US20030129587A1 - Antigen/antibody specificity exchanger - Google Patents

Antigen/antibody specificity exchanger Download PDF

Info

Publication number
US20030129587A1
US20030129587A1 US10/234,579 US23457902A US2003129587A1 US 20030129587 A1 US20030129587 A1 US 20030129587A1 US 23457902 A US23457902 A US 23457902A US 2003129587 A1 US2003129587 A1 US 2003129587A1
Authority
US
United States
Prior art keywords
antigen
antibody
peptide
sequence
hepatitis
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US10/234,579
Inventor
Matti Sallberg
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from SE9401460A external-priority patent/SE9401460D0/en
Application filed by Individual filed Critical Individual
Priority to US10/234,579 priority Critical patent/US20030129587A1/en
Priority to US10/372,735 priority patent/US6933366B2/en
Publication of US20030129587A1 publication Critical patent/US20030129587A1/en
Priority to US11/121,282 priority patent/US20060094862A1/en
Priority to US11/412,181 priority patent/US20070026502A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/081—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from DNA viruses
    • C07K16/082—Hepadnaviridae, e.g. hepatitis B virus
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
    • C07K16/1036—Retroviridae, e.g. leukemia viruses
    • C07K16/1045—Lentiviridae, e.g. HIV, FIV, SIV
    • C07K16/1063—Lentiviridae, e.g. HIV, FIV, SIV env, e.g. gp41, gp110/120, gp160, V3, PND, CD4 binding site
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/531—Production of immunochemical test materials
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011—Details
    • C12N2710/20011—Papillomaviridae
    • C12N2710/20022—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2730/00—Reverse transcribing DNA viruses
    • C12N2730/00011—Details
    • C12N2730/10011—Hepadnaviridae
    • C12N2730/10111—Orthohepadnavirus, e.g. hepatitis B virus
    • C12N2730/10122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16211—Human Immunodeficiency Virus, HIV concerning HIV gagpol
    • C12N2740/16222—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011—Details
    • C12N2770/24011—Flaviviridae
    • C12N2770/24211—Hepacivirus, e.g. hepatitis C virus, hepatitis G virus
    • C12N2770/24222—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011—Details
    • C12N2770/32011—Picornaviridae
    • C12N2770/32611—Poliovirus
    • C12N2770/32622—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00—Chemistry: molecular biology and microbiology
    • Y10S435/974—Aids related test

Definitions

  • the present invention relates to an antigen/antibody specificity exchanger, which comprises an amino-acid sequence which specifically binds to a certain antigen linked to an amino-acid sequence to which a certain antibody binds.
  • an antigen/antibody specificity exchanger of the invention can be used as a diagnostic reagent instead of antisera or monoclonal antibodies in testing systems, and in vivo it can be used to redirect antigens or antibodies to other antibodies or antigens, respectively, than they were originally directed to.
  • the widely used poliovirus vaccination together with the high rate of seropositivity to enteroviral proteins may be a suitable pool of antibodies to redirect against other pathogens, such as HIV.
  • the complementary determining regions (CDRs) of antibodies are responsible for the specificity of the antibody (1,2).
  • X-ray crystallography has shown that the three CDRs of the variable (V) region of the heavy chain and the three CDRs of the V region of the light chain may all have contact with the epitope in an antigen-antibody complex (3).
  • Single peptides corresponding to the CDRs of mAbs to various antigens have been shown to mimic the recognition capabilities of the respective mAb (4-10).
  • a peptide corresponding to CDRH3 of a mAb specific for the V3 region of human immuno deficiency virus-1 holds neutralizing capacity when assayed in vitro (9).
  • the CDRH2 of a mAb to hepatitis B core antigen (HBcAg) is capable of capturing HBcAg (10).
  • the present invention is, in one aspect, directed to an antigen/antibody specificity exchanger, which comprises
  • the amino-acid sequence of A) may comprise additional amino acids or sequences on one or both sides of the amino-acid sequence of an antibody which specifically binds to a certain antigen, including hapten. Such additional amino acids and sequences may be, but are not limited to, the amino acids and sequences naturally occurring in said antibody as extensions to the amino-acid sequence of A).
  • the number of amino-acid residues in the amino-acid sequence of A) is preferably at least 5, and is together with possible extensions preferably less than 35.
  • the amino-acid sequence of C) may comprise additional amino acids or sequences on one or both sides of the amino-acid sequence to which a certain antibody binds.
  • additional amino acids and sequences may be, but are not limited to, the amino acids and sequences naturally occurring as extensions to the amino-acid sequence of C).
  • the number of amino-acid residues in the amino-acid sequence of C) is preferably at least 5, and is together with possible extensions preferably less than 35.
  • said antigen/antibody specificity exchanger of the invention is one wherein said amino-acid sequence of A) corresponds to an amino-acid sequence of a complementarity determining region (CDR) or a framework region of a certain antibody.
  • CDR complementarity determining region
  • said antigen/antibody specificity exchanger of the invention is one wherein said amino-acid sequence of C) corresponds to an antibody-binding region of a certain protein, such as one of viral, bacterial or fungal origin.
  • said antigen/antibody specificity exchanger of the invention is one wherein said amino-acid sequence of A) is linked to said amino-acid sequence of C) by a link B), which is selected from the group consisting of a direct peptide bond and spacer molecules, such as an amino acid, an amino acid having two amino groups, linear or branched peptides or polypeptides and biotin-avidin-biotin.
  • said antigen/antibody specificity exchanger of the invention is one wherein said amino-acid sequence of A) is selected from the group consisting of Cys Asp Leu Ile Tyr Tyr Asp Tyr Glu Glu Asp Tyr Tyr Phe: SEQ ID NO:1 Cys Asp Leu Ile Tyr Tyr Asp Tyr Glu Glu Asp Tyr Tyr: SEQ ID NO:2 Thr Tyr Ala Met Asn SEQ ID NO:3 Arg Val Arg Ser Lys Ser Phe Asn Tyr Ala Thr Tyr Tyr Tyr Ala Asp Ser SEQ ID NO:4 Val Lys Gly and Pro Ala Gln Gly Ile Tyr Phe Asp Tyr Gly Gly Phe Ala Tyr SEQ ID NO:5
  • Peptide 1 SEQ ID NO: 13 Cys Asp Leu Ile Tyr Tyr Asp Tyr Glu Glu Asp Tyr Tyr Phe Pro Pro Asn Ala Pro Ile Leu Ser
  • Peptide 2 SEQ ID NO: 14 Cys Asp Leu Ile Tyr Tyr Asp Tyr Glu Glu Asp Tyr Tyr Phe Arg Pro Pro Asn Ala Pro Ile Leu Ser Thr
  • Peptide 3 SEQ ID NO: 15 Cys Asp Leu Ile Tyr Tyr Asp Tyr Glu Glu Asp Tyr Tyr Phe Lys Glu Ile Pro Ala Leu Thr Ala Val Glu Thr
  • Peptide 4 SEQ ID NO: 16 Cys Asp Leu Ile Tyr Tyr Asp Tyr Glu Glu Asp Tyr Tyr Phe Pro Ala His Ser Lys Glu Ile Pro Ala Leu Thr Ala Peptide 5: SEQ ID NO: 17 Cys Asp Leu Ile Tyr Tyr Tyr Asp Tyr Glu Glu
  • Another aspect of the invention is directed to a diagnostic reagent comprising an antigen/antibody specificity exchanger according to the invention.
  • Such a diagnostic reagent of the invention may be used to detect in vitro specific antigens in-biological samples, e.g. body fluid or tissue samples.
  • the diagnostic reagent of the invention may be used instead of antisera or monoclonal antibodies in in vitro testing systems, such as immunological tests, e.g. Enzyme-Linked Immunosorbent Assay (ELISA), Enzyme Immunoassay (EIA), Western Blot, Radioimmunoassay (RIA) etc.
  • ELISA Enzyme-Linked Immunosorbent Assay
  • EIA Enzyme Immunoassay
  • RIA Radioimmunoassay
  • Still another aspect of the invention is directed to a method of treating a disease or disorder caused by a known antigen in an individual in need of an increased number of antigen-specific antibodies, which comprises administration to said individual of a sufficient amount of a tailor-made antigen/antibody specificity exchanger according to the invention which binds to certain antibodies known to exist in said individual.
  • An individual in need of an increased number of antigen-specific antibodies against a known antigen, which causes a disease or disorder in said individual may be one who will benefit from getting a rapid increase in the number of such antigen-specific antibodies, or who even lacks or has insufficient ability to elicit antibodies against said known antigen.
  • Said individual may be a human or non-human mammal.
  • Such a tailor-made antigen/antibody specificity exhanger is designed so that certain antibodies existing in the patient in question, (e.g. antibodies against viral proteins, such as antibodies against poliovirus, antibodies against virus causing measles, antibodies against hepatitis B virus, antibodies against hepatitis C virus, antibodies against HIV-1, whether induced by natural infection or vaccination) binds to the amino-acid sequence of C) and the amino-acid sequence of A) binds to a known antigen causing a disease or disorder in said patient (e.g. HIV).
  • antibodies existing in the patient in question e.g. antibodies against viral proteins, such as antibodies against poliovirus, antibodies against virus causing measles, antibodies against hepatitis B virus, antibodies against hepatitis C virus, antibodies against HIV-1, whether induced by natural infection or vaccination
  • a specific example of an antigen/antibody specificity exchanger of the invention is a peptide which binds to antibodies against poliovirus and also binds specifically to HIV virus.
  • already high titres in a patient of antibodies against poliovirus may thus be used to fight HIV infection in said patient.
  • the antigen/antibody specificity exchanger of the invention is prepared in any suitable manner known in the art. It is in most cases a peptide, with the exception of the case when it comprises biotin-avidin-biotin as a linker. As is well-know in the art, peptides can be produced by genetic engineering methods or peptide synthesis. In peptide synthesis one amino-acid residue is coupled to the next one in liquid phase, or starting with the solid phase to which the C-terminal of the first amino acid is coupled, whereupon the C-terminal of the next amino acid is coupled to the N-terminal of the first amino acid, etc, finally releasing the build-up peptide from the solid phase.
  • the antigen/antibody specificity exchangers presented in Table 1 are all synthetic peptides synthesized according to a method for multiple peptide synthesis (21) and by a Milligen 9050 peptide synthesizer using 9-fluorenylmethoxy-carbonyl-protected amino acid esters (20). All peptides were analysed and/or purified by reverse phase HPLC using a Pep-S 5 m column (Pharmacia-LKB, Uppsala, Sweden), run with a gradient from 10% to 60% CH3CN against water containing 0.1% trifluoro-acetic acid.
  • Enzyme immuno assays EIAs.
  • Strain-specific HIV-1 V3 peptides were coated on microtiter wells (Nunc 96F Certificated; Nunc, Copenhagen, Denmark) in 100 ml portions at concentrations of from 10 mg/ml to 0.01 mg/ml in 0.05 M sodium carbonate buffer, pH 9.6, at +4° C. overnight. Excess peptides were removed by washing with PBS containing 0.05% Tween 20.
  • the peptide-coated plates were assayed for binding using the peptides of the invention diluted from 100 mg/ml to 0.01 mg/ml in PBS containing 1% BSA, 2% goat serum, and 0.05% Tween 20.
  • the dilutions of the peptides of the invention were added in 100 ml portions and incubated with the adsorbed V3 peptides for 60 minutes at +37° C. Excess test peptides were removed by washing and bound peptide was indicated by the respective mAb or anti-serum, by incubation for 60 minutes at +37° C.
  • the amount of bound antibody was indicated by an additional incubation of enzyme-labelled secondary antibody, rabbit anti-mouse Ig (P260, Dako, Copenhagen, Denmark) for mAbs, and goat anti-human IgG (A-3150; Sigma Chemicals, St. Louis, Mo.) for human antibodies.
  • the amount of bound conjugate was determined by addition of substrate and the absorbances were measured at 492 nm or 405 nm in a spectrophoto-meter.
  • the ability of the antigen/antibody specificity exchangers to redirect antibodies was further evaluated in a system where the CDRH1, CDRH2 and CDRH3 sequences from mAb C1-5 were added to the epitope sequence for mAb 14E11.
  • the antigen/antibody specificity exchangers, based on the C1-5 CDRs, were then added, and the amount bound CDR peptide was indicated by the epitope specific mAb 14E11.
  • the antigen/antibody specificity exchanger of the invention can redirect an existing HBc/eAg specific antibody to significantly bind to HIV-1 V3 peptides of several different subtypes.
  • the antigen/antibody exchanger of the invention forms the basis of a novel method for redirecting the specificity of monoclonal and polyclonal antibodies by modifying the antigenic surface of a viral protein.
  • the invention comprises antigen/antibody exchangers wherein included amino-acid sequences are chemically stabilized e.g. by cyclization and wherein included amino-acid sequences may have specific amino-acid deletions, additions and/or substitutions. Such modified amino-acid sequences may result in antigen/antibody exchangers exhibiting increased (or decreased) biological activities.
  • Antigen/antibody specificity exchangers of the invention represented by peptides containing the CDRH3 domain of mAb F58 or CDRH1, CDRH2, CDRH3 domain of mAb C1-5 (A) and different antigenic regions derived from viral proteins (C).
  • SEQ ID NO 1. peptide SEQ ID NO 6 HBc/eAg, 15 bond aas 134-141 2.
  • SEQ ID NO 1. peptide SEQ ID ID ID 7 HBc/eAg, 15 bond aas 133-142 3.
  • SEQ ID NO 1. peptide SEQ ID NO 8 Polio VP1,aas 39-50 16 bond 4.
  • SEQ ID NO 1. peptide SEQ ID NO 10 HIV-1 gp 41, 20 bond aas 596-605 6.
  • SEQ ID NO 1. peptide SEQ ID NO 10 HIV-1 gp 41, 20 bond aas 596-605 6.
  • Subtype C 1.261 0.514 0.111 0.077 0.051 0.020
  • Subtype D 0.17 0.079 0.065 0.028 0.029 0.026

Abstract

An antigen/antibody specificity exchanger is disclosed. It comprises: A) an amino-acid sequence corresponding to an amino-acid sequence of an antibody which specifically binds to a certain antigen, including hapten, B) linked by a link to C) an amino-acid sequence to which a certain antibody binds. Also, a diagnostic reagent comprising an antigen/antibody specificity exchanger according to the invention is disclosed. Said reagent may be e.g. used instead of antisera or monoclonal antibodies in in vitro testing systems, such as immunological tests. Further, a method of treating a disease or disorder caused by a known antigen in an individual in need of an increased number of antigen-specific antibodies is disclosed. In the method a tailor-made antigen/antibody specificity exchanger of the invention is issued. Said method may be e.g. used to redirect a patient's antibodies against poliovirus to fight HIV infection in said patient.

Description

    FIELD OF THE INVENTION
  • The present invention relates to an antigen/antibody specificity exchanger, which comprises an amino-acid sequence which specifically binds to a certain antigen linked to an amino-acid sequence to which a certain antibody binds. In vitro the antigen/antibody specificity exchanger of the invention can be used as a diagnostic reagent instead of antisera or monoclonal antibodies in testing systems, and in vivo it can be used to redirect antigens or antibodies to other antibodies or antigens, respectively, than they were originally directed to. [0001]
    • BACKGROUND
  • During the past decade the antigenic structure of several viral proteins have been characterized using synthetic peptides, such as the human immunodeficiency virus-1(HIV-1)gp160, and the hepatitis B virus core/e antigens (HBc/eAg). Recently it has been shown that a synthetic peptide corresponding to the complementarity determining region 3 of the heavy chain (CDRH3) of a monoclonal antibody (mAb; F58), directed to the variable third (V3) domain of HIV-1 gp160, may act as a mini antibody and neutralize HIV-1 in vitro. In the experimental part of the present specification, the construction of synthetic peptides combining the CDRH3 domain of the mAb F58, or CDRH1, CDRH2, CDRH3 domain of Ab C1-5, and antigenic regions derived from the HIV-1 gp41, HBc/e antigen, hepatitis C virus (HCV) core protein or from the poliovirus VP1, is shown. These peptides specifically bound the V3 domain of HIV-1. Thus, it was possible to modify the antigenic surface of HIV-1 V3 peptides. This antigen/antibody specificity exchanger will be used for redirecting the reactivity of circulating antibodies and using already existing antibody specificities for a predetermined purpose. It may also serve to alter the composition of the surface of proteins by the addition of foreign determinants. For example, the widely used poliovirus vaccination, together with the high rate of seropositivity to enteroviral proteins may be a suitable pool of antibodies to redirect against other pathogens, such as HIV. [0002]
  • The complementary determining regions (CDRs) of antibodies are responsible for the specificity of the antibody (1,2). X-ray crystallography has shown that the three CDRs of the variable (V) region of the heavy chain and the three CDRs of the V region of the light chain may all have contact with the epitope in an antigen-antibody complex (3). Single peptides corresponding to the CDRs of mAbs to various antigens have been shown to mimic the recognition capabilities of the respective mAb (4-10). Recently it was shown that a peptide corresponding to CDRH3 of a mAb specific for the V3 region of human immuno deficiency virus-1, holds neutralizing capacity when assayed in vitro (9). It was also observed that the CDRH2 of a mAb to hepatitis B core antigen (HBcAg) is capable of capturing HBcAg (10). [0003]
    • DESCRIPTION OF THE INVENTION
  • The present invention is, in one aspect, directed to an antigen/antibody specificity exchanger, which comprises [0004]
  • A) an amino-acid sequence corresponding to an amino-acid sequence of an antibody which specifically binds to a certain antigen, including hapten, [0005]
  • B) linked by a link to [0006]
  • C) an amino-acid sequence to which a certain antibody binds. [0007]
  • The amino-acid sequence of A) may comprise additional amino acids or sequences on one or both sides of the amino-acid sequence of an antibody which specifically binds to a certain antigen, including hapten. Such additional amino acids and sequences may be, but are not limited to, the amino acids and sequences naturally occurring in said antibody as extensions to the amino-acid sequence of A). The number of amino-acid residues in the amino-acid sequence of A) is preferably at least 5, and is together with possible extensions preferably less than 35. [0008]
  • Further, the amino-acid sequence of C) may comprise additional amino acids or sequences on one or both sides of the amino-acid sequence to which a certain antibody binds. Such additional amino acids and sequences may be, but are not limited to, the amino acids and sequences naturally occurring as extensions to the amino-acid sequence of C). The number of amino-acid residues in the amino-acid sequence of C) is preferably at least 5, and is together with possible extensions preferably less than 35. [0009]
  • In an embodiment of the above aspect of the invention said antigen/antibody specificity exchanger of the invention is one wherein said amino-acid sequence of A) corresponds to an amino-acid sequence of a complementarity determining region (CDR) or a framework region of a certain antibody. [0010]
  • In a further embodiment said antigen/antibody specificity exchanger of the invention is one wherein said amino-acid sequence of C) corresponds to an antibody-binding region of a certain protein, such as one of viral, bacterial or fungal origin. [0011]
  • In another embodiment said antigen/antibody specificity exchanger of the invention is one wherein said amino-acid sequence of A) is linked to said amino-acid sequence of C) by a link B), which is selected from the group consisting of a direct peptide bond and spacer molecules, such as an amino acid, an amino acid having two amino groups, linear or branched peptides or polypeptides and biotin-avidin-biotin. [0012]
  • In a preferred embodiment said antigen/antibody specificity exchanger of the invention is one wherein said amino-acid sequence of A) is selected from the group consisting of [0013]
    Cys Asp Leu Ile Tyr Tyr Asp Tyr Glu Glu Asp Tyr Tyr Phe: SEQ ID NO:1
    Cys Asp Leu Ile Tyr Tyr Asp Tyr Glu Glu Asp Tyr Tyr: SEQ ID NO:2
    Thr Tyr Ala Met Asn SEQ ID NO:3
    Arg Val Arg Ser Lys Ser Phe Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser SEQ ID NO:4
    Val Lys Gly
    and
    Pro Ala Gln Gly Ile Tyr Phe Asp Tyr Gly Gly Phe Ala Tyr SEQ ID NO:5
  • Specific examples of antigen/antibody specificity exchangers of the invention: [0014]
    Peptide 1:
    SEQ ID NO: 13
    Cys Asp Leu Ile Tyr Tyr Asp Tyr Glu Glu Asp Tyr Tyr Phe Pro Pro
    Asn Ala Pro Ile Leu Ser
    Peptide 2:
    SEQ ID NO: 14
    Cys Asp Leu Ile Tyr Tyr Asp Tyr Glu Glu Asp Tyr Tyr Phe Arg Pro
    Pro Asn Ala Pro Ile Leu Ser Thr
    Peptide 3:
    SEQ ID NO: 15
    Cys Asp Leu Ile Tyr Tyr Asp Tyr Glu Glu Asp Tyr Tyr Phe Lys Glu
    Ile Pro Ala Leu Thr Ala Val Glu Thr Gly
    Peptide 4:
    SEQ ID NO: 16
    Cys Asp Leu Ile Tyr Tyr Asp Tyr Glu Glu Asp Tyr Tyr Phe Pro Ala
    His Ser Lys Glu Ile Pro Ala Leu Thr Ala
    Peptide 5:
    SEQ ID NO: 17
    Cys Asp Leu Ile Tyr Tyr Asp Tyr Glu Glu Asp Tyr Tyr Phe Trp Gly
    Cys Ser Gly Lys Leu Ile Cys Thr
    Peptide 6:
    SEQ ID NO: 18
    Cys Asp Leu Ile Tyr Tyr Asp Tyr Glu Glu Asp Tyr Tyr Phe Cys Thr
    Thr Ala Val Pro Trp Asn Ala Ser
    Peptide 7:
    SEQ ID NO: 19
    Figure US20030129587A1-20030710-C00001
    Peptide 8:
    SEQ ID NO: 20
    Thr Tyr Ala Met Asn Pro Pro Asn Ala Pro Ile Leu Ser
    Peptide 9:
    SEQ ID NO: 21
    Arg Val Arg Ser Lys Ser Phe Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser
    Val Lys Gly Pro Pro Asn Ala Pro Ile Leu Ser
    Peptide 10:
    SEQ ID NO: 22
    Pro Ala Gln Gly Ile Tyr Phe Asp Tyr Gly Gly Phe Ala Tyr Pro Pro
    Asn Ala Pro Ile Leu Ser
    Peptide 11:
    SEQ ID NO: 23
    Cys Asp Leu Ile Tyr Tyr Asp Tyr Glu Glu Asp Tyr Tyr Gln Arg Lys
    Thr Lys Arg Asn Thr Asn Arg Arg
  • Another aspect of the invention is directed to a diagnostic reagent comprising an antigen/antibody specificity exchanger according to the invention. [0015]
  • Such a diagnostic reagent of the invention may be used to detect in vitro specific antigens in-biological samples, e.g. body fluid or tissue samples. Thus, the diagnostic reagent of the invention may be used instead of antisera or monoclonal antibodies in in vitro testing systems, such as immunological tests, e.g. Enzyme-Linked Immunosorbent Assay (ELISA), Enzyme Immunoassay (EIA), Western Blot, Radioimmunoassay (RIA) etc. Further, the diagnostic reagent of the invention may be used to investigate biological properties of biological systems. [0016]
  • Still another aspect of the invention is directed to a method of treating a disease or disorder caused by a known antigen in an individual in need of an increased number of antigen-specific antibodies, which comprises administration to said individual of a sufficient amount of a tailor-made antigen/antibody specificity exchanger according to the invention which binds to certain antibodies known to exist in said individual. [0017]
  • An individual in need of an increased number of antigen-specific antibodies against a known antigen, which causes a disease or disorder in said individual, may be one who will benefit from getting a rapid increase in the number of such antigen-specific antibodies, or who even lacks or has insufficient ability to elicit antibodies against said known antigen. Said individual may be a human or non-human mammal. [0018]
  • Such a tailor-made antigen/antibody specificity exhanger according to the invention is designed so that certain antibodies existing in the patient in question, (e.g. antibodies against viral proteins, such as antibodies against poliovirus, antibodies against virus causing measles, antibodies against hepatitis B virus, antibodies against hepatitis C virus, antibodies against HIV-1, whether induced by natural infection or vaccination) binds to the amino-acid sequence of C) and the amino-acid sequence of A) binds to a known antigen causing a disease or disorder in said patient (e.g. HIV). [0019]
  • Thus, existing antibodies in said patent are redirected to said known antigen (against which said patient e.g. lacks or has insufficient amount of desired antibodies). [0020]
  • A specific example of an antigen/antibody specificity exchanger of the invention is a peptide which binds to antibodies against poliovirus and also binds specifically to HIV virus. Thus, already high titres in a patient of antibodies against poliovirus may thus be used to fight HIV infection in said patient. [0021]
  • Preparation of the Antigen/Antibody Specificity Exchanger of the Invention [0022]
  • The antigen/antibody specificity exchanger of the invention is prepared in any suitable manner known in the art. It is in most cases a peptide, with the exception of the case when it comprises biotin-avidin-biotin as a linker. As is well-know in the art, peptides can be produced by genetic engineering methods or peptide synthesis. In peptide synthesis one amino-acid residue is coupled to the next one in liquid phase, or starting with the solid phase to which the C-terminal of the first amino acid is coupled, whereupon the C-terminal of the next amino acid is coupled to the N-terminal of the first amino acid, etc, finally releasing the build-up peptide from the solid phase. [0023]
  • The antigen/antibody specificity exchangers presented in Table 1 are all synthetic peptides synthesized according to a method for multiple peptide synthesis (21) and by a Milligen 9050 peptide synthesizer using 9-fluorenylmethoxy-carbonyl-protected amino acid esters (20). All peptides were analysed and/or purified by reverse phase HPLC using a Pep-S 5 m column (Pharmacia-LKB, Uppsala, Sweden), run with a gradient from 10% to 60% CH3CN against water containing 0.1% trifluoro-acetic acid. [0024]
  • Testing of the Antigen/Antibody Specificity Exchanger of the Invention [0025]
  • Monoclonal antibodies and human sera. The production and characterization of mAb to HBc/eAg has been described (15, 18). The mAb 14E11 recognizes the epitope at residues 135-141 (PNAPILS), of the HBc/eAg sequence (15). The monoclonal antibody 14E11 was kindly provided by Dr. Alexander Cimanis, Riga. Two human sera (A and B) reactive to a peptide covering residues 42-55 of VP1 of poliovirus 1 have previously been described (19). A monoclonal antibody against enteroviral VP1 was purchased from Dako (CBV; M7064, Dako, Copenhagen, Denmark) [0026]
  • Three human sera (C, D and E) positive for antibodies to hepatitis C virus (HCV) core residues 7-19 have previously been described (20). [0027]
  • Enzyme immuno assays (EIAs). Strain-specific HIV-1 V3 peptides were coated on microtiter wells (Nunc 96F Certificated; Nunc, Copenhagen, Denmark) in 100 ml portions at concentrations of from 10 mg/ml to 0.01 mg/ml in 0.05 M sodium carbonate buffer, pH 9.6, at +4° C. overnight. Excess peptides were removed by washing with PBS containing 0.05% Tween 20. [0028]
  • The peptide-coated plates were assayed for binding using the peptides of the invention diluted from 100 mg/ml to 0.01 mg/ml in PBS containing 1% BSA, 2% goat serum, and 0.05% Tween 20. The dilutions of the peptides of the invention were added in 100 ml portions and incubated with the adsorbed V3 peptides for 60 minutes at +37° C. Excess test peptides were removed by washing and bound peptide was indicated by the respective mAb or anti-serum, by incubation for 60 minutes at +37° C. The amount of bound antibody was indicated by an additional incubation of enzyme-labelled secondary antibody, rabbit anti-mouse Ig (P260, Dako, Copenhagen, Denmark) for mAbs, and goat anti-human IgG (A-3150; Sigma Chemicals, St. Louis, Mo.) for human antibodies. The amount of bound conjugate was determined by addition of substrate and the absorbances were measured at 492 nm or 405 nm in a spectrophoto-meter. [0029]
  • Antibody recognition of peptides of the invention. When adsorbed to microplates all peptides of the invention presented in Table 1 except for Nos. 4 (Table 2) and 7 (data not shown) were found to be reactive with the respective antibodies. [0030]
  • Antigen binding of the peptides of the invention. The anti-genically functional test peptides were further evaluated for binding of HIV-1 V3 peptide, MN-strain. All test peptides which had a functional antigenic region were found to directly bind to the HIV-1 V3 peptide (Tables 3 and 4). As shown in Tables 3 and 4, the reactivity to the HIV-1 V3 peptide was found to be dependent on both concentrations of the test peptides and of V3 peptides, indicating a specific reactivity. This clearly indicates that it was possible to redirect antibodies specific for HIV-1 gp41, HBc/eAg and poliovirus 1 VP1 to bind to the altered antigenic surface of the HIV-1 V3 peptide. It was also found, that pre-incubation of equimolar concentrations of mAb 14E11 and the corresponding test peptide of the invention, did not change the ability of the test peptide mAb complex to bind to the V3 peptide (data not shown). This indicates that it is possible to add antigenic domains to a CDR peptide with retained antigen binding ability of the CDR sequence. [0031]
  • The ability of the antigen/antibody specificity exchangers to redirect antibodies was further evaluated in a system where the CDRH1, CDRH2 and CDRH3 sequences from mAb C1-5 were added to the epitope sequence for mAb 14E11. A peptide corresponding to the epitope sequence for mAb C1-5, residues 71-90 of HBc/eAg with an Ile at position 80, was adsorbed to microplates. The antigen/antibody specificity exchangers, based on the C1-5 CDRs, were then added, and the amount bound CDR peptide was indicated by the epitope specific mAb 14E11. The results clearly showed that the mAb 14E11 which originally recognized residues 134-141 of the HBc/eAg sequence was redirected by the antigen/antibody specificity exhanger containing the CDRH2 sequence (Table 5). Also, this reactivity was dependent on the amount CDR added, indicating a specific reaction (p<0.01, Regression analysis; Table 5). [0032]
  • Further, in Table 7 is shown that the antigen/antibody specificity exchanger of the invention can redirect an existing HBc/eAg specific antibody to significantly bind to HIV-1 V3 peptides of several different subtypes. [0033]
  • Thus, it is evident that the antigen/antibody exchanger of the invention forms the basis of a novel method for redirecting the specificity of monoclonal and polyclonal antibodies by modifying the antigenic surface of a viral protein. [0034]
  • It should be understood that the invention comprises antigen/antibody exchangers wherein included amino-acid sequences are chemically stabilized e.g. by cyclization and wherein included amino-acid sequences may have specific amino-acid deletions, additions and/or substitutions. Such modified amino-acid sequences may result in antigen/antibody exchangers exhibiting increased (or decreased) biological activities. [0035]
    TABLE 1
    Antigen/antibody specificity exchangers of the
    invention represented by peptides containing the CDRH3 domain of
    mAb F58 or CDRH1, CDRH2, CDRH3 domain of mAb C1-5 (A) and
    different antigenic regions derived from viral proteins (C).
    Peptide Amino-acid Amino-acid Source of
    No. sequence (A) link (B) sequence (C) aas (C) Ref.
    1. SEQ ID NO 1. peptide SEQ ID NO 6 HBc/eAg, 15
    bond aas 134-141
    2. SEQ ID NO 1. peptide SEQ ID ID 7 HBc/eAg, 15
    bond aas 133-142
    3. SEQ ID NO 1. peptide SEQ ID NO 8 Polio VP1,aas 39-50 16
    bond
    4. SEQ ID NO 1. peptide SEQ ID NO 9 Polio VP1, aas 35-46 16
    bond
    5. SEQ ID NO 1. peptide SEQ ID NO 10 HIV-1 gp 41, 20
    bond aas 596-605
    6. SEQ ID NO 1. peptide SEQ ID NO 11 HIV-1 gp 41 20
    bond aas 603-612
    7. 2(SEQ ID NO 1) Lys SEQ ID NO 7 HBc/eAg, 15
    ass 133-142
    8. SEQ ID NO 3. peptide SEQ ID NO 6 HBc/eAg, 15
    bond aas 134-141
    9. SEQ ID NO 4. peptide SEQ ID NO 6 HBc/eAg, 15
    bond aas 134-141
    10. SEQ ID NO 5. peptide SEQ ID NO 6 HBc/eAg, 15
    bond aas 134-141
    11. SEQ ID NO 2. peptide SEQ ID NO 12 HCV core 8-18 22
    bond
  • [0036]
    TABLE 2
    Testing of antigen/antibody specificity exchanger of the invention
    represented by peptides passively adsorbed to polystyrene
    for ability to be recognized by antibodies specific for the
    antigenic region presented in the peptide. Values are given
    as the absorbance obtained at 492 or 405 nm.
    Peptide Antibody Amount peptide added (ng/0.1 ml) to solid phase
    No. used 1.000 100 10 1 0.1 0.01
    1 14E11 2.500 1.675 0.030 0.010 0.009 0.008
    2 14E11 2.500 1.790 0.008 0.006 0.008 0.006
    3 CBV 2.500 1.142 0.036 0.020 0.019 0.036
    human A 1.945 1.850 0.486 0.088 0.115 0.116
    human B 1.342 0.770 0.130 0.065 0.090 0.095
    4 CBV 0.020 0.018 0.015 0.016 0.017 0.018
    human A 0.059 0.081 0.108 0.109 0.097 0.100
    human B 0.052 0.072 0.091 0.098 0.083 0.100
  • [0037]
    TABLE 3
    Testing of the HIV-1 V3 peptide-antigen binding capability
    of the CDR sequence simultaneously with the ability to
    be recognized by monoclonal antibodies specific for the
    antigenic region on the test peptide of the invention.
    Values are given as the absorbance at 492 nm.
    a:
    Amount
    of
    test
    Anti- peptide Amount V3 peptide added
    Peptide body (ng/0.1 (ng/0.1 ml) to solid phase
    No. used ml) 1.000 500 250 125 62.5 31.25
    1 14E11 10,000 2.500 2.500 2.500 2.338 1.702 1.198
    5,000 2.500 2.500 2.500 2.190 1.622 1.122
    2,500 2.500 2.500 2.500 2.039 1.394 0.990
    1,250 2.500 2.500 2.500 1.712 0.930 0.771
    625 1.936 0.824 0.380 0.152 0.056 0.053
    312 0.196 0.085 0.044 0.043 0.030 0.025
    b:
    Amount
    of
    test
    Anti- peptide
    Peptide body (ng/0.1 Amount of V3 peptide added (ng/0.1 ml)
    No. used ml) 1.000 500 250 125 62.5 31.25
    4 14E11 10.000 2.500 2.500 2.133 1.560 1.070 0.829
    5.000 2.500 2.500 1.963 1.645 1.074 0.981
    2.500 2.500 2.500 1.729 1.404 0.962 0.747
    1.250 2.500 2.424 1.433 1.327 0.795 0.488
    625 0.835 0.359 0.200 0.120 0.088 0.073
    312 0.099 0.054 0.042 0.049 0.045 0.025
    c:
    Amount
    of
    test
    Anti- peptide Amount peptide added
    Peptide body (ng/0.1 (ng/0.1 ml) to solid phase
    No. used ml) 1.000 100 10 1 0.1 0.01
    3 CBV 10,000 0.523 0.498 0.162 0.161 0.017 0.017
    1,000 0.053 0.054 0.031 0.027 0.010 0.010
    100 0.034 0.037 0.025 0.029 0.010 0.010
    10 0.023 0.022 0.014 0.014 0.010 0.009
    1 0.013 0.044 0.014 0.017 0.027 0.009
    0.1 0.011 0.009 0.008 0.032 0.013 0.013
  • [0038]
    TABLE 4
    Testing of the HIV-1 V3 peptide antigen binding capability
    of the CDR sequence simultaneously with the ability to be recognized
    by human anti-polio VP1 polyclonal antibodies specific for
    the antigenic region on the test peptides of the invention.
    Values are given as the absorbance at 405 nm.
    Pep- Anti- Amount of Amount V3 peptide added
    tide body test peptide (ng/0.1 ml) to solid phase
    No. used (ng/0.1 ml) 1.000 500 250 125 62.5 31.25
    a:
    3 human 10,000 1.538 1.356 1.448 1.052 0.280 0.123
    A 5,000 1.179 1.050 1.006 0.557 0.136 0.087
    2,500 0.684 0.558 0.604 0.216 0.084 0.067
    1,250 0.367 0.358 0.332 0.162 0.075 0.062
    625 0.228 0.238 0.220 0.121 0.083 0.063
    312 0.171 0.154 0.154 0.103 0.072 0.060
    b:
    3 human 10,000 0.366 0.352 0.352 0.200 0.074 0.056
    B 5,000 0.206 0.217 0.188 0.131 0.063 0.053
    2,500 0.134 0.132 0.126 0.091 0.061 0.055
    1,250 0.107 0.114 0.108 0.077 0.060 0.054
    625 0.082 0.104 0.087 0.075 0.063 0.056
    312 0.083 0.091 0.094 0.077 0.068 0.060
  • [0039]
    TABLE 5
    Testing of the HIV-1 V3 peptide antigen capability of the
    CDR sequence simultaneous with the ability to be recognized
    by human anti-HCV core polyclonal antibodies specific for
    the antigenic region on the test peptides of the invention.
    Values are given as the absorbance at 405 nm.
    Amount
    of V3
    Anti- pepitide Amount of test peptide added
    Peptide body (ng/0.1 (ng/0.1 ml)
    No. used ml) 62 31 15 7.5 3.7 1.8
    11 human 625 2.500 2.416 2.097 1.473 0.973 0.630
    HCV-C 78 2.500 2.335 1.781 1.225 0.825 0.564
    39 2.389 2.287 1.626 1.081 0.664 0.389
    11 human 625 1.999 1.490 1.184 0.751 0.458 0.428
    HCV-D 78 1.758 1.370 1.025 0.612 0.468 0.380
    39 1.643 0.993 0.833 0.497 0.343 0.287
    11 human 625 2.368 2.165 1.656 1.104 0.645 0.462
    HCV-E 78 2.156 1.824 1.396 0.733 0.514 0.352
    39 1.893 1.683 1.110 0.756 0.310 0.272
  • [0040]
    TABLE 6
    Testing of C1-5 CDRs(10 ug/ml) (in test peptides of
    the invention) with a peptide corresponding to
    HBc/eAg corresponding to residues 71-90) coated on
    solid phase. Bound CDR was indicated by the epitope
    specific mAb 14E11.
    Amount
    c71-90
    Anti- peptide
    body (ng/0.1 Amount of test peptide added (ng/0.1 ml)
    CDR sequence used ml) 10.000 5.000 2.500 1.250 625 312
    Peptide 8: 14E11 625 0.003 0.002 0.002 0.002 0.002 0.002
    cDRH1 312 0.002 0.002 0.004 0.003 0.006 0.004
    (SEQ ID NO3) 78 0.003 0.003 0.005 0.005 0.003 0.003
    Peptide 9: 14E11 625 2.500 1.303 0.070 0.012 0.003 0.002
    CDRH2 312 2.500 1.070 0.058 0.011 0.003 0.002
    (SEQ ID NO4) 78 2.500 0.868 0.039 0.008 0.003 0.003
    Peptide 10: 14E11 625 0.004 0.003 0.004 0.003 0.003 0.003
    CDRH3 312 0.004 0.003 0.004 0.004 0.003 0.003
    (SEQ ID NO5) 78 0.005 0.004 0.005 0.005 0.004 0.004
  • [0041]
    TABLE 7
    Redirecting existing HBc/eAg specific antibody (14E11,
    from Dr. A. Tsimanis, Riga) to different subtype-specific
    HIV-1 V3 peptides (subtypes A-E) via specificity
    exchanger peptide containing CDRH3 sequence against
    HIV-1 and a HBc/eAg epitope for mAb 14E11.
    HIV-1 V3
    peptide
    attached Reactivity (absorbance at 405 nm) of specificity
    to solid- exchanger peptide added in the indicated amount (ng)
    phase 500 250 125 62.5 31.25 15.625
    Subtype A 0.378 0.126 0.078 0.068 0.062 0.017
    Subtype B 2.686 2.536 1.710 1.329 0.360 0.157
    Subtype C 1.261 0.514 0.111 0.077 0.051 0.020
    Subtype D 0.17 0.079 0.065 0.028 0.029 0.026
    Subtype E 0.22 0.090 0.093 0.032 0.063 0.030
  • [0042]
  • 1 23 14 amino acids amino acid single linear peptide 1 Cys Asp Leu Ile Tyr Tyr Asp Tyr Glu Glu Asp Tyr Tyr Phe 1 5 10 13 amino acids amino acid single linear peptide 2 Cys Asp Leu Ile Tyr Tyr Asp Tyr Glu Glu Asp Tyr Tyr 1 5 10 5 amino acids amino acid single linear peptide 3 Thr Tyr Ala Met Asn 1 5 19 amino acids amino acid single linear peptide 4 Arg Val Arg Ser Lys Ser Phe Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser 1 5 10 15 Val Lys Gly 14 amino acids amino acid single linear peptide 5 Pro Ala Gln Gly Ile Tyr Phe Asp Tyr Gly Gly Phe Ala Tyr 1 5 10 8 amino acids amino acid single linear peptide 6 Pro Pro Asn Ala Pro Ile Leu Ser 1 5 10 amino acids amino acid single linear peptide 7 Arg Pro Pro Asn Ala Pro Ile Leu Ser Thr 1 5 10 12 amino acids amino acid single linear peptide 8 Lys Gly Ile Pro Ala Leu Thr Ala Val Gly Thr Gly 1 5 10 12 amino acids amino acid single linear peptide 9 Pro Ala His Ser Lys Gly Ile Pro Ala Leu Thr Ala 1 5 10 10 amino acids amino acid single linear peptide 10 Trp Gly Cys Ser Gly Lys Leu Ile Cys Thr 1 5 10 10 amino acids amino acid single linear peptide 11 Cys Thr Thr Ala Val Pro Trp Asn Ala Ser 1 5 10 11 amino acids amino acid single linear peptide 12 Gln Arg Lys Thr Lys Arg Asn Thr Asn Arg Arg 1 5 10 22 amino acids amino acid single linear peptide 13 Cys Asp Leu Ile Tyr Tyr Asp Tyr Glu Glu Asp Tyr Tyr Phe Pro Pro 1 5 10 15 Asn Ala Pro Ile Leu Ser 20 24 amino acids amino acid single linear peptide 14 Cys Asp Leu Ile Tyr Tyr Asp Tyr Glu Glu Asp Tyr Tyr Phe Arg Pro 1 5 10 15 Pro Asn Ala Pro Ile Leu Ser Thr 20 26 amino acids amino acid single linear peptide 15 Cys Asp Leu Ile Tyr Tyr Asp Tyr Glu Glu Asp Tyr Tyr Phe Lys Glu 1 5 10 15 Ile Pro Ala Leu Thr Ala Val Glu Thr Gly 20 25 26 amino acids amino acid single linear peptide 16 Cys Asp Leu Ile Tyr Tyr Asp Tyr Glu Glu Asp Tyr Tyr Phe Pro Ala 1 5 10 15 His Ser Lys Glu Ile Pro Ala Leu Thr Ala 20 25 24 amino acids amino acid single linear peptide 17 Cys Asp Leu Ile Tyr Tyr Asp Tyr Glu Glu Asp Tyr Tyr Phe Trp Gly 1 5 10 15 Cys Ser Gly Lys Leu Ile Cys Thr 20 24 amino acids amino acid single linear peptide 18 Cys Asp Leu Ile Tyr Tyr Asp Tyr Glu Glu Asp Tyr Tyr Phe Cys Thr 1 5 10 15 Thr Ala Val Pro Trp Asn Ala Ser 20 25 amino acids amino acid single linear peptide 19 Cys Asp Leu Ile Tyr Tyr Asp Tyr Glu Glu Asp Tyr Tyr Phe Lys Arg 1 5 10 15 Pro Pro Asn Ala Pro Ile Leu Ser Thr 20 25 13 amino acids amino acid single linear peptide 20 Thr Tyr Ala Met Asn Pro Pro Asn Ala Pro Ile Leu Ser 1 5 10 27 amino acids amino acid single linear peptide 21 Arg Val Arg Ser Lys Ser Phe Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser 1 5 10 15 Val Lys Gly Pro Pro Asn Ala Pro Ile Leu Ser 20 25 22 amino acids amino acid single linear peptide 22 Pro Ala Gln Gly Ile Tyr Phe Asp Tyr Gly Gly Phe Ala Tyr Pro Pro 1 5 10 15 Asn Ala Pro Ile Leu Ser 20 24 amino acids amino acid single linear peptide 23 Cys Asp Leu Ile Tyr Tyr Asp Tyr Glu Glu Asp Tyr Tyr Gln Arg Lys 1 5 10 15 Thr Lys Arg Asn Thr Asn Arg Arg 20

Claims (21)

What is claimed is:
1. A method of redirecting the specificity of an antibody comprising:
contacting said antibody with an antigen/antibody specificity exchanger that comprises a first specific binding sequence that specifically binds to an antigen, wherein said antigen is not specifically recognized by said antibody, linked to a second sequence, which binds said antibody, wherein said second sequence is at least 5 and less than 35 amino acids in length; and
whereby said antibody is redirected to said antigen.
2. The method of claim 1, wherein said first specific binding sequence corresponds to an amino acid sequence of a complementarity determining region (CDR).
3. The method of claim 1, wherein said linkage is selected from the group consisting of a direct peptide bond and a spacer molecule.
4. The method of claim 1, wherein said linkage is biotin-avidin-biotin.
5. The method of claim 1, wherein said first specific binding sequence is specific for a hepatitis viral antigen.
6. The method of claim 5, wherein said hepatitis viral antigen is a hepatitis core antigen or a hepatitis e antigen.
7. The antigen/antibody exchanger of claim 1, wherein said second sequence corresponds to an amino acid sequence selected from the group consisting of a herpes simplex virus protein, a hepatitis B virus protein, a TT virus protein, and a poliovirus protein.
8. A method of redirecting the specificity of an antibody comprising:
contacting said antibody with an antigen/antibody specificity exchanger that comprises a first specific binding sequence that specifically binds to an antigen, wherein said antigen is not specifically recognized by said antibody, linked to a second sequence, which binds said antibody, wherein said first sequence is at least 5 and less than 35 amino acids in length; and
whereby said antibody is redirected to said antigen.
9. The method of claim 1, wherein said first specific binding sequence corresponds to an amino acid sequence of a complementarity determining region (CDR).
10. The method of claim 1, wherein said linkage is selected from the group consisting of a direct peptide bond and a spacer molecule.
11. The method of claim 1, wherein said linkage is biotin-avidin-biotin.
12. The method of claim 1, wherein said first specific binding sequence is specific for a hepatitis viral antigen.
13. The method of claim 12, wherein said hepatitis viral antigen is a hepatitis core antigen or a hepatitis e antigen.
14. The antigen/antibody exchanger of claim 1, wherein said second sequence corresponds to an amino acid sequence selected from the group consisting of a herpes simplex virus protein, a hepatitis B virus protein, a TT virus protein, and a poliovirus protein.
15. A method of redirecting the specificity of an antibody comprising:
contacting said antibody with an antigen/antibody specificity exchanger that comprises a first specific binding sequence that specifically binds to an antigen, wherein said antigen is not specifically recognized by said antibody, linked to a second sequence, which binds said antibody, wherein said first and second sequence are at least 5 and less than 35 amino acids in length; and
whereby said antibody is redirected to said antigen.
16. The method of claim 1, wherein said first specific binding sequence corresponds to an amino acid sequence of a complementarity determining region (CDR).
17. The method of claim 1, wherein said linkage is selected from the group consisting of a direct peptide bond and a spacer molecule.
18. The method of claim 1, wherein said linkage is biotin-avidin-biotin.
19. The method of claim 1, wherein said first specific binding sequence is specific for a hepatitis viral antigen.
20. The method of claim 19, wherein said hepatitis viral antigen is a hepatitis core antigen or a hepatitis e antigen.
21. The antigen/antibody exchanger of claim 1, wherein said second sequence corresponds to an amino acid sequence selected from the group consisting of a herpes simplex virus protein, a hepatitis B virus protein, a TT virus protein, and a poliovirus protein.
US10/234,579 1994-04-28 2002-08-30 Antigen/antibody specificity exchanger Abandoned US20030129587A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US10/234,579 US20030129587A1 (en) 1994-04-28 2002-08-30 Antigen/antibody specificity exchanger
US10/372,735 US6933366B2 (en) 1996-12-27 2003-02-21 Specificity exchangers that redirect antibodies to bacterial adhesion receptors
US11/121,282 US20060094862A1 (en) 1994-04-28 2005-05-03 Specificity exchangers that redirect antibodies to a pathogen
US11/412,181 US20070026502A1 (en) 1994-04-28 2006-04-26 Specificity exchangers that redirect antibodies to a pathogen

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
SE9401460-2 1994-04-28
SE9401460A SE9401460D0 (en) 1994-04-28 1994-04-28 Antigen / antibody specificity exhanger
US08/737,085 US5869232A (en) 1994-04-28 1995-04-27 Antigen/antibody specificity exchanger
US09/246,258 US6040137A (en) 1995-04-27 1999-02-08 Antigen/antibody specification exchanger
US09/532,106 US6245895B1 (en) 1994-04-28 2000-03-21 Antigen/antibody specificity exchanger
US09/839,666 US6469143B2 (en) 1994-04-28 2001-04-19 Antigen/antibody specificity exchanger
US10/234,579 US20030129587A1 (en) 1994-04-28 2002-08-30 Antigen/antibody specificity exchanger

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US09/839,666 Continuation US6469143B2 (en) 1994-04-28 2001-04-19 Antigen/antibody specificity exchanger

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US10/372,735 Continuation-In-Part US6933366B2 (en) 1994-04-28 2003-02-21 Specificity exchangers that redirect antibodies to bacterial adhesion receptors

Publications (1)

Publication Number Publication Date
US20030129587A1 true US20030129587A1 (en) 2003-07-10

Family

ID=22929932

Family Applications (4)

Application Number Title Priority Date Filing Date
US09/246,258 Expired - Lifetime US6040137A (en) 1994-04-28 1999-02-08 Antigen/antibody specification exchanger
US09/532,106 Expired - Lifetime US6245895B1 (en) 1994-04-28 2000-03-21 Antigen/antibody specificity exchanger
US09/839,666 Expired - Fee Related US6469143B2 (en) 1994-04-28 2001-04-19 Antigen/antibody specificity exchanger
US10/234,579 Abandoned US20030129587A1 (en) 1994-04-28 2002-08-30 Antigen/antibody specificity exchanger

Family Applications Before (3)

Application Number Title Priority Date Filing Date
US09/246,258 Expired - Lifetime US6040137A (en) 1994-04-28 1999-02-08 Antigen/antibody specification exchanger
US09/532,106 Expired - Lifetime US6245895B1 (en) 1994-04-28 2000-03-21 Antigen/antibody specificity exchanger
US09/839,666 Expired - Fee Related US6469143B2 (en) 1994-04-28 2001-04-19 Antigen/antibody specificity exchanger

Country Status (1)

Country Link
US (4) US6040137A (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011044133A2 (en) * 2009-10-05 2011-04-14 Opsonic Therapeutics Inc. High affinity adaptor molecules for redirecting antibody specifity

Families Citing this family (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6933366B2 (en) * 1996-12-27 2005-08-23 Tripep Ab Specificity exchangers that redirect antibodies to bacterial adhesion receptors
US6660842B1 (en) * 1994-04-28 2003-12-09 Tripep Ab Ligand/receptor specificity exchangers that redirect antibodies to receptors on a pathogen
US6040137A (en) * 1995-04-27 2000-03-21 Tripep Ab Antigen/antibody specification exchanger
US6417324B1 (en) * 2000-04-21 2002-07-09 Tripep Ab Synthetic peptides that bind to the hepatitis B virus core and e antigens
CA2328356A1 (en) 1999-12-22 2001-06-22 Itty Atcravi Recreational vehicles
US7645743B2 (en) * 1999-12-22 2010-01-12 Altermune, Llc Chemically programmable immunity
WO2004069873A2 (en) 2003-02-06 2004-08-19 Tripep Ab Antigen/antibody or ligand/receptor glycosylated specificity exchangers
US7335359B2 (en) * 2003-02-06 2008-02-26 Tripep Ab Glycosylated specificity exchangers
US20090092631A1 (en) * 2007-03-26 2009-04-09 Tripep Ab Glycosylated specificity exchangers that induce an antibody dependent cellular cytotoxicity (adcc) response
WO2009061739A1 (en) * 2007-11-06 2009-05-14 The Government Of The United States Of America, As Represented By The Secretary, Department Of Health & Human Services Neutralization of hcv
JP5883653B2 (en) * 2009-03-10 2016-03-15 ベイラー リサーチ インスティテュートＢａｙｌｏｒ Ｒｅｓｅａｒｃｈ Ｉｎｓｔｉｔｕｔｅ Antigen-presenting cell targeting antiviral vaccine
CN108373509A (en) * 2009-03-10 2018-08-07 贝勒研究院 The antiviral vaccine of target antigen presenting cells
CN102448989B (en) 2009-03-10 2015-09-30 贝勒研究院 Anti-CD 40 antibodies and uses thereof
EP2430033A4 (en) 2009-05-05 2012-11-07 Altermune Technologies Llc Chemically programmable immunity
CA2831294A1 (en) 2011-03-25 2012-10-04 Baylor Research Institute Compositions and methods to immunize against hepatitis c virus
WO2012172424A1 (en) 2011-06-15 2012-12-20 Crontech Pharma Ab Injection needle and device
WO2013173582A1 (en) 2012-05-17 2013-11-21 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Hepatitis c virus neutralizing antibody
WO2014064534A2 (en) 2012-10-05 2014-05-01 Chrontech Pharma Ab Injection needle, device, immunogenic compositions and method of use
US10286058B2 (en) 2014-01-13 2019-05-14 Baylor Research Institute Vaccines against HPV and HPV-related diseases
US10610585B2 (en) 2017-09-26 2020-04-07 Inserm (Institut National De La Sante Et De La Recherche Medicale) Methods and compositions for treating and preventing HIV

Citations (48)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US486530A (en) * 1892-11-22 Reversible plow
US4169138A (en) * 1974-05-29 1979-09-25 Pharmacia Diagnostics Ab Method for the detection of antibodies
US4376110A (en) * 1980-08-04 1983-03-08 Hybritech, Incorporated Immunometric assays using monoclonal antibodies
US4471058A (en) * 1982-07-26 1984-09-11 Board Of Trustees Operating Michigan State University Method for the detection and/or determination of a polyvalent antigen using at least two different monoclonal antibodies
US4589881A (en) * 1982-08-04 1986-05-20 La Jolla Cancer Research Foundation Polypeptide
US4946778A (en) * 1987-09-21 1990-08-07 Genex Corporation Single polypeptide chain binding molecules
US5091513A (en) * 1987-05-21 1992-02-25 Creative Biomolecules, Inc. Biosynthetic antibody binding sites
US5175096A (en) * 1989-05-11 1992-12-29 Alfa-Laval Agri International Aktiebolag Dna encoding a fibronectin binding protein as well as its preparation
US5189015A (en) * 1984-05-30 1993-02-23 Alfa-Laval Agri International Ab Method for prophylactic treatment of the colonization of a Staphylococcus aureus bacterial strain by bacterial cell surface protein with fibronectin and fibrinogen binding ability
US5196510A (en) * 1988-12-29 1993-03-23 Cytogen Corporation Molecular recognition units
US5260189A (en) * 1988-12-20 1993-11-09 Immunodiagnostics, Inc. Synthetic HIV-like peptides their compositions and uses
US5320951A (en) * 1987-06-01 1994-06-14 Hoeoek Magnus Fibronectin binding protein as well as its preparation
US5416021A (en) * 1988-05-20 1995-05-16 Alfa-Laval Agri International Aktiebolag Fibronectin binding protein-encoding DNA
US5440014A (en) * 1990-08-10 1995-08-08 H+E,Uml/Oo/ K; Magnus Fibronectin binding peptide
US5561049A (en) * 1994-09-21 1996-10-01 Behringwerke Ag Method for detecting antibodies
US5571514A (en) * 1987-06-01 1996-11-05 Alfa Laval Ab Fibronectin binding protein as well as its preparation
US5571511A (en) * 1990-10-22 1996-11-05 The U.S. Government Broadly reactive opsonic antibodies that react with common staphylococcal antigens
US5582975A (en) * 1991-09-04 1996-12-10 Gen-Probe Incorporated Nucleic acid probes to staphylococcus aureus
US5601830A (en) * 1995-03-31 1997-02-11 Wisconsin Alumni Research Foundation Staphylococcus aureus enterotoxin H and methods of use
US5627263A (en) * 1993-11-24 1997-05-06 La Jolla Cancer Research Foundation Integrin-binding peptides
US5700028A (en) * 1996-03-19 1997-12-23 General Motors Corporation Air bag module with energy absorbing mounting bracket
US5766951A (en) * 1992-11-12 1998-06-16 Quality Biological, Inc. Serum-free medium supporting growth and proliferation of normal bone marrow cells
US5766857A (en) * 1985-05-31 1998-06-16 La Jolla Cancer Research Foundation Isolation and use of fibronectin receptor
US5770208A (en) * 1996-09-11 1998-06-23 Nabi Staphylococcus aureus B-linked hexosamine antigen
US5776712A (en) * 1993-12-17 1998-07-07 Helsinki University Licensing, Ltd. Methods and materials for the detection of Staphylococcus aureus
US5789549A (en) * 1988-05-20 1998-08-04 Alfa Laval Agri International Aktiebolag Fibronectin binding protein
US5843774A (en) * 1990-12-03 1998-12-01 The Scripps Research Institute Polypeptides for promoting cell attachment
US5846536A (en) * 1996-10-04 1998-12-08 The Regents Of The University Of California Restoration of normal phenotype in cancer cells
US5869232A (en) * 1994-04-28 1999-02-09 Tripep Ab Antigen/antibody specificity exchanger
US5888738A (en) * 1993-11-26 1999-03-30 Hendry; Lawrence B. Design of drugs involving receptor-ligand-DNA interactions
US5929220A (en) * 1995-07-21 1999-07-27 The General Hospital Corporation Hepadnavirus receptor
US5942606A (en) * 1997-11-24 1999-08-24 Incyte Pharmaceuticals, Inc. Viral receptor protein
US5955078A (en) * 1993-02-05 1999-09-21 Smithkline Beecham P.L.C. Fibronectin binding protein polypeptides
US5981274A (en) * 1996-09-18 1999-11-09 Tyrrell; D. Lorne J. Recombinant hepatitis virus vectors
US5980908A (en) * 1991-12-05 1999-11-09 Alfa Laval Ab Bacterial cell surface protein with fibronectin, fibrinogen, collagen and laminin binding ability, process for the manufacture of the protein and prophylactic treatment
US6008341A (en) * 1994-08-22 1999-12-28 The Provost, Fellows And Scholars Of The College Of The Holy And Undivided Trinity Of Queen Elizabeth Near Dublin S. aureus fibrinogen binding protein gene
US6030613A (en) * 1995-01-17 2000-02-29 The Brigham And Women's Hospital, Inc. Receptor specific transepithelial transport of therapeutics
US6040137A (en) * 1995-04-27 2000-03-21 Tripep Ab Antigen/antibody specification exchanger
US6066648A (en) * 1997-12-17 2000-05-23 Merck & Co., Inc. Integrin receptor antagonists
US6077677A (en) * 1995-10-16 2000-06-20 Smithkline Beecham, P.L.C. Fibronectin binding protein B compounds
US6086875A (en) * 1995-01-17 2000-07-11 The Brigham And Women's Hospital, Inc. Receptor specific transepithelial transport of immunogens
US6087330A (en) * 1994-06-29 2000-07-11 Texas Biotechnology Corporation Process to inhibit binding of the integrin α4 β1 to VCAM-1 or fibronectin and cyclic peptides therefor
US6090388A (en) * 1998-06-20 2000-07-18 United Biomedical Inc. Peptide composition for prevention and treatment of HIV infection and immune disorders
US6090944A (en) * 1998-08-13 2000-07-18 Merck & Co., Inc. Alkanoic acid derivatives as αv integrin receptor antagonists
US6093539A (en) * 1986-08-21 2000-07-25 The Trustees Of Columbia University In The City Of New York DNA encoding the T cell surface protein T4 and use of fragments of T4 in the treatment of AIDS
US6245985B1 (en) * 1998-10-23 2001-06-12 Yamaha Corporation Data converter for enhancing resolution, method for converting data codes and keyboard musical instrument equipped with the data converter
US6417324B1 (en) * 2000-04-21 2002-07-09 Tripep Ab Synthetic peptides that bind to the hepatitis B virus core and e antigens
US6485726B1 (en) * 1995-01-17 2002-11-26 The Brigham And Women's Hospital, Inc. Receptor specific transepithelial transport of therapeutics

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8428487D0 (en) * 1984-11-12 1984-12-19 Ils Ltd Immunoassays
ES2102007T3 (en) * 1992-01-23 1997-07-16 Merck Patent Gmbh MONOMER AND DIMER ANTIBODY FRAGMENT FUSION PROTEINS.
DK0672142T3 (en) * 1992-12-04 2001-06-18 Medical Res Council Multivalent and multi-specific binding proteins as well as their preparation and use
GB9412166D0 (en) * 1993-09-22 1994-08-10 Medical Res Council Retargetting antibodies

Patent Citations (53)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US486530A (en) * 1892-11-22 Reversible plow
US4169138A (en) * 1974-05-29 1979-09-25 Pharmacia Diagnostics Ab Method for the detection of antibodies
US4376110A (en) * 1980-08-04 1983-03-08 Hybritech, Incorporated Immunometric assays using monoclonal antibodies
US4471058A (en) * 1982-07-26 1984-09-11 Board Of Trustees Operating Michigan State University Method for the detection and/or determination of a polyvalent antigen using at least two different monoclonal antibodies
US4589881A (en) * 1982-08-04 1986-05-20 La Jolla Cancer Research Foundation Polypeptide
US5189015A (en) * 1984-05-30 1993-02-23 Alfa-Laval Agri International Ab Method for prophylactic treatment of the colonization of a Staphylococcus aureus bacterial strain by bacterial cell surface protein with fibronectin and fibrinogen binding ability
US5766857A (en) * 1985-05-31 1998-06-16 La Jolla Cancer Research Foundation Isolation and use of fibronectin receptor
US6093539A (en) * 1986-08-21 2000-07-25 The Trustees Of Columbia University In The City Of New York DNA encoding the T cell surface protein T4 and use of fragments of T4 in the treatment of AIDS
US5091513A (en) * 1987-05-21 1992-02-25 Creative Biomolecules, Inc. Biosynthetic antibody binding sites
US5770702A (en) * 1987-06-01 1998-06-23 Hooek; Magnus Fibronectin binding protein as well as its preparation
US5571514A (en) * 1987-06-01 1996-11-05 Alfa Laval Ab Fibronectin binding protein as well as its preparation
US5320951A (en) * 1987-06-01 1994-06-14 Hoeoek Magnus Fibronectin binding protein as well as its preparation
US4946778A (en) * 1987-09-21 1990-08-07 Genex Corporation Single polypeptide chain binding molecules
US5416021A (en) * 1988-05-20 1995-05-16 Alfa-Laval Agri International Aktiebolag Fibronectin binding protein-encoding DNA
US6086895A (en) * 1988-05-20 2000-07-11 Alfa Laval Agri International Fibronectin binding protein
US5866541A (en) * 1988-05-20 1999-02-02 Alfa-Laval Agri International Aktiebolag Fibronection binding protein from Streptococcus dysgalactiae
US5789549A (en) * 1988-05-20 1998-08-04 Alfa Laval Agri International Aktiebolag Fibronectin binding protein
US5260189A (en) * 1988-12-20 1993-11-09 Immunodiagnostics, Inc. Synthetic HIV-like peptides their compositions and uses
US5196510A (en) * 1988-12-29 1993-03-23 Cytogen Corporation Molecular recognition units
US5840846A (en) * 1989-05-11 1998-11-24 Alfa-Laval Agri International Aktiebolag Fibronectin binding protein as well as its preparation
US5652217A (en) * 1989-05-11 1997-07-29 Alfa-Laval Agri International Aktiebolag Fibronectin binding protein
US5175096A (en) * 1989-05-11 1992-12-29 Alfa-Laval Agri International Aktiebolag Dna encoding a fibronectin binding protein as well as its preparation
US5440014A (en) * 1990-08-10 1995-08-08 H+E,Uml/Oo/ K; Magnus Fibronectin binding peptide
US5571511A (en) * 1990-10-22 1996-11-05 The U.S. Government Broadly reactive opsonic antibodies that react with common staphylococcal antigens
US5843774A (en) * 1990-12-03 1998-12-01 The Scripps Research Institute Polypeptides for promoting cell attachment
US5582975A (en) * 1991-09-04 1996-12-10 Gen-Probe Incorporated Nucleic acid probes to staphylococcus aureus
US5980908A (en) * 1991-12-05 1999-11-09 Alfa Laval Ab Bacterial cell surface protein with fibronectin, fibrinogen, collagen and laminin binding ability, process for the manufacture of the protein and prophylactic treatment
US5766951A (en) * 1992-11-12 1998-06-16 Quality Biological, Inc. Serum-free medium supporting growth and proliferation of normal bone marrow cells
US5955078A (en) * 1993-02-05 1999-09-21 Smithkline Beecham P.L.C. Fibronectin binding protein polypeptides
US5627263A (en) * 1993-11-24 1997-05-06 La Jolla Cancer Research Foundation Integrin-binding peptides
US5888738A (en) * 1993-11-26 1999-03-30 Hendry; Lawrence B. Design of drugs involving receptor-ligand-DNA interactions
US5776712A (en) * 1993-12-17 1998-07-07 Helsinki University Licensing, Ltd. Methods and materials for the detection of Staphylococcus aureus
US5869232A (en) * 1994-04-28 1999-02-09 Tripep Ab Antigen/antibody specificity exchanger
US6087330A (en) * 1994-06-29 2000-07-11 Texas Biotechnology Corporation Process to inhibit binding of the integrin α4 β1 to VCAM-1 or fibronectin and cyclic peptides therefor
US6008341A (en) * 1994-08-22 1999-12-28 The Provost, Fellows And Scholars Of The College Of The Holy And Undivided Trinity Of Queen Elizabeth Near Dublin S. aureus fibrinogen binding protein gene
US5561049A (en) * 1994-09-21 1996-10-01 Behringwerke Ag Method for detecting antibodies
US6030613A (en) * 1995-01-17 2000-02-29 The Brigham And Women's Hospital, Inc. Receptor specific transepithelial transport of therapeutics
US6485726B1 (en) * 1995-01-17 2002-11-26 The Brigham And Women's Hospital, Inc. Receptor specific transepithelial transport of therapeutics
US6086875A (en) * 1995-01-17 2000-07-11 The Brigham And Women's Hospital, Inc. Receptor specific transepithelial transport of immunogens
US5601830A (en) * 1995-03-31 1997-02-11 Wisconsin Alumni Research Foundation Staphylococcus aureus enterotoxin H and methods of use
US6040137A (en) * 1995-04-27 2000-03-21 Tripep Ab Antigen/antibody specification exchanger
US5929220A (en) * 1995-07-21 1999-07-27 The General Hospital Corporation Hepadnavirus receptor
US6077677A (en) * 1995-10-16 2000-06-20 Smithkline Beecham, P.L.C. Fibronectin binding protein B compounds
US5700028A (en) * 1996-03-19 1997-12-23 General Motors Corporation Air bag module with energy absorbing mounting bracket
US5770208A (en) * 1996-09-11 1998-06-23 Nabi Staphylococcus aureus B-linked hexosamine antigen
US5981274A (en) * 1996-09-18 1999-11-09 Tyrrell; D. Lorne J. Recombinant hepatitis virus vectors
US5846536A (en) * 1996-10-04 1998-12-08 The Regents Of The University Of California Restoration of normal phenotype in cancer cells
US5942606A (en) * 1997-11-24 1999-08-24 Incyte Pharmaceuticals, Inc. Viral receptor protein
US6066648A (en) * 1997-12-17 2000-05-23 Merck & Co., Inc. Integrin receptor antagonists
US6090388A (en) * 1998-06-20 2000-07-18 United Biomedical Inc. Peptide composition for prevention and treatment of HIV infection and immune disorders
US6090944A (en) * 1998-08-13 2000-07-18 Merck & Co., Inc. Alkanoic acid derivatives as αv integrin receptor antagonists
US6245985B1 (en) * 1998-10-23 2001-06-12 Yamaha Corporation Data converter for enhancing resolution, method for converting data codes and keyboard musical instrument equipped with the data converter
US6417324B1 (en) * 2000-04-21 2002-07-09 Tripep Ab Synthetic peptides that bind to the hepatitis B virus core and e antigens

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011044133A2 (en) * 2009-10-05 2011-04-14 Opsonic Therapeutics Inc. High affinity adaptor molecules for redirecting antibody specifity
WO2011044133A3 (en) * 2009-10-05 2011-08-25 Opsonic Therapeutics Inc. High affinity adaptor molecules for redirecting antibody specifity
US9284548B2 (en) 2009-10-05 2016-03-15 Tripep Ab High affinity adaptor molecules for redirecting antibody specifity

Also Published As

Publication number Publication date
US6040137A (en) 2000-03-21
US6469143B2 (en) 2002-10-22
US20020025513A1 (en) 2002-02-28
US6245895B1 (en) 2001-06-12

Similar Documents

Publication Publication Date Title
US20030129587A1 (en) Antigen/antibody specificity exchanger
US5869232A (en) Antigen/antibody specificity exchanger
Bettaieb et al. Presence of cross-reactive antibody between human immunodeficiency virus (HIV) and platelet glycoproteins in HIV-related immune thrombocytopenic purpura
JP4489351B2 (en) Monoclonal antibodies against human immunodeficiency virus and uses thereof
CA2406240C (en) Hcv anti-core monoclonal antibodies
IE870281L (en) Peptides for the diagnosis of HTLV-III antibodies, their¹preparation and use
WO1991004273A2 (en) Novel peptides associated with the cd4 binding region of gp120 and their methods of use
CA2009198C (en) Monoclonal antibody for differentiating hiv-2 from hiv-1 seropositive individuals
US5256561A (en) Monoclonal antibody to HIV-2 and uses thereof
JP3534417B2 (en) Method for simultaneous determination of HIV antigen and HIV antibody
BRPI0214188B1 (en) antibody or fragment thereof, nucleic acid molecule, use of monoclonal antibody or fragment thereof, diagnostic kit, pharmaceutical composition, recombinant expression vector, host cell transformed with recombinant expression vector and method for detecting antigen virus hepatitis and or the hepatitis virus antibody and in a sample
CA2252466C (en) Hepatitis b monoclonal antibodies
EP1328811B1 (en) Hcv mosaic antigen composition
AU621317B2 (en) Hiv peptides and methods for detection of hiv
KR910002690B1 (en) Htlv-iii/lav virus related peptides antibodies to the peptides vaccines passive and active immunization against aids virus and diagonostic test for the serological detection of the aids virus
JP2954597B2 (en) Monoclonal antibody against HIVIgp41 and method for immunological detection of antibody against HIVIgp41 using the same
CA1339363C (en) Monoclonal antibodies to specific antigenic regions of the human immunodeficiency virus and methods for use
JPH04506077A (en) Peptides and their derived antibodies for diagnosis, treatment and vaccination of HTLV-1 infection
US20030118985A1 (en) Mouse monoclonal antibody (5-21-3) to human immunodeficiency virus gp41 protein
Kantrong et al. A single amino acid substitution at N-terminal region of coat protein of turnip mosaic virus alters antigenicity and aphid transmissibility
EP1765867B1 (en) Monoclonal antibodies to hiv-1 vpr and methods of using same
Norrby et al. Immunochemistry of the dominating antigenic region Ala582 to Cys604 in the transmembranous protein of simian and human immunodeficiency virus.
JPH1072498A (en) Anti-hiv antibody as reference sample
JPH04505621A (en) T lymphotropic retrovirus monoclonal antibody
Hunt et al. Mouse monoclonal antibody 5-21-3 recognizes a contiguous, conformation-dependent epitope and maps to a hydrophilic region in HIV-1 gp41

Legal Events

Date Code Title Description
STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION