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WO1994013786A1 - Nouveau facteur de croissance de cellules precurseurs granulocytiques et procede associe - Google Patents

Nouveau facteur de croissance de cellules precurseurs granulocytiques et procede associe Download PDF

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Publication number
WO1994013786A1
WO1994013786A1 PCT/US1993/012127 US9312127W WO9413786A1 WO 1994013786 A1 WO1994013786 A1 WO 1994013786A1 US 9312127 W US9312127 W US 9312127W WO 9413786 A1 WO9413786 A1 WO 9413786A1
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WO
WIPO (PCT)
Prior art keywords
retinoic acid
trans retinoic
tissue
granulopoietic
levels
Prior art date
Application number
PCT/US1993/012127
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English (en)
Inventor
Gabriel Lopez-Berestein
Robert P. Lenk
Kapil Mehta
Original Assignee
Board Of Regents, The University Of Texas System
Argus Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Board Of Regents, The University Of Texas System, Argus Pharmaceuticals, Inc. filed Critical Board Of Regents, The University Of Texas System
Priority to AU58008/94A priority Critical patent/AU5800894A/en
Publication of WO1994013786A1 publication Critical patent/WO1994013786A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0634—Cells from the blood or the immune system
    • C12N5/0642—Granulocytes, e.g. basopils, eosinophils, neutrophils, mast cells
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/30—Hormones
    • C12N2501/38—Hormones with nuclear receptors
    • C12N2501/385—Hormones with nuclear receptors of the family of the retinoic acid recptor, e.g. RAR, RXR; Peroxisome proliferator-activated receptor [PPAR]

Definitions

  • This invention comprises a low systemic toxicity method of potentiating granulopoiesis.
  • Particular reference is made to granulocytes and the mature cells types of granulopoiesis, i.e., neutrophilic, eosinophilic, and basophilic granulocytes, as well as monocytes.
  • granulopoiesis is achieved by acute exposure of granulopoietic cells to maturation-inducing levels of all-trans retinoic acid, while, in in vivo or in situ applications non-haemopoietic tissue is sustained at levels about at or below the no-effect dosage level for all- trans retinoic acid.
  • in vivo, in vitro, extra corporeal and in situ methods are included herein. Further contemplated is the acute immune system maintenance of subjects in need of such treatment such as immune compromised subjects.
  • haemopoietic activity The general case of haemopoietic activity, and the specific case of granulopoietic activity is found in a number of sites in an animal. In an adult animal, haemopoietic activity is primarily exhibited in the bone marrow, liver and spleen. Haemopoietic activity is the replenishing of blood cells. Granulopoietic activity, is a subset of haemopoietic activity, referring to the replenishing of ganulocytes, neutrophils, eosinophils, and basophils, as well as monocytes.
  • pluripotent stem cells proliferate under the influence of a complex interrelationship of growth factors. These pluripotent or stem cells are capable of becoming any one of the blood cell types. While the 13786 _ ⁇ _
  • stem cells are proliferation, from time to time, one of these cells receives a signal which induces such cell to differentiate into a stem cell of more restricted possibility. Depending on the signal, this "partially differentiated" stem cell could become the precursor cell which eventually produces a platelet, or it could become the precursor cell which produces cells of the granulocyte or monocyte type.
  • Such cells include neutrophils, eosinophils, and basophils, as well as monocytes, monoblasts, promonocytes, myeoblasts, promyelocytes, and myelocytes.
  • mature granulocytic cells are neutrophils, eosinophils, and basophils, and monocytes.
  • glycoproteins that act as myeloid growth factors or colony stimulating factors. Such factors stimulate the proliferation and differentiation of several types of precursor cells. Such factors include granulocyte/macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), interleukin-3 (11-3), and macrophase colony- stimulating factor.
  • GM-CSF granulocyte/macrophage colony-stimulating factor
  • G-CSF granulocyte colony-stimulating factor
  • interleukin-3 (11-3) interleukin-3
  • macrophase colony- stimulating factor granulocyte/macrophage colony-stimulating factor
  • Potential toxic effects associated with administration of these glycoproteins include, local induration at the site of subcutaneous administration, thrombophlebitis at sites of intravenous infusion, fever, myalgias, fatigue, skin rashes, and gastrointestinal distress, bone pain, pericarditis, pleuritis,
  • This invention comprises a low systemic toxicity method of potentiating granulopoietic tissue to differentiate into granulocytic cell types of increased maturity (particularly mature cell types) comprising acute exposure of such cells to maturation-inducing levels of all-trans retinoic acid, while non-haemopoietic tissue is sustained at levels about at or below the no-effect dosage level for all-trans retinoic acid.
  • Mature cell types of the method include neutrophils, eosinophils, basophils, or monocytes.
  • the method comprises establishment of a level of at least one mature granulocytic cell type elevated at least about 50% (particularly neutrophils) as compared to an untreated animal of generally like condition for at least about 10 days, at least about 20 days, or at least about 28 days.
  • the all-trans retinoic acid is in liposomal form.
  • the invention further includes a method of potentiating granulopoietic tissue to differentiate into granulocytic cell types of increased maturity
  • treating further comprises sustaining non-haemopoietic tissue at levels about at or below the no- effect dosage level for all-trans retinoic acid, optionally using liposomal all-trans retinoic acid, including granulocytic-associating liposomes.
  • Contemplated granulopoietic tissue includes stem cells.
  • the invention yet further includes a method of maintaining maturation- inducing levels of all-trans retinoic acid in granulopoietic tissue, while sustaining systemic levels of all-trans retinoic acid about at or below the no-effect dosage for all-trans retinoic acid by administration of all-trans retinoic acid in liposomal form.
  • granulopoietic tissue is located in bone marrow as well as in hepatic tissue, and placenta.
  • granulopoietic tissue is maintained at maturation- inducing levels of all-trans retinoic acid which comprise from about 0.05 to about 20 ng drug/mg marrow, and preferably 1 to lOng drug/mg marrow.
  • levels of all-trans retinoic acid 2 to 3 hours post- introduction are sustained at less than about 20% of the total delivered dosage, and preferably less than about 5%.
  • the present invention also included a method of acute augmentation of immunoresponse in a subject in need of such treatment comprising treating the granulopoietic tissue of such subject with maturation-inducing levels of all-trans retinoic acid.
  • a unit dosage form comprising liposomal all-trans retinoic acid of from about 50 to 250mg all-trans retinoic acid in a suitable pharmaceutical carrier.
  • Specific embodiments are useful to screen for or identify subjects with conditions likely to benefit from the described treatment, or subjects with granulopoietic maturation defects.
  • Fig. 1 presents polymorphonuclear cell counts in a dog dose study of blood collected 6 hours post dosing.
  • “Maturation-inducing” shall mean that level of drug which causes stem cells to differentiate into a mature granulocytic cell type such that a subject animal expresses at least about a 50% increase as compared to an untreated animal of generally like condition.
  • Dosages of about 1 to about 125 mg/kg body weight, and particularly about 1 to about 50 mg/kg, and most particularly about 2 to lOmg/kg body weight are maturation-inducing. (Unless otherwise stated, references to dosages are to drug weight, here, all-trans retinoic acid weight.)
  • Gramulocytic tissue (also “granulocytic cells”) shall mean granulocytes, neutrophils, eosinophils, and basophils, as well as monocytes, monoblasts, promonocytes, myeoblasts, promyelocytes, and myelocytes.
  • Systemic toxicity shall mean side effects resulting from association with administration of all-trans retinoic acid. These include skin photosensitivity, erythema and xerosis, local induration at the site of subcutaneous administration, thrombophlebitis at sites of intravenous infusion, fever, myalgias, fatigue, skin rashes, and gastrointestinal distress, bone pain, pericarditis, pleuritis, pleural effusions, and pulmonary emboli.
  • Gramulopoietic-associating liposomes shall mean liposomes of size, charge, and character which results in their distribution and concentration in the haemopoietic tissue, particularly the marrow, while facilitating the rapid elimination from non- granulopoietic tissue.
  • liposomes may be produced with appropriate antibody type binding agents to facilitate their localization in the marrow.
  • Granulopoietic-associating is easily determined empirically. Particular reference is made to well-known markers or tags to disclose the location of liposomes.
  • No-effect shall mean that dosage or blood (or plasma) level above which toxic effects are observed. In certain applications a level “about” the no effect level is noted. This recognizes that dosage peaks occur upon administration and that there may be physiological fluctuation in the no effect level. "About" a no effect level would be that, where, even with a fluctuating no effect level, only minimal and relatively benign, limited or transient toxic effects are observed.
  • Mainntain refers to acute drug level of at least 3 and preferably 5 or more days above a maturation-inducing dose, but less than about 30 days in any 120 day period.
  • “Sustain” describes a drug level integrated over time and discount peaks encountered in the first at least about 2 or three hours post-administration of the retinoid.
  • the sustained level thus calculated will be, cumulatively, less then about 20%, and preferably less than about 5%, of the introduced dosage.
  • Neutrophil shall mean white blood cells referred to a neutrophils, polymorphs, and polymorphonuclear leukocytes. Further included are partially matured neutrophils wherein the nucleus is in a horseshoe like shape referred to in the literature as "band” or "stab” neutrophils.
  • Bridge refers to an acute or brief period during which granulopoiesis induction resulting in a subject animal expressing at least about a 50% increase in mature granulocyte cell types, particularly neutrophils, as compared to an untreated animal of generally like condition, will present a significant clinical benefit. Such periods are of at least about 10 to 15 days, preferable at least about 20 days, and most preferably, at least about 28 days are contemplated in such bridge.
  • a bridge would be beneficial in bone marrow transplant patients during the immediate post-transplant phase, or those subjects temporarily anemic from radiation exposure or antineoplastic chemotherapy.
  • this invention is useful in causing dramatic elevations in the number of circulating neutrophils, eosinophils, and monocytes. In particular embodiments, changes are rapidly observable, often in about 6 hours. In particular embodiments, neutrophil mobility increases are considered. In certain embodiments, this invention is useful in the acute treatment of neutropenia, aplastic anemia, myelodysplasia, AIDS. A specific embodiment involves the prevention, blunting or amelioration of neutropenia associated with chemotherapy and autologous bone marrow transplantation.
  • Dosage determinations will vary from subject to subject based on the dosage, subject, and presenting condition. However, a proper dosage is easily determined by conventional methods. Dosages may be "titrated" as to each subject by monitoring desired increase in a particular cell type. Beginning with a relatively low dosage of about 1 mg/kg and increasing the dosage until a response is observed, but below the maximum tolerated dosage. Alternatively, based upon a population of subjects, normative dosages are obtained.
  • All-trans retinoic acid may be encapsulated into liposomes by any of a number of means.
  • Unit dosage form for in vivo/in situ use is conveniently in liposomal form containing from about 50 to about 350 mg of all trans retinoic acid, and preferably about 25 to 200 mg, and more preferably about 75 to 150 mg.
  • particular unit dosages are suspended in a suitable pharmaceutical carrier.
  • the compositions of this invention possess valuable pharmacological properties. They potentiate the production of and differentiate into granulocytic cells and increase the immune response status of an organism, a cell population, and particularly in that of immunocompromised subjects. This therapeutic effect is particularly useful in cell populations or subjects with challenged or debilitated immune systems such as H.LV. infected cells, post-cancer chemotherapy or radiation exposed subjects. This effect can be demonstrated, for example, by administering increasing dosages of the composition to a subject, and, thereafter, performing blood cell type differential counts. Low toxicity dosages that prompt the stated maturation- inducing at least about 50% increase in target cell type are thus determined.
  • all-trans retinoic acid levels in granulopoietic tissue such as is located in bone marrow, are maintained at maturation-inducing levels of from about 0.05 to about 20 ng/mg marrow.
  • the liposomes after intravenous introduction of liposomal all-trans retinoic acid, the liposomes will be removed from circulation and the systemic or blood levels of all-trans retinoic acid, at least about 2 to three hours post-administration, will be, cumulatively, less than about 20% and preferably less than about 5% of the introduced dosage.
  • compositions can be used extra corporeally to treat granulopoietic tissues or cells such as bone marrow or umbilical/placental cells. Such treatment is preferably prior to introduction of the treated cells into a subject in need of such treatment.
  • Both diagnostic and screening uses include exposing a sample of granulopoietic tissue to all-trans retinoic acid and thereafter determining the maturation fate of such cells as compared with similar cells unexposed to all-trans retinoic acid. Tests either screen for or identify subjects with conditions likely to benefit from the described treatment. Furthermore, cell culture techniques are used as an empirical dosage determiner. Cultured granulopoietic cells are exposed to all-trans retinoic acid, and, thereafter, classified as to the maturation/fate of such cells as compared with similar cells unexposed to all-trans retinoic acid in a traditional assay. Assays include a checker board assay or the like.
  • marrow from an anemic subject may be plated and then challenged with all-trans retinoic acid.
  • One such technique is set forth in Welte et al., Proc. Natl. Acad. Sci., 82:1526-1530 (1985).
  • a positive response (often in as little as 6 hours), that is at least about a 50% increase in neutrophil population, indicates a condition which will benefit from this therapy.
  • the described composition can be employed in admixture with carriers, lipids, liposomes, micelles, or pharmaceutically acceptable diluents and excipients.
  • compositions of this invention are generally administered to cells and animal subjects, including, but not limited to, animal cells and animals including mammals and particularly humans.
  • the pharmacologically active compositions of this invention can be processed in accordance with conventional methods of Galenic pharmacy to produce medicinal agents for administration to cells and patients, e.g. , mammals including humans.
  • compositions of this invention can be employed in admixture with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral or topical use (in the case of extra corporeal or in vitro uses) which do not deleteriously react with the active compositions.
  • suitable pharmaceutically acceptable carriers include but are not limited to water and salt solutions, particularly isotonic solutions.
  • the pharmaceutical preparations can be sterilized and if desired mixed with auxiliary agents, e.g., preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, and the like which do not deleteriously react with the active compositions. They can also be combined where desired with other active agents, e.g., vitamins.
  • injectable, sterile solutions preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants, including suppositories.
  • Ampoules are convenient unit dosages.
  • Directed release compositions can be formulated, e.g., liposomes or those wherein the active component is protected with differentially degradable coatings, e.g., by microencapsulation, multiple coatings, etc. It is also possible to freeze- dry the new compositions and use the lyophilizates obtained, for example, for the preparation of products for injection.
  • compositions of this invention are dispensed in unit dosage form comprising 25 to 200 mg in a pharmaceutically acceptable carrier per unit dosage.
  • the dosage of the compositions according to this invention generally are 1 to 50 mg/kg/day, preferably 2 to 10 mg/kg/day, and preferably in liposomal form when administered to subjects, e.g., humans to augment the immune response, analogously (as to response) to the known agents G-CFS and GM-CSF.
  • compositions in a specific case will vary according to the specific compositions being utilized, the particular compositions formulated, the mode of application, and the particular situs and organism being treated. Dosages for a given host can be determined using conventional considerations, e.g., by customary comparison of the differential activities of the subject compositions and of a known agent, e.g., by means of an appropriate, conventional pharmacological protocol.
  • CD-I mice were administered either saline or liposomal all-trans retinoic acid (Tretinoin LF I.V., Argus Pharmaceuticals, Houston, Texas), I.V. daily for five consecutive days at a dose level of 50 mg tretinoin per kg body weight or 100 mg/kg. Blood was drawn for analysis twenty-four hours after the final injection (day 6) and again on the seventh day after the last injection (day 12).
  • All-trans retinoic acid (Tretinoin LF I.V., Argus Pharmaceuticals, Houston, Texas), lot BVL 595-08-0002, was administered by intravenous infusion once daily, 7 days per week, over a period of 28 consecutive days to three groups of twenty rats (ten/sex) at dose levels of 2.5 (low), 15.0 (mid) and 25.0 (high) mg/kg/day at a rate of 1 cc/min (2.0 mg/min). An additional group of twenty rats (ten/sex) was dosed with sterile 0.9% Sodium Chloride for Injection and served as the vehicle control group.
  • the purpose of this study was to determine the effect of liposomal all-trans retinoic acid (Tretinoin LF , I.V., Argus Pharmaceuticals, Houston, Texas) to be administered to dogs in a 28-day intravenous toxicity study.
  • Statistical results are set forth in Table 4.
  • the methods for this study were as follows: Four dogs (2 males and 2 females) were administered intravenous doses of Tretinoin LF , I.V. (Lot #R1238R1) twice weekly, ranging from 1 mg/kg to 16 mg/kg over a period of twenty-four days. The infusion rate was constant at 2 mg/minute except on two days when the rate was increased to 4 mg/minute. Body weights and food consumption were recorded daily.
  • Dose volumes were adjusted according to individual animal body weights. Animals were observed daily for clinical signs of systemic toxicity. Blood was collected for baseline, and terminal clinical chemistry and hematology evaluations. Blood was also collected for hematology evaluations six hours after each dose administration. On the final day of this study all animals were euthanized and a gross necropsy was performed. Histological evaluations were performed on gross lesions.
  • Fig. 1 graph shows the polymononuclear (PMN) cell numbers observed during the study in dogs.
  • PMN polymononuclear
  • Fig. 1 shows a fall off on the second dose at 16 mg/kg. This suggests that the myeloid tissues are depleted of the precursor cells by the previous treatments, and thus a neutropenia eventually takes place due to the absence of stem cells.

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Abstract

L'invention se rapporte à un procédé à faible toxicité systémique, servant à potentialiser la granulopoïèse. L'invention se réfère particulièrement à des granulocytes et aux types de cellules mûres de granulopoïèse, en d'autres termes des granulocytes neutrophiles, éosinophiles, basophiles ainsi que des monocytes. Selon le présent procédé, la granulopoïèse est effectuée par exposition aigüe de cellules granulopoïétiques à des niveaux d'acide rétinoïque tout-trans induisant la maturation, tandis que, dans des applications in vivo ou in situ, les tissus non hémopoïétiques sont maintenus à des niveaux égaux ou inférieurs au niveau de dosage dépourvu d'effets pour l'acide rétinoïque tout-trans. Des procédés in vivo, in vitro, in situ et extra-corporels sont décrits, ainsi que l'entretien du système immunitaire aigu de sujets nécessitant un tel traitement, tels que des sujets dont le système immunitaire est compromis.
PCT/US1993/012127 1992-12-15 1993-12-13 Nouveau facteur de croissance de cellules precurseurs granulocytiques et procede associe WO1994013786A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU58008/94A AU5800894A (en) 1992-12-15 1993-12-13 Novel granulocytic precursor cell growth factor and method

Applications Claiming Priority (2)

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US99071292A 1992-12-15 1992-12-15
US07/990,712 1992-12-15

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WO1994013786A1 true WO1994013786A1 (fr) 1994-06-23

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7803622B2 (en) 1998-05-20 2010-09-28 University Of Iowa Research Foundation Adeno-associated virus vectors

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989006977A1 (fr) * 1988-02-04 1989-08-10 Board Of Regents, The University Of Texas System Formulation et utilisation de retinoides dans le traitement du cancer et d'autres maladies

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989006977A1 (fr) * 1988-02-04 1989-08-10 Board Of Regents, The University Of Texas System Formulation et utilisation de retinoides dans le traitement du cancer et d'autres maladies

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
CANCER RESEARCH, Vol. 42, issued October 1982, OLSSON et al., "Induction of Differentiation of the Human Histiocytic Lymphoma Cell Line U-937 by Retinioc Acid and Cyclic Adenosine 3':5'-Monophosphate-Inducing Agents", pages 3924-3927. *
CANCER RESEARCH, Volume 46, issued March 1986, MEHTA et al., "Expression of Tissue Transglutaminase in Cultured Monocytiv Leukemia (THP-1) Cells During Differentiation", pages 1388-1394. *
J. EXP. MED., Volume 163, issued May 1986, MURTAUGH et al., "Retnoic Acid-Induced Gene Expression in Normal and Leukemic Myeloid Cells", pages 1325-1330. *
JOURNAL OF LEUKOCYTE BIOLOGY, Vol. 41, issued 1987, MEHTA et al., "Induction of Tissue Transglutaminase in Human Peripheral Blood Monocytes by Intracellular Delivery of Retinoids", pages 341-348. *
THE RETNOIDS, Vol. 2, issued 1984, ROBERTS et al., "Cellular Biology and Biochemistry of the Retnoids", pages 209-286. *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7803622B2 (en) 1998-05-20 2010-09-28 University Of Iowa Research Foundation Adeno-associated virus vectors

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