EP0929568A2 - Pharmaceutical compositions for the treatment of immune disorders - Google Patents

Pharmaceutical compositions for the treatment of immune disorders

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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
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.)
Withdrawn
Application number
EP97939105A
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German (de)
French (fr)
Inventor
Patrick Thomas Prendergast
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Individual
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Individual
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Publication of EP0929568A2 publication Critical patent/EP0929568A2/en
Withdrawn legal-status Critical Current

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    • 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
    • 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
    • A61K38/06—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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A—HUMAN NECESSITIES
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • 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
    • C07K14/46—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • 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]
    • C07K14/5428—IL-10
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • 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
    • C—CHEMISTRY; METALLURGY
    • 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
    • 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
    • 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
    • C12N2740/15011—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
    • 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
    • C12N2740/16111—Human Immunodeficiency Virus, HIV concerning HIV env
    • 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
    • C12N2740/16111—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

Herein is described a specific amino acid sequence which exhibits specific Ion (bridge) pair arrays enclosed on at least one side by non polar hydrophobic transmembrane segments, as a mechanism used by many infectious agents and a number of cytokine inhibitory factors, such as Interleukin 10 and Prolactin Inhibitory factor and alfa-fetoprotein, to not only undermine the hosts immune defences but to also allow for the infection of target lymphoid tissue. It has been demonstrated that certain vaccines, when inoculated into a host, produced a range of neutralising antibodies but failed to prevent infection when that host is later challenged with live infectious organism. This present patent illustrates that when such vaccine inoculation is coupled with passive immunisation with mono or polyclonal antibodies to these specific amino acid sequences as specified herein that the host is then capable of overcoming the infectious challenge. Herein is described the therapeutic use of mono or polyclonal antibodies to these said specific sequences as a treatment for Acquired Immune Deficiency Syndrome (AIDS) and other disease states that persist due to the presence of a cytokine inhibitory factor of viral, fungal, bacterial or host origin such as Chronic Fatique Syndrome where Interleukin 10 mimic molecules are responsible for a multitude of disease symptoms identified as indicative of Myalgic Encephalitis. Herein is described the therapeutic use of mono or polyclonal antibodies to these specific amino acid sequences as a combination therapy with vaccines and anti-viral agents to prevent side effects from certain immune modulation and anti-viral agents (e.g. DHEA and IL-12) which cause enhanced production of Interleukin 10 or AFP mimic molecules during therapy. Also herein is described the therapeutic use of these specific sequences either isolated from the organism source or produced by direct synthesis or recombinant protein synthesis. These peptides when administered to a patient suffering from an auto-immune disease, such as Multiple Sclerosis (MS), Lupus (systemic Lupus erythematoses) or diabetes or rheumatoid arthritis as limited examples or to transplant organ recipients, will allow the patient's immune state to be shifted to a Th2 antibody dependent immune response and curtail the Th1 (T cell dependent) immune attack which is evident in such immune malfunctions as MS and graft versus host disease. Certain dermatological conditions which are today treated by the use of corticosteroid creams and ointment may also be successfully treated by replacing the corticosteroid with these mimic immunosuppressive AFP/Interleukin 10 sequences outlined in this patent.

Description

IMMUNE DIRECTION THERAPY
It is identified in this patent that a very specific amino acid sequence which exhibits specific Ion bridge pair arrays, especially if enclosed on at least one side by a non-polar hydrophobic transmembrane segment of at least one amino acid, can, if presented with a carrier to a cell membrane, induce endocytosis and cause activation of specific intracellular and extracellular events which would normally only result from the interaction of an Antigen MHC-II complex with both the T cell receptor (TCR) and the CD3 membrane complexes. These specific amino acid Ion bridge pair sequences are only present within the cell membrane during proper functioning of the immune system and allow activating T cell clone expansion following antigen presentation. If this specific ion bridge pair enclosed on at least one side by hydrophobic segments is presented to the cell from a non immune source then increased cytoplasmic circulation from cell membrane of specific marker molecules occurs and this removes the normal immune functions of the cell types impacted by these specific peptide sequences. A proportion of amino acid sequences according to the present invention have demonstrated in a dose dependent manner the ability to down-regulate the expression of la molecules on human macrophages. Some in-vitro experiments suggest that direct T cell antigen interactions without the mediation of la bearing macrophages may result in the generation of antigen specific suppressor T cells. All experimental evidence indicates that the development of antigen-reactive clones of heiper T cells requires the presence of la bearing cells in the tissue. This inhibition of expression on the membrane surface of these class II molecules (la) as produced with alfa-fetoprotein and/or cytokine inhibitory factor, signals the immune system to accept the appearance of new antigens as self to the immune system. Hence the often reported observation that an immune activation on polyclonal B cell activation producing auto-antibodies follow certain viral, bacterial and parasitic infections (e g HIV Malaria) The effects of these specific peptide ion-bridge pairs attached to a hydrophobic amino acid sequence demonstrate that they are the component peptide segments within both the alpha-fetoprotein and the cytokines molecules that are involved in the process of inducing tolerance and maintaining the tolerant state to infectious organisms presenting these sequences
In identifying this specific type of sequence and its ability to generate specific immune signals together with its ability to enhance or trigger endocytosis of attached peptides or glycopeptides, we have been able to identify these specific ammo acid sequences as a mechanism used by many infectious agents to not only undermine the hosts' immune defenses but to also allow for the penetration or infection of target lymphoid tissue
Ammo acids and residues thereof (i e , ammo acids in which one or more hydrogen atoms have been removed) are referred to herein by their 3- letter abbreviations, (e.g , "Lys" for Lysine) well known to those skilled in the art
According to the present invention, there are therefore provided pharmaceutical compositions and methods of enhancing immune response in a patient suffering from immunodeficiency and/or one or more condition selected from the group consisting of
(a) immunodeficiency resultant from a viral infection,
(b) immunodeficiency resultant from one or more of bacterial mycoplasmic, fungal parasitic infections, (c) immunodeficiency resultant from the growth of neoplastic tissue
(d) immunodeficiency resultant from any cytokine or hormone imbalance or imbalance of any natural product within the patient
(e) myalgic encephalomyelitis (ME),
(f) post inoculation or viral infection fatigue syndrome (g) tuberculosis infection; and
(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:
C-X-A-B-Y-Z;
C-X-A-B-D;
C-X-A-B; D-A-B-Y-Z; and
A-B-Y-Z; wherein:
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;
and wherein said at least one compound comprises at least 4 am o acid residues In specific aspects of the present invention, the compound can consist of 16 or fewer am o acid residues, or of 8 or fewer ammo acid residues In specific aspects of the present invention, 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
In a preferred aspect of the present invention, 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.
In addition, 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- The present invention further relates to such compounds Suitable (3-amino acid) sequences which include a sub-sequence -H- A-B- or -H-B-A- for use in accordance with the present invention include the following
Ala-His-Asp; Ala-His-Glu; Ala-Lys-Asp, Ala-Lys-Glu, Ala-Arg-Asp, Ala-Arg-Glu; lle-His-Asp; lle-His-Glu; lle-Lys-Asp; lle-Lys-Glu; lle-Arg-Asp, lle-Arg-Glu;Leu-His-Asp;Leu-His-Glu;Leu-Lys-Asp;Leu-Lys-Glu,Leu-Arg-Asp, Leu-Arg-Glu; Met-His-Asp, Met-His-Glu, Met-Lys-Asp, Met-Lys-Glu, Met-Arg-Asp, Met-Arg-Glu, Phe-His-Asp, Phe-His-Glu, Phe-Lys-Asp, Phe-Lys-Glu, Phe-Arg-Asp;Phe-Arg-Glu, Pro-His-Asp, Pro-His-Glu, Pro-Lys-Asp; Pro-Lys-Glu; Pro-Arg-Asp, Pro-Arg-Glu, Trp-His-Asp, Trp-His-Glu, Trp-Lys-Asp, Trp-Lys-Glu, Trp-Arg-Asp, Trp-Arg-Glu, Val-His-Asp; Val-His-Glu; Val-Lys-Asp, Val-Lys-Glu, Val-Arg-Asp, Val-Arg-Glu, Ala-Asp-His, Ala-Glu-His, Ala-Asp-Lys, Ala-Glu-Lys Ala-Asp-Arg; Ala-Glu-Arg, lle-Asp-His, lle-Glu-His; lle-Asp-Lys; lle-Glu-Lys. lle-Asp-Arg, lle-Glu-Arg, Leu-Asp-His, Leu-Glu-His, Leu-Asp-Lys, Leu-Glu-Lys, Leu-Asp-Arg, Leu-Glu-Arg, Met-Asp-His, Met-Glu-His, Met-Asp-Lys, Met-Glu-Lys, Met-Asp-Arg, Met-Glu-Arg, Phe-Asp-His, Phe-Glu-His; Phe-Asp-Lys, Phe-Glu-Lys, Phe-Asp-Arg, Phe-Glu-Arg Pro-Asp-His; Pro-Glu-His, Pro-Asp-Lys, Pro-Glu-Lys, Pro-Asp-Arg, Pro-Glu-Arg; Trp-Asp-His, Trp-Glu-His, Trp-Asp-Lys, Trp-Glu-Lys, Trp-Asp-Arg; Trp-Glu-Arg, Val-Asp-His, Val-Glu-His, Val-Asp-Lys, Val-Glu-Lys; Val-Asp-Arg; and Val-Glu-Arg
Numerous suitable carrier compounds for use in accordance with the present invention would be readily apparent to those skilled in the art, and representative examples include Serum albumin precursor - rat, Acyl carrier protein - Escherichia coli; Serum Albumin precursor - human; S typhimuπum branched chain am o transport system II carrier, Branched - chain am o acid carrier; Ribosomal protein S16 - Escherichia coli, 3-Hydroxydecanoyl -{Acyl- Carπer-Protein} Dehydratase; 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); Phosphocarπer Protein HPR (Histidine-containing protein), Beta-Hexosaminidase alpha chain precursor; ACYL Carrier Protein (ACP), Surfactin synthetase component; Sterol carrier protein 2 precursor; Insulin- Like growth factor binding protein 3 Precursor (IGFBP-3); Mitochodrial Brown Fat Uncoupling Protein (UCP); Thioredoxin; Oleoyl-hydrolase, Platelet factor 4; Lactose Permease; Keyhole Lipid hemocyanin (KLH); and Bovine Serum Albumin (BSA). The antibodies of the present invention are humanised as per the following reference:
From cells to genes: how to make antibodies useful in human diagnosis and therapy. Zaccolo M, Malavasi F Dipartimeπto di Genetica, Universita di Torino, Italy. Int J Clin Lab Res 1993: 23(4): 192-198 The mono/polyclonal antibodies are made as per the following reference: Moller, G. (ed.): Engineered antibody molecules. Immunol Rev. 1992, 130:1-212.
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 );
HTLV-I gp21 E Gln-Asn-Arg-Arg-Gly-Leu-Glu-Leu-Leu-Phe-Trp-Glu- Gln-Gly-Gly-Leu-Cys-Lys-Ala-Leu-Gln-Glu-Gly-Cys-Arg-Phe (SEQ ID NO. 2) HTLV-II gp21 E Gln-Asn-Arg-Arg-Gly-Leu-Glu-Leu-Leu-Phe-Trp-Glu- Gln-Gly-Gly-Leu-Cys-Lys-Ala-lle-Gln-Glu-Gln-Cys-Cys-Phe (SEQ ID NO. 3) MoLV p15E Gln-Asn-Arg-Arg-Gly-Leu-Glu-Leu-Leu-Phe-Leu- Lys-Glu-Gly-Gly-Leu-Cys-Ala-Ala-Leu-Lys-Glu-Glu-Cys-Cys-Phe (SEQ ID NO. 4);
FeLV p15E Gln-Asn-Arg-Arg-Gly-Leu-Glu-lle-Leu-Phe-Leu- Gln-Glu-Gly-Gly-Leu-Cys-Ala-Ala-Leu-Lys-Glu-Glu-Cys-Cys-Phe (SEQ ID NO. 5); and Vivax-1.
A variety of analogs which would be suitable for use according to the present invention would be readily apparent to those skilled in the art Representative examples include analogs of Larginine including Lornithine, L-Citrulline, L-α-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-(α-arnino-ethyl)-L-cysteine), D/L 4 oxalysine, β-Lysine, N5-Hydroxy-L-Arginine.
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;
(b) immunodeficiency resultant from one or more of the following, bacterial, mycoplasmic, fungal and/or parasitic infections;
(c) immunodeficiency resultant from the growth of neoplastic tissue;
(d) immunodeficiency resultant from any cytokine or hormone imbalance or imbalance of any natural product within the patient;
(e) myalgic encephalomyelitis (ME);
(f) post inoculation or viral infection fatigue syndrome;
(g) tuberculosis infection; and (h) malarial infection, in a patient in need of such treatment, 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.
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
In accordance with another preferred aspect of the present invention, there are provided 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. In accordance with another preferred aspect of the present invention, there are provided 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,
Glu, Lys, Arg or His.
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 disclosed herein together with an antiviral therapy
The large scale efforts to produce a broad spectrum vaccine candidate for Influenza Virus has proved impossible due to the rapid rate of mutation of the outer coat of this virus However, without the ability to attach and fuse and signal host immune cells in the body using those specific polar single ion bridge pair arrays of ammo acid specific sequences, outlined herein, it is non-infectious If these ammo acid sequences are altered in the Influenza Virus, this virus then cannot undermine the hosts' immune system and achieve cell entry or create immune dysfunction This ability is restricted to a specific number of sequences, all of which must present to the cell membrane the charge distribution shown to activate endocytosis and TCR/CD3 cell activation and neutralise T cell immune surveillance as it relates to MHC-Class I and II Therefore, if the infected host, human or animal, already posses neutralising antibodies to these ammo acid changed dipole sequences as specified herein it will not be possible for infection to be established because these neutralising antibodies perform a dual function (A) they prevent anchorage and endocytosis of the infecting organism into the host cell thus preventing productive infection and (B) they prevent the circulation in the plasma of these mimic Interleukin 10 or AFP type molecules which are released by infecting organisms. These specific said sequences confuse the normal signalling system involved in immune T and B cell activation since when applied to cells they trigger an intracellular Biochemical signal similar to when a T cell receptor (TCR) molecule coupled to a CD3 molecule interact with a MHC-II antigen complex, together with the fact that these sequences also cause increased turnover of surface receptor molecules such as the Interleukin I receptor molecule, thus leading to an increase of Interleukin I levels and cause a shift in T cell performance due to the shifting Th1/Th2 cytokine balance.
It has been demonstrated with 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. When the initial vaccine inoculation is coupled with passive immunisation with mono or polyclonal antibodies to these said specific sequences of the present invention that 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 Th2 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 Th1 T cell response needed to clear intra-cellular infections. We have identified the specific polar array sequence on the coat protein of malaria which this organism uses like Influenza Virus to attach and activate endocytosis together with activating a Th2 (B cell) response and subsequently undermining the host's immune response and allowing infection to take hold while still producing an array of neutralising antibodies which creates mutational pressure for the generation of more virulent strains of the organism within the host.
Our studies clearly demonstrated in mouse models that polyclonal or monoclonal antibodies generated to the above polar sequence arrays to these specific amino acid sequences either taken from specific sequences present in human alfa-fetoprotein or human Interleukin 10 resulted in protection of mice from challenge by malaria sporozoites. Therefore 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 (because the immune system of primates including man appear to be blinded to these specific signal sequences) for protection 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 When 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
In malaria, as in other infections 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, Mycobacteπum Tuberculosis Leishmania, HIV and others are not able to cause metabolic and immune Th2 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 These 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 (Th2 cytokine) when a Th2 cytokine profile is required or to curtail the uncontrolled Th1 T4 cell immune response These immunosuppressive cytokines are particularly evident following vaccination to enhance humoral immunity and secure antibody formation, and often causes the temporary disappearance of the Tuberculin reaction which is associated with Th1 (DTH) response in patients following vaccination (C) Infectious agents such as viruses (RNA & DNA) mycoplasma, bacteria malaria and a wide array of human and animal parasites also carry these specific charged array of ammo acid sequences which cause the down regulation of the Th1 cytokine response and enhance the humoral (antibody mediated) immune response of their infected host
Now that these specific control sequences have been identified and verified we herewith outline a number of therapeutic modalities that result from this new found ability to intervene therapeutically to control, neutralise or enhance specific immune type reactions dependent upon the nature of the patient's or animal's own immune system status, infection or disease state Example
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, Th2 cytokines, viral or bacterial coat peptides In one embodiment, the host organism (man or animal) 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 Th2 cytokine and AFP type mimic immunosuppressive peptides and initiate a Th1 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 and parasitic infections which cause immunosuppression by any suitable route including enteric, parenteral, topical, oral, rectal, nasal or vaginal routes Parenteral routes include subcutaneous, intramuscular, intravenous and sublingual administration The preferred route of administration would be an intravenous one The present invention further provides pharmaceutical formulations for use in treatments against HIV/HTLV-I, II, III and other viral diseases and diseases caused by mycoplasma, bacteria or parasites
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 Th1 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 bπdge pair arrays capable of mimicking the actions of AFP or Th2 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. Peptide Sequence Section
Firstly a series of documented and identified immunosuppressive sequences, encompassing both a known immunosuppressive peptide (CKS- 17) and viral coat protein HTLV-III gp41 735-752 were selected and we by deletion or chemical modification of the referred ammo acids Table 1 demonstrated that by compromising the charged am o acid dipole arrays within the hydrophobic segment of these peptides it was possible to neutralize the immunosuppressive ability of these selected immunosuppressive sequences
Peptide synthesis and protein conjugation The peptides were assembled by solid-phase peptide synthesis on a Merπfield polystyrene resin as described previously (Kennedy, R C , Henkel, R D , Pauletti, D , Allan, J S Lee, T H , Essex, M , and Dreesman, G.R , Science 231 , 1556, 1986) (Chanh, T.C., Dreesman, G R , Kanda, P , Linette, G P , Sparrow, J T , Ho D H., and Kennedy, R.C , EMBO J. 5, 3065, 1986) Protection of amino acid side chains during synthesis and cleavage of the peptide from the support by anhydrous hydrogen fluoride (HF) have been described previously (Kmnunen, P.K ., Jackson, R.L., Smith, LC , Gottom, A.M., Jr , and Sparrow, J T , Proc Natl. Acad. Sci. USA 74, 4848, 1977) Peptides were purified by reverse- phase HPLC, and their compositions were verified by ammo acid analysis and the presence of a single peak by HPLC. 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 mitoαen-induced blastoαenesis
To assess the inhibitory effects of the peptides AA sequences outlined in Table 1 Normal human blastogenic response to mitogens, PMN cells from healthy donors were cultured in the absence or presence of various concentrations of peptides or peptides conjugated to carrier proteins followed by mitogen stimulation The results of the experiments are shown in Table 2 Preincubation of normal PMN with the immunosuppressive peptides chosen before signal sequence neutralization either conjugated to either KLH or BSA resulted in a preformed and dose - dependent suppression of PHA - induced proliferation Upon ammo acid signal sequence as specified in Table 1 chemical modification there was a significant reduction in the suppression of PHA induced proliferation
The viability of peptide treated PMN as determined by trypan blue exclusion staining was comparable to that of untreated PMN, showing that suppression of proliferation did not result from peptide-induced cytotoxicity Inhibition of the normal two - way mixed - lymphocyte reaction
The 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)
In-vitro proliferation assays Peripheral mononuclear cells (PMN) were obtained from normal HIV antibody-negative donors by density gradient centrifugation through Hιsopaque-1077 (Sigma Chemical Co , St Louis, MO). The in-vitro proliferation assays were performed by incubating 105 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). On the fourth day of culture, the cells were stimulated with phytohemagglutinin (PHA, Sigma) at a final dilution of 0 1 %, or Con A (Sigma), or pokeweed mitogen (PWM, Sigma) at final concentrations of 10 μg/ml The cultures were allowed to incubate for an additional 2 days at which time 1 μCi of [3H] thymidme (New England
Nuclear Co., Boston, MA) was added to each well After an additional 18hr in culture, the cells were harvested and processed for scintillation counting For PHA-induced proliferation of muπne cells, normal 3- to 5-week- old BALB/C mice (Jackson Laboratories, Bar Harbor, ME) were sacrificed and their spleen cells were obtained through density gradient centrifugation. The spleen cells were used at a density of 5x 104/we!l and the assay was done as described above
Two-way mixed-lymphocyte reaction Peripheral mononuclear cells from MHC-mismatched donors were obtained as described above Cells(5 x 104) from one individual were mixed with an equal number of cells from another individual in the absence of presence of peptides from Table 1 for 5 days The cultures were pulsed with [3H] -thymidme for the last 18 hr and harvested for scintillation counting
Table 1 Immunosuppressive Peptides Used
1 HTLV - III B gp41 AA Sequence: Tyr-Glu-Arg-Pro-Glu-Gly-lle-Glu-Glu-Glu-Gly-Gly-Glu-Arg-Glu-Arg-
Glu-Arg-Ser-Gly-Cys (SEQ. ID NO. 34) AA 735-752
2 CKS-17 AA Sequence: Leu-Gln-Asn-Arg-Arg-Gly-Leu-Asp-Leu-Leu-Phe-Leu-Lys-Glu-Gly- Gly-Leu (SEQ. ID NO. 35) CKS-17 (A)
1 (A) HTLV-III B gp41 modified
These peptides have their arginyl residues modified by the use of 1 ,2 cycloheranedione as outlined in Mahley, R.W., J of Biol. Chem 1977 Vol. 252 pgs. 7279-7287
Table 2
Suppression of Mitogen Induced Biastogenic Response
To Normal Human Mononuclear Cells
Percentage Suppression of
Biastogenic Response to
PHA ConA PWM
HTLV-IIIB gp41 - KLH 74 77 85
AA 735-752
5μg/ml
HLTV-IIIB gp41 - KLH
(modified) 6 7 4
Modified as per
Neutralization of charge
Distribution on dipole
CKS-17 64 80 76 5μM
Modified CKS-17 Modification caused by Chemical modification of The charge on dipole sequence
Table 3
Immunosuppressive Peptides Suppression
Of Mixed Lymphocyte Reaction
Thymidine Incorporation (cpm) with
Medium HTLV-III gp41 Modified HTLV-III gp41 735-752 (5μg/ml) 735-752 5μg/ml
(charged dipole neutralized)
5224 ± 256 2800 ± 120 (45%) 5236 ± 211 (0%)
5368 ± 106 2789 ± 163 (46%) 5334 ± 107 (0%) Medium CKS-17 CKS-17 (Modified) (charged dipole neutralized)
4738 ± 96 947 ± 68 (80%) 4526 ± 102 (0%)
5372 ± 173 1074 4 ± 03 (83%) 4834 ± 80 (19%)
The only detectable changes in the physical and chemical properties of the modified HTLV-III gp41 and CKS-17 was increased electrophoretic mobility which reflected the neutralization of the positive charge on the granido group of arginine
1(B) HTLV-III B gp41 Modification Reversed
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 This has been demonstrated for this patent Tables 2/3 to effectively remove any immunosuppressive characteristics and could very easily accomplish the same end for intact viruses or bacteria should their genetic codes be deleted for these specific ammo acids or their outer coats neutralized to these signal dipole sequences
Those of skill in the art would readily be able to determine where an ion bridge pair exists in a particular sequence, e g , an immunosuppressive sequence, and determine which ion bridge pairs are responsible for the immunosuppressive activity, by routine experimentation in view of the information contained herein
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 Th2 cytokines, for example, wherein the at least two Th2 cytokines include Interleukin 10 and Interleukin 4
In relation to the administration of anti-serum to lnterleukιn-10 and also the combination therapy of lnterleukιn-10 and lnterleukιn-4 the dose ranging were as follows lnterleukιn-10 alone - 2 mg per day over a period of 10 days by IV Combination therapy - two trials
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
Trial 2 infusion of 4 mg of a combination (50/50) of 1L-10/IL-4 on days 1 ,3,5,9,11 and 14 - This dose range would vary and the ratio of cytokines administered depending on the disease condition
These agents as per this patent are administered in an amount, which provides circulating levels of about 1 -150 μg/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
When rabbit antibodies to human Interleukin 10 was administered to AIDS patients for a one week period by an IV route their cytotoxic CD8 cells and natural killer cell numbers increased within 24 hours and this resulted in a simultaneous increase in viral load levels as measured by PCR (RNA). However, quantitative culture techniques showed a decline to zero levels. The reason for the above would appear to be that the enhanced CD8 cytotoxic and natural killer cell attack on HIV infected cells increased the amount of HIV viral RNA and viral peptide present in the blood as a result of the killing of infected cells. The fact that quantative culture decreased to zero means that the viral particles present were not viable or infectious viruses However, no improvement in percentage or absolute number of CD4 (T4) cells was recorded and the Th1 immune function did not show improvement. After 3 months from the termination of the above therapy with antibodies to Interleukin 10, HIV viral load returned to its pre-treatment level and his CD4 (T4) cell count decreased by 50% This demonstrated that the anti-serum to Interleukin 10 had been capable of activating CD8 cytotoxic and natural killer cells and causing a dramatic reduction in viral load. However, the CD4 (T4) immune system cells had not improved so that when following therapy his CD8 and natural killer cells lost their function, dormant virus was awakened by the Interleukin 10 antibody therapy and new viral replication could not be kept in check without a complement of active CD4 cells
This same patient was then administered a combination therapy which involved rabbit IgG antibodies generated to both human Interleukin 10 and human Interleukin 4. It had been determined from in-vitro studies with the patients blood that native Interleukin 4 levels were elevated and this was preventing the recovery of the CD4 (T4) cell component of his immune system.
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 However, on this occasion his CD4 (T4) cell count both in absolute number and percentage increase from 9% to 15% within 4 days of therapy commencing. After the 3 month period out from the termination of the combination therapy, CD4 (T4) cell count continued to remain elevated and HIV viral load was still non-detectable
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 However, 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 PROTOCOL FOR ADMINISTRATION OF AN IMMUNOGLOBULIN IgG o ANTIBODY AGAINST A COMBINATION OF TH2 CYTOKINES 1.0 INTRODUCTION
The Human Immunodeficiency Virus Type 1 (HIV-1 ) ts the etiological agent of Acquired Immune Deficiency Syndrome(AIDS) (Barre-Sinoussl, F Chermann, J.C., et al, Isolation of a T-lymphotrophic Retrovirus From a 5 Patient at Risk for Acquired Immunodeficiency Syndrome (AIDS), Science
(1984) 224, 500-503, Gallo, R C , Salahuddm, S.Z., et al, Frequent Detection and Isolation of Cytopathic Retroviruses (HTLV-III) From Patients with AIDS and at Risk for AIDS Science (1984) 224, 500-503) AIDS is characterised as a profound breakdown in host's cellular and humoral o immunity and increased susceptibility to a wide range of opportunistic infections One of the consequences of this immune dysfunction is a marked depletion in absolute CD4+ cells in HIV-infected individuals Studies over the past years have demonstrated that the destruction of the immune system by HIV-1 is a chronic process, starting at the moment of infection The results indicate that strategies for effective therapeutic intervention using antibodies to these specific mimic CD3/TCR peptide interaction dipole sequences should start early in infection to prevent irreversible damage occurring to the immune system, since it has been demonstrated in HIV that an early loss of CD3 TCR mediated T cell activation is evident This imbalance in turn effects monocyte and B cell function Recent studies have established the functional binding and immunosuppressive similarities between specific ammo acid charged sequences present on the alfa-fetoprotein molecule and on and Th2 cytokine peptides and certain HIV envelope am o acid sequences Laboratory data demonstrates that immunoglobulin G (IgG) or IgM to the said specific ammo acid sequence inhibits syncytial formation and prevents HIV-1 laboratory strains MN, RF, and IIIB replication in C8166-45 cells (lymphocyte cell-line) in-vitro In addition, IgG to the said am o acid sequence inhibits replication of HIV-1BAL in fresh macrophage culture in a dose-dependent manner 1.2 RATIONALE
The basic rationale for using this therapy is the understanding that there exists a functional binding and immunosuppression similarity between certain peptides containing specific ion pair arrangements of am o acids enclosed within two hydrophobic ammo acids present within the AFP molecule Interleukin 10 and specific external HIV glycoprotems together with other specific viral coat peptides and glycopeptides This discovery shows that as the body defends itself against the HIV virus by producing antibodies to specific viral coat proteins, these antibodies, while restricting in a normal antibody fashion the HIV virus, are themselves together with certain viral glycopeptides sequences identified herein and produced by the infecting virus are inherently immunosuppressive in that they perform a similar task as AFP or Th2 cytokine peptides in that they selectively down regulate the T cell dependent immune system in favour of a humoural, B cell response which although it produces neutralising antibodies to the infectious agent (e g malaria, HIV, Tuberculoses, Leishmania) also allows the infective agent to persist and reproduce within the host cells and to ultimately undermine its immune status
The major histocompatibility complex (MHC) 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 Tc 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-dependent cell-mediated cytotoxicity (ADCC) stimulated reduction in Viral Load as measured by the culturmg of peripheral blood mononuclear cells and following the removal of the mimic Th2 cytokme/AFP like viral peptide molecules and in the patient's blood we should see a re-awakening of a CD8 cytotoxic T cell reaction directed against HIV infected cells and this will coincide with a second HIV Viral Load reduction Also in patients who have received this antibody therapy we should see the generation of Interleukin 2 and gamma interferon and a dramatic increase in T4 cell number, together with a decrease in PCR and Quantitative Viral culture levels
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 Th2 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. Although the cytotoxic cells involved are non-specific, the specificity of the antibody to a common immunosuppressive mimic peptide present on Th2 cytokines peptides/AFP present on a large number of infecting organisms directs them to HIV infected target cells. This type of cytotoxicity is referred to as antibody-dependent cell-mediated cytotoxicity (ADCC). The variety of cells that have been shown to exhibit ADCC include NK cells, macrophages, monocytes, neutrophils, and eosinophils. 2.0 OBJECTIVES
2.1 To provide for an administration of monoclonal antibodies to these specified sequences present on AFP and Th2 cytokines and infectious organisms to HIV+ patients.
2.2 To monitor immune system functioning before and after the administration of these mono or polyclonal antibodies.
2.3 To monitor the effect of these type of antibody on cutanous lesions in those study participants who have Kaposi's Sarcoma.
2.4 To monitor viral load in patient's peripheral blood mononuclear cells prior to beginning, during and post this type of antibody infusion therapy. 2.5 To monitor the course or incidence of opportunistic infections in the study participants.
2.6 To determine the safety of these type of antibody administration in persons with HIV disease.
3.0 CLINICAL ENDPOINTS To confirm that these antibodies either poly or monoclonal are of therapeutic benefit for widespread use in HIV disease based on the following criteria - 3.1 Changes in T-cell phenotyping and cytokine profile
3.2 Changes in the size, colour intensity, and palpable skin characteristics of cutaneous Kaposi's sarcoma lesions
3.3 Changes in HIV load burden as indicated by endpoint - dilution culture quantitation in peripheral - blood mononuclear cells
3.4 Changes in p24 antigen level.
3.5 Changes in Beta-2-mιcroglobulιn level
3.6 Appearance of new or improvement of active opportunistic infections 3.7 Changes in system functioning (liver, kidney, haematology)

Claims

Claims:
1. A method of enhancing immune response in a patient suffering from a condition selected from the group consisting of:
(a) immunodeficiency resultant from a viral infection; (b) immunodeficiency resultant from one or more of the following, bacterial, mycoplasmic, fungai and/or parasitic infections;
(c) immunodeficiency resultant from the growth of neoplastic tissue;
(d) immunodeficiency resultant from any cytokine or hormone imbalance or imbalance of any natural product within the patient;
(e) myalgic encephalomyelitis (ME);
(f) post inoculation or viral infection fatigue syndrome;
(g) tuberculosis infection; and (h) malarial infection, 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: C-X-A-B-Y-Z; C-X-A-B-D;
C-X-A-B; D-A-B-Y-Z; and A-B-Y-Z; wherein: 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 Glu or Asp;
C is a carrier compound residue;
Z is a carrier compound residue.
2. A method as recited in claim 1 , wherein said at least one compound consists of 16 or fewer amino acid residues.
3. A method as recited in claim 1 , wherein said at least one compound consists of 8 or fewer amino acid residues.
4. A method as recited in claim 1 , wherein said at least one compound consists of 4 or fewer amino acid residues.
5. A method of enhancing immune response in a patient suffering from a condition selected from the group consisting of:
(a) immunodeficiency resultant from a viral infection;
(b) immunodeficiency resultant from one or more of the following, bacterial, mycoplasmic, fungal and/or parasitic infections;
(c) immunodeficiency resultant from the growth of neopiastic tissue;
(d) immunodeficiency resultant from any cytokine or hormone imbalance or imbalance of any natural product within the patient, (e) myalgic encephalomyelitis (ME);
(f) post inoculation or viral infection fatigue syndrome;
(g) tuberculosis infection; and (h) malarial infection, 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 ammo acid residue,
E is an ammo acid sub-sequence comprising at least one ammo acid residue, B is Glu or Asp, and wherein said at least one compound comprises at least 4 am o acid residues
6 A method as recited in claim 5, wherein said at least one compound consists of 16 or fewer ammo acid residues
7 A method as recited in claim 5, wherein said at least one compound consists of 8 or fewer ammo acid residues
8 A method of treating a condition selected from the group consisting of
(a) immunodeficiency resultant from a viral infection,
(b) immunodeficiency resultant from one or more of the following bacterial, mycoplasmic, fungal and/or parasitic infections,
(c) immunodeficiency resultant from the growth of neoplastic tissue,
(d) immunodeficiency resultant from any cytokine or hormone imbalance or imbalance of any natural product within the patient, (e) myalgic encephalomye tis (ME),
(f) post inoculation or viral infection fatigue syndrome,
(g) tuberculosis infection, and (h) malarial infection in a patient in need of such treatment comprising administering to said patient an
(a) immunodeficiency resultant from a viral infection;
(b) immunodeficiency resultant from one or more of the following, bacterial, mycoplasmic, fungal and/or parasitic infections; (c) immunodeficiency resultant from the growth of neoplastic tissue;
(d) immunodeficiency resultant from any cytokine or hormone imbalance or imbalance of any natural product within the patient;
(e) myalgic encephalomyelitis (ME); (f) post inoculation or viral infection fatigue syndrome;
(g) tuberculosis infection; or
(h) malarial infection, treatment 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:
C-X-A-B-Y-Z;
C-X-A-B-D;
C-X-A-B; D-A-B-Y-Z; and
A-B-Y-Z; wherein:
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 Glu or Asp;
C is a carrier compound residue; Z is a carrier compound residue.
9 A method as recited in claim 8, wherein said at least one compound consists of 16 or fewer ammo acid residues
10 A method as recited in claim 8, wherein said at least one compound consists of 8 or fewer ammo acid residues
11 A method as recited in claim 8, wherein said at least one compound consists of 4 or fewer am o acid residues
12 A method of treating a condition selected from the group consisting of
(a) immunodeficiency resultant from a viral infection (b) immunodeficiency resultant from one or more of the following, bacterial, mycoplasmic, fungal and/or parasitic infections,
(c) immunodeficiency resultant from the growth of neoplastic tissue,
(d) immunodeficiency resultant from any cytokine or hormone imbalance or imbalance of any natural product within the patient
(e) myalgic encephalomyehtis (ME),
(f) post inoculation or viral infection fatigue syndrome
(g) tuberculosis infection, and (h) malarial infection, in a patient in need of such treatment, comprising administering to said patient an
(a) immunodeficiency resultant from a viral infection,
(b) immunodeficiency resultant from one or more of the following bacterial, mycoplasmic, fungal and/or parasitic infections, (c) immunodeficiency resultant from the growth of neoplastic tissue,
(d) immunodeficiency resultant from any cytokine or hormone imbalance or imbalance of any natural product within the patient,
(e) myalgic Encephalomyehtis (ME), (f) post inoculation or viral infection fatigue syndrome,
(g) tuberculosis infection; or (h) malarial infection, treatment 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 ammo acid residue,
E is an amino acid sub-sequence comprising at least one am o acid residue,
A is Lys, Arg or His,
B is Glu or Asp; and wherein said at least one compound comprises at least 4 ammo acid residues
13. A method as recited in claim 12, wherein said at least one compound consists of 16 or fewer ammo acid residues
14 A method as recited in claim 12, wherein said at least one compound consists of 8 or fewer ammo acid residues
15. A method of enhancing immune response in a patient suffering from immunodeficiency, 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 C-X-A-B-Y-Z;
C-X-A-B-D;
C-X-A-B;
D-A-B-Y-Z; and A-B-Y-Z; wherein:
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 ammo acid sub-sequence comprising at least one amino acid residue;
D is an amino acid sub-sequence comprising at least one ammo acid residue;
A is Lys, Arg or His;
B is Glu or Asp; C is a carrier compound residue;
Z is a carrier compound residue.
16. A method of vaccinating against an immunodeficiency producing infection or condition selected from the group consisting of
(a) viral infections; (b) one or more of bacterial, mycoplasmic, fungal and parasitic infections;
(c) growth of neoplastic tissue;
(d) any cytokine or hormone imbalance or imbalance of any natural product within the patient; (e) myalgic encephalomyelitis (ME);
(f) post inoculation or viral infection fatigue syndrome;
(g) tuberculosis infection; and (h) malarial infection, in a patient in need of such vaccination, comprising administering to said patient a vaccination effective amount of a pharmaceutical formulation comprising: at least one vaccine against said condition; and 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: C-X-A-B-Y-Z;
C-X-A-B-D;
C-X-A-B;
D-A-B-Y-Z; and
A-B-Y-Z; wherein:
X is a covalent bond or an ammo acid sub-sequence comprising at least one amino acid residue;
Y is a covalent bond or an ammo acid sub-sequence comprising at least one amino acid residue; D is an am o acid sub-sequence comprising at least one ammo acid residue;
B is Glu or Asp;
C is a carrier compound residue; Z is a carrier compound residue.
17. A method as recited in claim 16, wherein said at least one compound consists of 16 or fewer amino acid residues
18. A method as recited in claim 16, wherein said at least one compound consists of 8 or fewer amino acid residues
19. A method as recited in claim 16, wherein said at least one compound consists of 4 or fewer amino acid residues
20. A method of vaccinating against a condition selected from the group consisting of' (a) immunodeficiency resultant from a viral infection,
(b) immunodeficiency resultant from one or more of the following, bacterial, mycoplasmic, fungal and/or parasitic infections,
(c) immunodeficiency resultant from the growth of neoplastic tissue,
(d) immunodeficiency resultant from any cytokine or hormone imbalance or imbalance of any natural product within the patient,
(e) myalgic encephalomyelitis (ME),
(f) post inoculation or viral infection fatigue syndrome, (g) tuberculosis infection, and
(h) malarial infection, in a patient in need of such vaccination, comprising administering to said patient a vaccination effective amount of a pharmaceutical formulation comprising at least one vaccine against said condition, and 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 ammo acid residue, E is an am o acid sub-sequence comprising at least one am o acid residue,
and wherein said at least one compound comprises at least 4 ammo acid residues
21 A method as recited in claim 20, wherein said at least one compound consists of 16 or fewer am o acid residues
22 A method as recited in claim 20, wherein said at least one compound consists of 8 or fewer ammo acid residues
23 A method of enhancing immune response in a patient suffering from a condition selected from the group consisting of
(a) immunodeficiency resultant from a viral infection,
(b) immunodeficiency resultant from one or more of the following bacterial, mycoplasmic, fungal and/or parasitic infections,
(c) immunodeficiency resultant from the growth of neoplastic tissue,
(d) immunodeficiency resultant from any cytokine or hormone imbalance or imbalance of any natural product within the patient,
(e) myalgic encephalomyehtis (ME),
(f) post inoculation or viral infection fatigue syndrome, (g) tuberculosis infection, and
(h) malarial infection, 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
C-X-H-A-B-Y-Z,
C-X-H-A-B-D,
C-X-H-A-B,
D-H-A-B-Y-Z, H-A-B-Y-Z,
C-X-A-B-H-Y-Z,
C-X-A-B-H-D,
C-X-A-B-H,
D-A-B-H-Y-Z, and A-B-H-Y-Z, wherein'
H is selected from the group consisting of Ala, He, Leu, Met, Phe, Trp, Val and Tyr;
X is a covalent bond or an ammo acid sub-sequence comprising at least one amino acid residue,
Y is a covalent bond or an ammo acid sub-sequence comprising at least one am o acid residue,
D is an amino acid sub-sequence comprising at least one ammo acid residue,
C is a carrier compound residue,
Z is a carrier compound residue
24 A method as recited in claim 23, wherein said at least one compound consists of 16 or fewer ammo acid residues
25 A method as recited in claim 23, wherein said at least one compound consists of 8 or fewer am o acid residues
26 A method as recited in claim 23, wherein said at least one compound consists of 4 or fewer ammo acid residues
27. A method of enhancing immune response in a patient suffering from a condition selected from the group consisting of
(a) immunodeficiency resultant from a viral infection,
(b) immunodeficiency resultant from one or more of the following, bacterial, mycoplasmic, fungal and/or parasitic infections, (c) immunodeficiency resultant from the growth of neoplastic tissue;
(d) immunodeficiency resultant from any cytokine or hormone imbalance or imbalance of any natural product within the patient, (e) myalgic encephalomyelitis (ME),
(f) post inoculation or viral infection fatigue syndrome,
(g) tuberculosis infection, and (h) malarial infection, 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-H-A-B-E, D-H-A-B,
H-A-B-E, D-A-B-H-E, D-A-B-H, and A-B-H-E, wherein
H is selected from the group consisting of Ala, He, Leu Met, Phe, Trp, Val and Tyr,
D is an am o acid sub-sequence comprising at least one ammo acid residue, E is an ammo acid sub-sequence comprising at least one ammo acid residue,
and wherein said at least one compound compπses at least 4 ammo acid residues
28 A method as recited in claim 27, wherein said at least one compound consists of 16 or fewer ammo acid residues
29 A method as recited in claim 27, wherein said at least one compound consists of 8 or fewer ammo acid residues
30 A method of treating a condition selected from the group consisting of
(a) immunodeficiency resultant from a viral infection,
(b) immunodeficiency resultant from one or more of the following bacterial, mycoplasmic, fungal and/or parasitic infections,
(c) immunodeficiency resultant from the growth of neoplastic tissue,
(d) immunodeficiency resultant from any cytokine or hormone imbalance or imbalance of any natural product within the patient (e) myalgic encephalomyehtis (ME),
(f) post inoculation or viral infection fatigue syndrome,
(g) tuberculosis infection, and (h) malarial infection, in a patient in need of such treatment, comprising administering to said patient an
(a) immunodeficiency resultant from a viral infection,
(b) immunodeficiency resultant from one or more of the following bacterial, mycoplasmic, fungal and/or parasitic infections,
(c) immunodeficiency resultant from the growth of neoplastic tissue,
(d) immunodeficiency resultant from any cytokine or hormone imbalance or imbalance of any natural product within the patient,
(e) myalgic encephalomyehtis (ME),
(f) post inoculation or viral infection fatigue syndrome, (g) tuberculosis infection, or
(h) malarial infection, treatment 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
C-X-H-A-B-Y-Z, C-X-H-A-B-D, C-X-H-A-B,
D-H-A-B-Y-Z,
H-A-B-Y-Z,
C-X-A-B-H-Y-Z, C-X-A-B-H-D,
C-X-A-B-H,
D-A-B-H-Y-Z, and
A-B-H-Y-Z, wherein H is selected from the group consisting of Ala, He, Leu, Met, Phe
Trp, Val and Tyr,
X is a covalent bond or an ammo acid sub-sequence comprising at least one ammo acid residue,
Y is a covalent bond or an am o acid sub-sequence comprising at least one ammo acid residue,
D is an ammo acid sub-sequence comprising at least one ammo acid residue,
A is Lys, Arg or His, C is a carrier compound residue,
Z is a carrier compound residue
31 A method as recited in claim 30, wherein said at least one compound consists of 16 or fewer ammo acid residues
32 A method as recited in claim 30, wherein said at least one compound consists of 8 or fewer ammo acid residues
33 A method as recited in claim 30, wherein said at least one compound consists of 4 or fewer ammo acid residues
34 A method of treating a condition selected from the group consisting of
(a) immunodeficiency resultant from a viral infection,
(b) immunodeficiency resultant from one or more of the following, bacterial, mycoplasmic, fungal and/or parasitic infections, (c) immunodeficiency resultant from the growth of neoplastic tissue,
(d) immunodeficiency resultant from any cytokine or hormone imbalance or imbalance of any natural product within the patient,
(e) myalgic encephalomyehtis (ME), (f) post inoculation or viral infection fatigue syndrome,
(g) tuberculosis infection, and (h) malarial infection, in a patient in need of such treatment, comprising administering to said patient an (a) immunodeficiency resultant from a viral infection,
(b) immunodeficiency resultant from one or more of the following bacterial, mycoplasmic, fungal and/or parasitic infections,
(c) immunodeficiency resultant from the growth of neoplastic tissue, (d) immunodeficiency resultant from any cytokine or hormone imbalance or imbalance of any natural product within the patient
(e) myalgic Encephalomyehtis (ME),
(f) post inoculation or viral infection fatigue syndrome,
(g) tuberculosis infection; or (h) malarial infection, treatment 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-H-A-B-E,
D-H-A-B,
H-A-B-E, D-A-B-H-E,
D-A-B-H, and
A-B-H-E, wherein H is selected from the group consisting of Ala, lie, Leu Met, Phe,
Trp, Val and Tyr,
D is an ammo acid sub-sequence comprising at least one ammo acid residue,
E is an ammo acid sub-sequence comprising at least one am o acid residue,
35 A method as recited in claim 34, wherein said at least one compound consists of 16 or fewer ammo acid residues
36 A method as recited in claim 34, wherein said at least one compound consists of 8 or fewer ammo acid residues
37 A method of enhancing immune response in a patient suffering from immunodeficiency, 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
C-X-H-A-B-Y-Z,
C-X-H-A-B-D, C-X-H-A-B,
D-H-A-B-Y-Z,
H-A-B-Y-Z,
C-X-A-B-H-Y-Z,
C-X-A-B-H-D, C-X-A-B-H;
D-A-B-H-Y-Z; and
A-B-H-Y-Z; wherein: H is selected from the group consisting of Ala, He, Leu, Met, Phe,
Trp, Val and Tyr;
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 ammo acid residue,
D is an amino acid sub-sequence comprising at least one ammo acid residue,
A is Lys, Arg or His; C is a carrier compound residue,
Z is a carrier compound residue
38 A method of enhancing immune response in a patient suffering from immunodeficiency, 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:
R1-R2-R3-R4 wherein: 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, and 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
39 A method of enhancing immune response in a patient suffering from immunodeficiency, 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 RA-RB-RC-RD, wherein
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 Glu, Lys, Arg or His,
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 wherein the Asp or Glu 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 and 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 ammo 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 Asp or Glu
40 A method of providing an immunosuppressive or immunoregulatory effect in a patient, comprising administering to said patient an immunosuppressive or immunoregulatory 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 C-X-A-B-Y-Z,
C-X-A-B-D,
C-X-A-B,
D-A-B-Y-Z, and A-B-Y-Z, wherein
X is a covalent bond or an ammo acid sub-sequence comprising at least one ammo acid residue,
Y is a covalent bond or an am o acid sub-sequence comprising at least one ammo acid residue,
D is an ammo acid sub-sequence comprising at least one am o acid residue,
A is Lys, Arg or His,
B is Glu or Asp, C is a carrier compound residue,
Z is a carrier compound residue
41 A method of providing an immunosuppressive or immunoregulatory effect in a patient, comprising administering to said patient an immunosuppressive or immunoregulatory effective amount of a pharmaceutical formulation comprising at least two Th2 cytokines
42 A method as recited in claim 41 , wherein said at least two Th2 cytokines include Interleukin 10 and Interleukin 4
43 A method of treatment of graft vs host disease in a patient in need of such treatment, comprising administering to said patient Interleukin 10 and Interieukin 4
44 A method of providing an immunosuppressive or immunoregulatory effect in a patient, comprising administering to said patient Interleukin 10, Interleukin 4 and at least one of antagonist of Interleukin 10 and antagonist of Interleukin 4
45 A method 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 Interleukin 4
46 A method 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
47 A method 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
48 A method 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
49 A method of enhancing immune response in a patient suffering from a condition selected from the group consisting of
(a) immunodeficiency resultant from a viral infection,
(b) immunodeficiency resultant from one or more of the following bacterial, mycoplasmic, fungal and/or parasitic infections,
(c) immunodeficiency resultant from the growth of neoplastic tissue,
(d) immunodeficiency resultant from any cytokine or hormone imbalance or imbalance of any natural product within the patient,
(e) myalgic encephalomyehtis (ME),
(f) post inoculation or viral infection fatigue syndrome, (g) tuberculosis infection; and
(h) malarial infection, 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
C-X-A-Q-B-Y-Z;
C-X-A-Q-B-D;
C-X-A-Q-B; D-A-Q-B-Y-Z; and
A-Q-B-Y-Z; wherein:
Q is a sub-sequence consisting of one or two amino acid residues,
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 ammo acid residue; A is Lys, Arg or His;
B is Glu or Asp;
C is a carrier compound residue;
Z is a carrier compound residue.
50. A method of enhancing immune response in a patient suffering from a condition selected from the group consisting of:
(a) immunodeficiency resultant from a viral infection;
(b) immunodeficiency resultant from one or more of the following bacterial, mycoplasmic, fungal and/or parasitic infections,
(c) immunodeficiency resultant from the growth of neoplastic tissue;
(d) immunodeficiency resultant from any cytokine or hormone imbalance or imbalance of any natural product within the patient,
(e) myalgic encephalomyelitis (ME),
(f) post inoculation or viral infection fatigue syndrome,
(g) tuberculosis infection; and (h) malarial infection, 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-Q-B-E,
D-A-Q-B, and
A-Q-B-E, wherein:
Q is a sub-sequence consisting of one or two ammo acid residues, D is an amino acid sub-sequence comprising at ieast one am o acid residue;
E is an amino acid sub-sequence comprising at Ieast one ammo acid residue,
A is Lys, Arg or His, B is Glu or Asp, and wherein said at Ieast one compound comprises at Ieast 4 ammo acid residues.
51. A method of vaccinating against an immunodeficiency producing infection or condition selected from the group consisting of (a) viral infections,
(b) one or more of bacterial, mycoplasmic, fungal and parasitic infections;
(c) growth of neoplastic tissue,
(d) any cytokine or hormone imbalance or imbalance of any natural product within the patient,
(e) myalgic encephalomyehtis (ME), (f) post inoculation or viral infection fatigue syndrome,
(g) tuberculosis infection; and (h) malarial infection, in a patient in need of such vaccination, comprising administering to said patient a vaccination effective amount of a pharmaceutical formulation comprising' at Ieast one vaccine against said condition; and at Ieast one polyclonal or monoclonal antibody, or at Ieast one Fab fragment thereof, generated to at Ieast one compound selected from the group consisting of.
C-X-A-Q-B-Y-Z, C-X-A-Q-B-D, C-X-A-Q-B; D-A-Q-B-Y-Z; and A-Q-B-Y-Z; wherein:
Q is a sub-sequence consisting of one or two ammo acid residues, X is a covalent bond or an ammo acid sub-sequence comprising at Ieast one amino acid residue, Y is a covalent bond or an ammo acid sub-sequence comprising at
Ieast one amino acid residue,
D is an amino acid sub-sequence comprising at Ieast one ammo acid residue;
A is Lys, Arg or His;
C is a carrier compound residue; Z is a carrier compound residue
52 A method of vaccinating against a condition selected from the group consisting of: (a) immunodeficiency resultant from a viral infection,
(b) immunodeficiency resultant from one or more of the following bacterial, mycoplasmic, fungal and/or parasitic infections,
(c) immunodeficiency resultant from the growth of neoplastic tissue,
(d) immunodeficiency resultant from any cytokine or hormone imbalance or imbalance of any natural product within the patient,
(e) myalgic encephalomyehtis (ME),
(f) post inoculation or viral infection fatigue syndrome,
(g) tuberculosis infection, and (h) malarial infection, in a patient in need of such vaccination, comprising administering to said patient a vaccination effective amount of a pharmaceutical formulation comprising at Ieast one vaccine against said condition, and at Ieast one polyclonal or monoclonal antibody, or at Ieast one Fab fragment thereof, generated to at Ieast one compound selected from the group consisting of
D-A-Q-B-E,
D-A-Q-B, and
A-Q-B-E, wherein
Q is a sub-sequence consisting of one or two am o acid residues
D is an am o acid sub-sequence comprising at Ieast one ammo acid residue,
E is an ammo acid sub-sequence comprising at Ieast one ammo acid residue,
A is Lys, Arg or His, and wherein said at Ieast one compound comprises at Ieast 4 ammo acid residues
53 A method of enhancing immune response in a patient suffering from a condition selected from the group consisting of (a) immunodeficiency resultant from a viral infection,
(b) immunodeficiency resultant from one or more of the following, bacterial, mycoplasmic, fungal and/or parasitic infections,
(c) immunodeficiency resultant from the growth of neoplastic tissue,
(d) immunodeficiency resultant from any cytokine or hormone imbalance or imbalance of any natural product within the patient,
(e) myalgic encephalomyehtis (ME),
(f) post inoculation or viral infection fatigue syndrome, (g) tuberculosis infection, and
(h) malarial infection, comprising administering to said patient an immune response enhancing effective amount of a pharmaceutical formulation comprising at Ieast one polyclonal or monoclonal antibody, or at Ieast one Fab fragment thereof, generated to at Ieast one compound selected from the group consisting of
C-X-H-A-Q-B-Y-Z;
C-X-H-A-Q-B-D;
C-X-H-A-Q-B,
D-H-A-Q-B-Y-Z; H-A-Q-B-Y-Z,
C-X-A-Q-B-H-Y-Z,
C-X-A-Q-B-H-D;
C-X-A-Q-B-H;
D-A-Q-B-H-Y-Z; and A-Q-B-H-Y-Z, wherein:
Q is a sub-sequence consisting of one or two am o acid residues,
H is selected from the group consisting of Ala, He, Leu, Met, Phe, Trp, Val and Tyr, X is a covalent bond or an ammo acid sub-sequence comprising at
Ieast one amino acid residue,
Y is a covalent bond or an am o acid sub-sequence comprising at least one am o acid residue,
D is an ammo acid sub-sequence comprising at Ieast one ammo acid residue,
C is a carrier compound residue,
Z is a carrier compound residue
54 A method of enhancing immune response in a patient suffering from a condition selected from the group consisting of (a) immunodeficiency resultant from a viral infection,
(b) immunodeficiency resultant from one or more of the following bacterial, mycoplasmic, fungal and/or parasitic infections
(c) immunodeficiency resultant from the growth of neoplastic tissue, (d) immunodeficiency resultant from any cytokine or hormone imbalance or imbalance of any natural product within the patient
(e) myalgic encephalomyehtis (ME),
(f) post inoculation or viral infection fatigue syndrome,
(g) tuberculosis infection, and (h) malarial infection comprising administering to said patient an immune response enhancing effective amount of a pharmaceutical formulation comprising at Ieast one polyclonal or monoclonal antibody, or at Ieast one Fab fragment thereof, generated to at Ieast one compound selected from the group consisting of D-H-A-Q-B-E,
D-H-A-Q-B,
H-A-Q-B-E,
D-A-Q-B-H-E,
D-A-Q-B-H, and A-Q-B-H-E, wherein Q is a sub-sequence consisting of one or two ammo acid residues,
H is selected from the group consisting of Ala, He, Leu, Met, Phe, Trp, Val and Tyr;
D is an amino acid sub-sequence comprising at Ieast one ammo acid residue;
E is an amino acid sub-sequence comprising at Ieast one ammo acid residue;
B is Glu or Asp; and wherein said at Ieast one compound comprises at Ieast 4 ammo acid residues.
55 A method of reducing immune response in a patient in need of such treatment, comprising administering to said patient an immune response reducing effective amount of a pharmaceutical formulation comprising at Ieast one compound selected from the group consisting of
C-X-A-B-Y-Z;
C-X-A-B-D;
C-X-A-B;
D-A-B-Y-Z; A-B-Y-Z;
D-A-B-E; D-A-B; and A-B-D; wherein: X is a covalent bond or an ammo acid sub-sequence comprising at
Ieast one amino acid residue,
Y is a covalent bond or an amino acid sub-sequence comprising at Ieast one amino acid residue;
D is an amino acid sub-sequence comprising at Ieast one ammo acid residue;
E is an amino acid sub-sequence comprising at Ieast one ammo acid residue;
A is Lys, Arg or His,
C is a carrier compound residue, Z is a carrier compound residue
56. A method as recited in claim 55, wherein said patient is suffering from one or more condition selected from the group consisting of
(a) septic shock,
(b) multiple sclerosis, (c) lupus erythematoses,
(d) auto-immune disease,
(e) replacement of corticosteroid and hydrocortisteroid in the therapy of auto-immune and dermatological indications where these steroids were used to induce immuno-suppression, and (f) graft vs, host disease to reduce immune activity in organ and tissue transplant rejection
57 A method of reducing immune response in a patient in need of such treatment, comprising administering to said patient an immune response reducing effective amount of a pharmaceutical formulation comprising at Ieast one compound selected from the group consisting of
C-X-H-A-B-Y-Z,
C-X-H-A-B-D,
C-X-H-A-B;
D-H-A-B-Y-Z, H-A-B-Y-Z;
D-H-A-B-E;
D-H-A-B;
A-B-H-D;
C-X-A-B-H-Y-Z, C-X-A-B-H-D, C-X-A-B-H,
D-A-B-H-Y-Z,
A-B-H-Y-Z,
D-A-B-H-E, D-A-B-H, and
A-B-H-D, wherein
H is selected from the group consisting of Ala, lie, Leu, Met, Phe Trp, Val and Tyr, X is a covalent bond or an am o acid sub-sequence comprising at
Ieast one am o acid residue,
Y is a covalent bond or an ammo acid sub-sequence comprising at Ieast one ammo acid residue,
D is an am o acid sub-sequence comprising at least one ammo acid residue,
E is an ammo acid sub-sequence comprising at Ieast one amino acid residue,
B is Glu or Asp, C is a carrier compound residue,
Z is a carrier compound residue
58 A method of vaccinating against at Ieast one immunosuppressive ammo acid sequence selected from the group consisting of Asp-Arg-Ala-Ala-Asp-Gly-Gln-Pro-Ala-Gly, (SEQ ID NO 1 )
HTLV-I gp21E Gln-Asn-Arg-Arg-Gly-Leu-Glu-Leu-Leu-Phe-Trp- Glu-Gln-Gly-Gly-Leu-Cys-Lys-Ala-Leu-Gln-Glu-Gly-Cys-Arg-Phe, (SEQ ID NO. 2)
HTLV-II gp21 E Gln-Asn-Arg-Arg-Gly-Leu-Glu-Leu-Leu-Phe-Trp- Glu-Gln-Gly-Gly-Leu-Cys-Lys-Ala-lle-Gln-Glu-Glu-Cys-Cys-Phe, (SEQ ID NO. 3) MoLV p15E Gln-Asn-Arg-Arg-Gly-Leu-Glu-Leu-Leu-Phe-Leu- Lys-Glu-Gly-Gly-Leu-Cys-Ala-Ala-Leu-Lys-Glu-Glu-Cys-Cys-Phe, (SEQ ID NO 4)
FeLV p15E Gln-Asn-Arg-Arg-Gly-Leu-Glu-lle-Leu-Phe-Leu- Gln-Glu-Gly-Gly-Leu-Cys-Ala-Ala-Leu-Lys-Glu-Glu-Cys-Cys-Phe, (SEQ ID NO 5) and
Vιvax-1 the immunosuppressive effect of which is caused by the presence in said at Ieast one sequence of one or more positive/negative group, defined as a two-ammo acid sub-sequence where a positive ammo acid selected from Lys, Arg and His is adjacent to a negative ammo acid selected from Glu and Asp, in a patient in need of such vaccination, comprising administering to said patient an immunosuppressive sequence vaccinating effective amount of a pharmaceutical formulation comprising at ieast one modified sequence, said modified sequence comprising a compound which is identical to said at Ieast one immunosuppressive sequence, except that at Ieast one ammo acid residue of the two ammo acid residues in said one or more positive/negative group is replaced with an antimetabohte of said at Ieast one ammo acid residue, the D-isomer of said at Ieast one ammo acid residue, or an analog of said at Ieast one ammo acid residue
59 A method of vaccinating against at Ieast one immunosuppressive ammo acid sequence which, when present in an animal, adversely affects the immune response of said animal, said sequence having a formula selected from the group consisting of
R-[M-R]n,
[M-S]n, and
[R-M]n, wherein n is a positive integer, each R is, independently an ammo acid sub-sequence comprising at least one amino acid residue; each M is independently selected from 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; wherein the immunosuppressive effect of said at Ieast one immunosuppressive amino acid sequence is caused by the presence in the sequence of the one or more instance of an M group, in a patient in need of such vaccination, comprising administering to said patient an immunosuppressive sequence vaccinating effective amount of a pharmaceutical formulation comprising at Ieast one compound which is identical to said at Ieast one immunosuppressive sequence, except that at Ieast one amino acid residue of the two ammo acid residues in said one or more instance of an M group is replaced with an antimetabolite of said at Ieast one amino acid residue, the D-isomer of said at Ieast one amino acid residue, or an analog of said at ieast one amino acid residue.
60. A method of treating a condition selected from the group consisting of:
(a) immunodeficiency resultant from a viral infection;
(b) immunodeficiency resultant from one or more of the following bacterial, mycoplasmic, fungal and/or parasitic infections;
(c) immunodeficiency resultant from the growth of neoplastic tissue;
(d) immunodeficiency resultant from any cytokine or hormone imbalance or imbalance of any natural product within the patient; (e) myalgic encephalomyelitis (ME);
(f) post inoculation or viral infection fatigue syndrome,
(g) tuberculosis infection; and (h) malarial infection, in a patient in need of such treatment, comprising deleting genetic material from an infectious organism to prevent said genetic material from generating one or both amino acids in an am o acid sub-sequence 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-
61. A method of treating a condition selected from the group 5 consisting of:
(a) immunodeficiency resultant from a viral infection,
(b) immunodeficiency resultant from one or more of the following bacterial, mycoplasmic, fungal and/or parasitic infections;
(c) immunodeficiency resultant from the growth of neoplastic o tissue,
(d) immunodeficiency resultant from any cytokine or hormone imbalance or imbalance of any natural product within the patient,
(e) myalgic encephalomyelitis (ME),
(f) post inoculation or viral infection fatigue syndrome, 5 (g) tuberculosis infection, and
(h) malarial infection, in a patient in need of such treatment, comprising deleting genetic material from an infectious organism to prevent said genetic material from generating one or more am o acids in an ammo acid sub-sequence o selected from the group consisting of H-K,
K-H; and H-K-H; wherein each H is independently selected from the group consisting 5 of Ala, He, Leu, Met, Phe, Trp, Val and Tyr;
K is 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-
62 Polyclonal or monoclonal antibody, or at Ieast one Fab fragment 0 thereof, generated to at Ieast one compound selected from the group consisting of
C-X-A-B-Y-Z,
C-X-A-B-D,
C-X-A-B, D-A-B-Y-Z, and
A-B-Y-Z, wherein
X is a covalent bond or an amino acid sub-sequence comprising at Ieast one ammo acid residue, Y is a covalent bond or an ammo acid sub-sequence comprising at
Ieast one ammo acid residue,
D is an ammo acid sub-sequence comprising at Ieast one ammo acid residue,
A is Lys, Arg or His,
C is a carrier compound residue,
Z is a carrier compound residue
63 Polyclonal or monoclonal antibody as recited in claim 62, wherein said at Ieast one compound consists of 16 or fewer ammo acid residues
64 Polyclonal or monoclonal antibody as recited in claim 62, wherein said at Ieast one compound consists of 8 or fewer ammo acid residues
65 Polyclonal or monoclonal antibody as recited in claim 62, wherein said at Ieast one compound consists of 4 or fewer am o acid residues
66 Polyclonal or monoclonal antibody, or at Ieast one Fab fragment thereof, generated to at ieast 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 Ieast one ammo acid residue,
E is an ammo acid sub-sequence comprising at Ieast one am o acid residue,
and wherein said at Ieast one compound comprises at Ieast 4 ammo acid residues
67 Polyclonal or monoclonal antibody as recited in claim 66, wherein said at Ieast one compound consists of 16 or fewer ammo acid residues
68 Polyclonal or monoclonal antibody as recited in claim 66 wherein said at Ieast one compound consists of 8 or fewer am o acid residues
69 A peptide having the formula R1-R2-R3-R4, wherein
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, wherein 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, and 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.
70. A pharmaceutical composition comprising at Ieast one compound selected from the group consisting of: C-X-A-B-Y-Z;
C-X-A-B-D;
C-X-A-B;
D-A-B-Y-Z;
A-B-Y-Z; D-A-B-E;
D-A-B; and
A-B-D; wherein:
X is a covalent bond or an amino acid sub-sequence comprising at Ieast one amino acid residue;
Y is a covalent bond or an amino acid sub-sequence comprising at Ieast one amino acid residue;
D is an amino acid sub-sequence comprising at Ieast one ammo acid residue; E is an amino acid sub-sequence comprising at Ieast one amino acid residue;
A is Lys, Arg or His;
B is Glu or Asp;
C is a carrier compound residue; Z is a carrier compound residue.
71. A compound selected from the group consisting of compounds corresponding to:
Asp-Arg-Ala-Ala-Asp-Gly-Gln-Pro-Ala-Gly; (SEQ ID NO. 1 ) HTLV-I gp21 E Gln-Asn-Arg-Arg-Gly-Leu-Glu-Leu-Leu-Phe-Trp- Glu-Gln-Gly-Gly-Leu-Cys-Lys-Ala-Leu-Gln-Glu-Gly-Cys-Arg-Phe; (SEQ ID NO. 2)
HTLV-II gp21 E Gln-Asn-Arg-Arg-Gly-Leu-Glu-Leu-Leu-Phe-Trp- Glu-Gln-Gly-Gly-Leu-Cys-Lys-Ala-lle-Gln-Glu-Gln-Cys-Cys-Phe, (SEQ ID NO. 3) MoLV p15E Gln-Asn-Arg-Arg-Gly-Leu-Glu-Leu-Leu-Phe-Leu-
Lys-Glu-Gly-Gly-Leu-Cys-Ala-Ala-Leu-Lys-Glu-Glu-Cys-Cys-Phe, (SEQ ID NO. 4)
FeLV p15E Gln-Asn-Arg-Arg-Gly-Leu-Glu-lle-Leu-Phe-Leu-
Gln-Glu-Gly-Gly-Leu-Cys-Ala-Ala-Leu-Lys-Glu-Glu-Cys-Cys-Phe, (SEQ ID NO 5) and
Vιvax-1 wherein at Ieast one sub-sequence of two am o acid residues where a positive ammo acid selected from Lys, Arg and His is adjacent to a negative am o acid selected from Glu and Asp, is replaced with at Ieast one modified sequence, said modified sequence comprising a compound which is identical to said at Ieast one sub-sequence, except that at Ieast one ammo acid residue of the two am o acid residues in said one or more positive/negative group is replaced with an antimetabohte of said at least one ammo acid residue, the D-isomer of said at Ieast one ammo acid residue, or an analog of said at Ieast one ammo acid residue
72 A peptide having the formula RA-RB-RC-RD, wherein 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 wherein the Asp or Glu 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, and
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 Asp or Glu.
73. A pharmaceutical composition comprising at Ieast two Th2 cytokines.
74. A pharmaceutical composition as recited in claim 73, wherein said at Ieast two Th2 cytokines include Interleukin 10 and Interleukin 4.
75. A pharmaceutical composition comprising Interleukin 10, Interleukin 4 and at Ieast one of antagonist of Interleukin 10 and antagonist of Interleukin 4.
76. A pharmaceutical composition comprising Interleukin 10, Interleukin 4 and at Ieast one of agonist of Interleukin 10 and agonist of Interleukin 4.
77. A pharmaceutical composition comprising anti-serum to Interleukin 10 and anti-serum to Interleukin 4.
78. A pharmaceutical composition comprising anti-serum to Interleukin 10 and at Ieast one of antagonist of Interleukin 4 and agonist of Interleukin 4.
79. A pharmaceutical composition comprising anti-serum to Interleukin 4 and at Ieast one of antagonist of Interleukin 10 and agonist of Interleukin 10.
80. Polyclonal or monoclonal antibody, or at Ieast one Fab fragment thereof, generated to at Ieast one compound selected from the group consisting of: C-X-A-Q-B-Y-Z;
C-X-A-Q-B-D;
C-X-A-Q-B;
D-A-Q-B-Y-Z; and A-Q-B-Y-Z; wherein:
Q is a sub-sequence consisting of one or two amino acid residues,
X is a covalent bond or an amino acid sub-sequence comprising at Ieast one amino acid residue; Y is a covalent bond or an amino acid sub-sequence comprising at
Ieast one amino acid residue;
D is an amino acid sub-sequence comprising at Ieast one amino acid residue;
A is Lys, Arg or His; B is Glu or Asp;
C is a carrier compound residue;
Z is a carrier compound residue.
81. Polyclonal or monoclonal antibody, or at Ieast one Fab fragment thereof, generated to at Ieast one compound selected from the group consisting of:
D-A-Q-B-E; D-A-Q-B; and A-Q-B-E; wherein: Q is a sub-sequence consisting of one or two amino acid residues;
D is an amino acid sub-sequence comprising at Ieast one amino acid residue;
E is an amino acid sub-sequence comprising at Ieast one amino acid residue; A is Lys, Arg or His;
B is Glu or Asp; and wherein said at Ieast one compound comprises at Ieast 4 ammo acid residues
82 Polyclonal or monoclonal antibody, or at Ieast one Fab fragment thereof, generated to at Ieast one compound selected from the group consisting of
C-X-A-Q-B-Y-Z, C-X-A-Q-B-D, C-X-A-Q-B, D-A-Q-B-Y-Z, and A-Q-B-Y-Z, wherein
Q is a sub-sequence consisting of one or two ammo acid residues, X is a covalent bond or an ammo acid sub-sequence comprising at Ieast one ammo acid residue, Y is a covalent bond or an ammo acid sub-sequence comprising at
Ieast one ammo acid residue,
D is an am o acid sub-sequence comprising at Ieast one ammo acid residue,
C is a carrier compound residue, Z is a carrier compound residue
83 Polyclonal or monoclonal antibody, or at Ieast one Fab fragment thereof, generated to at Ieast one compound selected from the group consisting of
D-A-Q-B-E,
D-A-Q-B, and
A-Q-B-E, wherein Q is a sub-sequence consisting of one or two ammo acid residues D is an amino acid sub-sequence comprising at Ieast one am o acid residue;
E is an amino acid sub-sequence comprising at Ieast one ammo acid residue; A is Lys, Arg or His;
B is Glu or Asp; and wherein said at Ieast one compound comprises at Ieast 4 amino acid residues.
84. Polyclonal or monoclonal antibody, or at Ieast one Fab fragment thereof, generated to at Ieast one compound selected from the group consisting of:
C-X-H-A-Q-B-Y-Z;
C-X-H-A-Q-B-D;
C-X-H-A-Q-B; D-H-A-Q-B-Y-Z;
H-A-Q-B-Y-Z;
C-X-A-Q-B-H-Y-Z;
C-X-A-Q-B-H-D;
C-X-A-Q-B-H; D-A-Q-B-H-Y-Z; and
A-Q-B-H-Y-Z; wherein:
Q is a sub-sequence consisting of one or two ammo acid residues,
H is selected from the group consisting of Ala, lie, Leu, Met, Phe, Trp, Val and Tyr;
X is a covalent bond or an amino acid sub-sequence comprising at Ieast one amino acid residue;
Y is a covalent bond or an amino acid sub-sequence comprising at Ieast one amino acid residue; D is an amino acid sub-sequence comprising at Ieast one ammo acid residue;
C is a carrier compound residue,
Z is a carrier compound residue
85 Polyclonal or monoclonal antibody, or at Ieast one Fab fragment thereof, generated to at Ieast one compound selected from the group consisting of
D-H-A-Q-B-E, D-H-A-Q-B, H-A-Q-B-E,
D-A-Q-B-H-E, D-A-Q-B-H, and A-Q-B-H-E, wherein Q is a sub-sequence consisting of one or two am o acid residues,
H is selected from the group consisting of Ala, He, Leu, Met, Phe, Trp, Val and Tyr,
D is an ammo acid sub-sequence comprising at Ieast one ammo acid residue, E is an ammo acid sub-sequence comprising at Ieast one ammo acid residue,
and wherein said at Ieast one compound comprises at Ieast 4 ammo acid residues
86 A method of assaying body fluid from an animal, comprising contacting said body fluid with at Ieast one antibody as recited in claim 62 or claim 66
87 A method of screening a vaccine, comprising contacting said vaccine with at Ieast one antibody as recited in claim 62 or 66.
88. A method of treatment of a patent, either animal or human against any one or more of the following indications or infections listed below. (a) Immunodeficiency resultant from a viral infection.
(b) Immunodeficiency resultant from one or more of the following, bacterial, mycoplasmic, fungal and/or parasitic infections
(c) Immunodeficiency resultant from the growth of neoplastic tissue. (d) Immunodeficiency resultant from any cytokine or hormone imbalance or imbalance of any natural product within the patient.
(e) Myalgic Encephalomyelitis (ME).
(f) Post inoculation or viral infection fatigue syndrome.
(g) Tuberculosis infection. (h) Malarial infection. wherein the treatment comprises administering an effective dosage of a pharmaceutical formulation comprising polyclonal or monoclonal antibodies generated to any one or more sequences selected from the group consisting of: Ala-His-Asp; Ala-His-Glu; Ala-Lys-Asp; Ala-Lys-Glu; Ala-Arg-Asp;
Ala-Arg-Glu; lle-His-Asp; lle-His-Glu; lle-Lys-Asp; lle-Lys-Glu; lle-Arg-Asp;
He-Arg-Glu;Leu-His-Asp;Leu-His-Glu;Leu-Lys-Asp;Leu-Lys-Glu;Leu-Arg-As p; Leu-Arg-Glu; Met-His-Asp; Met-His-Glu; Met-Lys-Asp; Met-Lys-Glu;
Met-Arg-Asp; Met-Arg-Glu; Phe-His-Asp; Phe-His-Glu; Phe-Lys-Asp; Phe-Lys-Glu; Phe-Arg-Asp;Phe-Arg-Glu; Pro-His-Asp; Pro-His-Glu;
Pro-Lys-Asp; Pro-Lys-Glu; Pro-Arg-Asp; Pro-Arg-Glu; Trp-His-Asp;
Trp-His-Glu; Trp-Lys-Asp; Trp-Lys-Glu; Trp-Arg-Asp; Trp-Arg-Glu;
Val-His-Asp; Val-His-Glu; Val-Lys-Asp; Val-Lys-Glu; Val-Arg-Asp;
Val-Arg-Glu; Ala-Asp-His; Ala-Glu-His; Ala-Asp-Lys; Ala-Glu-Lys; Ala-Asp-Arg; Ala-Glu-Arg; lle-Asp-His; lle-Glu-His; lle-Asp-Lys; lle-Glu-Lys; lle-Asp-Arg; lle-Glu-Arg; Leu-Asp-His; Leu-Glu-His; Leu-Asp-Lys; Leu-Glu-Lys, Leu-Asp-Arg, Leu-Glu-Arg, Met-Asp-His, Met-Glu-His, Met-Asp-Lys, Met-Glu-Lys, Met-Asp-Arg, Met-Glu-Arg, Phe-Asp-His, Phe-Glu-His, Phe-Asp-Lys, Phe-Glu-Lys, Phe-Asp-Arg, Phe-Glu-Arg, Pro-Asp-His; Pro-Glu-His, Pro-Asp-Lys, Pro-Glu-Lys, Pro-Asp-Arg, Pro-Glu-Arg, Trp-Asp-His, Trp-Glu-His, Trp-Asp-Lys, Trp-Glu-Lys, Trp-Asp-Arg, Trp-Glu-Arg, Val-Asp-His, Val-Glu-His, Val-Asp-Lys, Val-Glu-Lys, Val-Asp-Arg, and Val-Glu-Arg
89 A method of treatment of a patient, either animal or human against any one or more of the following indications (a) Septic Shock
(b) Multiple Sclerosis
(c) Lupus Erythematoses
(d) Auto-immune diseases - myasthema gravis, rheumatoid arthritis, sjogrens disease (e) Replacement of corticosteroid and hydrocortisteroid in the therapy of auto-immune and dermatological indications where these steroids were used to induce immuno-suppression
(f) Graft v host disease to reduce immune activity in organ and tissue transplant rejection The treatment comprises administration of an effective dosage of pharmaceutical formulation wherein the active constituent is one or more of the ammo-acid charged ion bridge pairs attached to a hydrophobic ammo acid or acids as outlined herein table
90 A method of preparation of a prophylactic vaccine antigen using inactivated coat or capsid peptides Since vaccine preparations whose antigens contain the specified ion bridge pair hydrophobic ammo acid sequences identified in the patient will not be capable of engendering protective immunity this preparation method for a vaccine that will produce both T & B cell memory response requires that when preparing the antigenic peptide it is necessary to delete or otherwise neutralise these specific sequences by the use of antibodies or deletion during synthesis. In live vaccine organism generation or synthesis this may be achieved by using anti-sense RNA and/or DNA strands to prevent synthesis in the organism of these cytokine like messenger signal sequences thus producing a viable infecting organism for use in vaccine preparation but one without the means to effect immunosuppression or avoidance of the T cell defendant immune system deletion chiron corporation malaria vaccine Antigen Vivax-1 and SmithKline Beecham Malaria Vaccine NSI81 V20 sequence Asp-Arg-Ala-Ala-Asp-Gly-Gln-Pro-Ala-Gly (SEQ ID NO. 6) both contain the specified sequences which are immunologically privileged and act as cytokine signal molecules similar to AFP and Interleukin 10. If these sequences are deleted and the vaccine antigen for malaria contained only the plasmodium vivax circumsporozoite (CS) protein minus ion bridge pairs associated with hydrophobic amino acid/or acids together with antibodies to these specific sequences as outlined in earlier claims then a proper response by both the T & B cell components of the immune system can be expected which will confer immunity. Another method capable of conferring immunity to infection by organisms which have previously resisted efforts to be good vaccine candidates and this applies to organisms such as Plasmodium which causes human malaria and to the HIV-1 HHV and influenza virus is to culture these organisms in the presence of antisense RNA or DNA to these specific sequences and then use the inactivated organisms produced to act as vaccine antigen. Also it is possible to make deletions to the infectious organisms genetic material so preventing it from generating these specific sequences, such genetically modified organisms could be used because they would infect, replicate and generate an immune system attack which would completely remove the infection since it would have been disarmed by not having these sequences to allow it shift the balance of the hosts immune attack on it and the vaccinated subject would retain a balanced complement of B & T cell memory defences against further infection.
91. A method whereby polyclonal or monoclonal antibodies generated to the specific sequences listed under Claim X can be used as a blood/serum or body fluid assay to determine the levels of these specific peptides since no antibody response would be expected by the affected human since these specific sequences are immunologically privileged and do not present as foreign. Since we have identified elevated levels of these peptides in patients suffering from Myalgic Encephalomyelitis this assay could be used for both diagnosis and for determining the progress of therapy in these and other conditions where elevated levels of these peptide cause disease states.
92 A method of immune treatment in human and/or animal with pharmaceutical formulations containing in whole or in part polyclonal or monoclonal antibodies generated to amino acid sequences which exhibit specific Ion bridge charged pair arrays of a positively charged ammo acid and a negatively charged amino acid aligned together enclosed on one or both sides by a hydrophobic transmembrane segment of amino acids There may be more than one Ion bridge pair separated by polar or non-polar amino acids present within the peptide to which the antibodies are generated.
93 A method of immune treatment in human and/or animal with a pharmaceutical formulation containing in whole or in part polyclonal or monoclonal antibodies generated to the peptide of sequence Leu-Arg-Asp-Leu-Arg-Asp-Ala (SEQ ID NO. 7) which encloses two ion bridge pairs within non-polar amino acids on both sides.
94. A method of immune treatment in human and/or animal with a pharmaceutical formulation containing in whole or in part polyclonal or monoclonal antibodies generated to the specific peptide sequence Val-Glu-Arg-Tyr-Leu-Lys-Asp-GIn (SEQ ID NO. 8) which encloses two ion bridge pairs within both polar and non-polar am o acids
95 A method of immune treatment in human and/or animal with a pharmaceutical formulation containing in whole or in part polyclonal or monoclonal antibodies generated to one or a combination of these specific peptide sequences
(a) Pro-Lys-Glu-lle-Ala (SEQ ID NO 9)
(b) Ala-Asp-Lys-Val-Met (SEQ ID NO 10) Val-Glu-Lys-Tyr (SEQ ID NO 11 ) Leu-Glu-Lys-Tyr (SEQ ID NO 12)
Tyr-Asp-Lys-lle (SEQ ID NO 13)
Leu-Glu-Lys-lle (SEQ ID NO 14)
Ser-Glu-Arg-Leu (SEQ ID NO 15)
Gly-Glu-Lys-lle (SEQ ID NO 16) Leu-Glu-Arg-Gly (SEQ ID NO 17)
Tyr-Glu-His-Val (SEQ ID NO 18)
Leu-Glu-Lys-Cys (SEQ ID NO 19)
Gly-Asp-Arg-Ala (SEQ ID NO 20)
Gly-Glu-Lys-Leu (SEQ ID NO 21 ) Thr-Glu-Arg-Val (SEQ ID NO 22)
Thr-Asp-Arg-Val (SEQ ID NO 23)
Val-Glu-Arg-Tyr (SEQ ID NO 24)
Gln-Asp-Lys-Leu (SEQ ID NO 25)
Thr-Glu-His-Leu (SEQ ID NO 26) Leu-Asp-Arg-Leu (SEQ ID NO 27)
Phe-Glu-Lys-Thr (SEQ ID NO 28) Ser-Arg-Asp-Leu (SEQ ID NO 29) Leu-Glu-Lys-Tyr (SEQ ID NO 30) Asn-Glu-Arg-Leu (SEQ ID NO 31 ) lle-Glu-Lys-Thr (SEQ ID NO 32) and
Asn-Glu-Lys-Phe (SEQ ID NO. 33)
96 A method according to Claims 88-91 wherein said antigenic peptide is selected from the group consisting in whole or in part, of human animal, synthetic or recombinant alpha-fetoprotem (AFP) and/or cytokine inhibitory factor (Interleukin 10), Malaria circumsporozite, Viral peptides
97 A method for treating a patient, comprising administering a pharmaceutical formulation containing polyclonal and/or monoclonal antibodies to sequences as specified in Claims 88-91 as a therapeutic for the binding and removal of peptides generated by the infected host or infecting organism which have been specifically enhanced by the infecting organism to render a down regulation in Th1 cell type dependent immune resistance to infection
98 A method as recited in any one of claims 1 -61 and 88-97, further comprising administering to said patient an antiviral therapy
99 A method as recited in claim 98, wherein said antiviral therapy comprises administration of AZT
100 A pharmaceutical composition as recited in any one of claims 70 and 73-79, further comprising administering to said patient an antiviral material
101 A pharmaceutical formulation as recited in claim 100, wherein said antiviral material comprises AZT
102 A pharmaceutical formulation comprising at Ieast one antibody as recited in any one of claims 62-68 and 80-85, together with an antiviral material
103 A pharmaceutical formulation as recited in claim 102, wherein said antiviral material comprises AZT
104 A pharmaceutical formulation comprising at Ieast one peptide as recited in any one of claims 69 and 72, together with an antiviral material
105 A pharmaceutical formulation as recited in claim 104, wherein said antiviral material comprises AZT
106 A pharmaceutical formulation comprising at Ieast one compound as recited in claim 71 , together with an antiviral material
107 A pharmaceutical formulation as recited in claim 106, wherein said antiviral material comprises AZT
108 A treatment for animals and humans suffering from immunosuppressive disease whereby the patient is administered a cellular receptor to a Th2 cytokine
109 A treatment for animals and humans suffering from immunosuppressive disease whereby the patient is administered cellular receptors to two or more Th2 cytokine in a combination therapy
110 A treatment according to claim 108 or 109 wherein the immunosuppressive disease is resultant from a viral infection
111 A treatment according to Claim 108 or 109 wherein the immunosuppressive disease is resultant from a bacterial infection
112 A treatment according to Claim 108 or 109 wherein the immunosuppressive disease is resultant from a fungal infection
113 A treatment according to Claim 108 or 109 where the cellular receptor to the Th2 cytokine is one or more of the following lnterleukιn-4 receptor, lnterleukιn-6 receptor and/or lnterleukιn-10 receptor
114 A treatment according to Claim 109 wherein the cellular receptors to the cytokines are administered in a specific ratio dependant on the disease state
115 A treatment according to any one of Claims 108-113 wherein the cellular receptor to the cytokines is administered by IV, enema or transdermal patch in dose amounts of between 10-500 ug per day
116 A treatment according to any one of claims 108-113 wherein the cellular receptor to the cytokines is administered as a soluble receptor
117 A treatment according to claim 108 or 109 wherein the treatment is for the removal of Th2 cytokines/AFP immunosuppressive mimic peptides of viral/vacteπal or parasitic origin
118 A method of achieving improved immune response in a patient, said method comprising administering an amount of an antagonist in the form of an ammo acid sequence of greater than two ammo acids in length, of Interleukin 10 (IL-10) or part thereof wherein one or more of the negatively charged R groups of IL-10 is a D ammo acid
119 A method of achieving improved immune response in a patient, said method comprising administering an amount of an antagonist in the form of an ammo acid sequence of greater than two ammo acids in length, of Interleukin 10 (IL-10) or part thereof wherein one or more of the positively charged R groups of IL-10 is a D am o acid
120 A method of achieving improved immune response in a patient, said method comprising administering an amount of an antagonist in the form of an ammo acid sequence of greater than two ammo acids in length, of Interleukin 10 (IL-10) or part thereof wherein one or more of each of the negatively and positively charged R groups of IL-10 is a D ammo acid
121 A method of achieving improved immune response in a patient, said method comprising administering an amount of an antagonist, in the form of an ammo acid sequence of greater than two ammo acids in length, of Interleukin 10 (IL-10) or part thereof wherein one or more of the polar uncharged R groups of IL-10 is a D ammo acid
122 A method of achieving improved immune response in a patient, said method comprising administering an amount of an antagonist in the form of an ammo acid sequence of greater than two am o acids in length, of Interleukin 10 (IL-10) or part thereof wherein one or more of the non-polar uncharged R groups of IL-10 is a D ammo acid
123 A method of achieving improved immune response in a patient, said method comprising administering an amount of an antagonist in the form of an ammo acid sequence of greater than two amino acids in length, of Interleukin 10 (IL-10) or part thereof wherein one or more of each of the non-polar and polar uncharged R groups of IL-10 is a D ammo acid
124 A method of achieving improved immune response in a patient, said method comprising administering an amount of an antagonist, in the form of an ammo acid sequence of greater than two am o acids in length, of Interleukin 10 (IL-10) or part thereof wherein one or more of each of the negatively charged, non-polar and polar uncharged R groups of IL-
125 A method of achieving improved immune response in a patient, said method comprising administering an amount of an antagonist in the form of an ammo acid sequence of greater than two ammo acids in length, of Interleukin 10 (IL-10) or part thereof wherein one or more of each of the positively charged, non-polar and polar uncharged R groups of IL-10 is a D amino acid.
126. A method of achieving improved immune response in a patient, said method comprising administering an amount of an antagonist, in the form of an amino acid sequence of greater than two amino acids in length, of Interleukin 10 (IL-10) or part thereof wherein one or more of each of the positively charged, negatively charged, non-polar and polar uncharged R groups of IL-10 is a D amino acid.
EP97939105A 1996-09-11 1997-09-10 Pharmaceutical compositions for the treatment of immune disorders Withdrawn EP0929568A2 (en)

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SE9900812D0 (en) 1999-03-08
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CN1230195A (en) 1999-09-29
NZ335039A (en) 2001-04-27
JP2001503613A (en) 2001-03-21
SE9900812L (en) 1999-03-08
CA2265885A1 (en) 1998-03-19

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