CN1642982A - Agents that activate or inhibit Toll-like receptor 9 - Google Patents

Agents that activate or inhibit Toll-like receptor 9 Download PDF

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CN1642982A
CN1642982A CN 02818821 CN02818821A CN1642982A CN 1642982 A CN1642982 A CN 1642982A CN 02818821 CN02818821 CN 02818821 CN 02818821 A CN02818821 A CN 02818821A CN 1642982 A CN1642982 A CN 1642982A
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tlr9
antibody
molecule
peptide
cpg
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安玲玲
吴和仁
M·S·C·冯
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Tanox Inc
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Tanox Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55516—Proteins; Peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55561—CpG containing adjuvants; Oligonucleotide containing adjuvants

Abstract

The present invention includes molecules that bind to a peptidic segment on TLR9 and mimic the effects of the CpG motif. The CpG mimicking agents include, but are not limited to, antibodies, small-molecule compounds, peptides, peptide mimetics, and nucleic acids, including compositions comprising molecules that bind to a peptidic segment on TLR9 and mimic the effects of the CpG motif suitable for administering to a patient in need of treatment, optionally in combination with, for example, an excipient, diluant, or carrier. In addition, the present invention includes those molecules which bind to the TLR9's CXXC motifs at 255Cys-Arg-Arg 258Cys as CRRC or at 265Cys-Met-GIu 268Cys as CMEC. The present invention includes methods for modulating the immune response by inducing a Th1-type response comprising administering molecules that bind to TLR9 and mimic CpG function. These molecules also shift the host cellular response away from a Th2-type response toward the Th1-type response. Thus, administering the molecules of the present invention that bind to TLR9 may avoid the risk of Th2-mediated, immunization-induced anaphylaxis, making this method useful in immunotherapy and asthma treatment. The molecules of the present invention may be administered in combination with a particular allergen.

Description

The reagent of activation or inhibition class Toll receptor 9
Technical field
The invention relates to cause with the interactional class Toll acceptor of CpG motif (TLR9) on the identification of antigenic determinant.
Prior art
Organic immunity comprises that it is useful on the protection mechanism of antagonism external environment reagent (for example microorganism, food, chemical, medicine or pollen).In vertebrates, immunity can be congenital or acquired (adaptability) two kinds.
The composition of being with was authorized when innate immunity was born by organism.These compositions comprise physical barriers (for example skin and mucous membrane (mucosal membranes)), inherent composition (for example have a fever and cough), number of chemical composition (for example Interferon, rabbit, serum protein, as lysozyme and polyamine) and cellular constituent (as scavenger cell, dendritic cell and granulocyte).
Show: the DNA of specific bacteria (rather than vertebrate DNA) can activate organic natural immunity (Tokunaga, people such as T., J.Natl.Cancer Institute72:955-962 (1984); Messina, people such as J.P., J.Immunol 147:1759-1764 (1991)).The adaptive immunity that congenital immunity cell (for example scavenger cell and dendritic cell) has a strong impact on T and bone-marrow-derived lymphocyte is reacted this fact and is nowadays also become clear.The congenital immunity cell mainly is to have vital role (Aderem, people such as A., Nature406:782-787 (2000)) aspect the Th1 or the angtigen presentation of Th2 reaction determining whether the T-cell thoroughly reacts and induce the T-cell response.Any antigenic immune response be can be one of Th1 and Th2, and each all induces different cytohormones, antibody and cell response.
In this innate immune response to DNA of bacteria of research, we confirm: recognizing bacterial dna is for " external " and bring out its enhancing immunity reaction of antagonism and may come from unmethylated among the DNA " CG " dinucleotides sequence (called after " CpG " sequence) section.Unmethylated CpG dinucleotides is very abundant (Bird, A.P., Nuc.Acids Res.8:1499-1504 (1980) in all bacterial genomes and virus and no vertebra eukaryotic gene group; Burge, C waits the people, Proc.Nat.Acad.Sci.USA 89:1358-1362 (1992)).In the vertebrates genome, the CpG motif only can find with low frequency, and about 70% is the Id that methylates in the vertebrates CpG motif of being found.If fundamental frequency is at random, so as expected, the CG sequence of only about 1/4th predicted number is present in (Bird, A.P., Trendsin Genetics 3:342-347 (1987)) in the vertebrates.CG is opposite with bacterium, human CG sequence is the most frequent be C preceding or G after.These human CG sequences are not invalid to immunity system, exactly even may cause immunoreactive inhibition.(Krieg, people such as A.M., Proc.Natl.Acad.Sci.USA 95:12631-12636 (1998)).
Bacterium CpG-DNA is effective class Th1 auxiliary, triggers strong Th1 antibody response partially, and is accompanied by inhibition Th2 reaction (Davis, people such as H.L., J.Immunol.160:870-876 (1998)).CpG-DNA also is effective single B-phytokinin, and its B-cell that can drive above 95% enters active state (Krieg, people such as A.M., Nature 374:546-549 (1995)).These innate immune responses can be simulated by the synthetic few thymus nucleic acid (CpG-ODN) that contains CpG that do not methylate.By the enhancing that bacterium CpG sequence or CpG-ODN activatory B-cell show major histocompatibility complex (MHC) molecule of surperficial II level and accompany stimulation molecule B7-1 and B7-2 express (Krieg, A.M.: Delivery Strategies For Antisense Oligonucleotide TherapeuticsIn, Ed.Akhtar, S., CRC Press, Inc., 177-190 page or leaf; Davis, people such as H.L., J.Immunol.160:870-876 (1998)).This CpG " motif " that has proposed to be made up of the CG dinucleotides can directly strengthen this possibility of B-cell antigen expressive function.Although the effect of CpG motif on the T-cell is also not clear, but show collaborative proliferative response to CpG by the highly purified T-cell of T-cell receptors excitation, indication one can promote the mechanism (Bendigs of antigen-special efficacy T-cell response by its CpG, S. wait the people, Eur.J.Immunol.29:1209-1218 (1999)).
CpG-ODN intense stimulus NK cytolysis enzymic activity and IFN-γ output (Tokunaga, people such as T, J.Natl.Cancer Institute 72:955-962 (1984); Yamamoto S., J.Immunol.148:4072-4076 (1992)).The antigen presentation cell, for example monocyte and dendritic cell, be activated by CpG-ODN, the result produces Th1 cytohormone (Jakob, people such as T, J.Immunol.161:3042-3049 (1998)), and produce secondary MHC molecule and collaborative B7-1 of stimulation and B7-2 molecule (Stacy, K.J. wait the people, J.Immunol.157:2116-2122 (1996); Sparwasser, people such as T., Eur.J.Immunol.28:2045-2054 (1998)).
Therefore, CpG-ODN is that effective various antigen relies on and non-antigen relies on immunoreactive inductor and excitation agent, and can be used to develop the vaccine of antagonism cancer and transmissible disease.Because CpG-ODN activation NK cell, so they can be effective to strengthen the antibody-dependent cellular cytotoxicity (ADCC) of anti-tumour antibody.CpG-ODN can be with t cell responses from the reaction of Th2 type reaction changing into Th1 type, and this can cause anaphylactoid (down-modulating) (Kline, people such as J.N., the J.Immunol.160:2555-2559 (1998) that adjust down; Sur, people such as S., J.Immunol.162:5575-5582 (1999); Shirota, people such as H., J.Immunol.164:5575-5582 (2000); Jahn-Schmid, people such as B., J.Allergy Clin.Immunol.104:1015-1023 (1999); Broide, people such as D.H., J.Clin.Immunol.21:175-182 (2001)).
What is interesting is that the innate immune response that CpG-DNA drives can be by becoming the CpG motif GC dinucleotides or being eliminated by the cytosine that methylates.This clearly structure-function relationship has hinted and has been exclusively used in the not existence of the acceptor of methylated CpG motif.Recently, in mouse gene knockout research, showed the place one's entire reliance upon class Toll receptor 9 (TLR9) (Hemmi, people such as H., Nature 408:740-745 (2000)) of recent findings of CpG function.Based in vitro research, think to be in the endosome with CpG motif after the CpG-DNA internalization and TLR9 interaction (Wagner, H., Immunity 14:499-502 (2001)).
TLR family comprises kind of a transmembrane protein that is the heredity preservation, and it can cause natural immunity and discern for microorganism is important.The zone, extracellular of these acceptors comprises how rich leucine and repeats (LRR) (multiple leucine-rich repeat) and have the rich domain cysteine of the carboxyl terminal identical with the tenuigenin territory of ILlR.First TLR, promptly dToll finds in fruit bat, and has vital role (Anderson, K.V., Curr.Opin.Immunol.12:13-19 (2000) for the innate immune response of fungi infestation; Means, T.K., Life Sci.68:241-258 (2000)).In other organism, find other TLR member subsequently.TLR2 causes the immune response of peptidoglycan (PGN) and TLR4 causes the immune response to lipopolysaccharides (LPS).(PDB goes into to hide registration number: AAF78037 to human TLR9, identification sequence number: 1) recently by clone (Chuang, people such as T-H, Eur.Cytokine Netw.11:372-378 (2000)).On TLR9, the exact end position of methylated CpG was not defined in the past as yet.
Summary of the invention
The present invention includes with TLR9 on peptide fragment (peptidic segment) molecule that combines and simulate CpG motif effect.The CpG simulant is including, but not limited to: antibody, micromolecular compound, peptide, peptide simulation and nucleic acid.In addition, the present invention includes contain with TLR9 on peptide fragment (peptidic segment) combine and simulate the composition of the molecule of CpG motif effect, it is fit to give can be used in combination with (for example) vehicle, thinner or supporting agent according to circumstances in the patient of needs treatment.
In addition, the present invention includes on the CXXC motif of those and TLR9 255Cys-Arg-Arg 258Cys (as CRRC) or 265Cys-Met-GIu 268Cys (as CMEC) bonded molecule.
The present invention also comprises the method that makes molecule be incorporated into TLR9 and simulate CpG motif effect.These methods comprise the monoclonal antibody of generation to the CpG antigenic determinant of TLR9.
In addition, the present invention includes the method for treatment by the caused disease of TLR-9, this method comprises and gives CpG simulant, and these simulants are including, but not limited to antibody, micromolecular compound, peptide, peptide simulation and nucleic acid.Nucleic acid comprises oligonucleotide.These molecules may be used for the treatment of, prevent or improve as tumour, cancer or transmitted pathogen disease diseases such as (as the transmitted pathogen diseases that is caused by virus, fungi, bacterium or parasite).
The present invention also comprises and is fit to the composition that gives to the patient who suffers from anaphylactic disease, and these compositions comprise with TLR9 and combine the also molecule of mimic CpG, can be used in combination with (for example) vehicle, thinner or supporting agent according to circumstances.
The present invention includes by inducing the Th-1 type to react and regulate immunoreactive method, it comprises the molecule that is incorporated into TLR9 and mimic CpG.These molecules also change by the Th-2 type host cell reaction to the Th-1 type.Therefore, the molecule that gives the TLR9 of being incorporated into of the present invention may be avoided the risk of anaphylaxis that caused by Th2, induction of immunity, makes this method can apply in immunotherapy and the treatment asthma.Molecule of the present invention can give with special allergen combination.
In addition, the present invention includes the molecule that is incorporated into TLR9 and mimic CpG, as the artificial auxiliary in the Mammalss such as the mouse or the mankind.The present invention includes by giving vaccine antigen or being encoded in the antigen of dna vaccination and coming vaccinated method the subject with molecule or composition that peptide fragment on the TLR9 combined and simulated CpG motif effect.
The present invention also comprises immunogen, this immunogen comprises from the DNA of TLR9 deutero-synthetic peptide, recombinant protein matter or encoded peptide or the recombinant protein matter that contains CRRC and/or CMEC, and these materials have been induced the antigenic determinant that is incorporated into TLR9, responsible production of antibodies in conjunction with CpG (especially at CRRC and/or CMEC) and activated receptor function.These immunogens can be given in the subject so that to cancer or anaphylaxis immunity.
Another embodiment of the present invention comprises the molecule that is incorporated into TLR9 and suppresses or resist function of receptors.The present invention includes the molecule of antagonism CpG effect.
Another embodiment of the present invention comprises and is incorporated into antibody or its pulsating gene constructs of TLR9 to be used for the treatment of.On the basis of introducing suitable host, TLR9 antibody gene construction will guide can be incorporated into TLR9 and mimic CpG or suppress the TLR9 function of receptors both one of the synthesizing of antibody (or its segment).The gene constructs of desire expression also codified is somebody's turn to do the antigenic determinant of being responsible for the interactional TLR9 of CpG.These constructions comprise gene and modification or the derivative form that is used for whole antibody molecules, comprise being similar to Fab, strand Fv (scFv) and F (ab ') 2Immunoglobulin fragments.Gene constructs can be introduced into main body by conventional gene therapy technology, and these technology comprise naked DNA, incorporate the DNA of liposome into, engage the DNA of lipid or lipid derivate or pass through suitable plastid or recombinant virus carrier.
Description of drawings
Fig. 1 has shown the cDNA sequence of human class Toll receptor 9.
Fig. 2 has shown the protein sequence of human class Toll receptor 9.
Embodiment
It is reported, not methylated CpG and peptide motif CXXC (two cysteine residues are connected with two amino acid flanks) combination (Voo, people such as K.S., Mol.Cell.Biol.20:2108-2121 (2000)).Based on this information, we have detected the aminoacid sequence of human TLR9.We have identified 255Cys-Arg-Arg- 258Cys (as CRRC) reaches 265Cys-Met-Glu- 268Two CXXC motifs on the Cys (as CMEC).Our proposition now has the peptide fragment (peptide segment) of these two kinds of CXXC motifs to be responsible for interacting with the CpG of TLR9, and therefore very important for the function that is caused by CpG.Therefore, the invention relates to be responsible for the interactional TLR9 of CpG motif on the evaluation of antigenic determinant.
The present invention also comprises the generation and the utilization of the peptide fragment that is incorporated into TLR9 (peptidic segment) being gone up and simulating the molecule of CpG effect.The CpG simulant can be but be not limited to: antibody, micromolecular compound, peptide, peptide simulation and nucleic acid.These novel agents can be used to human with treatment cancer and communicable disease, as those by germ disease in the cells such as similar leishmania, Listerella, Mark Lewis-Francis Pseudomonas, Schistosoma, Ebola virus, anthrax virus and malaria.In addition, these molecules can be used to treat anaphylactic disease, such as, but be not limited to: allergic rhinitis and asthma.These novel agents can by or use separately, perhaps be used in combination or when the administration of human time-like as associating agent (conjugate).
The monoclonal antibody of the antagonism TLR9 of mimic CpG can be by making animal as rodent etc. obtain immunity from the synthetic peptide of human TLR9 deutero-peptide fragment or recombinant protein matter to make to contain, wherein TLR9 comprise as, CRRC or CMEC or both.Perhaps, immunogen can be the DNA of coding from human TLR9 deutero-peptide fragment.Antibody molecule of the present invention comprises polyclone or monoclonal antibody, single-chain antibody, and functional segment.Monoclonal antibody comprises chimeric antibody or humanized antibody, human antibodies or Delmmunised TMAntibody.The segment of these antibody comprises Fv, Fab, F (ab ') 2, keep the strand or the double-stranded Fv segment of maternal antibody antigen combined function.This antibody can make by recombinant chou method known in any this technology and can in vitro or in vivo be made.Single-chain antibody (" ScFv ") and construction method thereof are described in United States Patent (USP) the 4th, 946, in No. 778.
The technology that produces antibody is as follows:
Monoclonal antibody
Monoclonal antibody can adopt the hybridoma method that proposes (Nature, 256:495 (1975)) first by people such as Kohler to make, and maybe can pass through recombinant DNA method (United States Patent (USP) the 4th, 816, No. 567) and make.
In hybridoma method, the quilt immunity as indicated above of a mouse or other suitable main body animal is to draw lymphocyte, and these lymphocytes produce and maybe might produce particular combination in the proteinic antibody that is used for immunity.Perhaps, lymphocyte may be in vitro by immunity.Then by use suitable fusogen (for example polyoxyethylene glycol) make lymphocyte and myeloma cell merge with the formation hybridoma (Goding, Monoclonal Antibodies:Principles and Practice, 59-103 page or leaf (Academic Press, 1986)).
Implanted suitable medium of the hybridoma that makes in this way (the preferable material that contains one or more parent myeloma cells that suppress not fusion growths or survival) and growth therein.For example, if the parent myeloma cell lacks enzyme hypoxanthine guanine phosphoribosyltransferase (HGPRT or HPRT), the substratum that then is used for hybridoma will comprise xanthoglobulin, aminopterinum and thymidine (HAT carrier) usually, and these materials stop the growth that lacks the HGPRT cell.
Preferable myeloma cell is effective fusion, support to carry out the stable high level production of antibody and for the myeloma cell of carrier sensitivities such as for example HAT carrier by selected antibody produced cell.In these myelomatosis, clone is Muridae myelomatosis system, for example those can be available from SalkInstitute Cell Distribution Center, San Diego, Calif.USA from MOPC-21 and MPC-11 mouse tumour deutero-system and available from American Type CultureCollection, Rockville, the SP2/0 of Md.USA. or X63-Ag8-653 cell.The heterogeneous myeloma cell line of human marrow knurl and mouse-people is also described (Kozbor, J.Immunol.133:3001 (1984) for producing the human monoclonal antibody; People such as Brodeur, Monoclonal Antibody Production Techniques and Applications,51-63 page or leaf (Marcel Dekker, Inc., New York, 1987)).Also can use rat bone marrow tumour cell is NSO (European Collection of Cell Cultures, Salisbury, Wiltshire UK).
The substratum that hybridoma grows in is wherein chemically examined to measure the production of this antigenic monoclonal antibody of antagonism.The binding specificity of the monoclonal antibody of being produced by hybridoma can be by immunoprecipitation or by in vitro chemical examination (for example radioimmunoassay (RIA or) or enzyme-linked immunosorbent assay (ELISA)) decide.
Identify produce have the hybridoma that needs specificity, affinity and/or active antibody after, this clone can be by the restriction dilution by subclone and by standard method (Goding, Monoclonal Antibodies:Principles and Practice, 59-103 page or leaf (Academic Press, 1986)) and growth.The suitable medium that is used for this purpose comprises, for example, and D-MEM or RPMI-1640 carrier.In addition, hybridoma can in vivo be grown, and for example ascites tumour is grown in animal body.
By routine immunization sphaeroprotein purge process (for example a-protein-agarose, hydroxyapatite chromatography method, gel electrophoresis, dialysis or affinity chromatography) will be by subclone the excretory monoclonal antibody from substratum, ascites fluid or serum appropriate separation.
(people such as Innis M. exists to use conventional process PCR Protocols.A Guide to Methods and Applications. in, Academic, San Diego, CA (1990), Sanger, F.S waits people Proc.Nat.Acad.Sci.74:5463-5467 (1977)) be easy to the DNA of coding monoclonal antibody is separated and ordering.Hybridoma is as this DNA source.In case it is separated, DNA may be placed in expression vector, this carrier then is transferred to as E.coli cell, ape COS cell, Chinese hamster ovary (CHO) cell or does not produce host cell such as the proteinic myeloma cell of immunoglobulin (Ig) in addition, so that obtain the synthetic of monoclonal antibody in recombinant host cell.Hereinafter will describe the recombinant chou production of antibody in detail.
In another embodiment, antibody or antibody fragment can be separated the antibody phage storehouse that technology produced described in the Nature 348:552-554 (1990) from using people such as McCafferty.People such as Clackson have described respectively in J.Mol.Biol.222:581-597 (1991) people such as Nature 352:624-628 (1991) and Marks and have used phage library to separate the murine and the mankind's antibody.Follow-up publication has been described by chain and slide have been produced high-affinity (nM scope) human antibodies (people such as Marks, Bio/Technology 10:779-783 (1992)), and will make up infect and body in recombinate as the strategy of the very large phage library of construction people such as (, Nuc.Acids.Res.21:2265-2266 (1993)) Waterhouse.Therefore, these technology are the feasible substitute technology that is used for the isolating traditional monoclonal antibody hybridoma technology of monoclonal antibody.
DNA also can be modified, and for example, substitutes corresponding murine sequence (United States Patent (USP) the 4th, 816, No. 567 by the encoding sequence with human heavy chain or light chain constant field; Morrison waits the people, Proc.Nat.Acad.Sci.USA 81:6851 (1984)), or the immunoglobulin coding sequence of all or part of encoding sequence by being covalently attached to the NIg polypeptide.
Usually, this NIg polypeptide is used to substitute the constant field of antibody, perhaps it is used to the variable domain of the compound position of an antigen of alternative antibody, producing a kind of chimeric bivalent antibody, this chimeric bivalent antibody comprises one to have the compound position of narrow spectrum antigen and another to a kind of antigen synantigen is not had the compound position of narrow spectrum antigen.
Another alternative method is to use electricity to merge rather than chemistry merges to form hybridoma.This technology is very perfect.Replace merging, also can use (for example) Epstein Barr virus or a kind of transformer, change the B-cell so that it is not dead.(referring to: for example, " the lasting hyperplasia human cell of predetermined properties is a synthetic antibody " (" Continuously ProliferatingHuman Cell Lines Synthesizing Antibody of PredeterminedSpecificity ") Zurawaki, V.R. wait the people, " monoclonal antibody " (MonoclonalAntibodies) in, people such as Kennett R.H. edit, Plenum Press, N.Y.1980,19-33 page or leaf.)
Produce specific anti--hybridoma of TLR9 monoclonal antibody can be by using derive antigenic ELISA and identify in conjunction with chemically examining by the cell that uses the human TLR9 of cell expressing of TLR9.This specificity activity of antagonist (not being that competitive (agonistic) (simulation CpG) is exactly antagonism (suppressing CpG)) will be by checking influence that their pair cell surface moleculars express and the influence of the production of the Th1-type cytohormone in the main medium of B-cell, T-cell, NK cell, monocyte/macrophage and dendritic cell being tested.Interesting antibody will further be tested in animal model (for example those for Sensitive disease and asthma, tumour, cell in cause of disease disease and vaccine) on the function.
Humanization and human antibodies
Humanized antibody has one or more amino-acid residues of introducing from the non-human source.These non-human amino-acid residues often are known as " introducing " residue, and it is usually from " introducing " variable domain.Can follow Winter and co-worker (people such as Jones, Nature 321:522-525 (1986); People such as Riechmann, Nature 332:323-327 (1988); Verhoeyen waits the people, Science, 239:1534-1536 (1988)) method, by substitute the corresponding sequence of human antibodies with multiple rodent CDR or CDR sequence, carry out humanization basically.Correspondingly, these have " humanization " antibody of fully being less than a complete human variable domain by from non-human species's corresponding sequence and substitute.In fact, the normally following human antibodies of humanized antibody, some of them CDR residue and more possible FR residues are replaced by the residue from similar position in the rodent animal antibody.
The selection of human variable domain (light and heavy both) that is used to produce humanized antibody is extremely important for reducing antigenicity.According to so-called " best-fit " method, the sequence of the variable domain of rodent animal antibody is screened (screen) according to the whole storehouse of known human variable domain sequence.Then be accepted with as the human framework (FR) of humanized antibody (people such as Sims, J.Immunol., 151:2296 (1993) near the human sequence of rodent sequence; People such as Chothia, J.Mol.Biol., 196:901 (1987)).Other method is used from the specific framework of concensus sequence deutero-of everyone antibody-like of the specific subgroup of light chain or heavy chain.Same architecture can be used for multiple different humanized antibody (people such as Carter, Proc.Natl.Acad.Sci.USA, 89:4285 (1992); People such as Presta, J.Immunol., 151:2623 (1993)).
The more important thing is, with the antibody humanization so that its have the confining force of antigen high-affinity and other good biological property.In order to reach this purpose, according to a preferred approach, the analytic process to parent sequence and multiple concept nature humanization product by the three-dimensional model that uses parent and humanization sequence carries out prepares humanized antibody.Usually can obtain three-dimensional immunoglobulin (Ig) model and it is familiar with by those who familiarize themselves with the technology.Can utilize the computer program of describing and showing the possible three-dimensional conformation structure of candidate's immunoglobulin sequences of being chosen.The observation of these demonstrations is allowed the analysis that may act on of residue in the functionalization of this candidate's immunoglobulin sequences, just, to the analysis of the residue that influences this candidate's immunoglobulin (Ig) and its antigen binding capacity.By this approach, the FR residue can be selected from receptor and important sequence and combination, so that the antibody characteristic that need to obtain the enhanced avidity of target antigen or a plurality of target antigens (for example to).Generally speaking, in influence to antigen-binding, the direct and main CDR residue that relates to.
Perhaps, skilled researcher can produce transgenosis animal (for example mouse), and this transgenosis animal is having the ability to give birth to the whole integral parts that produce human antibodies when immunoglobulin (Ig) is produced in lacking on the basis of immunization.This transgenosis mouse can be available from Abgenix Inc., Fremont, and California and Medarex, Inc., Annandale, New Jersey buys.According to description, chimeric and kind is the inhibition fully that the homozygosity disappearance of heavy chain calmodulin binding domain CaM (JH) gene of (germ-line) mutant mice antibody causes internally giving birth to antibody producing.Human racial immunity globulin gene array in this germ line mutation mouse shifts the generation that will cause human antibodies under the antigen stimulation.See: for example, people such as Jakobovits, Proc.Natl.Acad.Sci.USA 90:2551 (1993); People such as Jakobovits, Nature 362:255-258 (1993); People such as Bruggermann, Year in Immunol.7:33 (1993); With people Nature 355:258 (1992) such as Duchosal.Human antibodies also can from phage display library, derive (people such as Hoogenboom, J.Mol.Biol.227:381 (1991); People such as Marks, J.Mol.Biol.222:581-597 (1991); Vaughan waits the people, Nature Biotech14:309 (1996)).
Delmmunised TMAntibody
Delmmunised TMAntibody is the antigen that has been removed of potential T cell antigen determinant wherein, as described in international application PCT/GB98/01473.Therefore, we wish when being used for these antibody in vivo human immunity originality (immunogenicity) to be removed or fully reduced.
In addition, for example, antibody can be circulated half life to increase it by chemical modification by being covalently bonded in polymkeric substance.Preferable polymkeric substance and its method that invests peptide is described in United States Patent (USP) the 4th, 766, No. 106, the 4th, 179, No. 337, the 4th, 495, No. 285 and the 4th, 609, No. 546, it all is incorporated herein by reference in full.Preferable polymkeric substance is polyoxy ethylization polyvalent alcohol and polyoxyethylene glycol (PEG).PEG at room temperature water soluble and have preferable between 1000 to 40000, be more preferably under between 2000 to 20000, molecular-weight average between best 3000 to 12000.
Other molecule
Can will be suitable for other molecule of the present invention by ordinary method separates from compound library or screens (screen) and come out.A kind of automatic system that is used to produce and screen a compound library is described in United States Patent (USP) the 5th, 901, and No. 069 and the 5th, 463, in No. 564.A method of more being paid close attention to comprises the three-dimensional modelization of combination position, and then makes the molecule family of suitable this model.Then these molecules are screened, to select molecule with best combination characteristic.
Gene constructs
Gene constructs of the present invention can be merged in viral genome and be encapsulated into subsequently in the suitable virus particle, and this virus particle allows to carry out the high efficiency gene transmission by virus infection.The exemplary virus vector that is generally used for gene therapy comprises retrovirus carrier, adenovirus carrier and adeno-associated virus (AAV) (AAV) carrier.The virus vector of development recently that is suitable for gene therapy comprises slow virus (based on the carrier of HIV-1 or HIV-2) and alpha virus vector (based on Sindbis virus and Semliki Forest virus).Can by will make a copy of the unit subclone go into to contain the necessary sequence of virus encapsulation suitable boxlike carrier (cassette vecto) and with gene constructs incorporate retrovirus into, slowly in the viral genome of virus or AAV carrier.When the DNA with the gained construction was transfected in the suitable encapsulate cells system that produces virus ingredient, the recombinant virus genome can suitably be encapsulated into great-hearted virus particle.
For gene constructs being incorporated into the adenoviral gene group, need an additional step usually.Because the adenoviral gene group length is about 36Kbp, therefore antibody gene is directly inserted genome by limiting acid endo enzyme eupepsy and ligation inconvenience.Displaced method is that gene is inserted into a boxlike carrier (cassette vecto), for example pAvCvSv (people (1996) J.Biol.Chem.22:6852-60 such as Kobayashi K).It is key and contain adenovirus type 5 (Ad5) 5 ' and reverse terminal and repeat (ITR) that this carrier has pBR322, the duplicating of Ad5 basis, Ad5 encapsidate signal, Ela intensifying factor, polyclone position and as the pulsating Ad5 sequence from nucleosides position 3328 to 6246 of homologous recombination body.Then the gained plastid is gone into appropriate host cell system together with containing in a large number the adenoviral gene group cotransfection that has a disappearance at some hiv region (for example E1 nuclear E3 gene), 293 cells (Graham FL for example, Deng the people, J.Gen.Virol.36:59-72 (1977)).The homologous recombination body in crossover zone will allow to keep the genomic generation of recombinant virus of anti--TLR9 gene between two DNA.This recombinant gene group will be encapsulated into the great-hearted infective virus particle in 293 host cells subsequently.Can adopt similarity method to incorporate gene into alphavirus or other has the genome of the virus of big genome, to produce recombinant virus.
These gene constructs can be prepared as plastid, and this plastid can be passed to host cell or tissue directly or as a kind of in the naked DNA dual mode, or incorporate liposome into, engage with suitable lipid component or incorporate into virus vector as DNA.Preferable its injection is given being used to.Gene constructs will be used to guide the synthetic of the molecule that is incorporated into TLR9 or its antibody fragment by expectation, and these molecules will progress into blood flow to interact with TLR9.Can the recombinant virus construction be given in the individuality with anaphylactic disease by intramuscular route, intravenously route or subcutaneous route.Can determine dosage with extrapotation or in the human clinical trial, determine dosage by experimentation on animals.
In another embodiment, cell transfected with express specific at, be incorporated into or suppress the interior antibody (intrabody) of TLR9 acceptor." interior antibody " used herein is a kind of antibody, and this antibody is expressed in cell and had an activity.Interior antibody is not secretion usually but is directed to the cell inner expression target.Interior antibody is incorporated into intracellular target usually and therefore target is captured in the endocellular metabolism district (for example, ER).Those who familiarize themselves with the technology know interior antibody (referring to: as people such as Chen, Hum.Gene Therap.7:1515-1525 (1996); MarascoImmunotech. 1:119 (1995); Reach people Nature Med.1:667-673 (1995) such as Maciejewski).In theory, the high-affinity of interior antibody and selective binding character can be used for adjusting cells physiological and metabolism with number of mechanisms.For example, the combination of interior antibody can be used to block or stable macromolecule interaction, adjust the enzyme function, optionally can completely cut off matrix or enzyme is adjusted to active or nonactive conformation by an inaccessible active sites.Interior antibody also can be used for from its common cellular metabolism district transferring protein, for example, and by the intracytoplasmic transcription factor of obturation, or by the confining force among the protein ER that goes to cell surface.In this, interior antibody combines with the present invention, can cause the signal transduction of simulation CpG effectively.
Extra drug excipient can be used to control the active duration of molecule of the present invention.These vehicle can by trap in send in the system (for example liposome, albumin microsphere, microemulsion, nanoparticle and Nano capsule) by condensation technique or by gluey medicine or microcapsule that the interfacial polymerization (Walocel MT 20.000PV or gelatin microcapsule) in the big emulsion makes in.The method for preparing the liposome transmitting system is described in people such as Gabizon, Cancer Research42:4734 (1982); Cafiso, Biochem Biophys Acta 649:129 (1981); And Szoka, Ann Rev Biophys Eng 9:467 (1980).Other medicines transmission system is for known in this technology and be described in, for example, and people such as Poznansky: Drug Delivery Systems(R.L.Juliano edits, Oxford, N.Y.1980), the 253-315 page or leaf; M.L.Poznansky, Pharm Revs 36:277 (1984).
Composition of liquid medicine can be by freeze-drying to stop degeneration and to keep aseptic.Generally be familiar with the method that this operator understands the freeze-drying liquid composition.Only before use, said composition can be restored by sterile diluent (for example Ringer's solution, distilled water or Sterile Saline), and this sterile diluent may comprise extra composition.When restoring, said composition can be given in the patient.
Molecule of the present invention can be by any being given in the multiple route, and be given with the effective concentration of treatment indicated or that be used for the purpose of being sought.For achieving this end, can use in multiple this technology known acceptable vehicle to allocate these antibody.Usually, give these antibody by injection (in intravenous injection or the peritoneal injection dual mode a kind of).Generally be familiar with this operator and understand the method that this gives of finishing.Also may obtain can be by part or orally give, the composition that maybe can transmit through mucous membrane.
Dosage that gives and pattern will depend on individuality and with the reagent that is given and decide.Can determine dosage with extrapotation by the routine test in the clinical trial or by the effective zootype of antibody.
Foregoing description, term, expression and example only are exemplary and are not for restricted.The present invention includes the known and unknown equivalent embodiment of all the foregoing descriptions.The present invention only is subjected to following claim restriction and not limited by any statement of any other parts in this document or any other source.

Claims (30)

1. molecule, it combines and simulates this CpG motif effect with peptide fragment on the TLR9.
2. molecule as claimed in claim 1, it is antibody or its immunologic function segment, peptide, oligonucleotide, peptide simulation or organic compound.
3. composition, it comprises the molecule that combines and simulate this CpG motif effect with the peptide fragment on the TLR9.
4. composition as claimed in claim 3, wherein said molecule are antibody or its immunologic function segment, peptide, oligonucleotide, peptide simulation or an organic compound.
5. molecule as claimed in claim 1, wherein said molecule are incorporated into the Cys-Arg-Arg-Cys of TLR9 or at least one among the Cys-Met-Glu-Cys.
A gaonist anti--the TLR9 molecule, it combines with TLR9 and stimulates TLR9.
7. as each antibody in the claim 2,4 or 6, wherein said antibody is monoclonal antibody.
8. monoclonal antibody as claimed in claim 7, wherein said antibody are chimeric antibody, humanized antibody, Delmmunised TMAntibody or human antibodies.
9. clone, it produces as each antibody in the claim 2,4 or 6.
10. clone, it produces antibody as claimed in claim 9.
11. a method for the treatment of TLR-modulability disease, it comprises that the peptide fragment with on the TLR9 that gives significant quantity combines and simulate the molecule or the composition of this CpG motif effect.
12. as the method for claim 11, wherein said molecule is antibody or its immunologic function segment, peptide, oligonucleotide, peptide simulation or organic compound.
13. as the method for claim 12, wherein said molecule is to combine with TLR9 and stimulate the gaonist of TLR9 anti--the TLR9 molecule.
14. as the method for claim 12, wherein said molecule is a monoclonal antibody.
15. as the method for claim 14, wherein said monoclonal antibody is chimeric antibody, humanized antibody, Delmmunised TMAntibody or human antibodies.
16. as the method for claim 11, wherein said disease is an anaphylactic disease.
17. as the method for claim 11, wherein said disease is a communicable disease.
18. an enhancing is to the method for tumour or treatment for cancer, it comprises: combine and give with Anti-tumor or anti--cancer agent and TLR9 goes up peptide fragment bonded molecule or composition, thereby strengthen this Anti-tumor or resist-effect of cancer agent.
19. a method of inducing the reaction of Th1-type, it comprises that the peptide fragment with on the TLR9 that gives significant quantity combines and simulate the molecule or the composition of this CpG motif effect.
20. one kind makes the subject to the method because of the desensitization that contacts the anaphylaxis that specific allergen causes, it comprises to this subject and gives molecule or the composition that the peptide fragment with on the TLR9 of significant quantity combined and simulated this CpG motif effect.
21. a method that makes subject's immunity, it comprises molecule or the composition that gives antigen or be encoded in the antigen in the dna vaccination and combine and simulate this CpG motif effect with the peptide fragment on the TLR9 to the subject.
22. an immunogen, it comprises synthetic peptide, recombinant protein matter or from the encode DNA of this peptide or this recombinant protein matter of the TLR9 deutero-that contains CRRC and/or CMEC, it is induced and is incorporated into the production of antibodies of being responsible in conjunction with this TLR9 antigenic determinant of CpG.
23. as the immunogen of claim 22, wherein said molecule combines with CRRC and/or CMEC.
24. method that makes patient's immunity, it comprises and synthesizes peptide, recombinant protein matter or from the encode DNA of this peptide or this recombinant protein matter of the TLR9 deutero-that contains CRRC and/or CMEC, it is induced and is incorporated into the production of antibodies of being responsible in conjunction with this TLR9 antigenic determinant of CpG.
25. a molecule, it combines and suppresses the function of this receptor with the peptide fragment on the TLR9.
26. a method for the treatment of TLR-modulability disease, it comprises that the peptide fragment with on the TLR9 that gives significant quantity combines and suppress the molecule or the composition of the function of this receptor.
27. an encoding antibody or its pulsating nucleic acid construct thing, it combines and simulates this CpG motif effect with peptide fragment on the TLR9.
28. a recombinant expression vector, it comprises the nucleic acid as claim 27.
29. a cell, it is transformed by the nucleic acid as claim 27.
30. a method of inducing the peptide fragment bonded molecule of host cell expression and TLR9, it comprises the prescription as the nucleic acid of claim 27.
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