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WO1998010792A1 - Therapie a but immunitaire - Google Patents

Therapie a but immunitaire Download PDF

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Publication number
WO1998010792A1
WO1998010792A1 PCT/IB1996/000945 IB9600945W WO9810792A1 WO 1998010792 A1 WO1998010792 A1 WO 1998010792A1 IB 9600945 W IB9600945 W IB 9600945W WO 9810792 A1 WO9810792 A1 WO 9810792A1
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asp
lys
arg
immune
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Patrick T. Prendergast
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Definitions

  • the host is then capable of overcoming an infectious challenge without becoming infected or producing the usual antibody and autoantibody peak and subsequent immunosuppression normally associated with infections caused by organisms who utilise these specific amino acid sequences to direct the hosts immune signalling system towards a more pronounced B cell or Th 2 cytokine profiled response.
  • Malaria is one of the most important infectious diseases in the World, each year there are 270 million new infections resulting in over 100 million episodes of illness and approximately 2 million deaths. World-wide the malaria problem is getting worse each year.
  • the reason for this worsening situation include (A) increased levels of drug resistance on the part of the parasites, (B) increased levels of insecticide resistance on the part of the vectors .
  • No vaccine has yet been produced which can successfully induce a protective antibody response and the reason for this is that although antibodies which cross react with many epitopes of the P.
  • vivax circumsporozoite are produced in abundance by the current unprotective vaccine candidates, because of the immune blind spot or immunologically privileged sites offered by these specific sequences identified herein, like Interleukin 10 and AFP are not visible to the host immune system which both allow the parasite to gain access to the host cell and to cause the non-specific polyclonal B cell activation and immunosuppressive (Interleukin 10 and/or AFP) like effects which are so universal for people suffering from parasites such as malaria, and Leishmania, the host cannot gain enough immune reactive monocytes to overcome the infection initially because these Interleukin 10/AFP mimic molecules carried by the infecting organism shuts down the vital Th x T cell response needed to clear intra-cellular infections.
  • Interleukin 10 and AFP non-specific polyclonal B cell activation and immunosuppressive
  • a vaccine for malaria which will enable a human to raise a protective antibody titre against malaria sufficient to prevent infection may be manufactured using amino acid sequences displaying these specific polar arrays.
  • Another method expected to be more successful as a vaccine combination is to use passive immunisation with either polyclonal or monoclonal antibodies to these said specific sequences generated either in animal human and/or tissue culture given either before or simultaneously with any of the current malaria vaccine candidates which previously could not produce a protective immune response.
  • the said specific sequence when embedded in the cell membrane of the host activate the phosphatidylinositol pathway, which causes the release of Ca++, the phosphosylation of cell proteins and the activation or enhanced activity of certain enzymes related to metabolism. This does not occur in the presence of antibodies to the disclosed specific sequences and the organism like malaria, Mycobacterium Tuberculosis, Leishmania, HIV and others are not able to cause metabolic and immune Th 2 activation and exhaustion. It is an important coincidence that in certain malaria endemic areas that genetic mutations that have caused the deletion of the metabolic activity control enzyme glucose- 6 -phosphate dehydrogenase has conferred on the host immunity to malaria. By intervening at an early stage of infection and neutralising certain properties of the malaria parasite to alter cellular reactions by interfering with these specific membrane signal transduction sequences as defined herein it is possible to confer protective immunity to this organism.
  • the present invention utilises the novel discovery that certain amino 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.
  • Ion bridge
  • DTH delayed-type hypersensitivity
  • CD3/TCR mimic membrane interaction molecules which present as hydrophobic Ion bridge pairs are utilised by both the organism itself as specific peptides and by cytokines and also by infectious agents to modulate immune response (A) during periods of reproductive foetal gestation as with the alpha-fetoprotein molecule to prevent foetal rejection by the maternal immune system and (B) during cytokine control of immune functions as with cytokine synthesis inhibitory factor (Interleukin 10) when a Th 2 cytokine profile is required or to curtail the uncontrolled Th ⁇ T4 cell immune response.
  • cytokine This cytokine (IL-10) is particularly evident following vaccination to enhance humoral immunity and secure antibody formation, and often causes the temporary disappearance of the Tuberculin reaction which is associated with Th : (DTH) response in patients following vaccination.
  • 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 T4 cell response and enhance the humoral (antibody mediated) immune response of their infected host, see sample listing enclosed.
  • Anti-serum generated to these specific sequences as presented in AFP, Interleukin 10, EBV-BCRF1 and other peptides and as specified in amino acid sequence, listing enclosed, with this patent can be used to remove Interleukin 10 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 Thl cell mediated immune attack.
  • This invention relates to methods of treatment of persons and animals with indications of immunodeficiency, wherein the said indication is resultant from viral and/or retroviral infection and/or infectious parasites, bacteria and/or mycoplasma.
  • the invention further relates to treatment with the above antiserum either poly or monoclonal in nature for establishing improved immuno response for persons and prophylactic treatment for persons where immuno-malfunction due to genetic pre-disposition or infection is considered a future risk.
  • the invention further relates to a screening method for vaccines, manufactured by the use of coat or other peptides from viral, bacterial, parasitic or mycoplasma, to determine and remove and/or neutralise inherent immune suppressive properties - such suppressive potential properties is determined by the manufactured vaccine's reactivity with the said specific amino acid sequences as outlined herein, be they synthetic or natural in origin, e.g. AFP, Interleukin 10, viral or bacterial coat peptides.
  • the host organism man or animal
  • Treatments used according to this invention employing the poly or monoclonal antiserum to these specific cytokine inhibitory sequences are administered as treatments against viral, bacterial and mycoplasma and parasitic infections which cause immunosuppression by any suitable route including enteric, parenteral, topical, oral, rectal, nasal or vaginal routes.
  • Parenteral routes include subcutaneous, intramuscular, intravenous and sublingual administration. The preferred route of administration would be an intravenous one.
  • the present invention further provides pharmaceutical formulations, for use in treatments against HIV/HTLV- 1 , 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 with or without adjuvant, to produce an antibody response, the antibodies, mono or polyclonal will cause the binding of the immunosuppressive CD3/TCR mimic interaction molecules already present in the plasma of the infected host will be removed from the circulation of the infected host and normal immune function demonstrating a Th x cytokine profile, i.e. Interleukin 2 and gamma interferon, capable of resisting the infection will be re-established.
  • a Th x cytokine profile i.e. Interleukin 2 and gamma interferon
  • 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 Ion bridge pair arrays capable of mimicking the actions of AFP or Interleukin 10 and there 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 patent .
  • Suitable dosages in accordance with the present invention depend on many factors, e.g. the patient's weight, the mode of administration, the frequency of administration, the type of affliction being treated or prevented, whether the infection presently exists, and if so, to what degree. Suitable dosages for given situations can readily be determined by those skilled in the art without undue experimentation.
  • the total treatment time according to the present invention will vary from patient to patient based on sound medical judgement and factors particular to the patient being treated, such as, for example, the age and physical condition of the patient. Those skilled in the art can easily determine suitable total treatment time on a patient by patient basis.
  • HIV-1 Human Immunodeficiency Virus Type 1
  • AIDS Acquired Immune Deficiency Syndrome
  • AIDS is characterised as a profound breakdown in host's cellular and humoral immunity and increased susceptibility to a wide range of opportunistic infections.
  • One of the consequences of this immune dysfunction is a marked depletion in absolute CD4+ cells in HIV- infected individuals. Studies over the past years have demonstrated that the destruction of the immune system by HIV-1 is a chronic process, starting at the moment of infection.
  • the major histocompatibility complex is a collection of 40-50 genes arrayed within a long continuous stretch of DNA on chromosome 6 in humans .
  • the MHC is referred to as the HLA complex in humans.
  • the MHC genes are organised into regions encoding three classes of molecules: Class I, Class II and Class 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 T c cells.
  • the Class II genes encode glycoproteins expressed primarily on antigen-presenting cells (macrophages, dendritic cells, and B cells), where they present processed antigenic peptides to Th 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.
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • a number of white blood cells have cytotoxic potential and express membrane receptors for the Fc region of the antibody IgG molecule.
  • this antibody is specifically bound to a target cell which occurs when these specific poly or monoclonal antibodies to these sequences present on AFP, Interleukin 10 bind to HIV infected cells or free viral peptides causing immune Th2 shift.
  • Interleukin 10 bind to HIV infected cells or free viral peptides causing immune Th2 shift.
  • These cytotoxic Fc receptor-bearing cells can bind to the antibodies' Fc region, and thus to the infected HIV cells, and subsequently cause lysis of these cells.
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • the variety of cells that have been shown to exhibit ADCC include NK cells. Macrophages, monocytes, neutrophils, and eosinophils. 2.0 OBJECTIVES 2.1 To provide for an administration of monoclonal antibodies to these specified sequences present on AFP and Interleukin 10 and other cytokines and infectious organisms to HIV+ patients. 2.2 To monitor immune system functioning before and after the administration of these mono or polyclonal antibodies.
  • Beta-2-microglobulin level 3.6. Appearance of new or improvement of active opportunistic infections.

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  • General Physics & Mathematics (AREA)
  • Pregnancy & Childbirth (AREA)
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Abstract

L'invention concerne une séquence d'acides aminés présentant des groupes de paires d'ions spécifiques (ponts) ceints au moins d'un côté par des segments transmembranaires hydrophobes non polaires, en tant que mécanisme utilisé par de nombreux agents infectieux et plusieurs facteurs d'inhibition de la cytokine, tels que l'interleukine 10, le facteur d'inhibition de la prolactine et l'alpha-foeto-protéine. Ladite séquence n'est pas seulement utilisée pour amoindrir les défenses immunitaires des hôtes mais également pour permettre l'infection de tissus lymphoïdes cibles. Il a été prouvé que certains vaccins, lorsqu'ils sont inoculés à un hôte, produisent un certaine gamme d'anticorps neutralisants mais n'empêchent pas l'infection lorsque l'hôte est ensuite exposé à un organisme infectieux vivant. Dans la thérapie de l'invention, lorsque l'inoculation de ce type de vaccin est combinée à une immunisation passive au moyen d'anticorps mono ou polyclonaux dirigés contre lesdites séquences d'acides aminés, l'hôte est capable de surmonter l'agression infectieuse. L'invention se rapporte à l'utilisation thérapeutique d'anticorps mono ou polyclonaux dirigés contre lesdites séquences spécifiques pour le traitement du syndrome d'immunodéficience acquise (SIDA) et d'autres états pathologiques qui persistent en raison de la présence d'un facteur d'inhibition de la cytokine d'origine virale, bactérienne ou provenant de l'hôte, tel que le syndrome de fatigue chronique dans lequel les molécules d'imitation de l'interleukine 10 sont responsables d'une multitudes de symptômes identifiés comme indicateurs de l'encéphalomyélite. L'invention se rapporte à l'utilisation thérapeutique d'anticorps mono ou polyclonaux dirigés contre ces séquences d'acides aminés spécifiques, sous forme de thérapie associée au moyen de vaccins et d'agents antiviraux pour la prévention des effets secondaires de certains agents de modulation des défenses immunitaires et antiviraux (ex: DHEA et IL-12) qui provoquent la production accrue de molécules d'imitation de l'interleukine 10 ou de l'alpha-foetoprotéine pendant la thérapie. L'invention se rapporte encore à l'utilisation thérapeutique de ces séquences spécifiques soit isolées de la source de l'organisme source ou produits par synthèse directe ou synthèse de protéines recombinaison. Ces peptides, lorsqu'ils sont administrés à un patient souffrant d'une maladie auto-immune, tels que, entre autres, la sclérose en plaques, le lupus érythémateux (lupus érythémateux systémique), le diabète ou la polyarthrite rhumatoïde ou à des receveurs de transplant, permettent de modifier l'état immunitaire du patient de sorte que soit produite 'une réponse immunitaire dépendante de l'anticorps Th2 et que soit inhibée l'attaque immunitaire de Th1 (dépendant des lymphocytes) qui se manifeste dans ces types de déficiences immunitaires, telles que la sclérose en plaques et la réaction du greffon contre l'hôte. Certaines affections dermatologiques qui sont aujourd'hui traitées au moyen de crèmes et d'onguents corticostéroïdes peuvent être également traitées avec succès par le remplacement des corticostéroïdes par ces séquences immunosuppressives d'imitation de l'interleukine 10 et de l'alpha-foetoprotéine de l'invention.
PCT/IB1996/000945 1996-09-11 1996-09-13 Therapie a but immunitaire Ceased WO1998010792A1 (fr)

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AU68870/96A AU6887096A (en) 1996-09-11 1996-09-13 Immune direction therapy

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US2518096P 1996-09-11 1996-09-11
US60/025,180 1996-09-11

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PCT/IB1996/000945 Ceased WO1998010792A1 (fr) 1996-09-11 1996-09-13 Therapie a but immunitaire
PCT/IB1997/001086 Ceased WO1998010787A2 (fr) 1996-09-11 1997-09-10 Therapie a but immunitaire

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EP (1) EP0929568A2 (fr)
JP (1) JP2001503613A (fr)
CN (1) CN1230195A (fr)
AU (2) AU6887096A (fr)
CA (1) CA2265885A1 (fr)
IL (1) IL128806A0 (fr)
NZ (1) NZ335039A (fr)
SE (1) SE9900812L (fr)
WO (2) WO1998010792A1 (fr)

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US8283165B2 (en) 2008-09-12 2012-10-09 Genvault Corporation Matrices and media for storage and stabilization of biomolecules
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US8932829B2 (en) 2005-07-07 2015-01-13 Elena Dudich Recombinant alpha-fetoprotein and compositions thereof
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CN114163493B (zh) * 2021-11-18 2023-09-15 浙大宁波理工学院 一种可作为5型磷酸二酯酶抑制剂的多肽及其应用

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US7589184B2 (en) 2004-05-24 2009-09-15 Genvault Corporation Stable protein storage and stable nucleic acid storage in recoverable form
US7989590B2 (en) * 2005-03-22 2011-08-02 Rohto Pharmaceutical Co., Ltd Peptides that increase collagen or hyaluronic acid production
US7553932B1 (en) 2005-04-25 2009-06-30 La Jolla Institute For Allergy And Immunology Methods of treating viral infection with IL-10 receptor antagonists
US8283165B2 (en) 2008-09-12 2012-10-09 Genvault Corporation Matrices and media for storage and stabilization of biomolecules
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US9637513B2 (en) 2008-09-12 2017-05-02 Gentegra Llc Matrices and media for storage and stabilization of biomolecules
US10160997B2 (en) 2008-09-12 2018-12-25 Gentegra Llc Matrices and media for storage and stabilization of biomolecules
EP2989120A4 (fr) * 2013-04-25 2017-04-19 Carmel-Haifa University Economic Corp. Peptides anti-inflammatoires synthétiques et leur utilisation
US9850278B2 (en) 2013-04-25 2017-12-26 Carmel-Haifa University Economic Corp. Synthetic anti-inflammatory peptides and use thereof

Also Published As

Publication number Publication date
AU6887096A (en) 1998-04-02
JP2001503613A (ja) 2001-03-21
CN1230195A (zh) 1999-09-29
WO1998010787A2 (fr) 1998-03-19
IL128806A0 (en) 2000-01-31
EP0929568A2 (fr) 1999-07-21
WO1998010787A3 (fr) 1998-07-30
SE9900812D0 (sv) 1999-03-08
AU4132097A (en) 1998-04-02
NZ335039A (en) 2001-04-27
CA2265885A1 (fr) 1998-03-19
SE9900812L (sv) 1999-03-08

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