WO2002015931A9 - Immunologic method for the prevention of dental caries - Google Patents
Immunologic method for the prevention of dental caries Download PDFInfo
- Publication number
- WO2002015931A9 WO2002015931A9 PCT/US2000/023277 US0023277W WO0215931A9 WO 2002015931 A9 WO2002015931 A9 WO 2002015931A9 US 0023277 W US0023277 W US 0023277W WO 0215931 A9 WO0215931 A9 WO 0215931A9
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- prevention
- dental caries
- treatment
- mammal
- monoclonal antibody
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
- A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
- A61K8/9783—Angiosperms [Magnoliophyta]
- A61K8/9789—Magnoliopsida [dicotyledons]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/12—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria
- C07K16/1267—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-positive bacteria
- C07K16/1275—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-positive bacteria from Streptococcus (G)
-
- 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
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
- A61K2800/86—Products or compounds obtained by genetic engineering
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
Definitions
- This application relates to an immunologic methodology for the ⁇ - treatment and prevention of dental caries.
- This invention has special application to patients who are without the ability or motivation to apply established principles of self care, such as very young children, the infirm and poorly educated populations.
- Dental caries teeth decay
- periodontal disease are probably the most common chronic diseases in the world.
- the occurrence of cavities in teeth is the result of bacterial infection.
- the occurrence of dental caries is
- Streptococcus mutans is believed to be the principal cause of tooth decay in man. When S. mutans occurs in large numbers in dental plaque, and metabolizes complex sugars, the resulting organic acids cause
- antimicrobial agents are not selective for cariogenic organisms.
- Administration of non-specific bacteriocidal agents disturbs the balance of organisms that normally inhabit the oral cavity, with consequences that cannot be predicted, but may include creation of an environment that provides opportunities for pathogenic organisms.
- long term use of antimicrobial agents is known to select for organisms that are resistant to them. Hence long term and population-wide use of antimicrobial agents to prevent tooth decay is not practical.
- One drawback of this approach is that vaccination elicits production of predominantly IgG and IgM antibodies, but they are not secreted into saliva. The majority of antibodies present in saliva are of the IgA isotype, which can bind to, but cannot activate lymphocytes or complement components to kill bacteria. Accordingly, vaccination is not believed likely to be capable of producing antibodies that can trigger the immune system to kill cariogenic organisms in the mouth.
- IgA is a multivalent antibody
- a single molecule of IgA can bind to several different antigenic sites, resulting in clumping of bacteria.
- binding of IgA to bacterial surface antigens does not kill the bacteria. Rather, clumping is believed to hinder the ability of bacteria to bind to tooth surfaces.
- Another drawback of this approach is that repeated administration of mouse (i.e., heteroiogous) antibodies to humans has the potential to evoke an immune response to the antibodies.
- antibodies of the IgG and IgM classes have bacteriocidal effects. Binding of IgM or IgG antibodies to antigens present on the surface of cariogenic organisms may result in the destruction of the bacterial cells by two separate mechanisms: complement mediated cell lysis and antibody- dependent cell-mediated cytotoxicity. In either case, antibodies that selectively bind to certain microbial organisms target just those cells for destruction by the immune system. Both complement mediated cell lysis and antibody-dependent cell mediated cytotoxicity are part of the humoral immune response that is mediated by antibodies of the IgG and IgM classes.
- Dental caries may be prevented or treated by oral ingestion of human or humanized mouse monoclonal IgG and IgM antibodies that to bind surface antigens of cariogenic organisms, such as S. mutans.
- the genetically engineered monoclonal antibodies engage the effector apparatus of the human immune system when they bind to cariogenic organisms, resulting in their destruction.
- monoclonal antibodies to cariogenic organisms are produced by edible plants, including fruits and vegetables, transformed by DNA sequences that code on expression for the desired antibodies. The antibodies are applied by eating the plants.
- the monoclonal antibody technique permits preparation of a source of antibodies with extraordinary specificity.
- Monoclonal antibodies that bind to specific molecular structures can be produced using what are today considered standard techniques.
- the monoclonal antibodies that may be used in this invention are those that are directed to surface antigens of cariogenic organisms.
- Surface antigens are substances that are displayed on the surface of cells. Such o antigens are accessible to antibodies present in body fluids.
- surface antigens of cariogenic organisms are present on the surface of organisms that cause dental caries. While the role of bacterial activity in the genesis of carious lesions is well defined, establishing a cause and effect 5 relationship between a particular organism and the occurrence of dental caries has not been completely successful. To date, only S. mutans has been definitively associated with dental caries.
- a further requirement of the monoclonal antibodies that may be used in the practice of the present invention is that they are selective for cariogenic organisms.
- Monoclonal antibodies directed to antigens present on 5 cariogenic as well as non-cariogenic organisms may produce non-specific alterations in the makeup of the flora within the oral cavity. The consequences of such changes are not understood.
- the preferred monoclonal antibodies are directed to surface antigens of cariogenic organisms. That is to say, the preferred monoclonal antibodies bind specifically to organisms that cause dental caries. It should be clearly understood that the scope of the present invention is not limited to the prevention of tooth decay in man. Monoclonal antibodies in accordance with the present invention can be genetically engineered to engage the effector response of the immune system of other mammals, such as those that are domesticated as pets.
- Monoclonal antibodies are prepared by immunizing mice or other mammalian hosts with cell wall material isolated from cariogenic organisms.
- the cariogenic organisms are type c S. mutans (ATCC25175).
- the immunogenecity of molecules present in cell walls may be enhanced by a variety of techniques known in the art. In a preferred embodiment, immunogenecity of such molecules is enhanced by denaturation of the isolated cell material with formalin. Other techniques for modifying cell wall proteins to enhance immunogenecity are within the scope of this invention.
- hosts receive one or more subsequent injections of isolated bacterial cell fragments to increase the titer of antibodies prior to sacrifice and cloning.
- Spleen cells from hosts are harvested and cloned by limiting dilution using techniques that have become standard since the pioneering work of Kohler and Milstein.
- surviving hybridomas are screened for antibody directed to cariogenic organisms by ELISA assay against microtiter plates coated with formalinized bacterial cell material. Positive supernatants may be subjected to further screening to identify clones that secrete antibodies with the greatest affinity for the cariogenic organisms.
- clones with titers at least three times higher than background are screened again using an immunoprecipitation against denatured cell wall material from S. mutans.
- three clones were identified which bound detectably only to S. mutans strains ATCC25175, LM7, OMZ175 and ATCC31377. These clones were deposited with the American Type Culture
- Drawbacks to this approach include 1 ) administration of heteroiogous antibodies may aggregate the offending organisms, but will not kill them because such antibodies will not elicit an immune response; and 2) repeated administration of the antibody may elicit an immune response from the patient to the antibody.
- a preferable approach is to use recombinant techniques to prepare chimeric antibody molecules directed specifically to surface antigens of cariogenic 5 organisms, that will also elicit an effector response from the human immune system (when used in man) upon binding to the target organism. This can be accomplished by inserting variable regions or complementarity determining o regions ("CDR's") from mouse monoclonal antibodies that are specific to cariogenic organisms into antibodies of the IgG and/or IgM classes from the mammal to be treated.
- CDR's complementarity determining o regions
- the antibodies are said to be "humanized.” 5
- nucleic acid sequences that code on expression for human or humanized monoclonal antibodies to surface antigens of cariogenic organisms 1 ) Isolating mouse hybridomas which produce monoclonal antibodies against cariogenic organisms and cloning mouse genes that code on expression for those antibodies; 2) Using purified cariogenic organisms to screen a phage display random library made from human B ° lymphocytes to obtain genes that encode antibodies specific for cariogenic organisms; 3) Isolating human hybridomas that produce monoclonal antibodies against cariogenic organisms, using B lymphocytes recovered from heavily infected patients and cloning the human genes encoding for these antibodies; or 4) immunizing human B lymphocytes and spleen cells in vitro using purified cariogenic organisms, followed by fusion to form hybridomas to create immortal cell lines.
- the techniques required are known to those skilled in the art.
- mouse monoclonal antibodies are "humanized," Using the PCR or Southern blot technique, DNA fragments encoding the variable domains of mouse hybridomas secreting antibody specific to cell surface antigens of cariogenic organisms are isolated. Using gene cloning techniques, the variable regions of human IgG and 0 IgM immunoglobulin are replaced with the corresponding mouse variable regions or CDR's. The result of this genetic engineering is a chimeric antibody molecule with variable domains that selectively bind to surface antigens of cariogenic organisms, but which interacts with the human immune system through its constant regions to trigger a humoral immune response. 5
- the desired cell line transfected with IgG or IgM encoding ° sequences must be propagated.
- Existing technology permits large scale propagation of monoclonal antibodies in tissue culture.
- the transfected cell lines will secrete monoclonal antibodies into the tissue culture medium.
- the secreted monoclonal antibodies are recovered and purified by gel filtration and related 5 techniques of protein chemistry.
- Type c S. mutans strain ATCC25175 are grown to log phase in BHI medium and washed twice with phosphate buffered saline, pH 7.2 (PBS), by centrifugation at 3000xg for 5 min. The pellet is resuspended in 1% formalin/0.9% NaCI, mixed at room temperature for 30 min and washed twice with 0.9% NaCI.
- BALB/c mice (8-10 weeks) are immunized intraperitoneally with 100 FI of the antigen containing approximately 10 8 whole cells of formalinized intact S. mutans 0 bacteria emulsified with Freund's incomplete adjuvant (FIA). After 3-5 weeks, mice will receive a second dose of antigen (10 8 whole cells of bacteria in FIA). Three days prior to fusion, the mice are boosted intravenously with 10 8 whole cells in saline.
- the standard tissue culture media is RPM1 1640 (Gibco) medium supplemented with 2 mM L-glutamine, 1mM sodium pyruvate, and 10 mM HEPES and containing 100 ⁇ g/ml penicillin and 100 / ⁇ g/ml streptomycin with 5 10% fetal calf serum.
- Hybrids are selected in media containing HAT (100 ⁇ g
- Hypoxanthine 0.4. ⁇ M Aminopterin; 16 ⁇ M Thymidine).
- HT 100 ⁇ g Hypoxanthine; 16 ⁇ M Thymidine
- OPI 1 mM oxaloacetate, 0.45 mM pyruvate and 0.2 U/ml bovine insulin
- Hybridomas are raised according to the procedure reported by Liddell and Cryer (A Practical Guide to Monoclonal Antibodies, John Wiley & Sons, Chichester, England, 1991).
- the NSI/A94.1 mouse myeloma cell line is used as the fusion partner and grown in spinner 5 cultures in 5% C02 at 37°C and maintained in log phase of growth prior to fusion.
- the following approach is used for screening for species-specific monoclonal antibodies against S. mutans.
- the initial screening is performed using an ELISA assay, which selects for the culture supernatants containing ° antibodies that bind to S. mutans.
- Genomic DNA of mouse hybridoma cell lines is isolated using the QIAamp system (Qiagen, Valencia, CA). After digestion with various restriction enzymes, DNA fragments are fractionated through 0.8% agarose gel by electrophoresis and transferred to a nitrocellulose membrane. Southern blotting is performed to identify the immunoglobulin gene.
- the heavy chain gene is probed with a DNA fragment from a mouse IgG heavy-chain gene that includes 5 the J3 and J4 segments and the enhancer region.
- the light chain gene is probed with a DNA fragment from a mouse IgG light-chain gene containing J1-5 segments.
- DNA restriction fragments of the selected size identified through Southern blot analysis are purified from agarose gel using Qiagen DNA Clean-up and Gel extraction system.
- the DNA is ligated into the Lambda-Zap 11 vector (Stratagene) to construct heavy- and light-chain libraries of these mouse hybridomas in lambda phage.
- the libraries are screened with heavy- and light-chain J-region probes as mentioned above.
- DNA of the positive clones is isolated, subcloned and sequenced. To achieve the best accuracy, both sense and antisense strands are sequenced.
- BLAST search is employed to translate the nucleotide sequence into the amino acid sequence and compare it with the existing antibody genes.
- variable region of the heavy-chain is identified, 0 subcloned and inserted into an expression vector which contains a DNA fragment encoding the human IgG heavy chain constant region and the Ecogpt gene providing resistance to mycophenolic acid.
- variable region of the light-chain is also identified, subcloned and inserted into another expression vector which includes a DNA fragment encoding the human IgG light chain constant region and the neo gene giving resistance to G418. 5
- Organisms a) Producing human or humanized monoclonal antibodies in animal cells °
- the heavy and light chain of a human IgG gene are separately introduced or cotransfected into an animal cell line (such as SP2/0) using a lipofection reagent (BRL, Grand Island, NY).
- the transfected cells are incubated at 37°C in a 5% C02 atmosphere in 1x zinc option medium for 24 h and then in medium containing 10% fetal bovine serum. After 48 h incubation, the cells are transferred to a microtiter plate and grown in selection medium containing G418 and mycophenolic acid. The supernatants of drug-resistant cells are collected and screened for immuno-reactivity against S.
- Transgenic plants have been recognized as very useful systems to produce large quantities of foreign proteins at very low cost. Expressing human or humanized monoclonal antibodies against S. mutans in edible plants (vegetables or fruits) allows direct application of plant or plant extracts to the mouth to treat existing dental caries and to prevent future bacterial infection.
- the choice of transgenic, edible plants includes, but is not limited to, potato, tomato, broccoli, and banana.
- transgenic Arabidopsis an edible plant closely related to Brassica species including common vegetables such as cabbage, cauliflower and broccoli. It is chosen because many genetic and biochemical tools have been well developed for this plant.
- IgG immunoglobulin G
- One strategy is to first introduce the human IgG genes encoding the heavy chain and light chain to two separate transgenic lines. The two genes are brought together by genetic crossing and selection. Other methods involve sequential transformation, in which transgenic lines transformed with one IgG gene are re-transformed with the second gene.
- genes encoding the heavy chain and light chain are cloned into two different cloning sites in the same T-DNA transformation vector under the control of two promoters, and the expression of both genes can be achieved by the transformation of a single construct to plant.
- the separate transformation method is the simplest one and it usually results in higher antibody yield. Therefore, we present this strategy here. It is possible to transform other plants using similar techniques.
- the DNA fragments encoding the heavy and light chains of a human IgG gene are separately cloned into a Ti plasmid of Agrobacterium tumefaciens.
- the plasmid contains a promoter to express human heavy and light chains of IgG in Arabidopsis thaliana, an antibiotic marker for selection in Agrobacterium tumefaciens and an herbicide resistance gene for transformation selection in Arabidopsis.
- An Agrobacterium tumefaciens strain is transformed with these plasmids, grown to late log phase under antibiotic selection, and resuspended in infiltration medium described by Bethtold et al. (C.R. Acad. Sci. Paris Life Sci. 316:1194-1199, 1993). Transformation of Arabidopsis by Ti-plasmid containing
- Agrobacterium tumefaciens is performed through vacuum infiltration. Entire plants of Arabidopsis are dipped into the bacterial suspension. The procedure is performed in a vacuum chamber. Four cycles of 5 min vacuum (about 40 cm mercury) are applied. After each application, the vacuum is released and reapplied immediately. After infiltration, plants are kept horizontally for 24 h in a growth chamber. Thereafter, the plants are grown to maturity and their seeds are harvested. The harvested seeds are germinated under unselective growth condition until the first pair of true leaves emerged. At this stage, plants are sprayed with the herbicide Basta at concentration of 150 mg/l in water.
- the aribidopsis plants containing transformed Ti plasmids are resistant to the herbicide while the untransformed plants are bleached and killed. Such a selection continues to the second generation of the plants.
- total genomic DNA is isolated and probed with the DNA fragments encoding heavy and light chains of the IgG gene.
- the plant extracts from the positive transformants are prepared and screened for the expression of human
- IgG protein with Western blot using antibodies against heavy and light chains of constant regions of human IgG.
- the plants expressing human IgG heavy chain are sexually crossed with plants expressing human IgG light chain to produce progeny expressing both chains.
- Western blotting is used to screen the both heavy and light chains. Extracts from positive transformants are collected and screened for immuno-reactivity against S. mutans using the ELISA or precipitation assays mentioned above. 4. Using human or humanized monoclonal antibodies against
- Plant tissue extracts containing monoclonal antibodies to S. mutans are mixed with various concentrations of S. mutans in the presence and absence of purified human complement components or purified human polymorphonuclear neutrophilic leukocytes. After a two hour incubation, the mixtures are plated onto BHI plates to examine the bactericidal activity. Using the artificial plaque formation system developed by
Abstract
Description
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Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2000270698A AU2000270698A1 (en) | 2000-08-24 | 2000-08-24 | Immunologic method for the prevention of dental caries |
JP2002520852A JP2004506695A (en) | 2000-08-24 | 2000-08-24 | Immunological methods of caries prevention |
PCT/US2000/023277 WO2002015931A1 (en) | 2000-08-24 | 2000-08-24 | Immunologic method for the prevention of dental caries |
EP00959362A EP1313506A1 (en) | 2000-08-24 | 2000-08-24 | Immunologic method for the prevention of dental caries |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/US2000/023277 WO2002015931A1 (en) | 2000-08-24 | 2000-08-24 | Immunologic method for the prevention of dental caries |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2002015931A1 WO2002015931A1 (en) | 2002-02-28 |
WO2002015931A9 true WO2002015931A9 (en) | 2002-05-23 |
Family
ID=21741708
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2000/023277 WO2002015931A1 (en) | 2000-08-24 | 2000-08-24 | Immunologic method for the prevention of dental caries |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP1313506A1 (en) |
JP (1) | JP2004506695A (en) |
AU (1) | AU2000270698A1 (en) |
WO (1) | WO2002015931A1 (en) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030143234A1 (en) * | 1999-08-20 | 2003-07-31 | Wenyuan Shi | Anti-microbial targeting chimeric pharmaceutical |
US20020068066A1 (en) * | 1999-08-20 | 2002-06-06 | Wenyuan Shi | Method for the treatment and prevention of dental caries |
US7569542B2 (en) | 1999-08-20 | 2009-08-04 | The Regents Of The University Of California | Anti-microbial targeting chimeric pharmaceutical |
US7875598B2 (en) | 2004-03-04 | 2011-01-25 | The Regents Of The University Of California | Compositions useful for the treatment of microbial infections |
EP2801368B1 (en) | 2006-09-06 | 2018-08-29 | The Regents of The University of California | Selectively targeted antimicrobial peptides and the use thereof |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6028937A (en) * | 1983-07-25 | 1985-02-14 | Kitasato Inst:The | Noncariogenic antibody and composition |
JPS6038329A (en) * | 1983-08-11 | 1985-02-27 | Lion Corp | Preventive for dental caries |
US5352446A (en) * | 1986-03-25 | 1994-10-04 | Council Of Governors Of The United Medical And Dental Schools Of Guy's And St. Thomas's Hospitals | Method of treating dental caries with monoclonal antibodies against the antigen I and antigen I/II of streptococcus mutans |
JP2641228B2 (en) * | 1988-01-22 | 1997-08-13 | 鐘紡株式会社 | Antibody, caries preventive agent containing the same as an active ingredient, and methods for producing the same |
JPH02177899A (en) * | 1988-12-28 | 1990-07-10 | Nagase Sangyo Kk | Igd monoclonal antibody specifically reactive with streptococcus mutans |
GB9014932D0 (en) * | 1990-07-05 | 1990-08-22 | Celltech Ltd | Recombinant dna product and method |
JPH05227916A (en) * | 1992-01-11 | 1993-09-07 | Kanebo Ltd | Dental caries preventing food |
JPH06122633A (en) * | 1992-10-09 | 1994-05-06 | Lion Corp | Antibody having immunoactivity on streptococcus mutans and dental caries preventive |
US6046037A (en) * | 1994-12-30 | 2000-04-04 | Hiatt; Andrew C. | Method for producing immunoglobulins containing protection proteins in plants and their use |
CN1183802A (en) * | 1994-12-30 | 1998-06-03 | 行星生物技术有限公司 | Method for producing immunoglobulins contg. protection proteins in plants and their use |
AU756242B2 (en) * | 1998-08-21 | 2003-01-09 | Regents Of The University Of California, The | Monoclonal antibodies specific for streptococcus mutans, and uses thereof |
-
2000
- 2000-08-24 AU AU2000270698A patent/AU2000270698A1/en not_active Abandoned
- 2000-08-24 EP EP00959362A patent/EP1313506A1/en not_active Withdrawn
- 2000-08-24 JP JP2002520852A patent/JP2004506695A/en active Pending
- 2000-08-24 WO PCT/US2000/023277 patent/WO2002015931A1/en not_active Application Discontinuation
Also Published As
Publication number | Publication date |
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EP1313506A1 (en) | 2003-05-28 |
WO2002015931A1 (en) | 2002-02-28 |
JP2004506695A (en) | 2004-03-04 |
AU2000270698A1 (en) | 2002-03-04 |
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