WO2007095230A2

WO2007095230A2 - TREATMENT OF AUTOIMMUNE BLISTERING DISEASE USING ANTI-IgE ANTIBODY

Info

Publication number: WO2007095230A2
Application number: PCT/US2007/003788
Authority: WO
Inventors: Joel Gelfand
Original assignee: The Trustees Of The University Of Pennsylvania
Priority date: 2006-02-13
Filing date: 2007-02-12
Publication date: 2007-08-23
Also published as: WO2007095230A3

Abstract

This invention relates to the treatment of autoimmune blistering disease. Specifically, the invention relates to the use of anti-IgB antibody, its fragments, derivatives, metabolites or their combination in methods and compositions for the treatment of bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceous, cicatricial pemphigoid, anti-epiligrin pemphigoid, epidermolysis bullosa acquisita, herpes gestationis, dermatitis herpetiformis, bullous lupus, paraneoplastic pemphigous, or a combination or variants thereof.

Description

TREATMENT OF AUTOIMMUNE BLISTERING DISEASE USING ANTI-IGE

ANTIBODY

FIELD OF INVENTION

[0001] This invention is directed to the treatment of autoimmune blistering disease. Specifically, the invention relates to the use of anti-IgE antibody, its fragments, derivatives, metabolites or their combination in methods and compositions for the treatment of bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceous, cicatricial pemphigoid, anti- epiligrin pemphigoid, epidermolysis bullosa acquisita, herpes gestationϊs, dermatitis herpetiformis, bullous lupus, paraneoplastic pemphigous, or a combination or variants thereof.

BACKGROUND OF THE INVENTION

[0002] Pemphigus and pemphigoid are autoimmune skin blistering diseases. Pemphigoid is characterized by subepidermal blisters, inflammatory cell infiltration,, and the linear deposition of IgG autoantibodies and complement components at the basement membrane zone. Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disease. Pemphigus is characterized by intraepidermal blisters and epidermis-specific autoantibodies. The 2 major forms of the disease are pemphigus foliaceus (PF) and pemphigus vulgaris (PV). In PF, blisters occur in the superficial epidermis (subcorneal blister), whereas in PV the epidermal cell separation occurs just above the basal layer of the epidermis. [0003] These diseases are associated with severe morbidity as they result in denudation of skin and mucous membranes. Symptoms include severe itching, pain, weeping and oozing of the skin, malnutrition, and infection. Untreated, these disorders can lead to significant mortality risk. [0004] Treatment of these disorders is largely non -specific and involves long-term systemic corticosteroids and immunosuppressive agents. However, long-term treatment with these drugs often only partially controls the symptoms and may cause many dose-related adverse effects. (0005] Currently, there is an unmet medical need for therapies that can treat these serious diseases in a safe and effective manner.

SUMMARY OF THE INVENTION

[0006] In one embodiment, the invention provides a method for treating autoimmune blistering disease in a subject, comprising the step of administering to said subject an effective amount of a preparation comprising an anti-IgE antibody or a fragment, derivative or metabolite thereof. [0007] In another embodiment, the invention provides a composition for the treatment of autoimmune blistering disease comprising an anti-IgE antibody or a fragment, derivative or metabolite thereof, a pharmaceutically acceptable carrier, excipient, flow agent, processing aid, diluent or a combination thereof. [0008] In one embodiment, the invention provides a method of reducing serum levels of free anti-IgE antibody or a fragment, derivative or metabolite thereof in a subject comprising the step of administering to the subject an anti-IgE antibody.

DETAILED DESCRIPTION OF THE INVENTION

[0009] This invention relates in one embodiment to the use of anti-IgE antibody, its fragments, derivatives, metabolites or their combination in compositions and methods for the treatment of autoimmune blistering disease (AIBD), such as bullous pemphigoid, or pemphigus vulgaris, pemphigus foliaceous, cicatricial pemphigoid, anti-epiligrin pemphigoid, epidermolysis bulLosa acquisita, herpes gestationis, dermatitis herpetiformis, bullous lupus, paraneoplastic pemphigous, or a combination or variants thereof in other embodiments.

[00010] In one embodiment, the term "autoimmune disease" or "autoimmune blistering disease" refers to the consequence of a cellular and a humoral response to self-antigenes. An humoral dominant autoimmune condition includes a disease, illness, disorder or syndrome, in the course of which the patient produces antibodies that bind one or more of the patient's own antigenic epitopes, whether it is known today to be so or that may be diagnosed as such in the future.

[00011] Autoimmune diseases such as bullous pemphigous (BP) occur in one embodiment, when the immune system of an individual is triggered to recognize and attack self components. BP, is characterized histologically by dermoepidermal junction- (DEJ) separation with an inflammatory infiltrate and ϊmmunopathologically by in vivo deposition of autoantibodies and complement components along the basement membrane zone (BMZ). Being an autoimmune disease, it is characterized by both circulating and tissue-bound autoantibodies. These autoantibodies bind to the BMZ and activate complement. In another embodiment, these autoantibodies are directed against two major hemidesmosomal antigens of 230 kD (also referred to as BP230 or BPAGl in certain embodiments) and 180 kD (also referred to as BP180, BPAG2, or type XVII collagen in certain embodiments). [00012] Antibodies are classified into different classes based on the structure of their heavy chains. These include the immunoglobulins IgG, IgM, IgA and IgE. Antibodies having the same heavy chain structure are considered as being of the same isotype. Antibodies of the same isotype having different antigenic determinants as a result of the inheritance of different alleles are called allotypes. Antigenic determinants found primarily (but not exclusively) in the hypervariabie region of the antigen binding site of the antibody are called idiotopes. Antibodies having common or shared idiotopes are considered as members of the same idiotype. Antigenic determinants on the variable regions of L or/and H chains that are associated with antigen-binding site of an antibody are called idiotypes. Antibodies raised or which react against an idiotope are called anti-idiotypic antibodies (anti-id anti-Id). [00013] In one embodiment, the term "immunoglobulins" or "Ig" refers to proteins secreted by cells of the immune system known as B-cells or plasma cells. In one embodiment, each immunoglobulin consists of a complex of protein chains known as the heavy and light chains. Each heavy chain is linked to a single light chain via disulfide bonds. The resulting complex is in turn linked by additional disulfide bonds to an identical heavy-light chain complex. This basic unit can be assembled by the cell into several specialized forms by varying the structure and number of heavy chains. Different heavy chain structures produce differing molecules, known as "classes" of immunoglobulins. These classes may also have different numbers of the basic units described above.

[00014] In one embodiment, the term "immunoglobulin" is used synonymously with the term "antibody", and encompasses all classes of immunoglobulins including, without limitation, IgG, IgM, IgA, IgD and IgE and all subclasses of immunoglobulins such as the IgG subclasses IgGl, IgG2, IgG3, and IgG4 found in or produced by cells or animals including humans. The term "immunoglobulin" encompasses both membrane immunoglobulins and secreted immunoglobulins. Membrane immunoglobulins are transmembrane proteins of B cells, and act as the B cells' antigen receptor. Secreted immunoglobulins are structurally identical to their membrane counterparts except that they lack the trans-membrane region of amino acids at the C-terminus of membrane immunoglobulins. Secreted immunoglobulins are present in extracellular fluids and secretions. Antibodies include in another embodiment complete antibodies (e.g., bivalent IgG, pentavalent IgM) or fragments of antibodies in other embodiments, which contain an antigen binding site. Such fragment include in one embodiment Fab, F(ab')_2> Fv and single chain Fv (scFv) fragments. In one embodiment, such fragments may or may not include antibody constant domains. In another embodiment, F(ab)'s lack constant domains which are required for complement fixation. scFvs are composed of an antibody variable light chain (V_L) linked to a variable heavy chain (V_H) by a flexible linker. scFvs are able to bind antigen and can be rapidly produced in bacteria. The invention includes antibodies and antibody fragments which are produced in bacteria and in mammalian cell culture. An antibody obtained from a bacteriophage library can be a complete antibody or an antibody fragment. In one embodiment, the domains present in such a library are heavy chain variable domains (V_H) and light chain variable domains (V_L) which together comprise Fv or scFv, with the addition, in another embodiment, of a heavy chain constant domain (C_HI) and a light chain constant domain (C_L). The four domains (i.e., V_H - C_HI and V_L - C_L) comprise an Fab. Complete antibodies are obtained in one embodiment, from such a library by replacing missing constant domains once a desired V_H - V_L combination has been identified. [00015] The term "immunoglobulin" encompasses in one embodiment, fragments of immunoglobulins such as, for example, fragments F(ab')2, Fab', Fab, Fc, Facb, pFc', and Fd, as well as immunoglobulin derivatives and metabolites in another embodiment. In one embodiment, metabolites of immunoglobulin are products resulting from the metabolism of immunoglobulins by a living organism. A wide variety of derivatives of immunoglobulins may be prepared in other embodiments by known methods, which in one embodiment, involve breaking peptide or disulfide bonds in the immunoglobulin. Immunoglobulins may also be derivatized in one embodiment to include modified or synthetic or unnatural amino acids. In one embodiment derivatives of immunoglobulins comprise immunoglobulins conjugated to a moiety such as a toxin (e.g. cellular toxin, cisplatin), a labelling molecule (e.g. fluorescin, Texas Red), a radioactive atom or molecule (e.g. .¹²⁵I) for therapeutic or diagnostic use, an enzyme (e.g. avidin, horseradish peroxidase, alkaline phosphatase), et cetera. Immunoglobulins may include in other embodiments, post-translationai modifications such as phosphorylation, glyocsylation, myristilation, prenylation, ADP-ribosylation, methylation, acetylation, hydroxylation, carboxylation, and oxidation-reduction, or may be cationized or anionized to alter the overall charge of the immunoglobulin In one embodiment, the immunoglobulins fragments used in the methods and compositions described herein, are Fab, Fab¹, Fabl, Fab2, Fc, or monomeric IgE. [00016] In one embodiment, the term "autoantibody" as used herein, refers to an antibody produced by the body against self-antigens and implicated in or associated with the aetiology or symptoms or pathology of an autoimmune blistering disaese.

[00017] In one embodiment, BP autoantibodies recognize multiple epitopes that cluster within the largest non-collagen domain of the BP180 antigen. In another embodiment, these BP180NC16A-specific autoantibodies are predominantly IgE and IgG isotypes and IgGl and IgG4 subclasses. The serum levels of autoantibodies to BPl 80 NC16A are correlated in one embodiment with the severity of BP, and in another embodiment, with other similar autoimmune blistering diseases.

[00018] In one embodiment, the invention provides a composition for the treatment of autoimmune blistering disease, comprising an anti-IgE antibody or a fragment, derivative or metabolite thereof, a pharmaceutically acceptable carrier, excipient, flow agent, processing aid, diluent or a combination thereof. In one embodiment, the anti-IgE antibody used, is a humanized anti-IgE antibody, such as olamizumab in another embodiment. [00019] In one embodiment, the term "humanized antibody" refers to an immunoglobulin comprising a human framework, at least one CDR from a non-human antibody, and in which any constant region present is substantially identical to a human the constant region of a human IgE, e.g., at least about 60-90%, preferably at least 95% identical. Hence, all parts of a humanized IgE, except in one embodiment, maybe the CDR's, are substantially identical to corresponding parts of one or more native human IgE sequences. In some embodiments, the humanized IgE, in addition to CDRs from a non-human antibody, would include additional non-human residues in the human framework region.

[00020] In one embodiment, "Omalizurnab" refers to a humanized IgGL monoclonal antibody against IgE that recognizes and masks an epitope in^' the CH3 region of IgE responsible for binding to the high-affinity FcεR on mast cells and basophils. In one embodiment, omalizumab markedly reduces serum levels of free IgE and down-regulatates IgE receptors on circulating basophils. In another embodiment, the anti-IgE antibody used in the methods and compositions described herein, is omalizumab.

[00021] In one embodiment, omalizumab is a recombinant humanized monoclonal anti-IgE antibody that binds to IgE on the same Fc site as Fc Rl . In another embodiment, omalizumab reduces total serum IgE in atopic subjects, which attenuates the amount of antigen-specific IgB that can bind to and sensitize tissue mast cells and basophils. This, in one embodiment, leads to a decrease in symptoms of autoimmune blistering diseases. In one embodiment, omalizumab contains 5% murine sequences (needed for the IgE binding portion) and^' 95% human residues from a human IgG 1 kappa framework. [00022] In one embodiment, the compositions, or in another embodiments, the preparations used in the methods described herein, further comprise a pharmaceutically acceptable carrier, excipient, flow agent, processing aid, diluent or a combination thereof.

' [00023] In one embodiment, the invention provides a composition for the treatment of autoimmune blistering disease, comprising an anti-IgE antibody or a fragment, derivative or metabolite thereof, a pharmaceutically acceptable carrier, excipient, flow agent, processing aid, diluent or a combination thereof, wherein the composition is in a form suitable for oral, intravenous, intraaorteriai, intramuscular, subcutaneous, parenteral, transmucosal, transdermal, ocular, or topical administration. In one embodiment, anti-IgE antibody or a fragment, derivative or metabolite thereof, is present at a therapeutically effective amount which is adjusted specifically to the disease or disease severity sought to be treated.

[00024] As used herein, composition means therapeutically effective amounts of the agent together with suitable diluents, preservatives, solubilizers, emulsifiers, adjuvant and/or carriers. A "therapeutically effective amount" as used herein refers to that amount which provides a therapeutic effect for a given condition and administration regimen. Such compositions are liquids or lyphilized or otherwise dried formulations and include diluents of various buffer content (e.g., Tris-HCl., acetate, phosphate), pH and ionic strength, additives such as albumin or gelatin to prevent absorption to surfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acid salts), solubilizing agents (e.g., glycerol, polyethylene glycerol), antioxidants (e.g., ascorbic acid, sodium metabisulfϊte), preservatives (e.g., Thimerosal, benzyl alcohol, parabens), bulking substances or tonicity modifiers (e.g., lactose, mannitol), covalent attachment of polymers such as polyethylene glycol to the protein, complexatϊon with metal ions, or incorporation of the material into or onto particulate

. preparations of polymeric compounds such as polylactic acid, polglycolic acid, hydrogels, etc, or onto liposomes, microemulsions, micelles, unilamellar or multilamellar vesicles, erythrocyte ghosts, or spheroplasts. Such compositions will influence the physical state, solubility, stability, rate of In vivo release, and rate of in vivo clearance. Controlled or sustained release compositions include formulation in lipophilic depots (e.g., fatty acids, waxes, oils). Also comprehended by the invention are particulate compositions coated with polymers (e.g., poloxamers or poloxamines). Other embodiments of the compositions of the invention incorporate particulate forms protective coatings, protease inhibitors or permeation enhancers for various mutes of administration, including parenteral, pulmonary, nasal and oral. In one embodiment the pharmaceutical composition is administered parenterally, paracancerally, transmucosally, transdermally, intramuscularly, intravenously, intradermally, subcutaneously, intraperitonealy, intraventricularly, intracranially and intratumorally.

[00025] Further, as used herein pharmaceutically acceptable carrier are well known to those skilled in the art and include, but are not limited to, 0.01-O.lM and preferably 0.05M phosphate buffer or 0.8% saline. Additionally, such pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, foams, aerosols, sprays, suspensions, gels, creams, ointments and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic/aqueous solutions,- emulsions or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's or fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose, and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, antioxidants, collating agents, inert gases and the like. [00026] Controlled or sustained release compositions include formulation in lipophilic depots (e.g. fatty acids, waxes, oils). Also comprehended by the invention are particulate compositions coated with polymers (e.g. poloxamers or poloxamines) and the compound coupled to antibodies directed against tissue-specific receptors, Hgands or antigens or coupled to Hgands of tissue-specific receptors. Other embodiments of the compositions of the invention incorporate particulate forms protective coatings, protease inhibitors or permeation enhancers for various routes of administration, including parenteral, pulmonary, nasal and oral. Compounds modified by the covalent attachment of water-soluble polymers such as polyethylene glycol, copolymers of polyethylene glycol and polypropylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone or polyprolinε are known to exhibit substantially longer half-lives in blood following intravenous injection than do the corresponding unmodified compounds (Abuchowski et al., 1981; Newmark et al., 1982; and Katre et al., 1987). Such modifications may also increase the compound's solubility in aqueous solution, eliminate aggregation, enhance the physical and chemical stability of the compound, and greatly reduce the immunogenicity and reactivity of the compound. As a result, the desired in vivo biological activity may be achieved by administration of such polymer-compound abducts less frequently or in lower doses than with the unmodified compound.

[00027] In yet another embodiment, the composition and pharmaceutical preparations described herein, can be delivered in a controlled release system. For example, the agent may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration. In one embodiment, a pump may be used (see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng, 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989). In another embodiment, polymeric materials can be used. In yet another embodiment, a controlled release system can be placed in proximity of the therapeutic target, i.e., the brain, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984). Preferably, a controlled release device is introduced into a subject in proximity of the site of inappropriate immune activation or a tumor. Other controlled release systems are discussed in the review by Langer (Science 249:1527-1533 (1990).

[00028] In one embodiment the pharmaceutical preparation, or compositions.described herein can comprise the chemopreventive agent alone, or can further include a pharmaceutically acceptable carrier, and can be in solid or liquid foπn such as tablets, powders, capsules, pellets, solutions, suspensions, elixirs, emulsions, gels, creams, or suppositories, including rectal and urethral suppositories. Pharmaceutically acceptable carriers include gums, starches, sugars, cellulosic materials, and mixtures thereof. The pharmaceutical preparation containing the chemopreventive agent can be administered to a subject by, for example, subcutaneous implantation of a pellet, in a further embodiment, the pellet provides for controlled release of chemopreventive agent over a period of time. The preparation can also be administered by intravenous, intraarterial, or intramuscular injection of a liquid preparation, oral administration of a liquid or solid preparation, or by topical application. Administration can also be accomplished by use of a rectal suppository or a, urethral suppository. The pharmaceutical preparation can also be a parenteral formulation; in one embodiment, the composition comprises a liposome that includes a complex of an anti-IgE antibody, fragments, derivatives, metabolites or their combination.

[00029] Oral tablets may be prepared using a variety of well known methods and in a variety of conventional forms. Exemplary forms include dry powder compaction tablets, micro- particulate systems (e.g., wherein the active ingredient is spray-dried onto a scaffold particle), and hard or soft-gel capsules. The tablets may be optionally covered with an enteric coating, which remains intact in the stomach, but will dissolve and release the contents of the tablet once it reaches the small intestine. Most currently used enteric coatings are those which remain undissociated in the low pH environment of the stomach, but readily solubilize when the pH rises to about 4 or 5. A number of commercially available enteric coatings may be used depending on the target part of the intestinal tract, i.e., the site of the inflammatory bowel disorder in the patient. Such coatings include, for example, methacrylic acid- methacrylic acid ester-based copolymer, which is sold under the trade name "Eudragit"; anionic water-soluble, polymer cellulose ether, which is sold under the trade name "Aqualon"; cellulose acetate phthalate; polyvinyl acetate phthalate; hydroxypropyl rnethyjcellulose phthalate; and the like. Compositions comprising such carriers and adjuvants may be formulated, and tablets prepared from such compositions, using well known conventional materials and methods. Such materials and methods are described, for example, in Remington's Pharmaceutical Sciences, supra. [00030] As used herein, the term "topical" refers to application at the site of the bullous (Le., non-systemic administration), and includes, for example, oral, intranasal, intrabronchϊal, topical, vaginal, ocular and rectal routes of administration. The term "topical formulation" refers to a pharmaceutical formulation which is suitable for topical administration of the active ingredient. In another embodiment, it is preferable to apply the compositions described herein at a site which does not blister. [⁰⁰⁰³¹I The pharmaceutical preparations of the invention can be prepared by known dissolving, mixing, granulating, or tablet-forming processes. For oral administration, the chemopreventive agents or their physiologically tolerated derivatives such as salts, esters, N- oxides, and the like are mixed with additives customary for this purpose, such as vehicles, stabilizers, or inert diluent, and converted by customary methods into 2 suitable form for administration, such as tablets, coated tablets, hard or soft gelatin capsules, aqueous, alcoholic or oily solutions. Examples of suitable inert vehicles are conventional tablet bases such as lactose, sucrose, or cornstarch in combination with binders like acacia, cornstarch, gelatin, or with disintegrating agents such as cornstarch, potato starch, alginic acid, of with a lubricant like stearic acid or magnesium stearate. Examples of suitable oily vehicles or solvents are vegetable or animal oils such as sunflower oil or fish-liver oϊL Preparations can be effected both as dry and as wet granules. For parenteral administration (subcutaneous, intravenous, intraarterial, or intramuscular injection), the chemopreventive agents or their physiologically tolerated derivatives such as salts, esters, N-oxides, and the like are converted into a solution, suspension, or emulsion, if desired with the substances customary and suitable for this purpose, for example, solubilizers or other auxiliaries. Examples are: sterile liquids such as water and oils, with or without the addition of a surfactant and other pharmaceutically acceptable adjuvant. Illustrative oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, or mineral oil. In general, water, saline, aqueous dextrose and related sugar solutions, and glycols such as propylene glycols or polyethylene glycol are preferred liquid carriers, particularly for injectable solutions.

[00032] The aerosolized pharmaceutical preparation and compositions which contain an active component is well understood in the art. Typically, such compositions are prepared as an aerosol of the polypeptide delivered to the nasopharynx or as injectables, either as liquid solutions or suspensions, however, solid forms suitable for solution in, or suspension in, liquid prior to injection can also be prepared. The preparation can also be emulsified. The active therapeutic ingredient is often mixed with excipients which are pharmaceutically acceptable and compatible with the active ingredient Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol, or the like and combinations thereof. In addition, if desired, the composition can contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents which enhance the effectiveness of the active ingredient such as olamizumab in one embodiment, [00033] An active component can be formulated into the composition as neutralized pharmaceutically acceptable salt forms. Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the polypeptide or antibody molecule) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts, formed from the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium or feme hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino -ethanoL, histidine, procaine, and the like. [00034] Additional analogs and derivatives of the anti-IgE antibodies, or their fragments, which would be expected to retain or prolong their activity in whole or in part, and which are expected to be useful in the methods described herein, may also be easily made by one of skill in the art. One such modification may be the attachment of polyethylene glycol (PEG)onto moieties that can react with PEG or PEG derivatives into the analogues or derivatives by conventional techniques to enable the attachment of PEG moieties. [00035] For topical administration to body surfaces using, for example, creams, gels, drops, and the like, the chernopreventive agents or their physiologically tolerated derivatives such as salts, esters, N-oxϊdes, and the like are prepared and applied as solutions, suspensions, or emulsions in a physiologically acceptable diluent with or without a pharmaceutical carrier. [00036] In another embodiment, the active compound can be delivered in a vesicle, in particular a liposome (see Langer, Science 249:1527-1633 (1990); Treat et al., in Liposomes. in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds,), Liss, N.Y., pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generally ibid). [00037] Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fets. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral administration include water (partially containing additives as above), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and their derivatives, oils (e.g., peanut oil, sesame oil, olive oil, and coconut oil), and combinations of the above. Compositions comprising such carriers and adjuvants may be formulated using well known conventional materials and methods. Such materials and methods are described, for example, in Remington's Pharmaceutical Sciences, supra. [00038] The pharmaceutical compositions of the present invention are particularly useful for treating a subject having an autoimmune blistering disease, such as bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceous, cicatricial pemphigoid, anti-epiligrin pemphigoid, epidermolysis bullosa acquisita, herpes gestationis, dermatitis herpetiformis, bullous lupus, paraneoplastic pemphigous, or a combination or variants thereof. [00039] As will be appreciated by those of skill in the art, the preferred form of the pharmaceutical preparations or compositions as described herein, will depend on the intended mode of administration, which in turn will depend on the location and nature of the autoimmune blistering disease to be treated. For example, delivery to the mouth (e.g., for treatment of oral BP, EBA), head and/or neck (e.g., for treatment of BL) can be in the form of aqueous-based oral solutions, suspensions, emulsions, syrups, elixirs, gels, patches, lozenges, tablets, or capsules. Delivery to the gastrointestinal tract (e.g., for treatment of gastrointestinal AeCP or DH) can be in the form of oral solutions, gels, suspensions, tablets, capsules, and the like. Anti-IgE antibodies, their fragments, derivatives or analogs and ther combination, either alone or in combination with other components in a pharmaceutical composition, can be added to infant formula for delivery to the gastrointestinal tract of an infant suffering from or susceptible to AIBD. It is also possible to formulate the compositions described herein and the pharmaceutical preparation for rectal administration (e.g., for treatment of HG), e.g., in the form of enema, suppositories, rectal/vaginal-foam, and the like. Delivery to the eye (e.g., for treatment of ocular diseases such as OCP) can be in the form of solutions, gels, or suspensions. Delivery to the nose (e.g., for treatment of nasal CP) can be in the form of solutions, gels, or suspensions. The intranasal formulations may be formulated, for example, into an aqueous or partially aqueous solution, which can then be utilized in the form of a nasal drop or an aerosol. Delivery to the skin (e.g., for BP, PV and the like) can be in the form of aqueous-based solutions, gels, suspensions, lotions, creams, ointments, patches, and the like. In one embodiment, delivery of the compositions described herein is done using IV or parenteral routes of administration, such as subcutaneous or PO. [00040] In one embodiment, the compositions described herein, are used in the pharmaceutical preparations in the methods described herein. [00041] In one embodiment, the invention provides a method for treating autoimmune blistering disease in a subject comprising the step of administering to said subject an effective amount of a preparation comprising an anti-IgE antibody or a fragment, derivative or metabolite thereof. [00042] In one embodiment, BP180-specific autoreactive T cells are present in autoimmune disease and these T cells recognize epitopes located in the extracellular region of BP180. These T lymphocytes express in one embodiment, CD4 memory T cell surface markers which, in another embodiment these receptors are IgE isotype autoantibody receptors. In one embodiment autoimmune disease is a T and B cell-dependent and antibody-mediated autoimmune disease. [00043] In one embodiment, the term "autoimmune blistering disaese" refers to bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceous, cicatricial pemphigoid, anti- epiligrin pemphigoid, epidermolysis bullosa acquisita, herpes gestationis, dermatitis herpetiformis, bullous lupus, paraneoplastic pemphigous, or a combination or variants thereof. In one embodiment, the effective amount of the anti-IgE antibody its fragment, derivative or metabolite thereof, will vary according to the specific autoimmune blistering disease treated and the severity of symptoms exhibited.

[00044] In one embodiment, Bullous pemphigoid (BP) is a subepidermal blistering disease that is seen predominantly in the elderly. In BP patients basal keratinocytes of the epidermis detach from the underlying basement membrane producing tense, fluid-filled vesicles. Similar skin lesions were observed in a pregnancy-associated nonviral disorder, herpes gestationis (HG). Epidermolysis bullosa acquisita, refers in one embodiment to a polymorphic, however distinct, subepidermal blistering disease. In one embodiment patients with the dermolytic, or noninflammatory, variant of EBA have trauma-induced blisters and erosions on noninflamed skin, atrophic scars, milia, nail dystrophy, and/or oral erosions. In other embodiment, EBA patients have widespread inflammatory blisters that mimic those seen in patients with BP. In one embodiment, some EBA patients transition from the inflammatory to the dermolytic form of the disease. EBA is typically chronic and resistant to treatment; many patients also have underlying inflammatory bowel disease. Pemphigous Vulgaris (PV), refers in one embodiment to an auto-immune blistering disorder of the skin and mucous membranes where those afflicted suffer from burn-like lesions all over their bodies and in the mouth. The sores may never heal in some embodiments or may not heal for extended periods of time in other embodiments. In some embodiments of PV, patients can coexist with the disease for years, while others will die a slow and complicated death. [00045] Pemphigus foliaceous (PF) or "superficial pemphigus" refers in one embodiment to an autoimmune blistering disease where the intraepϊdermal separation occurs superficially in the granular layer. While sporadic PF affects middle-aged individuals and is rare in children in one embodiment, childhood PF is more common than PV of childhood and generally follows a less aggressive course than does the adult form of PF. In one embodiment, PF is characterized by the presence of scaly, crusted blisters, which overly an erythematous base. Small, flaccid blisters are often inconspicuous. Oral mucosal lesions are rarely seen. In one embodiment, PF may remain localized for many years in one embodiment, or may progress to a severe, generalized, exfoliative dermatitis in other embodiments. In one embodiment, using the methods and compositions described herein, will suppress, inhibit or delay the progression of PF to exfoliative dermatitis. In another embodiment of PF which may be treated with the methods and compositions described herein; in addition to acantholysis in

, the granular layer, subcorneal pustules comprised of neutrophils and acantholytic cells are often present. In one embodiment "Cicatricial Pemphigoid" (CP), or "Ocular cicatricial pemphigoid (OCP)" refers to one of the subsets of mucous membrane pemphigoid (MMP), a group of systemic autoimmune diseases characterized by T-lymphocyte dysregulation. In one embodiment, OCP affects the skin and other mucous membranes, such as oral mucosa in one embodiment, or pharynx, larynx, trachea, esophagus, vagina, urethra, anus in other embodiments, as well as chronic cicatrizing conjunctivitis n another embodiment. In one embodiment, systemic practolol therapy and topical antiglaucoma drugs, such as pilocarpine, timolol, epinephrine, Humorsol, idoxuridine, and phospholine iodide, which are known to have triggered the onset of OCP, do not trigger OCP when the methods and compositions described herein are used in the treatment of OCP, or CP. In one embodiment, a subset of CP, is antiepiligrin cicatricial pemphigoid (AeCP), characterized by blistering preference to the skin side rather than ocular or mucous oral membranes. In one embodiment AeCP, a known paraneoplatic disorder, may also be treated by the methods and compositions described herein thereby suppressing or inhibiting the onset of lung carcinoma or melanoma. [00046] Herpes gestationϊs (HG) refers in one embodiment, to a rare, intensely pruritic, vesiculobullous disease of pregnancy. In one embodiment, HG begins during the second or third trimester, or in the postpartum period in another embodiment. Although HG may not develop until after multiple normal pregnancies, once it appears it tends to occur earlier and to be more severe in subsequent pregnancies. In one embodiment, HG clinically demonstrate urticarial plaques and tense bullae, and histologically show subepidermal blisters. In one embodiment, patient treated according to the methods described herein, may reduce the severity in one embodiment, of the symptoms associated with HG in subsequent pregnancies. [00047] "Dermatitis herpetiformis" (DH) refers in one embodiment to an autoimmune blistering disorder associated with a gluten-sensitive. enteropathy (GSE). DH is characterized in one embodiment by grouped excoriations; erythematous, urticarial plaques; or papules with vesicles, or both in other embodiments. These are located on the extensor surfaces of the elbows, knees, buttocks, and back. In one embodiment, it is pruritic, and the vesicles are often excoriated to erosions by the time of physical examination. In one embodiment, direct immunofluorescence of a skin shows deposition of immunoglobulin A (IgA) in a granular pattern in the upper papillary dermis. In one embodiment, DH may treated with the methods and compositions described herein, preceding to, concurrent or following treatment with dapsone and with maintenance of a gluten-free diet.

[00048] In one embodiment, "Bullous Lupus" (BL) or "Bullous systemic lupus erythematosus" (BSLE) is characterized by cutaneous blistering in the setting of the autoimmune disease systemic lupus erythematosus. In one embodiment, patients exhibit widespread cutaneous vesiculobullous eruption, and histology of skin lesions demonstrate acute neutrophilic upper dermal infiltrate and subepidermal separation. An extensive vesiculobullous eruption develops suddenly. BL lesions may arise in one embodiment on erythematous areas or clinically normal skin in another, are typically tense, and range from herpetiform vesicles to large hemorrhagic bullae. In one embodiment, BL, unlike EBA, is not associated with skin fragility or healing of lesions with scars and milia. In one embodiment, lesions of BL may occur anywhere on the skin, or in another embodiment, the eruption tends to favor the upper part of the trunk and the proximal upper extremities. In one embodiment, BL lesions involve the mucosal surfaces of the mouth and pharynx. In one embodiment, treatment of BL patients with the methods and compositions described herein, either alone or in conjunction with steroids, such as dapsone, may alleviate symptoms, or reduce vesiculobollous eruptions, by either extent or number.

[00049] In one embodiment, the term "treating" includes preventative treatment, or in another embodiment disorder-remitative treatment, or in another embodiment palliative treatment. In one embodiment, the term "treating" refers to suppressing, reducing incidence, alleviating symptoms, inhibiting occurrence, increasing lagtime for onset or a combination thereof. In one embodiment, the term "reducing", refers to alleviating typical disease condition symptoms, or in another embodiment lowering the size of blisters, or in another embodiment, lowering the number of blisters, or in another embodiment, the extent of oozing, or in another embodiment, the extent and severity of resulting infections. In one embodiment, the term "inhibiting" refers to the lessening, or in another embodiment decreasing disease, or in another embodiment increasing the latency period between progression of disease stages or its onset, or in another embodiment affecting partial cure, or in another embodiment, complete cure, or in another embodiment stopping blistering from occurring altogether. [00050] In one embodiment, the term "progression" refers to increasing in scope, or in another embodiment severity, or in another embodiment advancing, or in another embodiment growing or or in another embodiment becoming worse. In one embodiment, the term "recurrence" refers to the return of a disease after a cure.

[00051] In one embodiment, the anti-IgE antibody used in the methods and compositions described herein is a humanized anti-IgE monoclonal antibody (humAb), which is, in another embodiment, omalizumab. In one embodiment, the term "humanized monoclonal antibody" (HumAb) refers to an antibody comprising portions of immunoglobulins of different origin, wherein at least one portion is of human origin. In one embodiment, the humanized antibody can comprise portions derived from an immunoglobulin of nonhuman origin with the requisite specificity, such as a mouse, and from immunoglobulin sequences of human origin (e.g., chimeric immunoglobulin). These portions can be joined together chemically in another embodiment, by conventional techniques (e.g., synthetic) or prepared as a contiguous polypeptide using genetic engineering techniques (e.g., DNA encoding the protein portions of the chimeric antibody can be expressed to produce a contiguous polypeptide chain). In another embodiment of a humanized antibody of the invention is an immunoglobulin containing one or more immunoglobulin chains comprising a CDR derived from an antibody of nonhuman origin and a framework region derived from a light and/or heavy chain of human origin (e.g., CDR-grafted antibodies with or without framework changes). Chimeric or CDR-grafted single chain antibodies are also encompassed by the term humanized antibody.

[00052] In another embodiment, the step of administering an anti-IgE antibody or a fragment, derivative or metabolite thereof according to the methods described herein, is done prior, during or after the administration of another therapeutic agent to the subject. In one embodiment, that other therapeutic agent is a steroid or other immune suppressant medication. In one embodiment, those additional treatments, center on the use of steroids such as prednisone or dapsone and other corticosteroid medications. In one embodiment, chemotherapeutic immunosuppressive drugs such as Imuran, Cytoxan, Cellcept, or the like are also administered to offset the disabling and toxic side effects of long-term prednisone use. In certain embodiments biologicals such as rituximab, TNF-a inhibitors may be used in conjunction with the compositions described herein. In one embodiment, the use of anti-IgE antibody, its fragment derivative or metabolite as described herein, allows lower use of other therapeutic agents, thereby reducing the severity of side effects resulting from long-term therapy. [00053] In one embodiment, the invention provides a method of reducing serum levels of a free anti-IgE antibody or a fragment, derivative or metabolite thereof in a subject comprising the step of administering to the subject an anti-IgE antibody.

[00054] In one embodiment, anti-IgE antibody, or in another embodiment, omalizumab

• markedly reduces serum levels of free IgE and down-regulatates IgE receptors on circulating basophils., Down regulation of IgE by omalizumab leads in one embodiment to reduction in eosinophils, mast cells, T cells and B ceils in the affected tissue of subjects exhibiting symptoms of AIBD.

[00055] Adhesion of basal keratinocytes to the underlying dermis is maintained by various structural proteins of hemidesmosomes, including the 230 kD bullous pemphigoid antigen (BP230), plectin, a6M integrin, BPl 80, and laminin 5. Directly or through other proteins these hemidesmosomal components associate with anchoring fibrils which originate in the lamina densa of the dermal-epidermal junction (DEJ) and extend into the subjacent connective tissue. The major component of anchoring fibrils is type VII collagen. A major component of the dermal-epidermal anchoring complex and a major target of autoantibodies is BPl 80. BPl 80 is a member of the collagen protein family and is also referred to as type XVII collagen. It is a transmembrane glycoprotein wherein the N-terminus localizes to the cytoplasm, ' whereas the C-terminal ectodomain consisting of about 1,000 amino acids projecting into the extracellular space. Rotary shadowing shows that BPl 80 contains an intracellular globular head, an extracellular rigid rod corresponding to the 16th noncollagenous (NC), forming a homotrimer. The NCl 6A domain adjacent to the cell membrane of basal keratinocytes has been identified as an immunodominant region of BPl 80 that is targeted by approximately 90% of BP sera. In one embodiment, patients with BP have pathogenic IgE antibodies directed towards the NC16A domain of BPl 80. an important cell adhesion molecule which in turn creates the symptomatic reaction observed. In another embodiment, serum levels of IgE to BP180 NC16A reflected disease activity. In one embodiment, reduction in the circulating IgE antibodies, or their fragments reduce the incidence of BP, pemphigoid (herpes) gestationis, lichen planus pemphigoides, cicatricial pemphigoid or their combination and can betreated using the methods described herein. [00056] In one embodiment, T lymphocytes play a major role in the regulation and induction of specific immune responses against self antigens. The inability to regulate in or control the reactivity of T cells to self antigens can lead in one embodiment to the initiation and the development of autoimmune diseases such as AIBD in certain embodiments. In one embodiment, disease-specific T lymphocytes from AIBD could recognize self antigens and participate in the initiation or progression of the respective autoimmune disease. Antibody production by B cells requires the participation of T helper (Th) cells in T cell-dependent antibody responses. During an antigen-driven activation of T cells, Th cells are induced to secrete lymphokines that are crucial in antibody production and IgE isotype switching by B cells. Since AIBD in one embodiment, or PV in another embodiment, is an autoimmune disease mediated by autoantibodies, T lymphocytes could participate in the pathogenesis of this disease in the stages leading to the production of pathogenic autoantibodies. In one embodiment, administering the compositions described herein, thereby reducing serum levels of IgE results in reducing the concentration of eosinophils, mast cells, T-cells, B-cells or their combination in a tissue of said subject, wherein the subject exhibits symptoms associated with autoimmune blistering disease. [00057] AIBD manifestations are initiated in one embodiment, by the aggregation of high affinity IgE receptors (FceRI)' expressed on mast cells and basophils, when FceRI-bound IgE antibodies bind multivalent antigens. FceRI are multichain-receptors composed of an IgE- binding α^' subunit, associated with a four-transmembrane domain β subunit and a homodimeric γ subunit. In one embodiment, consensus tyrosiπe-containing activation motif, in intracytoplasmic (IC) domains of FceRI β and γ subunits, account for the cell-activating properties of FceRJ. ^{• ■}

[00058] In one embodiment, the method of reducing serum levels of a free anti-IgE antibody or a fragment, derivative or metabolite thereof in a subject, comprising the step of administering to the subject an anti-IgE antibody, further comprises the step of downregulating IgE receptors on circulating basophils. In one embodiment, downregulating IgE receptors on circulating basophils is done by contacting the circulating basophils with ligands capable of reacting with IgE receptors disposed thereon. [00059] In one embodiment, IgE receptors expressed on circulating basophils are inhibited by cross-linking FceRI to low-affinity IgG receptors (FcyRH) which are constitutively expressed on mast cells and basophils. In another embodiment, wortmanin is used as a ligand to selectively block a subset of FceRI-mediated signaling responses. In one embodiment, the invention provides a method of reducing serum levels of a free IgE antibody or a fragment, ■ derivative or metabolite thereof in a subject comprising the step of administering to the subject an anti-IgE antibody such as omalizumab; downregulating IgE receptors on circulating basophils by cross-linking FceRI to low-affinity IgG receptors (FcyRH); and contacting the circulating basophils with ligands capable of reacting with IgE receptors disposed thereon, such as wortmanin. In one embodiment, reducing free IgE antibody results in the inhibition, suppression, alleviating symptoms, reducing incidence, inhibiting occurrence, increasing lagtime of symptoms onset or a combination thereof, of autoimmune blistering disease (AIBD), in the affected tissue of the afflicted subject, where the tissue affected is mucosa in one embodiment, or conjectϊva, epithelial membrane, skin or a combination thereof. [00060] In one embodiment, anti-IgE antibodies, fragments, receptors or Omalizumab in another embodiment, may improve auto-immune blistering diseases through the down regulation of IgE anti-bodies which may be pathogenic in causing blistering. [00061] The descriptions of the foregoing embodiments of the invention have been presented for purpose of illustration and description. They are not intended.to be exhaustive or to limit the invention to the precise forms disclosed herein, and obviously many modifications and variations are possible-in light of the above teaching. The embodiments were chosen and described in order to best explain the principles of the invention to thereby enable others skilled in the art to utilize the invention in various embodiments and with various modifications as are suited to the particular use contemplated. It is intended that the scope of the invention, be defined by the claims appended hereto.

Claims

What is claimed is:

1. A composition for the treatment of autoimmune blistering disease comprising an anti- IgE antibody or a fragment, derivative or metabolite thereof, a pharmaceutically acceptable carrier, excipient, flow agent, processing aid, diluent or a combination thereof.

2. The composition of claim 1, wherein the anti-IgE is a humanized anti-IgE monoclonal antibody (HumAb).

3. The composition of claim 1, wherein the anti-IgE fragment is Fab, Fab', F(ab)i, F(ab)2, Fc, monomelic IgE, or a combination thereof.

4. The composition of claim 2, wherein the humanized anti-IgE monoclonal antibody (humAb) is Omalizumab.

5. The composition of claim 1, wherein said composition is in a form suitable for oral, intravenous, intraaorterial, intramuscular, subcutaneous, parenteral, transmucosal, transdermal, ocular, or topical administration.

6. The composition of claim 5, wherein the composition is a topical application in the form of a cream, an ointment, a suspension, an emulsion, a gel or a combination thereof.

7. The composition of claim 1, wherein said carrier, excipient, lubricant, flow aid, processing aid or diluent is a gum, a starch, a sugar, a cellulosic material, an acrylate, calcium carbonate, magnesium oxide, talc, lactose monohydrate, magnesium stearate, colloidal silicone dioxide or mixtures thereof.

8. The composition of claim 1, comprising a binder, a disintegrant, a buffer, a protease inhibitor, an anticoagulant, a surfactant, a solubilizing agent, a plastϊcizer, an emulsifier, a stabilizing agent, a viscosity increasing agent, a sweetener, a film forming agent, or a combination thereof.

9. The composition of claim 1 , wherein said composition is a controlled release composition.

10. The composition of claim 1, wherein said composition is an immediate release composition.

11. The composition of claim 1, wherein said composition is a liquid dosage form.

12. The composition of claim 1 , wherein said composition is a solid dosage form.

13. A method for treating autoimmune blistering disease in a subject, comprising the step of administering to said subject an effective amount of a preparation comprising an anti-IgE antibody or a fragment, derivative or metabolite thereof.

14. The method of claim 13, wherein autoimmune blistering disease is bullous pemphigoid, . pemphigus vulgaris, pemphigus foliaceous, cicatricial pemphigoid, anti-epiligrin pemphigoid, epidermolysis bullosa acquisita, herpes gestationis, dermatitis herpetiformis, bullous lupus, paraneoplastic pemphigous, or a combination or variants, thereof.

15. The method of claim 13, wherein treating is suppressing, reducing incidence, alleviating symptoms, inhibiting occurrence, increasing Iagtime for onset or a combination thereof.

16. The method of claim 13, wherein the anti-IgE is a humanized anti-IgB monoclonal antibody (humAb).

17. The method of claim 13, wherein the anti-ϊgE fragment is Fab, Fab', F(ab)i, F(ab)₂, Fc, monomeric IgE, or a combination thereof.

18. The method of claim 16, wherein the humanized anti-IgE monoclonal antibody (humAb) is Omalizumab.

19. The method of claim 13, wherein the preparation further comprises a pharmaceutically acceptable carrier, excipient, flow agent, processing aid, diluent or a combination thereof.

20. The method of claim 13, wherein the step of administering is done prior, during or after the administration of another therapeutic agent to the subject.

21. The method of claim 20, wherein said other therapeutic agent is a steroid or other immune suppressant medication.

22. A method of reducing serum levels of a free IgE antibody or a fragment, derivative or metabolite thereof in a subject comprising the step of administering to the subject an anti-IgE antibody.

23. The method of claim 22, further comprising the step of downregulating IgE receptors on circulating basophils.

24. The method of claim 23, comprising the step of contacting the circulating basophils with ligands capable of reacting with IgE receptors disposed thereon.

25. The method of claim 22, wherein the step of reducing serum levels of IgE results in ^• reducing the concentration of eosinophils, mast cells, T-cells, B-cells or their combination- in a tissue of said subject, wherein the subject exhibits symptoms associated with autoimmune blistering disease.

26. The method of claim 22, wherein the anti-IgE is a humanized anti-IgE monoclonal antibody (Hum Ab).

27. The method of claim 22, wherein the anti-IgE fragment is Fab, Fab', F(ab)i, F(ab)₂, Fc, monomeric IgE, or a combination thereof.

28. The method of claim 26, wherein the humanized anti-IgE monoclonal antibody (HumAb) is Omalizumab.

29. The method of claim 22, wherein reducing free IgE antibody results in the inhibition, suppression, alleviating symptoms, reducing incidence, inhibiting occurrence, increasing lagtime of symptoms onset or a combination thereof, of autoimmune blistering disease (AIBD).

30. The method of claim 22, wherein the tissue is mucosa, coηjectϊva, epithelial membrane, skin or a combination thereof.