.42 25.3DE3-1 experimental grouies, 8 80 μ g DE3-1+Al (OH)
34810.8 ± 460.5 3.658 ± 0.37 26.3DE3-1 experimental grouies 8 20 μ g DE3-1+Al (OH)
34715.0 ± 434.8 3.455 ± 0.41 28.9DE3-1 experimental grouies 85 μ g DE3-1+Al (OH)
35563.7 ± 600.6 3.687 ± 0.45 22.4
Substantially is consistent to the growth of tumor suppression ratio with survey volume result from the DE3-1 various dose, and it is best that DE3-120 μ g dosage group suppresses effect, reaches about 28.9%.Experiment is taken out tumor after finishing to put to death mice, weigh, and the statistical analysis positive controls, each dosage group and negative control and blank have marked difference (P＜0.001, t test).They are 5 μ g when the 6th week, experiment finished, 20 μ g, and 80 μ g dosage groups are respectively 26.3%, 22.4% and 28.9% to the suppression ratio of tumor
4.B2 and B3 cross immunity originality experiment
The experiment of B2 and B3 cross immunity originality is whether to have cross immunity originality between the two for B2 and B3 albumen that understanding belongs to a family.The results are shown in Figure 17-18, B2 and B3 do not have cross immunity originality between the two as can be known by the result.Three. brief summary
In this research, new generation vaccine B3 and DE3-1 that we have found to design based on a new anticancer target ErbB-3 has that prophylaxis of tumours is had an effect and tumor is had the immunization therapy effect and has wide application prospect.
In research in the past, in part adenocarcinoma, exist the ErbB-2 receptor of high expressed, the past think always their form homodimer and and cancer close contact arranged.Think that the ErbB-2 high expressed is the main cause that part adenocarcinoma takes place, reason is 1) there is the amplification of ErbB-2 gene in ErbB-2 and causes the high expressed of ErbB-2,2 in tumor cells such as breast carcinoma, ovarian cancer) high expressed of ErbB-2 caused the phosphorylation in its endocellular function district to influence the interaction of endocellular signal molecule Shc and ErbB-2; 3) with wild type ErbB-2 transfection fibroblast, cause cell transformation; 4) can strengthen the ErbB-2 variant that the ErbB-2 homodimer forms and also can strengthen its cell transformation vigor.
And the inventor finds that before this ErbB-3 is another the new anticancer target outside the ErbB-2, and the high expressed that the inventor illustrates the ErbB-2 receptor causes the heterodimer of ErbB-2 receptor and the formation of ErbB-3 receptor to be only the reason that cancer takes place.The discovery of this target makes us that new anticancer method arranged again: with ErbB-3 cell membrane outskirt albumen is prevention and the treatment that anti-cancer vaccine is used for cancer, makes the incidence rate of breast carcinoma reduce and the effect of inhibition tumor growth.
Just be based on and causing ErbB-2 relevant research to take place with kinds of tumors to the ErbB-2 high expressed, and be the immense success of target Humanized monoclonal antibodies-herceptin at ErbB-2, yet because ErbB-2 and ErbB-4 receptor are at the coexpression of myocardial cell, cause the formation of ErbB-2 receptor and ErbB-4 receptor heterodimer, this heterodimer is extremely important to normal configuration and the function of keeping myocardial cell, therefore may destroy myocardial cell at the anticarcinogen of ErbB-2 receptor and cause heart failure, then not have this side effect at the anticarcinogen of ErbB-3 receptor.Thereby ErbB-3 is extremely important as the application process of specific tumour vaccine in prevention such as breast carcinoma, ovarian cancer, gastric cancer, carcinoma of prostate, rectal cancer and pulmonary carcinoma and treatment.
The foregoing description only is used for illustrative purpose, is not in order to limit scope of the present invention.To multiple variation recited above is possible.Because the modifications and variations to the above embodiments are conspicuous to those skilled in the art, so the present invention only is subjected to the scope restriction of appending claims.
Sequence table＜110〉Zesheng Science and Technology Development Co Ltd, Shanghai＜120〉take ERBB-3 as the basic method and composition that is used for oncotherapy＜130〉52401-20003.00＜160〉11＜170〉FastSEQ for Windows Version 4.0＜210〉1＜211〉1342＜212〉PRT＜213〉homo sapiens (Homo sapiens)＜400〉1Met Arg Ala Asn Asp Ala Leu Gln Val Leu Gly Leu Leu Phe Ser Leu, 15 10 15Ala Arg Gly Ser Glu Val Gly Asn Ser Gln Ala Val Cys Pro Gly Thr
20 25 30Leu?Asn?Gly?Leu?Ser?Val?Thr?Gly?Asp?Ala?Glu?Asn?Gln?Tyr?Gln?Thr
35 40 45Leu?Tyr?Lys?Leu?Tyr?Glu?Arg?Cys?Glu?Val?Val?Met?Gly?Asn?Leu?Glu
50 55 60Ile?Val?Leu?Thr?Gly?His?Asn?Ala?Asp?Leu?Ser?Phe?Leu?Gln?Trp?Ile65 70 75 80Arg?Glu?Val?Thr?Gly?Tyr?Val Leu?Val?Ala?Met?Asn?Glu?Phe?Ser?Thr
85 90 95Leu?Pro?Leu?Pro?Asn?Leu?Arg?Val?Val?Arg?Gly?Thr?Gln?Val?Tyr?Asp
100 105 110Gly?Lys?Phe?Ala?Ile?Phe?Val?Met?Leu?Asn?Tyr?Asn?Thr?Asn?Ser?Ser
115 120 125His?Ala?Leu?Arg?Gln?Leu?Arg?Leu?Thr?Gln?Leu?Thr?Glu?Ile?Leu?Ser
130 135 140Gly?Gly?Val?Tyr?Ile?Glu?Lys?Asn?Asp?Lys?Leu?Cys?His?Met?Asp?Thr145 150 155 160Ile?Asp?Trp?Arg?Asp?Ile?Val?Arg?Asp?Arg?Asp?Ala?Glu?Ile?Val?Val
165 170 175Lys?Asp?Asn?Gly?Arg?Ser?Cys Pro?Pro?Cys?His?Glu?Val?Cys?Lys?Gly
180 185 190Arg?Cys?Trp?Gly?Pro?Gly?Ser?Glu?Asp?Cys?Gln?Thr?Leu?Thr?Lys?Thr
195 200 205Ile?Cys?Ala?Pro?Gln?Cys?Asn?Gly?His?Cys?Phe?Gly?Pro?Asn?Pro?Asn
210 215 220Gln?Cys?Cys?His?Asp?Glu?Cys?Ala?Gly?Gly?Cys?Ser?Gly?Pro?Gln?Asp225 230 235 240Thr?Asp?Cys?Phe?Ala?Cys?Arg?His?Phe?Asn?Asp?Ser?Gly?Ala?Cys?Val
245 250 255Pro?Arg?Cys?Pro?Gln?Pro?Leu?Val?Tyr?Asn?Lys?Leu?Thr?Phe?Gln?Leu
260 265 270Glu?Pro?Asn?Pro?His?Thr?Lys?Tyr?Gln?Tyr?Gly?Gly?Val?Cys?Val?Ala
275 280 285Ser?Cys?Pro?His?Asn?Phe?Val?Val?Asp?Gln?Thr?Ser?Cys?Val?Arg?Ala
290 295 300Cys?Pro?Pro?Asp?Lys?Met?Glu?Val?Asp?Lys?Asn?Gly?Leu?Lys?Met?Cys305 310 315 320Glu?Pro?Cys?Gly?Gly?Leu?Cys?Pro?Lys?Ala?Cys?Glu?Gly?Thr?Gly?Ser
325 330 335Gly?Ser?Arg?Phe?Gln?Thr?Val?Asp?Ser?Ser?Asn?Ile?Asp?Gly?Phe?Val
340 345 350Asn?Cys?Thr?Lys?Ile?Leu?Gly?Asn?Leu?Asp?Phe?Leu?Ile?Thr?Gly?Leu
355 360 365Asn?Gly?Asp?Pro?Trp?His?Lys?Ile?Pro?Ala?Leu?Asp?Pro?Glu?Lys?Leu
370 375 380Asn?Val?Phe?Arg?Thr?Val?Arg?Glu?Ile?Thr?Gly?Tyr?Leu?Asn?Ile?Gln385 390 395 400Ser?Trp?Pro?Pro?His?Met?His?Asn?Phe?Ser?Val?Phe?Ser?Asn?Leu?Thr
405 410 415Thr?Ile?Gly?Gly?Arg?Ser?Leu?Tyr?Asn?Arg?Gly?Phe?Ser?Leu?Leu?Ile
420 425 430Met?Lys?Asn?Leu?Asn?Val?Thr?Ser?Leu?Gly?Phe?Arg?Ser?Leu?Lys?Glu
435 440 445Ile?Ser?Ala?Gly?Arg?Ile?Tyr?Ile?Ser?Ala?Asn?Arg?Gln?Leu?Cys?Tyr
450 455 460His?His?Ser?Leu?Asn?Trp?Thr?Lys?Val?Leu?Arg?Gly?Pro?Thr?Glu?Glu465 470 475 480Arg?Leu?Asp?Ile?Lys?His?Asn?Arg?Pro?Arg?Arg?Asp?Cys?Val?Ala?Glu
485 490 495Gly?Lys?Val?Cys?Asp?Pro?Leu?Cys?Ser?Ser?Gly?Gly?Cys?Trp?Gly?Pro
500 505 510Gly?Pro?Gly?Gln?Cys?Leu?Ser?Cys?Arg?Asn?Tyr?Ser?Arg?Gly?Gly?Val
515 520 525Cys?Val?Thr?His?Cys?Asn?Phe?Leu?Asn?Gly?Glu?Pro?Arg?Glu?Phe?Ala
530 535 540His?Glu?Ala?Glu?Cys?Phe?Ser?Cys?His?Pro?Glu?Cys?Gln?Pro?Met?Glu545 550 555 560Gly?Thr?Ala?Thr?Cys?Asn?Gly?Ser?Gly?Ser?Asp?Thr?Cys?Ala?Gln?Cys
565 570 575Ala?His?Phe?Arg?Asp?Gly?Pro?His?Cys?Val?Ser?Ser?Cys?Pro?His?Gly
580 585 590Val?Leu?Gly?Ala?Lys?Gly?Pro?Ile?Tyr?Lys?Tyr?Pro?Asp?Val?Gln?Asn
595 600 605Glu?Cys?Arg?Pro?Cys?His?Glu?Asn?Cys?Thr?Gln?Gly?Cys?Lys?Gly?Pro
610 615 620Glu?Leu?Gln?Asp?Cys?Leu?Gly?Gln?Thr?Leu?Val?Leu?Ile?Gly?Lys?Thr625 630 635 640His?Leu?Thr?Met?Ala?Leu?Thr?Val?Ile?Ala?Gly?Leu?Val?Val?Ile?Phe
645 650 655Met?Met?Leu?Gly?Gly?Thr?Phe?Leu?Tyr?Trp?Arg?Gly?Arg?Arg?Ile?Gln
660 665 670Asn?Lys?Arg?Ala?Met?Arg?Arg?Tyr?Leu?Glu?Arg?Gly?Glu?Ser?Ile?Glu
675 680 685Pro?Leu?Asp?Pro?Ser?Glu?Lys?Ala?Asn?Lys?Val?Leu?Ala?Arg?Ile?Phe
690 695 700Lys?Glu?Thr?Glu?Leu?Arg?Lys?Leu?Lys?Val?Leu?Gly?Ser?Gly?Val?Phe705 710 715 720Gly?Thr?Val?His?Lys?Gly?Val?Trp?Ile?Pro?Glu?Gly?Glu?Ser?Ile?Lys
725 730 735Ile?Pro?Val?Cys?Ile?Lys?Val?Ile?Glu?Asp?Lys?Ser?Gly?Arg?Gln?Ser
740 745 750Phe?Gln?Ala?Val?Thr?Asp?His?Met?Leu?Ala?Ile?Gly?Ser?Leu?Asp?His
755 760 765Ala?His?Ile?Val?Arg?Leu?Leu?Gly?Leu?Cys?Pro?Gly?Ser?Ser?Leu?Gln
770 775 780Leu?Val?Thr?Gln?Tyr?Leu?Pro?Leu?Gly?Ser?Leu?Leu?Asp?His?Val?Arg785 790 795 800Gln?His?Arg?Gly?Ala?Leu?Gly?Pro?Gln?Leu?Leu?Leu?Asn?Trp?Gly?Val
805 810 815Gln?Ile?Ala?Lys?Gly?Met?Tyr?Tyr?Leu?Glu?Glu?His?Gly?Met?Val?His
820 825 830Arg?Asn?Leu?Ala?Ala?Arg?Asn?Val?Leu?Leu?Lys?Ser?Pro?Ser?Gln?Val
835 840 845Gln?Val?Ala?Asp?Phe?Gly?Val?Ala?Asp?Leu?Leu?Pro?Pro?Asp?Asp?Lys
850 855 860Gln?Leu?Leu?Tyr?Ser?Glu?Ala?Lys?Thr?Pro?Ile?Lys?Trp?Met?Ala?Leu865 870 875 880Glu?Ser?Ile?His?Phe?Gly?Lys?Tyr?Thr?His?Gln?Ser?Asp?Val?Trp?Ser
885 890 895Tyr?Gly?Val?Thr?Val?Trp?Glu?Leu?Met?Thr?Phe?Gly?Ala?Glu?Pro?Tyr
900 905 910Ala?Gly?Leu?Arg?Leu?Ala?Glu?Val?Pro?Asp?Leu?Leu?Glu?Lys?Gly?Glu
915 920 925Arg?Leu?Ala?Gln?Pro?Gln?Ile?Cys?Thr?Ile?Asp?Val?Tyr?Met?Val?Met
930 935 940Val?Lys?Cys?Trp?Met?Ile?Asp?Glu?Asn?Ile?Arg?Pro?Thr?Phe?Lys?Glu945 950 955 960Leu?Ala?Asn?Glu?Phe?Thr?Arg?Met?Ala?Arg?Asp?Pro?Pro?Arg?Tyr?Leu
965 970 975Val?Ile?Lys?Arg?Glu?Ser?Gly?Pro?Gly?Ile?Ala?Pro?Gly?Pro?Glu?Pro
980 985 990His?Gly?Leu?Thr?Asn?Lys?Lys?Leu?Glu?Glu?Val?Glu?Leu?Glu?Pro?Glu
995 1000 1005Leu?Asp?Leu?Asp?Leu?Asp?Leu?Glu?Ala?Glu?Glu?Asp?Asn?Leu?Ala?Thr
1010 1015 1020Thr?Thr?Leu?Gly?Ser?Ala?Leu?Ser?Leu?Pro?Val?Gly?Thr?Leu?Asn?Arg1025 1030 1035 1040Pro?Arg?Gly?Ser?Gln?Ser?Leu?Leu?Ser?Pro?Ser?Ser?Gly?Tyr?Met?Pro
1045 1050 1055Met?Asn?Gln?Gly?Asn?Leu?Gly?Glu?Ser?Cys?Gln?Glu?Ser?Ala?Val?Ser
1060 1065 1070Gly?Ser?Ser?Glu?Arg?Cys?Pro?Arg?Pro?Val?Ser?Leu?His?Pro?Met?Pro
1075 1080 1085Arg?Gly?Cys?Leu?Ala?Ser?Glu?Ser?Ser?Glu?Gly?His?Val?Thr?Gly?Ser
1090 1095 1100 Glu?Ala?Glu?Leu?Gln?Glu?Lys?Val?Ser?Met?Cys?Arg?Ser?Arg?Ser?Arg1105 1110 1115 1120Ser?Arg?Ser?Pro?Arg?Pro?Arg?Gly?Asp?Ser?Ala?Tyr?His?Ser?Gln?Arg
1125 1130 1135His?Ser?Leu?Leu?Thr?Pro?Val?Thr?Pro?Leu?Ser?Pro?Pro?Gly?Leu?Glu
1140 1145 1150Glu?Glu?Asp?Val?Asn?Gly?Tyr?Val?Met?Pro?Asp?Thr?His?Leu?Lys?Gly
1155 1160 1165Thr?Pro?Ser?Ser?Arg?Glu?Gly?Thr?Leu?Ser?Ser?Val?Gly?Leu?Ser?Ser
1170 1175 1180Val?Leu?Gly?Thr?Glu?Glu?Glu?Asp?Glu?Asp?Glu?Glu?Tyr?Glu?Tyr?Met1185 1190 1195 1200Asn?Arg?Arg?Arg?Arg?His?Ser?Pro?Pro?His?Pro?Pro?Arg?Pro?Ser?Ser
1205 1210 1215Leu?Glu?Glu?Leu?Gly?Tyr?Glu?Tyr?Met?Asp?Val?Gly?Ser?Asp?Leu?Ser
1220 1225 1230Ala?Ser?Leu?Gly?Ser?Thr?Gln?Ser?Cys?Pro?Leu?His?Pro?Val?Pro?Ile
1235 1240 1245Met?Pro?Thr?Ala?Gly?Thr?Thr?Pro?Asp?Glu?Asp?Tyr?Glu?Tyr?Met?Asn
1250 1255 1260Arg?Gln?Arg?Asp?Gly?Gly?Gly?Pro?Gly?Gly?Asp?Tyr?Ala?Ala?Met?Gly1265 1270 1275 1280Ala?Cys?Pro?Ala?Ser?Glu?Gln?Gly?Tyr?Glu?Glu?Met?Arg?Ala?Phe?Gln
1285 1290 1295Gly?Pro?Gly?His?Gln?Ala?Pro?His?Val?His?Tyr?Ala?Arg?Leu?Lys?Thr
1300 1305 1310Leu?Arg?Ser?Leu?Glu?Ala?Thr?Asp?Ser?Ala?Phe?Asp?Asn?Pro?Asp?Tyr
1315 1320 1325Trp?His?Ser?Arg?Leu?Phe?Pro?Lys?Ala?Asn?Ala?Gln?Arg?Thr
1,330 1,335 1340＜210〉2＜211〉640＜212〉PRT＜213〉homo sapiens (Homo sapiens)＜400〉2Met Arg Ala Asn Asp Ala Leu Gln Val Leu Gly Leu Leu Phe Ser Leu, 15 10 15Ala Arg Gly Ser Glu Val Gly Asn Ser Gln Ala Val Cys Pro Gly Thr
20 25 30Leu?Asn?Gly?Leu?Ser?Val?Thr?Gly?Asp?Ala?Glu?Asn?Gln?Tyr?Gln?Thr
35 40 45Leu?Tyr?Lys?Leu?Tyr?Glu?Arg?Cys?Glu?Val?Val?Met?Gly?Asn?Leu?Glu
50 55 60Ile?Val?Leu?Thr?Gly?His?Asn?Ala?Asp?Leu?Ser?Phe?Leu?Gln?Trp?Ile65 70 75 80Arg?Glu?Val?Thr?Gly?Tyr?Val?Leu?Val?Ala?Met?Asn?Glu?Phe?Ser?Thr
85 90 95Leu?Pro?Leu?Pro?Asn?Leu?Arg?Val?Val?Arg?Gly?Thr?Gln?Val Tyr?Asp
100 105 110Gly?Lys?Phe?Ala?Ile?Phe?Val?Met?Leu?Asn?Tyr?Asn?Thr?Asn?Ser?Ser
115 120 125His?Ala?Leu?Arg?Gln?Leu?Arg?Leu?Thr?Gln?Leu?Thr?Glu?Ile?Leu?Ser
130 135 140Gly?Gly?Val?Tyr?Ile?Glu?Lys?Asn?Asp?Lys?Leu?Cys?His?Met?Asp?Thr145 150 155 160Ile?Asp?Trp?Arg?Asp?Ile?Val?Arg?Asp?Arg?Asp?Ala?Glu?Ile?Val?Val
165 170 175Lys?Asp?Asn?Gly?Arg?Ser?Cys?Pro?Pro?Cys?His?Glu?Val?Cys?Lys?Gly
180 185 190Arg?Cys?Trp?Gly?Pro?Gly?Ser?Glu?Asp?Cys?Gln?Thr?Leu?Thr?Lys?Thr
195 200 205Ile?Cys?Ala?Pro?Gln?Cys?Asn?Gly?His?Cys?Phe?Gly?Pro?Asn?Pro?Asn
210 215 220Gln?Cys?Cys?His?Asp?Glu?Cys?Ala?Gly?Gly?Cys?Ser?Gly?Pro?Gln?Asp225 230 235 240Thr?Asp?Cys?Phe?Ala?Cys?Arg?His?Phe?Asn?Asp?Ser?Gly?Ala?Cys?Val
245 250 255Pro?Arg?Cys?Pro?Gln?Pro?Leu?Val?Tyr?Asn?Lys?Leu?Thr?Phe?Gln?Leu
260 265 270Glu?Pro?Asn?Pro?His?Thr?Lys?Tyr?Gln?Tyr?Gly?Gly?Val?Cys?Val?Ala
275 280 285Ser?Cys?Pro?His?Asn?Phe?Val?Val?Asp?Gln?Thr?Ser?Cys?Val?Arg?Ala
290 295 300Cys?Pro?Pro?Asp?Lys?Met?Glu?Val?Asp?Lys?Asn?Gly?Leu?Lys?Met?Cys305 310 315 320Glu?Pro?Cys?Gly?Gly?Leu?Cys?Pro?Lys?Ala?Cys?Glu?Gly?Thr?Gly?Ser
325 330 335Gly?Ser?Arg?Phe?Gln?Thr?Val?Asp?Ser?Ser?Asn?Ile?Asp?Gly?Phe?Val
340 345 350Asn?Cys?Thr?Lys?Ile?Leu?Gly?Asn?Leu?Asp?Phe?Leu?Ile?Thr?Gly?Leu
355 360 365Asn?Gly?Asp?Pro?Trp?His?Lys?Ile?Pro?Ala?Leu?Asp?Pro?Glu?Lys?Leu
370 375 380Asn?Val?Phe?Arg?Thr?Val?Arg?Glu?Ile?Thr?Gly?Tyr?Leu?Asn?Ile?Gln385 390 395 400Ser?Trp?Pro?Pro?His?Met?His?Asn?Phe?Ser?Val?Phe?Ser?Asn?Leu?Thr
405 410 415Thr?Ile?Gly?Gly?Arg?Ser?Leu?Tyr?Asn?Arg?Gly?Phe?Ser?Leu?Leu?Ile
420 425 430Met?Lys?Asn?Leu?Asn?Val?Thr?Ser?Leu?Gly?Phe?Arg?Ser?Leu?Lys?Glu
435 440 445Ile?Ser?Ala?Gly?Arg?Ile?Tyr?Ile?Ser?Ala?Asn?Arg?Gln?Leu?Cys?Tyr
450 455 460His?His?Ser?Leu?Asn?Trp?Thr?Lys?Val?Leu?Arg?Gly?Pro?Thr?Glu?Glu465 470 475 480Arg?Leu?Asp?Ile?Lys?His?Asn?Arg?Pro?Arg?Arg?Asp?Cys?Val?Ala?Glu
485 490 495Gly?Lys?Val?Cys?Asp?Pro?Leu?Cys?Ser?Ser?Gly?Gly?Cys?Trp?Gly?Pro
500 505 510Gly?Pro?Gly?Gln?Cys?Leu?Ser?Cys?Arg?Asn?Tyr?Ser?Arg?Gly?Gly?Val
515 520 525Cys?Val?Thr?His?Cys?Asn?Phe?Leu?Asn?Gly?Glu?Pro?Arg?Glu?Phe?Ala
530 535 540His?Glu?Ala?Glu?Cys?Phe?Ser?Cys?His?Pro?Glu?Cys?Gln?Pro?Met?Glu545 550 555 560Gly?Thr?Ala?Thr?Cys?Asn?Gly?Ser?Gly?Ser?Asp?Thr?Cys?Ala?Gln?Cys
565 570 575Ala?His?Phe?Arg?Asp?Gly?Pro?His?Cys?Val?Ser?Ser?Cys?Pro?His?Gly
580 585 590Val?Leu?Gly?Ala?Lys?Gly?Pro?Ile?Tyr?Lys?Tyr?Pro?Asp?Val?Gln?Asn
595 600 605Glu?Cys?Arg?Pro?Cys?His?Glu?Asn?Cys?Thr?Gln?Gly?Cys?Lys?Gly?Pro
610 615 620Glu Leu Gln Asp Cys Leu Gly Gln Thr Leu Val Leu Ile Gly Lys Thr625,630 635 640＜210〉3＜211〉190＜212〉PRT＜213〉homo sapiens (Homo sapiens)＜400〉3Met Arg Ala Asn Asp Ala Leu Gln Val Leu Gly Leu Leu Phe Ser Leu, 15 10 15Ala Arg Gly Ser Glu Val Gly Asn Ser Gln Ala Val Cys Pro Gly Thr
20 25 30Leu?Asn?Gly?Leu?Ser?Val?Thr?Gly?Asp?Ala?Glu?Asn?Gln?Tyr?Gln?Thr
35 40 45Leu?Tyr?Lys?Leu?Tyr?Glu?Arg?Cys?Glu?Val?Val?Met?Gly?Asn?Leu?Glu
50 55 60Ile?Val?Leu?Thr?Gly?His?Asn?Ala?Asp?Leu?Ser?Phe?Leu?Gln?Trp?Ile65 70 75 80Arg?Glu?Val?Thr?Gly?Tyr?Val?Leu?Val?Ala?Met?Asn?Glu?Phe?Ser?Thr
85 90 95Leu?Pro?Leu?Pro?Asn?Leu?Arg?Val?Val?Arg?Gly?Thr?Gln?Val?Tyr?Asp
100 105 110Gly?Lys?Phe?Ala?Ile?Phe?Val?Met?Leu?Asn?Tyr?Asn?Thr?Asn?Ser?Ser
115 120 125His?Ala?Leu?Arg?Gln?Leu?Arg?Leu?Thr?Gln?Leu?Thr?Glu?Ile?Leu?Ser
130 135 140Gly?Gly?Val?Tyr?Ile?Glu?Lys?Asn?Asp?Lys?Leu?Cys?His?Met?Asp?Thr145 150 155 160Ile?Asp?Trp?Arg?Asp?Ile?Val?Arg?Asp?Arg?Asp?Ala?Glu?Ile?Val?Val
165 170 175Lys?Asp?Asn?Gly?Arg?Ser?Cys?Pro?Pro?Cys?His?Glu?Val?Cys
180 185 190＜210〉4＜211〉1914＜212〉DNA＜213〉 ( Homo sapiens )＜400〉4 agggcgaacg acgctctgca ggtgctgggc ttgcttttca gcctggcccg gggctccgag 60gtgggcaact ctcaggcagt gtgtcctggg actctgaatg gcctgagtgt gaccggcgat 120gctgagaacc aataccagac actgtacaag ctctacgaga ggtgtgaggt ggtgatgggg 180aaccttgaga ttgtgctcac gggacacaat gccgacctct ccttcctgca gtggattcga 240gaagtgacag gctatgtcct cgtggccatg aatgaattct ctactctacc attgcccaac 300ctccgcgtgg tgcgagggac ccaggtctac gatgggaagt ttgccatctt cgtcatgttg 360aactataaca ccaactccag ccacgctctg cgccagctcc gcttgactca gctcaccgag 420attctgtcag ggggtgttta tattgagaag aacgataagc tttgtcacat ggacacaatt 480gactggaggg acatcgtgag ggaccgagat gctgagatag tggtgaagga caatggcaga 540agctgtcccc cctgtcatga ggtttgcaag gggcgatgct ggggtcctgg atcagaagac 600tgccagacat tgaccaagac catctgtgct cctcagtgta atggtcactg ctttgggccc 660aaccccaacc agtgctgcca tgatgagtgt gccgggggct gctcaggccc tcaggacaca 720gactgctttg cctgccggca cttcaatgac agtggagcct gtgtacctcg ctgtccacag 780cctcttgtct acaacaagct aactttccag ctggaaccca atccccacac caagtatcag 840tatggaggag tttgtgtagc cagctgtccc cataactttg tggtggatca aacatcctgt 900gtcagggcct gtcctcctga caagatggaa gtagataaaa atgggctcaa gatgtgtgag 960ccttgtgggg gactatgtcc caaagcctgt gagggaacag gctctgggag ccgcttccag 1020actgtggact cgagcaacat tgatggattt gtgaactgca ccaagatcct gggcaacctg 1080gactttctga tcaccggcct caatggagac ccctggcaca agatccctgc cctggaccca 1140gagaagctca atgtcttccg gacagtacgg gagatcacag gttacctgaa catccagtcc 1200tggccgcccc acatgcacaa cttcagtgtt ttttccaatt tgacaaccat tggaggcaga 1260agcctctaca accggggctt ctcattgttg atcatgaaga acttgaatgt cacatctctg 1320ggcttccgat ccctgaagga aattagtgct gggcgtatct atataagtgc caataggcag 1380ctctgctacc accactcttt gaactggacc aaggtgcttc gggggcctac ggaagagcga 1440ctagacatca agcataatcg gccgcgcaga gactgcgtgg cagagggcaa agtgtgtgac 1500ccactgtgct cctctggggg atgctggggc ccaggccctg gtcagtgctt gtcctgtcga 1560aattatagcc gaggaggtgt ctgtgtgacc cactgcaact ttctgaatgg ggagcctcga 1620gaatttgccc atgaggccga atgcttctcc tgccacccgg aatgccaacc catggagggc 1680actgccacat gcaatggctc gggctctgat acttgtgctc aatgtgccca ttttcgagat 1740gggccccact gtgtgagcag ctgcccccat ggagtcctag gtgccaaggg cccaatctac 1800aagtacccag atgttcagaa tgaatgtcgg ccctgccatg agaactgcac ccaggggtgt 1860aaaggaccag agcttcaaga ctgtttagga caaacactgg tgctgatcgg caaa 1914＜210〉5＜211〉475＜212〉DNA＜213〉 ( Homo sapiens )＜400〉5gatcctgtcc tgggactctg aatggcctga gtgtgaccgg cgatgctgag aaccaatacc 60agacactgta caagctctac gagaggtgtg aggtggtgat ggggaacctt gagattgtgc 120tcacgggaca caatgccgac ctctccttcc tgcagtggat tcgagaagtg acaggctatg 180tcctcgtggc catgaatgaa ttctctactc taccattgcc caacctccgc gtggtgcgag 240ggacccaggt ctacgatggg aagtttgcca tcttcgtcat gttgaactat aacaccaact 300ccagccacgc tctgcgccag ctccgcttga ctcagctcac cgagattctg tcagggggtg 360tttatattga gaagaacgat aagctttgtc acatggacac aattgactgg agggacatcg 420tgagggaccg agatgctgag atagtggtga aggacaatgg cagaagctga ctcga 475＜210〉6＜211〉19＜212〉DNA＜213〉＜220〉＜223〉＜400〉6tctgcggagt catgagggc 19＜210〉7＜211〉48＜212〉DNA＜213〉＜220〉＜223〉＜400〉7tgtgaccacg actagccgtt tctgatgttc ctgctactgc tgttcact 48＜210〉8＜211〉25＜212〉DNA＜213〉＜220〉＜223〉＜400〉8tctagagatt ttctgcggag tcatg 25＜210〉9＜211〉15＜212〉DNA＜213〉＜220〉＜223〉＜400〉9gacgacgacg acaag 15＜210〉10＜211〉16＜212〉DNA＜213〉＜220〉＜223〉＜400〉10gccatggctg atatcg 16＜210〉11＜211〉23＜212〉DNA＜213〉＜220〉＜223〉＜400〉11gcaccaccac caccaccact gag 23
Claims (44)
1. a prevention, treat or delay the method for mammal tumor, this method comprises ErbB-3 albumen or its function fragment to needs or the administration effective dose wishing this prevention, treat or delay, perhaps the encode proteic nucleic acid of ErbB-3 or its function fragment, produce the immunoreation of anti-described tumor, thereby described tumor is prevented, is treated or delayed.
2. the described method of claim 1, wherein said mammal are human.
3. the described method of claim 1 is wherein used the proteic ectodomain of ErbB-3 of effective dose, or its function fragment, the nucleic acid of the proteic ectodomain of ErbB-3 of perhaps encoding, or its function fragment.
4. the described method of claim 1, wherein said ErbB-3 albumen comprises the aminoacid sequence described in the SEQ ID NO:1.
5. the described method of claim 1, the proteic ectodomain of wherein said ErbB-3, or its function fragment comprises the aminoacid sequence described in SEQ ID NO:2 or the SEQ ID NO:3.
6. the described method of claim 1 further comprises to administration immunoreation reinforcing agent.
7. the described method of claim 1, wherein said ErbB-3 albumen, or its function fragment, the proteic nucleic acid of ErbB-3 of perhaps encoding, or its function fragment is that original position is used for tumor.
8. the described method of claim 7 further comprises the tumor original position is used the immunoreation reinforcing agent.
9. the described method of claim 1, wherein said ErbB-3 albumen, or its function fragment, the proteic nucleic acid of ErbB-3 of perhaps encoding, or its function fragment and pharmaceutically acceptable carrier and excipient is common uses.
10. the described method of claim 1, wherein said ErbB-3 albumen, or its function fragment, the proteic nucleic acid of ErbB-3 of perhaps encoding, or its function fragment and anti-tumor agents is common uses.
11. the described method of claim 10, wherein said anti-tumor agents is selected from: anti-angiogenic agent, alkylating agent, antimetabolite, a kind of natural products, platinum coordination complex, amerantrone, substituted ureas, methylhydrazine derivant, adrenal cortex inhibitor, hormone, antagonist, oncogene inhibitor, tumor suppression subbase because of or albumen, Antioncogene antibody, Antioncogene antisense oligonucleotide, anticancer cell surface antigen antibody and other anti-tumor vaccine.
12. the described method of claim 1 is wherein prevented, treatment or the tumor that delays are selected from: the adrenal gland, anus, auditory nerve, biliary ductuli, bladder, bone, brain, breast, bruccal, the central nervous system, cervix uteri, colon, ear, endometrium, esophagus, eyes, eyelid, fallopian tube, gastrointestinal tract, incidence, heart, kidney, larynx, liver, lung, lower jaw, the lower jaw lateral condyle, upper jaw bone, mouth, nasopharynx, nose, the oral cavity, ovary, pancreas, the parotid gland, penis, auricle, hypophysis, prostate, rectum, retina, salivary gland, skin, small intestinal, spinal cord, stomach, testis, thyroid, tonsil, urethra, vagina, eighth cranial nerve and vaginal orifice tumor.
13. the described method of claim 1 wherein is selected from by the tumor of preventing, treating or delaying: breast, ovary, stomach, prostate, colon and pulmonary's cancer.
14. the described method of claim 1 is a breast carcinoma by the tumor of preventing, treating or delaying wherein.
15. isolating nucleic acid fragment, this isolating nucleic acid fragment comprises the proteic ectodomain of coding ErbB-3, the nucleotide sequence of its function fragment, the proteic ectodomain of this ErbB-3, or its function fragment comprises the aminoacid sequence described in SEQ ID NO:2 or the SEQ ID NO:3.
16. the described isolating nucleic acid fragment of claim 15, wherein said nucleic acid is DNA.
17. the described isolating nucleic acid fragment of claim 15, wherein said nucleic acid is RNA.
18. a plasmid, this plasmid comprise the described nucleic acid fragment of claim 16.
19. a cell, this cell comprise the described plasmid of claim 18.
20. the described cell of claim 19, it is selected from bacterial cell, yeast cells, fungal cell, plant cell, insect cell, zooblast and people's cell.
21. one kind produces the proteic ectodomain of ErbB-3, or the method for its function fragment, this method is included in the proteic ectodomain of cellular expression ErbB-3, or cultivate the described cell of claim 19 under the condition of its function fragment and reclaim the ErbB-3 albumen ectodomain of expressing, or its function fragment.
22. the albumen or the peptide of purification basically, this albumen or peptide comprise the proteic ectodomain of ErbB-3, its function fragment, the proteic ectodomain of this ErbB-3, or its function fragment comprises the aminoacid sequence described in SEQ ID NO:2 or the SEQ ID NO:3.
23. a conjugate, this conjugate comprises:
A) a kind of albumen or peptide comprise the proteic ectodomain of ErbB-3, or its function fragment, the proteic ectodomain of this ErbB-3, or its function fragment comprises the aminoacid sequence described in SEQ ID NO:2 or the SEQID NO:3; With
B) a kind of and the proteic ectodomain of ErbB-3 or its function fragment directly or the promoter that is connected by joint, wherein said promoter helps:
I) affine isolated or purified conjugate;
Ii) conjugate is adsorbed onto on the surface; Or
Iii) detect conjugate.
24. the described conjugate of claim 23, it is a kind of fusion rotein.
25. the described conjugate of claim 24, wherein when described conjugate was a kind of fusion rotein, promoter can also be i) Subcellular Localization sequence in cell after synthetic; The ii) sequence of enhance immunity originality; Or the iii) tumor antigen of other protide.
26. a pharmaceutical composition, said composition comprise the described isolating nucleic acid fragment of claim 15 and pharmaceutically acceptable carrier and excipient.
27. the described pharmaceutical composition of claim 26 further comprises immunoreation reinforcing agent and/or anti-tumor agents.
28. a pharmaceutical composition, said composition comprise albumen or peptide and the pharmaceutically acceptable carrier and the excipient of the described purification basically of claim 22.
29. the described pharmaceutical composition of claim 28 further comprises immunoreation reinforcing agent and/or anti-tumor agents.
30. antibody, this antibody combines with an epitope of the proteic ectodomain of ErbB-3 or its function fragment, the proteic ectodomain of this ErbB-3, or its function fragment comprises the aminoacid sequence of representing among SEQ ID NO:2 or the SEQ ID NO:3.
31. the described antibody of claim 30, it is polyclonal antibody or monoclonal antibody.
32. the described antibody of claim 30, it is people's antibody or humanized antibody.
33. a pharmaceutical composition, said composition comprise the described antibody of claim 30 and pharmaceutically acceptable carrier and excipient.
34. the described pharmaceutical composition of claim 33 further comprises a kind of anti-tumor agents.
35. a vaccine, this vaccine comprise the described isolating nucleic acid fragment of claim 15.
36. the described vaccine of claim 35 further comprises the immunoreation reinforcing agent.
37. a vaccine, this vaccine comprise the albumen or the peptide of the purification basically described in the claim 22.
38. the described vaccine of claim 37 further comprises the immunoreation reinforcing agent.
39. a test kit, this test kit comprise the operation instruction that the described isolating nucleic acid fragment of the claim 15 that places container and this isolating nucleic acid fragment are used for tumor prevention, treat and delay.
40. a test kit, this test kit comprise the albumen of the purification basically described in the claim 22 that places container or peptide and this albumen of purification or the operation instruction that peptide is used for tumor prevention, treats and delays basically.
41. a conjugate, this conjugate comprise described isolating nucleic acid fragment of claim 15 and anti-tumor agents.
42. the described conjugate of claim 41 further comprises pharmaceutically acceptable carrier and excipient.
43. a conjugate, this conjugate comprise albumen or the peptide and the anti-tumor agents of the described purification basically of claim 22.
44. the described conjugate of claim 43 further comprises pharmaceutically acceptable carrier and excipient.
Priority Applications (11)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB02116259XA CN1219882C (en) | 2002-03-18 | 2002-03-26 | Method and combination for treating tumors based on ERBB-3 |
| AU2003218600A AU2003218600C1 (en) | 2002-03-26 | 2003-03-26 | ERBB3 based methods and compositions for treating neoplasms |
| CA2480099A CA2480099C (en) | 2002-03-26 | 2003-03-26 | Erbb3 based methods and compositions for treating neoplasms |
| PCT/CN2003/000217 WO2003080835A1 (en) | 2002-03-26 | 2003-03-26 | Erbb3 based methods and compositions for treating neoplasms |
| EP11178809.7A EP2400021B1 (en) | 2002-03-26 | 2003-03-26 | ErbB3 based methods and compositions for treating neoplasms |
| US10/516,759 US7919098B2 (en) | 2002-03-26 | 2003-03-26 | ErbB-3 based methods and compositions for treating neoplasms |
| EP03711804.9A EP1495123B1 (en) | 2002-03-26 | 2003-03-26 | Erbb3 based methods and compositions for treating neoplasms |
| JP2003578561A JP4660094B2 (en) | 2002-03-26 | 2003-03-26 | ErbB3-based methods and compositions for treating neoplasms |
| CNB038067625A CN100424175C (en) | 2002-03-26 | 2003-03-26 | Methods and compositions for treating neoplasms by ERBB3 |
| JP2010101148A JP5249282B2 (en) | 2002-03-26 | 2010-04-26 | ErbB3-based methods and compositions for treating neoplasms |
| US13/035,244 US20110229478A1 (en) | 2002-03-26 | 2011-02-25 | Erbb3 based methods and compositions for treating neoplasms |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN02107357.0 | 2002-03-18 | ||
| CN02107357 | 2002-03-18 | ||
| CNB02116259XA CN1219882C (en) | 2002-03-18 | 2002-03-26 | Method and combination for treating tumors based on ERBB-3 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1444992A true CN1444992A (en) | 2003-10-01 |
| CN1219882C CN1219882C (en) | 2005-09-21 |
Family
ID=28042606
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB02116259XA Expired - Fee Related CN1219882C (en) | 2002-03-18 | 2002-03-26 | Method and combination for treating tumors based on ERBB-3 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1219882C (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101611150A (en) * | 2006-02-08 | 2009-12-23 | 利佳赛普特有限责任公司 | Bivalent erbb ligand binding molecules and preparation thereof and using method |
| US9249230B2 (en) | 2005-12-30 | 2016-02-02 | U3 Pharma Gmbh | Antibodies directed to HER-3 and uses thereof |
-
2002
- 2002-03-26 CN CNB02116259XA patent/CN1219882C/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9249230B2 (en) | 2005-12-30 | 2016-02-02 | U3 Pharma Gmbh | Antibodies directed to HER-3 and uses thereof |
| US10100124B2 (en) | 2005-12-30 | 2018-10-16 | Daiichi Sankyo Europe Gmbh | Antibodies directed to HER-3 and uses thereof |
| US11267900B2 (en) | 2005-12-30 | 2022-03-08 | Daiichi Sankyo Europe Gmbh | Antibodies directed to HER-3 and uses thereof |
| CN101611150A (en) * | 2006-02-08 | 2009-12-23 | 利佳赛普特有限责任公司 | Bivalent erbb ligand binding molecules and preparation thereof and using method |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1219882C (en) | 2005-09-21 |
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