WO1995007716A1 - Composition pharmaceutique comprenant des anticorps monoclonaux diriges contre le recepteur d'interferon et dotes d'une activite neutralisante a l'egard de l'interferon de type i - Google Patents

Composition pharmaceutique comprenant des anticorps monoclonaux diriges contre le recepteur d'interferon et dotes d'une activite neutralisante a l'egard de l'interferon de type i Download PDF

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WO1995007716A1
WO1995007716A1 PCT/EP1994/003114 EP9403114W WO9507716A1 WO 1995007716 A1 WO1995007716 A1 WO 1995007716A1 EP 9403114 W EP9403114 W EP 9403114W WO 9507716 A1 WO9507716 A1 WO 9507716A1
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ifn
human
pharmaceutical composition
anyone
interferon
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Michael G. Tovey
Eric Jacob Benizri
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LABORATOIRE EUROPEEN DE BIOTECHNOLOGIE SA
Laboratoire European de Biotechnologie SA
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LABORATOIRE EUROPEEN DE BIOTECHNOLOGIE SA
Laboratoire European de Biotechnologie SA
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Priority to EP94928371A priority Critical patent/EP0725654A1/fr
Priority to JP7509002A priority patent/JPH11501283A/ja
Priority to AU77828/94A priority patent/AU7782894A/en
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    • 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
    • C07K16/2866—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • interferons constitute a group of secreted proteins which exhibit a wide range of biological activities and are characterized by their capacity to induce an antiviral state in vertebrate cells (I. Gresser and M.G. Tovey Biochem Biophys. Acta 516-231. 1978).
  • IFN interferons
  • There are three antigenic classes of IFN : alpha ( ⁇ ) , beta ( ⁇ ) and gamma- IFN ⁇ and IFN3 together are known as the type I interferon.
  • Natural type I human interferon comprises 16 or more closely related proteins encoded by distinct genes with a high degree of structural homology (Weissmann and Weber, Prog. Nucl. Acid. Res. Mol. Biol. 33:251, 1986) .
  • the human IFN ⁇ locus comprises two subfamilies.
  • the first subfamily consists of 14 non allelic genes and 4 pseudogenes having at least 80% homology.
  • the second subfamily, all or omega ( ⁇ ) contains 5 pseudogenes and 1 functional gene which exhibits 70% homology with the IFN ⁇ genes (Weissmann and Weber 1986) .
  • IFN ⁇ The subtypes of IFN ⁇ have different specific activities but they possess the same biological spectrum (Streuli et al. PNAS-USA 7_8:2848, 1981) and have the same cellular receptor (Agnet M. et al. in "Interferon 5" Ed. I. Gresser p. 1-22, Academic Press, London 1983) .
  • the interferon ⁇ (IFN0) is encoded by a single gene which has approximately 50% homology with the IFN ⁇ genes.
  • interferon ⁇ subtypes and interferon ⁇ bind to the same receptor on the cell surface.
  • the interferon gamma (IFN gamma) is also encoded by a single copy, which has little homology with the IFN ⁇ and IFN/S genes.
  • the receptor for IFN gamma is distinct from the receptor of the ⁇ and ⁇ interferons.
  • the receptor of ⁇ and ⁇ classes of IFN will be designated IFN-R.
  • the group of proteins forming natural interferon ⁇ will be designated IFN ⁇ , and type I-IFN will represent both natural IFN ⁇ , IFN ⁇ , and IFN/- * .
  • interferon is a potent antiviral agent
  • many of the characteristic symptoms of acute virus diseases such as upper respiratory tract infections are caused by an overproduction of interferon alpha.
  • IFN alpha has been shown to contribute to the pathogenesis of certain chronic virus infections in experimental animals and the available evidence suggests that this is also the case for certain human chronic virus diseases such as those due to measles virus.
  • the interferons ⁇ are also potent immuno- regulatory molecules which stimulate polyclonal B-cell activation, enhance NK cell cytotoxicity, inhibit T- cell functions, and modulate the expression of the major histocompatibility complex (MHC) class 1 antigens, all of which are implicated in the induction of autoimmunity and in graft rejection.
  • MHC major histocompatibility complex
  • the abnormal production of interferon ⁇ is associated with a number of autoimmune diseases, immune deficiencies and inflammatory disorders including systemic lupus erythematosu ⁇ (SLE) , type I diabetes, psoriasis.
  • interferon ⁇ in the serum of patients with systemic lupus is correlated with both the clinical and humoral signs of increased disease activity.
  • the production of interferon ⁇ in HIV positive subjects is also highly predictive of disease evolution.
  • Interferon ⁇ has been reported to exacerbate underlying disease in patients with psoriasis and multiple sclerosis and to induce a SLE like syndrome in patients without a previous history of autoimmune disease.
  • Interferon ⁇ has also been shown to induce glomerulonephritis in normal mice (Gresser et al., 1976, Nature, 263:420) and to accelerate the outset of the spontaneous autoimmune disease of NZB/W mice (Adam et al., 1980, Clin. Exp. Immunol., 40:373) .
  • Interferon ⁇ is also produced during the course of graft-versus-host disease (GVHD) in parallel with the enhanced NK cell activity characteristic of systemic GVDH.
  • Interferon ⁇ is the principal modulator of NK cell cytotoxicity and administration of interferon ⁇ has been shown to enhance the intestinal consequences of GVDH in normal mice (Cleveland et al., 1987, Cell Immunol. 110:120).
  • the object of the present invention is to provide new antagonists against the biological activities of the human type I-IFN.
  • These antagonists could be used for therapeutical, including prophylaxis purposes, in cases where the type I-IFN (IFN ⁇ //?)is abnormaly produced and when this abnormal production is associated with pathological symptoms.
  • Such antagonists could also be used for the diagnosis of various diseases or for the study of the evolution of such diseases.
  • One object of the present invention is to provide an antagonist of the type I-IFN, which would be able to inhibit or neutralize, to a determined extent, the biological properties of the human type I-IFN, that is to say, to neutralize in vivo a mixture of ⁇ , ⁇ , ⁇ subspecies.
  • the present inventors having developed appropriate in vivo animal models, have been able to demonstrate that some monoclonal antibodies are capable to interact in vivo on the immune response, with the type I-IFN receptor, in a therapeutically efficient manner as regards various pathologies.
  • the inventors have been able to define conditions where the in vivo administration of monoclonal antibodies directed against the type I IFN receptor can interact and in some cases inhibit symptoms of viral diseases resulting from viral infections, especially infections due to the HIV or HT1V retroviruse ⁇ , or can inhibit allogenic graft rejection or can inhibit the effect of Graft Versus Host Disease.
  • immunomodulators will be utilized as such for the treatment of diseases involving abnormal production of interferon, or will be utilized in combination either simultaneously or separately, with other known immunomodulators or drugs especially viral drugs.
  • monoclonal antibodies directed against the type I IFN receptor can have a useful synergic effect with other therapeutic agents. This appears to be the case for instance when monoclonal antibodies against type I IFN receptor are associated with an immunosuppressive drug like cyclosporin A.
  • compositions comprising antibodies, especially monoclonal antibodies, which have the property of being antagonists to the type I-IFN due to their activity as immunomodulators. These antibodies are directed against the human type I-IFN receptor.
  • the invention thus relates to the use of a preparation of purified monoclonal antibodies in pharmaceutical compositions, for use as immunomodulator, for the in vivo treatment of symptoms associated with the abnormal production of type I-IFN.
  • monoclonal antibodies are also appropriate for the preparation of diagnosis reagents.
  • a particular monoclonal antibody appropriate for the preparation of the pharmaceutical compositions for use as immunomodulator according to the present invention is directed against the human type I- interferon receptor (IFN-R) and is characterized by the following properties : it recognizes the extracellular domain of the human IFN-R, and it has a neutralizing capacity against the biological properties of the human type I-IFN.
  • the ability to neutralize the biological properties of type I-IFN can be estimated as a function of the capacity of the monoclonal antibody to neutralize the antiviral activity of the type I-IFN.
  • Such a test is relevant in order to determine whether the antibody assayed is appropriate for the preparation of a pharmaceutical composition within the scope of the invention, although it is clear that the biological properties of type I-IFN are not limited to its antiviral properties. Detailed procedures are given in the examples in order to enable to perform such a test of the antiviral activity.
  • the cells tested can advantageously be Daudi-cells, which affinity for the type I-IFN is well known.
  • the main steps of such a test would consist in : incubating a determined concentration of human cells responsive to human type I-IFN, with human type I-IFN in the presence of a determined concentration of monoclonal antibodies to be assayed, for a time sufficient to allow the formation of a complex between the monoclonal antibodies and the IFN-R of the human cells and/or between the type I-IFN and the IFN-R of the human cells ; infecting the incubated cells with a determined virus, in a determined concentration, washing the cells, resuspending the cells in culture medium, incubating for a time sufficient to allow virus replication ; lysing the cells ; measuring the virus replication, or measuring the inhibition of the cytopathic effect.
  • the ability of the monoclonal antibodies of the invention to neutralize the biological properties of the human type I-IFN can be modulated as a function of the dose of antibodies used. Accordingly a 100% inhibition of the biological properties, or a partial inhibition can be obtained.
  • the monoclonal antibodies directed against the human type I-IFN receptor are further characterized by the fact that they are capable of inhibiting the binding of a human type I-IFN, to the human IFN-R.
  • a monoclonal antibody having the capacity to recognize the extracellar domain of the human IFN-R and capable of inhibiting the binding of the human type I- IFN to its receptor can be selected by the following steps : preincubating a determined concentration of purified monoclonal antibodies or a hybridoma culture supernatant containing monoclonal antibodies to be assayed, with human cells capable of harboring IFN-R ; adding labelled human type I-IFN, in a determined concentration, to the above preincubated medium ; incubating the medium containing the human cells, the monoclonal antibodies and the labelled type I-IFN for a time sufficient to allow an equilibrium to occur, between the monoclonal antibodies on the one hand and the type I-IFN on the other hand, with the cellular IFN-R ; washing the cells ; determining the formation of a binding complex between the human cells and the labelled type I- IFN by counting the amount of attached labelled type I-IFN.
  • Some of the monoclonal antibodies of the invention have also the capacity to neutralize the antiproliferative properties of the human type I-IFN. This property can also be assayed on Daudi cells, by performing the following steps : allowing cells to grow in presence of human type IFN and determined concentration of mAb ; counting the cells in order to detect an inhibition of the antiproliferative effect of the human type I-IFN.
  • a monocolonal antibody having an activity of immunomodulator appropriate for the preparation of a pharmaceutical composition of the invention, resides in its capacity to recognize the extracellular domain of the human IFN receptor.
  • This property of the monoclonal antibody can be assayed on human cells bearing the natural human receptor but also on the extracellular domain of a recombinant IFN-R such as expressed in a procaryotic cell, for instance in E.coli or a recombinant IFN-R such as expressed in a eucaryotic cell such as malian cell for instance a CHO-cell.
  • This receptor can indeed present different properties, depending on the fact that it is produced in a procaryotic or eucaryotic cell and accordingly depending on the fact that the post-translational maturation occurred or not.
  • the inventors interestingly showed that relevant assays, to evaluate the capacity of a monoclonal antibody according to the invention i.e. to recognize the cellular IFN-R, can be performed on a recombinant receptor expressed in malian cells. As a matter of fact, such recombinant receptor has the same properties as the cellular receptor, as far as its recognizing activity is concerned.
  • Monoclonal antibodies useful for the achievement of the invention can be obtained against various forms of the receptor, including the complete receptor, a particular domain or a peptide characteristic of the aminoacid sequence of the receptor represented in figure 3.
  • Monoclonal antibodies useful for the invention can for example be prepared against the soluble form of the receptor.
  • a hydrosoluble polypeptide corresponding to the soluble form of the INF-R is described on figure 2.
  • a soluble form of the IFN-R corresponds to a peptide or a polypeptide, capable of circulating in the body.
  • antibodies useful for the invention can also be prepared against a peptide comprised in the extracellular domain of the receptor as described on figure 2.
  • An advantageous peptide corresponds for instance to the aminoacid sequence comprised between aminoacid 1 and aminoacid 427.
  • the antibodies can be prepared against a polypeptide modified by substitution of one or more amino acids, provided that antibodies directed against the non modified extracellular domain of the IFN-R, recognize the modified polypeptide or peptide.
  • Preferred monoclonal antibodies according to the invention are those which are of the IgGl type.
  • an antibody which has the capacity of inhibiting the binding of the type I-IFN to its receptor is preferably characterized in that it inhibits the in vitro binding of human type IFN, to the human cellular IFN-R when it is co-incubated with cells harboring the hu-IFN-R, at a concentration of antibodies equal or inferior to 100 ⁇ g/ml, preferably equal or inferior to 50 ⁇ g/ml, advantageously inferior to 20 ⁇ g/ml, more preferably in the range of approximately 0.5 to 2 ⁇ g/ml.
  • the inventors have shown that the high affinity binding capacity of a monoclonal antibody is not sufficient to ensure that this antibody will be able to inhibit the binding activity of the human type I-IFN to the IFN-R. Nevertheless the high affinity binding capacity of the monoclonal antibody is necessary to investigate further the ability of the antibody to inhibit the binding of the type I-IFN to its cellular receptor.
  • Another monoclonal antibody is characterized in that it neutralizes in vitro the antiproliferative activity of human type I-IFN, on cells highly responsive to this human type I-IFN, for instance Daudi cells at a concentration in a range of 1 to 10 ⁇ g/ml.
  • a monoclonal antibody is also characterized in that it neutralizes in vitro the antiproliferative activity of human type IFN, on cells poorly responsive to this human IFN, for instance Ly28 cells, at a concentration in a range of 50 to 100 ⁇ g/ml.
  • a particular group of monoclonal antibodies appropriate for the preparation of compositions for use as immunomodulators according to the invention is characterized in that it neutralizes the antiviral activity of the human type I-IFN, on cells highly responsive to this human type I-IFN, for instance Daudi cells at a concentration in a range of 1 to 50 ⁇ g/ml, preferably 1 to 20 ⁇ g/ml, for a concentration of type I-IFN in the r-nge of 1 to 1000 units with reference to the international standard MRC 69/19.
  • the monoclonal antibody according to the invention is such that these antibodies do not bind to the human receptor for IFN gamma.
  • One particular antibody interesting for the preparation of pharmaceutical compositions of the invention is such as it directed against an epitope on the amino-acid sequence comprised between amino-acid 27 and amino-acid 427 of the extracellular domain of the human IFN-R as represented on figure 2.
  • One particularly interesting monoclonal antibody is the antibody designated 64G12 under n° 92022605 which has been deposited at the ECACC (European Collection of Animal Cell Cultures Porton Down Salisbury, Wiltshire SP4 056, United Kingdom) on February 26, 1992.
  • These antibodies may be prepared by conventional methods involving the preparation of hybridoma cells by the fusion of myeloma cells and spleen cells of an animal immunized beforehand with the peptide antigen, on the conditions such that the antigen against which the antibodies are formed is constituted by the extracellular domain of IFN-R or any polypeptide or peptide of this domain.
  • hybridomas are constructed according to the protocole of Kohler and Milstein (Nature, 1974, 256: 495-497) .
  • the hybridomas are derived from the fusion of the spleen cells above described with NSl mouse (BalbC) HGPRT " as myeloma cell.
  • a second procedure for the production of monoclonal antibodies according to the invention consists in carrying out the fusion between B-cells of blood immortalized with the Epstein/Barr virus and human B lymphocytes placed beforehand in contact with the extracellular domain or a fragment thereof of the IFN-R, against which it is decided to form monoclonal antibodies.
  • B-cells placed in contact beforehand with the extracellular domain of IFN-R or fragment thereof against which it is decided to form monoclonal antibodies may be obtained by in vitro culture contacted with the antigens, the recovery of the B- cells coated with these antigens being preceded by one or several cycles of stimulation.
  • the invention also concerns the use in the pharmaceutical compositions of human antibodies as obtained by carrying out the above procedure, having the above defined properties.
  • the invention also relates to the use in the pharmaceutical compositions of a monoclonal antibody characterized in that the variable or complementary determining regions of its heavy and/or light chains are grafted on the framework and/or constant regions of a human antibody.
  • a preferred pharmaceutical composition according to the invention is one which contains the purified preparation of monoclonal antibodies at a dose between around 0.05 mg/kg of bodyweight and 3 mg/kg, preferably between 0.5 mg/kg and 1 mg/kg.
  • composition of the invention can be administered by different ways and especially the active principle can be combined with a pharmaceuticle vehicle appropriate for the intravenous or intramuscular administration.
  • the monoclonal antibodies which have been defined hereabove can be used for a preparation of a drug having an immunomodulator effect sufficient to inhibit in vivo the disease due to the infection by a human retrovirus, especially by a human HIV or HTLV retrovirus.
  • such a drug can be used for the treatment of autoimmune and inflammatory diseases.
  • diseases include systemic lupus erythematosus, type 1 diabetes, psoriasis, rheumatoid arthritis, multiple sclerosis, Behcet's disease, asplatic anemia, acquired immunodeficiency syndrome (AIDS) , and severe combined immunodeficiency disease.
  • AIDS acquired immunodeficiency syndrome
  • the purified monoclonal antibodies defined above can be used for the preparation of a drug having an immunomodulator effect sufficient to inhibit in vivo the rejection of allografts or can be used for the preparation of a drug having an immunomodulator effect sufficent to inhibit in vivo the symptoms of the Graft Versus Host Disease.
  • Treatment of symptoms of acute virus diseases can also be performed with the antibodies of the invention.
  • upper respiratory tract infections chronic virus infections such as those due to measles virus, can be performed.
  • compositions of the invention can also be used for the in vitro diagnosis of the presence of the human soluble type I-IFN receptor or cells in a biological sample for instance in blood or in another fluid.
  • the test can be made by several techniques such as ELISA (figure 14(2)) or RIA.
  • the invention relates to a pharmaceutical composition for use as immunosuppressor, this composition being characterized in that it comprises as active principle, monoclonal antibodies having the above definition and as a combined preparation for simultaneous, separate or sequential use, an agent having an immunomodulator activity, especially an immunosuppressor activity such as cyclosporin A or FK 506.
  • an agent having an immunomodulator activity especially an immunosuppressor activity such as cyclosporin A or FK 506.
  • the monoclonal antibodies are present in a dose ranging from 0.05 mg/kg to 3 mg/kg, preferably from 0.5 mg/kg to 1 mg/kg and the agent having immunosuppressor activity, especially cyclosporin A.
  • Figure 1 binding of 15 I-labelled monoclonal antibodies 34F10 and 64G12 to :
  • IO 6 cells were incubated for 2 hours at 4°C in presence of different amounts of the labelled antibodies diluted in RPMI medium containing 10% fetal calf serum (FCS) .
  • FCS fetal calf serum
  • the cells were then washed 4 times in RPMI-1% FCS and counted for bound radioactivity. Nonspecific binding was measured by incubation with a 100 fold exces of cold antibodies and substracted from total counts.
  • Figure 2 nucleotide and corresponding amino-acid sequence of the extracellular domain of the human IFN-R
  • the monoclonal antibodies were produced against recombinant soluble forms of the human interferon alpha-beta receptor (IFN-R) synthetized in either procaryotic cells (E.coli) or a mammalian cell system (Cos cell) . These soluble forms were based on the DNA sequence described in figure 2.
  • IFN-R interferon alpha-beta receptor
  • This fragment was produced by the Polymerase Chain Reaction (PCR) and the resulting plasmids were sequenced to confirm both in- frame insertion with the Shine-Dalgarno sequence and the appropriate sequence coding for the receptor.
  • poly-histidyl tail introduced into the recombinant protein enables it to be purified rapidly by affinity chromatography on a chelated nickel support (NTA column) as described previously (Hochuli E. et al. Bio/technology, 1988, 1321-1325).
  • the plasmid was introduced into the E.coli strain, JM105, and protein synthesis induced by addition of IPTG to the culture medium (pKK233-2, tac promoter) .
  • Proteins were extracted from the bacterial pellet and the soluble receptor purified to homogeneity by affinity chromatography as described hereafter. This procedure yieled a protein that migrates as 2 bands around 50 kDa under reducing conditions and three bands under non-reducing conditions. The maximum concentration of the protein obtained by different procedures was approximately 20 ⁇ g/ml. The N-terminal sequence of the two proteins detected by gel electrophoresis has shown that both proteins are the expected fragment of the receptor.
  • NTA column Washes pH 8 urea 8M I pH 6,3 urea 8M
  • I dialysis PBS Using the same PCR approach, we also constructed an expression vector coding for the IFN-R amino acid sequence 1-427, with an additional 5-histidyl residues at the C-terminus, inserted in expression vector pXMT-3. The exact nucleotide sequence of the insert was also confirmed.
  • the resulting plasmid was introduced by electroporation into Cos7 cells for transient expression and the recombinant protein was purified to homogeneity by affinity chromotography followed by ion exchange chromatography on mono-Q (Pharmacia) as described hereafter.
  • mice were immunized by injection of recombinant soluble interferon (r sIFN-R) purified from E.coli or from a culture supernatant of Cos7 cells. Initially Balb/C mice were injected both intraperitoneally and subcutaneously with the purified protein in complete Freund's adjuvant. Subsequently mice were injected once a week intraperitoneally with the purified proteins diluted in buffered saline solution. Ten micrograms of recombinant proteins were injected each time.
  • r sIFN-R recombinant soluble interferon
  • spleen cells from the immunized animal were collected and fused to NSl (mouse) (Balbc) HGPRT " myeloma cells according to the method described by S. Fazekas et al. (J. Immunol. Methods 3J-- :1_32 / 1980). Briefly, 5xl0 7 spleen cells were fused to 3xl0 7 myeloma cells in 1ml of polyethylene glycol solution and distributed in five 96 well plates on a peritoneal macrophage feeder layer in HAT (hypoxanthine, aminoprotein and thymidine) medium. This procedure was repeated 4 times as 20xl0 7 spleen cells were obtained from the immunized mouse. Screening for specific hybridomas was undertaken when large colonies were detectable in culture wells.
  • ELISA plates were coated overnight at 4°C with purified E.coli-expressed or Cos7 cell-expressed sIFN-R diluted in PBS. Plates coated with BSA were used to detect non specific binding, b) Plates were saturated by incubation with 3% BSA in PBS for 1 hour at 37°C, c) Plates were incubated for 4 hours at room temperature with hybridoma supernatants diluted 1 in 4 with PBS-0.05% Tween 20, d) Bound antibodies were detected by a two step procedure, comprising a first incubation with goat anti-mouse biotinylated immunoglobulin followed by streptavidin-horseradish peroxidase complex (both from Amersham and diluted 1/1000 in PBS-0.05% Tween 20).
  • the reactivity of the monoclonal antibodies (mAbs) recognizing the recombinant sIFN-R was tested against the natural class I receptor expressed at the surface of Daudi cells, by membrane immunofluorescence. Briefly, 5xl0 5 Daudi cells were incubated in lOO ⁇ l of culture supernatant of chosen hybridomas for 30 min at 4°C. The cells were then washed 4 times in RPMI medium containing 1% BSA and further incubated with a diluted FITC labelled goat anti-mouse F(ab') for 30 min at 4°C. The cells were finally analyzed by flow cytometry after washing. One of the 35 tested antibodies produced against the E.coli recombinant receptor and 5 of the 6 tested antibodies produced against the COS recombinant receptor were found to recognize the natural receptor on the Daudi cells.
  • Monoclonal antibodies were purified from culture supernatants by protein G chromatography.
  • Inhibition of interferon binding to human cells was assayed as follows. IO 6 cells were preincubated at 4°C for 30 min with various dilutions of hybridoma culture supernatants or purified mAbs or with medium alone. 15 I-labelled IFN alpha 8 or alpha 2 was added at the concentration of lOOpM and cells incubated for a further 2 hours at 4°C. These incubations were performed in RPMI medium containing 20mM HEPES pH 7.4 and 10% foetal calf serum (FCS) . The cells were finally washed 4 times with RPMI - 1% FCS and counted to determine bound radioactivity.
  • FCS foetal calf serum
  • the mAb secreted by the hybridoma line 64G12 was shown in this assay to inhibit the binding of labelled IFN to the cells in a dose-dependent manner.
  • 50% inhibition of binding to the Daudi cells was obtained at a mAb concentration of 0.4 ⁇ g/ml.
  • K562 cells chronic myelogenous leukemia, Lozzio and Lozzio, Cell, 5:321-334, 1975
  • 50% inhibition was obtained at ll ⁇ g/ml for HL60 cells Promyelocytic leukemia, Collins S.J. et al., Nature, 220:347-349, 1977
  • 60 ⁇ g/ml for Ly28 cells Kerin G. et al. Int. J. Cancer, lO:44-57, 1972).
  • a dose-dependent inhibition of the antiviral activity of the various subtypes of type I IFN was demonstrated for the purified mAb 64G12.
  • the mAb 64G12 was demonstrated to block completely the antiviral activity of Leukocyte IFN (50U/ml) , recombinant IFN alpha 2
  • Daudi cells were seeded at a concentration of 10 5 cells per ml in a 96 well plate in the presence of interferon and purified inhibitory or control antibody. Cells were then counted after 24, 48 and 72 hours with a Coulter counter and checked for viability by trypan blue exclusion. Purified mAb 64G12 demonstrated a dose-dependent inhibition of the antiproliferative activity of interferon alpha 2.
  • interferon ⁇ 2 has been shown to exert an antiviral and antitumoral effect in AIDS patients with Kaposi sarcoma (Krown et al., 1991, J. Acquired Immune Deficiency Syndromes, :671), the production of inteferon does not prevent the development of AIDS in HIV infected individuals. Furthermore, the restriction of HIV replication by inteferon ⁇ may contribute to the development of a latent infection in macrophages (Gendelman et al., 1990, J. Exp. Pathol., 5:53; Gendelman et al., 1990, AIDS Res.
  • ⁇ inteferons are potent immunoregulatory molecules which enhance MHC class I antigen expression, MHC restricted T-cell killing, and non MHC restricted NK cell killing, of virus-infected cells all of which could contribute to the loss of CD 4 + T-lymphocytes observed in HIV infected individuals.
  • a marked reduction in the number of circulating CD 4 + T-lymphocytes has been observed in HIV infected individuals treated with recombinant interferon ⁇ 2 (Vento et al., 1993, The Lancet, 341:958) .
  • the product was then identified either by Southern hybridization as in the case of the IFN ⁇ and ⁇ genes or by direct di-deoxy sequencing using T7 DNA polymerase (Sequenase, USB) as in the case of the ⁇ inteferons following a further 15 cycle of asymetric amplification (using 0.5 pmol of one of the pair of specific oligonucleotide primers and 50 pmol of the other pair of primers) using standard procedures.
  • IFN ⁇ 5 was the majority species expressed in approximately 30 samples of peripheral blood cells from HIV infected individuals whereas IFN an (mainly IFN ⁇ l and IFN ⁇ 2) were the main interferon species expressed in peripheral blood cells from 5 HIV-seronegative individuals infected with rhinoviruses, influenza virus, or cytomegalovirus (Figure 5) .
  • IFN ⁇ 5 was found to be the main species expressed in cells chronically infected with HIV-1 whereas IFN ⁇ l and IFN ⁇ 2 were the most abundent species expressed in uninfected U937 cells induced with either Newcastle Disease Virus (NDV) or the polyribonucleotide Polyl-Poly C.
  • NDV Newcastle Disease Virus
  • polyclonal antibodies cannot be used for the therapeutical treatment of patients infected with HIV.
  • WISH cells a human amnion cell line
  • the anti-interferon receptor antibody 64G12 at a concentration of 50 ⁇ g/ml completely neutralized the antiviral activity of the endogenous interferon present in the serum of AIDS patients (Table 8) .
  • SIV-induced disease in macaques is characterized by lymphadenopathy, immune deficiency, and opportunistic infections and is considered to be an excellent experimental model of human AIDS (McClure et al., 1990, AIDS : Anti-HIV Agents, Therapies and Vaccines. Annals NY Academy of Sciences, 616:287) .
  • a group of 12 rhesus macaques infected with SIV and 9 uninfected control animals were followed for a period of some 30 months after infection. No interferon was detected in the sera of any of the uninfected control animals at any time during the 30-month observation period.
  • the development of AIDS-like disease in SIV-infected macaques was found to be preceded by a second peak of serum IFN ⁇ which occurs concomitantly with the loss of CD 4 + cells several months after primary infection. This second peak of interferon production, unlike that which is observed during primary infection, occurs over a period of several months, and precedes, the p27 antigenemia which occurs in late stage disease, in some cases by several months.
  • interferon response Three types of interferon response are seen in late stage disease; the production of a peak of interferon ⁇ some six to nine months post infection just prior to the development of the clinical signs of disease and death (Table 9, animals 483, 485, and 495, Figures 9-11) , the production of low levels of interferon ⁇ first detectable shortly after infection and which persist for up to 30 months (Table 9, animals 501, and 505, Figures 12-13), and the absence of detectable levels of interferon ⁇ during the whole 30 month observation period following infection with SIV (Table 9, animals 475, 456, 457, 489, and 489).
  • Inteferon ⁇ production was only observed in those animals which exhibited a weak or absence cytotoxic T- cell response (CTL) against autologous B-cells immortalized with Herpes papio virus and transfected with one of eight viral proteins (ENV, GAG, POL, NEF, VIF, REV, TAT, AND VPX) as described previously (Venet et al. 1992, J. Immunol., 148:2899) . None of the animals studied which exhibited a strong CTL response had detectable levels of circulating inteferon at any time during the two year period of observation. IFN ⁇ was not detected in the serum of SIV-infected macaques with normal CD 4 + counts and without signs of disease. Determination fo the Interferon Response in Chimpanzees Infected with HIV-1
  • the 64G12 antibody was well tolerated in rhesus macaques following intravenous administration at a dose of 0.5 to 1.0 mg/kg. No local reaction was observed at the site of injection. Furthermore no systemic reactions such as fever, oedema, etc. were observed in any of the animals injected with the antibody. Successive injections of the antibody were also well tolerated. The only reaction observed was a slight facial oedema seen in certain animals immediately after the third intravenous injection at 15 days (previous injections were at 0, and 5 days) . When the antibody was administered by intramuscular injection, at the third and subsequent injections no oedoma was observed.
  • An accident occured in a single monkey 20 minutes after the intravenous injection of a non-purified preparation of the 64G12 antibody at day following 4 previous intravenous injections of the antibody at days 0, 5, 10 and 15.
  • Pha ⁇ nacokinetics and Establishment of the Lowest Effective Dose of the Monoclonal Antibody 64G12 The level of the 64G12 antibody present in the serum of animals following intravenous injection was determined using an ELISA test based on the use of recombinant soluble receptor to capture antibodies which recognize the extracellular domain of the human interferon ⁇ receptor ( Figure 14) .
  • ELISA plates were coated with a recombinant protein corresponding to the extracellular domain (amino acids 1 to 427) of the human interferon ⁇ receptor produced in either COS or CHO cells at a maximum concentration of 10 to 20.0 ⁇ g/ml in either PBS or 100 mM carbonate buffer, pH 9.2.
  • the plates were then saturated with a 3% solution of bovine serum albumin or similar agent in PBS.
  • the plates were washed with PBS containing 0.5 to 1.0% Tween 20 or a similar detergent and serial dilutions of the samples to be tested, or reference preparation, were then applied to the plates.
  • the plates were then incubated overnight at 4°C or for 2 hours at 37°C, washed with PBS/Tween, and incubated for approximately 2 hours at 37°C with a polyclonal anti-mouse IgG conjugated with alkaline phosphatase, or horse-radish peroxidase.
  • Biotin- streptavidin reagents can also be used (Sheep anti- mouse lg and Streptavidin-biotinylated peroxidase performed complex from Amersham are suitable) .
  • the plates were then washed with PBS/Tween, incubated with the corresponding substrate (o-phenylene-diamine at a concentration of 0.4 mg/ml in a citrate buffer pH 5.5 is suitable for peroxidase; the reaction can then be stopped usually after 1 to 10 minutes by the addition of 0.5 M H 2 S0 4 ) and the optical density determined (at 405 nm for peroxidase reactions) according to standard procedures.
  • the corresponding substrate o-phenylene-diamine at a concentration of 0.4 mg/ml in a citrate buffer pH 5.5 is suitable for peroxidase; the reaction can then be stopped usually after 1 to 10 minutes by the addition of 0.5 M H 2 S0 4 ) and the optical density determined (at 405 nm for peroxidase reactions) according to standard procedures.
  • the intravenous injection of 1.0 mg/kg of the 64G12 anti- interferon receptor resulted in serum levels of approximately 60 ⁇ g/ml, 30 minutes after administration of the antibody which is in good keeping with the expected levels taking into account the blood volume of the animals.
  • a group of 8 rhesus macaques were infected with 10 macaque infectious dose 50 of a molecular clone of SIV strain 251.
  • Two macaques were injected intravenously with 0.5 mg/kg of the anti-interferon receptor antibody 64G12, 30 minutes prior to infection with SIV, and at days 5, 10 and 15 post infection.
  • One macaque was injected intravenously with 3.5 mg of a bull polyclonal anti-lymphoblastoid interferon IgG preparation, 30 minutes prior to infection and at days 5 post infection, and intramuscularly with 3.5 mg of the antibody at days 10 and 15 post infection.
  • the other 5 infected animals were left untreated.
  • EXAMPLE 6 The Effect of the Anti-interferon ⁇ Receptor Monoclonal Antibody on Skin Allograft Survival in Cynomologus Monkeys.
  • cytokines produced both by sensitized T-cells and non MHC restricted cells play an important role in the processes which lead to allograft rejection.
  • interferon ⁇ produced during the initial stages of recognition plays a determining role in the initiation of the processes which lead to graft rejection.
  • treatment of lethaly irradiated mice with interferon ⁇ has also been shown to enhance resistance to allogenic bone marrow grafts while treatment with antibody to interferon ⁇ was found to inhibit rejection (Affifi et al. 1985, J. Immunol., 134:3739).
  • interferon ⁇ also plays an important role in the development of graft-versus-host disease (GVHD) .
  • GVHD graft-versus-host disease
  • interferon ⁇ is produced during the course of graft-versus-host disease in parallel with the enhanced NK cell activity characteristic of systemic GVHD and administration of interferon ⁇ has been shown to enhance the intestinal consequences of GVHD in normal mice (Cleveland et al., 1987, Cell Immunol. 110:120) .
  • Human peripheral blood mononuclear cells from normal donors were isolated on a Ficoll gradient and typed for MHC class I and class II antigens by complement dependent micro-lymphocytoxicity.
  • the proliferation of the responder cells was determined by measuring the incorporation of 3 HTdR in response to allogenic stimulatory cells rendered non-proliferative by treatment with mitomycin-C.
  • Treatment of mixed lymphocyte cultures with the anti-interferon ⁇ receptor antibody resulted in a dose dependent inhibited the incorporation of 3 HTdR ( Figure 24) .
  • a mean inhibition of approximately 50% in the incorporation of 3 HTdR was observed in MLC treated with the 64G12 antibody at a concentration of 20 ⁇ g/ml of ( Figure 24) .
  • Skin allografts were exchanged between AOB compatible l to 3 year old male animals (Macaoa Fascicularis) differing in both MHC class I (Rh LA-A and B) and class II antigens (Th LA-DR) using standard procedures.
  • the grafts were taken and implanted in the left illiac fosse.
  • Animals were either left untreated, or treated (intramuscular injection) with cyclosporin A (5.0 mg/kg/day) one hour prior to grafting and each subsequent day, or with the 64G12 antibody (0.5 mg/kg) one hour prior to grafting and on day 5 and every subsequent 5th day (by intravenous injection for the first two injections and then by intramuscular injection subsequently) until day 85 or until rejection of the graft, or treated with cyclosporin A together with the 64G12 antibody at the same doses as used for each substance alone.
  • the grafts were examined daily for evidence of the clinical signs of rejection (colour, suppleness, etc.) and grafted tissue was biopsied at days 5, 10, 20, and 60 and at the day of rejection. Each biopsy was examined for histological signs of rejection and for the expression of MHC class I and Class II antigens.
  • the mean survival time of skin grafts in the untreated control animals was found to be 7.5 + 0.57 days, and 9.5 + 0.57 days in cyclosporin A treated animals (Table 12).
  • Treatment of animals with the 64G12 antibody was found to increase significantly the mean survival time of the grafted tissue (14.25 ⁇ 0.95 days) relative to both the untreated control animals (Wilcox test p ⁇ 0.01) and animals treated with cyclosporin A (Table 12) .
  • a single monkey in this group was lost at day 20 due to anaphylactic shock 20 minutes after the intravenous injection of an unpurified preparation of the 64G12 antibody.
  • the skin graft in this animal showed no macroscopic or microscopic signs or rejection at this time.
  • Biopsies taken from animals treated with cyclosporin A alone exhibited a dermic and hypodermic inflammatory infiltrate consisting essentially of mononuclear cells and some polynuclear neutrophiles with moderate oedema.
  • the skin allograft biopsies were also 'examined for the expression of MHC class I (HLA-ABC) and class II antigens (HLA-DR) -
  • HLA-ABC MHC class I
  • HLA-DR class II antigens
  • the biopsies from the untreated control animals exhibited a marked expression of both class I and class II antigens (Table 13) .
  • the expression of MHC class I antigens in the biopsies taken from animals treated with cyclosporin A was similar to that of untreated control animals while the expression of class II antigens was less intense (Table 13)
  • Such treatment regimens may also be applicable to the treatment of autoimmune disease particularly those diseases characterized by the abnormal, or prolonged production of interferon ⁇ .
  • Animals were either left untreated, or treated with anti-interferon ⁇ receptor antibody 30 minutes prior to grafting and on day 5 and every subsequent 5th day (by intravenous injection for the first two injections and by intramuscular injection thereafter) together with low dose cyclosporin A (5.0 mg/kg) 30 minutes after grafting and daily thereafter.
  • anti- interferon ⁇ receptor antibody given together with low dose cyclosporin A may be an effective treatment for GVHD.
  • Very few agents are effective in mitigating the acute from of GVHD seen in primates and in prolonging survival in these animals.
  • a beneficial effect in this model is considered to be predictive of a correspondingly greater beneficial effect in the less severe type of GVHD seen in patients receiving bone marrow from MHC matched donors.
  • Peripheral blood mononuclear cells from normal donors were typed for MHC class I class II antigens by complement dependent microlymphocytotoxicity for eacn pair of cultures.
  • Anti-IFN ⁇ receptor mAb IgG 14.25 ⁇ 0.95 (n 4)
  • CD4 + T lymphocytes and CD ⁇ + T lymphocytes were determined by FACS-SCAN using phycoerythrin conjugated anti-human CD4+ monoclonal antibody (OTK4 Ortho Diagnostics), and anti-human CD4+ monoclonal antibody (OTK4 Ortho Diagnostics), and anti-human CD4+ monoclonal antibody (OTK4 Ortho Diagnostics), and anti-human CD4+ monoclonal antibody (OTK4 Ortho Diagnostics), and anti-human
  • Leu2a monoclonal antibody (Becton-Dickinson) respectively.

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Abstract

L'invention se rapporte à des compositions pharmaceutiques utilisées en tant qu'immunomodulateurs, comprenant une préparation purifiée d'un anticorps monoclonal dirigé contre le récepteur d'interféron humain de la classe I (IFN-R), et caractérisées par les propriétés suivantes: reconnaissance du domaine extracellulaire de l'INF-R humain, et capacité de neutralisation dressée contre les propriétés biologiques de l'I-IFN de type humain. On a également prévu leur utilisation diagnostique.
PCT/EP1994/003114 1993-09-17 1994-09-16 Composition pharmaceutique comprenant des anticorps monoclonaux diriges contre le recepteur d'interferon et dotes d'une activite neutralisante a l'egard de l'interferon de type i Ceased WO1995007716A1 (fr)

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EP94928371A EP0725654A1 (fr) 1993-09-17 1994-09-16 Composition pharmaceutique comprenant des anticorps monoclonaux diriges contre le recepteur d'interferon et dotes d'une activite neutralisante a l'egard de l'interferon de type i
JP7509002A JPH11501283A (ja) 1993-09-17 1994-09-16 Ｉ型インターフェロンに対する中和活性を有する、インターフェロンレセプターに対するモノクローナル抗体を含んでなる医薬組成物
AU77828/94A AU7782894A (en) 1993-09-17 1994-09-16 Pharmaceutical composition comprising monoclonal antibodies against the interferon receptor, with neutralizing activity against type i interferon

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WO1997041229A1 (fr) * 1996-05-01 1997-11-06 Yeda Research And Development Co. Ltd. Anticorps agissant contre le recepteur de l'interferon alpha/beta
US6713609B1 (en) 1996-07-16 2004-03-30 Genentech, Inc. Monoclonal antibodies to type I interferon receptor
WO2004094473A3 (fr) * 2003-04-23 2005-06-02 Medarex Inc Anticorps humanises du recepteur 1 alpha d'interferon (ifnar-1)
WO2004093908A3 (fr) * 2003-04-23 2005-06-02 Medarex Inc Compositions et techniques destinees a la therapie d'une maladie intestinale inflammatoire
US7544357B2 (en) 2001-01-09 2009-06-09 Baylor Research Institute Methods for treating autoimmune diseases in a subject and in vitro diagnostic assays
US7662381B2 (en) 2004-06-21 2010-02-16 Medarex, Inc. Interferon alpha receptor 1 antibodies and their uses
US7741449B2 (en) 2003-12-10 2010-06-22 Medarex, Inc. Anti-interferon alpha antibodies
AU2007203559B2 (en) * 2003-04-23 2010-09-02 E. R. Squibb & Sons, L.L.C. Compositions and methods for the therapy of inflammatory bowel disease
AU2007202840B2 (en) * 2001-01-09 2011-07-28 Baylor Research Institute Methods for treating autoimmune diseases in a subject and in vitro diagnostic assays

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US6136309A (en) * 1996-05-01 2000-10-24 Yeda Research And Development Co. Ltd. Antibodies against the interferon (IFN) α/β receptor (IFNAR2) that preferentially block the activity of IFN-α
WO1997041229A1 (fr) * 1996-05-01 1997-11-06 Yeda Research And Development Co. Ltd. Anticorps agissant contre le recepteur de l'interferon alpha/beta
EP1739177A1 (fr) * 1996-05-01 2007-01-03 Yeda Research And Development Company, Ltd. Anticorps agissant contre le recepteur de l'interferon alpha/beta
US6713609B1 (en) 1996-07-16 2004-03-30 Genentech, Inc. Monoclonal antibodies to type I interferon receptor
US7544357B2 (en) 2001-01-09 2009-06-09 Baylor Research Institute Methods for treating autoimmune diseases in a subject and in vitro diagnostic assays
AU2007202840B2 (en) * 2001-01-09 2011-07-28 Baylor Research Institute Methods for treating autoimmune diseases in a subject and in vitro diagnostic assays
EP2404615A1 (fr) * 2003-04-23 2012-01-11 Medarex, Inc. Anticorps humanisés dirigés contre le récepteur 1 pour l'interféron alpha (IFNAR-1)
US8828393B2 (en) 2003-04-23 2014-09-09 Medarex, L.L.C. Methods for the therapy of inflammatory bowel disease using a type-1 interferon antagonist
KR100817351B1 (ko) * 2003-04-23 2008-03-26 메다렉스, 인코포레이티드 염증성 장질환 치료용 조성물
AU2004232362C1 (en) * 2003-04-23 2008-05-29 E. R. Squibb & Sons, L.L.C. Compositions and methods for the therapy of inflammatory bowel disease
CN100409897C (zh) * 2003-04-23 2008-08-13 梅达雷克斯公司 1型干扰素拮抗剂在制备治疗患有炎症性肠病的患者的药物中的用途
AU2004232362B2 (en) * 2003-04-23 2007-09-06 E. R. Squibb & Sons, L.L.C. Compositions and methods for the therapy of inflammatory bowel disease
US7619070B2 (en) 2003-04-23 2009-11-17 Medarex, Inc. Humanized antibodies to interferon alpha receptor-1 (IFNAR-1)
WO2004094473A3 (fr) * 2003-04-23 2005-06-02 Medarex Inc Anticorps humanises du recepteur 1 alpha d'interferon (ifnar-1)
US8758757B2 (en) 2003-04-23 2014-06-24 Medarex, L.L.C. Humanized antibodies to interferon alpha receptor-1 (IFNAR-1)
AU2007203559B2 (en) * 2003-04-23 2010-09-02 E. R. Squibb & Sons, L.L.C. Compositions and methods for the therapy of inflammatory bowel disease
US7888484B2 (en) 2003-04-23 2011-02-15 Medarex, Inc. Humanized antibodies to interferon alpha receptor-1 (IFNAR-1)
US7939076B2 (en) 2003-04-23 2011-05-10 Medarex, Inc. Methods for the therapy of Inflammatory Bowel Disease using a type-1 interferon antagonist
WO2004093908A3 (fr) * 2003-04-23 2005-06-02 Medarex Inc Compositions et techniques destinees a la therapie d'une maladie intestinale inflammatoire
AU2004233346B2 (en) * 2003-04-23 2008-03-06 Medarex, Inc. Humanized antibodies to interferon alpha receptor-1 (IFNAR-1)
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US8025882B2 (en) 2003-12-10 2011-09-27 Medarex, Inc. Interferon alpha antibodies and their uses
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US8722870B2 (en) 2003-12-10 2014-05-13 Medarex, L.L.C. Nucleic acids encoding interferon alpha antibodies
US7741449B2 (en) 2003-12-10 2010-06-22 Medarex, Inc. Anti-interferon alpha antibodies
US9765141B2 (en) 2003-12-10 2017-09-19 E. R. Squibb & Sons, L.L.C. Methods for preparing interferon alpha antibodies
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US7662381B2 (en) 2004-06-21 2010-02-16 Medarex, Inc. Interferon alpha receptor 1 antibodies and their uses
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