WO2013119957A1 - Réduction de poids par inactivation de médiateurs orexigéniques gastriques produisant des cellules - Google Patents

Réduction de poids par inactivation de médiateurs orexigéniques gastriques produisant des cellules Download PDF

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WO2013119957A1
WO2013119957A1 PCT/US2013/025353 US2013025353W WO2013119957A1 WO 2013119957 A1 WO2013119957 A1 WO 2013119957A1 US 2013025353 W US2013025353 W US 2013025353W WO 2013119957 A1 WO2013119957 A1 WO 2013119957A1
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ghrelin
targeting moiety
patient
target tissue
photosensitizing agent
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PCT/US2013/025353
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English (en)
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Neil H. Riordan
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Aidan Research And Consulting, Llc
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Publication of WO2013119957A1 publication Critical patent/WO2013119957A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6847—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a hormone or a hormone-releasing or -inhibiting factor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/26—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against hormones ; against hormone releasing or inhibiting factors

Definitions

  • the technology pertains to the area of weight loss interventions. More specifically, the technology pertains to methods of inactivating cells producing appetite inducing stimuli termed orexigenic mediators. More specifically, the technology deals with methods of inactivating such cells using photoceutical or drug-based approaches.
  • Roux-en-Y gastric bypass which reduces stomach volume by surgically forming a small pouch along the lesser curvature and rerouting of nutrient flow from the upper portion of the stomach into the mid- to distal jejunum. Essentially this results in the majority of the stomach, the duodenum, and proximal jejunum to be bypassed (Butner, K.L., Nickols-Richardson, S.M., Clark, S.F., Ramp, W.K., and Herbert, W.G. A review of weight loss following Roux-en-Y gastric bypass vs. restrictive bariatric surgery: impact on adiponectin and insulin.
  • one embodiment presented herein is a method of treating obesity and related disorders in a patient.
  • the method can include, for example, administering to the patient a therapeutically effective amount of a targeting moiety conjugate, the conjugate comprising a targeting moiety that localizes to ghrelin-producing cells; and a photosensitizing agent; and irradiating at least a portion of the target tissue of the patient such that production of ghrelin in the target tissue is reduced.
  • the method can further include identifying a patient in need of obesity treatment.
  • the target tissue can be any suitable tissue, including tissue that produces or is involved in the production of ghrelin, for example, oxyntic gastric mucosa; the gastric ruggae; the mucosa of the duodenum; the stomach fundus; the stomach body; and the stomach antrum.
  • tissue that produces or is involved in the production of ghrelin for example, oxyntic gastric mucosa; the gastric ruggae; the mucosa of the duodenum; the stomach fundus; the stomach body; and the stomach antrum.
  • the ghrelin-producing cells can be, for example, P/Dl cells; gastric X/A cells; gastric X/ A- like cells; X-type endocrine cells; gastric neuroendocrine cells; cells found in the oxyntic glands of the stomach fundus; cells of the stomach fundus; or cells of the stomach ruggae.
  • the targeting moiety can be, for example, a ghrelin- specific antibody or binding fragment thereof. In certain aspects, the targeting moiety can be, for example, an antibody against an epitope found predominantly on ghrelin- producing cells. In certain aspects, the targeting moiety and the photosensitizing agent can be the same. In certain aspects, the targeting moiety and the photosensitizing agent can be different different. In certain such aspects, the photosensitizing agent associates preferentially with ghrelin-producing cells. [0009] In certain aspects, the irradiating can be performed using light, the light having a waveband or wavelength corresponding at least in part to the characteristic light absorption waveband of the photosensitizing agent. In certain aspects, the intensity of the light used may be selected such that the ghrelin-producing cells are destroyed or impaired and the non-target tissue through which the light passes remains undamaged.
  • the irradiating can include for example endoscopic delivery of light to the target tissue.
  • the irradiating may include for example transcutaneous illumination.
  • the irradiating further can include targeting the ghrelin-producing cells by visualization using an endoscope-like device operably connected to a light-emitting source capable of activating the photosensitizing agent.
  • the device may include, for example, one or more of: an illuminating segment; and a visualization segment for the operator to visualize gastric anatomy.
  • the photosensitizing agent can be, for example, 5-delta-aminolevulinic acid, phthalocyanine, a porphyrin, a chlorin, a purpurin, an enlarged porphyrin, a naphthalocyanine, a phthalocyanine, a platyrin, a porphycene, a texaphyrin, a verdin, merocyanine 540, a xanthene, a cationic cyanic dye, a chalcogenapyrylium dye, a phenothiazinium derivative, tetracycline, berbine sulphate, acridine orange, and fluorescein.
  • the photosensitizing agent can be, for example, 5-delta-aminolevulinic acid, phthalocyanine, a porphyrin, a chlorin, a purpurin, an enlarged porphyrin, a naphthalocyanine,
  • the porphyrin may comprises a hematoporphyrin derivative such as Photofrin I or Photofrin II.
  • the xanthene may comprise Rhodamine 123 6 G&B.
  • administering can comprise intravenous administration or oral administration, for example.
  • the method can include for example: identifying a patient in need of obesity or weight treatment; administering to the patient a therapeutically effective amount of a photosensitizing agent; and irradiating at least a portion of the target tissue of the patient such that production of ghrelin in the target tissue is reduced.
  • the method further may include, for example, monitoring plasma ghrelin levels in the patient.
  • the method of administration of the photosensitizing agent can be oral administration, for example. Any other administration can be used to provide the photosensitizing agent to the patent so the agent can contact ghrelin-producing cells or cells otherwise involved in controlling the production of ghrelin.
  • the targeting moiety conjugate can include, for example, a targeting moiety that localizes to ghrelin- producing cells and a photosensitizing agent.
  • the targeting moiety conjugate can be an antibody, for example, an anti-ghrelin or anti-chromogranin A antibody.
  • the photosensitizing agent may be a photoreactive compound, for example, one or more of 5-delta-aminolevulinic acid, phthalocyanine, a porphyrin, a chlorin, a purpurin, an enlarged porphyrin, a naphthalocyanine, a phthalocyanine, a platyrin, a porphycene, a texaphyrin, a verdin, merocyanine 540, a xanthene, a cationic cyanic dye, a chalcogenapyrylium dye, a phenothiazinium derivative, tetracycline, berbine sulphate, acridine orange, and fluorescein.
  • the porphyrin can be a hematoporphyrin derivative such as Photofrin I or Photofrin II
  • the xanthene can be, for example, Rhodamine 123 6 G&B
  • Also presented herein is a method of reducing ghrelin production, comprising contacting a ghrelin producing cell with a photosensitizing agent; and exposing the photosensitizing agent to an energy that results in a reaction whereby the compound acts upon the cell to reduce ghrelin production.
  • the ghrelin producing cell is in a tissue.
  • the contacting step and/or exposing step can performed ex vivo or in vivo.
  • Roux-en-Y gastric bypass which reduces stomach volume by surgically forming a small pouch along the lesser curvature and rerouting of nutrient flow from the upper portion of the stomach into the mid- to distal jejunum.
  • current approaches are too invasive.
  • many obese patients are not sufficiently obese to qualify for existing surgical or other bariatric procedures.
  • there remains a great need to develop less invasive procedures which can help a wider range of patients suffering from obesity and related disorders.
  • the medical devices, compositions of matter, and procedures presented herein are useful for one or more of treating obesity, reducing appetite, preventing weight gain and promoting weight loss through selective or semi- selective inactivation of gastric cells producing appetite stimulating mediators.
  • one embodiment presented herein is a method of treating obesity and related disorders in a patient.
  • the method can include, for example, identifying a patient in need of obesity treatment; administering to the patient a therapeutically effective amount of a targeting moiety conjugate, the conjugate comprising a targeting moiety that localizes to ghrelin-producing cells and a photosensitizing agent; and irradiating at least a portion of the target tissue of the patient such that production of ghrelin in the target tissue is reduced.
  • a method of treating obesity and related disorders in a patient may include, for example, identifying a patient in need of obesity treatment; administering to the patient a therapeutically effective amount of a photosensitizing agent; and irradiating at least a portion of the target tissue of the patient such that production of ghrelin in the target tissue is reduced.
  • the method further can include, for example, monitoring plasma ghrelin levels in the patient.
  • the method of administration of the photosensitizing agent can be by oral administration, intravenous administration, injection or nasogastric tube, for example.
  • photodynamic therapy refers to a medical treatment that uses a photosensitizing drug and a light source to activate the applied drug. The result is an activated molecule that can destroy or impair nearby cells.
  • PDT can have at least three steps: First, a light-sensitizing drug (photosensitizer) is applied or administered to a target tissue. Second, there is an incubation period of minutes to days (including any period or subrange therein). Finally, the target tissue is then exposed to a specific wavelength or waveband of light that then activates the photosensitizing medication.
  • a light-sensitizing drug photosensitizer
  • a photosensitizing agent is applied or administered to a patient in such a way that the photosensitizing agent comes in contact with target cells within a target tissue. Then, at least a portion of the target tissue is irradiated.
  • target cells or target tissues refer to those cells or tissues, respectively that are intended to be impaired or destroyed by PDT delivered in accordance with the present disclosure.
  • Target cells or target tissues can take up or link with the photosensitizing agent, and, when sufficient light radiation of the waveband corresponding to the characteristic waveband of the photosensitizing agent is applied, these cells or tissues are impaired or destroyed.
  • the stomach can be at least one target tissue.
  • the target tissue can include, but is not limited to, the fundus of the stomach, lining of the stomach, or the ruggae of the stomach.
  • the target tissue can be, for example, oxyntic gastric mucosa; the gastric ruggae; the mucosa of the duodenum; the mucosa of the stomach fundus; the mucosa of the stomach body; and the mucosa of stomach antrum.
  • any tissue that contains ghrelin- producing cells can be a target tissue.
  • ghrelin-producing cells have been detected in relatively low amounts in the heart, kidney, pituitary, hypothalamus and in other parts of the gastrointestinal tract besides the stomach and duodenum.
  • the target cell can be a neuroendocrine cell of the stomach mucosa.
  • the target cell can be a chromogranin A (parathyroid secretory protein 1 or CHGA)-immunoreactive endocrine cell located in the mucosal layer of the stomach.
  • the target cell is a ghrelin- producing cell.
  • the term ghrelin-producing cell refers to a cell that produces and/or secretes the orexigenic hormone ghrelin.
  • the RNA encoding the ghrelin peptide is expressed in the target cell.
  • the ghrelin peptide is synthesized in the target cell. In some preferred embodiments, the ghrelin peptide is post-translationally modified within the target cell. Even more preferably, the target cell secretes ghrelin.
  • the ghrelin-producing cells can be, for example, P/Dl cells; gastric X/A cells; gastric X/A- like cells; X-type endocrine cells; gastric neuroendocrine cells; or any other CHGA- immunoreactive cells found in the oxyntic glands of the stomach fundus or ruggae.
  • a target cell may be a ghrelin- producing cell.
  • ghrelin-producing cell may be of interest.
  • Ghrelin is a hormone secreted by glands containing parietal cells located principally in the mucosal lining of the stomach. In the oxyntic mucosa, ghrelin is produced by neuroendocrine cells (A-like or X/A-like cells in the rat and mouse, and P/Dl cells in humans) in the fundus, and is secreted into the circulation.
  • non-target tissue and non-target cells are all the tissues and cells of a mammal that are not intended to be impaired, damaged, or destroyed by the treatment method rendered in accord with the present disclosure.
  • These non-target tissues and/or cells can include, but are not limited to, cells and tissues that do not produce ghrelin, and other normal tissue, not otherwise identified to be targeted.
  • a cell or tissue that produces ghrelin may be a non-target cell.
  • a part of the stomach produces ghrelin, it may be considered a non-target tissue.
  • a particular cell is a ghrelin-producing cell, it may be considered a non-target cell in certain embodiments.
  • the term “destroy” can mean to kill or irreversibly damage the desired target cell.
  • the term impair means to change the target cell in such a way as to interfere with the production and/or secretion of ghrelin, for example, to reduce production by an amount such as 5 -100 .
  • Target cells are understood to be impaired or destroyed even if the target cells are ultimately disposed of by macrophages.
  • a photosensitizing agent is applied to a target tissue.
  • the photosensitizing agent is administered such that the drug selectively binds to or is selectively taken up by a target tissue or cell.
  • the terms selectively binds, preferentially binds, preferentially associates, preferential association and like terms describe the preferential association between a photosensitizing agent and target tissue or cell. More specifically, preferential association by photosensitizing agent with target tissue can result in the destruction or inactivation of a target tissue or target cell upon irradiation.
  • the non-target tissue is inactivated or damaged to a lesser extent, for example where the photosensitizing agent clears more rapidly from non-target cells or tissues than it does from target tissue.
  • the photosensitizing agent binds or is taken up by a target cell with greater affinity compared to a non-target cell.
  • the photosensitizing agent binds with 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000 or more than 1000 times greater affinity compared to a non-target cell.
  • Selective binding may be a property of the photosensitizing agent itself.
  • the photosensitizing agent may preferentially associate with a target tissue, or cell type absent any additional targeting moiety.
  • preferential association is achieved by conjugating the photosensitizing agent with a targeting moiety.
  • preferential association is achieved by forming a non-covalent complex between the photosensitizing agent and a targeting moiety.
  • the photosensitizing agent may not selectively bind to target cells.
  • the administration of the drug can be performed in ways so as to selectively apply the photosensitizing agent to a particular tissue of interest.
  • the photosensitizing agent can be administered orally or directly to the stomach, for example via a nasogastric tube, so that the drug selectively contacts the stomach mucosa, but not other parts of the body.
  • the step of irradiating the target tissue provides a means of selectivity that allows the drug to become active in a selected tissue or cell.
  • the stomach fundus is the target tissue
  • the stomach fundus is irradiated using an endoscopic device that allows the fundus to be irradiated while leaving other parts of the stomach without irradiation.
  • targeting can be achieved through endoscopic photodynamic therapy to the stomach area associated with orexigenic mediator production subsequent to administration of a sensitizing agent such as 5-delta-aminolevulinic acid previously described (Rabenstein, T., May, A., Gossner, L., Manner, H., Pech, O., Gunter, E., Huijmans, J., Vieth, M., Stolte, M., and Ell, C. 2008. Invisible gastric carcinoma detected by random biopsy: long-term results after photodynamic therapy. Endoscopy 40:899-904, the content of which is hereby incorporated by reference in its entirety).
  • a sensitizing agent such as 5-delta-aminolevulinic acid previously described
  • the fundus area associated with high concentration of ghrelin producing cells may be targeted based on gross morphology.
  • One of skill in the art will understand that the amount of energy, directionality of energy and fluency of energy can be adjusted to induce partial inactivation of ghrelin production without inducing significant damage to non-ghrelin producing tissue.
  • targeting moieties that allow for precise targeting of photosensitive agents or drugs and compounds to specific target tissues or cells of a subject or patient. Targeting moieties thus allow for maximal cytotoxicity of the target tissue or cell, with minimal adverse side effects or collateral non-target tissue damage.
  • targeting moieties are conjugated to photosensitizing agents and allow for or enhance selective binding of the photosensitizing agent with a target cell.
  • targeting moiety refers to any natural or synthesized molecule that can target a photosensitizing agent to its target cell or tissue.
  • the targeting moiety can be a protein molecule containing an antigen-binding site.
  • targeting moieties include a full- length immunoglobulin molecule or any functional fragment, such as a variable domain fragment of a full-length immunoglobulin molecule, CDR regions, ScFv, Fab, F(ab)'2, or engineered antibody mimics or single domain binding moieties.
  • a particular targeting moiety may be selected in accordance with the desired target.
  • the targeting moiety can be selected to bind a cellular receptor or cell-surface antigen on a ghrelin- producing cell. Accordingly, in certain aspects, the targeting moiety maybe a ghrelin-specific antibody or binding fragment thereof. In certain other aspects, the targeting moiety is an antibody against an epitope found predominantly on ghrelin-producing cells.
  • Antibodies to ghrelin are commercially available and can be readily obtained by one of skill in the art.
  • anti-ghrelin monoclonal and polyclonal antibodies available from Phoenix Pharmaceuticals, Inc. (Belmont, CA) as well as from Santa Cruz Biotechnology Inc. (Santa Cruz, CA).
  • the targeting moiety may include, for example, a targeting molecule which is capable of being internalized within the cell.
  • the targeting moiety can be internalized through the cell penetrating action of a peptide conjugated thereto.
  • a peptide conjugated thereto Such peptides are referred to herein as membrane transporter peptides, and the like.
  • membrane transporter peptides or their active fragments, can be employed as the attached peptide.
  • the targeting moiety comprises a molecule such as an antibody, or binding fragment thereof. Either polyclonal or monoclonal antibodies can be used.
  • some such antibodies or their fragments preferably bind to their bind to their determinants with an affinity of 10 ⁇ 9 M or greater.
  • the antibody can comprise or be conjugated to a membrane transporter protein, or peptide fragment thereof.
  • a preferred membrane transporter fragment is a membrane translocation sequence (MTS) peptide.
  • MTS membrane translocation sequence
  • the targeting moiety may be any suitable natural or synthesized molecule that can target a photosensitizing agent to its target cell or tissue.
  • the targeting moiety can be a protein, a nucleic acid molecule, a synthetic organic compound or any other any suitable natural or synthesized molecule.
  • the targeting moiety and the photosensitizing agent are the same. In certain aspects, the targeting moiety and the photosensitizing agent are different molecules. In certain such aspects, the photosensitizing agent associates preferentially with ghrelin-producing cells, as described above.
  • the targeting moiety is in a conjugate that includes a photosensitizing agent conjugated to a targeting moiety that localizes to ghrelin-producing cells. Accordingly, a targeting moiety may be conjugated to one or more photosensitizing agents, forming a targeting moiety conjugate.
  • conjugated refers to any means of covalent or non- covalent attachment of a photosensitizing agents and a targeting moiety.
  • a targeting moiety may be covalently cross linked to a photosensitizing agent via direct crosslinking.
  • the targeting moiety and the photosensitizing agent are indirectly attached via non-covalent means.
  • the targeting moiety and the photosensitizing agent may be attached via a ligand-receptor binding pair. Examples of a suitable binding pair include but are not limited to: biotin-streptavidin, chemokine- chemokine receptor, growth factor-growth factor receptor, and antigen-antibody.
  • the term photosensitizing agent delivery system refers to a photosensitizing agent conjugate, which because of its conjugation, has increased selectivity in binding to a target tissue, target cells, or target composition.
  • the use of a photosensitizing agent delivery system is expected to reduce the required dose level of the conjugated photosensitizing agent, since the conjugate material is more selectively targeted at the desired tissue, cell, or composition, and less of it is wasted by distribution into other tissues whose destruction should be avoided.
  • ligand-receptor binding pairs including those known and those currently yet to be discovered. It will be appreciated that any ligand-receptor binding pair may be useful in practicing these methods, provided that the ligand-receptor binding pair demonstrates a specificity for the binding by the ligand to the receptor and further provided that the ligand-receptor binding pair permits the creation of a first conjugate comprising a first member of the ligand- receptor pair conjugated to an antibody or antibody fragment.
  • targeting moiety conjugates thus can take several forms.
  • the targeting moiety and photosensitizing agent are administered separately.
  • an antibody-biotin fusion is first administered to the target tissue. After sufficient time is allowed for binding of the targeting moiety to the target cells, and for clearance of the targeting moiety from non-target tissue, the other member of the targeting moiety pair is administered.
  • the photosensitizing agent linked to streptavadin is administered. The streptavadin-linked photosensitizing agent will associate with the biotin-linked antibody at the target cell, and all other photosensitizing agents are cleared from non-target tissues.
  • the targeting moiety and the photosensitizing agent are conjugated prior to administration.
  • Methods of chemical conjugation between antibodies and reactive and/or toxic compounds are well-known by those of skill in the art.
  • antibodies can be modified utilizing techniques that are well known in the art. See e.g., Vitetta Immunol Today 14:252 (1993). See also U.S. Patent No. 5,194,594; Hermanson GT Bioconjugate Techniques New York: Academic Press (1996); Aslam M, Dent AH. Bioconjugation: protein coupling techniques for the biomedical sciences. Houndsmills, England: Macmillan Publishers; (1999); Wong SS. Chemistry of protein conjugation and crosslinking Boca Raton, FL: CRC Press; (1991). The content of each of the above references is hereby incorporated by reference in its entirety.
  • the waiting time can allow for incubation of the photosensitizing agent with the target tissue. Incubation can be used to allow the photosensitizing agent to localize and/or bind to the target tissue.
  • the incubation time for the photosensitizing agent to localize to the target tissue is about 0.01, 0.10, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50 minutes or more, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 24 hours or more, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days or more.
  • a photosensitizing agent can be used that clears the non-target tissue of the skin in a short amount of time and is retained in the targeted tissue for a relatively longer period of time.
  • the targeting moiety can specifically localize and bind the photosensitizing agent to the target tissue, allowing it to remain in the target tissue because of preferential binding to the target tissue.
  • photosensitizing agents include LuteinTM (lutetium texaphyrin, brand; Pharmacyclics, Inc, Sunnyvale, Calif.) and bacterio-chlorophylls.
  • the waiting time for the photosensitizing agent to clear the non- target tissue is about 0.01, 0.10, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50 minutes or more, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 24 hours or more, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days or more.
  • the waiting time can depend upon the compound and its pharmacokinetics. In typical embodiments, such waiting times can be routinely determined clinically. In certain embodiments, the waiting time can be the shortest time that allows the photosensitizing agent to bind to target cells while cleared from non- target cells. In some embodiments, during the waiting time, a patient can be kept in a slightly darkened or completely darkened room before and after irradiation, in order to avoid irradiation of non-target tissue such as skin.
  • the photosensitizing agent has been administered, at least a portion of the target tissue is irradiated to activate the photosensitizing agent at the target cells.
  • the irradiating is performed using light, the light having a waveband or wavelength corresponding at least in part to the characteristic light absorption waveband or wavelength of the photosensitizing agent.
  • the intensity of the light used is selected such that the ghrelin-producing cells are destroyed or impaired and the non-target tissue through which the light passes remains undamaged.
  • irradiation, irradiating and like terms refer to the application of energy such as radiation to a target tissue.
  • radiation includes all wavelengths and wavebands.
  • waveband refers to a range of wavelengths or frequencies.
  • the radiation wavelength or waveband is selected to correspond with or at least overlap the wavelength(s) or wavebands that excite the photosensitive compound.
  • Photosensitive agents or compound typically have one or more absorption wavebands or wavelengths that excite them to produce the substances, which damage or destroy target tissue, target cells, or target compositions.
  • the radiation wavelength or waveband matches the excitation wavelength or waveband of the photosensitive compound and has low absorption by the non-target cells and the rest of the intact animal, including blood proteins.
  • a preferred wavelength of light for ICG is in the range 750nm to 850 nm.
  • While one preferred embodiment is drawn to the use of light energy for administering PDT to destroy ghrelin-producing cells, other forms of energy are within the scope of this disclosure, as will be understood by those of ordinary skill in the art.
  • forms of energy include, but are not limited to: thermal, sonic, ultrasonic, chemical, light, microwave, ionizing (such as x-ray and gamma ray), mechanical and electrical.
  • sonodynamically induced or activated agents include, but are not limited to: gallium-porphyrin complex (see Yumita et al., Cancer Letters 112: 79 86, (1997)), other porphyrin complexes, such as protoporphyrin and hematoporphyrin (see Umemura et al., Ultrasonics Sonochemistry 3:S187 S191, (1996)); other drugs, such as daunorubicin and adriamycin, used in the presence of ultrasound therapy (see Yumita et al., Japan J.
  • the radiation used to activate the photosensitive compound can be further defined by its intensity, duration, and timing with respect to dosing a target site.
  • the intensity or fluence rate preferably can be sufficient for the radiation to reach the target cells, target tissues, or target compositions.
  • the duration or total fluence dose can be sufficient to photoactivate enough photosensitive agent to achieve the desired effect on the target site. Both intensity and duration are preferably limited to avoid over treating the subject or animal. Timing with respect to the dosage of the photosensitive agent employed is important, because (Monkhouse, S.J., Morgan, J.D., Bates, S.E., and Norton, S.A. 2009. An overview of the management of morbid obesity.
  • Postgrad Med J 85:678-681 the content of which is hereby incorporated by reference in its entirety
  • the administered photosensitive agent requires some time to home in on target cells, tissue, or compositions at the treatment site, and (Butner, K.L., Nickols-Richardson, S.M., Clark, S.F., Ramp, W.K., and Herbert, W.G. A review of weight loss following Roux-en-Y gastric bypass vs. restrictive bariatric surgery: impact on adiponectin and insulin. Obes Surg 20:559-568, the content of which is hereby incorporated by reference in its entirety) the blood level of many photosensitive agents decreases with time.
  • PDT light sources include, without limitation, laser, intense pulsed light, light-emitting diodes (LEDs), blue light, red light, and many other visible lights (including natural sunlight). Photosensitizing agents may become activated by one or several types of light. The optimal light depends on the ideal wavelength for the particular drug used and target tissue.
  • the irradiating comprises endoscopic delivery of light to the target tissue.
  • the light may be delivered through small fiber-optic cables into the body cavity or area being treated.
  • one or more endoscopes (a thin, lighted, elongated tube that is inserted into a body space) are used to deliver the light into the lungs, stomach, or bladder.
  • ghrelin-producing cells can be targeted by visualization using an endoscope-like device. Such a device preferably combines a light-emitting source as well as a camera or other optical visualization component.
  • the device can include, for example, a scope operably connected to a light-emitting source capable of activating a photosensitizing agent.
  • the device may include, for example, an illuminating segment and a visualization segment for the operator to visualize gastric anatomy.
  • the operator can direct the emission of light to specific areas that are visualized by the visualization component.
  • the intensity of radiation used to treat the target cell or target tissue can be of any suitable amount. For example, it can be preferably between about 5 mW/cm2 and about 500 mW/cm 2 . More preferably, the intensity of radiation employed maybe between about 10 mW/cm 2 and about 100 mW/cm 2 . Most preferably, the intensity of radiation can be between about 15 mW/cm 2 and about 50 mW/cm 2 .
  • the duration of radiation exposure administered to a subject can be of a suitable duration. For example, it can be preferably between about 4 minutes and 72 hours. More preferably, the duration of radiation exposure maybe between about 60 minutes and about 48 hours. Most preferably, the duration of radiation exposure can be between about 2 hours and about 24 hours.
  • the intensity or power of the light used can be measured for example in watts, with each Joule equal to one watt-sec. Therefore, the intensity of the light used for irradiating may be less than 500 mW/cm 2 . Since the total fluence or amount of energy of the light in Joules is divided by the duration of total exposure time in seconds, the longer the amount of time the target is exposed to the irradiation, the greater the amount of total energy or fluence may be used without increasing the amount of the intensity of the light used.
  • the technology can employ an amount of total fluence of irradiation that is sufficient to activate a desired amount or number of the photosensitizing agent, as applicable, with a concomitant reduction in the intensity of light and collateral or non-target specific tissue damage.
  • an optimal total fluence for the light administered to a subject can be determined clinically, using a light dose escalation trial. It is further contemplated that the total fluence administered during a treatment preferably may be in the range of 30 Joules to 25,000 Joules, more preferably, in the range from 100 Joules to 20,000 Joules, and most preferably, in the range from 500 Joules to 10,000 Joules.
  • a targeted photosensitizing agent can be substantially and selectively photoactivated in the target cells and target tissues within a therapeutically reasonable period of time and without excess toxicity or collateral damage to non-target tissues.
  • a therapeutic window bounded by the targeted photosensitizing agent dosage and the radiation dosage.
  • the methods disclosed herein further can employ an energy source, e.g., a light source that is external to the target tissue, or even external to the patient.
  • an energy source e.g., a light source that is external to the target tissue, or even external to the patient.
  • the irradiation may administered, for example, transcutaneously, transdermally, or via interstitial transillumination.
  • transcutaneous refers to the passage of light through unbroken tissue. Where the tissue layer is skin or dermis, transcutaneous includes transdermal and it will be understood that the light source is external to the outer skin layer.
  • transillumination refers to the passage of light through a tissue layer.
  • organ transillumination refers to light irradiation through the outer surface layer of an organ, e.g., the liver, and it will be apparent that the light source is external to the organ, but internal or implanted within the subject or patient.
  • interstitial transillumination refers to light irradiation from a light source that is implanted or surgically positioned underneath the epidermal layer of tissue within an organ, such as the parenchymal or capsular layer of tissue of the organ, where the organ comprises the target tissue.
  • a photosensitizing agent is generally administered to the animal before the application of energy, such as radiation, to a target tissue.
  • photoreactive compound photoreactive drug, photosensitizing drug, photosensitizing medication, photosensitizing agent, photosensitizer agent, energy activated agent and the like can refer to a chemical compound that can be absorbed by or can be preferentially associated with one or more types of selected target cells and when exposed to energy such as light of an appropriate waveband, absorbs the light, causing substances to be produced that impair or destroy the target cells.
  • any suitable chemical compound that preferentially can be absorbed, that can be linked to or that otherwise can be brought into proximity of a selected target cell may be used in the methods described herein.
  • the compound is one that can absorb light or be activated, released, or uncased by light to cause the desired therapy to be effected.
  • the photosensitizing agent or compound is nontoxic to the animal to which it is administered or is capable of being formulated in a nontoxic composition that can be administered to the animal.
  • the photosensitizing agent in any resulting photodegraded form is also preferably nontoxic.
  • a comprehensive listing of photosensitive chemicals may be found in Kreimer- Birnbaum, Sem. Hematol 26: 157 73, (1989), hereby incorporated by reference in its entirety.
  • photosensitizing agents can absorb light having a wavelength or waveband in the range from 300 nm to 900 nm.
  • the photosensitizing agent can be administered in any suitable manner in order to be able to act upon the target tissue.
  • the agent can be administered, for example, locally or systemically, by oral ingestion, or by injection, which may be intravascular, subcutaneous, intramuscular, intraperitoneal or directly into a treatment site.
  • the photosensitizing agent can also be administered internally or topically via patches or implants, for example.
  • photosensitive agents or compounds include, but are not limited to, chlorins, bacteriochlorins, phthalocyanines, porphyrins, purpurins, merocyanines such as merocyanine 540, psoralens, benzoporphyrin derivatives (BPD), and porfimer sodium and pro-drugs such as delta-aminolevulinic acid and the like, which can produce photosensitive agents such as protoporphyrin IX.
  • photosensitive compounds include indocyanines such as indocyanine green (ICG), methylene blue, toluidine blue, texaphyrins, and any other agent that absorbs light in a range of 500 nm to 1100 nm.
  • ICG indocyanine green
  • methylene blue methylene blue
  • toluidine blue texaphyrins
  • any other agent that absorbs light in a range of 500 nm to 1100 nm any other agent that absorbs light in a range of 500 nm to 1100 nm.
  • the photosensitizing agent can be, for example, 5-delta-aminolevulinic acid, phthalocyanine, a porphyrin, a chlorin, a purpurin, an enlarged porphyrin, a naphthalocyanine, a phthalocyanine, a platyrin, a porphycene, a texaphyrin, a verdin, merocyanine 540, a xanthene, a cationic cyanic dye, a chalcogenapyrylium dye, a phenothiazinium derivative, tetracycline, berbine sulphate, acridine orange, and fluorescein.
  • the porphyrin can be a hematoporphyrin derivative such as Photofrin I or Photofrin ⁇ .
  • the xanthene comprises Rhodamine 123 6 G&B.
  • photosensitizing agents include, but are not limited to, benzoporphyrin derivative monoacid tube A (BPD-MA) and mono-l-aspartyl chlorine 6 (NPe6), with absorbance maxima in the range of about 660-690 nm, ATX-106, and indocyanine green (ICG).
  • BPD-MA benzoporphyrin derivative monoacid tube A
  • NPe6 mono-l-aspartyl chlorine 6
  • ICG indocyanine green
  • the selection of the photosensitive agent can depend upon several factors. These factors can include, for example, the site or sites of tissue distribution requiring treatment, the mechanisms of action of the agents themselves, and their specific optimal absorption wavelengths.
  • tin ethyl etiopurpurin SnET2
  • SnET2 can have several advantages, such as lower persistence and severity of skin photosensitivity, absorption at longer wavelengths yielding better tissue penetration, a higher extinction coefficient resulting in increased potency and efficiency, ease of synthesis, and ability to be produced in a highly pure form.
  • the photosensitizing agent can be inert.
  • inert refers to a compound not manifesting biologically and/or chemically therapeutic or detrimental properties but having the potential to manifest such properties upon exposure to the appropriate wavelength or waveband energy source.
  • inert photosensitizing agent or ligand-receptor binding pair conjugate is selectively absorbed by, or preferentially associated with, targeted cells is not meant to affect this interpretation.
  • prodrug is used herein to mean any of a class of substances that are not themselves photosensitive agents, but when introduced into the body, through metabolic, chemical, or physical processes, are converted into a photosensitive agent.
  • An aminolevulinic acid (ALA) is one example of such a prodrug. After being administered to a patient ALA is metabolically converted into a porphyrin compound that is an effective photosensitive agent.
  • One embodiment provides a method for providing a medical therapy to an animal, and the term animal includes, but is not limited to, humans and other mammals.
  • mammals or mammalian subject include farm animals, such as cows, hogs and sheep, as well as pet or sport animals such as horses, dogs, and cats, and can also include lab animals such as mice, rats, guinea pigs, and the like.
  • Reference herein to intact animal means that the whole, undivided animal is available to be exposed to radiation. No part of the animal is removed for exposure to the radiation, in contrast with photophoresis, in which an animal's blood is circulated outside its body for exposure to radiation. However, in the presently disclosed methods, the entire animal need not be exposed to radiation. Only a portion of the intact animal subject may or need be exposed to radiation, sufficient to ensure that the radiation is administered to the treatment site where the target tissue, cells, or compositions are disposed.
  • the subject can be a cell or cells, tissue sample, tissue culture, a harvested organ or tissue, and the like.
  • the subject of patient can be of any age.
  • adult but not elderly
  • adult including elderly, elderly, youth, child, non adult and non elderly, and the like.
  • a photosensitizing agent can be administered in a dry formulation, such as pills, capsules, suppositories or patches.
  • the photosensitizing agent also may be administered in a liquid formulation, either alone, with water, or with pharmaceutically acceptable excipients, as are known in the art.
  • the liquid formulation also can be a suspension or an emulsion.
  • liposomal or lipophilic formulations are desirable. If suspensions or emulsions are utilized, suitable excipients include water, saline, dextrose, glycerol, and the like. These compositions may contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, antioxidants, pH buffering agents, and the like.
  • compositions and formulations disclosed herein also can include one or more pharmaceutically acceptable carrier materials or excipients.
  • Such compositions can be prepared for storage and for subsequent administration.
  • Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in the incorporated material of Remington: The Science and Practice of Pharmacy (2003).
  • carrier material or excipient herein can mean any substance, not itself a therapeutic agent, used as a carrier and/or diluent and/or adjuvant, or vehicle for delivery of a therapeutic agent to a subject or added to a pharmaceutical composition to improve its handling or storage properties or to permit or facilitate formation of a dose unit of the composition into a discrete article such as a capsule or tablet suitable for oral administration.
  • Excipients can include, by way of illustration and not limitation, diluents, disintegrants, binding agents, adhesives, wetting agents, polymers, lubricants, glidants, substances added to mask or counteract a disagreeable taste or odor, flavors, dyes, fragrances, and substances added to improve appearance of the composition.
  • Acceptable excipients include lactose, sucrose, starch powder, maize starch or derivatives thereof, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride, and the like.
  • suitable excipients for soft gelatin capsules include vegetable oils, waxes, fats, semisolid and liquid polyols.
  • Suitable excipients for the preparation of solutions and syrups include, without limitation, water, polyols, sucrose, invert sugar and glucose.
  • Suitable excipients for injectable solutions include, without limitation, water, alcohols, polyols, glycerol, and vegetable oils.
  • the pharmaceutical compositions can additionally include preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, buffers, coating agents, or antioxidants.
  • Sterile compositions for injection can be formulated according to conventional pharmaceutical practice as described in the incorporated material in Remington: The Science and Practice of Pharmacy (2003).
  • dissolution or suspension of the active compound in a vehicle such as water or naturally occurring vegetable oil like sesame, peanut, or cottonseed oil or a synthetic fatty vehicle like ethyl oleate or the like may be desired.
  • Buffers, preservatives, antioxidants and the like can be incorporated according to accepted pharmaceutical practice.
  • the compound can also be made in microencapsulated form.
  • the injectable pharmaceutical compositions may contain minor amounts of nontoxic auxiliary substances, such as wetting agents, pH buffering agents, and the like.
  • absorption enhancing preparations for example, liposomes), can be utilized.
  • compositions and formulations can include any other agents that provide improved transfer, delivery, tolerance, and the like.
  • These compositions and formulations can include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as LipofectinTM), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax.
  • any of the foregoing mixtures may be appropriate in treatments and therapies in accordance with the presently disclosed methods and compositions, provided that the active ingredient in the formulation is not inactivated by the formulation and the formulation is physiologically compatible and tolerable with the route of administration. See also Baldrick P. "Pharmaceutical excipient development: the need for preclinical guidance.” Regul. Toxicol. Pharmacol. 32(Butner, K.L., Nickols-Richardson, S.M., Clark, S.F., Ramp, W.K., and Herbert, W.G. A review of weight loss following Roux-en-Y gastric bypass vs. restrictive bariatric surgery: impact on adiponectin and insulin.
  • the dose of photosensitizing agent can vary with the target tissue, cells, or composition, the optimal blood level, the animal's weight, route of administration, and the timing and duration of the radiation administered. Depending on the photosensitizing agent used, an equivalent optimal therapeutic level can be empirically established. Where the agent is administered intravenously, the dose can be calculated to obtain a desired blood level of the photosensitizing agent, which can be between about 0.01 ⁇ g/ml and 100 ⁇ g/ml. More preferably, the dose will produce a blood level of the photosensitizing agent between about 0.01 ⁇ g/ml and 10 ⁇ g/ml.
  • Such photosensitizing agents are to be administered in any therapeutically effective manner.
  • the photosensitizing agent can be administered intravenously and at a dosage of from about 0.05 to about 100 mg/kg.
  • the dosage may be determined as about 0.15 to about 50.0 mg/ kg. More preferably, such dosage is from about 1.0 to 50 mg/kg or about 5 to about 30 mg/ kg.
  • the photosensitizing agent is administered orally.
  • Oral administration can be any form of administration that allows the photosensitizing agent to contact the target ghrelin-producing cells in the target tissue.
  • the photosensitizing agent can be administered in the form of a pill, capsule, and the like.
  • the photosensitizing agent can be administered orally in a bolus as an aqueous solution or suspension at a concentration of about 60 mg/kg body weight or intravenously at a concentration of 30 mg/kg body weight.
  • kits for the methods described herein can include one or more of the agents (including compounds, formulations, medications, etc.) and devices described herein as well as methodology and instructions for performing the methods and/or using the agents and devices described herein.
  • the kits can include software for directing the devices and energy sources appropriately for the particular agents, including particular sensitizing agents.
  • the kits can include, for example, one or more of instructions for energy amounts to be used, instructions for regions to be targeted, instructions for how to use the devices, etc.
  • Ghrelin-specific antibodies are conjugated to verteporfin.
  • Verteporfin is a synthetic, chlorin-like porphyrin.
  • the antibody-verteporfin conjugates are diluted 1: 1000 in buffer and the solution is incubated with a section of pig stomach for 4 hours at 37°C in total darkness. After incubation, the sample is rinsed with PBS. After rinsing, the photoactive compound is activated by light at 50 J/cm2 (absorbance peak of drug) from a non-thermal laser (for example, a diode laser) set at an intensity of 600 mW/cm2 and a wavelength of 689 nm. Once activated, it generates singlet oxygen and other reactive oxygen radicals that selectively damage ghrelin-producing cells. A control sample is treated with the antibody-verteporfin conjugate, but is not irradiated.
  • the sample of stomach tissue is further incubated for 72 hours in nutrient medium at 37°C. Following incubation, the sample is homogenized and analyzed for ghrelin production using peptide quantification as described previously (Hosoda et al. /. Biol. Chem. (2003) 278;64-70.)
  • mice Normal, healthy rats are obtained and housed in an approved facility.
  • the rats are NPO ("non per os" or nothing by mouth) for 6 hours and are then sedated.
  • Each sedated rat is administered a liquid solution containing 80 ⁇ g of anti-ghrelin antibody conjugated to chlorin e6.
  • the liquid solution is allowed to incubate in the stomach for 30 minutes, and then is aspirated and the stomach is washed and aspirated.
  • An endoscope is inserted through the mouth to the stomach of each animal.
  • Treated rats are administered a dose of 660 nm light for about 4 hours.
  • Control rats are administered a dose of light at a wavelength that does not activate the chlorin.
  • the rats are revived and allowed to resume a normal diet. Circulating levels of ghrelin in the blood serum are monitored daily by ELISA for two months.
  • An obese 40-year old male is not eligible for bariatric surgery. He is selected for photodynamic therapy targeted at ghrelin-producing cells in the fundus of the stomach.
  • a targeted antibody-photosensitizer conjugate is constructed using a ghrelin- specific monoclonal antibody conjugated to 5 -aminolevulinic acid (ALA).
  • ALA is a prodrug that is metabolized to protoporphyrin IX, the active photosensitizing agent.
  • the APC is administered intravenously at a concentration of 60 mg/kg body weight.
  • the APC binds selectively to ghrelin-producing cells.
  • the sensitizer bound to the ghrelin-producing cells is activated by an intragastric positioned light source probe that is passed via the nasopharynx.
  • Endoscopy is conducted with the patient under conscious sedation with intravenous midazolam and meperidine.
  • the light source is directed towards the tissue of the fundus.
  • a dye laser KTP/YAG XP 800; Laserscope, San Jose, CA
  • the light dosage is calculated as joules per square centimeter and is derived from the time of exposure, the power delivered, and the exposed area.
  • the delivered light has an energy dosage of 105 J/m 2 and a power density of 100 mW/cm 2 , [0091]
  • the vital signs and blood chemistry of the patient are monitored until the patient is discharged.
  • an endoscopic check-up shows no signs of bleeding or perforation.
  • An obese 52-year old female is not eligible for bariatric surgery. She is selected for photodynamic therapy targeted at ghrelin-producing cells in the fundus of the stomach.
  • a targeted antibody-photosensitizer conjugate is constructed using a ghrelin- specific monoclonal antibody conjugated to 5 -aminolevulinic acid (ALA).
  • the APC compound is ingested as a mixture with juice or mineral water and releases the conjugate into the stomach.
  • the stomach should have been evacuated by fasting or aspiration and lavage.
  • the targeted photosensitizer will bind to the ghrelin-producing cells and any unbound APC is diluted by gastric juice and carried distally by peristalsis to be eliminated from the body in fecal matter.
  • the sensitizer bound to the ghrelin-producing cells is activated by an intragastric positioned light source probe that is passed via the nasopharynx. Endoscopy is conducted with the patient under conscious sedation with intravenous midazolam and meperidine. The light source is directed towards the tissue of the fundus.
  • a dye laser KTP/YAG XP 800; Laserscope, San Jose, CA
  • the light dosage is calculated as joules per square centimeter and is derived from the time of exposure, the power delivered, and the exposed area.
  • the delivered light has an energy dosage of 105 J/m 2 and a power density of 100 mW/cm 2 .
  • the patient reports experiencing decreased hunger. Over a six-month period, the patient loses a 20% of her weight and is classified as having a normal weight for her height and build.
  • a 55-year old male is severely obese. He is selected for photodynamic therapy targeted at ghrelin-producing cells in the fundus of the stomach.
  • a targeted antibody-photosensitizer conjugate is constructed using a ghrelin-specific monoclonal antibody conjugated to chlrorin e6.
  • the APC compound is ingested as a mixture with juice or mineral water and releases the conjugate into the stomach.
  • the stomach should have been evacuated by fasting or aspiration and lavage.
  • the liquid solution is allowed to incubate in the stomach for 30 minutes, and then is aspirated and the stomach is washed and aspirated.
  • the sensitizer bound to the ghrelin-producing cells is activated by a transcutaneous light source probe that is positioned outside the body and directed towards the fundus of the stomach.
  • the light irradiation is at a wavelength of 660 nm.
  • the light emitting device is energized, the light is transmitted noninvasively through the skin and intervening tissues to the treatment site.
  • the length of time of treatment may be optimized in a clinical trial using standard clinical practice and procedures. It is expected that at least one hour of treatment will be necessary to ensure that an adequate number of photochemical reactions occurs in order to completely destroy the target tissue so that cellular repair is not feasible.
  • the ghrelin-producing cells which have selectively taken up the photosensitizer compound, are destroyed during the PDT process.
  • a 60-year old female is severely obese. She is selected for photodynamic therapy targeted at ghrelin-producing cells in the fundus of the stomach.
  • ALA alone is administered, without a targeting moiety.
  • ALA is administered orally in a bolus as an aqueous solution at a concentration of about 60 mg/kg body weight or intravenously at a concentration of 30 mg/kg body weight.
  • the sensitizer bound to the ghrelin-producing cells is activated by a intragastric positioned light source probe that is passed via the nasopharynx. Endoscopy is conducted with the patient under conscious sedation with intravenous midazolam and meperidine. The light source is directed towards the tissue of the fundus.
  • a dye laser KTP/YAG XP 800; Laserscope, San Jose, CA
  • the light dosage is calculated as joules per square centimeter and is derived from the time of exposure, the power delivered, and the exposed area.
  • the delivered light has an energy dosage of 105 J/m 2 and a power density of 100 mW/cm 2 .
  • the patient reports experiencing decreased hunger. Over a six-month period, the patient loses a 20% of her weight and is classified as having a normal weight for her height and build.

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Abstract

La présente invention concerne des interventions de perte de poids, comprenant des méthodes d'inactivation de cellules produisant des stimuli induisant l'appétit, appelés médiateurs orexigéniques. La présente invention concerne particulièrement des compositions et des méthodes permettant d'inactiver de tels cellules au moyen d'une thérapie photodynamique dirigée sur les cellules produisant des médiateurs orexigéniques.
PCT/US2013/025353 2012-02-10 2013-02-08 Réduction de poids par inactivation de médiateurs orexigéniques gastriques produisant des cellules WO2013119957A1 (fr)

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