CA2265885A1 - Pharmaceutical compositions for the treatment of immune disorders - Google Patents
Pharmaceutical compositions for the treatment of immune disorders Download PDFInfo
- Publication number
- CA2265885A1 CA2265885A1 CA002265885A CA2265885A CA2265885A1 CA 2265885 A1 CA2265885 A1 CA 2265885A1 CA 002265885 A CA002265885 A CA 002265885A CA 2265885 A CA2265885 A CA 2265885A CA 2265885 A1 CA2265885 A1 CA 2265885A1
- Authority
- CA
- Canada
- Prior art keywords
- amino acid
- glu
- asp
- sequence
- arg
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
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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 IL12) 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
wo 98/10787 110152025CA 02265885 1999-03-08PCT/IB97/01086IMMUNE DIRECTION THERAPYIt is identified in this patent that a very specific amino acid sequencewhich exhibits speciï¬c Ion bridge pair arrays, especially if enclosed on at leastone side by a non-polar hydrophobic transmembrane segment of at least oneamino acid, can, if presented with a carrier to a cell membrane, induceendocytosis and cause activation of specific intracellular and extracellularevents which would normally only result from the interaction of an AntigenMHCâll complex with both the T cell receptor (TCR) and the CD3 membranecomplexes. These specific amino acid Ion bridge pair sequences are onlypresent within the cell membrane during proper functioning of the immunesystem and allow activating T cell clone expansion following antigenpresentation. If this specific ion bridge pair enclosed on at least one side byhydrophobic segments is presented to the cell from a non immune source thenincreased cytoplasmic circulation from cell membrane of specific markermolecules occurs and this removes the normal immune functions of the celltypes impacted by these specific peptide sequences. A proportion of aminoacid sequences according to the present invention have demonstrated in adose dependent manner the ability to downâregulate the expression of lamolecules on human macrophages. Some in-vitro experiments suggest thatdirect T cell antigen interactions without the mediation of la bearingmacrophages may result in the generation of antigen specific suppressor Tcells. All experimental evidence indicates that the development ofantigen-reactive clones of helper T cells requires the presence of la bearingcells in the tissue. This inhibition of expression on the membrane surface ofthese class II molecules (la) as produced with alfa-fetoprotein and/or cytokineinhibitory factor, signals the immune system to accept the appearance of newantigens as self to the immune system. Hence the often reported observationthat an immune activation on polyclonal B cell activation producingW0 98/ 1078710152025I ll 'CA 02265885 1999-03-08PCTIIB97/_010862autoâantibodies follow certain viral, bacterial and parasitic infections (e.g. HIV,Malaria). The effects of these specific peptide ion-bridge pairs attached to ahydrophobic amino acid sequence demonstrate that they are the componentpeptide segments within both the alpha-fetoprotein and the cytokinesmolecules that are involved in the process of inducing tolerance andmaintaining the tolerant state to infectious organisms presenting thesesequences.In identifying this specific type of sequence and its ability to generatespecific immune signals together with its ability to enhance or triggerendocytosis of attached peptides or glycopeptides, we have been able toidentify these specific amino acid sequences as a mechanism used by manyinfectious agents to not only undermine the hostsâ immune defenses but toalso allow for the penetration or infection of target lymphoid tissue.Amino acids and residues thereof (i.e., amino acids in which one ormore 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 theart.According to the present invention, there are therefore providedpharmaceutical compositions and methods of enhancing immune response ina patient suffering from immunodeficiency and/or one or more conditionselected 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) immunodeï¬ciency resultant from the growth of neoplastic tissue;(d) immunodeficiency resultant from any cytokine or hormoneimbalance or imbalance of any natural product within the patient;(e) myalgic encephalomyelitis (ME);(f) post inoculation or viral infection fatigue syndrome;CA 02265885 1999-03-08W0 98,10-,87 PCTIIB97/_0l0863(g) tuberculosis infection; and(h) malarial infection,comprising administering to the patient an immune response enhancingeffective amount of a pharmaceutical formulation comprising at least one5 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-AâBâY-Z;C-X-A-B-D;CâX-A-B;10 D-A-BâY-Z; andAâBâY-Z;wherein:X is a covalent bond or an amino acid subâsequence comprising atleast one amino acid residue;15 Y is a covalent bond or an amino acid subâsequence comprising atleast one amino acid residue;D is an amino acid subâsequence comprising at least one amino acidresidue;A is Lys, Arg or His;20 B is Glu or Asp;C is a carrier compound residue;Z is a carrier compound residue.The present invention also provides pharmaceutical compositions andmethods of enhancing immune response, e.g., in a patient suffering from a25 condition as set forth above, comprising administering to said patient animmune response enhancing effective amount of a pharmaceutical formulationcomprising at least one polyclonal or monoclonal antibody, or at least one Fabfragment thereof, generated to at least one compound selected from the groupconsisting of:I ll ICA 02265885 1999-03-0sWO 93/10737 PCT/[B97/010864D-AâB-E;D-AâB; andA-BâE;wherein:5 D is an amino acid subâsequence comprising at least one amino acidresidue;E is an amino acid subâsequence comprising at least one amino acidresidue;A is Lys, Arg or His;10 B is Glu or Asp;152025and wherein said at least one compound comprises at least 4 aminoacid residues. in speciï¬c aspects of the present invention, the compound canconsist of 16 or fewer amino acid residues, or of 8 or fewer amino acidresidues.in speciï¬c aspects of the present invention, at least one compound canconsist of 16 or fewer amino acid residues, 8 or fewer amino acid residues,or 4 or fewer amino acid residues.In a preferred aspect of the present invention, the sub-sequence -A-B-further includes a hydrophobic amino acid residue ie, an amino acidresidue selected from Ala, lle, Leu, Met, Phe, Trp, Val and Tyr on either end,i.e., âHâA-B- or -A-B-Hâ.The present invention further relates to the antibodies used in themethods of the invention.In addition, any of the antibodies in accordance with the presentinvention can be administered to a patient in addition to any known vaccine.I The present invention further relates to methods of reducing a patientsimmune response, by administering any of the compounds described abovewhich have a subâsequence âA-B- or -B-A, preferably âHâA-B- or -H-BâA-. Thepresent invention further relates to such compounds.WO 98/1078710152025CA 02265885 1999-03-08PCT/[B97/4010865Suitable (3-amino acid) sequences which include a sub-sequence -H-A-B- or âHâB-A- for use in accordance with the present invention include thefollowing:Ala-His-Asp; AlaâHis-Glu; AlaâLys-Asp; AIaâLys-Glu; Ala-ArgâAsp;Ala-Arg-Glu; lle-His-Asp; lle-HisâG|u; lle-LysâAsp; lle-Lys-Glu; lle-Arg-Asp;lle-Arg-Glu;LeuâHis~Asp;Leu-His-Glu;LeuâLys-Asp;Leu-LysâGlu;Leu-Arg-Asp;Leu-ArgâG|u; Met-His-Asp; Met-HisâGlu; Met-Lys-Asp; Met-LysâG|u;MetâArg-Asp; Met-Arg-Glu; Phe-His-Asp; Phe-His-Glu; Phe-Lys-Asp;Phe-Lys-Glu; Phe-ArgâAsp;Phe-ArgâGlu; Pro-His-Asp; Pro-HisâGlu;Pro-Lys-Asp; ProâLys-Glu; ProâArg-Asp; Pro-Arg-Glu; Trp-HisâAsp;Trp-HisâGlu; TrpâLysâAsp; Trp-LysâGlu; Trp-Arg-Asp; Trp-Arg-Glu;Val-HisâAsp; Val-His-Glu; ValâLys-Asp; Val-LysâGlu; Val-ArgâAsp;Val-ArgâGlu; Ala-Asp-His; Ala-Glu-His; Ala-Asp-Lys; A|aâGluâLys:Ala-Asp-Arg; Ala-G|uâArg; lle-AspâHis; lle-Glu-His; lle-AspâLys; lle-GluâLys;|leâAsp-Arg; lle-Glu-Arg; Leu-Asp-H is; LeuâGlu-His; Leu-AspâLys;LeuâGlu-Lys; LeuâAsp-Arg; LeuâGluâArg; MetâAspâHis; MetâGluâHis;Met-Asp-Lys; Met-GluâLys; Met-AspâArg; Met-Glu-Arg; Phe-AspâHis;Phe-Glu-His; Phe-Asp-Lys; Phe-GluâLys; Phe-AspâArg; Phe-Glu-Arg;Pro-Asp-His; Pro-GluâHis; Pro-Glu-Lys;Pro-Glu-Arg; TrpâAspâHis; TrpâGlu-His; TrpâAspâLys; Trp-GluâLys;Trp-Asp-Arg; Trp-Glu-Arg; Val-Asp-His; ValâGluâHis; Val-AspâLys;Val-Glu-Lys; Val-AspâArg; and Val-Glu-Arg.Numerous suitable carrier compounds for use in accordance with theProâAsp-Lys; ProâAsp-Arg;present invention would be readily apparent to those skilled in the art, andrepresentative examples include Serum albumin precursor - rat; Acyl carrierprotein - Escherichia coli; Serum Albumin precursor - human; S. typhimuriumbranched chain amino transport system ll carrier; Branched â chain amino acidcarrier; Ribosomal protein 816 - Escherichia coli; 3-Hydroxydecanoyl â{Acy|âCarrier-Protein} Dehydratase; Excitatory amino acid transporter 3 (sodium-WO 9811078710152025I ll 'CA 02265885 1999-03-08PCTIIB97/4010866dependent; glutamate/aspartate transporter 3) (excitatory amino-acid carrier1); Glutaredoxin 3; Cytochrome B5/C6; Transthyretin Precursor (prealbumin)(TBPA) ('l'|'R); Phosphocarrier Protein HPR (Histidineâcontaining protein);BetaâHexosaminidase 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 BrownFat Uncoupling Protein (UCP); Thioredoxin; Oleoyl-hydrolase; Platelet factor4; Lactose Permease; Keyhole Lipid hemocyanin (l<LH); and Bovine SerumAlbumin (BSA).The antibodies of the present invention are humanised as per thefollowing reference:From cells to genes: how to make antibodies useful in humandiagnosis and therapy. Zaccolo M, Malavasi F. Dipartimento di Genetica,Universita di Torino, ltaly. Int J Clin Lab Res 1993: 23(4): 192-198.The mono/polyclonal antibodies are made as per the followingreference: Moller, G. (ed.): Engineered antibody molecules. lmmunol.Rev. 1992, 13031-212.The present invention further relates to methods of vaccinating apatient against immunosuppressive sequences, by administering a compoundwhich corresponds with an immunosuppressive sequence, except that one orboth of the members of at least one -AâB- sub-sequence is replaced with ananalog, an antimetabolite or a D-amino acid corresponding to the replacedamino acid. The present invention also relates to such compounds.Examples of such immunosuppressive sequences include:Asp-Arg-AlaâAla-AspâGly-Gin-ProâAlaâGly (SEQ ID NO. 1);HTLV-I gp21E GlnâAsn-ArgâArg-Gly-Leu-Glu-LeuâLeuâPhe-TrpâGlu-Gln-GIy-Gly-Leu-Cys-LysâAla-LeuâGIn-G|uâG|yâCys-Arg-Phe (SEQ ID NO. 2);HTLV-ll gp21E GIn-Asn-Arg-Arg-Gly-LeuâGluâLeuâLeuâPheâTrp-Glu-Gln-Gly-G|yâLeu-Cys-Lys-Alaâlle-G|nâGluâGln-CysâCysâPhe (SEQ ID NO. 3):W0 98/1078710152025CA 02265885 1999-03-08PCT/IB97/4010867MoLV p15E Gin-AsnâArg-Arg-Gly-Leu-Glu-Leu-LeuâPhe-Leu-Lys-GluâGly-GlyâLeu-Cys-Ala-Ala-LeuâLys-GluâGlu-Cys-CysâPhe (SEQ IDNO. 4);FeLV p15E GIn-Asn-Arg-ArgâGly-Leu-GluâlleâLeuâPhe-Leu-G|nâGlu-G|yâGly-Leu-CysâA|a-Ala-Leu-Lys-Glu-GluâCysâCysâPhe (SEQ IDNO. 5); andVivax-1.A variety of analogs which would be suitable for use according to thepresent invention would be readily apparent to those skilled in the art.Representative examples include analogs of Larginine including Lornithine,L-Citrulline, Lâoi-Aminobutyrate, Agmatine (4-aminoâ1âguanidinobutane)(glycocyamylglycine,LâHomoarginine,Putrescine (1,4-diaminobutane), glycocyamine,taurocyamine, methylguanidine, LâArgininosuccinicanhydride (l), L~Argininic acid, L-Argininosuccinic anhydride (ll), L-Argininosuccinate (Ill), LâArgininosuccinate anhydride (IV), and LnitroArginine;and analogs of Lysine including L-thialysine (Sâ(oi-aminoâethyl)-Lâcysteine),D/L 4 oxalysine, BâLysine, N5âHydroxyâL-Arginine.The present invention further relates to a method of treating a conditionselected 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) immunodeï¬ciency resultant from the growth of neoplastic tissue;(d) immunodeficiency resultant from any cytokine or hormoneimbalance 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,W0 98/1078710152025CA 02265885 1999-03-08PCT/IB97l_0l0868in a patient in need of such treatment, comprising deleting geneticmaterial from an infectious organism to prevent said genetic material fromgenerating one or both amino acids in an amino acid sub-sequence "K"selected from the group consisting of Lys-Glu, LysâAsp, ArgâGlu, Arg-Asp,His-Glu, His-Asp, Glu-Lys, Asp-Lys, Glu-Arg, Asp-Arg, GluâHis and Asp-His,and sub-sequences K which have at least one adjacent hydrophobic aminoacid.The present invention further relates to methods and pharmaceuticalcompositions described above, wherein the component A and the componentB 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 fromthe group Lysine and/or ArginineR2 is a short region of up to 2AA which does not contain any of thefollowing Asp, Glu, Lys, Arg or HisR3 is a region of up to 7AA within which there may be one or two AAfrom the group Aspartic acid and/or Glutamic acid. The Aspartic acid orGlutamic closest to the R4 region is positioned within R3 to allow a minimumof two AA between these said acids and the R4 region.R4 is a region of two AA containing one AA of either Lysine or Arginineattaching to region R3 and the other AA is either Aspartic acid or Glutamicacid.Regions R1, R2 and R3 are considered the positioning regions of thisspecific AA sequence as they allow alignment of the AA sequence with cellmembrane whereas R4 is considered the signalling sequence as this duo ofpeptides activates cell stimulation. This said peptide may be administeredwith a carrier moiety wherein the said carrier protein comprises bovine serumW0 98/ 1078710152025CA 02265885 1999-03-08PCTlIB97_/010869albumin, human serum albumin, an immunoglobulin or a hormone. Thesepeptides may be made to further possess sugar groups, normal serumcomponents, lipids, phospholipids, etc. Naturally occurring organisms usingpeptides similar to those described herein for immune attack may be treatedto deactivate their peptide immune activation mechanism by altering, bymeans known to those skilled in the art, one or more of either Lysine orArginine existing in Region R1 and preferably in addition altering one or twoof 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 fromthe group Lysine and/or ArginineRB 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 AAfrom the group Aspartic acid and/or Glutamic acid. The Aspartic acid orGlutamic closest to the RD region is positioned within RC to allow a minimumof two AA between this said AA, if one exists, and the RD region. RD is aregion of three or four AA containing one AA of either Lysine or Arginineattaching to region RC and one or two amino acids in the middle of the regioncontaining AA from Polar and/or non-Polar with another AA at the end of theregion which is either Aspartic acid or Glutamic acid.Regions RA, RB and RC are considered the positioning regions of thisspecific AA sequence as they allow alignment of the AA sequence with cellmembrane whereas RD is considered the signalling sequence as this duo ofpeptides activates cell stimulation. This said peptide may be administeredwith a carrier moiety wherein the said carrier protein comprises bovine serumWO 98/1078710152025I ll 'CA 02265885 1999-03-08PCT/IB97/0108610albumin, human serum albumin, an immunoglobulin or a hormone. Thesepeptides may be made to further possess sugar groups, normal serumcomponents, lipids, phospholipids etc. Naturally occurring organisms usingpeptides similar to those described herein for immune attack may be treatedto deactivate their peptide immune activation mechanism be altering, bymeans known to those skilled in the art, one or more of either Lysine orArginine existing in Region RA and preferably in addition altering one or twoof the charged AA in region RD to remove the charge distribution of the saidpeptide. Vaccines may be manufactured using such techniques.The present invention also relates to treatments comprisingadministering to a patient any pharmaceutical formulations disclosed hereintogether with an antiviral therapy.The large scale efforts to produce a broad spectrum vaccine candidatefor Influenza Virus has proved impossible due to the rapid rate of mutation ofthe outer coat of this virus. However, without the ability to attach and fuse andsignal host immune cells in the body using those specific polar single ionbridge pair arrays of amino acid specific sequences, outlined herein, it isnonâinfectious. If these amino acid sequences are altered in the InfluenzaVirus, this virus then cannot undermine the hostsâ immune system andachieve cell entry or create immune dysfunction. This ability is restricted toa specific number of sequences, all of which must present to the cellmembrane the charge distribution shown to activate endocytosis andTCRICD3 cell activation and neutralise T cell immune surveillance as itrelates to MHC-Class l and ll. Therefore, if the infected host, human oranimal, already posses neutralising antibodies to these amino acid changeddipole sequences as specified herein it will not be possible for infection to beestablished because these neutralising antibodies perform a dual function (A)they prevent anchorage and endocytosis of the infecting organism into thehost cell thus preventing productive infection and (B) they prevent theW0 98/1078710152025CA 02265885 1999-03-08PCT/IB97/01086llcirculation in the plasma of these mimic Interleukin 10 or AF P type moleculeswhich are released by infecting organisms. These specific said sequencesconfuse the normal signalling system involved in immune T and B cellactivation since when applied to cells they trigger an intracellular Biochemicalsignal similar to when a T cell receptor (TCR) molecule coupled to a CD3molecule interact with a MHC-ll antigen complex, together with the fact thatthese sequences also cause increased turnover of surface receptor moleculessuch as the Interleukin I receptor molecule, thus leading to an increase ofInterleukin I levels and cause a shift in T cell performance due to the shiftingTh,/Th2 cytokine balance.It has been demonstrated with non-protective vaccine candidateantigens which when previously inoculated into a host produced a range ofneutralising antibodies but failed to prevent infection being established whenthat host was later challenged with live infectious organism. When the initialvaccine inoculation is coupled with passive immunisation with mono orpolyclonal antibodies to these said specific sequences of the presentinvention that an immune response to the vaccine antigen from both T celland B cell immune components results which includes antibodies to thesehitherto unchallenged sequences results, the host is then capable ofovercoming an infectious challenge without becoming infected or producingtheimmunosuppression normally associated with infections caused by organismsusual antibody and autoantibody peak and subsequentwho utilise these specific amino acid sequences to direct the hosts immunesignalling system towards a more pronounced B cell or Th2 cytokine profiledresponse.Malaria is one of the most important infectious diseases in the World;each year there are 270 million new infections resulting in over 100 millionWorld-wide themalaria problem is getting worse each year. The reason for this worseningepisodes of illness and approximately 2 million deaths.WO 98/1078710152025CA 02265885 1999-03-08PCT/IB97/0108612situation include (A) increased levels of drug resistance on the part of theparasites, (B) increased levels of insecticide resistance on the part of thevectors. No vaccine has yet been produced which can successfully induce aprotective antibody response. The reason for this is that although antibodieswhich cross react with many epitopes of the P. vivax circumsporozoite areproduced in abundance by the current unprotective vaccine candidates,because of the immune blind spot or immunologically privileged sites offeredby these specific sequences identified herein, like interleukin 10 and AFP.these sequences are not visible to the host immune system which both allowthe parasite to gain access to the host cell and to cause the non-specificpolyclonal B cell activation and immunosuppressive (Interleukin 10 and/orAFP) like effects which are so universal for people suffering from parasitessuch as malaria, and Leishmania, the host cannot gain enough immunereactive monocytes to overcome the infection initially because theseinterleukin 10/AFP mimic molecules carried by the infecting organism shutsdown the vital Th1 T cell response needed to clear intra-cellular infections.We have identified the specific polar array sequence on the coat protein ofmalaria which this organism uses like Influenza Virus to attach and activateendocytosis together with activating a Th2 (B cell) response and subsequentlyundermining the host's immune response and allowing infection to take holdwhile still producing an array of neutralising antibodies which createsmutational pressure for the generation of more virulent strains of the organismwithin the host.Our studies clearly demonstrated in mouse models that polyclonal ormonoclonal antibodies generated to the above polar sequence arrays to thesespeciï¬c amino acid sequences either taken from specific sequences presentin human alfa-fetoprotein or human Interleukin 10 resulted in protection ofmice from challenge by malaria sporozoites. Therefore a vaccine for malariawhich will enable a human to raise a protective antibody titre against malariaW0 98/1078710152025CA 02265885 1999-03-08PCT/IB97/0108613sufficient to prevent infection may be manufactured by deleting from theantigenic peptide to be used in the vaccine these amino acid sequencesdisplaying the specific polar arrays outlined in this patent. Another methodexpected to be more successful as a vaccine combination (because theimmune system of primates including man appear to be blinded to thesespeciï¬c signal sequences) for protection is to use passive immunisation witheither polyclonal or monoclonal antibodies to these said specific dipoleimmunosuppressive sequences generated either in animal human and/ortissue culture given either before or simultaneously with any of the currentmalaria vaccine candidates which previously could not produce a protectiveimmune response. When these mono or polyclonal antibodies are given tothe host in conjunction with the antigen the hostâs immune system does notproduce the well documented polyclonal B cell activation of the host immunesystem and the immune system of the host so challenged will produce aprotective antibody and T cell immune response which allows it to dealeffectively with any later malaria infection challenge.In malaria, as in other infections the said specific sequences, identifiedas a dipole amino acid sequence in this patient, when embedded in the cellmembrane of the host activates the phosphatidylinositol pathway, whichcauses the release of Ca++, the phosphosylation of cell proteins and theactivation or enhanced activity of certain enzymes related to metabolism. Thisdoes not occur in the presence of antibodies to the disclosed specificsequences and the organism like malaria, Mycobacterium Tuberculosis,Leishmania, HIV and others are not able to cause metabolic and immune Th2activation and exhaustion. It is an important coincidence that in certainmalaria endemic areas that genetic mutations that have caused the deletionof the metabolic activity control enzyme glucose-6âphosphate dehydrogenasehas conferred on the host immunity to malaria. By intervening at an earlystage of infection and neutralising certain properties of the malaria parasiteW0 98/1078710152025CA 02265885 1999-03-08PCT/IB97/0108614to alter cellular reactions by interfering with these specific membrane signaltransduction sequences as defined herein it is possible to confer protectiveimmunity to this organism.The present invention utilises the novel discovery that certain aminoacid sequences which exhibit specific ion (bridge) pair arrays enclosed on atleast one side by non-polar hydrophobic transmembrane segments can beutilised to enhance the humoral antibody response and down-regulate the Tcell or delayed-type hypersensitivity (DTH) response of humans and animals.These CD3fTCR mimic membrane interaction molecules which present ashydrophobic Ion bridge pairs are utilised by both the organism itself asspecific peptides and by cytokines and also by infectious agents to modulateimmune response (A) during periods of reproductive foetal gestation as withthe alpha-fetoprotein molecule to prevent foetal rejection by the maternalimmune system and (B) during cytokine control of immune functions as withcytokine synthesis inhibitory factor (Th2 cytokine) when a Th2 cytokine profileis required or to curtail the uncontrolled Th1 T4 cell immune response. Theseimmunosuppressive cytokines are particularly evident following vaccinationto enhance humoral immunity and secure antibody formation, and oftencauses the temporary disappearance of the Tuberculin reaction which isassociated with Th1 (DTH) response in patients following vaccination. (C)Infectious agents such as viruses (RNA & DNA) mycoplasma, bacteriaâmalaria and a wide array of human and animal parasites also carry thesespecific charged array of amino acid sequences which cause the downregulation of the Th1 cytokine response and enhance the humoral (antibodymediated) immune response of their infected host.Now that these specific control sequences have been identified andveriï¬ed we herewith outline a number of therapeutic modalities that result fromthis new found ability to intervene therapeutically to control, neutralise orenhance specific immune type reactions dependent upon the nature of theW0 98/ 1078710152025CA 02265885 1999-03-08PCT/IB97/0108615patient's or animal's own immune system status, infection or disease state.ExampleAnti-serum generated to these specific sequences as presented inAFP, Interleukin 10, EBV-BCRF1 and other peptides and as specified inamino acid sequence, listing enclosed, with this patent can be used to removeAFP mimic molecules from the circulation of immunosuppressed patientssuffering from viral and/or bacterial and/or fungal, mycoplasmic or parasiticinfections, which infection's principle method of defence against the host is tostimulate a Th2 cytokine response and curtail or abolish the Th1 cell mediatedimmune attack.This invention relates to methods of treatment of persons and animalswith indications of immunodeficiency, wherein the said indication is resultantfrom viral and/or retroviral infection and/or infectious parasites, bacteriaand/or mycoplasma, The invention further relates to treatment with the aboveantiserum either poly or monoclonal in nature for establishing improvedimmuno response for persons and prophylactic treatment for persons whereimmunoâmalfunction due to genetic preâdisposition or infection is considereda 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 inherentimmune suppressive properties - such suppressive potential properties aredetermined by the manufactured vaccine's reactivity with the said specificamino acid sequences as outlined herein, be they synthetic or natural inorigin, e.g. AFP, Th2 cytokines, viral or bacterial coat peptides. In oneembodiment, the host organism (man or animal) is treated with mono orpolyclonal antibodies to any one or combination of the specific amino acidsequences as defined herein. This will result in the removal of Th2 cytokineand AFP type mimic immunosuppressive peptides and initiate a Th, cellW0 98/1078710152025I U |CA 02265885 1999-03-08PCT/IB97I,0108616response, allowing Interleukin 2 and gamma interferon synthesis to occur.Treatments used according to this invention employing the poly or monoclonalantiserum to these specific immune system inhibitory sequences areadministered as treatments against viral, bacterial and mycoplasma andparasitic infections which cause immunosuppression by any suitable routeincluding enteric, parenteral, topical, oral, rectal, nasal or vaginal routes.Parenteral routes include subcutaneous, intramuscular, intravenous andsublingual administration. The preferred route of administration would be anintravenous one.The present invention further provides pharmaceutical formulations, foruse in treatments against HlV/HTLVâl, ll, Ill and other viral diseases anddiseases caused by mycoplasma, bacteria or parasites.The present invention also relates to a method comprising inoculatinginto a patient a human, animal, synthetic or recombinant amino acid sequencewith or without adjuvant, to produce an antibody response, the antibodies,mono or polyclonal will cause the binding of the immunosuppressiveCD3/TCR mimic interaction molecules already present in the plasma of theinfected host will be removed from the circulation of the infected host andnormal immune function demonstrating a Th1 cytokine profile, i.e. Interleukin2 and gamma interferon, capable of resisting the infection will bereâestablished.Vaccines manufactured by the use of coat or other peptides from viral,bacterial, parasitic or mycoplasma may be screened to determine whetherthey posses these speciï¬c amino acid sequences which exhibit these specificlon bridge pair arrays capable of mimicking the actions of AFP or Th2cytokines and their inherent immune suppressive properties â suchsuppressive potential properties is determined by the manufactured vaccineâsreactivity with any of the said specific amino acid sequences listed hereinwhich may be removed or neutralised by the antiserum specified in thisWO 98/1078710152025CA 02265885 1999-03-08PCT/IB97/,0 108617patent.The present invention also relates to a method of assaying body fluidfrom an animal, comprising contacting said body fluid with at least oneantibody as described above.The present invention further relates to a method of screening avaccine, comprising contacting said vaccine with at least one antibody asdescribed above.Eeptide Seguence §ectionFirstly a series of documented and identified immunosuppressivesequences, encompassing both a known immunosuppressive peptide (CKSâ17) and viral coat protein HTLV-lll gp41 735-752 were selected and we bydeletion or chemical modification of the referred amino acids Table 1demonstrated that by compromising the charged amino acid dipole arrayswithin the hydrophobic segment of these peptides it was possible to neutralizethe immunosuppressive ability of these selected immunosuppressivesequences.Peptide synthesis and protein conjugation. The peptides wereassembled by solidâphase peptide synthesis on a Merrifield polystyrene resinas 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 acidside chains during synthesis and cleavage of the peptide from the support byanhydrous hydrogen ï¬uoride (HF) have been described previously (Kinnunen,P.KJ., Jackson, R.L., Smith, L.C., 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 amino acid analysis andthe presence of a single peak by HPLC. A tyrosine residue was added toeither the amino or the carboxy terminus for monitoring peptide purificationWO 98/1078710152025CA 02265885 1999-03-08PCT/IB97/0108618and radiodination. A cysteine residue was added to either terminus forcoupling via its free sulfhydryl to the carrier proteins keyhole limpethemocyanin (KLH) or bovine serum albumin (BSA) using the MBSheterobifunctional crosslinker.KLH- Keyhole Limpet HemocyaninBSA- Bovine Serum AlbuminInhibition of mitogen-induced blastogenesisTo assess the inhibitory effects of the peptides AA sequences outlinedin Table 1. Normal human blastogenic response to mitogens, PMN cells fromhealthy donors were cultured in the absence or presence of variousconcentrations of peptides or peptides conjugated to carrier proteins followedby mitogen stimulation. The results of the experiments are shown in Table 2.Preincubation of normal PMN with the immunosuppressive peptides chosenbefore signal sequence neutralization either conjugated to either KLH or BSAresulted in a preformed and dose - dependent suppression of PHA â inducedproliferation. Upon amino acid signal sequence as specified in Table 1chemical modification there was a significant reduction in the suppression ofPHA induced proliferation.The viability of peptide treated PMN as determined by trypan blueexclusion staining was comparable to that of untreated PMN, showing thatsuppression of proliferation did not result from peptideâinduced cytotoxicity.Inhibition of the normal two - wav mixed â lvmphocvte reactionThe immunosuppressive peptides which clearly suppressed theproliferation of normal PMN in a two-way mixed lymphocyte reaction (MLR)were not capable of demonstrating any form of suppression when the specificdipole signalling sequence as designated in Table 1 were chemically modifiedto 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 densityW0 98/10787101520CA 02265885 1999-03-08PCT/IB97l{0108619gradient centrifugation through Hisopaque-1077 (Sigma Chemical Co., St.Louis, MO). The in-vitro proliferation assays were performed by incubating105 cells/well in 96-well roundâbottom microtiter plates in the absence orpresence of various dilutions of peptides for 4 days in RPMI 1640 culturedmedium (Grand Island Biological Co.. Grand Island, NY) supplementedwith 10% fetal calf serum (FCS). On the fourth day of culture, the cellswere stimulated with phytohemagglutinin (PHA, Sigma) at a final dilution of0.1%, or Con A (Sigma), or pokeweed mitogen (PWM, Sigma) at finalconcentrations of 10 pg/ml. The cultures were allowed to incubate for anadditional 2 days at which time 1 pCi of [3H] thymidine (New EnglandNuclear Co., Boston, MA) was added to each well. After an additional 18hrin culture, the cells were harvested and processed for scintillation counting.For PHAâinduced proliferation of murine cells, normal 3- to 5-week-old BALB/C mice (Jackson Laboratories, Bar Harbor, ME) were sacrificedand their spleen cells were obtained through density gradientcentrifugation. The spleen cells were used at a density of 5x 104/well andthe assay was done as described above.Two-way mixed-/ymphocyte reaction. Peripheral mononuclear cellsfrom MHC-mismatched donors were obtained as described above. Cells(5x 104) from one individual were mixed with an equal number of cells fromanother individual in the absence of presence of peptides from Table 1 for5 days. The cultures were pulsed with [3H]âthymidine for the last 18 hr and harvested for scintillation counting.CA 02265885 1999-03-08W0 98/ 10787 PCT/IB97l,0l08620Table 1lmmunosuppressive Peptides Used1 HTLV - III B gp41 AA Sequence:5 TyrâG|u-Arg-Pro-Glu-Gly-Ile-GluâGlu-GIu-G|y-GIy-G|u-ArgâG|u-Arg-Glu-Arg-Ser-GlyâCys (SEQ. ID NO. 34)AA 735â7522 CKS-17 AA Sequence:Leu-GlnâAsn-ArgâArg-Gly-Leu-AspâLeu-Leu-PheâLeu-Lys-Giu-G|y-10 G|yâLeu (SEQ. ID NO. 35)CKS-17 (A)1(A) HTLV-III B gp41 modifiedThese peptides have their arginyl residues modified by the use of15 1,2 cycloheranedione as outlined in Mahley, R.W., J. of Biol. Chem. 1977Vol. 252 pgs. 7279-7287CA 02265885 1999-03-08wo 98/10787 PCT/[B97/D108621Table 2Suppression of Mitogen Induced Blastogenic ResponseTo Normal Human Mononuclear CellsPercentage Suppression of5 Blastogenic Response toPHA ConA PWMHTLV-HEB gp4âl - KLH 74 77 85AA 735-752Sug/ml10 HLTV-lllB gp41 - KLH(modified) 6 7 4Modified as perNeutralization of chargeDistribution on dipole15 CKS-17 64 80 765uMModified CKS-17Modification caused byChemical modification of20 The charge on dipole sequenceIlI ICA 02265885 1999-03-08wo 98/10787 PCTIIB97/0108622Table 3immunosuppressive Peptides SuppressionOf Mixed Lymphocyte ReactionThymidine Incorporation (cpm) with5 Medium HTLV-Ill gp41 Modified HTLVâ|ll gp41735-752 (5pg/ml) 735-752 5pg/ml(charged dipole neutralized)5224 :l: 256 2800 :t 120 (45%) 5236 i 211 (0%)5368 i 106 2789 i 163 (46%) 5334 i 107 (0%)10 Medium CKS-17 CKS-17 (Modified)(charged dipole neutralized)4738 :t 96 947 1 68 (80%) 4526 1 102 (0%)5372 3; 173 1074.4 1 03 (83%) 4834 3; 80 (19%)1520The only detectable changes in the physical and chemical propertiesof the modified HTLVâ||| gp41 and CKS-17 was increased electrophoreticmobility which reflected the neutralization of the positive charge on thegranido group of arginine.1(B) HTLV-Ill B gp41 Modification ReversedThis modified peptide is essentially restored to its originalimmunosuppressive capability when the modification to the arginyl residueis reversed by treatment with hydrosylamine.W0 98/107871015202530CA 02265885 1999-03-08PCT/IB97/(0108623The immunosuppressive peptides designed as per this patent maybe neutralized in their ability to effect immune function if the amino acidcharged dipole sequence is deleted or chemically modified so that thecharged chemical groups on the dipole amino acides, be they positive ornegative, are either both or individually left without an electrostatic chargecomponent. This has been demonstrated for this patent Tables 2/3 toeffectively remove any immunosuppressive characteristics and could veryeasily accomplish the same end for intact viruses or bacteria should theirgenetic codes be deleted for these specific amino acids or their outer coatsneutralized to these signal dipole sequences.Those of skill in the art would readily be able to determine where anion bridge pair exists in a particular sequence, e.g., an immunosuppressivesequence, and determine which ion bridge pairs are responsible for theimmunosuppressive activity, by routine experimentation in view of theinformation contained herein.The present invention further relates to pharmaceutical compositionsand methods of providing an immunosuppressive or immunoreguiatoryeffect in a patient. comprising administering to the patient animmunosuppressive or immunoreguiatory effective amount of apharmaceutical formulation comprising at least two Th2 cytokines, forexample, wherein the at least two Th2 cytokines include interleukin 10 andInterleukin 4.In relation to the administration of anti-serum to Interleukin-10 andalso the combination therapy of lnterleukinâ1O and Interleukin-4 the doseranging were as follows:Interleukin-10 alone - 2 mg per day over a period of 10 days by lV.Combination therapy - two trials.Trial 1 : 2 mg per day of antiâserum to IL-10 on each alternative day and 2mg 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 IL-10/IL-4 on days1,3,5,9,11 and 14. - This dose range would vary and the ratio of cytokinesW0 98/107871015202530I 1- 'CA 02265885 1999-03-08PCT/IB97/0108624administered depending on the disease condition.These agents as per this patent are administered in an amount,which provides circulating levels of about 1-150 pg/ml of each agent.The present invention further relates to pharmaceutical compositionsand methods of treatment of graft vs. host disease in a patient in need ofsuch treatment, comprising administering to the patient lnterleukin 10 andInterleukin 4.The present invention further relates to pharmaceutical compositionsand methods of providing an immunosuppressive or immunoregulatoryeffect in a patient, comprising administering to the patient Interleukin 10,lnterleukin 4 and at least one of antagonist of lnterleukin 10 and antagonistof lnterleukin 4.The present invention further relates to pharmaceutical compositionsand methods of providing an immunosuppressive or immunoregulatoryeffect in a patient, comprising administering to said patient Interleukin 10and Interleukin 4 and at least one of agonist of lnterleukin 10 and agonistof Interleukin 4.The present invention further relates to pharmaceutical compositionsand methods of providing an immunosuppressive or immunoregulatoryeffect in a patient, comprising administering to said patient anti-serum toInterleukin 10 and antiâserum to Interleukin 4The present invention further relates to pharmaceutical compositionsand methods of providing an immunosuppressive or immunoregulatoryeffect in a patient, comprising administering to said patient antiâserum tolnterleukin 10 and at least one of antagonist of lnterleukin 4 and agonist ofInterleukin 4.The present invention further relates to pharmaceutical compositionsand methods of providing an immunosuppressive or immunoregulatoryeffect in a patient, comprising administering to said patient antiâserum toInterleukin 4 and at least one of antagonist of Interleukin 10 and agonist oflnterleukin 10.When rabbit antibodies to human Interleukin 10 was administered toWO 98/107871015202530CA 02265885 1999-03-08PCT/IB97[0108625AIDS patients for a one week period by an IV route their cytotoxic CD8cells and natural killer cell numbers increased within 24 hours and thisresulted in a simultaneous increase in viral load levels as measured byPCR (RNA). However, quantitative culture techniques showed a decline tozero levels. The reason for the above would appear to be that theenhanced CD8 cytotoxic and natural killer cell attack on HIV infected cellsincreased the amount of HIV viral RNA and viral peptide present in theblood as a result of the killing of infected cells. The fact that quantativeculture decreased to zero means that the viral particles present were notviable or infectious viruses. However, no improvement in percentage orabsolute number of CD4 (T4) cells was recorded and the Th1 immunefunction did not show improvement. After 3 months from the termination ofthe above therapy with antibodies to interleukin 10, HIV viral load returnedto its pre-treatment level and his CD4 (T4) cell count decreased by 50%.This demonstrated that the anti-serum to Interleukin 10 had been capableof activating CD8 cytotoxic and natural killer cells and causing a dramaticreduction in viral load. However, the CD4 (T4) immune system cells hadnot improved so that when following therapy his CD8 and natural killer cellslost their function, dormant virus was awakened by the Interleukin 10antibody therapy and new viral replication could not be kept in checkwithout a complement of active CD4 cells.This same patient was then administered a combination therapywhich involved rabbit lgG antibodies generated to both human interleukin10 and human Interleukin 4. It had been determined from inâvitro studieswith the patients blood that native Interleukin 4 levels were elevated andthis was preventing the recovery of the CD4 (T4) cell component of hisimmune system.The patient was administered the two antibodies to Interleukin 10and Interleukin 4 for 2 weeks. Following this the patientâs HIV viral loadagain increased when monitored by PCR RNA and decreased to zero after4 weeks. However, on this occasion his CD4 (T4) cell count both in 0absolute number and percentage increase from 9% to 15% within 4 days ofW0 98/107871015202530I I. ICA 02265885 1999-03-08PCT/IB97/0108626therapy commencing. After the 3 month period out from the termination ofthe combination therapy, CD4 (T4) cell count continued to remain elevatedand HIV viral load was still nonâdetectabIe.Suitable dosages in accordance with the present invention dependon many factors, e.g. the patient's weight, the mode of administration, thefrequency of administration, the type of affliction being treated orprevented, whether the infection presently exists, and if so, to what degree.Suitable dosages for given situations can readily be determined by thoseskilled in the art without undue experimentation.The total treatment time according to the present invention will varyfrom patient to patient based on sound medical judgement and factorsparticular to the patient being treated, such as, for example, the age andphysical condition of the patient. Those skilled in the art can easilydetermine suitable total treatment time on a patient-by-patient basis.The following is a description of a suitable protocol in accordancewith the present invention. However, the present invention is not limited bythe following Example, and variations will be apparent to those skilled inthe art without departing from the spirit of the present invention.PROTOCOL FOR ADMINISTRATION OF AN IMMUNOGLOBULIN lgGANTIBODY AGAINST A COMBINATION OF TH2 CYTOKINES.1.0 INTRODUCTIONThe Human Immunodeficiency Virus Type 1 (HIV-1) is the etiologicalagent of Acquired Immune Deficiency Syndrome(AIDS) (Barre-Sinoussl, F.,Chermann, J.C., et al, Isolation of a T-lymphotrophic Retrovirus From aPatient at Risk for Acquired Immunodeficiency Syndrome (AIDS), Science(1984) 224, 500-503; Gallo, R.C., Salahuddin, S.Z., et al, FrequentDetection and Isolation of Cytopathic Retroviruses (HTLVâIII) From Patientswith AIDS and at Risk for AIDS. SAGE (1984) 224, 500-503). AIDS ischaracterised as a profound breakdown in host's cellular and humoralimmunity and increased susceptibility to a wide range of opportunisticinfections. One of the consequences of this immune dysfunction is amarked depletion in absolute CD4+ cells in HIV-infected individuals,.m.w._i...._s.. . _ » I 9 »~ ~ - - iW0 98/ 107871015202530CA 02265885 1999-03-08PCT/IB97/0108627Studies over the past years have demonstrated that the destruction of theimmune system by HIV-1 is a chronic process, starting at the moment ofinfection. The results indicate that strategies for effective therapeuticintervention using antibodies to these specific mimic CD3/T CR peptideinteraction dipole sequences should start early in infection to preventirreversible damage occurring to the immune system, since it has beendemonstrated in HIV that an early loss of CD3/TCR mediated T cellactivation is evident. This imbalance in turn effects monocyte and B cellfunction.Recent studies have established the functional binding andimmunosuppressive similarities between specific amino acid chargedsequences present on the alfa-fetoprotein molecule and on and Th2cytokine peptides and certain HIV envelope amino acid sequences.Laboratory data demonstrates that immunoglobulin G (lgG) or lgM to thesaid specific amino acid sequence inhibits syncytial formation and preventsHIV-1 laboratory strains MN, RF, and |llB replication in C8166-45 cells(lymphocyte cell-line) in-vitro. In addition, lgG to the said amino acidsequence inhibits replication of HIV-1BAL in fresh macrophage culture in adoseâdependent manner.1.2 RATIONALEThe basic rationale for using this therapy is the understanding thatthere exists a functional binding and immunosuppression similaritybetween certain peptides containing specific ion pair arrangements ofamino acids enclosed within two hydrophobic amino acids present withinthe AFP molecule Interleukin 10 and specific external HIV glycoproteinstogether with other specific viral coat peptides and glycopeptides. Thisdiscovery shows that as the body defends itself against the HIV virus byproducing antibodies to specific viral coat proteins, these antibodies, whilerestricting in a normal antibody fashion the HIV virus, are themselvestogether with certain viral glycopeptides sequences identified herein andproduced by the infecting virus are inherently immunosuppressive in thatthey perform a similar task as AFP or Th2 cytokine peptides in that theyWO 98/107871015202530CA 02265885 1999-03-08PCT/IB97/0108628selectively down regulate the T cell dependent immune system in favour ofa humoural, B cell response which although it produces neutralisingantibodies to the infectious agent (e.g. malaria, HIV, Tuberculoses,Leishmania) also allows the infective agent to persist and reproduce withinthe host cells and to ultimately undermine its immune status.The major histocompatibility complex (MHC) is a collection of 40-50genes arrayed within a long continuous stretch of DNA on chromosome 6in humans. The MHC is referred to as the HLA complex in humans. TheMHC genes are organised into regions encoding three classes ofmolecules: Class l, Class ll and Class III. The Class I genes encodeglycoproteins expressed on the surface of nearly all nucleated cells, wherethey present peptide antigens of altered se|fâcells necessary for theactivation of TC cells. The Class ll genes encode glycoproteins expressedprimarily on antigenâpresenting cells (macrophages, dendritic cells, and Bcells), where they present processed antigenic peptides to T cells. TheClass lll genes encode somewhat different products that are alsoassociated with the immune process. These include a number of solubleserum proteins (including components of the complement system), steroid21-hydroxylase enzymes, and tumour necrosis factors.The administration of antibodies poly or mono clonal to thesespecific CD3lTCR mimic molecules will cause an immediateantibody-dependent cell-mediated cytotoxicity (ADCC) stimulated reductionin Viral Load as measured by the culturing of peripheral blood mononuclearcells and following the removal of the mimic Th2 cytokine/AFP like viralpeptide molecules and in the patient's blood we should see a re-awakeningof a CD8 cytotoxic T cell reaction directed against HIV infected cells andthis will coincide with a second HlV Viral Load reduction. Also in patientswho have received this antibody therapy we should see the generation ofInterleukin 2 and gamma interferon and a dramatic increase in T4 cellnumber, together with a decrease in PCR and Quantitative Viral culturelevels.A number of white blood cells have cytotoxic potential and express,V_,,M,_,_,,_? 1- 4 ...,.,...s, ,. .._ . . , , V,WO 98/107871015202530CA 02265885 1999-03-08PCT/IB97/0108629membrane receptors for the Fc region of the antibody lgG molecule. Whenthis antibody is specifically bound to a target cell which occurs when thesespecific poly or monoclonal antibodies to these sequences present on AFP,and Th2 cytokines bind to HIV infected cells or free viral peptides causingimmune Th2 shift. These cytotoxic Fc receptor-bearing cells can bind tothe antibodiesâ Fc region, and thus to the infected HIV cells, andsubsequently cause lysis of these cells. Although the cytotoxic cellsinvolved are non-specific, the specificity of the antibody to a commonimmunosuppressive mimic peptide present on Th2 cytokines peptides/AFPpresent on a large number of infecting organisms directs them to HIVinfected target cells. This type of cytotoxicity is referred to asantibody-dependent cellâmediated cytotoxicity (ADCC). Thevariety of cells that have been shown to exhibit ADCC include NK cells,macrophages, monocytes, neutrophils, and eosinophils.2.0 OBJECTIVES2.â! To provide for an administration of monoclonal antibodies to thesespecified sequences present on AFP and Th2 cytokines and infectiousorganisms to HlV+ patients.2.2administration of these mono or polyclonal antibodies.23in those study participants who have Kaposi's Sarcoma.2.4prior to beginning, during and post this type of antibody infusion therapy.2.5study participants.2.6persons with HIV disease.3.0 CLINICAL ENDPOINTSTo confirm that these antibodies either poly or monoclonal are ofTo monitor immune system functioning before and after theTo monitor the effect of these type of antibody on cutanous lesionsTo monitor viral load in patient's peripheral blood mononuclear cellsTo monitor the course or incidence of opportunistic infections in theTo determine the safety of these type of antibody administration intherapeutic benefit for widespread use in HIV disease based on thefollowing criteria.-W0 98/1078710I D ICA 02265885 1999-03-08PCT/[B97/01086303.1 Changes in T-cell phenotyping and cytokine profile.3.2characteristics of cutaneous Kaposi's sarcoma lesions.3.3culture quantitation in peripheral - blood mononuclear cells.3.43.5 Changes in Beta-2-microglobulin level3.6.infections.Changes in the size, colour intensity, and palpable skinChanges in HIV load burden as indicated by endpoint â dilutionChanges in p24 antigen level.Appearance of new or improvement of active opportunistic3.7 Changes in system functioning (liver, kidney, haematology).
Claims (126)
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, 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:
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.
(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:
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 11 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 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-B-E;
D-A-B; and A-B-E;
wherein:
D is an amino acid sub-sequence comprising at least one amino acid residue;
E is an amino acid sub-sequence comprising at least one amino acid residue;
A is Lys, Arg or His;
B is Glu or Asp;
and wherein said at least one compound comprises at least 4 amino acid residues.
(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-B-E;
D-A-B; and A-B-E;
wherein:
D is an amino acid sub-sequence comprising at least one amino acid residue;
E is an amino acid sub-sequence comprising at least one amino acid residue;
A is Lys, Arg or His;
B is Glu or Asp;
and wherein said at least one compound comprises at least 4 amino acid residues.
6. A method as recited in claim 5, wherein said at least one compound consists of 16 or fewer amino acid residues.
7. A method as recited in claim 5, wherein said at least one compound consists of 8 or fewer amino 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) myatgic 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 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.
(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) myatgic 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 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 amino acid residues.
10. A method as recited in claim 8, wherein said at least one compound consists of 8 or fewer amino acid residues.
11. A method as recited in claim 8, wherein said at least one compound consists of 4 or fewer amino 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 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 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:
D-A-B-E;
D-A-B; and A-B-E;
wherein:
D is an amino acid sub-sequence comprising at least one amino acid residue;
E is an amino acid sub-sequence comprising at least one amino acid residue;
A is Lys, Arg or His;
B is Glu or Asp;
and wherein said at least one compound comprises at least 4 amino acid residues.
(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 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:
D-A-B-E;
D-A-B; and A-B-E;
wherein:
D is an amino acid sub-sequence comprising at least one amino acid residue;
E is an amino acid sub-sequence comprising at least one amino acid residue;
A is Lys, Arg or His;
B is Glu or Asp;
and wherein said at least one compound comprises at least 4 amino acid residues.
13. A method as recited in claim 12, wherein said at least one compound consists of 16 or fewer amino acid residues.
14. A method as recited in claim 12, wherein said at least one compound consists of 8 or fewer amino 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 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.
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.
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 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.
(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 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.
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 amino acid sub-sequence comprising at least one amino acid residue;
E is an amino acid sub-sequence comprising at least one amino acid residue;
A is Lys, Arg or His;
B is Glu or Asp;
and wherein said at least one compound comprises at least 4 amino acid residues.
(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 amino acid sub-sequence comprising at least one amino acid residue;
E is an amino acid sub-sequence comprising at least one amino acid residue;
A is Lys, Arg or His;
B is Glu or Asp;
and wherein said at least one compound comprises at least 4 amino acid residues.
21. A method as recited in claim 20, wherein said at least one compound consists of 16 or fewer amino acid residues.
22. A method as recited in claim 20, wherein said at least one compound consists of 8 or fewer amino 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 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-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, lle, 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 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.
(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:
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, lle, 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 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.
24. A method as recited in claim 23, wherein said at least one compound consists of 16 or fewer amino acid residues.
25. A method as recited in claim 23, wherein said at least one compound consists of 8 or fewer amino acid residues.
26. A method as recited in claim 23, wherein said at least one compound consists of 4 or fewer amino 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, lle, Leu, Met, Phe, Trp, Val and Tyr;
D is an amino acid sub-sequence comprising at least one amino acid residue;
E is an amino acid sub-sequence comprising at least one amino acid residue;
A is Lys, Arg or His;
B is Glu or Asp;
and wherein said at least one compound comprises at least 4 amino acid residues.
(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, lle, Leu, Met, Phe, Trp, Val and Tyr;
D is an amino acid sub-sequence comprising at least one amino acid residue;
E is an amino acid sub-sequence comprising at least one amino acid residue;
A is Lys, Arg or His;
B is Glu or Asp;
and wherein said at least one compound comprises at least 4 amino acid residues.
28. A method as recited in claim 27, wherein said at least one compound consists of 16 or fewer amino acid residues.
29. A method as recited in claim 27, wherein said at least one compound consists of 8 or fewer amino 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 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 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-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, lle, 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 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.
(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 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-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, lle, 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 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.
31. A method as recited in claim 30, wherein said at least one compound consists of 16 or fewer amino acid residues.
32. A method as recited in claim 30, wherein said at least one compound consists of 8 or fewer amino acid residues.
33. A method as recited in claim 30, wherein said at least one compound consists of 4 or fewer amino 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 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 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:
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, lle, Leu, Met, Phe, Trp, Val and Tyr;
D is an amino acid sub-sequence comprising at least one amino acid residue;
E is an amino acid sub-sequence comprising at least one amino acid residue;
A is Lys, Arg or His;
B is Glu or Asp.
(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 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:
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, lle, Leu, Met, Phe, Trp, Val and Tyr;
D is an amino acid sub-sequence comprising at least one amino acid residue;
E is an amino acid sub-sequence comprising at least one amino acid residue;
A is Lys, Arg or His;
B is Glu or Asp.
35. A method as recited in claim 34, wherein said at least one compound consists of 16 or fewer amino acid residues.
36. A method as recited in claim 34, wherein said at least one compound consists of 8 or fewer amino 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, lle, 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 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.
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, lle, 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 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.
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:
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.
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 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.
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 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.
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 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.
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.
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 Interleukin 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 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-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 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.
(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:
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 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.
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 amino acid residues;
D is an amino acid sub-sequence comprising at least one amino acid residue;
E is an amino acid sub-sequence comprising at least one amino acid residue;
A is Lys, Arg or His;
B is Glu or Asp;
and wherein said at least one compound comprises at least 4 amino acid residues.
(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 amino acid residues;
D is an amino acid sub-sequence comprising at least one amino acid residue;
E is an amino acid sub-sequence comprising at least one amino acid residue;
A is Lys, Arg or His;
B is Glu or Asp;
and wherein said at least one compound comprises at least 4 amino 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 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 pharmaceuticai 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-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 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.
(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 pharmaceuticai 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-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 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.
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 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-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 least one amino acid residue, E is an amino acid sub-sequence comprising at least one amino acid residue;
A is Lys, Arg or His;
B is Glu or Asp;
and wherein said at least one compound comprises at least 4 amino acid residues.
(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-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 least one amino acid residue, E is an amino acid sub-sequence comprising at least one amino acid residue;
A is Lys, Arg or His;
B is Glu or Asp;
and wherein said at least one compound comprises at least 4 amino 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 encephatomyelitis (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-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 amino acid residues;
H is selected from the group consisting of Ala, lle, 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 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.
(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 encephatomyelitis (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-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 amino acid residues;
H is selected from the group consisting of Ala, lle, 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 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.
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 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-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 amino acid residues;
H is selected from the group consisting of Ala, lle, Leu, Met, Phe, Trp, Val and Tyr;
D is an amino acid sub-sequence comprising at least one amino acid residue;
E is an amino acid sub-sequence comprising at least one amino acid residue;
A is Lys, Arg or His;
B is Glu or Asp;
and wherein said at least one compound comprises at least 4 amino acid residues.
(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-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 amino acid residues;
H is selected from the group consisting of Ala, lle, Leu, Met, Phe, Trp, Val and Tyr;
D is an amino acid sub-sequence comprising at least one amino acid residue;
E is an amino acid sub-sequence comprising at least one amino acid residue;
A is Lys, Arg or His;
B is Glu or Asp;
and wherein said at least one compound comprises at least 4 amino 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 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;
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 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;
E 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.
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 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;
E 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.
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.
(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 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;
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, lle, 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 amino acid residue;
D is an amino acid sub-sequence comprising at least one amino acid residue;
E 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.
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, lle, 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 amino acid residue;
D is an amino acid sub-sequence comprising at least one amino acid residue;
E 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.
58. A method of vaccinating against at least one immunosuppressive amino 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 gp21E 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 Vivax-1 the immunosuppressive effect of which is caused by the presence in said at least one sequence of one or more positive/negative group, defined as a two-amino acid sub-sequence where a positive amino acid selected from Lys, Arg and His is adiacent to a negative amino 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 least one modified sequence, said modified sequence comprising a compound which is identical to said at least one immunosuppressive sequence, except that at least one amino acid residue of the two amino acid residues in said one or more positive/negative group is replaced with:
an antimetabolite of said at least one amino acid residue;
the D-isomer of said at least one amino acid residue; or an analog of said at least one amino acid residue.
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 gp21E 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 Vivax-1 the immunosuppressive effect of which is caused by the presence in said at least one sequence of one or more positive/negative group, defined as a two-amino acid sub-sequence where a positive amino acid selected from Lys, Arg and His is adiacent to a negative amino 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 least one modified sequence, said modified sequence comprising a compound which is identical to said at least one immunosuppressive sequence, except that at least one amino acid residue of the two amino acid residues in said one or more positive/negative group is replaced with:
an antimetabolite of said at least one amino acid residue;
the D-isomer of said at least one amino acid residue; or an analog of said at least one amino acid residue.
59. A method of vaccinating against at least one immunosuppressive amino 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 amino 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 least 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 least one compound which is identical to said at least one immunosuppressive sequence, except that at least one amino acid residue of the two amino acid residues in said one or more instance of an M group is replaced with an antimetabolite of said at least one amino acid residue, the D-isomer of said at least one amino acid residue, or an analog of said at least one amino acid residue.
R-[M-R]n;
[M-S]n; and [R-M]n;
wherein:
n is a positive integer;
each R is, independently an amino 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 least 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 least one compound which is identical to said at least one immunosuppressive sequence, except that at least one amino acid residue of the two amino acid residues in said one or more instance of an M group is replaced with an antimetabolite of said at least one amino acid residue, the D-isomer of said at least one amino acid residue, or an analog of said at least 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 amino 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-His.
(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 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.
61. 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 andlor 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 more amino acids in an amino acid sub-sequence selected from the group consisting of:
H-K;
K-H; and H-K-H;
wherein each H is independently selected from the group consisting of Ala, lle, 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-His and Asp-His.
(a) immunodeficiency resultant from a viral infection;
(b) immunodeficiency resultant from one or more of the following, bacterial, mycoplasmic, fungal andlor 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 more amino acids in an amino acid sub-sequence selected from the group consisting of:
H-K;
K-H; and H-K-H;
wherein each H is independently selected from the group consisting of Ala, lle, 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-His and Asp-His.
62. 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.
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.
63. Polyclonal or monoclonal antibody as recited in claim 62, wherein said at least one compound consists of 16 or fewer amino acid residues.
64. Polyclonal or monoclonal antibody as recited in claim 62, wherein said at least one compound consists of 8 or fewer amino acid residues.
65. Polyclonal or monoclonal antibody as recited in claim 62, wherein said at least one compound consists of 4 or fewer amino acid residues.
66. 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 amino acid sub-sequence comprising at least one amino acid residue;
E is an amino acid sub-sequence comprising at least one amino acid residue;
A is Lys, Arg or His;
B is Glu or Asp;
and wherein said at least one compound comprises at least 4 amino acid residues.
D-A-B-E;
D-A-B; and A-B-E;
wherein:
D is an amino acid sub-sequence comprising at least one amino acid residue;
E is an amino acid sub-sequence comprising at least one amino acid residue;
A is Lys, Arg or His;
B is Glu or Asp;
and wherein said at least one compound comprises at least 4 amino acid residues.
67. Polyclonal or monoclonal antibody as recited in claim 66, wherein said at least one compound consists of 16 or fewer amino acid residues.
68. Polyclonal or monoclonal antibody as recited in claim 66, wherein said at least one compound consists of 8 or fewer amino 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.
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 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;
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 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;
E 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.
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 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;
E 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.
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 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 gp21E Gln-Asn-Arg-Arg-Gly-Leu-Glu-Leu-Leu-Phe-Trp-Glu-Gln-Gly-Gly-Leu-Cys-Lys-Ala-Ile-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-Ile-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 wherein at least one sub-sequence of two amino acid residues where a positive amino acid selected from Lys, Arg and His is adjacent to a negative amino acid selected from Glu and Asp, is replaced with at least one modified sequence, said modified sequence comprising a compound which is identical to said at least one sub-sequence, except that at least one amino acid residue of the two amino acid residues in said one or more positive/negative group is replaced with:
an antimetabolite of said at least one amino acid residue;
the D-isomer of said at least one amino acid residue; or an analog of said at least one amino acid residue.
compounds corresponding to:
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 gp21E Gln-Asn-Arg-Arg-Gly-Leu-Glu-Leu-Leu-Phe-Trp-Glu-Gln-Gly-Gly-Leu-Cys-Lys-Ala-Ile-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-Ile-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 wherein at least one sub-sequence of two amino acid residues where a positive amino acid selected from Lys, Arg and His is adjacent to a negative amino acid selected from Glu and Asp, is replaced with at least one modified sequence, said modified sequence comprising a compound which is identical to said at least one sub-sequence, except that at least one amino acid residue of the two amino acid residues in said one or more positive/negative group is replaced with:
an antimetabolite of said at least one amino acid residue;
the D-isomer of said at least one amino acid residue; or an analog of said at least one amino 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, 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 M between this said M, 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.
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 M between this said M, 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 least two Th2 cytokines.
74. A pharmaceutical composition as recited in claim 73, wherein said at least two Th2 cytokines include Interleukin 10 and Interleukin 4.
75. A pharmaceutical composition comprising Interleukin 10, Interleukin 4 and at least one of antagonist of Interleukin 10 and antagonist of Interleukin 4.
76. A pharmaceutical composition comprising Interleukin 10, Interleukin 4 and at least 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 least one of antagonist of Interleukin 4 and agonist of Interleukin 4.
79. A pharmaceutical composition comprising anti-serum to Interleukin 4 and at least one of antagonist of Interleukin 10 and agonist of Interleukin 10.
80. 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 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.
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 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 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 amino acid residues;
D is an amino acid sub-sequence comprising at least one amino acid residue;
E is an amino acid sub-sequence comprising at least one amino acid residue;
A is Lys, Arg or His;
B is Glu or Asp;
and wherein said at least one compound comprises at least 4 amino acid residues.
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 least one amino acid residue;
E is an amino acid sub-sequence comprising at least one amino acid residue;
A is Lys, Arg or His;
B is Glu or Asp;
and wherein said at least one compound comprises at least 4 amino acid residues.
82. 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 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.
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 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.
83. 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 amino acid residues;
D is an amino acid sub-sequence comprising at least one amino acid residue;
E is an amino acid sub-sequence comprising at least one amino acid residue;
A is Lys, Arg or His;
B is Glu or Asp;
and wherein said at least one compound comprises at least 4 amino acid residues.
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 least one amino acid residue;
E is an amino acid sub-sequence comprising at least one amino acid residue;
A is Lys, Arg or His;
B is Glu or Asp;
and wherein said at least one compound comprises at least 4 amino acid residues.
84. 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-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 amino acid residues;
H is selected from the group consisting of Ala, Ile, 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 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.
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 amino acid residues;
H is selected from the group consisting of Ala, Ile, 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 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.
85. 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-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 amino acid residues;
H is selected from the group consisting of Ala, Ile, Leu, Met, Phe, Trp, Val and Tyr;
D is an amino acid sub-sequence comprising at least one amino acid residue;
E is an amino acid sub-sequence comprising at least one amino acid residue;
A is Lys, Arg or His;
B is Glu or Asp;
and wherein said at least one compound comprises at least 4 amino acid residues.
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 amino acid residues;
H is selected from the group consisting of Ala, Ile, Leu, Met, Phe, Trp, Val and Tyr;
D is an amino acid sub-sequence comprising at least one amino acid residue;
E is an amino acid sub-sequence comprising at least one amino acid residue;
A is Lys, Arg or His;
B is Glu or Asp;
and wherein said at least one compound comprises at least 4 amino acid residues.
86. A method of assaying body fluid from an animal, comprising contacting said body fluid with at least one antibody as recited in claim 62 or claim 66.
87. A method of screening a vaccine, comprising contacting said vaccine with at least 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; Ile-His-Asp; Ile-His-Glu; Ile-Lys-Asp; Ile-Lys-Glu; Ile-Arg-Asp;
Ile-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; Ile-Asp-His; Ile-Glu-His; Ile-Asp-Lys; Ile-Glu-Lys;
Ile-Asp-Arg; Ile-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.
(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; Ile-His-Asp; Ile-His-Glu; Ile-Lys-Asp; Ile-Lys-Glu; Ile-Arg-Asp;
Ile-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; Ile-Asp-His; Ile-Glu-His; Ile-Asp-Lys; Ile-Glu-Lys;
Ile-Asp-Arg; Ile-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 amino-acid charged ion bridge pairs attached to a hydrophobic amino acid or acids as outlined herein table
(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 amino-acid charged ion bridge pairs attached to a hydrophobic amino 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 amino 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.
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 amino 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.
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-Gln (SEQ ID NO. 8) which encloses two ion bridge pairs within both polar and non-polar amino 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-Ile-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-Ile (SEQ ID NO. 13) Leu-Glu-Lys-Ile (SEQ ID NO. 14) Ser-Glu-Arg-Leu (SEQ ID NO. 15) Gly-Glu-Lys-Ile (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) Ile-Glu-Lys-Thr (SEQ ID NO. 32) and Asn-Glu-Lys-Phe (SEQ ID NO. 33).
(a) Pro-Lys-Glu-Ile-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-Ile (SEQ ID NO. 13) Leu-Glu-Lys-Ile (SEQ ID NO. 14) Ser-Glu-Arg-Leu (SEQ ID NO. 15) Gly-Glu-Lys-Ile (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) Ile-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-fetoprotein (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 least 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 least 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 least 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 Interleukin-4 receptor, Interleukin-6 receptor and/or Interleukin-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/vacterial 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 amino acid sequence of greater than two amino 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 amino 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 amino acid sequence of greater than two amino 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 amino 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 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 negatively and positively charged R groups of IL-10 is a D
amino acid.
amino 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 amino acid sequence of greater than two amino 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 amino 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 amino acid sequence of greater than two amino 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 amino 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 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 non-polar and polar uncharged R groups of IL-10 is a D amino 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 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 negatively charged, non-polar and polar uncharged R groups of IL-10 is a D amino acid.
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 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, 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.
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US2518096P | 1996-09-11 | 1996-09-11 | |
US60/025,180 | 1996-09-11 | ||
PCT/IB1997/001086 WO1998010787A2 (en) | 1996-09-11 | 1997-09-10 | Pharmaceutical compositions for the treatment of immune disorders |
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CA002265885A Abandoned CA2265885A1 (en) | 1996-09-11 | 1997-09-10 | Pharmaceutical compositions for the treatment of immune disorders |
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JP (1) | JP2001503613A (en) |
CN (1) | CN1230195A (en) |
AU (2) | AU6887096A (en) |
CA (1) | CA2265885A1 (en) |
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NZ (1) | NZ335039A (en) |
SE (1) | SE9900812L (en) |
WO (2) | WO1998010792A1 (en) |
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WO2000009150A2 (en) * | 1998-08-17 | 2000-02-24 | Prendergast Patrick T | Cytokine and cytokine receptor, agonist, antagonist and/or antibody combination for therapeutic use |
AU1579700A (en) * | 1998-12-15 | 2000-07-03 | Hollis-Eden Pharmaceuticals | Cytokine combination therapy |
AU4545301A (en) * | 2000-03-14 | 2001-09-24 | Nat Jewish Med & Res Center | Method and composition for treating airway hyperresponsiveness |
FI118263B (en) | 2002-10-09 | 2007-09-14 | Timo Kalevi Korpela | Peptides that regulate caspase activity |
JP2008509226A (en) | 2004-05-24 | 2008-03-27 | ジェンボールト コーポレイション | Stable protein storage and stable nucleic acid storage in recoverable format |
EA008925B1 (en) * | 2004-12-14 | 2007-08-31 | Товарищество С Ограниченной Ответственностью "Реал Мед Компани" | Method of protection immune state in an organism suffering from diabetes mellitus |
EP1866328B1 (en) * | 2005-03-22 | 2011-01-12 | Rohto Pharmaceutical Co., Ltd. | Peptides which increase collagen or hyaluronic acid production |
US7553932B1 (en) | 2005-04-25 | 2009-06-30 | La Jolla Institute For Allergy And Immunology | Methods of treating viral infection with IL-10 receptor antagonists |
US8932829B2 (en) | 2005-07-07 | 2015-01-13 | Elena Dudich | Recombinant alpha-fetoprotein and compositions thereof |
US8283165B2 (en) | 2008-09-12 | 2012-10-09 | Genvault Corporation | Matrices and media for storage and stabilization of biomolecules |
WO2014174517A1 (en) * | 2013-04-25 | 2014-10-30 | Carmel-Haifa University Economic Corp. | Synthetic anti-inflammatory peptides and use thereof |
CN103275222B (en) * | 2013-05-15 | 2014-04-16 | 中山康方生物医药有限公司 | Monoclonal antibody for blocking 12p40 function of interleukin as well as coding gene and application thereof |
CN114163493B (en) * | 2021-11-18 | 2023-09-15 | 浙大宁波理工学院 | Polypeptide capable of serving as type 5 phosphodiesterase inhibitor and application thereof |
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MX7528E (en) * | 1981-01-09 | 1989-08-02 | New York Blood Center Inc | PROCEDURE FOR THE PREPARATION OF A SYNTHETIC VACCINE |
US4822606A (en) * | 1986-04-07 | 1989-04-18 | Duke University | Immunosuppressive synthetic peptides and analogs thereof based on retroviral envelope sequences |
EP0300031A4 (en) * | 1987-01-28 | 1990-05-14 | Ortho Pharma Corp | Immunosuppressive peptides and methods of use. |
JPH01502751A (en) * | 1987-03-23 | 1989-09-21 | ハイヴァー リミテッド | New vaccines |
SE8705197D0 (en) * | 1987-12-30 | 1987-12-30 | Jonas Blomberg | NEW PEPTIDES, TWO DIAGNOSTIC METHODS USING THE PEPTIDES AND A MEDICATION BASED ON THE PEPTIDES |
IL97629A0 (en) * | 1990-03-26 | 1992-06-21 | Schering Corp | Bcrf1 antagonists for treating epstein-barr virus infections |
WO1993011157A1 (en) * | 1991-11-27 | 1993-06-10 | The Council Of The Queensland Institute Of Medical Research | MALARIAL VACCINE AND PEPTIDES COMPRISING HUMAN T-CELL EPITOPE OF CIRCUMSPOROZOITE PROTEIN OF $i(P.VIVAX) |
ZA931489B (en) * | 1992-03-04 | 1993-10-28 | Schering Corp | Use of interleuken-10 to suppress graft-vs-host disease |
WO1993018783A1 (en) * | 1992-03-20 | 1993-09-30 | Schering Corporation | Use of interleukin-10 to induce the production of interleukin-1 receptor antagonist |
AU4856793A (en) * | 1992-09-18 | 1994-04-12 | Government Of The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services, The | Restoration of immunocompetency to t helper cells in hiv infected patients |
EP0715633A4 (en) * | 1993-07-28 | 1997-11-19 | Medvet Science Pty Ltd | Haemopoietic growth factor antagonists |
ES2236703T3 (en) * | 1994-01-14 | 2005-07-16 | Matthias Dr Med Rath | USE OF METHODS TO IDENTIFY HYDROPHYL SIGNAL OLIGOPEPTIDES. |
WO1997026278A1 (en) * | 1996-01-18 | 1997-07-24 | Steeno Research Group A/S | Synthetic il-10 analogues |
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CN1230195A (en) | 1999-09-29 |
WO1998010792A1 (en) | 1998-03-19 |
AU4132097A (en) | 1998-04-02 |
EP0929568A2 (en) | 1999-07-21 |
SE9900812D0 (en) | 1999-03-08 |
NZ335039A (en) | 2001-04-27 |
SE9900812L (en) | 1999-03-08 |
AU6887096A (en) | 1998-04-02 |
IL128806A0 (en) | 2000-01-31 |
JP2001503613A (en) | 2001-03-21 |
WO1998010787A2 (en) | 1998-03-19 |
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