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WO2001007914A1 - Fenretinide augmentant la cytotoxicite cellulaire dependant des anticorps (ccda) - Google Patents

Fenretinide augmentant la cytotoxicite cellulaire dependant des anticorps (ccda) Download PDF

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WO2001007914A1
WO2001007914A1 PCT/US2000/019838 US0019838W WO0107914A1 WO 2001007914 A1 WO2001007914 A1 WO 2001007914A1 US 0019838 W US0019838 W US 0019838W WO 0107914 A1 WO0107914 A1 WO 0107914A1
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fenretinide
cells
immunocytokine
hyperproliferative
treatment
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Robert C. Seeger
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Childrens Hospital Los Angeles
Childrens Hospital Los Angeles Research Institute
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Childrens Hospital Los Angeles
Childrens Hospital Los Angeles Research Institute
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Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3053—Skin, nerves, brain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/203—Retinoic acids ; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/193—Colony stimulating factors [CSF]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/2013—IL-2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
    • A61K47/6813—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin the drug being a peptidic cytokine, e.g. an interleukin or interferon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention concerns combination chemotherapy treatments for disorders such as cancer.
  • Fenretinide [HPR; all-tr ⁇ ns-N-(4-hydroxyphenyl)retinamide; CAS Registry number 65646-68-6] is known to have certain antitumor properties. See, e.g., D. Delia et al., Carcinogenesis 18, 943-948 (1997); N. Oridate et al., J. Natl. Cancer Inst. 89, 1191-1198 (1997). Fenretinide has been effective both in chemoprevention and chemotherapy of mammary gland tumors in experimental animals, does not accumulate in the liver, and exhibits a mild toxicity.
  • U.S. Patent No. 5,650,150 to Gillies describes recombinant antibody cytokine fusion proteins, where the fusion proteins are comprised of an immunoglobulin specific for a target cell such as a cancer or virus infected cell, and a cytokine such as lymphotoxin, TNF- ⁇ , IL-2, or GM-CSF.
  • a method of treating a hyperproliferative disorder in a subject in need of such treatment comprises administering to the subject, in combination, a treatment effective amount of: (a) an immunocytokine that specifically binds to hyperproliferative cells (e.g., cancer cells) in said patient; and (b) a retinoid or a pharmaceutically acceptable salt thereof.
  • the retinoid and the immunocytokine are preferably given in amounts that achieve a cytotoxic or cytostatic effect on the cells to which the immunocytokine specifically binds that is at least as great, and preferably greater than, the sum of the cytotoxic or cytostatic effect achieved by the same amounts of the compounds when given separately.
  • a synergistic amount of the two compounds is administered.
  • Figure 1 shows 18 hour antibody dependent cellular cytotoxicity (ADCC) as percent neuroblastoma survival for a first patient. Circles represent neutrophils + neuroblastoma; triangles represent neutrophils + neuroblastoma + hul4.18/GM-CSF.
  • ADCC antibody dependent cellular cytotoxicity
  • Plot A represents pre-fenretinide ADCC survival
  • plot B represents post fenretinide
  • FIG. 2 shows 18 hour antibody dependent cellular cytotoxicity (ADCC) as percent neuroblastoma survival for a second patient. Circles represent neutrophils + neuroblastoma; triangles represent neutrophils + neuroblastoma + hul4.18/GM-CSF.
  • Plot A represents pre-fenretinide ADCC survival
  • plot B represents post fenretinide
  • FIG. 3 shows 18 hour antibody dependent cellular cytotoxicity (ADCC) as percent neuroblastoma survival for a third patient. Circles represent neutrophils + neuroblastoma; triangles represent neutrophils + neuroblastoma + hul4.18/GM-CSF.
  • Plot A represents pre-fenretinide ADCC survival
  • plot B represents post fenretinide
  • FIG. 4a shows that fenretinide (4-HPR) increases neutrophil-mediated
  • SMS-K.CNR neuroblastoma cells were pre-incubated with indicated concentrations of fenretinide for 6 hours.
  • Figure 4b shows that fenretinide (4-HPR) increases neutrophil-mediated ADCC against neuroblastoma cells targeted with hul4.18/GM-CSF.
  • CHLA-90 neuroblastoma cells were preincubated with fenretinide (10 ⁇ M or with its vehicle (0.1% ethanol: V) for 6 hours.
  • Figures 5a-b shows that fenretinide increases neutrophil mediated ADCC.
  • Figure 5a shows neutrophils from a patient receiving fenretinide 450 mg/m 2 /day were tested in the morning on day zero before fenretinide. E:T ratios are as graphed; 2000 LA-N-1 target cells pre-labeled with calcein. DIMSCAN analysis to quantify fluorescence remaining in target cells after 18 hours of ADCC.
  • Figure 5b shows neutrophils from the patient of Figure 5 a tested six hours after taking fenretinide. E:T ratios are as graphed; 2000 LA-N-1 target cells pre- labeled with calcein. DIMSCAN analysis to quantify fluorescence remaining in target cells after 18 hours of ADCC.
  • the treatments employed herein may be used to inhibit growth and/or to induce cytotoxicity (by necrotic or apoptotic mechanisms, or both) in the target cells, which are generally hyperproliferative cells (including tumors, cancers, and neoplastic tissue, along with pre-malignant and non-neoplastic or non-malignant hyperproliferative cells).
  • tumors, cancers, and neoplastic tissue that can be treated by the present invention include but are not limited to malignant disorders such as breast cancers; osteosarcomas; angiosarcomas; f ⁇ brosarcomas and other sarcomas; leukemias; lymphomas; sinus tumors; ovarian, uretal, bladder, prostate and other genitourinary cancers; colon esophageal and stomach cancers and other gastrointestinal cancers; lung cancers; myelomas; pancreatic cancers; liver cancers; kidney cancers; endocrine cancers; skin cancers; and brain or central and peripheral nervous (CNS) system tumors, malignant or benign, including gliomas and neuroblastomas.
  • malignant disorders such as breast cancers; osteosarcomas; angiosarcomas; f ⁇ brosarcomas and other sarcomas
  • leukemias such as breast cancers; osteosarcomas; angiosar
  • premalignant and non-neoplastic or non-malignant hyperproliferative disorders include but are not limited to myelodysplastic disorders; cervical carcinoma-in-situ; familial intestinal polyposes such as Gardner syndrome; oral leukoplakias; histiocytoses; keloids; hemangiomas; hyperproliferative arterial stenosis, inflammatory arthritis; hyperkeratoses and papulosquamous eruptions including arthritis.
  • viral induced hyperproliferative diseases such as warts and EBV induced disease (i.e., infectious mononucleosis), scar formation, and the like.
  • the methods of treatment disclosed herein may be employed with any subject known or suspected of carrying or at risk of developing a hyperproliferative disorder as defined herein.
  • treatment refers to methods of killing, inhibiting or slowing the growth or increase in size of a body or population of hyperproliferative cells or tumor or cancerous growth, reducing hyperproliferative cell numbers, or preventing spread to other anatomic sites, as well as reducing the size of a hyperproliferative growth or numbers of hyperproliferative cells.
  • treatment is not necessarily meant to imply cure or complete abolition of hyperproliferative growths.
  • a treatment effective amount is an amount effective to result in the killing, the slowing of the rate of growth of hyperproliferative cells, the decrease in size of a body of hyperproliferative cells, and/or the reduction in number of hyperproliferative cells.
  • the potentiating agent (or agents) is included in an amount sufficient to enhance the activity of the first compound, such that the two (or more) compounds together have greater therapeutic efficacy than the individual compounds given alone (e.g., due to synergistic interaction; reduced combined toxicity, etc.).
  • the administration of two or more compounds "in combination” means that the two compounds are administered closely enough in time that the presence of one alters the biological effects of the other.
  • the two compounds may be administered simultaneously (concurrently) or sequentially.
  • Simultaneous administration may be carried out by mixing the compounds prior to administration, or by administering the compounds at the same point in time but at different anatomic sites or using different routes of administration.
  • compositions are administered at the same point in time or immediately following one another. In the latter case, the two compounds are administered at times sufficiently close that the results observed are indistinguishable from those achieved when the compounds are administered at the same point in time.
  • Subjects to be treated by the methods of the present invention include both human subjects and animal subjects for veterinary purposes. Animal subjects are preferably mammalian subjects including horses, cows, dogs, cats, rabbits, sheep, and the like. 1. Retinoids.
  • Retinoids or retinoic acid derivatives that can be used to carry out the present invention include those described in U.S. Patent No. 4,190,594 to Gander (the disclosures of all patent references cited herein are incorporated herein by reference).
  • retinoids include retinoic acid or all trans-retinoic acid (ATRA), and retinoic acid derivatives, including but not limited to:
  • X is a member selected from the group consisting of:
  • Y is a member selected from the group consisting of: cholesteryloxy; phenyl; 4-bromophenyl; 4-methoxyphenyl; 4-nitrophenyl; 4-hydroxyphenyl; 4-methylphenyl; 4-cyanophenyl; 4-ethoxyphenyl; 4-acetoxyphenyl; 2-naphthyl; 4-biphenyl; 2,5- dimethoxyphenyl; 2,4-dichlorophenyl; 2,4-dimethylphenyl; 3,4-diacetoxyphenyl; 3,4,5-trirnethoxyphenyl; and 2,4,6-trimethylphenyl; and
  • Z is a member selected from the group consisting of: n-propylamino; tert- butylamino;l,l,3,3-tetramethylbutylamino; l-morpholino; 4-hydroxyphenylamino; 4- carbomethoxy-2-hydroxyphenylamino; beta-(3 ,4-dimethoxyphenyl)-ethylamino; 2- benzothiazolylamino; 1-imidazolyl; l-(2-nicotinoylhydrazolyl); 1-benzotriazolyl; 1- (1,2,4-triazolyl);
  • all-tr ⁇ «s-N-(4-hydroxyphenyl)retinamide, also called fenretinide, which has CAS registry number 65646-68-6, and has the structure:
  • Additional retinoids that can be used to carry out the present invention include
  • R is COOH, CH 2 OH, or H, and n is 0 or 1.
  • Such compounds include: 4-(retinamido)phenyl-C- glucuronide; 4-(retinamido)phenyl-C-glucoside; 4-(retinamido)phenyl-C-xyloside; 4- (retinamido)benzyl-C-glucuronide; 4-(retinamido)benzyl-C-glucoside; 4-
  • an immunocytokine comprises a conjugate of an immunoglobulin and a cytokine.
  • the immunoglobulin is selected to specifically bind (i.e., preferentially bind through the immunoglobulin hypervariable region) to the hyperproliferative cells (e.g., cancer cells) in the subject being treated.
  • the conjugate may be of any type, covalent conjugates are preferred.
  • Irnmonocytokines are known and described in, for example, U.S. Patent No. 5,650,150 to Gillies, the disclosure of which is incorporated herein by reference in its entirety.
  • the immunocytokine may comprise any cytokine, including but not limited to interleukins such as interleukin-2 (IL-2), hematopoietic factors such as granulocyte- macrophage colony stimulating factor (GM-CSF), and tumor necrosis factor alpha, lymphokines such as lymphotoxins, etc. IL-2 and GM-CSF are particularly preferred.
  • the cytokine may be of any species of origin, but is preferably of mammalian origin and, in the practice of the present invention for humans, is preferably a human cytokine.
  • the immunoglobulin in the cytokine may be of any type, but is preferably an Ig heavy chain.
  • the immunoglobulin may be of any species of origin, but is preferably mammalian.
  • the immunoglobulin may be chimeric or humanized (that is, may comprise a recombinant molecule containing human portions and non human portions).
  • the immunoglobulin and cytokine may be conjugated to one another in any suitable manner.
  • an Ig heavy chain and a cytokine which elicits a cytokine-specific biological response by a cell bearing a receptor for said cytokine may be used, said Ig heavy chain comprising an N-terminal variable region specific for a cell bearing a cell surface antigen (and preferably includes the CHI, CH2, and optionally the CH3 domains), said Ig heavy chain being joined at its carboxy-terminus by a peptide bond to the ammo terminal amino acid of the cytokine, as described in U.S. Patent No. 5,650,150 to Gillies.
  • the active compounds described above may be formulated for administration in a single pharmaceutical carrier or in separate pharmaceutical carriers for the treatment of a variety of conditions.
  • the active compounds including the physiologically acceptable salts thereof, or the acid derivatives of either thereof are typically admixed with, inter alia, an acceptable carrier.
  • the carrier must, of course, be acceptable in the sense of being compatible with any other ingredients in the formulation and must not be deleterious to the patient.
  • the carrier may be a solid or a liquid, or both, and is preferably formulated with the compound as a unit-dose formulation, for example, a tablet, which may contain from 0.5% to 95% by weight of the active compound.
  • One or more active compounds may be incorporated in the formulations of the invention, which may be prepared by any of the well known techniques of pharmacy consisting essentially of admixing the components, optionally including one or more accessory ingredients.
  • the formulations of the invention include those suitable for oral, rectal, topical, buccal (e.g., sub-lingual), vaginal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), topical (i.e., both skin and mucosal surfaces, including airway surfaces) and transdermal administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and on the nature of the particular active compound which is being used.
  • Formulations suitable for oral administration may be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion.
  • Such formulations may be prepared by any suitable method of pharmacy which includes the step of bringing into association the active compound and a suitable carrier (which may contain one or more accessory ingredients as noted above).
  • the formulations of the invention are prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the resulting mixture.
  • a tablet may be prepared by compressing or molding a powder or granules containing the active compound, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, and/or surface active/dispersing agent(s).
  • Molded tablets may be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid binder.
  • Formulations suitable for buccal (sub-lingual) administration include lozenges comprising the active compound in a flavored base, usually sucrose and acacia or tragacanth; and pastilles comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia.
  • Formulations of the present invention suitable for parenteral or vaginal administration conveniently comprise sterile aqueous preparations of the active compound, which preparations are preferably isotonic with the blood of the intended recipient. These preparations may be administered by means of subcutaneous, intravenous, intramuscular, or intradermal injection. Such preparations may conveniently be prepared by admixing the compound with water or a glycine buffer and rendering the resulting solution sterile and isotonic with the blood.
  • Formulations suitable for rectal administration are preferably presented as unit dose suppositories. These may be prepared by admixing the active compound with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.
  • Formulations suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil.
  • Carriers which may be used include Vaseline, lanolin, polyethylene glycols, alcohols, transdermal enhancers, and combinations of two or more thereof.
  • Formulations suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Formulations suitable for transdermal administration may also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3 (6):318 (1986)) and typically take the form of an optionally buffered aqueous solution of the active compound. Suitable formulations comprise citrate or bisVtris buffer (pH 6) or ethano I/water and contain from 0.1 to 0.2M active ingredient.
  • the present invention provides pharmaceutical formulations comprising the active compounds (including the pharmaceutically acceptable salts thereof), in pharmaceutically acceptable carriers for oral, rectal, topical, buccal, parenteral, intramuscular, intradermal, or intravenous, and transdermal administration.
  • the therapeutically effective dosage of any one active agent will vary somewhat from compound to compound, patient to patient, and will depend upon factors such as the condition of the patient and the route of delivery. Such dosages can be determined in accordance with routine pharmacological procedures known to those skilled in the art, particularly in light of the disclosure provided herein.
  • a dose to achieve a plasma level of about 1, 2, or 3 ⁇ M to 10 or 20 ⁇ M will be employed; typically (for oral dosing) 50 or 100 to 500 or 1000, 2000 or even 3000 mg/m 2 body surface area per day.
  • the agent may be given at a dosage of .1 or .2 to 2, 4, or 8, 12 or 16 mg/m /day, for two, four, six or eight days. More particularly, the agent may be given to adults as a four hour intravenous infusion for four days at a dosage of 2 mg/m /day. For children, the dosage may be 250 ⁇ g/m /day for four days. The length of infusion may be increased up to 20 hours if desired.
  • the invention may also be employed for the treatment of subjects infected with infectious agents, such as bacterial, fungal and viral agents with immunocytokines that specifically bind to target infectious agents.
  • infectious agents such as bacterial, fungal and viral agents with immunocytokines that specifically bind to target infectious agents.
  • infectious agents include both gram positive and gram negative bacteria.
  • bacteria and other infectious agents include, but are not limited to, Salmonella, Escherichia coli, Staphylococcus aureus, Listeria monocytogenes, Pseudomonas aeruginosa, Candida species, etc. Dosages, formulations and routes of administration as described above may be employed for the treatment of such infections.
  • EXAMPLE 1 Neutrophils from Pediatric Neuroblastoma Patients on Fenretinide Therapy Effectively Eradicate Tumor Cells Neuroblastoma, one of the most common solid childhood tumors, originates from neural crest cells.
  • ADCC neutrophil mediated antibody dependent cellular cytotoxicity
  • Figures 1-3 illustrate the increased kill of tumor cells by neutrophils.
  • Neuroblastoma survival decreases significantly for all patients in the Post-Fenretinide period (B). To see a progressive increase in cytotoxicity, neutrophils to neuroblastoma ratios of 10:1, 25:1 and 50:1 were plotted. The greatest cytotoxicity is seen in plot (B), with neutrophikneuroblastoma 50:1, where the neuroblastoma survival decreased to 9% of the control (100% survival).
  • the hul4.18/GM-CSF provided by Steve Gillies and described in S Gillies et al., Bioconjug. Chem. 4, 230-
  • cytokine an antibody fusion protein (immunocytokine) which (1) allows the neutrophils to target neuroblastoma cells, and (2) localizes a cytokine, GM-CSF, to the tumor site to trigger neutrophil activity against neuroblastoma.
  • GM-CSF a cytokine
  • Our experiments demonstrate for the first time that neutrophils are activated by Fenretinide in vivo to kill neuroblastoma cells more effectively in vitro. These date indicate that fenretinide is useful in combination with immunocytokine therapy in the treatment of cancer. Furthermore, we have shown that fenretinide treatment of tumor cells renders them more susceptible to neutrophil killing with the immunocytokine (see Figure 4).
  • EXAMPLE 2 Neutrophils from patients receiving fenretinide according to a phase 1 protocol who are treated at Children's Hospital Los Angeles have been evaluated with the calcein-DIMSCAN ADCC assay. Data is available for 6 patients and 15 time points (pre and 6 hours post fenretinide); patients received 450, 600 or 800 mg/m 2 /day of fenretinide. A representative case is shown in Figure 5. Comparing pre and 6 hours post fenretinide ADCC with a nested analysis of variance demonstrated no effect upon cytotoxicity without immunocytokine. For hul4.18 alone, there was a trend for fewer viable cells at 25 and 50:1 effector to target (E:T) ratios.

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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention porte sur un procédé de traitement d'une affection hyperproliférante chez un individu nécessitant un tel traitement. Le procédé consiste à administrer au patient, en combinaison, une quantité thérapeutique efficace de : (a) une immunocytokine qui se lie de manière spécifique aux cellules hyperproliférantes (des cellules cancéreuses par exemple) chez ledit patient, et (b) un rétinoïde ou un sel pharmaceutiquement acceptable de ce dernier. Le rétinoïde et l'immunocytokine sont de préférence administrés dans des quantités qui produisent un effet cytotoxique ou cytostatique sur les cellules auxquelles l'immunocytokine se lie de manière spécifique qui est au moins aussi important et de préférence plus important que la somme de l'effet cytotoxique ou cytostatique produit par les mêmes quantités des composés administrés séparément. De préférence, une quantité synergique des deux composés est administrée. On décrit également des procédés de traitement d'agents infectieux.
PCT/US2000/019838 1999-07-26 2000-07-21 Fenretinide augmentant la cytotoxicite cellulaire dependant des anticorps (ccda) Ceased WO2001007914A1 (fr)

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AU62274/00A AU6227400A (en) 1999-07-26 2000-07-21 Fenretinide increases antibody cellular toxicity

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US14558099P 1999-07-26 1999-07-26
US60/145,580 1999-07-26
US61676300A 2000-07-14 2000-07-14
US09/616,763 2000-07-14

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EP1959945A4 (fr) * 2005-12-13 2011-05-11 Univ Mcgill Procédé de correction d'un déséquilibre lipidique chez un sujet
US8946187B2 (en) 2010-11-12 2015-02-03 The Ohio State University Materials and methods related to microRNA-21, mismatch repair, and colorectal cancer
US9017939B2 (en) 2006-01-05 2015-04-28 The Ohio State University Methods for diagnosing breast, colon, lung, pancreatic and prostate cancer using miR-21 and miR-17-5p
US9085804B2 (en) 2007-08-03 2015-07-21 The Ohio State University Research Foundation Ultraconserved regions encoding ncRNAs
US9249468B2 (en) 2011-10-14 2016-02-02 The Ohio State University Methods and materials related to ovarian cancer
US9434995B2 (en) 2012-01-20 2016-09-06 The Ohio State University Breast cancer biomarker signatures for invasiveness and prognosis
US9481885B2 (en) 2011-12-13 2016-11-01 Ohio State Innovation Foundation Methods and compositions related to miR-21 and miR-29a, exosome inhibition, and cancer metastasis
US10758619B2 (en) 2010-11-15 2020-09-01 The Ohio State University Controlled release mucoadhesive systems

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1959945A4 (fr) * 2005-12-13 2011-05-11 Univ Mcgill Procédé de correction d'un déséquilibre lipidique chez un sujet
US8680153B2 (en) 2005-12-13 2014-03-25 The Royal Institution For The Advancement Of Learning/Mcgill University Method for correcting a lipid imbalance in a subject
US9017939B2 (en) 2006-01-05 2015-04-28 The Ohio State University Methods for diagnosing breast, colon, lung, pancreatic and prostate cancer using miR-21 and miR-17-5p
US9017940B2 (en) 2006-01-05 2015-04-28 The Ohio State University Methods for diagnosing colon cancer using MicroRNA signatures
US9085804B2 (en) 2007-08-03 2015-07-21 The Ohio State University Research Foundation Ultraconserved regions encoding ncRNAs
US8946187B2 (en) 2010-11-12 2015-02-03 The Ohio State University Materials and methods related to microRNA-21, mismatch repair, and colorectal cancer
US10758619B2 (en) 2010-11-15 2020-09-01 The Ohio State University Controlled release mucoadhesive systems
US11679157B2 (en) 2010-11-15 2023-06-20 The Ohio State University Controlled release mucoadhesive systems
US9249468B2 (en) 2011-10-14 2016-02-02 The Ohio State University Methods and materials related to ovarian cancer
US9481885B2 (en) 2011-12-13 2016-11-01 Ohio State Innovation Foundation Methods and compositions related to miR-21 and miR-29a, exosome inhibition, and cancer metastasis
US9434995B2 (en) 2012-01-20 2016-09-06 The Ohio State University Breast cancer biomarker signatures for invasiveness and prognosis

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