WO1994006473A1 - Retablissement de l'immunosuffisance des lymphocytes t auxiliaires chez des patients contamines par le vih - Google Patents

Retablissement de l'immunosuffisance des lymphocytes t auxiliaires chez des patients contamines par le vih Download PDF

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Publication number
WO1994006473A1
WO1994006473A1 PCT/US1993/008562 US9308562W WO9406473A1 WO 1994006473 A1 WO1994006473 A1 WO 1994006473A1 US 9308562 W US9308562 W US 9308562W WO 9406473 A1 WO9406473 A1 WO 9406473A1
Authority
WO
WIPO (PCT)
Prior art keywords
antibodies
antagonist
helper cells
interleukin
antibody
Prior art date
Application number
PCT/US1993/008562
Other languages
English (en)
Inventor
Mario Clerici
Robert L. Coffman
Gene M. Shearer
Original Assignee
Schering Corporation
The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Schering Corporation, The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services filed Critical Schering Corporation
Priority to AU48567/93A priority Critical patent/AU4856793A/en
Priority to JP6508193A priority patent/JPH08501549A/ja
Priority to EP93921492A priority patent/EP0667789A1/fr
Publication of WO1994006473A1 publication Critical patent/WO1994006473A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244—Interleukins [IL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/2066—IL-10
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/54—Interleukins [IL]
    • C07K14/5428—IL-10

Definitions

  • This invention relates to the use of antagonists against IL-10 for pharmaceutical administration to patients infected with a immunodeficiency virus.
  • the administration of these antagonists restores the ability of T helper cells to produce IL-2.
  • This invention provides methods of increasing the level of IL-2 produced by T helper cells in a patient infected with a human immunodeficiency virus.
  • the method comprises administering an amount of an antagonist of interleukin 10 wherein said amount is effective to increase the patient's T helper cell production of IL-2.
  • the antagonists are preferably administered intravenously.
  • a preferred antagonist is an antibody specific for binding to IL-10.
  • the antibodies can be chimeric, recombinant, polyclonal or monoclonal. Autologous antibodies, human or humanized antibodies are preferred for safety when human patients are being treated.
  • the preferred single dosage of antibodies is 1-10 mg/kg body weight per antibody. Alternatively the amount of the antibody administered in a single dose is about 10 to about 100 ⁇ g per milliliter of patient sera.
  • This invention provides an effective means for increasing production of IL-2 in T helper cells when said levels are being inhibited by excessive levels of IL-10 attendant an infection of lentiviruses known as the human immunodeficiency virus [HIV].
  • HIV human immunodeficiency virus
  • This chronic and often fatal viral infection is typified by an imbalance in T helper cellular responses.
  • the result of this imbalance is an inhibition of IL-2 production by nonvirally infected T helper cells due to excessive levels of IL-10.
  • the IL-10 is produced by a number of different cells including a subset of the T helper cells.
  • IL-2 is responsible for T cell proliferation and is a key indicator of the status of the immune system.
  • Antagonists of IL-10 can be made by mutating the amino acid sequence of IL-10 using standard mutagenesis methods. Such methods include the use of M13 vectors to introduce single site mutations, to delete random amino acids from IL-10 or to add amino acids. The resulting muteins are then tested in standard assays for the ability to compete with nonmutated IL-10. Suitable assays are described below and include in vitro cell assays where IL-2 dependent proliferation is initiated by the presence of exogenous IL-10. This strategy have been used to characterize the functional domains of numerous proteins such as thrombomodulin, human growth factor and tissue plasminogen activator.
  • the antagonist can be an antibody specific for binding to IL-10 [ ⁇ IL-10] and which interferes with its binding to the T- helper receptor, ⁇ IL-10 is produced in a variety of conventional ways.
  • a general review of antibody production can be found in Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Pubs., N.Y. (1988) or in Colligan et al. Eds., 1991 and Suppl. Current Protocols in Immunology, Green Wiley, NY, NY.
  • Antibodies can be a polyclonal mixture or monoclonal.
  • Antibodies can be intact immunoglobulins derived from natural sources or from recombinant sources. Antibodies also include the immunore active portions of intact immunoglobulins.
  • ⁇ IL-10 antibodies involve administering an amount of antigen sufficient to induce a humoral response in a mammal.
  • the antibodies are either collected from the mammal's sera or lymphocytes removed, immortalized and those cell clones secreting the desired antibodies isolated and cultured for harvest of the desired antibodies.
  • Antibodies against IL-10 are described by Mosmann et al, 1990 /. Immunol. 145:2938.
  • the antigens can either be intact IL-10 or immunoreactive peptides.
  • Recombinant expression of IL-10 is a convenient means for obtaining IL-10 for use as antigens.
  • Specific techniques for expressing and purifying IL-10 are known. Expression of IL-10 is described in PCT/US/03554 (WO/91 /00349) and in Malefyt, et al., 1992, Curr. Opin. Immunology, 4:314-320.
  • peptide synthesis may be used to obtain intact or immunoreactive portions of IL-10.
  • the antibodies for use in this invention are preferably autologous for the patient thereby minimizing further immunological problems. Immunodefi ⁇ ent individuals will tend to be less reactive to non-self antibodies, and thus non-self antibodies derived from cells of the same species are also useful. Antibodies of different species are useful but means to control possible adverse immi oreactions must be undertaken. For example, humanized rat antibodies can minimize immune responses in human patients.
  • the antibodies for use in this invention are typically neutralizing antibodies and will preferably have binding constants which are greater than or approximates the affinity of IL-10 for its natural receptor. Antibodies having a binding constant 100-fold less than these cytokines for their corresponding receptors are less preferred. Binding comparisons are carried out using standard equilibrium methods. The basic technology is described in Chapter 25 of Vol. 1: Immunochemistry, Ed. D.M. Weir, 4th Ed. 1986, Blackwell Scientific Publ. 25. 1-25.30. Alternatively, one can use an assay for determining the molar excess of antibody which neutralizes a defined amount of IL-10 in a standard in vitro bioassay. Examples of such assays are found in Mosmann and Fong, 1989, /. Immunol.
  • the means of adinudistration of the antagonists are typically parenteral, preferably intravenous.
  • the antagonists are infused into the patient using standard intravenous techniques.
  • the antagonists are first suspended into a sterile, physiologically-compatible media, such as phosphate buffered saline.
  • Pharmaceutically acceptable excipients such as lecithin, glucose, dextrose, antibiotics may also be included with the antagonists.
  • the antagonists are antibodies, they are administered in an amount which provides circulating levels of ⁇ IL-10 at about 1 to 150 ⁇ g/ml and preferably 10 to 100 ⁇ g/ml of sera for each antibody.
  • the antibodies have a 2-7 day half -life and repeated administration is necessary when levels of ⁇ IL-10 are below these levels.
  • Total amount of ⁇ IL-10 applied per administration are between 1 and 10 mg/kg of body weight for each antibody.
  • the method will increase IL-2 production and it is preferred that said levels approach or exceed 100% of normal. Increases of greater than 50% of the IL-2 production before treatment are considered good. Treatment can be terminated when the T helper cells are producing levels of IL-2 at 10 to 100% of normal when measured by any number of conventional assays.
  • the first category are bioassays that measure IL-2 dependent proliferation of any of several immortal cell lines which proliferate in the presence of IL-2.
  • An example of such a cell line is CTLL.
  • Cell division is measured by radiolabelled thymidine uptake.
  • the second category are functional assays and involve the use of immunoassays directly measuring IL-2 such as ELISA.
  • ELISA immunoassays directly measuring IL-2

Abstract

Cette invention concerne l'utilisation d'antagonistes de IL-10 tels que des anticorps anti-IL-10 destinés à l'administration pharmaceutique pour des patients contaminés par le virus de déficience immunitaire. L'administration de ces anticorps restaure la capacité des lymphocytes T auxiliaires à produire l'IL-2.
PCT/US1993/008562 1992-09-18 1993-09-16 Retablissement de l'immunosuffisance des lymphocytes t auxiliaires chez des patients contamines par le vih WO1994006473A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU48567/93A AU4856793A (en) 1992-09-18 1993-09-16 Restoration of immunocompetency to t helper cells in hiv infected patients
JP6508193A JPH08501549A (ja) 1992-09-18 1993-09-16 Ｈｉｖ感染された患者におけるｔヘルパー細胞の免疫担当能力の回復
EP93921492A EP0667789A1 (fr) 1992-09-18 1993-09-16 Retablissement de l'immunosuffisance des lymphocytes t auxiliaires chez des patients contamines par le vih

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US94731692A 1992-09-18 1992-09-18
US07/947,316 1992-09-18

Publications (1)

Publication Number Publication Date
WO1994006473A1 true WO1994006473A1 (fr) 1994-03-31

Family

ID=25485948

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1993/008562 WO1994006473A1 (fr) 1992-09-18 1993-09-16 Retablissement de l'immunosuffisance des lymphocytes t auxiliaires chez des patients contamines par le vih

Country Status (6)

Country Link
EP (1) EP0667789A1 (fr)
JP (1) JPH08501549A (fr)
AU (1) AU4856793A (fr)
CA (1) CA2144648A1 (fr)
MX (1) MX9305713A (fr)
WO (1) WO1994006473A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19529026A1 (de) * 1995-07-28 1997-01-30 Robert Sabat Monoklonale Antikörper gegen humanes Interleukin-10
WO1998010792A1 (fr) * 1996-09-11 1998-03-19 Prendergast Patrick T Therapie a but immunitaire
WO2001012224A1 (fr) * 1999-08-13 2001-02-22 Tegenero Gmbh Utilisation d'anticorps monoclonaux specifiques de cd28 pour preparer une composition pharmaceutique appropriee au traitement d'infections virales
US7579439B2 (en) 2000-09-14 2009-08-25 Beth Israel Deaconess Medical Center, Inc. Modulation of IL-2- and IL-15-mediated T cell responses

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0405980A1 (fr) * 1989-06-28 1991-01-02 Schering Corporation Facteur inhibant la synthˬse de cytokine (CSIF), antagonistes et utilisations
EP0541214A2 (fr) * 1991-08-06 1993-05-12 Schering Corporation Utilisation d'analogues ou d'antagonistes de l'interleukine-10 pour le traitement de la toxicité due à une endotoxine ou à un superantigène

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0405980A1 (fr) * 1989-06-28 1991-01-02 Schering Corporation Facteur inhibant la synthˬse de cytokine (CSIF), antagonistes et utilisations
EP0541214A2 (fr) * 1991-08-06 1993-05-12 Schering Corporation Utilisation d'analogues ou d'antagonistes de l'interleukine-10 pour le traitement de la toxicité due à une endotoxine ou à un superantigène

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19529026A1 (de) * 1995-07-28 1997-01-30 Robert Sabat Monoklonale Antikörper gegen humanes Interleukin-10
WO1998010792A1 (fr) * 1996-09-11 1998-03-19 Prendergast Patrick T Therapie a but immunitaire
WO2001012224A1 (fr) * 1999-08-13 2001-02-22 Tegenero Gmbh Utilisation d'anticorps monoclonaux specifiques de cd28 pour preparer une composition pharmaceutique appropriee au traitement d'infections virales
US7579439B2 (en) 2000-09-14 2009-08-25 Beth Israel Deaconess Medical Center, Inc. Modulation of IL-2- and IL-15-mediated T cell responses

Also Published As

Publication number Publication date
CA2144648A1 (fr) 1994-03-31
AU4856793A (en) 1994-04-12
MX9305713A (es) 1994-05-31
JPH08501549A (ja) 1996-02-20
EP0667789A1 (fr) 1995-08-23

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