EP0980390A2 - Anticorps monoclonaux specifiques de la molecule cd28 humaine pour activation de cellules t de maniere non specifique de l'antigene - Google Patents

Anticorps monoclonaux specifiques de la molecule cd28 humaine pour activation de cellules t de maniere non specifique de l'antigene

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Publication number
EP0980390A2
EP0980390A2 EP98934848A EP98934848A EP0980390A2 EP 0980390 A2 EP0980390 A2 EP 0980390A2 EP 98934848 A EP98934848 A EP 98934848A EP 98934848 A EP98934848 A EP 98934848A EP 0980390 A2 EP0980390 A2 EP 0980390A2
Authority
EP
European Patent Office
Prior art keywords
cells
human
monoclonal antibodies
mouse
antibodies
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP98934848A
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German (de)
English (en)
Inventor
Thomas HÜNIG
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Theramab LLC
Original Assignee
TeGenero AG
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Filing date
Publication date
Application filed by TeGenero AG filed Critical TeGenero AG
Publication of EP0980390A2 publication Critical patent/EP0980390A2/fr
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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
    • 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
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/70521—CD28, CD152
    • 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
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered

Definitions

  • the invention relates to monoclonal antibodies which are specific for human CD28 and which activate T-lymphocytes without occupying an antigen receptor of the T-lymphocytes and thus antigen-nonspecifically, hybridoma cells for producing such antibodies, a method for producing such antibodies and uses of such antibodies.
  • Monoclonal antibodies are antibodies that are produced by hybrid cell lines (so-called hybridomas) that are formed by fusing an antibody-producing B cell of animal or human origin with a suitable myeloma tumor cell.
  • CD28 is a cell surface molecule of known amino acid sequence expressed on T lymphocytes of human and animal origin, which is part of the international "Human
  • T-lymphocytes means the increase in metabolic activity, increase in cell volume, synthesis of immunologically important molecules and entry into the cell division (proliferation) of T-lymphocytes due to an external stimulus. For example these processes are triggered by occupation of the CD28 molecule on T cells by special CD28-specific monoclonal antibodies
  • the activation of T lymphocytes with the described side effects is part of the physiological immune reaction, but can get out of control there in pathological situations (lymphoproliferative diseases ), or inadequate (immunodeficiency).
  • the following technological background is important for understanding the invention.
  • the activation of resting T cells for proliferation and functional differentiation first requires the occupation of two surface structures, so-called receptors: 1. the antigen receptor, which has a different specificity from cell to cell and for the detection of antigens, e.g. B. viral fission products is necessary; as well as the CD28 molecule expressed equally on all resting T cells, which naturally binds to ligands on the surface of other cells of the immune system.
  • receptors 1. the antigen receptor, which has a different specificity from cell to cell and for the detection of antigens, e.g. B. viral fission products is necessary; as well as the CD28 molecule expressed equally on all resting T cells, which naturally binds to ligands on the surface of other cells of the immune system.
  • costimulation of the antigen-specific immune reaction by CD28. In cell culture, these processes can be simulated by filling the antigen receptor and the CD28 molecule with suitable monoclonal antibodies. In the classic system of costimulation, neither the occupation of the antigen
  • Monoclonal antibodies of the type mentioned are known.
  • IL-2 growth factor interleukin-2
  • CD28-specific monoclonal antibodies with different functional properties were described: "classic antibodies” which only stimulate the activation of resting T cells when the antigen receptor is occupied; and "direct”, which can activate T lymphocytes of all classes in vitro and in the test animal for proliferation without the occupation of the antigen receptor. Both monoclonal antibodies known in this respect result from an immunization with cells on which rat CD28 is expressed and are obtainable by different selections directed towards their respective described properties.
  • CD28-specific monoclonal antibodies which have the direct activating effect bind to T-lymphocytes much more slowly than classic CD28-specific monoclonal antibodies; however, binding to a mouse fibroblast cell line (L-929), on the surface of which the CD28 molecule is artificially expressed by transfection, is for classic and "directly" stimulating CD28-specific monoclonal antibodies at the same rate.
  • the "directly" stimulating CD28-specific monoclonal antibodies known in this respect recognize an active form of the CD28 molecule, the presence of which on suppressed T cells is suppressed by a hitherto unknown mechanism, which, however, occurs when the molecule is expressed in non- T tumor cell lines is accessible.
  • the monoclonal antibodies known in this respect are, on the one hand, specific against rat CD28 and, on the other hand, mouse antibodies. For both reasons, therefore, they are not suitable for therapeutic purposes in humans.
  • the invention is based on the technical problem of providing "direct" human CD28-specific monoclonal antibodies which, on the one hand, are also compatible with humans and, on the other hand, to a large extent on human T cells activate assets.
  • the invention teaches human-compatible monoclonal antibodies which are specific for human CD28 and which activate human T-lymphocytes from several or all subgroups without occupying an antigen receptor of the human T-lymphocytes and thus antigen-nonspecifically, preferably with human constant components.
  • - Constant components of an antibody are areas that are not important for antigen recognition, in contrast to the variable areas that define the antigen specificity of an antibody.
  • constant components differ in the case of antibodies of different types and consequently also animals and humans.
  • the constant ranges of an antibody must correspond to those of antibodies of an organism that is to be treated with the antibodies in order to be compatible.
  • Monoclonal antibodies according to the invention are therefore on the one hand compatible with human beings, either per se or through humanization, and on the other hand can be used to treat various diseases which are based on insufficient T-lymphocyte activity, since the antibodies against human CD28 are specific and because the activation of the T-lymphocytes is comprehensive.
  • the invention naturally includes a wide variety of derivatives of monoclonal antibodies, provided that the claimed features are met.
  • Derivatives of monoclonal antibodies are to be understood as meaning modifications of the monoclonal antibody which have been produced by customary biochemical or genetic engineering manipulations. This is the case, for example, with the humanization of a mouse monoclonal antibody by partially replacing structural (constant) components of the mouse antibody with those of a human.
  • monoclonal antibodies according to the invention are obtainable by: A) producing hybridoma cells capable of producing monoclonal human CD28-specific animal antibodies by immunization with non-T tumor cell lines on which human CD28 is expressed, B) optionally humanization the monoclonal animal antibodies obtainable from hybridoma cells according to stage A by biochemical or genetic engineering exchange of constant components of the animal antibodies with analog constant components of a human antibody or replacement of the components of corresponding genes of the hybridoma cells, C) secretion of the antibodies in hybridoma cell cultures and
  • monoclonal antibodies can be obtained which are not only specific against human CD28, but which also cause a "direct" activation to a considerable extent.
  • monoclonal antibodies according to the invention have specificity for determinants of the human CD28 molecule which are difficult to access on the naturally expressed CD28 molecule and whose occupation by the novel monoclonal antibodies leads to the activation of the T cells.
  • a determinant is to be understood as the region of a molecule which is defined by the binding specificity of one or more antibodies.
  • hybridoma cells for the humanization and for the production of the monoclonal antibodies from (humanized) hybridoma cells are well known to the person skilled in the art and need not be explained in more detail here. Basically, all known, freely available cell lines which are customary, in particular, for the production of the hybridoma cells can be used. In addition to the procedure described below, the recombinant expression which is well known to the person skilled in the art can in principle be used to produce the monoclonal antibodies.
  • the hybridoma cells capable of producing monoclonal human CD28-specific animal antibodies are obtainable by a) creation a plasmid by inserting human CD28 cDNA into the pH ⁇ APr-1-neo vector after excision of the Sall-Hindlll fragment and production of protoplasts from Escherichia coli (MC1061) which carry the plasmid, b) fusion of the protoplasts with mouse A20J and / or L929 tumor cells using polyethylene glycol, c) culturing the transfected cells obtained in stage b, d) screening the transfected mouse A20J and / or L929 cells for the expression of human CD28 and selection of human CD28 expressing mouse A20J and / or L929 Cells, e) immunization of BALB / c mice with the mouse CD20 expressing mouse A20J and / or L929 cells (for example by injections 6 x ip and then 1 x iV),
  • the pHßAPr-1-neo Vector is freely available from the authors of the Gunning reference, P, et al., 1987, "A human ⁇ -actin expression vector system directs high-level accumulation of antisense transcripts", Proc. Natl. Acad. Be. USA, 84: 4831. "neo” stands for neomycin resistance. Step c) is therefore carried out in the presence of neomycin.
  • the cell lines and / or microorganisms mentioned above are freely available and can be purchased from the American Type Culture Collection (ATCC).
  • the invention accordingly also relates to hybridoma cells according to claim 4 and a method for producing antibodies according to the invention according to claims 5 and 6.
  • monoclonal antibodies according to the invention for the production of medicaments, in particular for the treatment of diseases with pathologically reduced CD4 T cell numbers, such as AIDS or in the case of stem cell transplantation after chemotherapy of leukemic diseases, for potentiation and / or qualitative influencing of immune reactions in vaccinations and / or influencing the quality of the T cell reaction, in particular influencing the production of different effector molecules, for example cytokines and chemokines and their receptors, for example in autoimmune diseases and AIDS.
  • the pharmaceutical preparation of the pharmaceuticals for the various administration forms is well known to the person skilled in the art and need not be explained in more detail here.
  • the quality of the T cell reaction is, in particular, the production of certain Understanding cytokine patterns that can be pro- or anti-inflammatory, for example, or can selectively lead to the production of certain immunoglobulin classes in B lymphocytes (classic examples of different qualities of the T cell reaction are the functional TH1 and TH2 phenotypes, as described in the following examples ).
  • the invention also encompasses methods of curing the diseases mentioned above and below using monoclonal antibodies according to the invention.
  • CMY-2 Human CD28 from a cDNA library was recombinantly expressed in A20J and / or L929 cell lines.
  • a plasmid was first created by inserting human CD28 cDNA into the pH ⁇ APr-1-neo vector after excision of the Sall-HindIII fragment.
  • Protoplasts carrying the plasmid were produced from Escherichia coli (MC1061). The protoplasts were then fused with mouse A20J and / or L929 tumor cells using polyethylene glycol. The transfected cells thus obtained were cultivated in the usual way.
  • the transfected mouse A20J and / or L929 cells were then screened for the expression of human CD28 and selection of mouse A20J and / or L929 cells expressing human CD28.
  • FIG. 2 shows that the monoclonal antibody CMY-2 isolated in this way distinguishes transfected and untransfected cells by different fluorescence intensities.
  • Differential screening for antibodies against human CD28 was carried out as follows. 50 ⁇ l of supernatant each from cultured cell hybridomas were removed and incubated for 15 min with a mixture of L929 cells and L929-CD28 transfectants. After washing, the cells were stained with DaMIg-PE. Part A shows the negative control. The cells were incubated with DaMIg-PE only. Part B shows staining with a supernatant that was slightly positive but showed no difference in either cell. Part C shows the cells stained with a supernatant from CMY-2.
  • CMY-2 is a human CD28-specific antibody.
  • CMY-2 was then tested for classical costimulatory and for "direct" stimulating activity with human T-lymphocytes enriched from peripheral blood on approximately 80%.
  • the T cell proliferation was measured by incorporating 3 H thyme between the 2nd and 3rd day of culture. The following results were achieved:
  • CD3-specific antibody 3111 cp CD3-specific antibody + CMY-2 51676 cpm
  • Ant ⁇ -CD3 provides T cell receptor stimulation (CD3 is part of the TCR complex).
  • CMY-2 was used in the form of an unpurified culture supernatant (50% final volume).
  • the effective mAb concentration to be expected is suboptimal for direct activation, but sufficient for costimulation.
  • the experiment shows that CMY-2 has direct activating properties.
  • Hybridoma cells according to the invention which produce CMY-2 have been deposited with the DSMZ, German Collection of Microorganisms and Cell Cultures GmbH, Mascheroder Weg lb, D-38124 Braunschweig, under the number DSM ACC2353 (20.05.1998).
  • DSMZ German Collection of Microorganisms and Cell Cultures GmbH, Mascheroder Weg lb, D-38124 Braunschweig, under the number DSM ACC2353 (20.05.1998).
  • B-lymphocytes for the differentiation of further CD4 T cells to TH2 cells and thus the polarization of the immune system away from the inflammatory and towards the humoral immune response, and IL-10 is the central factor for the suppression of inflammatory (THl) reactions. Only the more important results of the in vivo treatment of rats are shown. Even clearer effects were found in vitro.
  • FIG. 3 shows the expressed cytokine profile of lymph nodes and spleen cells of young LEW rats three days after ip injection of the directly activating mAb JJ316, the costimulator JJ319, the TCR-specific mAb R73 or the vehicle PBS.
  • the illustration is a so-called RNAse protection test in which radioactively labeled antisense mRNA samples are protected from degradation of added RNAse by hybridization with the RNA extracted from the tissue. These give defined bands on the gel and make it possible to see at a glance the expressed cytokine profile at the mRNA level of a tissue.
  • the two smallest fragments, L32 and GADPH, are "household genes", the uniform expression of which is used to control the same amount of RNA used in the individual batches. The test was carried out using a kit commercially available from Pharmingen.
  • JJ316 but not JJ319 or R73, massively induce IL-10 and, to a lesser extent, IL-4 mRNA.
  • the effects are particularly evident in the spleen, but are also visible in the lymph nodes.
  • the cytokine IL-4 is detected at the protein and at the single cell level by flow cytophotometric analysis.
  • the cells are first stained with mAb against the surface molecule CD4, then fixed and permeabilized, so that in a subsequent cytoplasmic staining with an IL-4-specific mAb, which is labeled with a second fluorochrome, the IL-4 protein is detected can be.
  • the evaluation is carried out in the flow cytophotometer, each point represents a cell.
  • the quadrants introduced represent the boundaries between the background and the positive reaction.
  • the methodology is also described in detail in the Pharmingen catalog.
  • FIG. 5 A biological effect of the increased IL-4 production is shown in FIG. 5: The level of detectable antibodies of the class IGE increases significantly as a result of the treatment with mAb JJ316 and demonstrates the in vivo effectiveness of the "direct" CD28-specific monoclonal antibodies induced IL-4 secretion.
  • FIGS. 6 and 7 show so-called EMSAs (Electrophoretic Mobility Shift Assays) for the detection of the induction of transcription factors which promote the development of anti-inflammatory TH2 cells. The technique is as follows. T cells are stimulated in vitro for different lengths of time, then the proteins from the cell nuclei are brought into solution and incubated with a radioactively labeled short gene probe, the sequence of which they should recognize as transcription factors.
  • EMSAs Electrophoretic Mobility Shift Assays
  • Core receptors used chemokine receptors are switched off and the production of chemokines that bind to such receptors and thus block them for HIV I viruses are induced.
  • FIG. 9 shows this for lymph nodes of the rat which had received 1 mg on day 0 of the "directly” stimulating CD28-specific monoclonal antibody (JJ316) or of the "classic” CD28-specific monoclonal antibody (JJ319).
  • CD4 T cell number is only temporarily increased; this is because healthy animals have been treated with normal CD4 T cell counts.
  • the due to the Proliferation stimulation of "excess" cells is broken down by homeostatic mechanisms.
  • FIG. 10 shows an experiment for this, namely for the so-called adjuvant arthritis in the rat, a model system for certain forms of rheumatoid arthritis in humans.
  • "Paw volume increase” indicates the increase in the volume of the paws.
  • Days stands for days.
  • Healthy data points indicate values for healthy animals.
  • a monoclonal antibody of the same immunoglobulin class with specificity for an irrelevant human cell surface molecule was used for the isotype control.
  • AA stands for adjuvant arthritis.
  • PBS stands for "phosphate buffered saline".
  • W3 / 25 stands for a monoclonal antibody with specificity for the CD4 molecule of the rat.
  • the adjuvant arthritis is mediated by so-called THl cells.
  • THl cells arise from resting CD4 T cells in the course of activation under the influence of certain soluble factors of the immune system, so-called cytokines.
  • the antagonists of the TH1 cells are the anti-inflammatory TH2 cells, the production of which is controlled by other cytokines.
  • FIGS. 10 and 11 the development of the adjuvant arthritis, read from the joint swelling (FIG. 10) and the arthritic index (FIG.
  • monoclonal antibodies according to the invention can effect an immunomodulation.
  • classic monoclonal antibodies which are specific for human CD28 (and / or can be obtained by immunization with T cells) can effect an immunomodulation.
  • classic monoclonal antibodies is also not known.
  • the invention therefore also relates to the use of monoclonal antibodies specific for human CD28 (obtainable according to the above basic procedures, when immunized with T cell lines expressing human CD28 or non-T cell lines) for the production of medicaments for modulating immune reactions, and namely immunosuppression (for example with human CD28 analogs to JJ319) or immune enhancement (for example with human CD28 analogs to JJ316 such as CMY-2).

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Abstract

L'invention se caractérise en ce qu'elle apprend à des anticorps monoclonaux tolérés chez l'homme, qui sont spécifiques à l'encontre de la molécule CD28 humaine, à activer des cellules T humaines de plusieurs à tous les sous-groupes, sans occuper de récepteur d'antigène des cellules T humaines, et par conséquent de manière non spécifique de l'antigène.
EP98934848A 1997-05-28 1998-05-28 Anticorps monoclonaux specifiques de la molecule cd28 humaine pour activation de cellules t de maniere non specifique de l'antigene Ceased EP0980390A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19722888A DE19722888A1 (de) 1997-05-28 1997-05-28 Human-CD28 spezifische monoklonale Antikörper zur antigenunspezifischen Aktivierung von T-Lymphozyten
DE19722888 1997-05-28
PCT/DE1998/001499 WO1998054225A2 (fr) 1997-05-28 1998-05-28 Anticorps monoclonaux specifiques de la molecule cd28 humaine pour activation de cellules t de maniere non specifique de l'antigene

Publications (1)

Publication Number Publication Date
EP0980390A2 true EP0980390A2 (fr) 2000-02-23

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EP98934848A Ceased EP0980390A2 (fr) 1997-05-28 1998-05-28 Anticorps monoclonaux specifiques de la molecule cd28 humaine pour activation de cellules t de maniere non specifique de l'antigene

Country Status (6)

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US (3) US6987171B1 (fr)
EP (1) EP0980390A2 (fr)
JP (1) JP2002502244A (fr)
AU (1) AU8432498A (fr)
DE (1) DE19722888A1 (fr)
WO (1) WO1998054225A2 (fr)

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DE10212108A1 (de) * 2002-03-13 2003-10-02 Tegenero Ag Verwendung einer an CD28 bindenden Wirksubstanz zur Herstellung einer pharmazeutischen Zusammensetzung
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EP1460088A1 (fr) * 2003-03-21 2004-09-22 Biotest AG Anticorps humanisé contre CD4 avec des caractéristiques immunosuppressives
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GB0920944D0 (en) 2009-11-30 2010-01-13 Biotest Ag Agents for treating disease
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CN113797332B (zh) 2013-06-24 2024-08-09 耐克西缪恩公司 用于免疫疗法的组合物和方法
CN107936189B (zh) 2013-08-28 2021-06-01 株式会社日本触媒 聚丙烯酸(盐)系吸水性树脂粉末及其制品
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US20110009602A1 (en) 2011-01-13
WO1998054225A3 (fr) 1999-03-25
US20060039909A1 (en) 2006-02-23
DE19722888A1 (de) 1998-12-03
AU8432498A (en) 1998-12-30
US6987171B1 (en) 2006-01-17
US8334102B2 (en) 2012-12-18
WO1998054225A2 (fr) 1998-12-03
JP2002502244A (ja) 2002-01-22

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