WO2007095293A2 - Plasma from vitiligo patients for treatment of melanoma - Google Patents

Plasma from vitiligo patients for treatment of melanoma Download PDF

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Publication number
WO2007095293A2
WO2007095293A2 PCT/US2007/003919 US2007003919W WO2007095293A2 WO 2007095293 A2 WO2007095293 A2 WO 2007095293A2 US 2007003919 W US2007003919 W US 2007003919W WO 2007095293 A2 WO2007095293 A2 WO 2007095293A2
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Prior art keywords
melanoma
vitiligo
patient
composition
plasma
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PCT/US2007/003919
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French (fr)
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WO2007095293A3 (en
Inventor
Yehuda Shoenfeld
Pnina Fishman
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Gammacan Ltd.
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Priority to CA002642572A priority Critical patent/CA2642572A1/en
Publication of WO2007095293A2 publication Critical patent/WO2007095293A2/en
Publication of WO2007095293A3 publication Critical patent/WO2007095293A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A61K35/16—Blood plasma; Blood serum

Definitions

  • This invention is directed to compositions and methods of treating melanoma in a subject. Specifically, the invention is directed to the use of plasma containing antibodies directed against melanoma in the treatment of melanoma.
  • lymphocytes within melanoma deposits. These lymphocytes, when isolated, are capable of recognizing specific tumor antigens on autologous and allogeneic melanomas in an MHC restricted fashion.
  • Topalia ⁇ S. L., et al, (1989) J. Immunol. 142: 3714-3725; Darrow, T. L., et al., (1989) J. Immunol. 142: 3329-3335; Horn, S. S., et al., (1991) J. Immunother. 10:153-164; Kawakami, Y., et al.,
  • TIL from patients with metastatic melanoma recognize shared antigens including melanocyte-melanoma lineage specific tissue antigens in vitro (Kawakami, Y., et al.,
  • the invention provides a composition for the treatment of melanoma in a subject, comprising: plasma isolated from a vitiligo patient.
  • the invention provides a composition for the treatment of melanoma in a subject, comprising: plasma isolated from a melanoma patient.
  • the invention provides a method for treating melanoma in a subject, comprising the step of administering to the subject a preparation comprising plasma isolated from a vitiligo patient.
  • the invention provides a method for treating melanoma in a subject, comprising the step of administering to the subject a preparation comprising plasma isolated from a melanoma patient.
  • the invention provides an article of manufacture comprising a suitable packaging material and plasma isolated from a vitiligo patient.
  • the invention provides an article of manufacture comprising a suitable packaging material and plasma isolated from a melanoma patient.
  • This invention relates in one embodiment to the use of plasma comprising antibodies to melanoma antigens in the treatment of melanoma.
  • his invention relates to plasma from a group of vitiligo patients or pooled from a group of vitiligo pat ⁇ entsJn
  • the invention provides a composition for the treatment of melanoma in a subject, comprising: plasma isolated from a vitiligo patient, or in another embodiment, the plasma used in the compositions and methods described herein is isolated from a melanoma patient
  • his invention relates to plasma from a group of melanoma patients or pooled from a group of melanoma patients.
  • the term "vitiligo" may be referred to as leucoderma.
  • the depigmented areas are lacking in the skin pigment melanin, and in another embodiment, the disease is the result of the destruction or inhibition of the melanin secreting melanocytes in the affected areas.
  • there may be some hereditary component to the disease since approximately 30% of the cases have a familial correlation.
  • the disease may be the result of an autoimmune or a specific metabolic defect may be involved, or, environmental factors to play a role in the aetiology of the disease in another embodiment.
  • vitiligo is subdivided into two clinical types: vitiligo non segmentalis (type A) and vitiligo segmentalis (type B).
  • Type A is more common, has a potential lifelong evolution and is associated with Koebner phenomenon and frequently with autoimmune diseases, such as Sutton nevus, thyroid disorders, juvenile diabetes mellitus, pernicious anemia and Addison's disease.
  • Type B is rarer and has a dermatomal distribution , wherein following a rapid onset and evolution it usually exhibits a stable course. The natural course of the disease is unpredictable in one embodiment, but it is progressive in other embodiments. In one embodiment some degree of spontaneous repigmentation occurs in 10- 20% of patients, occurring in a perifollicular pattern.
  • the prognosis in melanoma patients is better when hypo-pigmentation develops [Koh HK, Sober AJ, Nakagawa H, et al. Malignanat melanoma and vitiligo-l ⁇ ke leukoderma: An electron microscopic study. J Am Acad Dermatol 9:696-708, 1983, Nordlund JJ, Kirkwood JM, Forget BM, et al. Vitiligo in patients with metastatic melanoma: A good prognostic sign. J Am Acad Dermatol 9:689-96, 1983 ⁇ ⁇ .
  • the selective destruction of pigmented cells occurring in vitiligo is natural immunotherapy for melanoma, and plasma used in the composition described herein, which is isolated from melanoma patients in which vitiligo developed, or in another embodiment, from vitiligo patients, is useful in the treatment of melanoma according to the methods described herein.
  • the plasma used in the compositions and methods of the invention is isolated from vitiligo patients in which the vitiligo is characterized as diffuse vitiligo.
  • vitiligo refers in one embodiment to "generalized vitiligo", or “vitiligo non segmentalis (type A)", wherein the patchy white areas are often symmetrical, flat, have definite borders, and may affect or spread to any part of the body.
  • the plasma used in the methods and compositions described herein developed in a subject suffering from melanoma, in which the vitiligo developed as a response to the melanoma treatment.
  • metastatic melanoma responds to a variety of immunotherapies, including in one embodiment, the administration of IL-23 and the adoptive transfer of T cells along with IL-2.
  • some melanoma patients develop vitiligo during or after immunotherapy, and T cells that are reactive to both melanoma cells and cultured melanocytes have been detected in these patients, indicating that in one embodiment, T cells may be involved in the destruction of melanoma and melanocytes.
  • T cells specific for melanocyte proteins play an important role in melanoma rejection and in the development of vitiligo in vivo.
  • the vitiligo developed in melanoma or metastatic melanoma might not be caused by autoimmunity, or in another embodiment, the immune responses might not be strong enough to detect the antibodies specific to the melanoma cell phenotype or the metastatic melanoma cell phenotype, which, are different from on another.
  • the plasma used for the treatment of melanoma in a subject in the compositions and methods described herein is isolated from a patient, or pool of patients, in which vitiligo is shown to have been autoimmune in nature.
  • plasma refers to the liquid medium in which blood cells are suspended and which contains salts, proteins and other organic compounds.
  • fresh blood plasma or in another embodiment, frozen (stored) and subsequently thawed plasma, recovered plasma, or source plasma is used for purposes of the compositions and methods described herein.
  • Source plasma is defined in one embodiment, as plasma collected by plasmapheresis and intended for further use such as fractionation into other materials in certain embodiments.
  • source plasma is used as a transfusion product in the compositions and methods described herein.
  • Frozen (stored) plasma is maintained in one embodiment at sub-fieezing temperatures, such as at storage conditions of -20 to -80 degrees centigrade until thawed and used.
  • “Fresh” plasma is refrigerated in one embodiment or maintained on ice until transfusion in another embodiment.
  • the plasma used for transfusion according to the methods described herein is fresh-frozen plasma, recovered plasma, source plasma or combination thereof.
  • blood from a vitiligo patient, or in another embodiment, from a melanoma patient in which antibodies to melanoma antigens are identified is drawn by standard methods into a collection bag, or a plastic collection bottle for example, sodium citrate, CPD, CPD Al, ACD, heparin, or similar anticoagulants for preparation of plasma.
  • the plasma is separated from whole blood prior to being frozen.
  • fresh plasma is separated from whole blood by centrifugation, or fractionated by other standard methods in other embodiments.
  • the plasma is collected by plasmapheresis wherein the plasma is separated during or the collection procedure by a variety of techniques.
  • the term "plasmapheresis" refers to the separation of blood into plasma fraction and cellular component fraction providing for the collection of plasma alone, with the cellular components being returned to the donor with a suitable portion of replacement fluid
  • compositions described herein, or the preparations used in the methods described herein comprise plasma that is isolated from vitiligo patients and further comprise a pharmaceutically acceptable carrier, or excipient, flow agent, processing aid, diluent or a combination thereof in other embodiments.
  • the carrier, excipient, lubricant, flow aid, processing aid or diluent is a gum, or a starch, a sugar, a cellulosic material, an acrylate, calcium carbonate, magnesium oxide, talc, lactose monohydrate, magnesium stearate, colloidal silicone dioxide or mixtures thereof in other embodiments.
  • the formulation may in one embodiment, be in the form of a bolus, or in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions.
  • solutions and suspensions may be prepared from sterile powders or granules having one or more pharmaceutically-acceptable carriers or diluents, or a binder such as gelatin or hydroxypropyl-methyl cellulose, together with one or more of a lubricant, anticoagulant, preservative, surface-active or dispersing agent or a combination thereof.
  • the composition further comprises a binder, a disintegrant, a buffer, a protease inhibitor, a surfactant, a solubilizing agent, a plasticizer, an emulsifier, a stabilizing agent, a viscosity increasing agent, a sweetner, a film forming agent, or any combination thereof.
  • the composition is a particulate composition coated with a polymer (e.g., poloxamers or poloxamines).
  • a polymer 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 routes of administration, including parenteral, pulmonary, nasal and oral.
  • the pharmaceutical composition is administered topically, parenterally, paracancerally, transmucosally, transdermally, intramuscularly, intravenously, intradermally, subcutaneously, intraperitonealy, intraventricularly, intratumorically, or intracranially.
  • compositions of this invention may be in the form of a pellet, a tablet, a capsule, a solution, a suspension, a dispersion, an emulsion, an elixir, a gel, an ointment, a cream, or a suppository.
  • the composition is in a form suitable for oral, intravenous, intraaorterial, intramuscular, subcutaneous, parenteral, transmucosal, transdermal, or topical administration.
  • the composition is a controlled release composition.
  • the composition is an immediate release composition.
  • the composition is a liquid dosage form.
  • the composition is a solid dosage form.
  • the compounds utilized in the methods and compositions of the present invention may be present in the form of free bases in one embodiment or pharmaceutically acceptable acid addition salts thereof in another embodiment.
  • pharmaceutically-acceptable salts embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically-acceptable.
  • Suitable pharmaceutically-acceptable acid addition salts of compounds of Formula I are prepared in another embodiment, from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.
  • organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, example of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fiimaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embon ⁇ c (pamoic), methanesulfonic, ethanesulfonic, benzenesulfon ⁇ c, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylarninosulfonic, ' stearic, algenic, b-hydroxybutyric, salicylic, gal
  • Suitable pharmaceut ⁇ cally-acceptable base addition salts include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N'-dibenzyIethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared by conventional means from the corresponding compound by reacting, in another embodiment, the appropriate acid or base with the compound.
  • the term "pharmaceutically acceptable carriers” includes, but is not limited to, may refer to 0.01-O.lM and preferably 0.05M phosphate buffer, or in another embodiment 0.8% saline. Additionally, such pharmaceutically acceptable carriers may be in another embodiment aqueous or non-aqueous solutions, suspensions, 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.
  • compositions described herein may include 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 polyproline 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 the administration of such polymer- compound abducts less frequently or in lower doses than with the unmodified compound.
  • water-soluble polymers such as polyethylene glycol, copolymers of polyethylene glycol and polypropylene glyco
  • compositions described herein which may be used in the preparations used in the methods described herein, can be prepared by known dissolving, mixing, granulating, or tablet-forming processes.
  • the active ingredients, or their physiologically tolerated derivatives in another embodiment such as salts, esters, N-oxides, and the like are mixed with additives customary for this purpose, such as vehicles, stabilizers, or inert diluents, and converted by customary methods into suitable forms for administration, such as tablets, coated tablets, hard or soft gelatin capsules, aqueous, alcoholic or oily solutions-
  • suitable inert vehicles are conventional tablet bases such as lactose, sucrose, or cornstarch in combination with binders such as acacia, cornstarch, gelatin, with disintegrating agents such as cornstarch, potato starch, alginic acid, or with a lubricant such as stearic acid or magnesium stearate.
  • suitable oily vehicles or solvents are vegetable or animal oils such as sunflower oil or fish-liver oil. Preparations can ' be effected both as dry and as wet granules.
  • the active ingredients 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.
  • sterile liquids such as water and oils, with or without the addition of a surfactant and other pharmaceutically acceptable adjuvants.
  • Illustrative oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, or mineral oil.
  • 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.
  • 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.
  • An active component which, in one embodiment is the plasma isolated from a vitiligo patient, or in another embodiment, from a melanoma patient in which antibodies to melanoma antigens are identified, 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), 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 ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.
  • inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.
  • the plasma isolated from a vitiligo patient, or in another embodiment, from a melanoma patient in which antibodies to melanoma ant jgens • are identified is administered in a therapeutically effective amount
  • the actual amount administered, and the rate and time-course of administration, will depend in one embodiment, on the nature and severity of the condition being treated. Prescription of treatment, e.g.
  • targeting therapies may be used in another embodiment, to deliver the plasma compositions described herein, more specifically to certain types of cell, by the use of targeting systems such as antibodies or cell specific ligands.
  • Targeting may be desirable in one embodiment, for a variety of reasons, e.g. if the agent is unacceptably toxic, or if it would otherwise require too high a dosage, or if it would not otherwise be able to enter the target cells.
  • compositions described herein are formulated in one embodiment for oral delivery, wherein the active compounds which in one embodiment is plasma isolated from a vitiligo patient, or in another embodiment, from a melanoma patient in which antibodies to melanoma antigens are identified, may be incorporated with excipients and used in the form of ingestible tablets, buccal tables, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • the tablets, troches, pills, capsules and the like may also contain the following: a binder, as gum tragacanth, acacia, cornstarch, or gelatin; excipients, such as dicalcium phosphate; a disintegrating agent, such as corn starch, potato starch, alginic acid and the like; a lubricant, such as magnesium stearate; an anticoagulant, such as sodium citrate or any of the whole blood anticoagulant-preservative solution such as ACD, CPD, CPD-Al, Adsol and the like; and a sweetening agent, such as sucrose, lactose or saccharin may be added or a flavoring agent, such as peppermint, oil of wintergreen, or cherry flavoring.
  • a binder as gum tragacanth, acacia, cornstarch, or gelatin
  • excipients such as dicalcium phosphate
  • a disintegrating agent such as corn starch, potato starch, alginic acid and the
  • the dosage unit form When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar, or both. Syrup of elixir may contain the active compound sucrose as a sweetening agent methyl and propylparabens as preservatives, a dye and flavoring, such as, cherry or orange flavor. In addition, the active compounds may be incorporated into sustained-release, pulsed release, controlled release or postponed release preparations and formulations [00037] Controlled or sustained release compositions include formulation in lipophilic.depots (e.g.
  • fatty acids e.g. fatty acids, waxes, oils.
  • particulate compositions coated with polymers e.g. poloxamers or poloxamines
  • the compound coupled to antibodies directed against tissue-specific receptors, ligands or antigens or coupled to ligands of tissue-specific receptors are also comprehended by the invention.
  • the composition described herein, or the preparation used in the methods described herein can be delivered in a controlled release system.
  • the plasma isolated from a vitiligo patient, or.in another embodiment, from a melanoma patient in which antibodies to melanoma antigens are identified may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, coHoidosomes, polymerosomes or other modes of administration.
  • a pump may be used (see Langer, supra; Sefion, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et aL.
  • a controlled release system can be placed in proximity to the therapeutic target, i.e., the melanoma site, 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). Other controlled release systems are discussed in the review by Langer (Science 249:1527-1533 (1990).
  • compositions are in one embodiment liquids or lyophilized 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), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite), 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, complexation with metal ions, or incorporation of the material into or onto particulate preparations of polymeric compounds such as polylactic acid,
  • buffer content
  • Controlled or sustained release compositions include formulation in lipophilic depots (e.g., fatty acids, waxes, oils).
  • 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 routes of administration, including parenteral, pulmonary, nasal, and oral.
  • compositions of this invention comprise one • or more, pharmaceutically acceptable carrier materials.
  • the carriers for use within such compositions are biocompatible, and in another embodiment, biodegradable.
  • the formulation may provide a relatively constant level of release of one active component. In other embodiments, however, a more rapid rate of release immediately upon administration may be desired.
  • release of the plasma isolated from a vitiligo patient, or in another embodiment, from a melanoma patient in which antibodies to melanoma antigens are identified may be event-triggered. The events triggering the release of , the plasma isolated from a vitiligo patient, or in another embodiment, from a melanoma patient in which antibodies to melanoma antigens are identified, may be the same in one embodiment, or different in another embodiment.
  • Events triggering the release of the active components may be exposure to moisture in one embodiment, lower pH in another embodiment, or temperature threshold in another embodiment.
  • the formulation of such compositions is well within the level of ordinary skill in the art using known techniques.
  • Illustrative carriers useful in this regard include microparticles of poly ⁇ lactide- co-glycolide), polyacrylate, latex, starch, cellulose, dextran and the like.
  • Other illustrative postponed- release carriers include supramolecular biovectors, which comprise a non-liquid hydrophilic core (e.g., a cross-linked polysaccharide or oligosaccharide) and, optionally, an external layer comprising an amphiphilic compound, such as phospholipids.
  • the amount of active compound contained in one embodiment, within a sustained release formulation depends upon the site of administration, the rate and expected duration of release and the nature of the condition to be treated suppressed or inhibited.
  • the plasma isolated from a vitiligo patient, or in another embodiment, plasma from a melanoma patient is isolated from a single patient, or from a pool of patients.
  • blood is collected into a container that already has an appropriate anticoagulant, or anticoagulant-preservative solution in it and stored for later separation.
  • the separated plasma is then frozen for later use as an active agent in the compositions and methods as described herein.
  • the isolated plasma is frozen at a rate that ensures the viability of the components.
  • the frozen plasma is further lyophilized.
  • the plasma isolated from a melanoma patient in which antibodies to melanoma antigens such as HMW-MAA or tyrosinase are identified is used in the methods and compositions of the invention.
  • melanoma is immunogenic and can activate host immune responses capable of controlling the disease and, causing tumor regression.
  • the term "antibody” include 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.
  • fragments may or may not include antibody constant domains.
  • 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.
  • the domains present in such a library are heavy chain variable domains (VH) 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
  • 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.
  • the plasma is isolated from melanoma patients wherein the melanoma tumour remains localized for long periods with no detectable spread (stage I melanoma) and comprises antibodies able to cause the death of autologous tumour cells.
  • the plasma isolated from a melanoma patient in which antibodies to melanoma antigens are identified are taken from a melanoma patient or pool of patients where the disease is at an early stage of the disease or from a patient or pool of patients in which the disease is at an advanced stage.
  • the isolated plasma is taken from a patient or pool of patients where the tumour is a primary tumor at stage I.
  • plasma is isolated from melanoma patients whose lesions are excised and are presumed cured.
  • the term disease stage refers in one embodiment to the different stages of melanoma cancer. Stage I is divided into stages IA and IB. In stage IA, the tumor is not more than 1 millimeter thick, with no ulceration.
  • the tumor is in the epidermis (outer layer of skin) and upper layer of the dermis (inner layer of skin).
  • stage IB the tumor is either not more than 1 millimeter thick, with ulceration, and may have spread into the dermis or the tissue below the skin; or 1 to 2 millimeters thick, with no ulceration.
  • Stage II is divided into stages HA, IIB, and HC.
  • stage HA the tumor is either 1 to 2 millimeters thick, with ulceration; or 2 to 4 millimeters thick, with no ulceration.
  • stage ⁇ B the tumor is either 2 to 4 millimeters thick, with ulceration; or more than 4 millimeters thick, with no ulceration.
  • stage II C the tumor is more than 4 millimeters thick, with ulceration.
  • the tumor may be of any thickness, with or without ulceration, and may have spread to 1 or more nearby lymph nodes.
  • Stage III is divided into stages IIIA, IUB, and IHC.
  • stage IHA the cancer may have spread to as many as 3 nearby lymph nodes, but can be seen only with a microscope.
  • stage HIB the cancer has spread to as many as 3 lymph nodes and may not be visible without a microscope, or has satellite tumors (additional tumor growths within 1 inch of the original tumor) and has not spread to lymph nodes.
  • stage HIC the cancer either has spread to as many as 4 or more lymph nodes and can be seen without a microscope, or has lymph nodes that may not be moveable, or has satellite tumors and may have spread to lymph nodes.
  • the plasma used in the compositions and methods described herein is taken from a patient or pool of patients wherein the Vitiligo developed prior to the isolation of plasma.
  • compositions described herein are used to treat melanoma in a subject.
  • the invention provides a method for treating melanoma in a subject, comprising the step of administering to the subject a preparation comprising plasma isolated from a vitiligo patient.
  • the term “treat” or “treating” refers to suppressing, inhibiting, increasing lag time before development of symptoms, reducing or alleviating symptoms associated with melanoma, extending the periods at a single disease stage, preventing or inhibiting metastases, reducing number and size of metastases loci and the like.
  • the plasma is isolated from a melanoma patient whose melanoma metastasized and as a response to treatment, developed Vitiligo, at which point plasma was isolated and used for the compositions described herein. In one embodiment, that plasma may be later used to suppress, inhibit or reduce the metastases.
  • the methods described herein are used with at least one other treatment ' modality, prior to, during or after the administration of the preparation of plasma isolated from a vitiligo • patient, a melanoma patient where antimelanoma antibodies were identified, or a melanoma patient where vitiligo developed prior to isolation of plasma.
  • the other treatment modality is" chemotherapy, immunotherapy, radiation therapy, surgery or a combination thereof.
  • the other treatment modality is surgery, and the method comprises in one embodiment further removing surgically the melanoma prior to, during or after the administration of the preparation plasma isolated * from a vitiligo patient a melanoma patinet where antimelanoma antibodies were identified, or. a melanoma patient where vitiligo developed prior to isolation of plasma.
  • the plasma donor for the compositions and methods described herein is a vitiligo patient, or a Vitiligo patient who has a diffuse vitiligo; a patient in which the vitiligo developed in response to melanoma; a melanoma patient, a melanoma patient where anti-melanoma antibodies were identified; or a combination thereof in other embodiments.
  • the donor is a pool of donors.
  • mice Female C57BL/6J mice are purchased at 6-8 wks of age at study initiation. Administration of the plasma takes place following veterinary Inspection and 1-Wk acclimatization, marking and randomization.
  • Results show that pooled plasma from donors exhibiting diffuse vitiligo shows a marked decrease in the number and size of melanoma metastases, as well as at least a tumoristatic effect on the metastasized melanoma tumors.
  • Example 2 Vitiligo Plasma for the Treatment of Human Melanoma in a Mouse Model
  • mice Female CB17-SCID mice are purchased at 6-8 wks of age at study initiation. Administration of the plasma takes place following veterinary Inspection and 1-Wk acclimatization, marking and randomization.
  • Results show that pooled plasma from donors exhibiting diffuse vitiligo shows a marked decrease in the number and size of melanoma metastases, as well as at least a tumoristatic effect on the metastasized melanoma tumors.
  • mice Female C57BL/6J mice are purchased at 6-8 wks of age at study initiation. Administration of the plasma takes place following veterinary Inspection and 1-Wk acclimatization, marking and randomization.
  • Results show that pooled plasma from donors exhibiting diffuse vitiligo shows a marked decrease in the number and size of melanoma metastases, as well as at least a tumoristatic effect on the metastasized melanoma tumors.
  • mice Female CB17-SCID mice are purchase at 6-S wks of age at study initiation. Administration of the plasma takes place following veterinary Inspection and 1-Wk acclimatization, marking and randomization.
  • Results show that pooled plasma from donors exhibiting diffuse vitiligo shows a marked decrease in the number and size of melanoma metastases, as well as at least a tumor ⁇ static effect on the metastasized melanoma tumors.
  • Example 5 Vitileo Plasma Administered for the Treatment of Patients with Stage III or Stage IV
  • the purpose of the example is to evaluate whether plasma obtained from donors with Vitiligo, can be administered for the treatment of patients with stage III or IV inoperable melanoma.
  • the phase 1 part of the study is designed to determine whether the Vitiligo-derived plasma can be safely administered, and the phase 2 part of the study is designed to provide additional safety data and to gain an understanding of whether administrating Vitiligo plasma can improve the clinical outcome for melanoma patients versus the currently available data.
  • Vitiligo plasma is administered as an intravenous infusion on consecutives days followed by a rest period for a treatment cycles of 28 days.
  • 1 st cohort - 5 patients are randomized to each of the 3 treatment doses (100/ 200/ 400 mg/kg bodyweight) — total of 15 patients. Patients are randomized to 1 of the 3 plasma dose levels. Each patient is infused twice every 28 eight days and is followed for 28 days post the last infusion to detect potential safety issues. The 2 nd cohort does not start accrual, prior to a satisfactory safety analysis from the 1 st cohort. Nevertheless, the 1 st cohort patients continue treatment for up to the copmet ⁇ on of 6 cycles (each cycle being 28 days) unless the patient develops progressive disease or intolerable toxicity.
  • 2 nd cohort Upon positive results from the safety analysis of the first cohort, 5 patients are randomized to each of the three above described treatment doses to a total of 15 patients. Patients' treatments are administered similarly as to the 1 st cohort. Patients are replaced under the same conditions as of the 1 st cohort. Although recruitment is not suspended until after enrollment is completed for this cohort, a safety analysis is done to include the first 30 patients, including two infusions each and a follow up period.
  • 3 rd cohort - Additional 9 patients are randomized to each of the 3 treatment doses (total of 27 patients). Patients' treatment is administered as described above. A Simon two-stage designs is used to evaluate the efficacy of the treatment, after 6 cycles at each of the above described doses. Patients are replaced if they do not complete at least 2 cycles of treatment and have at least 1 post-treatment disease assessment performed (unless there is clear evidence of clinical progression after two (2) cycles).
  • 4 th cohort Additional 21 patients (maximum of 63 patients) are randomized to those treatment arms (doses, as descibed above) which have shown at least one response (as desciribed above) at the 3 rd cohort stage and are treated as described above. At the completion of the 4 th cohort, if four or more responses are observed for any dose level, then it is concluded that this dose level is a candidate for further clinical study. Patients are replaced in a similar method as in previous cohorts.
  • Results indicate that vitilogo plasma is a safe and effective compound for the treatment of stage III or rv inoperable melanoma.

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Abstract

This invention relates to compositions and methods for treating melanoma in a subject. Specifically, the invention is directed to the use of plasma obtained from target donors containing antibodies for melanoma in the treatment of melanoma.

Description

PLASMA FROM VITILIGO PATIENTS FOR TREATMEINfT OF MELANOMA
CROSS REFERENCE TO RELATED APPLICATIONS
[00011 This application claims priority from US Provisional Application Number 60/773,335, filed February 15, 2006 , which is incorporated herein by reference in its entirety
FIELD OF INVENTION
[0002] This invention is directed to compositions and methods of treating melanoma in a subject. Specifically, the invention is directed to the use of plasma containing antibodies directed against melanoma in the treatment of melanoma.
BACKGROUND OF THE INVENTION
[0003] Melanomas are aggressive, frequently metastatic tumors derived from either melanocytes or melanocyte related nevus cells ("Cellular and Molecular Immunology" (1991) (eds) Abbas A. K., Lechtman, A. H., Pober, J. S.; W. B. Saunders Company, Philadelphia: pages 340-341). Melanomas make up approximately three percent of all skin cancers and the worldwide increase in melanoma is unsurpassed by any other neoplasm with the exception of lung cancer in women ("Cellular and Molecular Immunology" (1991) (eds) Abbas, A. K., Lechtiman, A. H., Pober, J. S.; W. B. Saunders Company Philadelphia pages:. 340-342; Kirkwood and Agarwala (1993) Principles and Practice of Oncology 7:1-16). Even when melanoma is apparently localized to the skin, up to 30% of the patients will develop systemic metastasis and the majority will die (Kirkwood and Agarwala (1993) Principles and Practice of Oncology 7:1-16). Classic modalities of treating melanoma include surgery, radiation and chemotherapy. In the past decade immunotherapy and gene therapy have emerged as hew and promising methods for treating melanoma .
[0004] Strong evidence that an immune response to cancer exists in humans is provided by the existence of lymphocytes within melanoma deposits. These lymphocytes, when isolated, are capable of recognizing specific tumor antigens on autologous and allogeneic melanomas in an MHC restricted fashion. (Itoh, K. et al. (1986), Cancer Res. 46: 3011-3017; Muul, L: M., et al. (1987), J. Immunol 138:989-995); Topaliaπ, S. L., et al, (1989) J. Immunol. 142: 3714-3725; Darrow, T. L., et al., (1989) J. Immunol. 142: 3329-3335; Horn, S. S., et al., (1991) J. Immunother. 10:153-164; Kawakami, Y., et al.,
(1992) J. Immunol. 148: 638-643; Horn, S. S-, et al., (1993) J. Immunother. 13:18-30; O1NeH, B. H., et al., (1993) J. Immunol. 151: 1410-1418). TIL from patients with metastatic melanoma recognize shared antigens including melanocyte-melanoma lineage specific tissue antigens in vitro (Kawakami, Y., et al.,
(1993) J. Immunother. 14: 88-93; Anichini, A. et aL, (1993) et al., J. Exp. Med 177: 989-998). Anti- melanoma T cells appear to be enriched in TlL probably as a consequence of clonal expansion and accumulation at the tumor site in vivo (Sensi, M., et al., (1993) J. Exp. Med 178:1231-1246). The fact that many melanoma patients mount cellular and humoral responses against these tumors and that melanomas express both MHC antigens and tumor associated antigens (TAA) indicate that identification, characterization and use of additional melanoma antigens will be important for immunotherapy of patients with melanoma.
SUMMARY OF THE INVENTION
[0005] In one embodiment, the invention provides a composition for the treatment of melanoma in a subject, comprising: plasma isolated from a vitiligo patient.
[0006] In another embodiment, the invention provides a composition for the treatment of melanoma in a subject, comprising: plasma isolated from a melanoma patient.
[0007] In one embodiment, the invention provides a method for treating melanoma in a subject, comprising the step of administering to the subject a preparation comprising plasma isolated from a vitiligo patient.
[0008] In another embodiment, the invention provides a method for treating melanoma in a subject, comprising the step of administering to the subject a preparation comprising plasma isolated from a melanoma patient.
{0009] In one embodiment, the invention provides an article of manufacture comprising a suitable packaging material and plasma isolated from a vitiligo patient. [OOOIO] In another embodiment, the invention provides an article of manufacture comprising a suitable packaging material and plasma isolated from a melanoma patient.
[00011] Other features and advantages of the present invention will become apparent from the following detailed description examples and figures. It should be understood, however, that the detailed description and the specific examples while indicating preferred embodiments of the invention are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description
DETAILED DESCRIPTION OF THE BSfVENTION
[00012] This invention relates in one embodiment to the use of plasma comprising antibodies to melanoma antigens in the treatment of melanoma. In another embodiment his invention relates to plasma from a group of vitiligo patients or pooled from a group of vitiligo patϊentsJn one embodiment, the invention provides a composition for the treatment of melanoma in a subject, comprising: plasma isolated from a vitiligo patient, or in another embodiment, the plasma used in the compositions and methods described herein is isolated from a melanoma patient In another embodiment his invention relates to plasma from a group of melanoma patients or pooled from a group of melanoma patients.
[00013] In another embodiment, the term "vitiligo" may be referred to as leucoderma. In one embodiment, the depigmented areas are lacking in the skin pigment melanin, and in another embodiment, the disease is the result of the destruction or inhibition of the melanin secreting melanocytes in the affected areas. In yet other embodiments, there may be some hereditary component to the disease, since approximately 30% of the cases have a familial correlation. In one embodiment, the disease may be the result of an autoimmune or a specific metabolic defect may be involved, or, environmental factors to play a role in the aetiology of the disease in another embodiment.
[00014] In one embodiment, vitiligo is subdivided into two clinical types: vitiligo non segmentalis (type A) and vitiligo segmentalis (type B). Type A is more common, has a potential lifelong evolution and is associated with Koebner phenomenon and frequently with autoimmune diseases, such as Sutton nevus, thyroid disorders, juvenile diabetes mellitus, pernicious anemia and Addison's disease. Type B is rarer and has a dermatomal distribution , wherein following a rapid onset and evolution it usually exhibits a stable course. The natural course of the disease is unpredictable in one embodiment, but it is progressive in other embodiments. In one embodiment some degree of spontaneous repigmentation occurs in 10- 20% of patients, occurring in a perifollicular pattern.
[00015} In one embodiment, there is a relationship between vitiligo and melanoma [Horning R, Cui J, Bystryn JC. Relation between the incidence and level of pigment cell antibodies and disease activity in vitiligo. J Invest Dermatol 97: 1078-80, 1991; Fishman P, Azisi E, Shoenβld Y, et al. Vitiligo autoantibodies are effective against melanoma. Cancer 72: 2365-2369, 1993. ; Gilhar A, Zelickson B, Ulman Y, EtzioniA. In vivo destruction of melanocytes by the IgG fraction of serum from patients with vitiligo. J Invest Dermatol 105: 683-686, 1995.; Rigel DS, Rogers GS, Friedman RJ. Prognosis in malignant melanoma. Dermatol Clin North Am 3:309-14, 1985. Bystryn JC, Rigel D, Friedman RJ, Kopf A. Prognostic significance of hyperpigmentation in malignant melanoma. Arch Dermatol 123: 1053-5, 1987; D'aelio R, Frati C, Fattarossi A, Aiuti F. Peripheral T cell subset imbalance inpatients with vitiligo and in their apparently healthy first degree relatives. Ann Allergy 65: 143-5, 1990.; Bystryn JC, Naughton GK. Immunity to pigmented cells in vitiligo and melanoma. Fed Proc 43:1664-5, 1984.; Lerner AB, Nordlund JJ. Should vitiligo.be induced in patients after resection of primary melanoma? Editorial. Arch Dermatol 113: 421, 1977; Donaldson RC, Canaan SA Jr, McLean RB, Ackerman LV. • Uveitis and vitiligo associated with BCG treatment for malignant melanoma. Surgery 76:771-8, 1974; Naughton GK, Eising M, Bystryn JC. Detection of autoantibodies to melanocytes in vitiligo by specific immunoprecipitation. Arch Dermatol 81:540-2, 1983; Norris DA, Kissinger RM1 Naughton GK , Bystryn JC. Evidence for immunologic mechanisms in human vitiligo: patients ' sera induce damage to human melanocytes in vitro by complement-mediated damage and antibody dependent cellular cytotoxicity (ADCC). J Invest Dermatol 90:783-9, 1988] and in another embodiment, in patients with malignant melanoma, circulating antibodies against melanoma cells are present. Because these antibodies also destroy normal, non-røalignant melanocytes, vitiligo develops in other embodiments, in malignant, melanoma patients. In one embodiment, the prognosis in melanoma patients is better when hypo-pigmentation develops [Koh HK, Sober AJ, Nakagawa H, et al. Malignanat melanoma and vitiligo-lϊke leukoderma: An electron microscopic study. J Am Acad Dermatol 9:696-708, 1983, Nordlund JJ, Kirkwood JM, Forget BM, et al. Vitiligo in patients with metastatic melanoma: A good prognostic sign. J Am Acad Dermatol 9:689-96, 1983~\. Therefore in one embodiment, the selective destruction of pigmented cells occurring in vitiligo is natural immunotherapy for melanoma, and plasma used in the composition described herein, which is isolated from melanoma patients in which vitiligo developed, or in another embodiment, from vitiligo patients, is useful in the treatment of melanoma according to the methods described herein. [00016] In one embodiment, the plasma used in the compositions and methods of the invention, is isolated from vitiligo patients in which the vitiligo is characterized as diffuse vitiligo. The term "diffuse vitiligo" refers in one embodiment to "generalized vitiligo", or "vitiligo non segmentalis (type A)", wherein the patchy white areas are often symmetrical, flat, have definite borders, and may affect or spread to any part of the body.
[00017] In one embodiment, the plasma used in the methods and compositions described herein, developed in a subject suffering from melanoma, in which the vitiligo developed as a response to the melanoma treatment.
[00018] In one embodiment - melanoma, or in another embodiment, metastatic melanoma responds to a variety of immunotherapies, including in one embodiment, the administration of IL-23 and the adoptive transfer of T cells along with IL-2. In another embodiment, some melanoma patients develop vitiligo during or after immunotherapy, and T cells that are reactive to both melanoma cells and cultured melanocytes have been detected in these patients, indicating that in one embodiment, T cells may be involved in the destruction of melanoma and melanocytes. In one embodiment, T cells specific for melanocyte proteins play an important role in melanoma rejection and in the development of vitiligo in vivo. In one embodiment, the vitiligo developed in melanoma or metastatic melanoma might not be caused by autoimmunity, or in another embodiment, the immune responses might not be strong enough to detect the antibodies specific to the melanoma cell phenotype or the metastatic melanoma cell phenotype, which, are different from on another. In one embodiment, the plasma used for the treatment of melanoma in a subject in the compositions and methods described herein, is isolated from a patient, or pool of patients, in which vitiligo is shown to have been autoimmune in nature.
[00019] In one embodiment, plasma refers to the liquid medium in which blood cells are suspended and which contains salts, proteins and other organic compounds. In one embodiment, "fresh" blood plasma, or in another embodiment, frozen (stored) and subsequently thawed plasma, recovered plasma, or source plasma is used for purposes of the compositions and methods described herein. "Source plasma" is defined in one embodiment, as plasma collected by plasmapheresis and intended for further use such as fractionation into other materials in certain embodiments. In one embodiment, source plasma is used as a transfusion product in the compositions and methods described herein. Frozen (stored) plasma is maintained in one embodiment at sub-fieezing temperatures, such as at storage conditions of -20 to -80 degrees centigrade until thawed and used. "Fresh" plasma is refrigerated in one embodiment or maintained on ice until transfusion in another embodiment. In one embodiment, the plasma used for transfusion according to the methods described herein, is fresh-frozen plasma, recovered plasma, source plasma or combination thereof.
[00020] In one embodiment, blood from a vitiligo patient, or in another embodiment, from a melanoma patient in which antibodies to melanoma antigens are identified, is drawn by standard methods into a collection bag, or a plastic collection bottle for example, sodium citrate, CPD, CPD Al, ACD, heparin, or similar anticoagulants for preparation of plasma. In one embodiment, the plasma is separated from whole blood prior to being frozen. In one embodiment, fresh plasma is separated from whole blood by centrifugation, or fractionated by other standard methods in other embodiments. In another embodiment the plasma is collected by plasmapheresis wherein the plasma is separated during or the collection procedure by a variety of techniques. In one embodiment, the term "plasmapheresis" refers to the separation of blood into plasma fraction and cellular component fraction providing for the collection of plasma alone, with the cellular components being returned to the donor with a suitable portion of replacement fluid
[00021] In one embodiment, the compositions described herein, or the preparations used in the methods described herein comprise plasma that is isolated from vitiligo patients and further comprise a pharmaceutically acceptable carrier, or excipient, flow agent, processing aid, diluent or a combination thereof in other embodiments. In one embodiment, the carrier, excipient, lubricant, flow aid, processing aid or diluent is a gum, or a starch, a sugar, a cellulosic material, an acrylate, calcium carbonate, magnesium oxide, talc, lactose monohydrate, magnesium stearate, colloidal silicone dioxide or mixtures thereof in other embodiments.
[00022] The formulation may in one embodiment, be in the form of a bolus, or in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more pharmaceutically-acceptable carriers or diluents, or a binder such as gelatin or hydroxypropyl-methyl cellulose, together with one or more of a lubricant, anticoagulant, preservative, surface-active or dispersing agent or a combination thereof. [00023] In another embodiment, the composition further comprises a binder, a disintegrant, a buffer, a protease inhibitor, a surfactant, a solubilizing agent, a plasticizer, an emulsifier, a stabilizing agent, a viscosity increasing agent, a sweetner, a film forming agent, or any combination thereof.
[00024] In one embodiment, the composition is a particulate composition coated with a polymer (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 routes of administration, including parenteral, pulmonary, nasal and oral. In one embodiment the pharmaceutical composition is administered topically, parenterally, paracancerally, transmucosally, transdermally, intramuscularly, intravenously, intradermally, subcutaneously, intraperitonealy, intraventricularly, intratumorically, or intracranially.
[00025] In one embodiment, the compositions of this invention may be in the form of a pellet, a tablet, a capsule, a solution, a suspension, a dispersion, an emulsion, an elixir, a gel, an ointment, a cream, or a suppository.
[00026] In another embodiment, the composition is in a form suitable for oral, intravenous, intraaorterial, intramuscular, subcutaneous, parenteral, transmucosal, transdermal, or topical administration. In one embodiment the composition is a controlled release composition. In another embodiment, the composition is an immediate release composition. In one embodiment, the composition is a liquid dosage form. In another embodiment, the composition is a solid dosage form.
[00027] The compounds utilized in the methods and compositions of the present invention may be present in the form of free bases in one embodiment or pharmaceutically acceptable acid addition salts thereof in another embodiment. In one embodiment, the term "pharmaceutically-acceptable salts" embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically-acceptable. Suitable pharmaceutically-acceptable acid addition salts of compounds of Formula I are prepared in another embodiment, from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, example of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fiimaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonϊc (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonϊc, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylarninosulfonic,' stearic, algenic, b-hydroxybutyric, salicylic, galactaric and galacturonic acid. Suitable pharmaceutϊcally-acceptable base addition salts include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N'-dibenzyIethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared by conventional means from the corresponding compound by reacting, in another embodiment, the appropriate acid or base with the compound.
[00028] In one embodiment, the term "pharmaceutically acceptable carriers" includes, but is not limited to, may refer to 0.01-O.lM and preferably 0.05M phosphate buffer, or in another embodiment 0.8% saline. Additionally, such pharmaceutically acceptable carriers may be in another embodiment aqueous or non-aqueous solutions, suspensions, 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.
[00029] In one embodiment, the compositions described herein, may include 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 polyproline 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 the administration of such polymer- compound abducts less frequently or in lower doses than with the unmodified compound.
[00030] The compositions described herein, which may be used in the preparations used in the methods described herein, can be prepared by known dissolving, mixing, granulating, or tablet-forming processes. For oral administration, the active ingredients, or their physiologically tolerated derivatives in another embodiment, such as salts, esters, N-oxides, and the like are mixed with additives customary for this purpose, such as vehicles, stabilizers, or inert diluents, and converted by customary methods into suitable forms 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 such as acacia, cornstarch, gelatin, with disintegrating agents such as cornstarch, potato starch, alginic acid, or with a lubricant such as stearic acid or magnesium stearate.
[00031] Examples of suitable oily vehicles or solvents are vegetable or animal oils such as sunflower oil or fish-liver oil. Preparations can' be effected both as dry and as wet granules. For parenteral administration (subcutaneous, intravenous, intraarterial, or intramuscular injection), the active ingredients 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 adjuvants. 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] In addition, 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.
[00033] An active component which, in one embodiment is the plasma isolated from a vitiligo patient, or in another embodiment, from a melanoma patient in which antibodies to melanoma antigens are identified, 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), 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 ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like. [O0O34J In one embodiment, the plasma isolated from a vitiligo patient, or in another embodiment, from a melanoma patient in which antibodies to melanoma ant jgens • are identified, is administered in a therapeutically effective amount The actual amount administered, and the rate and time-course of administration, will depend in one embodiment, on the nature and severity of the condition being treated. Prescription of treatment, e.g. decisions on dosage, timing, etc., is within the responsibility of general practitioners or specialists, and typically takes account of the disorder to be treated, the condition of the individual patient, the site of delivery, the method of administration and other factors known to practitioners. Examples of techniques and protocols can be found in Remington's Pharmaceutical Sciences.
[00035] Alternatively, targeting therapies may be used in another embodiment, to deliver the plasma compositions described herein, more specifically to certain types of cell, by the use of targeting systems such as antibodies or cell specific ligands. Targeting may be desirable in one embodiment, for a variety of reasons, e.g. if the agent is unacceptably toxic, or if it would otherwise require too high a dosage, or if it would not otherwise be able to enter the target cells.
[00036] The compositions described herein, are formulated in one embodiment for oral delivery, wherein the active compounds which in one embodiment is plasma isolated from a vitiligo patient, or in another embodiment, from a melanoma patient in which antibodies to melanoma antigens are identified, may be incorporated with excipients and used in the form of ingestible tablets, buccal tables, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. The tablets, troches, pills, capsules and the like may also contain the following: a binder, as gum tragacanth, acacia, cornstarch, or gelatin; excipients, such as dicalcium phosphate; a disintegrating agent, such as corn starch, potato starch, alginic acid and the like; a lubricant, such as magnesium stearate; an anticoagulant, such as sodium citrate or any of the whole blood anticoagulant-preservative solution such as ACD, CPD, CPD-Al, Adsol and the like; and a sweetening agent, such as sucrose, lactose or saccharin may be added or a flavoring agent, such as peppermint, oil of wintergreen, or cherry flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar, or both. Syrup of elixir may contain the active compound sucrose as a sweetening agent methyl and propylparabens as preservatives, a dye and flavoring, such as, cherry or orange flavor. In addition, the active compounds may be incorporated into sustained-release, pulsed release, controlled release or postponed release preparations and formulations [00037] 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, ligands or antigens or coupled to ligands of tissue-specific receptors.
[00038] In one embodiment, the composition described herein, or the preparation used in the methods described herein, can be delivered in a controlled release system. For example, the plasma isolated from a vitiligo patient, or.in another embodiment, from a melanoma patient in which antibodies to melanoma antigens are identified, may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, coHoidosomes, polymerosomes or other modes of administration. In one embodiment, a pump may be used (see Langer, supra; Sefion, 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 another embodiment, a controlled release system can be placed in proximity to the therapeutic target, i.e., the melanoma site, 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). Other controlled release systems are discussed in the review by Langer (Science 249:1527-1533 (1990).
[00039] Such compositions are in one embodiment liquids or lyophilized 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), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite), 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, complexation 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, microemulsϊons, 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 routes of administration, including parenteral, pulmonary, nasal, and oral.
(00040] In another embodiment, the compositions of this invention comprise one • or more, pharmaceutically acceptable carrier materials.
[00041] In one embodiment, the carriers for use within such compositions are biocompatible, and in another embodiment, biodegradable. In other embodiments, the formulation may provide a relatively constant level of release of one active component. In other embodiments, however, a more rapid rate of release immediately upon administration may be desired. In other embodiments, release of the plasma isolated from a vitiligo patient, or in another embodiment, from a melanoma patient in which antibodies to melanoma antigens are identified, may be event-triggered. The events triggering the release of , the plasma isolated from a vitiligo patient, or in another embodiment, from a melanoma patient in which antibodies to melanoma antigens are identified, may be the same in one embodiment, or different in another embodiment. Events triggering the release of the active components may be exposure to moisture in one embodiment, lower pH in another embodiment, or temperature threshold in another embodiment. The formulation of such compositions is well within the level of ordinary skill in the art using known techniques. Illustrative carriers useful in this regard include microparticles of poly<lactide- co-glycolide), polyacrylate, latex, starch, cellulose, dextran and the like. Other illustrative postponed- release carriers include supramolecular biovectors, which comprise a non-liquid hydrophilic core (e.g., a cross-linked polysaccharide or oligosaccharide) and, optionally, an external layer comprising an amphiphilic compound, such as phospholipids. The amount of active compound contained in one embodiment, within a sustained release formulation depends upon the site of administration, the rate and expected duration of release and the nature of the condition to be treated suppressed or inhibited.
[00042] In one embodiment, the plasma isolated from a vitiligo patient, or in another embodiment, plasma from a melanoma patient is isolated from a single patient, or from a pool of patients. In one embodiment, blood is collected into a container that already has an appropriate anticoagulant, or anticoagulant-preservative solution in it and stored for later separation. The separated plasma is then frozen for later use as an active agent in the compositions and methods as described herein. In one embodiment, the isolated plasma is frozen at a rate that ensures the viability of the components. In another embodiment, following the freezing of the plasma, the frozen plasma is further lyophilized. [00043] In one embodiment, the plasma isolated from a melanoma patient in which antibodies to melanoma antigens such as HMW-MAA or tyrosinase are identified, is used in the methods and compositions of the invention. In one embodiment, melanoma is immunogenic and can activate host immune responses capable of controlling the disease and, causing tumor regression. •
[00044] In one embodiment, the term "antibody" include 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 (VL) linked to a variable heavy chain (VH) 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 (VH) and light chain variable domains (VL) which together comprise Fv or scFv, with the addition, in another embodiment, of a heavy chain constant domain (CHI) and a light chain constant domain (CL)- The four domains (i.e., VH - CHI and VL - CL) comprise an Fab. Complete antibodies are obtained in one embodiment, from such a library by replacing missing constant domains once a desired VH - VL combination has been identified.
[00045] In one embodiment, the plasma is isolated from melanoma patients wherein the melanoma tumour remains localized for long periods with no detectable spread (stage I melanoma) and comprises antibodies able to cause the death of autologous tumour cells. In one embodiment, the plasma isolated from a melanoma patient in which antibodies to melanoma antigens are identified, are taken from a melanoma patient or pool of patients where the disease is at an early stage of the disease or from a patient or pool of patients in which the disease is at an advanced stage. A person skilled in the art will recognize that at each stage of the melanoma, different melanoma-associated antigens (MAA's) may be present, which will create a different profile of circulating antibodies in the isolated plasma. In one embodiment, the isolated plasma is taken from a patient or pool of patients where the tumour is a primary tumor at stage I. In one embodiment, plasma is isolated from melanoma patients whose lesions are excised and are presumed cured. [00046] The term disease stage refers in one embodiment to the different stages of melanoma cancer. Stage I is divided into stages IA and IB. In stage IA, the tumor is not more than 1 millimeter thick, with no ulceration. The tumor is in the epidermis (outer layer of skin) and upper layer of the dermis (inner layer of skin). In stage IB, the tumor is either not more than 1 millimeter thick, with ulceration, and may have spread into the dermis or the tissue below the skin; or 1 to 2 millimeters thick, with no ulceration. Stage II is divided into stages HA, IIB, and HC. In stage HA, the tumor is either 1 to 2 millimeters thick, with ulceration; or 2 to 4 millimeters thick, with no ulceration. In stage πB, the tumor is either 2 to 4 millimeters thick, with ulceration; or more than 4 millimeters thick, with no ulceration. In stage II C, the tumor is more than 4 millimeters thick, with ulceration. The tumor may be of any thickness, with or without ulceration, and may have spread to 1 or more nearby lymph nodes. Stage III is divided into stages IIIA, IUB, and IHC. In stage IHA, the cancer may have spread to as many as 3 nearby lymph nodes, but can be seen only with a microscope. In stage HIB, the cancer has spread to as many as 3 lymph nodes and may not be visible without a microscope, or has satellite tumors (additional tumor growths within 1 inch of the original tumor) and has not spread to lymph nodes. In stage HIC, the cancer either has spread to as many as 4 or more lymph nodes and can be seen without a microscope, or has lymph nodes that may not be moveable, or has satellite tumors and may have spread to lymph nodes.
[00047] In one embodiment, the plasma used in the compositions and methods described herein, is taken from a patient or pool of patients wherein the Vitiligo developed prior to the isolation of plasma.
[00048] In one embodiment, the compositions described herein, are used to treat melanoma in a subject. In another embodiment, the invention provides a method for treating melanoma in a subject, comprising the step of administering to the subject a preparation comprising plasma isolated from a vitiligo patient.
[00049] In one embodiment, the term "treat" or "treating" refers to suppressing, inhibiting, increasing lag time before development of symptoms, reducing or alleviating symptoms associated with melanoma, extending the periods at a single disease stage, preventing or inhibiting metastases, reducing number and size of metastases loci and the like. In one embodiment, the plasma is isolated from a melanoma patient whose melanoma metastasized and as a response to treatment, developed Vitiligo, at which point plasma was isolated and used for the compositions described herein. In one embodiment, that plasma may be later used to suppress, inhibit or reduce the metastases. [00050] In one embodiment, the methods described herein are used with at least one other treatment ' modality, prior to, during or after the administration of the preparation of plasma isolated from a vitiligo • patient, a melanoma patient where antimelanoma antibodies were identified, or a melanoma patient where vitiligo developed prior to isolation of plasma. In one embodiment the other treatment modality is" chemotherapy, immunotherapy, radiation therapy, surgery or a combination thereof. In one embodiment, the other treatment modality is surgery, and the method comprises in one embodiment further removing surgically the melanoma prior to, during or after the administration of the preparation plasma isolated* from a vitiligo patient a melanoma patinet where antimelanoma antibodies were identified, or. a melanoma patient where vitiligo developed prior to isolation of plasma.
[O0O5I] In one embodiment, the plasma donor for the compositions and methods described herein is a vitiligo patient, or a Vitiligo patient who has a diffuse vitiligo; a patient in which the vitiligo developed in response to melanoma; a melanoma patient, a melanoma patient where anti-melanoma antibodies were identified; or a combination thereof in other embodiments. In one embodiment, the donor is a pool of donors.
[00052] The term "about" as used herein means in quantitative terms plus or minus 5%, or in another embodiment, plus or minus 10%, or in another embodiment plus or minus 15%, or in another embodiment plus or minus 20%. , •
[00053] The following examples are presented in order to more fully illustrate the preferred embodiments of the invention. They should in no way be construed, however, as limiting the broad scope of the invention.
EXAMPLES
Example 1: Vitiligo Plasma for the Treatment of Melanoma in Mouse Models
[00054] These experiments are done to evaluate the anti tumor effect of plasma obtained from individual and pooled vitiligo and controls subjects in the B16-F10 experimental metastasis model in syngeneic mice. Animals
[00055] Female C57BL/6J mice are purchased at 6-8 wks of age at study initiation. Administration of the plasma takes place following veterinary Inspection and 1-Wk acclimatization, marking and randomization.
Experimental Procedures
[00056] Over a 4-wk experimental duration, purchase, propagation and preparation for injection of tumor cells takes place. Intravenous injection of tumor cells is carried out, while daily morbidity and mortality are checked Body weight measurements are done twice weekly. Vitiligo sourced plasma is injected intraperitoneally once daily (including weekends). Mice are euthanized, their lungs excised, weighed and fixated, followed by metastasis count.
[00057] The following table describes the treatment grouping done:
Figure imgf000017_0001
[00058] Results show that pooled plasma from donors exhibiting diffuse vitiligo shows a marked decrease in the number and size of melanoma metastases, as well as at least a tumoristatic effect on the metastasized melanoma tumors.
Example 2: Vitiligo Plasma for the Treatment of Human Melanoma in a Mouse Model
[00059] These experiments are done to evaluate the anti tumor effect of plasma obtained from individual and pooled vitiligo and controls subjects, in a human melanoma experimental metastasis model in SCID mice.
Animals [00060] Female CB17-SCID mice are purchased at 6-8 wks of age at study initiation. Administration of the plasma takes place following veterinary Inspection and 1-Wk acclimatization, marking and randomization.
Experimental Procedures
[00061] Over a 4-vvk experimental duration, purchase, propagation and preparation for injection of tumor cells takes place. Intravenous injection of human melanoma A375 tumor cells is carried out, while daily morbidity and mortality are checked. Body weight measurements are done twice weekly. Vitiligo sourced plasma is injected intraperitoneally once daily (including weekends). Mice are euthanized once the first mouse dies, or for humane reasons, their lungs excised, weighed and fixated in formalin or Bulin Solution, followed by metastasis count.
[00062] The following table describes the Tumor cells dosing validation -
Figure imgf000018_0001
[00063] The following table describes the Grouping Protocol
Figure imgf000018_0002
[00064] Results show that pooled plasma from donors exhibiting diffuse vitiligo shows a marked decrease in the number and size of melanoma metastases, as well as at least a tumoristatic effect on the metastasized melanoma tumors.
Example 3; Effect of Vitiligo Plasma on Mouse Melanoma cells
[00065] These experiments are done to evaluate the anti tumor metastases effect of plasma obtained from individual and pooled vitiligo and control subjects in the B16-F10 experimental metastasis model in syngeneic mice.
Animals
[00066] Female C57BL/6J mice are purchased at 6-8 wks of age at study initiation. Administration of the plasma takes place following veterinary Inspection and 1-Wk acclimatization, marking and randomization.
Experimental Procedures
[00067] Over a 4-wk experimental duration, purchase, propagation and preparation for injection of tumor cells takes place. Intravenous injection of tumor cells is carried out, while daily morbidity and mortality are checked. Body weight measurements are done twice weekly. Vitiligo sourced plasma is injected 7 days following the injevtion of tujmor cells and is done intraperitoneally once daily (including weekends). Mice are euthanized, their lungs excised, weighed and fixated, followed by metastasis count.
[00068] The following table describes the treatment grouping done:
Figure imgf000019_0001
Figure imgf000020_0001
[00069] Results show that pooled plasma from donors exhibiting diffuse vitiligo shows a marked decrease in the number and size of melanoma metastases, as well as at least a tumoristatic effect on the metastasized melanoma tumors.
Example 4: Vitiligo Plasma Effects on Human Melanoma Cells
[00070] These experiments are done to evaluate the anti tumor effect of plasma obtained from individual and pooled vitiligo and controls subjects, in a human melanoma experimental metastasis model in SCID mice.
Animals
[00071] Female CB17-SCID mice are purchase at 6-S wks of age at study initiation. Administration of the plasma takes place following veterinary Inspection and 1-Wk acclimatization, marking and randomization.
Experimental Procedures
[00072] Over a 4-wk experimental duration, purchase, propagation and preparation for injection of tumor cells takes place. Intravenous injection of human melanoma A375 tumor cells is carried out, while daily morbidity and mortality aie checked Body weight measurements are done twice weekly. Vitiligo sourced plasma is injected intraperitoneally once daily (including weekends) starting 8 days after the tumor cell injection, and are continued for 17 days thereafter. Mice are euthanized at the 17lh day, their lungs excised, weighed and fixated in formalin or Bulin Solution, followed by metastasis count.
[00073] The following table describes the Grouping Protocol
Figure imgf000020_0002
Figure imgf000021_0001
[00074] Results show that pooled plasma from donors exhibiting diffuse vitiligo shows a marked decrease in the number and size of melanoma metastases, as well as at least a tumorϊstatic effect on the metastasized melanoma tumors.
Example 5; Vitileo Plasma Administered for the Treatment of Patients with Stage III or Stage IV
Inoperable Melanoma
[00075] The purpose of the example is to evaluate whether plasma obtained from donors with Vitiligo, can be administered for the treatment of patients with stage III or IV inoperable melanoma. The phase 1 part of the study is designed to determine whether the Vitiligo-derived plasma can be safely administered, and the phase 2 part of the study is designed to provide additional safety data and to gain an understanding of whether administrating Vitiligo plasma can improve the clinical outcome for melanoma patients versus the currently available data.
[00076] This is a randomized, multicenter, study where Vitiligo plasma is administered as an intravenous infusion on consecutives days followed by a rest period for a treatment cycles of 28 days.
[00077] 1st cohort - 5 patients are randomized to each of the 3 treatment doses (100/ 200/ 400 mg/kg bodyweight) — total of 15 patients. Patients are randomized to 1 of the 3 plasma dose levels. Each patient is infused twice every 28 eight days and is followed for 28 days post the last infusion to detect potential safety issues. The 2nd cohort does not start accrual, prior to a satisfactory safety analysis from the 1st cohort. Nevertheless, the 1st cohort patients continue treatment for up to the copmetϊon of 6 cycles (each cycle being 28 days) unless the patient develops progressive disease or intolerable toxicity. When there is evidence of clinical benefit (stable disease or tumor response defined as partial or complete response), patients may continue treatment beyond 6 cycles so long as toxicity remains within acceptable limits; these patients are taken off study after cycle 6, but receive treatment under compassionate access while following the same study schedule. Patients are replaced if they do not complete at least treatment 2 cycles and have at least one post-treatment disease assessment performed (unless there is a clear evidence of clinical progression after two (2) cycles).
[00078] 2nd cohort — Upon positive results from the safety analysis of the first cohort, 5 patients are randomized to each of the three above described treatment doses to a total of 15 patients. Patients' treatments are administered similarly as to the 1st cohort. Patients are replaced under the same conditions as of the 1st cohort. Although recruitment is not suspended until after enrollment is completed for this cohort, a safety analysis is done to include the first 30 patients, including two infusions each and a follow up period.
[00079] 3rd cohort - Additional 9 patients are randomized to each of the 3 treatment doses (total of 27 patients). Patients' treatment is administered as described above. A Simon two-stage designs is used to evaluate the efficacy of the treatment, after 6 cycles at each of the above described doses. Patients are replaced if they do not complete at least 2 cycles of treatment and have at least 1 post-treatment disease assessment performed (unless there is clear evidence of clinical progression after two (2) cycles).
[00080] 4th cohort — Additional 21 patients (maximum of 63 patients) are randomized to those treatment arms (doses, as descibed above) which have shown at least one response (as desciribed above) at the 3rd cohort stage and are treated as described above. At the completion of the 4th cohort, if four or more responses are observed for any dose level, then it is concluded that this dose level is a candidate for further clinical study. Patients are replaced in a similar method as in previous cohorts.
[00081] Results indicate that vitilogo plasma is a safe and effective compound for the treatment of stage III or rv inoperable melanoma.
[00082] 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 possibte-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 following claims appended hereto.

Claims

What is claimed is:
1. A composition for the treatment of melanoma in a subject, comprising:, plasma isolated from a vitiligo patient.
2. The composition of claim 1, wherein the vitiligo patient has a diffuse vitiligo.
3. The composition of claim 1, wherein the vitiligo patient is a patient in which the vitiligo developed in response to melanoma.
4. The composition of claim 1, further comprising a pharmaceutically acceptable carrier, excipient, flow agent, processing aid, diluent or a combination thereof.
5. The composition of claim 1, wherein said composition is in a form suitable for oral, intravenous, intratumoral, intraaorterial, intramuscular, subcutaneous, parenteral, transmucosal, transdermal, or topical administration.
6. The composition of claim 4, 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 4, 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 plasticizer, an emulsifier, a stabilizing agent, a viscosity increasing agent, a sweetener, a film forming agent, or a combination thereof.
9. The composition of claim 4, wherein said composition is a controlled release composition.
10. The composition of claim 4, 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, wherem said composition is a solid dosage form.
S 13. The composition of claim 1 , wherein the plasma is collected from a single Vitiligo patient, a pool of Vitiligo patients, a melanoma patient, a melanoma patient in which Vitiligo developed as a response to treatment, a pool of melanoma patients in which Vitiligo developed as a response to treatment or a combination thereof.
o 14. A composition for the treatment of melanoma in a subject, comprising: plasma isolated from a melanoma patient.
15. The composition of claim 14, wherein the plasma comprises anti-melanoma antibodies.
5 16. The composition of claim 14, wherein the melanoma patient developed Vitiligo prior to the isolation of plasma.
17. The composition of claim 15, wherein the plasma is isolated from a single melanoma patient or a pool of melanoma patients. 0
18. A method for treating melanoma in a subject, comprising the step of administering to the subject a preparation comprising plasma isolated from a vitiligo patient.
19. The method of claim 18, further comprising the step of subjecting the subject to at least one other 5 treatment modality, prior to, during or after the administration of the preparation of plasma isolated from a vitiligo patient.
20. The method of claim 19, wherein the other treatment modality is chemotherapy, immunotherapy, radiation therapy, surgery or a combination thereof.
30
21. The method of claim 20, further comprising surgically removing the melanoma prior to, during or after the administration of the preparation plasma isolated from a vitiligo patient.
22. The method of claim 18, wherein the vitiligo patient has a diffuse vitiligo.
23. The composition of claim 18, wherein the vitiligo patient is a patient in which the vitiligo developed in response to melanoma.
24. The method of claim 18, wherein the plasma is collected from a single Vitiligo patient, a pool of Vitiligo patients, a melanoma patient in which Vitiligo developed as a response to treatment, a pool of melanoma patients in which Vitiligo developed as a response to treatment, or a combination thereof.
25. The method of claim 18, wherein treating is inhibiting, suppressing, reducing incidence of, reducing the severity of, or a combination thereof.
26. A method for treating melanoma in a subject, comprising the step of administering to the subject a preparation comprising plasma isolated from a melanoma patient.
27. The method of claim 26, wherein the plasma comprises anti-melanoma antibodies.
28. The method of claim 26, wherein the melanoma patient developed Vitiligo prior to the isolation of plasma.
29. The method of claim 26, wherein the plasma is isolated from a single melanoma patient or a pool of melanoma patients.
30. An article of manufacture comprising a suitable packaging material and plasma isolated from a vitiligo patient.
31. The article of claim 30, wherein the vitiligo patient has a diffuse vitiligo.
32. The article of claim 30, wherein the vitiligo patient is a patient in which the vitiligo developed in response to melanoma
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5731325A (en) * 1995-06-06 1998-03-24 Andrulis Pharmaceuticals Corp. Treatment of melanomas with thalidomide alone or in combination with other anti-melanoma agents

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5731325A (en) * 1995-06-06 1998-03-24 Andrulis Pharmaceuticals Corp. Treatment of melanomas with thalidomide alone or in combination with other anti-melanoma agents

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
FISHMAN ET AL.: 'Autoimmunity and Cancer - Beneficial relationships: a new concept for the production of human monoclonal antibodies' INTL. J. OF ONCOLOGY vol. 10, 1997, pages 901 - 904 *

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