NZ335039A - Enhancing immune response by administering antibody raised to amino acid sequences with specific ion bridge pair arrays - Google Patents

Enhancing immune response by administering antibody raised to amino acid sequences with specific ion bridge pair arrays

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Publication number
NZ335039A
NZ335039A NZ335039A NZ33503997A NZ335039A NZ 335039 A NZ335039 A NZ 335039A NZ 335039 A NZ335039 A NZ 335039A NZ 33503997 A NZ33503997 A NZ 33503997A NZ 335039 A NZ335039 A NZ 335039A
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New Zealand
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amino acid
glu
arg
asp
sequence
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NZ335039A
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Patrick Thomas Prendergast
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Patrick Thomas Prendergast
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Publication of NZ335039A publication Critical patent/NZ335039A/en

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    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
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    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56983—Viruses
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Abstract

Antibodies generated to the compounds represented by the formula below may be used in pharmaceuticals to enhance immune responses in patients suffering from immunodeficiency resultant from a viral infection; immunodeficiency resultant from bacterial, mycoplasmic, fungal and/or parasitic infections; immunodeficiency resultant from the growth of neoplastic tissue; immunodeficiency resultant from any cytokine or hormone imbalance or imbalance of any natural product within the patient; myalgic encephalomyelitis (ME); post inoculation or viral infection fatigue syndrome; tuberculosis infection; and malarial infection. 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 A-B-E In the compounds above; 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; and Z is a carrier compound residue. Other embodiments of the compounds include a sub-sequence consisting of one or two amino acid residues within the A-B sub-sequence, or a hydrophobic amino acid on one side of the A-B subsequence.

Description

WO 98/10787 ! PCT/IB97/01086 IMMUNE DIRECTION THERAPY It is identified in this patent that a very specific amino acid sequence which exhibits specific Ion bridge pair arrays, especially if enclosed on at least one side by a non-polar hydrophobic transmembrane segment of at least one 5 amino acid, can, if presented with a carrier to a cell membrane, induce endocytosis and cause activation of specific intracellular and extracellular events which would normally only result from the interaction of an Antigen MHC-II complex with both the T cell receptor (TCR) and the CD3 membrane complexes. These specific amino acid Ion bridge pair sequences are only 10 present within the cell membrane during proper functioning of the immune system and allow activating T cell clone expansion following antigen presentation. If this specific ion bridge pair enclosed on at least one side by hydrophobic segments is presented to the cell from a non immune source then increased cytoplasmic circulation from cell membrane of specific marker 15 molecules occurs and this removes the normal immune functions of the cell types impacted by these specific peptide sequences. A proportion of amino acid sequences according to the present invention have demonstrated in a dose dependent manner the ability to down-regulate the expression of la molecules on human macrophages. Some in-vitro experiments suggest that 20 direct T cell antigen interactions without the mediation of la bearing macrophages may result in the generation of antigen specific suppressor T cells. All experimental evidence indicates that the development of antigen-reactive clones of helper T cells requires the presence of la bearing cells in the tissue. This inhibition of expression on the membrane surface of 25 these class II molecules (la) as produced with alfa-fetoprotein and/or cytokine inhibitory factor, signals the immune system to accept the appearance of new antigens as self to the immune system. Hence the often reported observation that an immune activation on polyclonal B cell activation producing Printed from Mimosa 04/13/1999 12:25:50 page 3 WO 98/10787 PCT/IB97/01086 auto-antibodies follow certain viral, bacterial and parasitic infections (e.g. HIV, Malaria). The effects of these specific peptide ion-bridge pairs attached to a hydrophobic amino acid sequence demonstrate that they are the component peptide segments within both thB alpha-fetoprotein and the cytokines 5 molecules that are involved in the process of inducing tolerance and maintaining the tolerant state to infectious organisms presenting these sequences.
In identifying this specific type of sequence and its ability to generate specific immune signals together with its ability to enhance or trigger 10 endocytosis of attached peptides or glycopeptides, we have been able to identify these specific amino acid sequences as a mechanism used by many infectious agents to not only undermine the hosts' immune defenses but to also allow for the penetration or infection of target lymphoid tissue.
Amino acids and residues thereof (i.e., amino acids in which one or 15 more hydrogen atoms have been removed) are referred to herein by their 3-letter abbreviations, (e.g., "Lys" for Lysine) well known to those skilled in the art.
According to the present invention, there are therefore provided pharmaceutical compositions and methods of enhancing immune response in 20 a patient suffering from immunodeficiency and/or one or more condition selected from the group consisting of: (a) immunodeficiency resultant from a viral infection; (b) immunodeficiency resultant from one or more of bacterial, mycoplasmic, fungal parasitic infections; (c) immunodeficiency resultant from the growth of neoplastic tissue, (d) immunodeficiency resultant from any cytokine or hormone imbalance or imbalance of any natural product within the patient; (e) myalgic encephalomyelitis (ME); (f) post inoculation or viral infection fatigue syndrome; Printed from Mimosa 04/13/1999 12:25:50 page 4 WO 98/10787 PCT/IB97/01086 (g) tuberculosis infection; and (h) malarial infection, comprising administering to the patient an immune response enhancing effective amount of a pharmaceutical formulation comprising at least one 5 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; BisGluorAsp; C is a carrier compound residue; Z is a carrier compound residue.
The present invention also provides pharmaceutical compositions and methods of enhancing immune response, e.g., in a patient suffering from a 25 condition as set forth above, comprising administering to said patient an immune response enhancing effective amount of a pharmaceutical formulation comprising at least one polyclonal or monoclonal antibody, or at least one Fab fragment thereof, generated to at least one compound selected from the group consisting of: Printed from Mimosa 04/13/1999 12:25:50 page 5 WO 98/10787 PCT/IB97/01086 4 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; BisGluorAsp; and wherein said at least one compound comprises at least 4 amino acid residues. In specific aspects of the present invention, the compound can consist of 16 or fewer amino acid residues, or of 8 or fewer amino acid residues.
In specific aspects of the present invention, at least one compound can consist 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 "H", i.e., an amino acid 20 residue selected from Ala, lie, Leu, Met, Phe, Trp, Val and Tyr on either end, i.e., -H-A-B- or -A-B-H-.
The present invention further relates to the antibodies used in the methods of the invention.
In addition, any of the antibodies in accordance with the present 25 invention can be administered to a patient in addition to any known vaccine.
The present invention further relates to methods of reducing a patient's immune response, by administering any of the compounds described above which have a sub-sequence -A-B- or -B-A, preferably -H-A-B- or -H-B-A- The present invention further relates to such compounds.
Printed from Mimosa 04/13/1999 12:25:50 page -6- Suitable (3-amino acid) sequences which include a sub-sequence -H-A-B- or -H-B-A- for use in accordance with the present invention include the following.
Ala-His-Asp; Ala-His-Glu; Ala-Lys-Asp; Ala-Lys-Glu; Ala-Arg-Asp 5 Ala-Arg-Glu; lle-His-Asp; lle-His-Glu; lle-Lys-Asp; lle-Lys-Glu; lle-Arg-Asp lle-Arg-Glu;Leu-His-Asp;Leu-His-Glu;Leu-Lys-Asp;Leu-Lys-Glu;Leu-Arg-Asp Leu-Arg-Glu; Met-His-Asp; Met-His-Glu; Met-Lys-Asp; Met-Lys-Glu Met-Arg-Asp; Met-Arg-Glu; Phe-His-Asp; Phe-His-Glu; Phe-Lys-Asp Phe-Lys-Glu; Phe-Arg-Asp;Phe-Arg-Glu; Pro-His-Asp; Pro-His-Glu; 10 Pro-Lys-Asp; Pro-Lys-Glu; Pro-Arg-Asp; Pro-Arg-Glu; Trp-His-Asp; Trp-His-Glu; Trp-Lys-Asp; Trp-Lys-Glu; Trp-Arg-Asp; Trp-Arg-Glu; Val-His-Asp; Val-His-Glu; Val-Lys-Asp; Val-Lys-Glu; Val-Arg-Asp Val-Arg-Glu; Ala-Asp-His; Ala-Glu-His; Ala-Asp-Lys; Ala-Glu-Lys Ala-Asp-Arg; Ala-Glu-Arg; lle-Asp-His; lle-Glu-His; lle-Asp-Lys; lle-Glu-Lys 15 lle-Asp-Arg; lle-Glu-Arg; Leu-Asp-His; Leu-Glu-His; Leu-Asp-Lys Leu-Glu-Lys; Leu-Asp-Arg; Leu-Glu-Arg; Met-Asp-His; Met-Glu-His Met-Asp-Lys; Met-Glu-Lys; Met-Asp-Arg; Met-Glu-Arg; Phe-Asp-His Phe-Glu-His; Phe-Asp-Lys; Phe-Glu-Lys; Phe-Asp-Arg; Phe-Glu-Arg Pro-Asp-His; Pro-Glu-His; Pro-Asp-Lys; Pro-Glu-Lys; Pro-Asp-Arg 20 Pro-Glu-Arg; Trp-Asp-His; Trp-Glu-His; Trp-Asp-Lys; Trp-Glu-Lys; Trp-Asp-Arg; Trp-Glu-Arg; Val-Asp-His; Val-Glu-His; Val-Asp-Lys; Val-Glu-Lys; Val-Asp-Arg; and Val-Glu-Arg.
Numerous suitable carrier compounds for use in accordance with the present invention would be readily apparent to those skilled in the art, and 25 representative examples include Serum albumin precursor - rat; Acyl carrier protein - Escherichia coli; Serum Albumin precursor - human; S. typhimurium branched chain amino transport system II carrier; Branched - chain amino acid carrier; Ribosomal protein S16 - Escherichia coli; 3-Hydroxydecanoyl -{Acyl-Carrier-Protein} Dehydratase; Excitatory amino acid transporter 3 (sodium- Printed from Mimosa 04/13/1999 12:25:50 page -7 WO 98/10787 PCT/1B97/01086 6 dependent; glutamate/aspartate transporter 3) (excitatory amino-acid carrier 1); Glutaredoxin 3; Cytochrome B5/C6; Transthyretin Precursor (prealbumin) (TBPA) (TTR); Phosphocarrier Protein HPR (Histidine-containing protein); Beta-Hexosaminidase alpha chain precursor; ACYL Carrier Protein (ACP); Surfactin synthetase component; Sterol carrier protein 2 precursor; Insulin-Like growth factor binding protein 3 Precursor (IGFBP-3); Mitochodrial Brown Fat Uncoupling Protein (UCP); Thioredoxin; Oleoyl-hydrolase; Platelet factor 4; Lactose Permease; Keyhole Lipid hemocyanin (KLH); and Bovine Serum Albumin (BSA).
The antibodies of the present invention are humanised as per the following reference: From cells to genes: how to make antibodies useful in human diagnosis and therapy. Zaccolo M, Malavasi F. Dipartimento di Genetica, Universita di Torino, Italy. Int J Clin Lab Res 1993: 23(4): 192-198. 15 The mono/polyclonal antibodies are made as per the following reference: Moller, G. (ed.): Engineered antibody molecules. Immunol. Rev. 1992,130:1-212.
The present invention further relates to methods of vaccinating a patient against immunosuppressive sequences, by administering a compound 20 which corresponds with an immunosuppressive sequence, except that one or both of the members of at least one -A-B- sub-sequence is replaced with an analog, an antimetabolite or a D-amino acid corresponding to the replaced amino acid. The present invention also relates to such compounds. Examples of such immunosuppressive sequences include: 25 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-Gln-Cys-Cys-Phe (SEQ ID NO. 3) Printed from Mimosa 04/13/1999 12:25:50 page -8- 7 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-Gin-Glu-G!y-G)y-Leu-Cys-A!a-A!a-Leu-Lys-Glu-Glu-Cys-Cys-Phe (SEQ ID NO. 5); and Vivax-1.
The term Vivax-1 as used in the specification is well known in the art and is described as corresponding to approximately 60% of the length of the entire CS protein of P.vivax (Belem, Brazil strain. It contains the entire repeat regions (DRA(A/D)DGQPAG)2o plus 15 amino acids of the amino terminal and 48 amino acids of the carboxy-terminal sequences flanking the repeat region of the CS protein.
A variety of analogs which would be suitable for use according to the present invention would be readily apparent to those skilled in the art. Representative examples include analogs of Larginine including Lornithine, L-Citrulline, L-a-Aminobutyrate, Agmatine (4-amino-1-guanidinobutane). Putrescine (1,4-diaminobutane), glycocyarnylgiycine, gl-ycocyamine, taurocyamine, methylguanidine, L-Homoarginine, L-Argininosuccinic anhydride (I), L-Argininic acid, L-Argininosuccinic anhydride (II), L-Argininosuccinate (ill), L-Argininosuccinate anhydride (IV), and LnitroArginine; and analogs of Lysine including L-thialysine (S-(a-amino-ethyl)-L-cysteine), D/L 4 oxalysine, p-Lysine, N5-Hydroxy-L-Arginine.
The present invention further relates to a method of treating a condition selected from the group consisting of: (a) immunodeficiency resultant from a viral infection; (b) immunodeficiency resultant from one or more of the following, bacterial, mycoplasmic, fungal and/or parasitic infections; (c) immunodeficiency resultant from the growth of neoplastic tissue; ■(d) immunodeficiency resultant from any cytokine or hormone imbalance or imbalance of any natural product within the patient; (e) myalgic encephalomyelitis (ME); (f) post inoculation or viral infection fatigue syndr (g) tuberculosis infection; and (h) malarial infection, 'OFFICE 1 2 mar 2001 received WO 98/10787 PCT/IB97/01086 8 in a patient in need of such treatment, comprising deleting genetic material from an infectious organism to prevent said genetic material from generating one or both amino acids in an amino acid sub-sequence "K" selected from the group consisting of Lys-Glu, Lys-Asp, Arg-Glu, Arg-Asp, 5 His-Glu, His-Asp, Glu-Lys, Asp-Lys, Glu-Arg, Asp-Arg, Glu-His and Asp-His, and sub-sequences K which have at least one adjacent hydrophobic amino acid.
The present invention further relates to methods and pharmaceutical compositions described above, wherein the component A and the component 10 B are separated by 1 or 2 amino acid residues In accordance with another preferred aspect of the present invention, there are provided sequences which consist of four distinct regions, i.e., R1-R2-R3-R4, in which: R1 is a region of up to 5AA within which there is one to three AA from 15 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 20 Glutamic closest to the R4 region is positioned within R3 to allow a minimum of two AA between these said acids and the R4 region.
R4 is a region of two AA containing one AA of either Lysine or Arginine attaching to region R3 and the other AA is either Aspartic acid or Glutamic acid.
Regions R1, R2 and R3 are considered the positioning regions of this specific AA sequence as they allow alignment of the AA sequence with cell membrane whereas R4 is considered the signalling sequence as this duo of peptides activates cell stimulation. This said peptide may be administered with a carrier moiety wherein the said carrier protein comprises bovine serum Printed from Mimosa 04/13/1999 12:25:50 page -10 WO 98/10787 PCT/IB97/01086 9 albumin, human serum albumin, an immunoglobulin or a hormone. These peptides may be made to further possess sugar groups, normal serum components, lipids, phospholipids, etc. Naturally occurring organisms using peptides similar to those described herein for immune attack may be treated 5 to deactivate their peptide immune activation mechanism by altering, by means known to those skilled in the art, one or more of either Lysine or Arginine existing in Region R1 and preferably in addition altering one or two of the AA in region R4 to remove the charge distribution of the said peptide. Vaccines may be manufactured using such techniques. 10 In accordance with another preferred aspect of the present invention, there are provided sequences which consist of four distinct regions, i.e., RA-RB-RC-RD, in which: RA is a region of up to 5 AA within which there is one to three AA from the group Lysine and/or Arginine 15 RB is a short region of up to 2AA which does not contain any of: Asp, Glu, Lys, Arg or His.
RC is a region of up to 7AA within which there may be one or two AA from the group Aspartic acid and/or Glutamic acid. The Aspartic acid or Glutamic closest to the RD region is positioned within RC to allow a minimum 20 of two AA between this said AA, if one exists, and the RD region. RD is a region of three or four AA containing one AA of either Lysine or Arginine attaching to region RC and one or two amino acids in the middle of the region containing AA from Polar and/or non-Polar with another AA at the end of the region which is either Aspartic acid or Glutamic acid.
Regions RA, RB and RC are considered the positioning regions of this specific AA sequence as they allow alignment of the AA sequence with cell membrane whereas RD is considered the signalling sequence as this duo of peptides activates cell stimulation. This said peptide may be administered with a carrier moiety wherein the said carrier protein comprises bovine serum Printed from Mimosa 04/13/1999 12:25:50 page -11- WO 98/10787 PCT/IB97/010B6 albumin, human serum albumin, an immunoglobulin or a hormone. These peptides may be made to further possess sugar groups, normal serum components, lipids, phospholipids etc. Naturally occurring organisms using peptides similar to those described herein for immune attack may be treated 5 to deactivate their peptide immune activation mechanism be altering, by means known to those skilled in the art, one or more of either Lysine or Arginine existing in Region RA and preferably in addition altering one or two of the charged AA in region RD to remove the charge distribution of the said peptide. Vaccines may be manufactured using such techniques. 10 The present invention also relates to treatments comprising administering to a patient any pharmaceutical formulations disclosed herein together with an antiviral therapy.
The large scale efforts to produce a broad spectrum vaccine candidate for Influenza Virus has proved impossible due to the rapid rate of mutation of 15 the outer coat of this virus. However, without the ability to attach and fuse and signal host immune cells in the body using those specific polar single ion bridge pair arrays of amino acid specific sequences, outlined herein, it is non-infectious. If these amino acid sequences are altered in the Influenza Virus, this virus then cannot undermine the hosts' immune system and 20 achieve cell entry or create immune dysfunction. This ability is restricted to a specific number of sequences, all of which must present to the cell membrane the charge distribution shown to activate endocytosis and TCR/CD3 cell activation and neutralise T cell immune surveillance as it relates to MHC-Class I and II. Therefore, if the infected host, human or 25 animal, already posses neutralising antibodies to these amino acid changed dipole sequences as specified herein it will not be possible for infection to be established because these neutralising antibodies perform a dual function (A) they prevent anchorage and endocytosis of the infecting organism into the host cell thus preventing productive infection and (B) they prevent the Printed from Mimosa 04/13/1999 12:25:50 page -12- WO 98/10787 PCT/1B97/01086 11 circulation in the plasma of these mimic Interleukin 10 or AFP type molecules which are released by infecting organisms. These specific said sequences confuse the normal signalling system involved in immune T and B cell activation since when applied to cells they trigger an intracellular Biochemical 5 signal similar to when a T cell receptor (TCR) molecule coupled to a CD3 molecule interact with a MHC-II antigen complex, together with the fact that these sequences also cause increased turnover of surface receptor molecules such as the Interleukin I receptor molecule, thus leading to an increase of Interleukin I levels and cause a shift in T cell performance due to the shifting 10 Th^hj cytokine balance.
It has been demonstrated with non-protective vaccine candidate antigens which when previously inoculated into a host produced a range of neutralising antibodies but failed to prevent infection being established when that host was later challenged with live infectious organism. When the initial 15 vaccine inoculation is coupled with passive immunisation with mono or polyclonal antibodies to these said specific sequences of the present invention that an immune response to the vaccine antigen from both T cell and B cell immune components results which includes antibodies to these hitherto unchallenged sequences results, the host is then capable of 20 overcoming an infectious challenge without becoming infected or producing the usual antibody and autoantibody peak and subsequent immunosuppression normally associated with infections caused by organisms who utilise these specific amino acid sequences to direct the hosts immune signalling system towards a more pronounced B cell or Th2 cytokine profiled 2 5 response.
Malaria is one of the most important infectious diseases in the World; each year there are 270 million new infections resulting in over 100 million episodes of illness and approximately 2 million deaths. World-wide the malaria problem is getting worse each year. The reason for this worsening Printed from Mimosa 04/13/1999 12:25:50 page 13 WO 98/10787 PCT/IB97/01086 12 situation include (A) increased levels of drug resistance on the part of the parasites, (B) increased levels of insecticide resistance on the part of the vectors. No vaccine has yet been produced which can successfully induce a protective antibody response. The reason for this is that although antibodies 5 which cross react with many epitopes of the P. vivax circumsporozoita are produced in abundance by the current unprotective vaccine candidates, because of the immune blind spot or immunologically privileged sites offered by these specific sequences identified herein, like Interleukin 10 and AFP, these sequences are not visible to the host immune system which both allow io the parasite to gain access to the host cell and to cause the non-specific polyclonal B cell activation and immunosuppressive (Interleukin 10 and/or AFP) like effects which are so universal for people suffering from parasites such as malaria, and Leishmania, the host cannot gain enough immune reactive monocytes to overcome the infection initially because these 15 Interleukin 10/AFP mimic molecules carried by the infecting organism shuts down the vital Th, T cell response needed to clear intra-cellular infections. We have identified the specific polar array sequence on the coat protein of malaria which this organism uses like Influenza Virus to attach and activate endocytosis together with activating a Th2 (B cell) response and subsequently 20 undermining the host's immune response and allowing infection to take hold while still producing an array of neutralising antibodies which creates mutational pressure for the generation of more virulent strains of the organism within the host.
Our studies clearly demonstrated in mouse models that polyclonal or 25 monoclonal antibodies generated to the above polar sequence arrays to these specific amino acid sequences either taken from specific sequences present in human alfa-fetoprotein or human Interleukin 10 resulted in protection of mice from challenge by malaria sporozoites. Therefore a vaccine for malaria which will enable a human to raise a protective antibody titre against malaria Printed from Mimosa 04/13/1999 12:25:50 page -14- WO 98/10787 PCT/IB97/01086 13 sufficient to prevent infection may be manufactured by deleting from the antigenic peptide to be used in the vaccine these amino acid sequences displaying the specific polar arrays outlined in this patent. Another method expected to be more successful as a vaccine combination (because the 5 immune system of primates including man appear to be blinded to these specific signal sequences) for protection is to use passive immunisation with either polyclonal or monoclonal antibodies to these said specific dipole immunosuppressive sequences generated either in animal human and/or tissue culture given either before or simultaneously with any of the current 10 malaria vaccine candidates which previously could not produce a protective immune response. When these mono or polyclonal antibodies are given to the host in conjunction with the antigen the host's immune system does not produce the well documented polyclonal B cell activation of the host immune system and the immune system of the host so challenged will produce a 15 protective antibody and T cell immune response which allows it to deaf effectively with any later malaria infection challenge.
In malaria, as in other infections the said specific sequences, identified as a dipole amino acid sequence in this patient, when embedded in the cell membrane of the host activates the phosphatidylinositol pathway, which 20 causes the release of Ca++, the phosphosylation of cell proteins and the activation or enhanced activity of certain enzymes related to metabolism This does not occur in the presence of antibodies to the disclosed specific sequences and the organism like malaria, Mycobacterium Tuberculosis Leishmania, HIV and others are not able to cause metabolic and immune Th2 25 activation and exhaustion. It is an important coincidence that in certain malaria endemic areas that genetic mutations that have caused the deletion of the metabolic activity control enzyme glucose-6-phosphate dehydrogenase has conferred on the host immunity to malaria. By intervening at an early stage of infection and neutralising certain properties of the malaria parasite Printed from Mimosa 04/13/1999 12:25:50 page 15 14 to alter cellular reactions by interfering with these specific membrane signal transduction sequences as defined herein it is possible to confer protective immunity to this organism.
The present invention utilises the novel discovery that certain amino 5 acid sequences which exhibit specific ion (bridge) pair arrays enclosed on at least one side by non-polar hydrophobic transmembrane segments can be utilised to enhance the humoral antibody response and down-regulate the T cell or delayed-type hypersensitivity (DTH) response of humans and animals These CD3/TCR mimic membrane interaction molecules which present as io hydrophobic Ion bridge pairs are utilised by both the organism itself as specific peptides and by cytokines and also by infectious agents to modulate immune response (A) during periods of reproductive foetal gestation as with the alpha-fetoprotein molecule to prevent foetal rejection by the maternal immune system and (B) during cytokine control of immune functions as with 15 cytokine synthesis inhibitory factor (Th2 cytokine) when a Th2 cytokine profile is required or to curtail the uncontrolled Th., T4 cell immune response. These immunosuppressive cytokines are particularly evident following vaccination to enhance humoral immunity and secure antibody formation, and often causes the temporary disappearance of the Tuberculin reaction which is 20 associated with Th1 (DTH) response in patients following vaccination. (C) Infectious agents such as viruses (RNA & DNA) mycoplasma, bacteria, malaria and a wide array of human and animal parasites also carry these specific charged array of amino acid sequences which cause the down regulation of the Th1 cytokine response and enhance the humoral (antibody 25 mediated) immune response of their infected host.
Now that these specific control sequences have been identified and verified we herewith outline a number of therapeutic modalities that result from this new found ability to intervene therapeutically to control, neutralise or enhance specific immune type reactions dependent upon the nature of the Printed from Mimosa 04/13/1999 12:25:50 page -16- WO 98/10787 PCT/IB97/01086 patient's or animal's own immune system status, infection or disease state. Example Anti-serum generated to these specific sequences as presented in AFP, Interleukin 10, EBV-BCRF1 and other peptides and as specified in 5 amino acid sequence, listing enclosed, with this patent can be used to remove AFP mimic molecules from the circulation of immunosuppressed patients suffering from viral and/or bacterial and/or fungal, mycoplasmic or parasitic infections, which infection's principle method of defence against the host is to stimulate a Th2 cytokine response and curtail or abolish the Th1 cell mediated 10 immune attack.
This invention relates to methods of treatment of persons and animals with indications of immunodeficiency, wherein the said indication is resultant from viral and/or retroviral infection and/or infectious parasites, bacteria and/or mycoplasma. The invention further relates to treatment with the above 15 antiserum either poly or monoclonal in nature for establishing improved immuno response for persons and prophylactic treatment for persons where immuno-malfunction due to genetic pre-disposition or infection is considered a future risk.
The invention further relates to a screening method for vaccines, 2 0 manufactured by the use of coat or other peptides from viral, bacterial, parasitic or mycoplasma, to determine and remove and/or neutralise inherent immune suppressive properties - such suppressive potential properties are determined by the manufactured vaccine's reactivity with the said specific amino acid sequences as outlined herein, be they synthetic or natural in 25 origin, e.g. AFP, Th2 cytokines, viral or bacterial coat peptides. In one embodiment, the host organism (man or animal) is treated with mono or polyclonal antibodies to any one or combination of the specific amino acid sequences as defined herein. This will result in the removal of Th2 cytokine and AFP type mimic immunosuppressive peptides and initiate a Th1 cell Printed from Mimosa 04/13/1999 12:25:50 page 17 WO 98/10787 PCT/EB97/01086 16 response, allowing Interleukin 2 and gamma interferon synthesis to occur. Treatments used according to this invention employing the poly or monoclonal antiserum to these specific immune system inhibitory sequences are administered as treatments against viral, bacterial and mycoplasma and 5 parasitic infections which cause immunosuppression by any suitable route including enteric, parenteral, topical, oral, rectal, nasal or vaginal routes Parenteral routes include subcutaneous, intramuscular, intravenous and sublingual administration. The preferred route of administration would be an intravenous one.
The present invention further provides pharmaceutical formulations, for use in treatments against HIV/HTLV-I, II, III and other viral diseases and diseases caused by mycoplasma, bacteria or parasites The present invention also relates to a method comprising inoculating into a patient a human, animal, synthetic or recombinant amino acid sequence 15 with or without adjuvant, to produce an antibody response, the antibodies, mono or polyclonal will cause the binding of the immunosuppressive CD3/TCR mimic interaction molecules already present in the plasma of the infected host will be removed from the circulation of the infected host and normal immune function demonstrating a Th1 cytokine profile, i.e. Interleukin 20 2 and gamma interferon, capable of resisting the infection will be re-established.
Vaccines manufactured by the use of coat or other peptides from viral, bacterial, parasitic or mycoplasma may be screened to determine whether they posses these specific amino acid sequences which exhibit these specific 25 Ion bridge pair arrays capable of mimicking the actions of AFP or Th2 cytokines and their inherent immune suppressive properties - such suppressive potential properties is determined by the manufactured vaccine's reactivity with any of the said specific amino acid sequences listed herein which may be removed or neutralised by the antiserum specified in this Printed from Mimosa 04/13/1999 12:25:50 page -18- 17 patent.
The present invention also relates to a method of assaying body fluid from an animal, comprising contacting said body fluid with at least one antibody as described above.
The present invention further relates to a method of screening a vaccine, comprising contacting said vaccine with at least one antibody as described above.
Peptide Sequence Section Firstly a series of documented and identified immunosuppressive 10 sequences, encompassing both a known immunosuppressive peptide (CKS-17) and viral coat protein HTLV-lli gp41 735-752 were selected and we by deletion or chemical modification of the referred amino acids Table 1 demonstrated that by compromising the charged amino acid dipole arrays within the hydrophobic segment of these peptides it was possible to neutralize 15 the immunosuppressive ability of these selected immunosuppressive sequences.
Peptide synthesis and protein conjugation. The peptides were assembled by solid-phase peptide synthesis on a Merrifield polystyrene resin as described previously (Kennedy, R.C., Henkel, R.D., Pauletti, D., Allan, J S 20 Lee, T.H., Essex, M., and Dreesman, G.R., Science 231, 1556, 1986) (Chanh, T.C., Dreesman, G.R., Kanda, P., Linette, G.P., Sparrow, J.T., Ho: D.H., and Kennedy, R.C., EMBO J. 5, 3065, 1986). Protection of amino acid side chains during synthesis and cleavage of the peptide from the support by anhydrous hydrogen fluoride (HF) have been described previously (Kinnunen, 25 P.K.J., 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 and the presence of a single peak by HPLC. A tyrosine residue was added to either the amino or the carboxy terminus for monitoring peptide purification Printed from Mimosa 04/13/1999 12:25:50 page -19 WO 98/10787 PCT/IB97/01086 18 and radiodination. A cysteine residue was added to either terminus for coupling via its free sulfhydryl to the carrier proteins keyhole limpet hemocyanin (KLH) or bovine serum albumin (BSA) using the MBS heterobifunctional crosslinker.
KLH- Keyhole Limpet Hemocyanin BSA- Bovine Serum Albumin Inhibition of mitoaen-induced blastoaenesis To assess the inhibitory effects of the peptides AA sequences outlined in Table 1. Normal human blastogenic response to mitogens, PMN cells from io healthy donors were cultured in the absence or presence of various concentrations of peptides or peptides conjugated to carrier proteins followed by mitogen stimulation. The results of the experiments are shown in Table 2. Preincubation of normal PMN with the immunosuppressive peptides chosen before signal sequence neutralization either conjugated to either KLH or BSA 15 resulted in a preformed and dose - dependent suppression of PHA - induced proliferation. Upon amino acid signal sequence as specified in Table 1 chemical modification there was a significant reduction in the suppression of PHA induced proliferation.
The viability of peptide treated PMN as determined by trypan blue 20 exclusion staining was comparable to that of untreated PMN, showing that suppression of proliferation did not result from peptide-induced cytotoxicity. Inhibition of the normal two - way mixed - lymphocyte reaction The immunosuppressive peptides which clearly suppressed the proliferation of normal PMN in a two-way mixed lymphocyte reaction (MLR) 2 5 were not capable of demonstrating any form of suppression when the specific dipole signalling sequence as designated in Table 1 were chemically modified to neutralize the charge distribution on the dipole (Table 3).
In-vitro proliferation assays. Peripheral mononuclear cells (PMN) were obtained from normal HIV antibody-negative donors by density Printed from Mimosa 04/13/1999 12:25:50 page -20- WO 98/10787 PCT/IB97/01086 19 gradient centrifugation through Hisopaque-1077 (Sigma Chemical Co., St. Louis, MO). The in-vitro proliferation assays were performed by incubating 105 cells/well in 96-well round-bottom microtiter plates in the absence or presence of various dilutions of peptides for 4 days in RPMI 1640 cultured 5 medium (Grand Island Biological Co., Grand Island, NY) supplemented with 10% fetal calf serum (FCS). On the fourth day of culture, the cells were stimulated with phytohemagglutinin (PHA, Sigma) at a final dilution of 0.1%, or Con A (Sigma), or pokeweed mitogen (PWM, Sigma) at final concentrations of 10 |jg/ml. The cultures were allowed to incubate for an 10 additional 2 days at which time 1 pCi of [3H] thymidine (New England Nuclear Co., Boston, MA) was added to each well. After an additional 18hr in culture, the cells were harvested and processed for scintillation counting. For PHA-induced proliferation of murine cells, normal 3- to 5-week-old BALB/C mice (Jackson Laboratories, Bar Harbor, ME) were sacrificed 15 and their spleen cells were obtained through density gradient centrifugation. The spleen cells were used at a density of 5x 104/well and the assay was done as described above.
Two-way mixed-lymphocyte reaction. Peripheral mononuclear cells from MHC-mismatched donors were obtained as described above. Cells(5 20 x 104) from one individual were mixed with an equal number of cells from another individual in the absence of presence of peptides from Table 1 for 5 days. The cultures were pulsed with [3H] -thymidine for the last 18 hr and harvested for scintillation counting.
Printed from Mimosa 04/13/1999 12:25:50 page 21 WO 98/10787 PCT/IB97/01086 Table 1 Immunosuppressive Peptides Used 1 HTLV - III B gp41 AA Sequence: Tyr-Glu-Arg-Pro-Glu-Gly-lle-Glu-Glu-Glu-Gly-Gly-Glu-Arg-Glu-Arg- Glu-Arg-Ser-Gly-Cys (SEQ. ID NO. 34) AA 735-752 2 CKS-17 AA Sequence: Leu-Gln-Asn-Arg-Arg-Gly-Leu-Asp-Leu-Leu-Phe-Leu-Lys-Glu-Gly- Gly-Leu (SEQ. ID NO. 35) CKS-17 (A) 1(A) HTLV-III B gp41 modified These peptides have their arginyl residues modified by the use of 15 1,2 cycloheranedione as outlined in Mahley, R.W., J. of Biol. Chem. 1977 Vol. 252 pgs. 7279-7287 Printed from Mimosa 04/13/1999 12:25:50 page -22- WO 98/10787 PCT/1B97/01086 21 Table 2 Suppression of Mitogen Induced Biastogenic Response To Normal Human Mononuclear Cells Percentage Suppression of Biastogenic Response to PHA ConA PWM HTLV-IIIB gp41 - KLH 74 77 . 85 AA 735-752 5pg/ml HLTV-IIIB gp41 - KLH (modified) 6 7 4 Modified as per Neutralization of charge Distribution on dipole CKS-17 64 80 76 5pM Modified CKS-17 Modification caused by Chemical modification of The charge on dipole sequence Printed from Mimosa 04/13/1999 12:25:50 page 23 WO 98/10787 PCT/IB97/01086 22 Table 3 Immunosuppressive Peptides Suppression Of Mixed Lymphocyte Reaction Thymidine Incorporation (cpm) with Medium HTLV-III gp41 Modified HTLV-III gp41 735-752 (5pg/ml) 735-752 5pg/ml (charged dipole neutralized) 5224 ± 256 2800 ± 120 (45%) 5236 ± 211 (0%) 5368 ±106 2789 ± 163 (46%) 5334 ± 107 (0%) Medium CKS-17 CKS-17 (Modified) (charged dipole neutralized) 4738 ± 96 947 ± 68 (80%) 4526 ± 102 (0%) 5372 ±173 1074.4 ±03 (83%) 4834 ±80 (19%) The only detectable changes in the physical and chemical properties 15 of the modified HTLV-III gp41 and CKS-17 was increased electrophoretic mobility which reflected the neutralization of the positive charge on the granido group of arginine. 1(B) HTLV-III B gp41 Modification Reversed This modified peptide is essentially restored to its original 20 immunosuppressive capability when the modification to the arginyl residue is reversed by treatment with hydrosylamine.
Printed from Mimosa 04/13/1999 12:25:50 page -24- WO 98/10787 PCT/1B97/01086 23 The immunosuppressive peptides designed as per this patent may be neutralized in their ability to effect immune function if the amino acid charged dipole sequence is deleted or chemically modified so that the charged chemical groups on the dipole amino acides, be they positive or 5 negative, are either both or individually left without an electrostatic charge component. This has been demonstrated for this patent Tables 2/3 to effectively remove any immunosuppressive characteristics and could very easily accomplish the same end for intact viruses or bacteria should their genetic codes be deleted for these specific amino acids or their outer coats 10 neutralized to these signal dipole sequences.
Those of skill in the art would readily be able to determine where an ion bridge pair exists in a particular sequence, e.g., an immunosuppressive sequence, and determine which ion bridge pairs are responsible for the immunosuppressive activity, by routine experimentation in view of the 15 information contained herein.
The present invention further relates to pharmaceutical compositions and methods of providing an immunosuppressive or immunoregulatory effect in a patient, comprising administering to the patient an immunosuppressive or immunoregulatory effective amount of a 20 pharmaceutical formulation comprising at least two Th2 cytokines, for example, wherein the at least two Th2 cytokines include Interleukin 10 and Interleukin 4.
In relation to the administration of anti-serum to lnterleukin-10 and also the combination therapy of lnterleukin-10 and lnterleukin-4 the dose 2 5 ranging were as follows: lnterleukin-10 alone - 2 mg per day over a period of 10 days by IV. Combination therapy - two trials.
Trial 1 : 2 mg per day of anti-serum to IL-10 on each alternative day and 2 mg per day of anti-serum to lL-4 on each other alternative day. 3 0 Administration by IV.
Trial 2 : infusion of 4 mg of a combination (50/50) of IL-10/IL-4 on days 1,3,5,9,11 and 14. - This dose range would vary and the ratio of cytokines Printed from Mimosa 04/13/1999 12:25:50 page -25 WO 98/10787 PCT/IB97/01086 24 administered depending on the disease condition.
These agents as per this patent are administered in an amount, which provides circulating levels of about 1-150 (jg/ml of each agent.
The present invention further relates to pharmaceutical compositions 5 and methods of treatment of graft vs. host disease in a patient in need of such treatment, comprising administering to the patient Interleukin 10 and Interleukin 4.
The present invention further relates to pharmaceutical compositions and methods of providing an immunosuppressive or immunoregulatory 10 effect in a patient, comprising administering to the patient Interleukin 10, Interleukin 4 and at least one of antagonist of Interleukin 10 and antagonist of Interleukin 4.
The present invention further relates to pharmaceutical compositions and methods of providing an immunosuppressive or immunoregulatory 15 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.
The present invention further relates to pharmaceutical compositions and methods of providing an immunosuppressive or immunoregulatory 20 effect in a patient, comprising administering to said patient anti-serum to Interleukin 10 and anti-serum to Interleukin 4 The present invention further relates to pharmaceutical compositions and methods of providing an immunosuppressive or immunoregulatory effect in a patient, comprising administering to said patient anti-serum to 25 Interleukin 10 and at least one of antagonist of Interleukin 4 and agonist of Interleukin 4.
The present invention further relates to pharmaceutical compositions and methods of providing an immunosuppressive or immunoregulatory effect in a patient, comprising administering to said patient anti-serum to 30 Interleukin 4 and at least one of antagonist of Interleukin 10 and agonist of Interleukin 10.
When rabbit antibodies to human Interleukin 10 was administered to Printed from Mimosa 04/13/1999 12:25:50 page -26- WO 98/10787 PCT/IB97/01086 AIDS patients for a one week period by an IV route their cytotoxic CD8 cells and natural killer cell numbers increased within 24 hours and this resulted in a simultaneous increase in viral load levels as measured by PCR (RNA). However, quantitative culture techniques showed a decline to 5 zero levels. The reason for the above would appear to be that the enhanced CD8 cytotoxic and natural killer cell attack on HIV infected cells increased the amount of HIV viral RNA and viral peptide present in the blood as a result of the killing of infected cells. The fact that quantative culture decreased to zero means that the viral particles present were not 10 viable or infectious viruses. However, no improvement in percentage or absolute number of CD4 (T4) cells was recorded and the Th1 immune function did not show improvement. After 3 months from the termination of the above therapy with antibodies to Interleukin 10, HIV viral load returned to its pre-treatment level and his CD4 (T4) cell count decreased by 50%. 15 This demonstrated that the anti-serum to Interleukin 10 had been capable of activating CD8 cytotoxic and natural killer cells and causing a dramatic reduction in viral load. However, the CD4 (T4) immune system cells had not improved so that when following therapy his CD8 and natural killer cells lost their function, dormant virus was awakened by the Interleukin 10 20 antibody therapy and new viral replication could not be kept in check without a complement of active CD4 cells.
This same patient was then administered a combination therapy which involved rabbit IgG antibodies generated to both human Interleukin 10 and human Interleukin 4. It had been determined from in-vitro studies 25 with the patients blood that native Interleukin 4 levels were elevated and this was preventing the recovery of the CD4 (T4) cell component of his immune system.
The patient was administered the two antibodies to Interleukin 10 and Interleukin 4 for 2 weeks Following this the patient's HIV viral load 30 again increased when monitored by PCR RNA and decreased to zero after 4 weeks. However, on this occasion his CD4 (T4) cell count both in absolute number and percentage increase from 9% to 15% within 4 days of Printed from Mimosa 04/13/1999 12:25:50 page 27- WO 98/10787 PCT/IB97/01086 26 therapy commencing. After the 3 month period out from the termination of the combination therapy, CD4 (T4) cell count continued to remain elevated and HIV viral load was still non-detectable Suitable dosages in accordance with the present invention depend 5 on many factors, e.g. the patient's weight, the mode of administration, the frequency of administration, the type of affliction being treated or prevented, whether the infection presently exists, and if so, to what degree. Suitable dosages for given situations can readily be determined by those skilled in the art without undue experimentation.
The total treatment time according to the present invention will vary from patient to patient based on sound medical judgement and factors particular to the patient being treated, such as, for example, the age and physical condition of the patient. Those skilled in the art can easily determine suitable total treatment time on a patient-by-patient basis. 15 The following is a description of a suitable protocol in accordance with the present invention. However, the present invention is not limited by the following Example, and variations will be apparent to those skilled in the art without departing from the spirit of the present invention. PROTOCOL FOR ADMINISTRATION OF AN IMMUNOGLOBULIN IgG 2 o ANTIBODY AGAINST A COMBINATION OF TH2 CYTOKINES 1.0 INTRODUCTION The Human Immunodeficiency Virus Type 1 (HIV-1) is the etiological agent of Acquired Immune Deficiency Syndrome(AIDS) (Barre-Sinoussl, F.. Chermann, J.C., et al, Isolation of a T-lymphotrophic Retrovirus From a 2 5 Patient at Risk for Acquired Immunodeficiency Syndrome (AIDS). Science (1984) 224, 500-503; Gallo, R.C., Salahuddin, S.Z., et al, Frequent Detection and Isolation of Cytopathic Retroviruses (HTLV-III) From Patients with AIDS and at Risk for AIDS. Science (1984) 224, 500-503). AIDS is characterised as a profound breakdown in host's cellular and humoral 3 o immunity and increased susceptibility to a wide range of opportunistic infections. One of the consequences of this immune dysfunction is a marked depletion in absolute CD4+ cells in HIV-infected individuals Printed from Mimosa 04/13/1999 12:25:50 page -28 WO 98/10787 PCT/IB97/01086 27 Studies over the past years have demonstrated that the destruction of the immune system by HIV-1 is a chronic process, starting at the moment of infection. The results indicate that strategies for effective therapeutic intervention using antibodies to these specific mimic CD3/TCR peptide 5 interaction dipole sequences should start early in infection to prevent irreversible damage occurring to the immune system, since it has been demonstrated in HIV that an early loss of CD3/TCR mediated T cell activation is evident. This imbalance in turn effects monocyte and B cell function.
Recent studies have established the functional binding and immunosuppressive similarities between specific amino acid charged sequences present on the alfa-fetoprotein molecule and on and Th2 cytokine peptides and certain HIV envelope amino acid sequences. Laboratory data demonstrates that immunoglobulin G (IgG) or IgM to the said specific amino acid sequence inhibits syncytial formation and prevents HIV-1 laboratory strains MN, RF, and IIIB replication in C8166-45 cells (lymphocyte cell-line) in-vitro. In addition, IgG to the said amino acid sequence inhibits replication of HIV-1 BAL in fresh macrophage culture in a dose-dependent manner. 2 0 1.2 RATIONALE The basic rationale for using this therapy is the understanding that there exists a functional binding and immunosuppression similarity between certain peptides containing specific ion pair arrangements of amino acids enclosed within two hydrophobic amino acids present within the AFP molecule Interleukin 10 and specific external HIV glycoproteins together with other specific viral coat peptides and glycopeptides. This discovery shows that as the body defends itself against the HIV virus by producing antibodies to specific viral coat proteins, these antibodies, while restricting in a normal antibody fashion the HIV virus, are themselves 3 o together with certain viral glycopeptides sequences identified herein and produced by the infecting virus are inherently immunosuppressive in that they perform a similar task as AFP or Th2 cytokine peptides in that they Printed from Mimosa 04/13/1999 12:25:50 page -29- WO 98/10787 PCT/IB97/01086 28 selectively down regulate the T cell dependent immune system in favour of a humoural, B cell response which although it produces neutralising antibodies to the infectious agent (e.g. malaria, HIV, Tuberculoses, Leishmanial also allows the infective agent to persist and reproduce within 5 the host cells and to ultimately undermine its immune status.
The major histocompatibility complex (MHC) is a collection of 40-50 genes arrayed within a long continuous stretch of DNA on chromosome 6 in humans. The MHC is referred to as the HLA complex in humans. The MHC genes are organised into regions encoding three classes of 10 molecules: Class I, Class II and Class III. The Class I genes encode glycoproteins expressed on the surface of nearly all nucleated cells, where they present peptide antigens of altered self-cells necessary for the activation of Tc cells. The Class II genes encode glycoproteins expressed primarily on antigen-presenting cells (macrophages, dendritic cells, and B 15 cells), where they present processed antigenic peptides to T cells. The Class III genes encode somewhat different products that are also associated with the immune process. These include a number of soluble serum proteins (including components of the complement system), steroid 21-hydroxylase enzymes, and tumour necrosis factors. 2 0 The administration of antibodies poly or mono clonal to these specific CD3/TCR mimic molecules will cause an immediate antibody-dependent cell-mediated cytotoxicity (ADCC) stimulated reduction in Viral Load as measured by the culturing of peripheral blood mononuclear cells and following the removal of the mimic Th2 cytokine/AFP like viral 25 peptide molecules and in the patient's blood we should see a re-awakening of a CD8 cytotoxic T cell reaction directed against HIV infected cells and this will coincide with a second HIV Viral Load reduction. Also in patients who have received this antibody therapy we should see the generation of Interleukin 2 and gamma interferon and a dramatic increase in T4 cell 30 number, together with a decrease in PCR and Quantitative Viral culture levels.
A number of white blood cells have cytotoxic potential and express Printed from Mimosa 04/13/1999 12:25:50 page -30- WO 98/10787 PCT/IB97/01086 29 membrane receptors for the Fc region of the antibody IgG molecule When this antibody is specifically bound to a target cell which occurs when these specific poly or monoclonal antibodies to these sequences present on AFP, and Th2 cytokines bind to HIV infected cells or free viral peptides causing 5 immune Th2 shift. These cytotoxic Fc receptor-bearing cells can bind to the antibodies' Fc region, and thus to the infected HIV cells, and subsequently cause lysis of these cells. Although the cytotoxic cells involved are non-specific, the specificity of the antibody to a common immunosuppressive mimic peptide present on Th2 cytokines peptides/AFP 10 present on a large number of infecting organisms directs them to HIV infected target cells. This type of cytotoxicity is referred to as antibody-dependent cell-mediated cytotoxicity (ADCC). The variety of cells that have been shown to exhibit ADCC include NK cells, macrophages, monocytes, neutrophils, and eosinophils. 15 2.0 OBJECTIVES 2.1 To provide for an administration of monoclonal antibodies to these specified sequences present on AFP and Th2 cytokines and infectious organisms to HIV+ patients. 2.2 To monitor immune system functioning before and after the 20 administration of these mono or polyclonal antibodies. 2.3 To monitor the effect of these type of antibody on cutanous lesions in those study participants who have Kaposi's Sarcoma. 2.4 To monitor viral load in patient's peripheral blood mononuclear cells prior to beginning, during and post this type of antibody infusion therapy. 2.5 To monitor the course or incidence of opportunistic infections in the study participants. 2.6 To determine the safety of these type of antibody administration in persons with HIV disease. 3.0 CLINICAL ENDPOINTS 30 To confirm that these antibodies either poly or monoclonal are of therapeutic benefit for widespread use in HIV disease based on the following criteria - Printed from Mimosa 04/13/1999 12:25:50 page -31- 3.1 Changes in T-cell phenotyping and cytokine profile. 3.2 Changes in the size, coiour intensity, and palpable skin characteristics of cutaneous Kaposi's sarcoma lesions. 3.3 Changes in HIV load burden as indicated by enapoint - dilution cuiture quantitation in peripheral - blood mononuclear cells. 3.4 Changes in p24 antigen level. 3.5 Changes in Beta-2-microglobulin level 3.6. Appearance of new or improvement of active opportunistic infections. 3.7 Changes in system functioning (liver, kidney, naematology).
As used throughout the specification and claims the passage "at least one compound of 15-mers or less in length" is to be limited to comopunds wherein one or both of A and B, as specified, are bonded on one side to at least one hydrophobic amino acid residue selected from Ala, lie, Leu, Met, Phe, Trp, Val and Tyr, with the proviso that compounds containing the following sequences (1) Ala-Lys-Leu-Arg-Glu-Leu-Lys-GIn, where at least 5 contiguous residues are present that contain an ion pair; (2) Arg-Gly-Leu-Asp-Ile; (3) Leu-Ala-Val-Glu-Arg-Tyr-Leu-Lys-Asp-Gln-GIn where at least 5 contiguous resides are present that contain an ion pair; (4) Leu-Phe-Leu-Lys-Glu; (5) Arg-Gly-Leu-Asp-Leu; (6) Glu-Arg-Geu-Lys-GIn; (7) Leu-Asp-Asn-Arg-Arg; (8) Arg-Gly-Leu-Asp-Ile; (9) Ala-Ala-Leu-Lys-Glu; (10) Arg-Ile-Leu-Ala-Val-Glu-Arg-Tyr-Leu-Lys-Asp; and (11) the 360 sequences disclosed in WO 95/19568 are excluded,-- 31 3350.59

Claims (87)

Claims:
1. The use, in the manufacture of a medicament, of 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 of 15-mers or less in length as herein before defined 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, for treating a patient suffering from a condition selected from the group consisting of (a) immunodeficiency resultant from a viral infection; (b) immunodeficiency resultant from one or more of the following, bacterial, mycoplasmic, fungai and/or parasitic infections; (c) immunodeficiency resultant from the growth of neoplastic tissue; Intellectual Property Office of NZ - 5 JAN 2001 received 32 (d) imbalance (e) (f) (g) ..(h)
2. The use as recited in claim 1, wherein said at least on compound consists of 14 or fewer amino acid residues.
3. The use as recited in claim 1, wherein said at least one compound consists of 8 or fewer amino acid residues.
4. The use as recited in claim 1, wherein said at least one compound consists of 4 or fewer amino acid residues.
5. The use, in the manufacture of a medicament of 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 of 15-mers or less in length as herein before defined selected from the group consisting of: D-A-B-E; D-A-B; and A-B-E; j wherein: I D is an amino acid sub-sequence comprising at least one amino i 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, for treating a patient suffering from a condition selected from the group consisting of Intellectual Property Office of N2 - 5 JAN 2001 'jf> r >>"r'i \t r *> immunodeficiency resultant from any cytokine or hormone or imbalance of any natural product within the patient; myalgic encephalomyelitis (ME); post inoculation or viral infection fatigue syndrome; tuberculosis infection; and malarial infection. 33 (a) immunodeficiency resultant from a viral infection; (b) immunodeficiency resultant from one or more of the following, bacterial, mycoplasmic, fungai and/or parasitic infections; (c) immunodeficiency resultant from the growth of neoplastic tissue; (d) immunodeficiency resultant from any cytokine or hormone imbalance or imbalance of any natural product within the patient; (e) myaigic encephalomyelitis (ME); (f) post inoculation or viral infection fatigue syndrome; (g) tuberculosis infection; and (h) malarial infection,
6. The use as recited in'claim 5, wherein said at least one compound consists of 14 or fewer amino acid residues.
7. The use as recited in claim 5, wherein said at least one compound consists of 8 or fewer amino acid residues.
8. The use, in the manufacture of a medicament of a 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 of 15-mers or less in length as herein before defined 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; Intellectual Property Office of NZ - 5 jan 2001 RFC.PIVRD 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, for treating a patient suffering from a condition selected from (a) immunodeficiency resultant from a viral infection; (b) immunodeficiency resultant from one or more of the following, bacterial, mycopiasmic, 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.. 35
9. The use as recited in claim 8, wherein said at least one compound consists of 14 or fewer amino acid residues.
10. The use as recited in claim 8, wherein said at least one compound consists of 8 or fewer amino acid residues.
11. The use as recited in claim 8, wherein said at least one compound consists of 4 or fewer amino acid residues.
12. The use, in the manufacture of a medicament of a 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, of 15-mers or less in length as herein before defined 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, for treating a patient suffering from a condition selected from (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 syndr<^|f|ect a| p ^ (g) tuberculosis infection; and Office of NZ 5 JAN 2001 36
13. The use as recited in claim 12, wherein said at least one compound consists of 14 or fewer amino acid residues.
14. The use as recited in claim 12, wherein said at least one compound consists of 8 or fewer amino acid residues.
15. The use, in the manufacture of a medicament of 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 of 15-mers or less in length as herein before defined, 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; INTELLECTUAL PROPERTY OFFICE OF N.Z. 1 2 mar 2001 received 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, for enhancing an immune response in a patient suffering from immuno-deficiency.
16. The use, in the manufacture of a medicament of 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 of 15-mers or less in length as herein before defined, 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, for treating a patient requiring vaccination 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; '^effectual ProDertv Office of M7 (e) myalgic encephalomyelitis (ME); ■ (f) post inoculation or viral infection fatigue syndrome; - 5 JAN 2001 received 38 (g) tuberculois infection; and (h) malarial infection. 335039
17. The use as recited in claim 16, wherein said at least one compound consists of 14 or fewer amino acid residues.
18. The use as recited in claim 16, wherein said at least one compound consists of 8 or fewer amino acid residues.
19. The use as recited in claim 16, wherein said at least one compound consists of 4 or fewer amino acid residues.
20. The use, in the manufacture of a medicament, of 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 of 15-mers or less in length as herein before defined, 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, for use in vaccinating a patient 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 Intellectual Property Office of NZ - 5 jan 2001 received 39 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,,
21. The use as recited in claim 20, wherein said at least one compound consists of 14 or fewer amino acid residues.
22. The use as recited in claim 20, wherein said at least one compound consists of 8 or fewer amino acid residues.
23. The use, in the manufacture of a medicament, of 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 of 15-mers or less in length as herein before defined, 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, lie, Leu, Met, Phe, Trp, Val and Tyr; X is a covaient bond or an amino acid sub-sequence comprising at least one amino acid residue; fntellectuaf Property Office of ' ~ -5 Rsreiueh 33 503 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, for 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 fh) malarial infection,
24. The use as recited in claim 23, wherein said at least one compound consists of 14 or fewer amino acid residues.
25. The use as recited in claim 23, wherein said at least one compound consists of 8 or fewer amino acid residues.
26. The use as recited in claim 23, wherein said at least one compound consists of 4 or fewer amino acid residues.
27. The use, in the manufacture of a medicament of 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 Intellectual Property Office of NZ - 5 jan 2001 RECEIVED j3 5 0 to at least one compound of 15-mers or less in length as herein before defined, selected from the group consisting of: D-H-A-B-E; D-H-A-B; H-A-B-E; D-A-B-H-E; D-A-B-H; and A-B-H-E; wherein: H is selected from the group consisting of Ala, lie, Leu, Met, Phe,. Trp, Val and Tyr; D is an 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 4 amino acid residues, for enhancing immune response in a patient suffering from a condition selected from (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 fromjhe 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. Intellectual Property Office of NZ -1 jan 2001 RECEIVED 42 3503a
28. The use as recited in claim 27, wherein said at least one compound consists of 14 or fewer amino acid residues.
29. The use as recited in claim 27, wherein said at least one compound consists of 8 or fewer amino acid residues.
30. The use, in the manufacture of a medicament of a 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 of 15-mers or less in length as herein before defined, 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, lie, 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; Intellectual Property Office of NZ -5 JAN. 2001 RECEIVED Z is a carrier compound residue, for 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) myaigic encephalomyelitis (ME); (f) post inoculation or viral infection fatigue syndrome; (g) tuberculosis infection; and (h) malarial infection.
31. The use as recited in claim 30, wherein said at least one compound consists of 14 or fewer amino acid residues.
32. The use as recited in claim 30, wherein said at least one compound consists of 8 or fewer amino acid residues. 44
33. The use as recited in claim 30, wherein said at least one compound consists of 4 or fewer amino acid residues.
34. The use, in the manufacture of a medicament of a 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 of 15-mers or less in length as herein before defined selected from the group consisting of: D-H-A-B-E; D-H-A-B; H-A-B-E; D-A-B-H-E; D-A-B-H; and A-B-H-E; wherein: H is selected from the group consisting of Ala, lie, Leu, Met, Phe, Trp, Val and Tyr; D is an 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, for 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; Intellectual Property Office of NZ -5 JAN 2001 45 (g) tuberculosis infection; and (h) malarial infection.
35. The use as recited in claim 34, wherein said at least one compound consists of 14 or fewer amino acid residues.
36. The use as recited in claim 34, wherein said at least one compound consists of 8 or fewer amino acid residues.
37. The use, in the manufacture of a medicament of 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 of 15-mers or less in length as herein before defined, 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; INTELLECTUAL PROPERTY OFFICE OF N.Z. 1 2 mar 2001 received 46 5059 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, lie, 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, for enhancing an immune response in a patient suffering from immunodeficiency.
38. The use, in the manufacture of a medicament, of 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 of 15-mers or less in length as herein before defined, selected from the group consisting of: R1-R2-R3-R4 wherein: R1 is a region of up to 5 amino acids within which there is one to three amino acids from the group Lysine and/or Argine; R2 is a short region of up to 2 amino acids which do not contain any of the following Asp, Glu, Lys, Arg or His; R3 is a region of up to 7 amino acids within which there may be one or two amino acids from the group Aspartic acid and/or Glutamic acid; and R4 is a region of two amino acids containing one amino acid of either Lysine or Arginine attaching to region R3 and the other amino acid is either Aspartic acid or Glutamic acid, for enhancing an immune response in a patient suffering from immunodeficiency. . . ^ Intellectual Property Office of NZ - 5 jan 2001 RECEIVED 47
39. The use, in the manufacture of a medicament of 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 of 15-mers or less in length as herein before defined, selected from the group consisting of: RA-RB-RC-RD, wherein: RA is a region of up to 5 amino acids within which there is one to three amino acids from the group Lysine and/or Arginine; RB is a short region of up to two amino acids which do not contain any Asp, Glu, Lys, Arg or His; RC is a region of up to 7 amino acids within which there may be one or two amino acids from the 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 amino acids between this said amino acid, if one exists, and the RD region; and RD is region of three or four amino acids containing one amino acid of either Lysine or Arginine attaching to region RC and one or two amino acids in the middle of the region containing amino acid from Poiar and/or non-Polar with another amino acid at the end of the region which is either Asp or Glu, for enhancing an immune response in a patient suffering from immunodeficiency.
40. The use, in the manufacture of a medicament of an immunosuppresive 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 of 15-mers or less in length as herein before defined 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; Intellectual Property Office of NZ \ - 5 jam 2001 RECEIVED 48 335039 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; Bis Glu or Asp; C is a carrier compound residue; Z is a carrier compound residue, for providing an immunosuppresive or immunoregulatory effect in a patient.
41. The use in the manufacture of a medicament of 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 of 15-mers or less in length as herein before defined, 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; i Bis Glu or Asp; C is a carrier compound residue; Z is a carrier compound residue, for enhancing immune response in a patient suffering from a condition selected from the group consisting of: Intellectual Property Office of NZ - 5 jan 2001 RECEIVED (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.
42. The use in the manufacture of a medicament, of 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 of 15-mers or less in length as herein before defined, 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, for enhancing immune response in a patient suffering from a condition selected from the group consisting of: fnteTlectual Property Office of NZ -5 jan 2001 RECEIVED (a) immunodeficiency resultant from a viral infection; (b) immunodeficiency resultant from one or more of the following, bacterial, mycopiasmic, 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.
43. The use in the manufacture of a medicament of a vaccination effective amount of a pharmaceutical formulation comprising: at least one vaccine against said condition; and at least one poiycionai or monoclonal antibody, or at least one Fab fragment thereof, generated to at least one compound of 15-mers or less in length as herein before defined 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 Giu or Asp; C is a carrier compound residue; Intellectual Property Office of HZ - 5 jan 2001 RECEIVED Z is a carrier compound residue, for 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) myaigic encephaiomyeiitis (ME); (f) post inoculation or viral infection fatigue syndrome; (g) tuberculosis infection; and (h) malarial infection.
44. The use in the manufacture of a medicament of 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 of 15-mers or less in length as herein before defined selected from the group consisting of: D-A-Q-B-E; D-A-Q-B; and A-Q-B-E; wherein; Q is a sub-sequence consisting of one or two amino acid residues; D is an amino acid sub-sequence comprising at ieast one amino acid residue; E is an amino acid sub-sequence comprising at least one amino acid residue; A is Lys, Arg or His; Bis Glu or Asp; and wherein said at least one compound comprises at least 4 amino (Intellectual Property Office of NZ - 5 JAN 2001 acid residues, for 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, mycopiasmic, 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) myaigic encephalomyelitis (ME); (f) post inoculation or viral infection fatigue syndrome; (g) tuberculosis infection; and (h) malarial infection.
45. The use in the manufacture of a medicament, of 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 of 15-mers or less in length as herein before defined, 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, lie, Leu, Met, Phe, Trp, Val and Tyr; Intellectual Property Office of NZ - 5 jan 2001 ppr.Fivpn 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, for 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, mycopiasmic, 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.
46. The use, in the manufacture of a medicament, of 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 of 15-mers or less in length as herein before defined, 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; Intellectual Property Office of NZ - 5 jan 2001 54 M5039 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, lie, 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, for 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.
47. The use, in the manufacture of a medicament, of an immune response reducing effective amount of a pharmaceutical formulation comprising at least one compound of 15-mers or less in lengths herein before defined selected from the group consisting of: intellectual Property Office of NZ - 5 JAN 2001 RECEIVED 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, for reducing immune response in a patient in need of such treatment.
48. The use as recited in claim 47, 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. , ^ ^ K Intellectual Property Office of NZ - 5 jan 2001 n crcivcn 56 9
49. The use, in the manufacture of a medicament of an immune response reducing effective amount of a pharmaceutical formulation comprising at least one compound of 15-mers or less in length as herein before defined 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, He, Leu, Met, Phe, Trp, Val and Tyr; X is a covalent bond or an amino acid sub-sequence comprising at least one amino acid residue; Y is a covalent bond or an amino acid sub-sequence comprising at least one 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; . Intellectual Property B is Glu or Asp; Office of NZ C is a carrier compound residue; 5 2QQ] RECEIVED 33 503 Z is a carrier compound residue, for reducing immune response in a patient in need of such treatment. 50. The use in the manufacture of a medicament of an immunosuppresive sequence vaccinating effective amount of a pharmaceutical formulation comprising at least one modified sequence comprising a compound which is identical to said at least one immunosuppressive sequence, wherein one or more positive/negative group defined as a two amino acid subsequence where a positive amino acid is selected from the group consisting of Lys, Arg and His is adjacent to a negative amino acid selected from the group consisting of Glu and Asp is present in said at least one 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, for vaccinating against at least one immunosuppresive 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 G In-Asn-Arg-Arg-G ly-Leu-G lu-Leu-Leu-P he-T rp-Glu-Gln-Gly-Gly-Leu-Cys-Lys-Ala-Leu-Gln-Glu-Gly-.Cys-Arg-Phe; (SEQ ID NO. 2) ' HTLV-I I 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-Aia-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; for treating a patient in need of such vaccination. i INTELLECTUAL PROPERTY \ OFFICE OF N.z. i 1 2 mar 2001 ED 57 Z is a carrier compound residue, for reducing immune response in a patient in need of such treatment.
50. The use in manufacture of a medicament of an immunosuppresive sequence vaccinating effective amount of a pharmaceutical formulation comprising at least one 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, for vaccinating against at least one immunosuppresive 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-I I gp21E Gln-Asn-Arg-Arg-Gly-Leu-Glu-Leu-Leu-Phe-Trp- -Glu-Gln-Gly-Gly-Leu-Cys-Lys-A!a-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-Aia-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 adjacent to a negative amino acid selected from Glu and Asp, in a patient in need of such vaccination. Intellectual Property Office of NZ - 5 jan 2001 ** m> I * f If"
51. The use in the manufacture of a medicament of an immunosuppresive sequence vaccinating effective amount of a pharmaceutical formulation comprising at least one compound which is identical to said at least one immunosuppresive 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, for 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 of 15-mers or less in length as herein before defined 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 comprisina 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; 1 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. Intellectual Property Office of NZ - 5 jan 2001 received 59 9
52. Polyclonal or monoclonal antibody, or at least one Fab fragment thereof, generated to at least one compound of 15-mers or less in length as herein before defined 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.
53. Polyclonal or monoclonal antibody as recited in claim 52, wherein said at least one compound consists of 14 or fewer amino acid residues.
54. Polyclonal or monoclonal antibody as recited in claim 52, wherein said at least one compound consists of 8 or fewer amino acid residues.
55. Polyclonal or monoclonal antibody as recited in claim 52, wherein sad at least one compound consists of 4 or fewer amino-acid residues.
56. Polyclonal or monoclonal antibody, or at least one Fab fragment thereof, generated to at least one compound of 15-mers of less in length as herein before defined selected from the group consisting of: Intellectual Property Office of NZ - 5 jan 2001 received jss0j9 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.
57. Polyclonal or monoclonal antibody as recited in claim 56, wherein said at least one compound consists of 14 or fewer amino acid residues.
58. Polyclonal or monoclonal antibody as recited in claim 56, wherein said at least one compound consists of 8 or fewer amino acid residues.
59. A peptide of 15-mers or less in length_as herein before defined having the formula R1-R2-R3-R4, wherein R1 is a region of up to 5 amino acids within which there is one to three amino acids from the group Lysine and/or Arginine; R2 is a short region of up to 2 amino acids which does not contain any of the following: Asp, Glu, Lys, Arg or His; Intellectual Property Office of NZ - 5 jan 2001 RECEIVED 61 ^ I J! r ; ; R3 is a region of up to 7 amino acids within which there may be one or two amino acids 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 amino acids between these said acids and the R4 region; and Lysine or Arginine attaching to region R3 and the other amino acid is either Aspartic acid or Glutamic acid.
60. A pharmaceutical composition comprising at least one compound of 15-mers or less in length as herein before defined 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 R4 is a region of two amino acids containing one amino acid of either residue; A is Lys, Arg or His; B is Glu or Asp; Intellectual Property Office of NZ - 5 jan 2001 RECEIVED 62 C is a carrier compound residue; Z is a carrier compound residue. \
61. A compound selected from the group consisting of: sequences 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-G!u-Gln-Gly-Gly-Leu-Cys-Lys-Ala-Leu-Gln-G!u-Gly-Cys-Arg-Phe; (SEQ ID NO. 2) HTLV-II gp21E Gln-Asn-Arg-Arg-Gly-LeuM3lu-Leu-Leu-Phe-Trp- r%- Glu-Gln-Gly-Gly-Leu-Cys-Lys-Ala-lle-Gln-Glu-Gln-Cys-Cys-Phe; (SEQ ID NO. 3) MoLV p15E Gln-Asn-Arg-Arg-Gly-Leu-Glu-Leu-Leu-Phe-Leu-Lys-Glu-Gly-Gly-Leu-Cys-Ala-A!a-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 and 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 a modified sequence, said modified sequence comprising at least one amino acid residue of the two amino acid residues in said one or more positive/negative group being 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.
62. A peptide of 15-mers or less in length as herein before defined having the formula RA-RB-RC-RD, wherein: UnteTlectual Property Office of NZ - 5 jan 2001 RECEIVED 63 RA is a region of up to 5 amino acids within which there is one to three amino acids from the group Lysine and/or Arginine; RB is a short region of up to 2 amino acids which does not contain any of Asp, Glu, Lys, Arg or His; RC is a region of up to 7 amino acids within which there may be one or two amino acids 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 amino acids between this said amino acid, if one exists, and the RD region; and RD is a region of three or four amino acids containing one amino acid of either Lysine or Arginine attaching to region RC and one or two amino acids in the middie of the region containing amino acid from Polar and/or non-Polar with another amino acid at the end of the region which is either Asp or Glu.
63. Polyclonal or monoclonal antibody, or at least one Fab fragment thereof, generated to at least one compound of 15-mers or less in length as herein before defined 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 covaient 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. Intellectual Property Office of NZ - 5 jan 2001 RECEIVED 64 / ^ "W \
64. Polyclonal or monoclonal antibody, or at least one Fab fragment thereof, generated to at least one compound of 15-mers or less in length as herein before defined 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.
65. Polyclonal or monoclonal antibody, or at least one Fab fragment thereof, generated to at least one compound of 15-mers or less in length as herein before defined 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; Intellectual Property Office of NZ - 5 jan 2001 RECEIVED D is an amino acid sub-sequence comprising at ieast one amino acid residue; A is Lys, Arg or His; B is Glu or Asp; C is a carrier compound residue; Z is a carrier compound residue.
.. 66. Polyclonal or monoclonal antibody, or at least one Fab fragment thereof, generated to at least one compound of 15-mers or less in length as herein before defined 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.
67. Polyclonal or monoclonal antibody, or at least one Fab fragment thereof, generated to at least one compound of 15-mers or less in length as herein before defined 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; Intellectual Property C-X-A-Q-B-H-Y-Z; 0ff,C8 °f NZ C-X-A-Q-B-H-D; - 5 jan 2001 RECEIVED 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, lie, 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.
68. Polyclonal or monoclonal antibody, or at least one Fab fragment thereof, generated to at least one compound of 15-mers or less in length as herein before defined 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, lie, Leu, Met, Phe, Trp, Val and Tyr; D is an amino acid sub-sequence comprising at least one amino acid residue; Intellectual Property Office of NZ - 5 jan 2001 RECEIVED E is an amino acid sub-sequence comprising at least one^amino acic -jj < residue; A is Lys, Arg or His; Bis Glu or Asp; and wherein said at least one compound comprises at least 4 amino acid residues.
69. An in vitro method of assaying body fluid from an animal, comprising contacting said body fluid with at least one antibody as recited in claim 52 or claim 56.
70. An in vitro method of screening a vaccine, comprising contacting said vaccine with at least one antibody as recited in claim 52 or 56.
71. The use, in the manufacture of a medicament of an effective dosage of a pharmaceutical formulation comprising polyclonal or monoclonal antibodies generated to any one or more sequences selected from the group consisting of: Ala-His-Asp; Ala-His-Glu; Ala-Lys-Asp; Ala-Lys-Glu; Ala-Arg-Asp; Ala-Arg-Glu; lle-His-Asp; lle-His-Glu; lle-Lys-Asp; lle-Lys-Glu; lle-Arg-Asp; lle-Arg-Glu;Leu-His-Asp;Leu-His-G!u;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-Giu; Phe-Arg-Asp;Phe-Arg-GIu; Pro-His-Asp; Pro-His-Giu; 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; lle-Asp-Lys; lle-Glu-Lys; lle-Asp-Arg; lie-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-G!u-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-A^^cg^TUAL property I OFFICE OF N.Z. Pro-Glu-Arg; Trp-Asp-His; Trp-Glu-His; Trp-Asp-Lys; Trp-3lu-Lys; 1 2 mar 2001 received Trp-Asp-Arg; Trp-Giu-Arg; Val-Asp-His; Va!-G!u-His; Vai-Asp-Lys; Val-Glu-Lys; Val-Asp-Arg; and Val-Glu-Arg, for the treatment of a patient, 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) Tuberculois infection; or (h) Malarial infection.
72. The use, in the manufacture of a medicament of an effective dosage of pharmaceutical formulation wherein the active constituent is one or more of the peptides defined in any one of claims 1, 5, 15, 23, 27, 38, 39, 41, 42, 45, 46, 47, 49, 50 or 51 for the 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; or (f) Graft v host disease to reduce immune activity in organ and tissue transplant rejection.
73. An in vitro method comprising contacting an antibody that is generated against a peptide defined in any of claims 1, 5, 15, 23, 27, 38, 39, 41, 42, 45, 46,47, 49, 50 or 51 with a blood, serum or body fluid sample to determine the level of a peptide that comprises an amino acid sequence defined in any of claims 1, 5, 15, 23, 27, 38, 39, 41, 42, 45, 46, 47, 49, 50 or 51 and measuring the level of anti-body peptide complex that is generated. Intellectual Property Office of NZ -5 jan 2001 69
74. The use in the manufacture of a medicament for modulating an immune response in a human or an animal, wherein the medicament comprises an acceptable carrier and a polyclonal or monoclonal antibody generated to a peptide defined in any of claims 1, 5, 15, 23, 27, 38, 39, 41, 42, 45, 46, 47, 49, 50 or 51.
75. The use in the manufacture of a medicament, of a 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, for immune treatment in a human and/or animal.
76. The use in the manufacture of a medicament, of a whole or in part polyclonal or monoclonal antibodies generated to the specific peptide sequence Val-Glu-Arg-Tyr-Leu-Lys-Asp-GIn (SEQ ID N0.8) which encloses two ion bridge pairs within both polar and non-polar amino acids, for immune treatment of a human and/or animal.
77. The use in the manufacture of a medicament, of a whole or in part polyclonal or monoclonal antibodies generated to one or a combination of these specific peptide sequences having 15-mers or less in length as herein before defined: (a) Pro-Lys-Glu-lle-Ala (SEQ ID NO. 9) (b) Ala-Asp-Lys-Val-Met (SEQ ID NO. 10) Val-Glu-Lys-Tyr (SEQ ID NO. 11) Leu-Glu-Lys-Tyr (SEQ ID NO. 12) Tyr-Asp-Lys-ile (SEQ ID NO. 13) ^ Leu-Glu-Lys-lle (SEQ ID NO. 14) Ser-Glu-Arg-Leu (SEQ ID NO. 15) Gly-Glu-Lys-lle (SEQ ID NO. 16) Leu-Glu-Arg-GIy (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) Intellectual Property Office of NZ - 5 jan 2001 received Thr-Glu-Arg-Va! (SEQ ID NO. 22) Thr-Asp-Arg-Val (SEQ ID NO. 23) Vai-GIu-Arg-Tyr (SEQ ID NO. 24) . - ' . Gln-Asp-Lys-Leu (SEQ ID NO. 25) Thr-Glu-His-Leu (SEQ ID NO. 26) Leu-Asp-Arg-Leu (SEQ ID-NO. 27) Phe-Glu-Lys-Thr (SEQ ID NO. 28) Ser-Arg-Asp-Leu (SEQ ID NO. 29) Leu-Glu-Lys-Tyr (SEQ ID NO. 30) Asn-Glu-Arg-Leu (SEQ ID NO. 31) lle-Glu-Lys-Ttir (SEQ ID NO. 32) and Asn-Glu-Lys-Phe (SEQ ID N0.33), for immune treatment in a human and/or animal. 78. The use according to any one of Claims 70-72 or an in vitro method according to claim 73, 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. 79. The use, in the manufacture of a medicament, of one or more polyclonal and /or monoclonal antibodies to sequences as specified in Claims 70-73 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 Thj. cell type dependent immune resistance to infection, for providing immune treatment to a patient in need thereof. 80. The use as recited in any one of claims 70-72 and 74-79 or an in vitro method according to claim 73, further comprising administering to said patient an antiviral therapy. 81. The use as recited in claim 80, wherein said antiviral therapy comprises administration of zidovudine. 82. A pharmaceutical formulation comprising at least one antibody as recited in any one of claims 52-58 and 63-68, together with an antiviral mater 83. A pharmaceutical formulation as recited in claim 82, whe therapy comprises zidovudine. INTELLECTUAL PROPERTY OFFICE OF N.Z. rein ^ai^l ^ M01 REC ElVED 70 •' ~ ' sJ) 0 Thr-Glu-Arg-Val (SEQ ID NO. 22)' Thr-Asp-Arg-Val (SEQ ID NO. 23) Val-Glu-Arg-Tyr (SEQ ID NO. 24) Gln-Asp-Lys-Leu (SEQ ID NO. 25) Thr-Glu-His-Leu (SEQ ID NO. 26) Leu-Asp-Arg-Leu (SEQ ID-NO. 27) Phe-Glu-Lys-Thr (SEQ ID NO. 28) Ser-Arg-Asp-Leu (SEQ ID NO. 29) Leu-Glu-Lys-Tyr (SEQ ID NO. 30) Asn-Glu-Arg-Leu (SEQ ID NO. 31) lle-Glu-Lys-Thr (SEQ ID NO. 32) and Asn-Glu-Lys-Phe (SEQ ID N0.33), for immune treatment in a human and/or
78. The use according to any one of claims 71 or 72 or an in vitro method according to claim 70 or claim 73, 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.
79. The use, in the manufacture of a medicament, of one or more polyclonal and /or monoclonal antibodies to sequences as specified in claims 70-73 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 Thi cell type dependent immune resistance to infection, for providing immune treatment to a patient in need thereof.
80. The use as recited in any one claims 71-79 or an in vitro method according to claim 70 or claim 73, further comprising administering to said patient an antiviral therapy. ~
81. The use as recited in claim 80, wherein said antiviral therapy comprises administration of zidovudine.
82. A pharmaceutical formulation comprising at least one antibody as recited in any one of claims 52-58 and 63-68, together with an antiviral material.
83. A pharmaceutical formulation as recited in claim 82, wherein said antiviral therapy comprises zidovudine. animal. 71
84. A pharmaceutical formulation comprising at least one peptide as recited in any one of claims 59 and 62, together with an antiviral material.
85. A pharmaceutical formulation as recited in claim 84, wherein said antiviral therapy comprises zidovudine.
86. A pharmaceutical formulation comprising at least one compound as recited in claim 61, together with an antiviral material.
87. A pharmaceutical formulation as recited in claim 86, wherein said antiviral therapy comprises zidovudine. Intellectual Property Office of NZ -5 jan 2001 REQ ElVED
NZ335039A 1996-09-11 1997-09-10 Enhancing immune response by administering antibody raised to amino acid sequences with specific ion bridge pair arrays NZ335039A (en)

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