EP1328298A1 - Procedes et compositions servant a moduler l'activation des lymphocytes t et leurs utilisations - Google Patents

Procedes et compositions servant a moduler l'activation des lymphocytes t et leurs utilisations

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Publication number
EP1328298A1
EP1328298A1 EP01981352A EP01981352A EP1328298A1 EP 1328298 A1 EP1328298 A1 EP 1328298A1 EP 01981352 A EP01981352 A EP 01981352A EP 01981352 A EP01981352 A EP 01981352A EP 1328298 A1 EP1328298 A1 EP 1328298A1
Authority
EP
European Patent Office
Prior art keywords
ncam
cell
fragment
cell activation
functional derivative
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.)
Withdrawn
Application number
EP01981352A
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German (de)
English (en)
Other versions
EP1328298A4 (fr
Inventor
Anthony Montgomery
Larissa Balaian
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University of California
Scripps Research Institute
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Scripps Research Institute
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Publication of EP1328298A1 publication Critical patent/EP1328298A1/fr
Publication of EP1328298A4 publication Critical patent/EP1328298A4/fr
Withdrawn legal-status Critical Current

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    • 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
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/1777—Integrin superfamily
    • 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
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • 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
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/1774—Immunoglobulin superfamily (e.g. CD2, CD4, CD8, ICAM molecules, B7 molecules, Fc-receptors, MHC-molecules)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • 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
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], 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
    • 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
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy

Definitions

  • This invention relates generally to the field of immunology or neuroimmunology.
  • the invention provides a method for reducing or inhibiting T cell activation, which method comprises administering an effective amount of an antagonist of NCAM LI to a mammal, wherein reduction or inhibition of T cell activation is desirable, thereby reducing or inhibiting T cell activation in said mammal.
  • Combinations and combinatorial methods for modulating T cell activation are further provided.
  • the invention also provides a method for potentiating T cell activation, which method comprises administering an effective amount of a multimerized neural cell adhesion molecule LI (NCAM LI), or a functional derivative or fragment thereof, or a nucleic acid encoding said LI or functional derivative or fragment thereof, or an agent that enhances production and/or costimulatory function of said LI to a mammal, wherein T cell activation is desirable, thereby potentiating T cell activation in said mammal.
  • NCAM LI neural cell adhesion molecule LI
  • T-cell activation requires two signals; the first being provided by occupancy of the T-cell receptor (TCR) by MHC/antigen complex, the second being provided by one or more costimulatory ligands on the surface of the APC (1).
  • An array of molecules on the surface of the APC can function as costimulatory ligands including members of the immunoglobulin superfamily (IgSF) such as B7-1, B7-2 and ICAM-1 (1).
  • IgSF immunoglobulin superfamily
  • LI a neuronal CAM that also belongs to the IgSF (2).
  • LI function has almost exclusively been linked to neurological processes, including axonal guidance (3, 4). While such Ll-mediated processes have primarily been attributed to homophilic LI -LI ligation (5), this CAM can also interact with multiple heterophilic ligands including axonin 1/TAG 1, chondroitin sulfate proteoglycans, laminin and certain integrins (6,7). LI has also been shown to support cis-interactions with the heat stable antigen CD24 (8) and the tetraspan molecule CD9 (9).
  • LI expression has recently been described on cells of both lymphoid and myelomonocytic origin (10, 11). Specifically, LI can be detected on freshly isolated peripheral blood monocytes and on functionally mature monocyte-derived dendritic cells (DC) and on follicular DC in situ (11). Further constitutive expression is evident on a subset of B-cells and has been described on CD4+ T-cells (10,11). Despite these findings, little is known of the function of LI in the immune system. One recent study has shown that LI is important for the maintenance of lymph node architecture (12).
  • LI can function as a costimulatory molecule in T-cell activation. In this capacity, LI contributes to the initiation of human immune responses in normal and disease processes including those involving the nervous system.
  • the invention relates generally to the field of immunology or neuroimmunology.
  • the invention provides a method for potentiating T cell activation, which method comprises administering an effective amount of a multimerized neural cell adhesion molecule LI (NCAM LI), or a functional derivative or fragment thereof, or a nucleic acid encoding said LI or functional derivative or fragment thereof, or an agent that enhances production and/or costimulatory function of said LI to a mammal, wherein T cell activation is desirable, thereby potentiating T cell activation in said mammal.
  • NCAM LI multimerized neural cell adhesion molecule LI
  • any multimerized, e.g., dimerized, NCAM LI, or a functional derivative or fragment thereof, that can function as a stimulatory molecule in T cell activation, and any nucleic acids encoding such NCAM LI, or functional derivative or fragment thereof, can be used in the present methods.
  • the NCAM LI, or a functional derivative or fragment thereof is capable of Ll-Ll homophilic interaction, e.g., mediating a Ll-Ll ligation between an antigen presentation cell (APC) and a T cell.
  • APC antigen presentation cell
  • NCAM LI supports an interaction with an integrin involved in T cell activation, e.g., supporting a trans or cis interaction with the integrin c ⁇ l or ⁇ v/33.
  • the NCAM LI, or a functional derivative or fragment thereof supports an interaction with a ligand involved in costimulation, e.g., supporting a czs-type interaction with CD9 and/or CD24.
  • any agents that enhances production and/or costimulatory function of NCAM LI can be used in the present methods.
  • the agents used therein enhance Ll-Ll homophilic interaction between two NCAM LI, or a functional derivative or fragment thereof, or interaction between a NCAM LI, or a functional derivative or fragment thereof, and an integrin involved in T cell activation, or interaction between a NCAM LI, or a > functional derivative or fragment thereof, and a ligand involved in costimulation.
  • One exemplary agent is the anti-NCAM LI monoclonal antibody 557.B6 (Appel et al., J.
  • NCAM LI or a functional derivative or fragment thereof, from any mammalian origins
  • the mammal to be treated is a human
  • the NCAM LI, or a functional derivative or fragment thereof, of human origin is used.
  • the present methods can be used to activate CD4 + T cells, CD8 + T cells or both.
  • the present methods can be used to treat, either prophylactically or therapeutically, mammals with diseases or disorders associated with deficient T cell activation.
  • diseases or disorders include, but are not limited to, tumors, cancers and infections.
  • Mammals, preferably humans, with tumors, cancers or infections are treated with the present methods.
  • the invention is directed to a combination, which combination comprises: a) an effective amount of multimerized NCAM LI or a functional derivative or fragment thereof, or a nucleic acid encoding said LI or functional derivative or fragment thereof, or an agent that enhances production and/or costimulatory function of said LI; and b) an effective amount of another costimulatory molecule.
  • the combination is in the form of a pharmaceutical composition.
  • the invention is directed to a method for potentiating T cell activation, which method comprises administering an effective amount of multimerized NCAM LI or a functional derivative or fragment thereof, or a nucleic acid encoding said LI or functional derivative or fragment thereof, or an agent that enhances production and/or costimulatory function of said LI and an effective amount of another costimulatory molecule to a mammal, wherein T cell activation is desirable, thereby potentiating T cell activation in said mammal.
  • Any costimulatory molecules can be used in the above combinations and methods.
  • the costimulatory molecules used are CD28, OX40, 4-1BB or ICOS.
  • the costimulatory molecule is derived from an antigen presenting cell (APC), e.g., LFA-1, LFA-3, ICAM-1, ICAM-2, ICAM-3, CD 40 or B7.
  • APC antigen presenting cell
  • the invention also provides a method for reducing or inhibiting T cell activation, which method comprises administering an effective amount of an antagonist of NCAM LI to a mammal, wherein reduction or inhibition of T cell activation is desirable, thereby reducing or inhibiting T cell activation in said mammal.
  • the antagonists can be NCAM LI anti- sense oligonucleotides, anti-NCAM LI antibodies, especially monoclonal antibodies such as mAb 5G3, soluble NCAM LI, or derivatives or fragments thereof.
  • the antagonists can reduce or inhibit Ll-Ll homophilic interaction, e.g., Ll-Ll ligation between an antigen presentation cell and a T cell.
  • the antagonists can reduce or inhibit a Ll-Ll ligation without simultaneously causing NCAM LI clustering and signaling.
  • the antagonists can reduce or inhibit NCAM Li's interaction with an integrin involved in T cell activation, e.g. ,
  • the NCAM Ll antagonists used in the methods or combinations are protein, polypeptide or peptide antagonists.
  • the NCAM Ll antagonists used in the methods or combinations are small molecule antagonists, e.g., ethanol (Bearer et al., J. Biol. Chem., 274(19 ⁇ :13264-13270 (1999)).
  • the present methods can be used to reduce or inhibit activation of CD4 + T cells, CD8 + T cells or both.
  • the present methods can be used to treat, either prophylactically or therapeutically, mammals with diseases or disorders associated with undesirable T cell activation.
  • the invention is directed to a combination, which combination comprises: a) an effective amount of an antagonist of NCAM Ll; and b) an effective amount of another costimulatory inhibitory molecule.
  • the combination is in the form of a pharmaceutical composition.
  • the invention is directed to a method for reducing or inhibiting T cell activation, which method comprises administering an effective amount of an antagonist of NCAM Ll and an effective amount of another costimulatory inhibitory molecule to a mammal, wherein T cell reduction or inhibition is desirable, thereby reducing or inhibiting T cell activation in said mammal.
  • Any costimulatory inhibitory molecules can be used in the above combinations and methods.
  • the costimulatory inhibitory molecules used is T-lymphocyte-associated antigen 4 (CTLA-4).
  • CD34+-cells were enriched from normal cord blood and expanded for 21 days prior to staining for Ll -expression. Enriched CD34+-cells were also stained for Ll prior to culture (Day 0). The cells were stained with mAb 5G3 directly conjugated to FITC.
  • DC+ Cord blood derived DC
  • B Cord blood derived DC
  • Cells were cultured in the presence or absence of anti-Ll mAb 5G3 or with control antibody UPCIO.
  • CD34-negative cord blood cells cultured under identical conditions as the CD34+ enriched fraction were also tested as stimulators (non-DC). Cultures were pulsed with [3H]-thymidine during the last 18 hours of a three day coculture. Treatments were performed in triplicate. Error bars are ⁇ ISE.
  • FIG. 1 Anti-Ll antibody 5G3 and soluble Ll inhibit autologous T-cell responses to mitogen.
  • PBMC were treated with PHA (lOmg/ml) in the absence or presence of mAb 5G3, or in the presence of control antibody UPCIO. Further PBMC were cultured in the presence of soluble recombinant Ll-ECD (sLl; lOOmg/ml).
  • sLl soluble recombinant Ll-ECD
  • B PBMC were treated with range of PHA concentrations in the absence or presence of mAb 5G3, or in the presence of control antibody UPCIO. Cultures were pulsed with [3H]-thymidine during the last 18 hours of a three day coculture.
  • Wells of a 96-well plate were pretreated with anti-CD3 antibody (OKT3: 25U/ml), with purified Ll-ectodomain (40mg/ml) or with a combination of both Ll and the antibody.
  • PBMCs were added to the precoated wells or to untreated wells for 72 hours.
  • PBMC were cultured in the absence or presence of mAb 5G3, or in the presence of control antibody UPCIO. Cultures were pulsed with [3H]-thymidine during the last 18 hours of a three day coculture. Treatments were performed in triplicate. Error bars are ⁇ ISE.
  • FIG. 4 Transfection and de novo expression of Ll enhances MLR.
  • a & B Irradiated wildtype (WT cells) or Ll-transfected J558L myeloma cells (L1+ cells) were cocultured with PBMC (A) or enriched CD4+ or CD8+ T-cell subsets (B) in an one way MLR.
  • L1+ J558L myeloma cells were co-cultured in the presence or absence of anti-Ll mAb 5G3 (80mg/ml) or in the presence of control mAb UPCIO (80mg/ml).
  • A, inset Irradiated wildtype (WT cells) or Ll-transfected J558L myeloma cells (L1+ cells) were cocultured with PBMC (A) or enriched CD4+ or CD8+ T-cell subsets (B) in an one way MLR.
  • Inhibitory antibody 5G3 blocks Ll-Ll mediated adhesion by Ll- transfected myeloma cells. Wildtype (WT) or Ll-transfected (L1+) myeloma cells were allowed to adhere to immobilized recombinant Ll in the presence of absence of control mAb (UPCIO) or anti-Ll mAb (5G3). Adherent cells were counted per unit area with a 40X high powered objective. Experimental treatments were performed in triplicate with four areas counted per well. Error bars represent ⁇ 1 SD.
  • T cell activation refers to cellular activation of resting T cell manifesting a variety of responses that include T cell proliferation, cytokine secretion and/or effector function.
  • T cell activation may be induced by stimulation of the T cell receptor (TCR) with antigen/MHC complex.
  • T cell activation may be induced by specified lectins, e.g., phytohemagglutinin, or monoclonal antibody(ies) to TCR.
  • costimulatory molecule refers to molecules that modulate the outcome of prior engagement of the TCR augmenting T cell activation events including T- cell proliferation and effector function. Signals provide by costimulatory molecules are not antigen specific nor MHC-restricted, and by themselves, i.e., in the absence of TCR engagement, are unable to induce a significant response in T cells. Engagement of the TCR in the absence of costimulatory molecules result in no immune response or hyporesponsiveness .
  • neural cell adhesion molecule Ll refers to a neural cell adhesion molecule that belongs to the IgSF superfamily and can function as a costimulatory molecule in T cell activation.
  • NCAM Ll can exerts its costimulatory function through Ll-Ll homophilic interaction, e.g., mediating a Ll-Ll ligation between APCs and T cells or through interaction with an integrin involved in T cell activation, e.g., the integrin c ⁇ l or ⁇ v/33, or through interaction with a ligand involved in costimulation, e.g., CD9 and/or CD24.
  • NCAM Ll has 6 immunoglobulin like domains, and has 5 fibronectin type III like domains, and is a membrane-penetrating type glycoprotein expected to penetrate the membrane at a region having sufficient number, e.g., 23, hydrophobic amino acid residues starting with an amino acid with a small side chain, e.g., glycine (EP 0,572,664 Al; and Moos et al., Nature, 334: 701-703 (1988)). It is intended that ⁇ CAM Ll includes those variants with conservative amino acid substitutions that do not substantially alter its costimulatory activity. Suitable conservative substitutions of amino acids are known to those of skill in this art and may be made generally without altering the biological activity of the resulting molecule.
  • medium stringency 0.2 x SSPE, 0.1% SDS, 50°C
  • low stringency 1.0 x SSPE, 0.1% SDS, 50°C
  • a "functional derivative or fragment of NCAM Ll” refers to a derivative or fragment of NCAM Ll that still substantially retains its function as a costimulatory molecule. Normally, the derivative or fragment retains at least 1%, 10%,
  • the derivative or fragment retains at least 60%, 70%, 80%, 90%, 95%, 99% and 100% of its costimulatory activity.
  • Functional derivative or fragment of NCAM Ll also encompasses peptide or polypeptide derivative or fragment of NCAM Ll that substantially retains its function as a costimulatory molecule.
  • an "agent that enhances production of NCAM Ll” refers to a substance that increases transcription and or translation of a NCAM Ll gene, or a substance that increases post-translational modification and/or cellular trafficking of a NCAM Ll precursor, or a substance that prolongs half-life of a NCAM Ll protein.
  • an “agent mat enhances costimulatory function of NCAM Ll” refers to a substance that increases potency of NCAM Li's costimulatory activity, or a substance that increases sensitivity of a NCAM Li's natural ligand in a costimulatory signally pathway, or a substance that decreases potency of a NCAM Ll 's antagonist.
  • integralins refers to a family of cell membrane glycoproteins that are heterodimers composed of - and /3-chain subunits. They serve as glycoprotein receptors involved in cell-cell or cell-substrate adhesion, e.g., the mediation of adhesion of neutrophils to endothelial cells, or to extracellular matrix such as collagen.
  • neoplasm neoplasia
  • neoplastic proliferation persists even in the absence of the original stimulus.
  • cancer refers to a general term for diseases caused by any type of malignant tumor.
  • an "antagonist of NCAM Ll (or NCAM Ll antagonist)" refers to a substance that decreases production and/or costimulatory function of NCAM Ll .
  • Such an antagonist can decrease production of NCAM Ll by decreasing transcription and or translation of a NCAM Ll gene, or by decreasing post-translational modification and/or cellular trafficking of a NCAM Ll precursor, or by shortening half-life of a NCAM Ll protein.
  • NCAM Ll antagonist can decrease costimulatory function of NCAM Ll by decreasing potency of NCAM Ll 's costimulatory activity, or by decreasing sensitivity of a NCAM Ll 's natural ligand in a costimulatory signally pathway, or by increasing potency of a NCAM Ll 's antagonist.
  • NCAM Ll antagonist can be any type of substances, including protein, polypeptide, peptide, or small molecule antagonist.
  • antibody includes antibody fragments, such as Fab fragments, which are composed of a light chain and the variable region of a heavy chain.
  • composition refers to a any mixture of two or more products or compounds. It may be a solution, a suspension, liquid, powder, a paste, aqueous, non- aqueous or any combination thereof.
  • antisense polynucleotides refer to synthetic sequences of nucleotide bases complementary to rnRNA or the sense strand of double stranded DNA. Admixture of sense and antisense polynucleotides under appropriate conditions leads to the binding of the two molecules, or hybridization. When these polynucleotides bind to (hybridize with) rnRNA, inhibition of protein synthesis (translation) occurs. When these polynucleotides bind to double stranded DNA, inhibition of RNA synthesis (transcription) occurs. The resulting inhibition of translation and/or transcription leads to an inhibition of the synthesis of the protein encoded by the sense strand.
  • an "NCAM Ll antisense oligonucleotide” refers to any oligomer that prevents production or expression of NCAM Ll polypeptide.
  • the size of such an oligomer can be any length that is effective for this purpose.
  • the antisense oligomer is prepared in accordance with the nucleotide sequence of a portion of the transcript of NCAM Ll that includes the translation initiation codon and contains a sufficient number of complementary nucleotides to block translation.
  • an "autoimmunity” refers to specific humoral or cell-mediated immune response to the body's own tissues.
  • the invention provides a method for potentiating T cell activation, which method comprises administering an effective amount of a multimerized neural cell adhesion molecule Ll (NCAM Ll), or a functional derivative or fragment thereof, or a nucleic acid encoding said Ll or functional derivative or fragment thereof, or an agent that enhances production and/or costimulatory function of said Ll to a mammal, wherein T cell activation is desirable, thereby potentiating T cell activation in said mammal.
  • NCAM Ll neural cell adhesion molecule Ll
  • Any multimerized, e.g., dimerized, NCAM Ll, or a functional derivative or fragment thereof, that can function as a stimulatory molecule in T cell activation, and any nucleic acids encoding such NCAM Ll, or functional derivative or fragment thereof, can be used in the present methods.
  • NCAM Ll proteins with the following GenBank accession numbers can be used: T30532 (Fugu rubripes); T30581 (zebra fish); S36126 (rat); A43425 (chicken); S05479 (mouse); A41060 (human); NP_032504 (Mus museums); NP_006605 (close homologue of Ll sapiens); NP_000416 (Homo sapiens); AAF22153 (Mus musculus); CAB57301 (Mus musculus); P32004 (HUMAN); Q05695 (RAT); PI 1627 (MOUSE); AAD28610 (Cercopithecus aethiops); CAB37831 (Homo sapiens); AAC51746
  • any proteins derived from, or are portion of, the above NCAM Ll proteins that still substantially retain their costimulatory activities can be used.
  • such NCAM Ll derivatives or fragments can be recognized by antibodies that specifically recognize the NCAM Ll proteins from which the derivatives or fragments originate.
  • nucleic acids encoding NCAM Ll proteins with the following GenBank accession numbers can be used: AC005775 (Homo sapiens); AC 004690 (Homo sapiens);
  • M28231 (Drosophilamelanogasterneuroglian precursor); AH006326 (Drosophila melanogaster neuroglian (nrg), alternative splice products); AF050085 (Drosophila melanogaster neuroglian (nrg) gene; AF172277 (Homo sapiens); AF133093 (Mus musculus); AJ239325 (Homo sapiens); AL021940 (Homo sapiens); AF129167 (Chlorocebus aethiops); AJO 11930 (Homo sapiens); U52112 (Homo sapiens); M97161 (Rattus norvegicus); AC005626 (Homo sapiens); AF026198 (Fugu rubripes); M77640 (Homo sapiens); U55211 (Carassius auratus); M74387 (Human), h addition, any nucleic acids derived from, or are portion of, the above nucleic acids encoding
  • such NCAM Ll nucleic acid derivatives or fragments can hybridize under low, middle or high stringency with the NCAM Ll nucleic acids from which the derivatives or fragments originate.
  • the NCAM Ll, or a functional derivative or fragment thereof is capable of Ll-Ll homophilic interaction, e.g., mediating a Ll-Ll ligation between an antigen presentation cell (APC) and a T cell.
  • the NCAM Ll, or a functional derivative or fragment thereof supports an interaction with an integrin involved in T cell activation, e.g., supporting a trans or cis interaction with the integrin c ⁇ l (Ruppert et al., J. CellBiol, 131:1881-1891 (1995)), or integrin c ⁇ /33 (Sturmhofel et al., J. Immunol,
  • the NCAM Ll supports an interaction with a ligand involved in costimulation, e.g., supporting a cts-type interaction with CD9 and/or CD24
  • the NCAM Ll, or functional derivative or fragment thereof, or the nucleic acid encoding the NCAM Ll, or functional derivative or fragment thereof can be administered to the mammal by any methods know in the art.
  • the NCAM Ll, or functional derivative or fragment thereof, or the nucleic acid encoding the NCAM Ll, or functional derivative or fragment thereof can be administered directly to the mammal.
  • the NCAM Ll, or functional derivative or fragment thereof, or the nucleic acid encoding the NCAM Ll, or functional derivative or fragment thereof can be delivered into antigen presenting cells, e.g., macrophages and dendritic cells, and the antigen presenting cells containing the NCAM Ll or the nucleic acid are then administered to the mammal.
  • antigen presenting cells e.g., macrophages and dendritic cells
  • any agents that enhances production and/or costimulatory function of NCAM Ll can be used in the present methods.
  • the agents used therein enhance Ll-Ll homophilic interaction between two NCAM Ll, or a functional derivative or fragment thereof, or interaction between a NCAM Ll, or a functional derivative or fragment thereof, and an integrin involved in T cell activation, or interaction between a NCAM Ll, or a functional derivative or fragment thereof, and a ligand involved in costimulation.
  • NCAM Ll, or a functional derivative or fragment thereof, from any mammalian origins can be used.
  • the mammal to be treated is a human
  • the NCAM Ll, or a functional derivative or fragment thereof, of human origin is used. when the mammal to be treated is a human.
  • the present methods can be used to activate CD4 + T cells, CD8 + T cells or both.
  • the present methods can be used to treat, either prophylactically or therapeutically, mammals with diseases or disorders associated with deficient T cell activation.
  • diseases or disorders include, but are not limited to, tumors, cancers or infections.
  • tumors or cancers that can be treated with the present methods include breast cancer, Burkitt lymphoma, colon cancer, small cell lung carcinoma, melanoma, multiple endocrine neoplasia (MEN), neurofibromatosis, p53-associated tumor, pancreatic carcinoma, prostate cancer, Ras-associated tumor, retinoblastoma and Von-Hippel Lindau disease (NHL).
  • tumors or cancers that originate from immune system and/or nervous system are treated.
  • Any mammals such as, mice, rats, rabbits, cats, dogs, pigs, cows, ox, sheep, goats, horses, monkeys and other non-human primates, with tumors, cancers or infections can be treated with the present methods.
  • humans with tumors or cancers are treated with the present methods.
  • the invention is directed to a method for reducing or inhibiting T cell activation, which method comprises administering an effective amount of an antagonist of ⁇ CAM Ll to a mammal, wherein T cell reduction or inhibition is desirable, thereby reducing or inhibiting T cell activation in said mammal.
  • the antagonists used therein are ⁇ CAM Ll anti-sense oligonucleotides, anti- ⁇ CAM Ll antibodies, especially monoclonal antibodies such as mAb 5G3 (Balaian et al, Eur. J. Immunol, 300 ⁇ :938-43 (2000)), soluble ⁇ CAM Ll, or derivatives or fragments thereof.
  • ⁇ CAM Ll used reduce or inhibit Ll-Ll homophilic interaction, e.g., Ll-Ll ligation between an antigen presentation cell and a T cell. More preferably, the antagonists reduce or inhibit a Ll-Ll ligation without simultaneously causing NCAM Ll clustering and signaling.
  • the antagonists of NCAM Ll used reduce or inhibit NCAM Li's interaction with an integrin involved in T cell activation, e.g., NCAM Ll 's trans or cis interaction with the integrin c ⁇ l, v ⁇ 3, CD1 lc, a ⁇ 2 integrin or VLA integrin family, or reduce or inhibit NCAM Ll 's interaction with a ligand involved in costimulation, e.g., NCAM Ll 's interaction with CD9 and/or CD24.
  • an integrin involved in T cell activation e.g., NCAM Ll 's trans or cis interaction with the integrin c ⁇ l, v ⁇ 3, CD1 lc, a ⁇ 2 integrin or VLA integrin family
  • NCAM Ll 's interaction with a ligand involved in costimulation e.g., NCAM Ll 's interaction with CD9 and/or CD24.
  • the NCAM Ll antagonists used in the methods or combinations are protein, polypeptide or peptide antagonists.
  • the NCAM Ll antagonists used in the methods or combinations are small molecule antagonists, e.g., ethanol (Bearer et al., J. Biol. Chem., 274(19 :13264-13270 (1999)).
  • the present methods can be used to reduce or inhibit activation of CD4 + T cells, CD8 + T cells or both.
  • the present methods can be used to treat, either prophylactically or therapeutically, mammals with diseases or disorders associated with undesirable T cell activation. Examples of such diseases or disorders include, but are not limited to, autoimmunity, graft rejection and neuroimmunological disorders. Mammals, preferably humans, with autoimmunity, graft rejection and neuroimmunological disorders are treated with the present methods.
  • the invention is directed to a combination, which combination comprises: a) an effective amount of multimerized NCAM Ll or a functional derivative or fragment thereof, or a nucleic acid encoding said Ll or functional derivative or fragment thereof, or an agent that enhances production and/or costimulatory function of said Ll; and b) an effective amount of another costimulatory molecule, or an immunostimulant such as an agonist of costimulatory molecules, or certain cytokines, e.g., IL-2.
  • the combination is in the form of a pharmaceutical composition.
  • the invention is directed to a method for potentiating T cell activation, which method comprises administering an effective amount of multimerized NCAM Ll or a functional derivative or fragment thereof, or a nucleic acid encoding said Ll or functional derivative or fragment thereof, or an agent that enhances production and/or costimulatory function of said Ll and an effective amount of another costimulatory molecule or an immunostimulant to a mammal, wherein T cell activation is desirable, thereby potentiating T cell activation in said mammal.
  • Any costimulatory molecules can be used in the above combinations and methods.
  • the costimulatory molecules used are CD28, OX40, 4-lBB or ICOS.
  • CD28 is the primary positive T cell costimulatory molecule, as defined by the ability to enhance T cell activation in the presence of TCR stimulation that is insufficient for T cell proliferation (see generally Chambers and Allison, Curr. Opin. Cell. Biol, 11(2 :203-10 (1999)).
  • CD28 is an immunoglobulin supergene family glycoprotein that is expressed as homodimers on T cells. It binds to ligands B7.1 and B7.2 via the MYPPPY
  • CD28 protein with the following GenBank accession numbers can be used in the combination and combinatorial treatment method: NP_006130 (Homo sapiens); B45895 (human); 149584
  • nucleic acids encoding CD28 with the following GenBank accession numbers can be used in the combination and combinatorial treatment method: AB025316 (Felis catus); AF130427 (Marmota monax); AF222343 (Homo sapiens); AF222342 (Homo sapiens); AF222341 (Homo sapiens); D49841 (rabbit); AF092739 (ovis aries); Al 528690 (mouse); AI386096 (human); AI327367 (mouse); AI324382 (mouse); AII52205 (mouse); AA940559 (mouse); U57754 (Felis catus); AA17418 (human); AA163825 (mouse); J02988 (human); M34563 (mouse).
  • OX40 protein with the following GenBank accession numbers can be used in the combination and combinatorial treatment method:
  • 137552 (OX40 homolog-human); JE0351 (rat); 148700 (mouse); S48290 (mouse); S12783 (rat); 1D0AL 1D0AK (Chain L, Human); 1D0AJ (Chain J, Human); 1D0AI (Chain I, Human); 1D0AH (Chain H, Human); 1D0AG (Chain G, Human); 1D0AF (Chain F, Human); 1D0AE Chain E, Human); 1D0AD (Chain D, Human); 1D0AC (Chain C, Human); 1D0AB (Chain B, Human); 1D0AA (Chain A, Human); NP 003318 (Homo sapiens); CAA18438 (Homo sapiens); 002765 (rabbit); P47741 (MOUSE); P43488
  • nucleic acids encoding OX40 with the following GenBank accession numbers can be used in the combination and combinatorial treatment method: AL022310 (human); AF037067 (Rattus norvegicus); AB003912 . (rabbit); U12763 (Mus musculus).
  • 4- IBB protein with the following GenBank accession numbers can be used in the combination and combinatorial treatment method: 138427 (human); 138426 (human); 153384 (mouse); B32393 (mouse); P41273 (human);
  • nucleic acids encoding 4-1BB with the following GenBank accession numbers can be used in the combination and combinatorial treatment method: AI664286; AII57872; AA109726; AA389045; AA155147; AA087107; W62906;
  • ICOS CD28/CTLA-4 homologue
  • ICOS has an structure similar to CD28 and CTLA-4 but does not have a conserved MYPPY motif, suggesting that it binds to unique ligand(s).
  • Antibody cross- linking of ICOS enhances anti CD3-mediated T cell proliferation and cytokine production, although, unlike CD28, it does not enhance IL-2 production.
  • ICOS protein and nucleic acid encoding ICOS protein with the following GenBank accession numbers can be used in the combination and combinatorial treatment method: S78540 (human) and AJ250559 (Mus musculus).
  • the costimulatory molecule is derived from an antigen presenting cell (APC), e.g., LFA-1, LFA-3, ICAM-1, ICAM-2, ICAM-3, CD 40 or B7.
  • APC antigen presenting cell
  • the invention is directed to a combination, which combination comprises: a) an effective amount of an antagonist of NCAM Ll; and b) an effective amount of another costimulatory inhibitory molecule.
  • the combination is in the form of a pharmaceutical composition.
  • the invention is directed to a method for reducing or inhibiting T cell activation, which method comprises administering an effective amount of an antagonist of NCAM Ll and an effective amount of another costimulatory inhibitory molecule to a mammal, wherein T cell reduction or inhibition is ' desirable, thereby reducing or inhibiting T cell activation in said mammal.
  • costimulatory inhibitory molecules can be used in the above combinations and methods.
  • the costimulatory inhibitory molecules can be antagonists of costimulatory molecules including the costimulatory molecules described above such as CD28, OX40, 4-1BB or ICOS and the costimulatory molecule is derived from an antigen presenting cell (APC), e.g., LFA-1, LFA-3, ICAM-1, ICAM-2, ICAM-3, CD 40 or B7.
  • APC antigen presenting cell
  • the costimulatory inhibitory molecules used is T-lymphocyte-associated antigen 4 (CTLA-4) (Chambers and Allison, Curr. Opin. Cell. Biol, 11(2):203-
  • CTLA-4 is an immunoglobulin supergene family glycoprotein that is expressed as homodimers on T cells. It binds to ligands B7.1 and B7.2 via the MYPPPY (in the single letter code for amino acids) motif in the immunoglobulin domain. CTLA-4 has a 10-fold higher affinity and a 100-fold higher avidity for B7 ligands compared to CD28 and exhibits distinct binding kinetics.
  • the cytoplasmic tail of CTLA-4 possess tyrosine-containing motifs postulated to be involved in signal transduction and protein trafficking.
  • CTLA-4 protein with the following GenBank accession numbers can be used in the combination and combinatorial treatment method: 146696 (rabbit); BAA08644 (oryctolagus cuniculus); P42081 (human); P42072; P16410; P09793; P33681; AAD50988 (Felis catus); AAD00698; AAD00697; (Rattus norvegicus);
  • nucleic acids encoding CTLA-4 with the following GenBank accession numbers can be used in the combination and combinatorial treatment method: AF130428 (Marmota monax); D49844 (rabbit); AF143204 (canis familiaris breed beagle); AF1701725 (Felis catus); AF092740
  • compositions (Ovis aries); AF153202 (Felix catus); U90271 (Rattus norvegicus); U37121 (Rattus norvegicus); L15006 (Homo sapiens); U17722 (Human).
  • the formulation, dosage and route of administration of the above-described compositions, combinations, preferably in the form of pharmaceutical compositions, can be determined according to the methods known in the art (see e.g., Remington: The Science and Practice of Pharmacy, Alfonso R. Gennaro (Editor) Mack Publishing Company, April 1997; Therapeutic Peptides and Proteins: Formulation, Processing, and Delivery Systems,
  • compositions, combinations or pharmaceutical compositions can be formulated for oral, rectal, topical, inhalational, buccal (e.g., sublingual), parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), transdermal administration or any other suitable route of administration.
  • buccal e.g., sublingual
  • parenteral e.g., subcutaneous, intramuscular, intradermal, or intravenous
  • transdermal administration e.g., transdermal administration or any other suitable route of administration.
  • the most suitable route in any given case will depend on the nature and severity of the condition being treated and on the nature of the particular composition, combination or pharmaceutical composition which is being used.
  • DCs are characterized as the most proficient APC in the immune system and are recognized to be the principal stimulators of primary MLR.
  • DC were produced from enriched CD34+ stem cells (>76% purity) using a combination of
  • DC morphology and phenotype (CDla ⁇ , CD80+, CD86+, CD3-, CD14-, CD19-, CD56-)
  • Ll-ligation potentiates T-cell responses to PHA and to CD3
  • blockade of Ll by this mAb significantly reduced T-cell proliferation within the PBMC fraction (Fig. 2 A & B) and reduced the proliferation of enriched T-cell subsets, in particular CD4+ cells (Fig. 2C).
  • Inhibtion by antibody 5G3 was observed over a range of PHA concentrations (Fig. 2B) and as early as 18 hours after PHA stimulation (Fig. 2B inset).
  • Ll-ECD purified recombinant Ll
  • Ll can function as a potent costimulatory molecule, and indicates that homophilic Ll-Ll binding rather than direct Ll -integrin binding is the stimulatory mechanism. Ll-transfection of myeloma cells promotes adhesion via a homophilic mechanism and potentiates MLR
  • T-cell activation may depend upon the use of antagonists that can block Ll -ligation without simultaneously causing Ll clustering and signalling. Supporting this concept we did not observe any significant inhibition of T-cell activation using an anti-Ll polyclonal antibody (data not shown). In this regard, it has been documented that polyclonal antibodies to Ll (unlike most mAbs and isolated soluble
  • Ll expression by 'professional' APC of both myelomonocytic and lymphoid origin, including B-cells, activated monocytes, monocyte derived DC, and foUicular DC (11).
  • Ll expression on monocyte-derived DC was induced after treatment with LPS (11) which is known to promote functional maturation or the acquisition of optimal costimulatory capacity. Based on these findings, and those present in this study, we propose that Ll expressed by such 'professional' APC can function as a costimulatory molecule in T-cell activation.
  • Ll -mediated signalling potentiates T-cell costimulation and to determine how Ll ranks along side other costimulatory molecules.
  • a comparison with previous studies suggests that Ll is less important for T-cell co-stimulation than, for example, members of the B7 family.
  • B7.1/B7.2 has been shown to reduce T cell proliferation to PHA and to allogeneic DC by up to 75 and 95% respectively (15, 16, 17).
  • Ll-mediated costimulation may be compared with other well documented co-stimulatory molecules such as CD58.
  • blockade of CD2:CD58 binding has been shown to inhibit T-cell proliferation to PHA and to allogeneic DC by 30-35 and 45-50% respectively (16, 17).
  • Ll can undergo multiple cis and trans interactions with other heterophilic ligands (6).
  • Ll has recently been shown to support a trans interaction with the integrin a5bl (18); an integrin which has also been implicated in
  • Ll may contribute to the development of autoimmunity, graft rejection, and anti-tumor responses and in this context may prove to be a useful and novel target for immunotherapeutic intervention.
  • the finding that soluble Ll can inhibit T-cell activation may prove significant given reports that aggressive neuroectodermal tumors can secrete large amounts of Ll (13, 22).
  • high levels of Ll -expression on post mitotic neurons and Schwann cells (2,6) suggest that this CAM may function as an important intermediary between nervous and immune system, particularly in the development of neuroimmunological disorders.
  • CD34+ cells were purified from normal cord blood using M-450 Dynabeads coated with an anti-CD34 mAb according to the manufacturers instructions.
  • CD34+-enriched (>76%) or CD34 negative cell populations were then cultured in the presence of granulocyte-macrophage colony-stimulating factor (lOng/ml), human stem cell factor (40 ng/ml), human interleukin-3 (10 ng/ml), human tumor necrosis factor-a (100 U/mL) and human interleukin-4 (400U/mL). After expansion for 7-21 days the levels of Ll expression on the cells was determined using anti-Ll mAb 5G3 directly conjugated to fluorescein isothiocyanate (FITC).
  • FITC fluorescein isothiocyanate
  • CD4+ and CD8+ cells were isolated from PBMC using M-450 Dynabeads coated with anti-CD4 or anti-CD8 mAbs. Isolation was according the manufacturers recommendations (Dynal, Fort Lee, N.J.). This method does not induce T-cell activation and resulted in approximately 95% purity.
  • PBMC, or enriched CD4+, or CD8+ cells were cultured in 96- well round bottom plates (1 x 105 cells/well), with or without PHA (Sigma; 20 mg/ml).
  • PHA PHA
  • MLR assays PBMCs (1 x 105 cells/well) or enriched CD4+, or CD8+ cells were co- cultured with irradiated wildtype or Ll-transfected J558L cells at 1 x 104 cells/well or with irradiated cord blood derived dendritic cells (1 x 104 cells/well).
  • Mitogen treated cells and cocultures were maintained for 3 days and the cultures pulsed with [3H]-thymidine (1 mCi/well) during the last 18 hours of the three-day culture.
  • the contribution of Ll to both mitogen and MLR assays was assessed by the incorporation of anti-Ll mAb 5G3 (80mg/mi). Where appropriate an IgG2a isotype-matched control antibody (UPCIO; 80mg/ml) was also added.
  • Lagenaur, C. and Lemmon, V. An Ll-like molecule, the 8D9 antigen, is a potent substrate for neurite extension. Proc. Natl. Acad. Sci. USA 1987.84: 7753-7757.
  • Costimulation of superantigen-actiavted T lymphocytes by autologous dandritic cells is dependent on B7. Cell. Immunol. 1994. 156: 220-229.
  • the B7/BB1 antigen provides one of several costimulatory signals for the activation of CD4+ T lymphocytes by human blood dendritic cells in vitro. J. Clin. Invest. 90: 229-237.
  • the Ll adhesion molecule is a cellular ligand for VLA-5. J. Cell Biol. 1995. 131: 1881-1891.

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Abstract

L'invention concerne de façon générale le domaine de l'immunologie ou de la neuroimmunologie. Elle concerne, en particulier, un procédé servant à diminuer ou à inhiber l'activation des lymphocytes T et consistant à administrer une quantité efficace d'un antagoniste de NCAM L1 à un mammifère nécessitant la diminution ou l'inhibition de l'activation des lymphocytes T, ce qui permet de diminuer ou d'inhiber l'activation des lymphocytes T chez ledit mammifère. Elle concerne, de plus, des combinaisons et des procédés combinés servant à moduler l'activation des lymphocytes T. Elle concerne également un procédé servant à potentialiser l'activation des lymphocytes T et consistant à administrer une quantité efficace d'une molécule d'adhérence aux cellules neurales multimérisée L1 (NCAM L1) ou un de ses dérivés ou fragments fonctionnels, ou un acide nucléique codant L1 ou ledit dérivé fonctionnel ou ledit fragment, ou un agent amplifiant la production et/ou la fonction de stimulation combinée dudit L1 à un mammifère nécessitant l'activation des lymphocytes T, ce qui permet de potentialiser l'activation des lymphocytes T chez ledit mammifère.
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