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WO1997010004A1 - Procedes de traitement de la cystite interstitielle - Google Patents

Procedes de traitement de la cystite interstitielle Download PDF

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Publication number
WO1997010004A1
WO1997010004A1 PCT/US1996/014548 US9614548W WO9710004A1 WO 1997010004 A1 WO1997010004 A1 WO 1997010004A1 US 9614548 W US9614548 W US 9614548W WO 9710004 A1 WO9710004 A1 WO 9710004A1
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Prior art keywords
ige
die
antagonist
antibody
patient
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PCT/US1996/014548
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English (en)
Inventor
Mary Haak-Frendscho
Paula Jardieu
Ricardo Saban
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Genentech, Inc.
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Application filed by Genentech, Inc. filed Critical Genentech, Inc.
Priority to AU71569/96A priority Critical patent/AU7156996A/en
Publication of WO1997010004A1 publication Critical patent/WO1997010004A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/42—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins
    • C07K16/4283—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an allotypic or isotypic determinant on Ig
    • C07K16/4291—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an allotypic or isotypic determinant on Ig against IgE
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide

Definitions

  • This invention relates to methods of treatment of interstitial cystitis with IgE antagonists, including anti- IgE antibodies.
  • Interstitial cystitis is a condition ofthe bladder characterized by urinary frequency, urgency, and suprapubic pain and pressure. Typically, the disease is diagnosed on the basis of cytoscopic appearance or pathological findings.
  • Immunological responses are associated with numerous urological diseases such as IC, bladder cancer, and bladder infection (Van de Merwe et al. J. Rheumatol. 20: 962, 1993). These responses include an increased number of macrophages, activated lymphocytes, and vascular endothelial cells expressing HLA class II molecules widiin the submucosa (Christmas et al. Clin. EXP. Immunol. 87:450, 1992), increased expression of
  • Anti-IgE antibodies which block die binding of IgE to its receptor on basophils and which fail to bind to IgE bound to the receptor, thereby avoiding histamine release are disclosed, for example, by Rup and Kahn (supra), by Baniyash et al. (Molecular Immunology 25:705-711, 1988), and by Hook et al. (Federation of American Societies for Experimental Biology. 71st Annual Meeting, Abstract #6008, 1987). Antagonists of IgE in the form of receptors, anti-IgE antibodies, binding factors, or fragments thereof have been disclosed in the art. For example, U.S.
  • 4,962,035 discloses DNA encoding the alpha-subunit of he mast cell IgE receptor or an IgE binding fragment thereof.
  • Hook et al. disclose monoclonal antibodies, of which one type is anti-idiotypic, a second type binds to common IgE determinants, and a third type is directed towards determinants hidden when IgE is on the basophil surface.
  • U.S.4,946,788 discloses a purified IgE binding factor and fragments thereof, and monoclonal antibodies which react with IgE binding factor and lymphocyte cellular receptors for IgE, and derivatives thereof.
  • U.S. 5,091,313 discloses antigenic epitopes associated wid the extracellular segment ofthe domain which anchors immunoglobulins to the B cell membrane. The epitopes recognized are present on IgE-bearing B cells but not basophils or in the secreted, soluble form of IgE.
  • U.S. 5,252,467 discloses a method for producing antibodies specific for such antigenic epitopes.
  • U.S. 5,231,026 discloses DNA encoding murine- human antibodies specific for such antigenic epitopes.
  • U.S. 4,714,759 discloses an imrnunotoxin in the form of an antibody or an antibody fragment coupled to a toxin to treat allergy.
  • Presta et al. J. Immunol. 151 :2623-2632 ( 1993) disclose a humanized anti-IgE antibody that prevents the binding of free IgE to FceRI but does not bind to FceRI-bound IgE.
  • Copending WO93/04173 discloses polypeptides which bind differentially to die high- and low-affinity IgE receptors.
  • Copending WO93/04173 discloses IgE antagonists comprising one or more ofthe FceRI receptor-binding determinant sites of human IgE.
  • U.S. 5,428,133 discloses anti-IgE antibodies as a therapy for allergy, especially antibodies which bind to IgE on B cells, but not IgE on basophils.
  • U.S. 5,422,258 discloses a method for making such antibodies.
  • FCeRI-IgG immunoadhesin which is a fusion ofthe extracellular portion ofthe human ⁇ -chain of FCeRI, which contains d e high affinity binding site for IgE, with a truncated human IgGl heavy chain constant region.
  • One embodiment ofthe invention is a method of treatment of interstitial cystitis in a patient comprising administering a therapeutic dose of an IgE antagonist to the patient.
  • Another embodiment of die invention is a method of reducing histamine release from mast cells in the bladder tissue of a patient widi interstitial cystitis comprising administering a therapeutic dose of an IgE antagonist to the patient.
  • BRIEF DESCRIPTION OF THE FIGURES Figure 1 is a graph depicting representative concentration-dependent contraction of human bladder tissue segments sensitized by incubation widi serum from a ragweed allergic patient and induced by cumulative addition of ragweed antigen (antigen E or AgE).
  • the change in the symbols represents cumulative addition of increasing concentrations of AgE (0.01, 0.1, 1.0, and 3.0 ⁇ g/ml) or KCI (200 mM).
  • the maximal effect was obtained with 1.0 ⁇ g/ml AgE.
  • the graph represents tissue contractability and viability results obtained widi eight different bladders.
  • Figure 2 is a graph depicting concentration-dependent contraction of sensitized human bladder tissue segments induced by addition of a single concentration of AgE ((0.01, 0.1, 1.0, and 3.0 ⁇ g/ml). Responses are represented as a percentage ofthe maximum obtained in response to KCI (200 mM) added at the end of die experiment. The graph represents results obtained widi eight different bladders.
  • Figure 3 represents polygraph tracings representative of tissues isolated from eight different bladders. Adjacent segments of each bladder were passively sensitized, suspended in vitro, and challenged with AgE (1 ⁇ g/ml) at 10 min (first arrow). Contractions are expressed as grams of tension. Segment A was a non- sensitive negative control; segment B was a sensitized positive control incubated widi control IgG; segment C was incubated widi anti-IgE monoclonal antibody E25 (1 :1 concentration of E25 to IgE) during sensitization; segment D was incubated wid E25 (5: 1 concentration of E25 to IgE) during sensitization. KCI (200 mM) was added at the end ofthe experiment (second arrow).
  • Figure 4 represents IgE antagonist blocking of histamine release (A) and tissue contraction (B) in a concentration-dependent manner in sensitized human bladder tissue.
  • Human bladder strips were incubated widi a 1 : 10 dilution of human ragweed serum for 20 hr. in the presence of equimolar, 5-fold, or 10-fold excess concentrations of E25 or a 10-fold concentration of control IgG in excess ofthe serum IgE concentration.
  • IgG had no detectable effect on either histamine release (A) or tissue contraction (B).
  • E25 blocked both histamine release and tissue contraction in response to IgE challenge in a concentration-dependent manner.
  • Data are presented as the mean ⁇ SEM of eight separate experiments. Peak histamine release occurred at 3 min. and correlated with the onset of contraction.
  • Figure 5 represents IgE antagonist blocking of histamine release (A) and tissue contraction (B) in a concentration-dependent manner in sensitized Rhesus monkey bladder tissue.
  • Rhesus monkey bladder strips were incubated widi a 1 : 10 dilution of human ragweed serum for 20 hr in the presence of equimolar, 5-fold, or 10-fold excess concentrations of E25 or a 10-fold concentration of control IgG in excess ofthe serum IgE concentration.
  • IgG had no detectable effect on either histamine release (A) or tissue contraction (B).
  • a and B represents IgE antagonist blocking of histamine release (A) and tissue contraction (B) in a concentration-dependent manner in sensitized Rhesus monkey bladder tissue.
  • Rhesus monkey bladder strips were incubated widi a 1 : 10 dilution of human ragweed serum for 20 hr in the presence of equimolar, 5-fold, or 10-fold excess concentrations of E25 or a 10-fold
  • Bladder segments were passively sensitized with ragweed serum, washed with PSS and challenged with 1 ⁇ g/ml E25. Positive control bladders challenged with AgE exhibited vigorous bladder contraction (percent of KCI maximum and histamine release (ng/g of tissue). In contrast, challenge with E25 did not result in any detectable histamine release or tissue contraction. Non-sensitized bladders segments (negative control) challenged widi AgE did not respond. Results are expressed as die mean responses of tissue from five human bladders and 10 monkey bladders. Asterisks and SEM are not shown for sake of clarity. A significant difference (p ⁇ 0.05) was found between AgE and E25 challenge of sensitized tissues. DETAILED DESCRIPTION OF THE INVENTION
  • interstitial cystitis as used herein is intended to refer to a bladder condition characterized by urinary frequency, urgency, and suprapubic pain and pressure.
  • IgE antagonist refers to a substance which inhibits the biological activity of IgE.
  • Such antagonists include but are not limited to anti-IgE antibodies, immunoadhesins, IgE receptors, anti- IgE receptor antibodies, variants of IgE antibodies, ligands for die IgE receptors, and fragments thereof.
  • Antibody antagonists can be ofthe IgA, IgD, IgG, IgE, or IgM class. Bispecific antibodies can also be used.
  • Variant IgE antibodies typically have amino acid substitutions or deletions at one or more amino acid residues.
  • Ligands for IgE receptors include but are not limited to IgE and anti-receptor antibodies, and fragments thereof capable of binding to die receptors, including amino acid substitution and deletion variants, and cyclized variants.
  • IgE antagonists act by blocking the binding of IgE to its receptors on B cells, mast cells, or basophils, either by blocking die binding site on die IgE molecule or blocking its receptors. Additionally, in some embodiments of die invention, IgE antagonists act by binding soluble IgE and thereby removing it from circulation. The IgE antagonists of the invention can also act by binding to IgE on B cells, thereby eliminating clonal populations of B cells. The IgE antagonists ofthe instant invention can also act by inhibiting IgE production. Preferably, die IgE antagonists ofthe instant invention do not result in histamine release from mast cells or basophils.
  • terapéutica amount denotes an amount at prevents or ameliorates symptoms of a disorder or responsive patiiologic physiological condition.
  • Polypeptide as used herein refers generally to peptides and proteins having at least about two amino acids.
  • free IgE refers to IgE not complexed to a binding partner, such an anti-IgE antibody.
  • total IgE refers to the measurement of free IgE and IgE complexed to a binding partner, such as an anti-IgE antibody.
  • baseline IgE refers to the level of free IgE in a patient's serum before treatment with an IgE antagonist.
  • polyol denotes a hydrocarbon including at least two hydroxyls bonded to carbon atoms, such as polyethers (e.g. polyediylene glycol), trehalose, and sugar alcohols (such as mannitol).
  • polyether as used herein denotes a hydrocarbon containing at least three ether bonds. Polyethers can include other functional groups. Polyethers useful for practicing die invention include polyediylene glycol (PEG).
  • PEG polyediylene glycol
  • Animals ordinarily are immunized against the cells or immunogenic conjugates or derivatives by combining 1 mg or 1 ⁇ g of IgE with Freund's complete adjuvant and injecting die solution intradermally at multiple sites.
  • the animals are boosted widi 1/5 to 1/10 die original amount of conjugate in Freund's incomplete adjuvant by subcutaneous injection at multiple sites.
  • Seven to 14 days later animals are bled and die serum is assayed for anti-IgE titer. Animals are boosted until die titer plateaus.
  • die animal is boosted widi a conjugate of the same IgE, but conjugated to a different protein and/or dirough a different cross-linking agent.
  • Conjugates also can be made in recombinant cell culture as protein fusions. Also, aggregating agents such as alum can be used to enhance die immune response.
  • Monoclonal antibodies are prepared by recovering spleen cells from immunized animals and immortalizing the cells in conventional fashion, e.g. by fusion widi myeloma cells or by Epstein-Barr (EB)-virus transformation and screening for clones expressing die desired antibody.
  • EB Epstein-Barr
  • the hybrid cell lines can be maintained in vitro in cell culture media.
  • the cell lines producing die antibodies can be selected and/or maintained in a composition comprising the continuous cell line in hypoxandiine-aminopterin thymidine (HAT) medium.
  • HAT hypoxandiine-aminopterin thymidine
  • the hybrid cell lines can be stored and preserved in any number of conventional ways, including freezing and storage under liquid nitrogen. Frozen cell lines can be revived and cultured indefinitely widi resumed syndiesis and secretion of monoclonal antibody.
  • the secreted antibody is recovered from tissue culture supernatant by conventional methods such as precipitation, ion-exchange chromatography, affinity chromatography, or die like.
  • the antibodies described herein are also recovered from hybridoma cell cultures by conventional metiiods for purification of IgG or IgM, as die case may be, that heretofore have been used to purify tiiese immunoglobulins from pooled plasma, e.g., ethanol or polyethylene glycol precipitation procedures.
  • the purified antibodies are sterile-filtered.
  • die invention is not so limited; in fact, human antibodies can be used. Such antibodies can be obtained, for example, by using human hybridomas (Cote et al., Monoclonal Antibodies and Cancer Therapy. Alan R. Liss, p. 77 (1985)).
  • human hybridomas Cote et al., Monoclonal Antibodies and Cancer Therapy. Alan R. Liss, p. 77 (1985).
  • die invention techniques developed for die production of chimeric antibodies (Cabilly et al., U.S. 4,816,567, Morrison et al., Proc. Natl. Acad. Sci. 81: 6851 (1984); Boulianne et al., jjyjs 312: 643-646 (1984); Neuberger et al., Nature.
  • chimeric antibody is used herein to describe a polypeptide comprising at least the antigen binding portion of an antibody molecule linked to at least part of another protein (typically an immunoglobulin constant domain).
  • such chimeric antibodies contain about one diird rodent (or odier non-human species) sequence and thus are capable of eliciting a significant anti-globulin response in humans.
  • diird rodent or odier non-human species
  • Humanized antibodies are used to reduce or eliminate any anti-globulin immune response in humans.
  • humanized antibodies are typically human antibodies in which some amino acid residues from the complementarity determining regions (CDRs), the hypervariable regions in die variable domains which are directly involved widi formation of die antigen-binding site, and possibly some amino acids from the framework regions (FRs), die regions of sequence diat are somewhat conserved widiin die variable domains, are substituted by residues from analogous sites in rodent antibodies.
  • CDRs complementarity determining regions
  • FRs framework regions
  • the invention also encompasses die use of human antibodies produced in transgenic animals.
  • DNA encoding the antibody of interest is isolated and stably incorporated into die germ line of an animal host.
  • the antibody is produced by die animal and harvested from die animal's blood or odier body fluid.
  • a cell line that expresses the desired antibody can be isolated from die animal host and used to produce die antibody in vitro, and the antibody can be harvested from die cell culture by standard mediods.
  • Anti-IgE antibody fragments can also be used in die methods of die invention. Any fragment of an anti- IgE antibody capable of blocking or disrupting IgE interaction widi its receptor is suitable for use herein.
  • Suitable anti-IgE antibody fragments can be obtained by screening combinatorial variable domain libraries for DNA capable of expressing the desired antibody fragments. These techniques for creating recombinant DNA versions ofthe antigen-binding regions of antibody molecules which bypass the generation of monoclonal antibodies, are encompassed widiin die practice of diis invention. One typically extracts antibody- specific messenger RNA molecules from immune system cells taken from an immunized animal, transcribes these into complementary DNA (cDNA), and clones die cDNA into a bacterial expression system. "Phage display” libraries are an example of such techniques. One can rapidly generate and screen great numbers of candidates for those diat bind die antigen of interest Such IgE-bindi ⁇ g molecules are specifically encompassed widiin die term "antibody” as it is defined, discussed, and claimed herein.
  • soluble IgE receptor can be used as die IgE antagonist.
  • Soluble receptors suitable for use herein include, for example, molecules comprising die IgE binding site in die extracellular domain (exodomain) ofthe FceRI a chain.
  • the ⁇ chain of FceRI can be genetically modified such diat die exodomain is secreted as a soluble protein in a recombinant expression system according to the mediod of Blank et al., J. Biol. Chem..26£: 2639-2646 (1991) or Qu et al., J. Exp. Med.. 167: 1195.
  • the invention also encompasses die use of IgE-binding peptides in addition to anti-IgE antibodies and soluble receptor. Any IgE-binding peptide capable of disrupting or blocking die interaction between IgE and its receptors is suitable for use herein.
  • die invention encompasses die use of IgE antagonists which disrupt IgE/receptor interaction by competing with IgE for binding to its receptor, thereby lowering die available IgE receptor.
  • IgE variants are an example of a receptor-binding competitor that is suitable for use in the methods of die invention.
  • IgE variants are forms of IgE possessing an alteration, such as an amino acid substitution or substitutions and/or an amino acid deletion or deletions, wherein die altered IgE molecule is capable of competing with IgE for binding to its receptors.
  • Fragments of IgE variants are also suitable for use herein. Any fragment of an IgE variant capable of competing witii IgE for binding to its receptors can be used in die mediods ofthe invention.
  • the invention also encompasses die use of IgE receptor-binding peptides in addition to IgE variants and fragments thereof. Any IgE receptor-binding peptide capable of disrupting or blocking the interaction between
  • IgE and its receptors is suitable for use herein.
  • the amount of IgE antagonist delivered to the patient to be used in therapy will be formulated and dosages established in a fashion consistent with good medical practice taking into account the disorder to be treated, die condition of die individual patient the site of delivery, the method of administration and odier factors known to practitioners.
  • die dose of die IgE antagonist administered will be dependent upon die properties of die IgE antagonist employed, e.g. its binding activity and in vivo plasma half-life, die concentration of die IgE antagonist in die formulation, die administration route, die site and rate of dosage, die clinical tolerance ofthe patient involved, die pathological condition afflicting die patient and the like, as is well widiin die skill of die physician.
  • IgE antagonists are administered by intramuscular, intravenous, intrabronchial, intraperitoneal, intravesical, subcutaneous or other suitable routes.
  • the antagonists can be administered before and/or after the onset of symptoms.
  • a "loading" dose of an IgE antagonist is useful to obtain a rapid and sustained decrease in free IgE.
  • a loading dose is typically a first dose of IgE antagonist that is greater dian a subsequent or "maintenance" dose of IgE antagonist.
  • patients can be loaded in other ways. For example, patients can be loaded by administering a dose of antagonist diat is greater than or equal to the same mg/kg amount as die maintenance dose, but increasing the frequency of administration in a "loading regimen".
  • the patient can be loaded by administering 1 mg/kg weekly for two or more weeks in a row, then administering die maintenance dose of 1 mg/kg biweekly.
  • patients can be loaded during a course of treatment widi a maintenance dose of IgE antagonist by administering larger or more frequent doses than die maintenance dose.
  • loading dose is intended as used herein to include such single loading doses, multiple loading doses, loading regimens, and combinations diereof.
  • a sustained decrease in free IgE can be obtained by administration of a maintenance dose of die antagonist
  • Maintenance doses are delivered widi a frequency of about every day to about every 90 days, more preferably weekly to biweekly, depending on die severity ofthe patient's symptoms, die concentration and in vivo properties of antagonist delivered, and the formulation of die antagonist. For example, slow release formulations can allow less frequent administration.
  • Maintenance doses can be adjusted upwards or downwards over time, depending on the response of die patient.
  • die dose of IgE antagonist is sufficient to reduce free IgE in the patient's serum to less an about 40 ng/ml.
  • about 0.05 to 10 mg/kg, more preferably about 0.1 to 1 mg/kg, most preferably about 0.5 mg/kg IgE antagonist can be administered on a weekly basis to a patient having about 40- 200 IU/ml baseline IgE.
  • patients are preferably "loaded" with about 1 to about 10 mg/kg, more preferably about 1 to about 5 mg/kg, most preferably about 2 mg/kg, IgE antagonist followed by weekly or biweekly administration of about 0.1 to about 10 mg/kg, most preferably about 1 mg/kg.
  • a maintenance dose of IgE antagonist averaging about 0.0005 to 0.05 mg/kg/week for every IU/ml baseline IgE, more preferably 0.001 to about 0.01 mg/kg/week for every IU/ml baseline IgE is used.
  • This maintenance regimen can follow an initial loading dose of about 1 to 10 mg/kg, more preferably about 1 to 5 mg kg IgE antagonist.
  • sufficient IgE antagonist is provided dirough die maintenance dose, and, optionally, die loading dose, to achieve about a 1 to 20 fold, preferably about 3 to 5 fold, most preferably about a 5 fold greater serum concentration than total serum IgE concentration in die patient.
  • IgE levels are typically assayed by standard ELISA techniques well known in the art.
  • Total serum IgE can be measured by commercially available assays, such as Abbott Laboratories' Total IgE assay.
  • Free IgE, e.g., IgE not bound to antibody can be measured by a capture type assay in which, for example, IgE receptor is bound to a solid support.
  • IgE complexed to an anti-IgE antibody which binds at or near the site on IgE which binds to die receptor will be blocked from binding die receptor, and tiius only free or unbound IgE can react with die receptor bound to die solid support in diis assay.
  • An anti-IgE antibody which recognizes IgE even when die IgE is bound to its receptor can be used to detect die IgE captured by die receptor on the solid support.
  • This anti-IgE antibody can be labeled widi any of a variety of reporter systems, such as alkaline phosphatase, etc.
  • diat injections intravenous, intramuscular or subcutaneous
  • diat injections will be die primary route for therapeutic administration of die IgE antagonist of this invention, although delivery through catheter or other surgical tubing is also used.
  • Alternative routes include suspensions, tablets, capsules and die like for oral administration, commercially available nebulizers for liquid formulations, and inhalation of lyophilized or aerosolized microcapsules, and suppositories for rectal or vaginal administration.
  • Liquid formulations can be utilized after reconstitution from powder formulations. Additional pharmaceutical memods may be employed to control the duration of action of die antagonists of this invention.
  • the antagonists also may be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (for example, hydroxymethylcellulose or gelatin- microcapsules and poly-(meti ⁇ ylmethacylate) microcapsules, respectively), in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules), or in macroemulsions.
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules
  • the formulations of the subject invention can contain other components in amounts not detracting from die preparation of stable forms and in amounts suitable for effective, safe pharmaceutical administration.
  • odier pharmaceutically acceptable excipients well known to those skilled in die art can form a part of the subject compositions. These include, for example, salts, various bulking agents, additional buffering agents, chelating agents, antioxidants, cosolvents and die like; specific examples of tiiese include tris-(hydroxymeti ⁇ yl)aminometi ⁇ ane salts ("Tris buffer”), and disodium edetate.
  • IgE antagonist formulations comprise a buffer, a salt optionally, a polyol, and optionally, a preservative.
  • One exemplary formulation of die invention is a liquid formulation of about 1 - 100 mg/ml IgE antagonist in 10 mM acetate buffer, pH 5.0-6.5, 100-200 mM sodium chloride, and about 0.01% polysorbate 20, more preferably about 5 mg/ml IgE antagonist in 10 mM acetate buffer, pH 5.2, 142 mM sodium chloride, and 0.01% polysorbate 20.
  • the formulation may be freeze-dried and reconstituted for administration.
  • anti-IgE antibody can be formulated at about 25 mg/ml in 5 M histidine, pH 6.0, and 88 M sucrose, freeze-dried, and reconstituted in water to 100 mg/ml antibody for administration.
  • Mixed sugars can also be used, such as a combination of sucrose and mannitol, etc.
  • die abbreviations used for the designation of amino acids and die protective groups used tiierefor are based on recommendations of the IUPAC-IUB Commission of Biochemical Nomenclature (Biochemistry. 11 : 1726-1732 (1972).
  • the nomenclature used to define compounds ofthe invention is diat specified by die IUPAC, published in European Journal of Biochemistry 138:9-37 (1984).
  • Interstitial cystitis can be combined widi odier known therapies for allergy and or interstitial cystitis, including corticosteroids, immunosuppressive drugs, anti-inflammatory drugs, antihistami ⁇ es, pentosanpolyphosphate, heparin, arnitriptyline. dimetiiyl sulfoxide, oxychlorosene sodium, silver nitrate, disodium chromoglycate, etc. Further details ofthe invention can be found in die following examples, which further define die scope of the invention. All references cited herein are expressly incorporated by reference in their entireties.
  • bladder tissue was cleansed and prepared as entire (neck to dome) full diickness strips (5 X 18 mm). Tissue segments were placed in physiologic salt solutions (PSS) ofthe following composition: 119 mM NaCl/ 4.7 mM KCI/ 1.0 mM NaH 2 P0 4 / 0.5 mM MgCl 2 / 2.5 mM CaC 25 mM N21HCO3/ 1 1 mM glucose at pH 7.4, gassed wim 95% O and 5% C0 2 , and maintained at 37° C.
  • PSS physiologic salt solutions
  • Bladder segments were washed four times with 50 ml PSS, placed in 50 ml of PSS, and passively sensitized by incubation for 15 to 20 hr at 25°C widi a 1:10 dilution of serum from a ragweed-allergic patient.
  • the total IgE content of the serum was 1250 ng/ml, as determined by ELISA.
  • tissues were sensitized in the presence of anti-IgE antibody E25 (Presta et al., supra) at concentrations 1, 5, and 10 times die amount of serum IgE or with control IgG at 10 times the concentration of serum IgE.
  • Tissues incubated widi PSS only were used as negative controls, and those incubated with ragweed serum oniy were preserved as positive controls.
  • each tissue was suspended in an air-filled tissue chamber and superfused with PSS. All solutions, as well as die tissue chamber, were maintained at 37° C.
  • PSS was pumped from a reservoir through Tygon tubing to a water-jacketed coiled glass tube heat exchanger using a Gilson Minipulse II peristaltic pump. To remove excess sera, tissues were allowed to equilibrate for 90 minutes while perfused with PSS ( 1 ml min) and maintained at a tension of 1.5 g. Changes in tension were recorded via force displacement transducers (FT- 03, Grass Instruments, Quincy, MA) on a polygraph (Model 7D, Grass Instruments, Quincy, MA).
  • tissues were superfused (1 ml/min) with ragweed antigen (AgE) (0.01 to 3 ⁇ g/ml) diluted in PSS.
  • AgE ragweed antigen
  • Superfusate samples were collected at 60 second intervals, beginning one minute before and continuing 16 minutes during challenge with IgE. Contractile responses were calculated as a percent of maximal contraction induced by KCI (200 M) added at the end of each experiment. After collection, superfusate samples were placed on crushed ice for subsequent analysis of histamine content. The remaining tissue histamine was extracted widi 0.4 N perchloric acid.
  • bladder segments were suspended in tissue batiis containing 10 ml of PSS (37° C) and maintained at a tension of 1.5 g for 1 hr of equilibration during which the PSS was changed every 15 minutes. Changes in tension were recorded via force displacement transducers (FT-03) on a Grass polygraph (Model 7D). After the equilibration period, tissues were challenged for 30 min widi E25 (10 ⁇ g/ml) or AgE (1 ⁇ g ml), die latter used as a positive control.
  • Histamine content ofthe superfusate and tissues was analyzed by an automated fluorometric method widi a sensitivity of 1.5 ng/ml.
  • the net concentration of histamine (release minus spontaneous) in each superfusate sample was expressed as a per cent of total histamine in each tissue prior to collection.
  • FIG. 3 illustrates representative contractile responses typically observed widi antigen challenge of tissues obtained from eight different human bladders utilized in this experiment.
  • the tissue segment in Figure 3A was not sensitized and served as a negative control.
  • Adjacent segments of die same human bladder (3B, C, and D) were passively sensitized in vitro.
  • AgE (1 ⁇ g/ml) challenge failed to induce contraction ofthe non-sensitized bladder segment ( Figure A), which exhibited only spontaneous motility.
  • E25 blocked AgE-induced histamine release and tissue contraction in a concentration-dependent manner.
  • Equimolar concentrations of serum IgE and E25 resulted in significant inhibition of botii histamine release and tissue contraction.
  • Five-fold excess concentration of E25 completely blocked the response to AgE challenge.
  • tissues preincubated widi ragweed serum and a 10-fold excess concentration of control IgG had histamine release and tissue contraction indistinguishable from die positive control tissues. Similar results were observed witii the Rhesus monkey bladder tissue ( Figure 5 A-B).

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Abstract

Procédés de traitement de la cystite interstitielle avec des antagonistes d'IgE, y compris des anticorps anti-IgE, des variantes d'IgE, des antagonistes peptidiques, la peptidomimétique et d'autres petites molécules.
PCT/US1996/014548 1995-09-13 1996-09-12 Procedes de traitement de la cystite interstitielle WO1997010004A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU71569/96A AU7156996A (en) 1995-09-13 1996-09-12 Methods for treatment of interstitial cystitis

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US52739795A 1995-09-13 1995-09-13
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US7060268B2 (en) 1995-07-27 2006-06-13 Genentech, Inc. Protein formulation
US9180189B2 (en) 1995-07-27 2015-11-10 Genentech, Inc. Treating a mammal with a formulation comprising an antibody which binds IgE
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US7371724B2 (en) 2005-06-09 2008-05-13 Novartis Ag KAPREKY peptidomimetics and analogues thereof

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