EP1986690A2 - ANTICORPS ANTI-FcRn UTILISES DANS LE TRAITEMENT D'ETATS AUTO/ALLO-IMMUNS - Google Patents

ANTICORPS ANTI-FcRn UTILISES DANS LE TRAITEMENT D'ETATS AUTO/ALLO-IMMUNS

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Publication number
EP1986690A2
EP1986690A2 EP07762598A EP07762598A EP1986690A2 EP 1986690 A2 EP1986690 A2 EP 1986690A2 EP 07762598 A EP07762598 A EP 07762598A EP 07762598 A EP07762598 A EP 07762598A EP 1986690 A2 EP1986690 A2 EP 1986690A2
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EP
European Patent Office
Prior art keywords
antibody
fcrn
antibodies
ivig
human
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EP07762598A
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German (de)
English (en)
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EP1986690A4 (fr
Inventor
Joseph P. Balthasar
Ryan J. Hansen
Jin Feng
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Research Foundation of State University of New York
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Research Foundation of State University of New York
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Priority claimed from US11/634,676 external-priority patent/US7662928B2/en
Application filed by Research Foundation of State University of New York filed Critical Research Foundation of State University of New York
Publication of EP1986690A2 publication Critical patent/EP1986690A2/fr
Publication of EP1986690A4 publication Critical patent/EP1986690A4/fr
Withdrawn legal-status Critical Current

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    • 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
    • C07K16/283—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 against Fc-receptors, e.g. CD16, CD32, CD64
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues

Definitions

  • the present invention relates generally to the field of autoimmune and alloimmune diseases.
  • Humoral autoimmune and alloimmune conditions are mediated by pathogenic antibodies.
  • Some examples of autoimmune diseases include immune neutropenia, myasthenia gravis, multiple sclerosis, lupus and immune thrombocytopenia (ITP).
  • ITP is primarily a disease of increased peripheral platelet destruction, where most patients develop antibodies that bind to specific platelet membrane glycoproteins.
  • the antiplatelet antibodies effectively opsonize platelets, leading to rapid platelet destruction by cells of the reticulo-endothelial system (e.g., macrophages). Relative marrow failure may contribute to this condition, since studies show that most patients have either normal or diminished platelet production.
  • attempts to treat ITP include suppressing the immune system, and consequently causing an increase in platelet levels.
  • ITP affects women more frequently than men, and ITP is considered to be an autoimmune disease that is common in children and adults.
  • the incidence is 1 out of 10,000 people.
  • the incidence of ITP in adults is approximately 66 cases per 1,000,000 per year.
  • An average estimate of the incidence in children is 50 cases per 1,000,000 per year.
  • TVIG human immunoglobulin
  • therapies used for the treatment of autoimmune / alloimmune conditions other than rVIG include polyclonal anti-D immunoglobulin, corticosteroids, immuno-suppressants (including chemotherapeutics), cytokines, plasmapheresis, extracorporeal antibody adsorption (e.g., using Prosorba columns), surgical interventions such as splenectomy, and others.
  • these therapies are also complicated by incomplete efficacy and high cost.
  • compositions and methods for treatment of autoimmune and alloimmune conditions comprise agents which function non-competitively to inhibit the transport of IgG by FcRn receptors.
  • Noncompetitive receptor inhibitors demonstrate inhibitory activity that is independent of the concentration of the receptor ligand (e.g., IgG).
  • IgG concentration of the receptor ligand
  • non-competitive inhibition may be achieved by non-competitive binding of inhibitors to FcRn at physiological pH, and incomplete dissociation of the inhibitor-FcRn complex during the time-course of endosomal sorting and transit.
  • non-competitive inhibition may be achieved by binding to a site that is distant from, and/or not identical to, the ligand binding site.
  • the antibodies of the present invention bind to the FcRn such that binding of pathogenic antibodies to the FcRn is inhibited thereby improving the clearance of the pathogenic antibodies from an individual's body.
  • the agents which binds to FcRn are polyclonal or monoclonal antibodies directed to the heavy chain or the light chain of the FcRn.
  • the present invention provides polyclonal and monoclonal antibodies to the human FcRn receptors.
  • the antibodies are chimeric or humanized.
  • the invention also provides a method for ameliorating an autoimmune or alloimmune condition comprising administering to an individual a composition comprising an agent which functions as a non-competitive inhibitor of IgG for binding to FcRn and which binds to the FcRn such that binding of pathogenic antibodies to the FcRn is inhibited.
  • the agent is polyclonal, monoclonal, chimeric or humanized antibodies directed to FcRn, particularly human FcRn receptors.
  • the antibodies are directed to the heavy chain of the FcRn receptor.
  • Figure 2. Plasma 7E3 pharmacokinetics following IVIG treatment. Rats (3-4 per group) were dosed intravenously with IVIG (0-2 g/kg) followed by 7E3 (S mg/kg).
  • Panel A shows plasma 7E3 pharmacokinetic data for each animal given saline (1), 0.4 g/kg IVIG (2), 1 g/kg rVIG (3), or 2 g/kg IVIG (4).
  • Panel B Average plasma pharmacokinetic data for animals receiving 7E3 and IVIG. Treatment groups are designated as follows: saline (•), 0.4 g/kg ( ⁇ ), 1 g/kg (A), and 2 g/kg ( ⁇ ). 7E3 concentrations were determined via ELISA.
  • Error bars represent the standard deviation about the mean concentration at each time point. rVIG treatment significantly increased the clearance of 7E3 (p ⁇ 0.001), calculated from the concentration vs. time profiles shown in this figure.
  • IVIG does not directly bind 7E3.
  • 7E3 or control IgG
  • IVIG were combined in vitro, at a constant IVIG concentration (25 mg/ml) and varying 7E3 concentrations (0-0.1 mg/ml).
  • the positive control was a mouse anti-human IgG.
  • Samples were then added to a microplate coated with anti-human IgG.
  • Murine IgG binding was visualized using a secondary anti-mouse IgG-alkaline phosphatase conjugate.
  • FIG. 4 Plasma AMI pharmacokinetics following IVIG treatment. Rats (3 per group) were dosed intravenously with saline (•) or 2 g/kg ( ⁇ ) IVIG, followed by AMI (8 mg/kg). AMI concentrations were determined via ELISA. Error bars represent the standard deviation about the mean concentration at each time point. IVIG treatment significantly increased the clearance of AMI (p ⁇ 0.001), calculated from the concentration vs. time profiles shown in this figure. IVIG's effects on antibody pharmacokinetics are not specific for 7E3.
  • FIG. 5 IVIG effects on 7E3-platelet binding as determined by flow cytometry.
  • 7E3 was incubated with human platelets in the presence or absence of IVIG.
  • the histograms plot platelet count verses relative fluorescence intensity.
  • the bottom panel shows the fluorescence histogram obtained for control mouse IgG incubated with platelets (median fluorescence intensity (MFI) was 1.3).
  • FIG. 7E3 pharmacokinetics following IVIG treatment in control and FcRn- deficient mice Mice (3-5 per group) were dosed intravenously with IVIG (1 g/kg) followed by 7E3 (8 mg/kg). Treatment groups are designated as follows: 7E3+saline in control mice (•); 7E3+IVIG in control mice ( ⁇ ); 7E3+saline in knockout mice (O); and 7E3+IVIG in knockout mice ( ⁇ ). 7E3 concentrations were determined via ELISA. Error bars represent the standard deviation about the mean concentration at each time point. IVIG treatment significantly increased the clearance of 7E3 in control mice (p ⁇ 0.001), but not in FcRn- deficient mice. Figure 8.
  • FIG. 9 Plasma AMI pharmacokinetics following different doses of 4C9. Rats (3-4) per group were dosed intravenously with 4C9 (0-60 mg/kg) four hours before administration of AMI (8mg/kg i.v.). Blood samples were collected, and plasma samples were analyzed for AMI concentrations via ELISA. Treatment groups are designated as follows: saline (•), 3 mg/kg ( ⁇ ), 15 mg/kg (A), 60 mg/kg ( ⁇ ). Error bars represent standard deviation about the mean AMI concentration at each point. The 15 and 60 mg/kg significantly increased (p ⁇ 0.01) the clearance of AMI compared to control. Figure 10. Reactivity of hybridoma supernatant against human FcRn.
  • Hybridomas were generated which secrete antibodies against the light chain of hFcRn. Plates were coated with the light chain of human FcRn and incubated with supernatants from the indicated hybridomas. Goat anti-mouse Fab fragment conjugated to alkaline phosphatase was used to identify positive clones. Eight hybridomas producing antibodies specific for the light chain of human FcRn were identified.
  • Figure 11 Effect of presence of IgG on the reactivity of anti-hFcRn against FcRn. 293 cells expressing hFcRn were incubated with anti-FcRn antibodies with or without human IgG. Binding was detected by second antibody conjugated to FITC. Cell fluorescence was assessed by a fluorometer.
  • Figure 12. Effect of presence of IgG on the reactivity of anti-hFcRn (heavy chain) against FcRn. 293 cells expressing hFcRn were incubated with anti-hFcRn (heavy chain) antibodies with or without human IgG. Binding was detected by second antibody conjugated to FITC. Cell fluorescence was assessed by a fluorometer.
  • pathogenic antibodies refers to antibodies that beget morbid conditions or disease. Such antibodies include anti-platelet antibodies.
  • compositions and methods for increasing the clearance of pathogenic antibodies are useful for treatment of autoimmune and alloimmune conditions.
  • the compositions and methods of the present invention are directed to binding FcRn (also known as: Fc-receptor of the neonate, FcRP,
  • FcRB and the Brambell Receptor
  • the antibodies or fragments thereof are non-competitive inhibitors of IgG binding to, or transport by, human FcRn.
  • the antibodies or fragments may be of any isotype (e.g., IgA, IgD, IgE, IgG, IgM, etc.), and the antibodies maybe generated in any species (e.g., mouse, rat, etc.).
  • antibodies of the IgG isotype may competitively inhibit the binding of IgG to human FcRn.
  • Such antibodies can be used, provided that they also act as noncompetitive inhibitors of IgG binding to FcRn.
  • an antibody that is both a noncompetitive and a competitive inhibitor of IgG binding to FcRn may be used.
  • FcRn binds its ligand (i.e., IgG) with pH dependent affinity. It shows virtually no affinity for IgG at physiologic pH.
  • anti-FcRn antibodies that bind FcRn at physiologic pH may act as non-competitive inhibitors, such that the binding of the anti-FcRn antibody to FcRn is not influenced by the presence of IgG.
  • the ability of the antibodies of the present invention to bind to FcRn in a pH-independent manner in the range of pH 6 to 8 and also in a non-competitive manner allows functional inhibition of FcRn- mediated transport of IgG at concentrations much lower than those required for competitive inhibitors. While not intending to be bound by any particular theory, it is hypothesized that pH independence in the range of pH 6-8 allows such inhibitors to bind to FcRn on the cell surface (physiological pH), and to remain bound to FcRn during the course of intracellular transit, thereby inhibiting FcRn binding to IgG within endosomes at acidic pH ( ⁇ 6).
  • IVIG mediates a dose-dependent increase in elimination of pathogenic antibody in animal models of ITP, and this effect is mediated by rVTG interaction with FcRn.
  • very high doses of IVIG are required to produce substantial increases in the clearance of pathogenic antibody (i.e., the typical clinical dose of IVIG is 2 g/kg) in part due to the putative mechanism of IVIG inhibition of FcRn binding with pathogenic antibody (i.e., competitive inhibition), and in part due to the fact that IgG shows very low affinity for FcRn at physiologic pH (i.e., pH 7.2 - 7.4).
  • the present invention is for specific anti-FcRn therapies that provide non-competitive inhibition of FcRn binding to pathogenic antibodies at physiologic pH and allow noncompetitive inhibition of FcRn binding to pathogenic antibodies.
  • the present invention provides a method of preventing pathogenic antibodies from binding FcRn as a treatment for autoimmune and aUoimmune disorders.
  • the present method also provides compositions useful for specifically inhibiting FcRn in a manner sufficient to prevent pathogenic antibodies from binding FcRn.
  • the compositions and methods of the present invention preferably effect, in the recipient of the treatment, both an increase in the rate of elimination of pathogenic antibodies and palliation of morbidity and disease caused by the pathogenic antibodies.
  • the present invention provides anti FcRn (heavy chain) antibodies.
  • These antibodies can be generated by using the whole heavy chain or peptides corresponding to sequences of the heavy chain. Examples of such antibodies are presented in Examples 12- 15. The antibodies were observed to not bind to b2 microglobulin. However, since they bind to the FcRn complex (comprising both the heavy chain and the b2 microglobulin) and were generated against a sequence of the heavy chain of FcRn, it is most likely that these antibodies bind to the heavy chain of human FcRn.
  • compositions and methods of the present invention are accordingly suitable for use with autoimmune disorders including but not limited to immune cytopenias, immune neutropenia, myasthenia gravis, multiple sclerosis, lupus and other conditions where antibodies cause morbidity and disease.
  • autoimmune disorders including but not limited to immune cytopenias, immune neutropenia, myasthenia gravis, multiple sclerosis, lupus and other conditions where antibodies cause morbidity and disease.
  • the antibodies of the present invention can be used in other species also.
  • compositions of the present invention comprise an agent that can inhibit FcRn from binding pathogenic antibodies such as anti-platelet antibodies.
  • Such compositions include but are not limited to monoclonal antibodies, polyclonal antibodies and fragments thereof.
  • the antibodies may be chimeric or humanized, antibody fragments, peptides, small- molecules or combinations thereof that can prevent pathogenic antibodies from binding the FcRn receptor.
  • Antibody fragments that include antigen binding sites may also be used.
  • Such fragments include, but are not limited to, Fab, F(ab) 5 2, Fv, and single-chain Fv (i.e., ScFv).
  • Such fragments include all or part of the antigen binding site and such fragments retain the specific binding characteristics of the parent antibody.
  • the antibodies of the present invention may be chimeric antibodies, humanized antibodies.
  • "Chimeric" antibodies are encoded by immunoglobulin genes that have been genetically engineered so that the light and heavy chain genes are composed of immunoglobulin gene segments belonging to different species.
  • the variable (V) segments of the genes from a mouse monoclonal antibody may be joined to human constant (C) segments.
  • Such a chimeric antibody is likely to be less antigenic to a human than antibodies with mouse constant regions as well as mouse variable regions.
  • Humanized antibodies are immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab', F(ab') 2 or other antigen-binding subsequences of antibodies) which contain minimal sequence derived from non-human immunoglobulin.
  • Humanized antibodies include human immunoglobulins in which residues from a complementary determining region (CDR) are replaced by residues from a CDR of a non-human species such as mouse, rat or rabbit having the desired specificity, affinity and capacity.
  • CDR complementary determining region
  • Fv framework residues of the human immunoglobulin are replaced by corresponding non- human residues.
  • Humanized antibodies may also comprise residues which are found neither in the human antibody nor in the non-human imported CDR or framework sequences.
  • the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence.
  • a humanized antibody has one or more amino acid residues introduced into it from a source which is non-human. These non-human amino acid residues can be referred to as "import" residues, which are typically taken from an "import” variable domain. Humanization can be essentially performed following the method of Winter and co-workers (Jones et al., Nature, 321:522 525 (1986); Riechmann et al., Nature, 332:323 327 (1988); Verhoeyen et al. Science, 239:1534 1536 (1988)), by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. In practice, humanized antibodies are typically human antibodies in which some CDR residues and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies.
  • Polyclonal antibodies directed to FcRn or a fragment thereof such as the light chain or the heavy chain can be prepared by immunizing a suitable subject with FcRn or portions thereof such as the light chain, the heavy chain, and peptide sections included within the molecule.
  • the anti- FcRn or a fragment thereof antibody titer in the immunized subject can be monitored over time by standard techniques, such as ELISA using immobilized FcRn or a fragment thereof.
  • the antibody molecules directed against FcRn or a fragment thereof can be isolated from the mammal (e.g., from the blood) and further purified by well known techniques, such as protein A chromatography to obtain the IgG fraction.
  • Monoclonal antibodies directed toward FcRn or a fragment thereof can also be produced by standard techniques, such as the hybridoma technique originally described by Kohler and Milstein (1975, Nature 256:495-497). Briefly, an immortal cell line (typically a myeloma) is fused to lymphocytes (typically splenocytes) from a mammal immunized with FcRn or a fragment thereof, and the culture supernatants of the resulting hybridoma cells are screened to identify a hybridoma producing a monoclonal antibody that binds FcRn.
  • an immortal cell line typically a myeloma
  • lymphocytes typically splenocytes
  • the immortal cell line e.g., a myeloma cell line
  • the immortal cell line is derived from the same mammalian species as the lymphocytes.
  • Hybridoma cells producing a monoclonal antibody of the invention are detected by screening the hybridoma culture supernatants for antibodies that bind FcRn using standard ELISA assay.
  • Human hybridomas can be prepared in a similar way.
  • An alternative to preparing monoclonal antibody-secreting hybridomas is to identify and isolate monoclonal antibodies by screening a recombinant combinatorial immunoglobulin library (e.g., an antibody phage display library) with FcRn or a fragment thereof.
  • a recombinant combinatorial immunoglobulin library e.g., an antibody phage display library
  • compositions of the present invention can be carried out by methods known to those skilled in the art.
  • administration may be carried out by, for example, intravenous, intramuscular or subcutaneous injection, cannula or other methods known to those skilled in the art.
  • administration of small molecules effective to prevent binding of anti-platelet antibodies to FcRn receptors can be carried out by methods well known to those skilled in the art.
  • the inhibitor antibody or antibodies of the present invention can be administered. It will be appreciated by those skilled in the art that the effects of the inhibitor antibodies on the elimination of pathogenic antibodies in a particular individual will likely be dependent on the dosing regimen, the pharmacokinetics of the inhibitor antibodies (i.e., the rate and extent of inhibitor distribution and elimination), the affinity of the inhibitor antibodies for FcRn, the transport capacity of FcRn and, potentially, on the turnover of the FcRn receptor. Animal studies presented herein have demonstrated that a model inhibitor antibody led to a dose-dependent, transient increase in IgG elimination in rats.
  • the transient nature of the effect may allow control of the duration of FcRn blockade, and may allow minimization of any risks associated with FcRn blockade (e.g., risk for infection).
  • the pH 6 to 8 independent and non-competitive inhibitors of the present invention should cause parallel decreases in the concentrations of endogenous pathogenic and nonpathogenic IgG antibodies.
  • the influence of high affinity, non-competitive inhibitors of FcRn on pathogenic antibody concentrations may be estimated based on the effects of the inhibitors on total serum concentrations of endogenous IgG.
  • the FcRn inhibitors may be administered as single and/or multiple-doses.
  • 1-2000 mg/kg, preferably 1-200 mg/kg, and a more preferably, 1-40 mg/kg may be administered to patients afflicted with autoimmune or alloimmune conditions, and these regimens are preferably designed to reduce the serum endogenous IgG concentration to less than 75% of pretreatment values. Intermittent and/or chronic (continuous) dosing strategies may be applied.
  • This example describes the general methods used.
  • 7E3 a murine antiglycoprotein Hb/IIIa (GPIIb/IIIa) monoclonal antibody, was produced from hybridoma cells obtained from American Type Culture Collection (Manassas, VA). Hybridoma cells were grown in serum-free media (Life Technologies®, Rockville, MD) and antibodies were purified from the media using protein G chromatography.
  • IVIG preparations were obtained from Baxter Healthcare® (Hyland Division, Glendale, CA) and Bayer ® (Pharmaceutical Division, Elfchart, EN).
  • Both IVIG preparations are solvent/detergent-treated and are manufactured via cold ethanol fractionation of human plasma.
  • Outdated human platelets were obtained from the American Red Cross (Buffalo, NY and Salt Lake City, UT).
  • a murine antimethotrexate IgGl monoclonal antibody (AMI) was generated and purified in our laboratory.
  • Goat antihuman IgG (no cross-reactivity to goat and mouse serum proteins) and alkaline phosphatase-conjugated goat antimouse IgG were both obtained from Rockland (Gilbertsville, PA).
  • Mouse antihuman IgG, fluorescein isothiocyanate (FITC)- labeled antimouse IgG, and p-nitrophenyl phosphate were from Pierce® (Rockford, Illinois).
  • Bovine serum albumin (BSA) and buffer reagents were obtained from Sigma ® (St Louis, MO). Buffers were phosphate-buffered saline (PBS, pH 7.4), 0.02 M Na2HPO4 (PB), and PB plus 0.05% Tween-20 (PB-Tween).
  • Examples 2-5 illustrate the effect IVIG on antiplatelet antibody. These examples illustrates that IVIG is able to attenuate the effects of an antiplatelet antibody in a rat model of ITP in a dose-dependent manner, and that IVIG has a dramatic, and apparently nonspecific, effect on antiplatelet antibody clearance.
  • Platelet count data were normalized by the initial platelet count because of large interanimal variability in initial platelet counts. By normalizing the data, the effects of 7E3 and IVIG can be better compared between animals. Blood samples (0.15 mL) were taken for pharmacokinetic analysis at 1, 3, 6, 12, 24, 48, 96, and 168 hours after 7E3 dosing. 7E3 plasma concentrations were determined using an enzyme-linked immunosorbent assay (ELISA) as follows. Human GPHb/IIIa was diluted 1 :500 in PB, and added to Nunc Maxisorp plates (0.25 ml/well). Plates were incubated overnight at 4° C.
  • ELISA enzyme-linked immunosorbent assay
  • each group had comparable mean initial platelet counts, with control, 0.4-, 1-, and 2-g/kg IVIG groups having absolute initial counts of 326 ⁇ 62, 323 ⁇ 137, 272 ⁇ 111, and 301 ⁇ 69 x 10 9 platelets/L, respectively.
  • absolute platelet count may be important in assessing bleeding risk
  • the percentage of rats reaching a threshold value of thrombocytopenia decreased with dose for animals pretreated with IVIG, with 75%, 50%, and 25% of rats in the 0.4-, 1-, and 2-g/kg IVIG groups having nadir platelet counts less than 30% of initial.
  • EXAMPLE 3 This example describes the pharmacokinetic of the effects of IVIG on 7E3.
  • 7E3 plasma concentrations following pretreatment of the rats with IVIG were measured. It was observed that IVIG enhanced the clearance of 7E3, as can be seen from Figure 2 and Table 1.
  • An ANOVA revealed highly significant differences between the clearance values calculated for the 4 treatment groups (P ⁇ .001). Differences in 7E3 clearance were shown to be statistically significant for all pairs of treatment groups, except for the comparison of data from animals receiving 0.4 versus 1 g/kg IVIG (Tukey multiple comparisons test). Significant differences from control were seen in 7E3 concentrations at each time point at 12 hours and longer for the 2-g/kg IVIG group, and at least 48 hours for the 0.4- and 1 -g/kg IVIG groups.
  • IVIG altered the pharmacokinetics of 7E3.
  • rVIG was found to induce a dramatic increase in the clearance of the antiplatelet antibody (P ⁇ .001). Clearance, which serves as a time-and-concentration-averaged measure of 7E3 elimination, is a better metric for evaluation of IVIG effects on 7E3 elimination, because rVIG effects on elimination rate (and half-life) may be expected to decrease with time following rVIG administration.
  • EXAMPLE 4 This example demonstrates that IVIG does not bind to anti-FcRn antibody.
  • Goat a ⁇ tihuman IgG (diluted 1:500 in PB, 0.25 mL/well) was added to the wells of aNunc® Maxisorp® 96-well microplate (Nunc® model no. 4-42404, Roskilde, Denmark), and the plate was allowed to incubate at 4°C, overnight.
  • IVIG 25 mg/mL
  • 7E3 (0, 0.01, 0.05, and 0.10 mg/mL
  • Positive control samples consisted of IVIG incubated with mouse antihuman IgG (Pierce®), at the same concentrations as indicated for 7E3. Samples and controls were diluted by 1000 into 1% BSA, in PBS, and then added to the microplate (0.25 mL/well) and allowed to incubate for 2 hours at room temperature. Alkaline phosphatase— labeled antimouse IgG (diluted 1 :500 in PB, 0.25 mL/well) was then added to the plate and allowed to incubate for 45 minutes, also at room temperature.
  • jp-nitrophenyl phosphate (4 mg/mL in diethanolamine buffer, pH 9.8) was added, 0.2 mL/well, and the plate was read at 405 nm on a plate reader (Spectra Max® 340PC, Molecular Devices®, Sunnyvale, CA). The plate was read over a period of 10 minutes, and the slopes of the absorbance verses time curves were used to assess assay response (dA/dt). Each sample was assayed in triplicate, and responses are shown as mean ⁇ SD. Between each step of the assay, the wells of the microplate were washed 3 times with PB-Tween.
  • Figure 3 shows the results obtained from the experiment designed to detect 7E3-IVIG binding.
  • IVIG and 7E3 were incubated, in vitro, at 37°C, for 2 hours. Following this incubation, the samples were diluted and added to a microplate coated with antihuman IgG. Thus, if 7E3 did bind to IVIG, a secondary antimouse IgG would detect the presence of 7E3.
  • the concentration ratios of 7E3/TVIG in this experiment were designed to be similar to what would be expected in the in vivo experiments.
  • Figure 4 demonstrates that IVIG also increased the clearance of AMI, with AMI clearance increasing from 0.44 ⁇ 0.05 to 1.17 ⁇ 0.05 mL hour "1 kg *1 from the control to the IVTG-treated group (P ⁇ .001). Furthermore, the relative degree of increased clearance due to IVIG treatment was similar between groups, with a 2.37-fold increase in clearance seen for 7E3, and a 2.66-fold increase in clearance seen for AMI, following 2-g/kg IVIG treatment.
  • This example describes qualitative and quantitative studies to determine if IVIG could inhibit the binding of 7E3 to human platelets, hi a qualitative study, 10 ⁇ g/mL 7E3 was incubated for 1.5 hours with human platelets (1 x 10 7 platelets/mL) in the presence or absence of IVIG (2.5 mg/niL). Control mouse IgG was a negative control. The samples were centrifuged at 4000 rpm for 6 minutes, washed with PBS (twice), and then incubated for 45 minutes with 100 ⁇ L of a 1:10 dilution (in PBS) of FITC-labeled antimouse IgG solution.
  • Ff is the free fraction of 7E3
  • K A is the apparent for 7E3-platelet binding
  • [7E3]f is the unbound molar 7E3 concentration
  • R t is the total receptor concentration.
  • Standard non-compartmental pharmacokinetic analyses were performed to determine the clearance and terminal half life of 7E3 for the various treatment groups (11), using WINNONLIN software (Pharsight Corp., Palo Alto, CA). Unpaired T-tests were performed using GraphPad Instat (GraphPad Software, Inc., San Diego, CA).
  • An example of an agent suitable to specifically inhibit binding of anti-platelet antibodies to FcRn receptors is a monoclonal anti-FcRn antibody.
  • Hybridomas secreting monoclonal anti-FcRn antibodies were obtained from the American Type Culture Collection (ATCC#: CRL-2437, designation: 4C9V The hvh ⁇ i ⁇ cmna TM]u w/ ere grown in culture in standard media supplemented with 1% fetal bovine sera. Culture supernatant was collected, centrifuged, and subjected to protein-G chromatography to allow purification of IgG.
  • This embodiment describes the effects of 4C9 on another antibody, AMI.
  • 4C9 Four hours after the administration of 4C9, AMI (8 mg/kg) was administered through the cannula, and blood samples (150 ul) were collected at 1,3,6,12,24,48, 72 and 96 hours. Cannula patency was maintained for flushing with approximately 200 ul heparinized saline. Blood was centrifuged at 13,000 g for 3-4 minutes and the plasma was isolated and stored at 4C until analyzed. Plasma AMI concentrations were determined by ELISA
  • This example demonstrates the generation of monoclonal antibodies to the human FcRn.
  • the light chain of human FcRn i.e., human beta-2-microglobulin, Sigma Chemical, St. Louis, Mo.
  • emulsified in Freund's incomplete adjuvant (Sigma Chemical) was used to repetitively immunize six Balb/c mice (Harlan, Indianapolis, IN). Animals were bled from the saphenous vein 7-10 days after immunization, and antibodies directed against the human FcRn light chain were detected with an antigen capture enzyme-linked immunosorbent assay (ELISA).
  • ELISA antigen capture enzyme-linked immunosorbent assay
  • the animal with the highest ELISA response was selected for use as a splenocyte donor, and fusion was performed with murine SP20 myeloma cells (ATCC, Manassas, VA). Briefly, the mouse was sacrificed with ketamine (150 mg/kg) and xylazine (30 mg/kg), and the spleen was rapidly removed using aseptic technique, Splenocytes were teased out of spleen tissue with the use of sterile 22-gauge needles, suspended in RPMI 1640, and fused with SP20 cells by centrifugation with polyethylene glycol, using standard techniques (e.g., as described in: Harlow E and Lane D. 1988. Antibodies: A laboratory manual. New York: Cold Spring Harbor Laboratory).
  • Fused cells were selected through application of HAT selection medium (Sigma Chemical) and cloned by the method of limiting dilution. Tissue culture supernatant was assayed for anti-FcRn activity by evaluating ELISA response against human beta-2-microglobulin. Ninety-one viable hybridoma clones were identified, and tissue culture supernatant was obtained from the culture of each clone to screen for the presence of anti-human FcRn light chain antibodies. Briefly, the human FcRn light chain was coated on 96-well microplates overnight at 4 0 C.
  • This example describes the effect of anti-FcRn light chain antibodies on the binding of human IgG to 293 cells that express human FcRn.
  • 293 cells expressing human FcRn were obtained from Dr. Neil Simister of Brandeis University.
  • Human IgG was labeled with FITC by standard procedures.
  • Tissue culture supernatant was obtained from cultures of four hybridomas (11E4, 11F12, 1H5, 10E7) that were found to secrete antibodies directed against the light chain of human FcRn (Example 9).
  • 293 cells were treated with trypsin. ⁇ DTA and suspended in medium. The cell suspension was centrifuged at 300g for 5 min, re-suspended in buffered saline, and cells were counted by a hemocytometer. Approximately 3.6xlO 6 cells/ml of 293 cells were added to each centrifuge tube within buffered saline at pH 6 or 8. Cells were incubated with buffered saline alone, or with FITC-IgG at a concentration of 1 ⁇ g/ml in the presence or absence of cell culture supernatant obtained from the hybridoma cells.
  • reaction mixture was incubated at room temperature for 1.5 h, and cells were then washed and re-suspended in buffered saline.
  • Cell-associated fluorescence was analyzed with a fluorometer, with excitation and emission wavelengths set at 494 and 520 nm, respectively.
  • the cell-associated fluorescence was found to be 253000 and 10800 for 293 cells incubated with 1 ⁇ g/ml FITC-human-IgG at pH 6.0 and 8.0, respectively. In contrast, for cells incubated in the absence of FITC-IgG, cell associated fluorescence was found to be 5220 and 5300 at pH 6.0 and 8.0, respectively. For cells incubated at pH 6.0 with FITC-IgG and the culture supernatant obtained from cells secreting anti-FcRn antibodies, cell associated fluorescence was decreased by 80 - 84% (see Table 3, below).
  • N/A indicates not applicable.
  • the antibodies of the present invention are non-competitive inhibitors of IgG bind ⁇ ncr tn ⁇ ?ri?n i-tin/Uwrr ⁇ f ⁇ ouse
  • IgG to 293 cells expressing hFcRn was determined in the presence or absence of the anti-hFcRn antibodies was determined as follows. 293 cells were incubated with PBS, with cell culture supernatant from two hybridomas that were identified as secreting anti-human FcRn light chain antibodies, and with cell culture supernatant obtained from cells secreting monoclonal anti- methotrexate mlgGl (AMI, as a negative control).
  • This incubation was performed in duplicate, with or without co-incubation with human IgG (1 mg/ml). Following this incubation, the cells were incubated with an anti-mouse IgG antibody labeled with FITC (i.e., to detect the presence of murine anti-FcRn antibody bound to human FcRn on the surface of the 293 cells). Cells were washed and cell associated fluorescence was assessed via a fluorometer. All incubations were performed at pH 7.4.
  • Figure 11 show significant binding of mouse IgG to 293 cells expressing hFcRn following the incubation of cells with culture supernatant from hybridoma cells ( 11E4 & 1H5 from Example 9). These binding data show that co-incubation with human IgG did not lead to a significant change in the assay response, which is consistent with "non- competitive" binding (i.e., where the apparent affinity of the anti-FcRn antibodies for hFcRn is not altered by the presence of the natural ligand - human IgG).
  • results from incubation of the 293 cells with supernatant from cells that secrete murine monoclonal IgGl antibodies directed against methotrexate i.e., as a negative control.
  • Incubation of the 293 cells with the anti-methotrexate antibody did not lead to a significant assay response. This is (again) consistent with the hypothesis that specific anti-hFcRn antibodies are responsible for the significant binding observed following incubation of cells with 11E4 & 1H5 supernatant.
  • EXAMPLE 12 This example describes the generation of monoclonal antibodies with specificity for human FcRn.
  • the peptide sequence GEEFMNFDLKQGT (Invitrogen Corp., Carlsbad, CA), selected from the primary sequence of the human FcRn heavy chain, was conjugated with keyhole limpet hemocyanin (KXH) (Pierce Biotechnology Inc., Rockford, IL), emulsified in Freund's incomplete adjuvant (Sigma Chemical) and used to repetitively immunize six Balb/c mice (Harlan, Indianapolis, IN).
  • Animals were bled from the saphenous vein 7-10 days after immunization, and antisera were assessed for activity in inhibiting the binding of human IgG to cells expressing human FcRn with a cell binding assay. Briefly, serum samples from the animals were incubated with 293 cells expressing human FcRn and with 50 ⁇ g/ml FITC- labeled human IgG, at pH 6, 37 0 C, for 2 hours. The mixture was then centrifuged at 25Og for 5 minutes and the cells were washed with PBS at pH 6. After centrifugation, the cells were resuspended in PBS at pH 7.4. Fluorescence was assessed by fluorometry. The excitation and emission wavelength were set at 494 and 520 run respectively.
  • the animal associated with the anti-sera demonstrating maximum inhibition of the fluorescence signal was selected for use as a splenocyte donor.
  • Spleen cells were obtained and fused with murine SP20 myeloma cells (ATCC, Manassas, VA). Briefly, the mouse was sacrificed with ketamine (150 mg/kg) and xylazine (30 mg/kg), and the spleen was rapidly removed using aseptic technique.
  • Splenocytes were teased out of spleen tissue with the use of sterile 22-gauge needles, suspended in RPMI 1640, and fused with SP20 cells by centrifugation with polyethylene glycol, using standard techniques (e.g., as described in: Harlow E and Lane D. 1988.
  • Antibodies A laboratory manual. New York: Cold Spring Harbor Laboratory). Fused cells were selected through application of HAT selection medium (Sigma Chemical) and cloned by the method of limiting dilution. Tissue culture supernatant was assayed for inhibition of the binding of human IgG to 293 cells expressing human FcRn, using an approach modified from that described above. Thirty-two viable hybridoma clones were identified, and tissue culture supernatant was obtained from the culture of each clone to screen for the presence of anti- human FcRn antibodies.
  • HAT selection medium Sigma Chemical
  • tissue culture supematants from all the viable clones were incubated with human FcRn-transfected 293 cells and 30 ⁇ g/ml FITC-labeled human IgG at pH 6, 37 0 C, for 2 hours. After incubation, the cells were washed and then resuspended in PBS at pH 7.4. Sample fluorescence was analyzed by fluorometry. From the 32 viable potential anti-human FcRn clones, 2 positive clones were identified. These clones were 1D6 and 1 ICl ( Figure 13).
  • IgGl antibody with high affinity for methotrexate failed to inhibit the binding of human IgG to the human FcRn-transfected 293 cells.
  • EXAMPLE 14 This example describes the evaluation of 1D6 and 1 ICl binding to human beta-2- microglobulin to further support that 1D6 and IICI are directed against the heavy-chain of FcRn.
  • human beta-2-microglobulin (b2m, 3 ug/ml in phosphate buffer, 250 ul) was used to coat wells of 96-well microplates. Plates were incubated at 4C overnight. Plates were then washed with phosphate-buffered saline and DDW. Culture supernatant from 11E4 (anti-human beta-2-microglobulin), 4C9 (anti-rat beta-2-microglobulin), 1D6, and
  • Tukey post t test shows significant differences between 11E4 and all other IgGs (P ⁇ 0.001) post t test shows no difference between 4C9, 1D6, and 1 ICl
  • RNA was prepared from pelleted hybridoma cells that express 1D6 and 1 ICl monoclonal antibodies via the SV total RNA isolation system (Promega).
  • cDNA was synthesized using oligdT primers and reverse transcriptase (Invitrogen). The variable regions of the 1D6 heavy chain and light chain were amplified from first-strand cDNA using Taq
  • DNA polymerase with 35 cycles of PCR (1 cycle is 1 min at 93°C, 30 seconds at 45 0 C, and 1 min at 72 0 C).
  • the variable regions of the 1 ICl heavy chain were amplified from first-strand cDNA using Taq DNA polymerase with 35 cycles of PCR (1 cycle is 1 min at 93°C, 30 seconds at 56 0 C, and 1 min at 72 0 C).
  • the variable regions of the 1 ICl light chain were amplified from first-strand cDNA using Taq DNA polymerase with 35 cycles of PCR (1 cycle is 1 min at 93°C, 30 seconds at 60 0 C 3 and 1 min at 72 0 C).
  • the PCR products were purified and cloned into PCR2.1 -TOPO vector.
  • the PCR2.1-TOPO vector containing the variable regions of 1D6 and 1 ICl was sequenced and the results were confirmed by alignment analysis.
  • the baculovirus cassette vector, pAC-K-CE ⁇ was used to clone the heavy and light chain genes of variable regions.
  • the heavy chain variable regions were amplified by PCR using the primers containing Xhol and Nhel cutting sites; the light chain variable regions were amplified by PCR using the primers containing Sad and HindIII cutting sites.
  • the pAC-K-CHa containing the variable regions of both heavy chain and light chain were sequenced to confirm the insertion.
  • the PAC-K-CH3 containing the variable regions of both heavy chain and light chain and linearized baculovirus DNA were co-transfected into Sf9 insect cells.
  • Recombinant baculoviruses were prepared by homologous recombination using the BaculoGold transfection kit (BD Biosciences) according to the manufacturer's instructions.
  • Recombinant baculovirus was harvested 7-8 days after transfection from supernatants of SF9 cells culture medium. Subsequent two rounds of amplification were carried out to obtain high titer recombinant virus.
  • Sf9 cells were infected with the recombinant viruses expressing IgG antibody, and grown in serum-free medium (Orbigen), incubated in T75 flasks, at 27 0 C until approximately 50-60% of dead cells were observed.

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Abstract

Cette invention concerne des anticorps dirigés contre la chaîne lourde du récepteur FcRn humain qui jouent le rôle d'inhibiteurs non compétitifs de la liaison de l'immunoglobuline G (IgG) au récepteur FcRn. Les anticorps peuvent être polyclonaux, monoclonaux, chimériques ou humanisés ou des fragments de liaison à l'antigène de ceux-ci. Ces anticorps peuvent servir à réduire la concentration d'immunoglobulines G pathogènes chez des individus et sont par conséquent utilisés comme outil thérapeutique contre des états auto-immuns et allo-immuns.
EP07762598A 2006-01-25 2007-01-23 ANTICORPS ANTI-FcRn UTILISES DANS LE TRAITEMENT D'ETATS AUTO/ALLO-IMMUNS Withdrawn EP1986690A4 (fr)

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WO2009080764A2 (fr) * 2007-12-20 2009-07-02 Abylnx N.V. Administration orale ou nasale de composés comprenant des séquences d'acides aminés
AU2009238605B2 (en) * 2008-04-25 2014-11-06 Biogen Idec Hemophilia Inc. Antibodies against FcRn and use thereof
AU2015200004B2 (en) * 2008-04-25 2017-02-16 Bioverativ Therapeutics Inc. Antibodies against fcrn and use thereof
BR112013030352B1 (pt) 2011-06-02 2020-05-19 Dyax Corp anticorpo anti-fcrn isolado, composição farmacêutica que compreende o dito anticorpo, ácido nucleico isolado, vetor, célula e uso terapêutico do dito anticorpo
GB201208370D0 (en) 2012-05-14 2012-06-27 Ucb Pharma Sa Antibodies
GB201320066D0 (en) 2013-11-13 2013-12-25 Ucb Pharma Sa Biological products
US10336825B2 (en) 2014-04-30 2019-07-02 Hanall Biopharma Co., Ltd. Antibody binding to FcRn for treating autoimmune diseases
MX2016014210A (es) 2014-04-30 2017-05-01 Hanall Biopharma Co Ltd Anticuerpo que se une a fcrn para tratar enfermedades autoinmunes.
LT3250610T (lt) 2015-01-30 2023-09-25 Momenta Pharmaceuticals, Inc. Fcrn antikūnai ir jų panaudojimo būdai
CN108025066B (zh) 2015-05-12 2022-04-12 Synt免疫公司 人源化亲和力成熟的抗FcRn抗体
GB201508180D0 (en) 2015-05-13 2015-06-24 Ucb Biopharma Sprl Antibodies
HRP20240048T1 (hr) 2016-07-29 2024-03-29 Momenta Pharmaceuticals, Inc. Fcrn antitijela i postupci njihove uporabe
AU2018285577A1 (en) * 2017-06-15 2020-01-30 UCB Biopharma SRL Method for the treatment of immune thrombocytopenia
KR20200098604A (ko) 2017-12-13 2020-08-20 모멘타 파머슈티컬스 인코포레이티드 FcRn 항체 및 이의 사용 방법
AU2019361247A1 (en) 2018-10-16 2021-05-27 UCB Biopharma SRL Method for the treatment of Myasthenia Gravis
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