EP0929568A2 - Compositions pharmaceutiques pour therapie a but immunitaire - Google Patents

Compositions pharmaceutiques pour therapie a but immunitaire

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Publication number
EP0929568A2
EP0929568A2 EP97939105A EP97939105A EP0929568A2 EP 0929568 A2 EP0929568 A2 EP 0929568A2 EP 97939105 A EP97939105 A EP 97939105A EP 97939105 A EP97939105 A EP 97939105A EP 0929568 A2 EP0929568 A2 EP 0929568A2
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EP
European Patent Office
Prior art keywords
glu
ieast
sequence
asp
patient
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EP97939105A
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German (de)
English (en)
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Patrick Thomas Prendergast
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Individual
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Individual
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/2026—IL-4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/2066—IL-10
    • 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
    • A61K39/385—Haptens or antigens, bound to carriers
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
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    • A61P25/00—Drugs for disorders of the nervous system
    • 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
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4715—Pregnancy proteins, e.g. placenta proteins, alpha-feto-protein, pregnancy specific beta glycoprotein
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    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/54—Interleukins [IL]
    • C07K14/5428—IL-10
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    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/54—Interleukins [IL]
    • C07K14/5434—IL-12
    • 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
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244—Interleukins [IL]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244—Interleukins [IL]
    • C07K16/247—IL-4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K4/00—Peptides having up to 20 amino acids in an undefined or only partially defined sequence; Derivatives thereof
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • 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
    • G01N33/56983—Viruses
    • G01N33/56988—HIV or HTLV
    • 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
    • C—CHEMISTRY; METALLURGY
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    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
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    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/15011—Lentivirus, not HIV, e.g. FIV, SIV
    • C12N2740/15022—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
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    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16111—Human Immunodeficiency Virus, HIV concerning HIV env
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    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16111—Human Immunodeficiency Virus, HIV concerning HIV env
    • C12N2740/16122—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

Definitions

  • Ammo acids and residues thereof are referred to herein by their 3- letter abbreviations, (e.g , "Lys” for Lysine) well known to those skilled in the art
  • (h) malarial infection comprising administering to the patient an immune response enhancing effective amount of a pharmaceutical formulation comprising at least one polyclonal or monoclonal antibody, or at least one Fab fragment thereof, generated to at least one compound selected from the group consisting of:
  • X is a covalent bond or an amino acid sub-sequence comprising at least one amino acid residue
  • Y is a covalent bond or an amino acid sub-sequence comprising at least one amino acid residue
  • D is an amino acid sub-sequence comprising at least one amino acid residue
  • A is Lys, Arg or His;
  • B is Giu or Asp;
  • C is a carrier compound residue
  • Z is a carrier compound residue.
  • the present invention also provides pharmaceutical compositions and methods of enhancing immune response, e.g., in a patient suffering from a condition as set forth above, comprising administering to said patient an immune response enhancing effective amount of a pharmaceutical formulation comprising at least one polyclonal or monoclonal antibody, or at least one Fab fragment thereof, generated to at least one compound selected from the group consisting of: D-A-B-E; D-A-B; and A-B-E; wherein: D is an ammo acid sub-sequence comprising at least one am o acid residue;
  • E is an ammo acid sub-sequence comprising at least one am o acid residue
  • the compound can consist of 16 or fewer am o acid residues, or of 8 or fewer ammo acid residues
  • at least one compound can consist of 16 or fewer ammo acid residues, 8 or fewer ammo acid residues, or 4 or fewer ammo acid residues
  • the sub-sequence -A-B- further includes a hydrophobic ammo acid residue "H", i e , an ammo acid residue selected from Ala, He, Leu, Met, Phe, Trp, Val and Tyr on either end i.e , -H-A-B- or -A-B-H-
  • the present invention further relates to the antibodies used in the methods of the invention.
  • any of the antibodies in accordance with the present invention can be administered to a patient in addition to any known vaccine
  • the present invention further relates to methods of reducing a patient's immune response, by administering any of the compounds described above which have a sub-sequence -A-B- or -B-A, preferably -H-A-B- or -H-B-A-
  • Serum albumin precursor - rat Acyl carrier protein - Escherichia coli
  • Serum Albumin precursor - human S typhimu ⁇ um branched chain am o transport system II carrier, Branched - chain am o acid carrier
  • Excitatory ammo acid transporter 3 (sodium- dependent; glutamate/aspartate transporter 3) (excitatory ammo-acid carrier 1); Glutaredoxin 3; Cytochrome B5/C6; Transthyretin Precursor (prealbumin) (TBPA) (TTR); Phosphocar ⁇ er Protein HPR (Histidine-containing protein), Beta-Hexosaminidase alpha
  • the present invention further relates to methods of vaccinating a patient against immunosuppressive sequences, by administering a compound which corresponds with an immunosuppressive sequence, except that one or both of the members of at least one -A-B- sub-sequence is replaced with an analog, an antimetabolite or a D-amino acid corresponding to the replaced amino acid.
  • the present invention also relates to such compounds Examples of such immunosuppressive sequences include: Asp-Arg-Ala-Ala-Asp-Gly-Gln-Pro-Ala-Gly (SEQ ID NO 1 );
  • analogs of Larginine including Lornithine, L-Citrulline, L- ⁇ -Aminobutyrate, Agmatine (4-amino-1-guanidinobutane) : Putrescine (1 ,4-diaminobutane), glycocyamylglycine, glycocyamine, taurocyamine, methylguanidine, L-Homoarginine, L-Argininosuccinic anhydride (I), L-Argininic acid, L-Argininosuccinic anhydride (II), L- Argininosuccinate (III), L-Argininosuccinate anhydride (IV), and LnitroArginine; and analogs of Lysine including L-thialysine (S-( ⁇ -arnino-ethyl)-L-cysteine), D/L 4 oxalysine
  • the present invention further relates to a method of treating a condition selected from the group consisting of: (a) immunodeficiency resultant from a viral infection;
  • tuberculosis infection comprising deleting genetic material from an infectious organism to prevent said genetic material from generating one or both amino acids in an amino acid sub-sequence "K" selected from the group consisting of Lys-Glu, Lys-Asp, Arg-Glu, Arg-Asp, His-Glu, His-Asp, Glu-Lys, Asp-Lys, Glu-Arg, Asp-Arg, Glu-His and Asp-His, and sub-sequences K which have at least one adjacent hydrophobic ammo acid.
  • K amino acid sub-sequence
  • the present invention further relates to methods and pharmaceutical compositions described above, wherein the component A and the component B are separated by 1 or 2 amino acid residues
  • sequences which consist of four distinct regions, i.e , R1 -R2-R3-R4, in which:
  • R1 is a region of up to 5AA within which there is one to three AA from the group Lysine and/or Arginine
  • R2 is a short region of up to 2AA which does not contain any of the following Asp, Glu, Lys, Arg or His
  • R3 is a region of up to 7AA within which there may be one or two AA from the group Aspartic acid and/or Glutamic acid
  • the Aspartic acid or Glutamic closest to the R4 region is positioned within R3 to allow a minimum of two AA between these said acids and the R4 region
  • R4 is a region of two AA containing one AA of either Lysine or Arginine attaching to region R3 and the other AA is either Aspartic acid or Glutamic acid. Regions R1 , R2 and R3 are considered the positioning regions of this specific AA sequence as they allow alignment of the AA sequence with cell membrane whereas R4 is considered the signalling sequence as this duo of peptides activates cell stimulation.
  • This said peptide may be administered with a carrier moiety wherein the said carrier protein comprises bovine serum albumin, human serum albumin, an immunoglobulin or a hormone. These peptides may be made to further possess sugar groups, normal serum components, lipids, phospholipids, etc.
  • Naturally occurring organisms using peptides similar to those described herein for immune attack may be treated to deactivate their peptide immune activation mechanism by altering, by means known to those skilled in the art, one or more of either Lysine or Arginine existing in Region R1 and preferably in addition altering one or two of the AA in region R4 to remove the charge distribution of the said peptide.
  • Vaccines may be manufactured using such techniques.
  • sequences which consist of four distinct regions i.e. , RA-RB-RC-RD, in which:
  • RA is a region of up to 5 AA within which there is one to three AA from the group Lysine and/or Arginine RB is a short region of up to 2AA which does not contain any of: Asp,
  • RC is a region of up to 7AA within which there may be one or two AA from the group Aspartic acid and/or Glutamic acid.
  • the Aspartic acid or Glutamic closest to the RD region is positioned within RC to allow a minimum of two AA between this said AA, if one exists, and the RD region.
  • RD is a region of three or four AA containing one AA of either Lysine or Arginine attaching to region RC and one or two amino acids in the middle of the region containing AA from Polar and/or non-Polar with another AA at the end of the region which is either Aspartic acid or Glutamic acid.
  • Regions RA, RB and RC are considered the positioning regions of this specific AA sequence as they allow alignment of the AA sequence with cell membrane whereas RD is considered the signalling sequence as this duo of peptides activates cell stimulation.
  • This said peptide may be administered with a carrier moiety wherein the said carrier protein comprises bovine serum albumin, human serum albumin, an immunoglobulin or a hormone These peptides may be made to further possess sugar groups, normal serum components, pids, phospholipids etc Naturally occurring organisms using peptides similar to those described herein for immune attack may be treated to deactivate their peptide immune activation mechanism be altering, by means known to those skilled in the art, one or more of either Lysine or Arginine existing in Region RA and preferably in addition altering one or two of the charged AA in region RD to remove the charge distribution of the said peptide Vaccines may be manufactured using such techniques
  • the present invention also relates to treatments comprising administering to a patient any pharmaceutical formulations
  • non-protective vaccine candidate antigens which when previously inoculated into a host produced a range of neutralising antibodies but failed to prevent infection being established when that host was later challenged with live infectious organism.
  • an immune response to the vaccine antigen from both T cell and B cell immune components results which includes antibodies to these hitherto unchallenged sequences results
  • the host is then capable of overcoming an infectious challenge without becoming infected or producing the usual antibody and autoantibody peak and subsequent immunosuppression normally associated with infections caused by organisms who utilise these specific amino acid sequences to direct the hosts immune signalling system towards a more pronounced B cell or Th 2 cytokine profiled response.
  • Malaria is one of the most important infectious diseases in the World, each year there are 270 million new infections resulting in over 100 million episodes of illness and approximately 2 million deaths. World-wide the malaria problem is getting worse each year
  • the reason for this worsening situation include (A) increased levels of drug resistance on the part of the parasites, (B) increased levels of insecticide resistance on the part of the vectors. No vaccine has yet been produced which can successfully induce a protective antibody response. The reason for this is that although antibodies which cross react with many epitopes of the P.
  • vivax circumsporozoite are produced in abundance by the current unprotective vaccine candidates, because of the immune blind spot or immunologically privileged sites offered by these specific sequences identified herein, like Interleukin 10 and AFP, these sequences are not visible to the host immune system which both allow the parasite to gain access to the host cell and to cause the non-specific polyclonal B cell activation and immunosuppressive (Interleukin 10 and/or AFP) like effects which are so universal for people suffering from parasites such as malaria, and Leishmania, the host cannot gain enough immune reactive monocytes to overcome the infection initially because these Interleukin 10/AFP mimic molecules carried by the infecting organism shuts down the vital Th 1 T cell response needed to clear intra-cellular infections.
  • Interleukin 10 and/or AFP non-specific polyclonal B cell activation and immunosuppressive
  • a vaccine for malaria which will enable a human to raise a protective antibody titre against malaria sufficient to prevent infection may be manufactured by deleting from the antigenic peptide to be used in the vaccine these ammo acid sequences displaying the specific polar arrays outlined in this patent
  • Another method expected to be more successful as a vaccine combination is to use passive immunisation with either polyclonal or monoclonal antibodies to these said specific dipole immunosuppressive sequences generated either in animal human and/or tissue culture given either before or simultaneously with any of the current malaria vaccine candidates which previously could not produce a protective immune response
  • these mono or polyclonal antibodies are given to the host in conjunction with the antigen the host's immune system does not produce the well documented polyclonal B cell activation of the host immune system and the immune system of the host so challenged will produce a protective antibody and T cell immune response which allows it to deal effectively with any later malaria infection challenge
  • the said specific sequences identified as a dipole am o acid sequence in this patient, when embedded in the cell membrane of the host activates the phosphatidylinositol pathway, which causes the release of Ca++, the phosphosylation of cell proteins and the activation or enhanced activity of certain enzymes related to metabolism This does not occur in the presence of antibodies to the disclosed specific sequences and the organism like malaria, Mycobacte ⁇ um Tuberculosis Leishmania, HIV and others are not able to cause metabolic and immune Th 2 activation and exhaustion It is an important coincidence that in certain malaria endemic areas that genetic mutations that have caused the deletion of the metabolic activity control enzyme glucose-6-phosphate dehydrogenase has conferred on the host immunity to malaria By intervening at an early stage of infection and neutralising certain properties of the malaria parasite to alter cellular reactions by interfering with these specific membrane signal transduction sequences as defined herein it is possible to confer protective immunity to this organism.
  • the present invention utilises the novel discovery that certain am o acid sequences which exhibit specific ion (bridge) pair arrays enclosed on at least one side by non-polar hydrophobic transmembrane segments can be utilised to enhance the humoral antibody response and down-regulate the T cell or delayed-type hypersensitivity (DTH) response of humans and animals
  • CD3/TCR mimic membrane interaction molecules which present as hydrophobic Ion bridge pairs are utilised by both the organism itself as specific peptides and by cytokines and also by infectious agents to modulate immune response (A) during periods of reproductive foetal gestation as with the alpha-fetoprotein molecule to prevent foetal rejection by the maternal immune system and (B) during cytokine control of immune functions as with cytokine synthesis inhibitory factor (Th 2 cytokine) when a Th 2 cytokine profile is required or to curtail the uncontrolled Th 1 T4 cell immune response
  • Th 2 cytokine cytokine synthesis inhibitory factor
  • Anti-serum generated to these specific sequences as presented in AFP, Interleukin 10, EBV-BCRF1 and other peptides and as specified in ammo acid sequence, listing enclosed, with this patent can be used to remove AFP mimic molecules from the circulation of immunosuppressed patients suffering from viral and/or bacterial and/or fungal, mycoplasmic or parasitic infections, which infection's principle method of defence against the host is to stimulate a Th2 cytokine response and curtail or abolish the Th1 cell mediated immune attack
  • This invention relates to methods of treatment of persons and animals with indications of immunodeficiency, wherein the said indication is resultant from viral and/or retroviral infection and/or infectious parasites, bacteria and/or mycoplasma
  • the invention further relates to treatment with the above antiserum either poly or monoclonal in nature for establishing improved immuno response for persons and prophylactic treatment for persons where immuno-malfunction due to genetic pre-disposition or infection is considered a future risk
  • the invention further relates to a screening method for vaccines manufactured by the use of coat or other peptides from viral, bacterial parasitic or mycoplasma, to determine and remove and/or neutralise inherent immune suppressive properties - such suppressive potential properties are determined by the manufactured vaccine's reactivity with the said specific ammo acid sequences as outlined herein, be they synthetic or natural in origin, e g AFP, Th 2 cytokines, viral or bacterial coat peptides
  • the host organism is treated with mono or polyclonal antibodies to any one or combination of the specific ammo acid sequences as defined herein This will result in the removal of Th 2 cytokine and AFP type mimic immunosuppressive peptides and initiate a Th 1 cell response, allowing Interleukin 2 and gamma interferon synthesis to occur
  • Treatments used according to this invention employing the poly or monoclonal antiserum to these specific immune system inhibitory sequences are administered as treatments against viral, bacterial and mycoplasma
  • the present invention also relates to a method comprising inoculating into a patient a human, animal, synthetic or recombinant ammo acid sequence with or without adjuvant, to produce an antibody response, the antibodies mono or polyclonal will cause the binding of the immunosuppressive CD3 TCR mimic interaction molecules already present in the plasma of the infected host will be removed from the circulation of the infected host and normal immune function demonstrating a Th 1 cytokine profile, i e Interleukin 2 and gamma interferon, capable of resisting the infection will be re-established
  • Vaccines manufactured by the use of coat or other peptides from viral bacterial, parasitic or mycoplasma may be screened to determine whether they posses these specific am o acid sequences which exhibit these specific Ion b ⁇ dge pair arrays capable of mimicking the actions of AFP or Th 2 cytokines and their inherent immune suppressive properties - such suppressive potential properties is determined by the manufactured vaccine's reactivity with any of the said specific ammo acid sequences listed herein which may be removed or neutralised by the antiserum specified in this patent
  • the present invention also relates to a method of assaying body fluid from an animal, comprising contacting said body fluid with at least one antibody as described above.
  • the present invention further relates to a method of screening a vaccine, comprising contacting said vaccine with at least one antibody as described above.
  • a tyrosine residue was added to either the am o or the carboxy terminus for monitoring peptide purification and radiodination
  • a cysteine residue was added to either terminus for coupling via its free sulfhydryl to the carrier proteins keyhole limpet hemocyanin (KLH) or bovine serum albumin (BSA) using the MBS heterobifunctional cross nker KLH- Keyhole Limpet Hemocyanin BSA- Bovine Serum Albumin Inhibition of mito ⁇ en-induced blasto ⁇ enesis
  • immunosuppressive peptides which clearly suppressed the proliferation of normal PMN in a two-way mixed lymphocyte reaction (MLR) were not capable of demonstrating any form of suppression when the specific dipole signalling sequence as designated in Table 1 were chemically modified to neutralize the charge distribution on the dipole (Table 3)
  • Peripheral mononuclear cells were obtained from normal HIV antibody-negative donors by density gradient centrifugation through H ⁇ sopaque-1077 (Sigma Chemical Co , St Louis, MO).
  • the in-vitro proliferation assays were performed by incubating 10 5 cells/well in 96-well round-bottom microtiter plates in the absence or presence of various dilutions of peptides for 4 days in RPMI 1640 cultured medium (Grand Island Biological Co., Grand Island, NY) supplemented with 10% fetal calf serum (FCS).
  • FCS fetal calf serum
  • This modified peptide is essentially restored to its original immunosuppressive capability when the modification to the arginyl residue is reversed by treatment with hydrosylamine
  • the immunosuppressive peptides designed as per this patent may be neutralized in their ability to effect immune function if the ammo acid charged dipole sequence is deleted or chemically modified so that the charged chemical groups on the dipole ammo acides, be they positive or negative, are either both or individually left without an electrostatic charge component
  • the present invention further relates to pharmaceutical compositions and methods of providing an immunosuppressive or immunoregulatory effect in a patient, comprising administering to the patient an immunosuppressive or immunoregulatory effective amount of a pharmaceutical formulation comprising at least two Th 2 cytokines, for example, wherein the at least two Th 2 cytokines include Interleukin 10 and Interleukin 4
  • Trial 1 2 mg per day of anti-serum to IL-10 on each alternative day and 2 mg per day of anti-serum to IL-4 on each other alternative day Administration by IV
  • agents as per this patent are administered in an amount, which provides circulating levels of about 1 -150 ⁇ g/ml of each agent
  • the present invention further relates to pharmaceutical compositions and methods of treatment of graft vs host disease in a patient in need of such treatment, comprising administering to the patient Interleukin 10 and Interleukin 4
  • the present invention further relates to pharmaceutical compositions and methods of providing an immunosuppressive or immunoregulatory effect in a patient, comprising administering to the patient Interleukin 10, Interleukin 4 and at least one of antagonist of Interleukin 10 and antagonist of Interleukin 4
  • the present invention further relates to pharmaceutical compositions and methods of providing an immunosuppressive or immunoregulatory effect in a patient, comprising administering to said patient Interleukin 10 and Interleukin 4 and at least one of agonist of Interleukin 10 and agonist of Interieukin 4
  • the present invention further relates to pharmaceutical compositions and methods of providing an immunosuppressive or immunoregulatory effect in a patient, comprising administering to said patient anti-serum to Interleukin 10 and anti-serum to Interleukin 4
  • the present invention further relates to pharmaceutical compositions and methods of providing an immunosuppressive or immunoregulatory effect in a patient, comprising administering to said patient anti-serum to Interleukin 10 and at least one of antagonist of Interleukin 4 and agonist of Interleukin 4.
  • the present invention further relates to pharmaceutical compositions and methods of providing an immunosuppressive or immunoregulatory effect in a patient, comprising administering to said patient anti-serum to Interleukin 4 and at least one of antagonist of Interleukin 10 and agonist of Interleukin 10
  • the patient was administered the two antibodies to Interleukin 10 and Interleukin 4 for 2 weeks Following this the patient's HIV viral load again increased when monitored by PCR RNA and decreased to zero after 4 weeks
  • Suitable dosages in accordance with the present invention depend on many factors, e.g. the patient's weight, the mode of administration, the frequency of administration, the type of affliction being treated or prevented, whether the infection presently exists, and if so, to what degree Suitable dosages for given situations can readily be determined by those skilled in the art without undue experimentation
  • the total treatment time according to the present invention will vary from patient to patient based on sound medical judgement and factors particular to the patient being treated, such as, for example, the age and physical condition of the patient Those skilled in the art can easily determine suitable total treatment time on a patient-by-patient basis 5
  • the following is a description of a suitable protocol in accordance with the present invention
  • the present invention is not limited by the following Example, and variations will be apparent to those skilled in the art without departing from the spirit of the present invention
  • HIV-1 Human Immunodeficiency Virus Type 1
  • AIDS Human Immunodeficiency Virus Type 1
  • the major histocompatibility complex is a collection of 40-50 genes arrayed within a long continuous stretch of DNA on chromosome 6 in humans
  • the MHC is referred to as the HLA complex in humans
  • the MHC genes are organised into regions encoding three classes of molecules Class I, Class II and Class 111
  • the Class I genes encode glycoprotems expressed on the surface of nearly all nucleated cells where they present peptide antigens of altered self-cells necessary for the activation of T c cells
  • the Class II genes encode glycoprotems expressed primarily on antigen-presenting cells (macrophages, dendritic cells and B cells), where they present processed antigenic peptides to T cells
  • the Class III genes encode somewhat different products that are also associated with the immune process These include a number of soluble serum proteins (including components of the complement system) steroid 21 -hydroxy lase enzymes, and tumour necrosis factors
  • the administration of antibodies poly or mono clonal to these specific CD3/TCR mimic molecules will cause an immediate antibody
  • a number of white blood cells have cytotoxic potential and express membrane receptors for the Fc region of the antibody IgG molecule When this antibody is specifically bound to a target cell which occurs when these specific poly or monoclonal antibodies to these sequences present on AFP. and Th 2 cytokines bind to HIV infected cells or free viral peptides causing immune Th2 shift. These cytotoxic Fc receptor-bearing cells can bind to the antibodies' Fc region, and thus to the infected HIV cells, and subsequently cause lysis of these cells.
  • ADCC antibody-dependent cell-mediated cytotoxicity

Abstract

L'invention concerne une séquence d'acides aminés présentant des groupes de paires d'ions spécifiques (ponts) ceints au moins d'un côté par des segments transmembranaires hydrophobes non polaires, en tant que mécanisme utilisé par de nombreux agents infectieux et plusieurs facteurs d'inhibition de la cytokine, tels que l'interleukine 10, le facteur d'inhibition de la prolactine et l'alpha-foeto-protéine. Ladite séquence n'est pas seulement utilisée pour amoindrir les défenses immunitaires des hôtes mais également pour permettre l'infection de tissus lymphoïdes cibles. Il a été prouvé que certains vaccins, lorsqu'ils sont inoculés à un hôte, produisent un certaine gamme d'anticorps neutralisants mais n'empêchent pas l'infection lorsque cet hôte est ensuite exposé à un organisme infectieux vivant. Dans la thérapie de l'invention, lorsque l'inoculation de ce type de vaccin est combinée à une immunisation passive au moyen d'anticorps mono ou polyclonaux dirigés contre lesdites séquences d'acides aminés, l'hôte est capable de surmonter l'agression infectieuse. L'invention se rapporte à l'utilisation thérapeutique d'anticorps mono ou polyclonaux dirigés contre lesdites séquences spécifiques, comme traitement du syndrome d'immunodéficience acquise (SIDA) et d'autres états pathologiques qui persistent en raison de la présence d'un facteur d'inhibition de la cytokine d'origine virale, bactérienne ou provenant de l'hôte, tel que le syndrome de fatigue chronique dans lequel les molécules d'imitation de l'interleukine 10 sont responsables d'une multitudes de symptômes identifiés comme indicateurs de l'encéphalomyélite. L'invention se rapporte à l'utilisation thérapeutique d'anticorps mono ou polyclonaux dirigés contre ces séquences d'acides aminés spécifiques, sous forme de thérapie associée au moyen de vaccins et d'agents antiviraux pour la prévention des effets secondaires de certains agents de modulation des défenses immunitaires et antiviraux (ex: DHEA et IL-12) qui provoquent la production accrue de molécules d'imitation de l'interleukine 10 ou de l'alpha-foetoprotéine pendant la thérapie. L'invention se rapporte encore à l'utilisation thérapeutique de ces séquences spécifiques, soit isolées de la source de l'organisme source, soit produites par synthèse directe ou synthèse de protéines recombinaison. Ces peptides, lorsqu'ils sont administrés à un patient souffrant d'une maladie auto-immune, tels que, entre autres, la sclérose en plaques, le lupus érythémateux (lupus érythémateux systémique), le diabète ou la polyarthrite rhumatoïde ou à des receveurs de transplant, permettent de modifier l'état immunitaire du patient de sorte que soit produite une réponse immunitaire dépendante de l'anticorps Th2 et que soit inhibée l'attaque immunitaire de Th1 (dépendant des lymphocytes) qui se manifeste dans ces types de déficiences immunitaires, telles que la sclérose en plaques et la réaction du greffon contre l'hôte. Certaines affections dermatologiques qui sont aujourd'hui traitées au moyen de crèmes et d'onguents corticostéroïdes peuvent être également traitées avec succès par le remplacement des corticostéroïdes par ces séquences immunosuppressives d'imitation de l'interleukine 10 et de l'alpha-foetoprotéine de l'invention.
EP97939105A 1996-09-11 1997-09-10 Compositions pharmaceutiques pour therapie a but immunitaire Withdrawn EP0929568A2 (fr)

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WO1998010787A3 (fr) 1998-07-30
IL128806A0 (en) 2000-01-31
WO1998010787A2 (fr) 1998-03-19
SE9900812L (sv) 1999-03-08
AU4132097A (en) 1998-04-02
NZ335039A (en) 2001-04-27
WO1998010792A1 (fr) 1998-03-19
CA2265885A1 (fr) 1998-03-19
JP2001503613A (ja) 2001-03-21

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