EP0058192A1 - Administration de composants biologiquement actifs d'isolats d'interferons d'especes heterologues - Google Patents

Administration de composants biologiquement actifs d'isolats d'interferons d'especes heterologues

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Publication number
EP0058192A1
EP0058192A1 EP81902402A EP81902402A EP0058192A1 EP 0058192 A1 EP0058192 A1 EP 0058192A1 EP 81902402 A EP81902402 A EP 81902402A EP 81902402 A EP81902402 A EP 81902402A EP 0058192 A1 EP0058192 A1 EP 0058192A1
Authority
EP
European Patent Office
Prior art keywords
interferon
species
cells
isolated
bovine
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP81902402A
Other languages
German (de)
English (en)
Inventor
Joseph M. Cummins, Jr.
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Illinois
University of Illinois Foundation
Original Assignee
University of Illinois
University of Illinois Foundation
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 University of Illinois, University of Illinois Foundation filed Critical University of Illinois
Publication of EP0058192A1 publication Critical patent/EP0058192A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K38/21—Interferons [IFN]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/555—Interferons [IFN]
    • C07K14/565—IFN-beta
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates generally to therapeutic uses of interferon and more specifically to treatment of mammals, including humans, with isolates of interferon glycoprotein derived from cells of heterologous mammalian species origin.
  • Interferon is a term generically comprehending a group of vertebrate glycoproteins which are known to exert broad spectrum biological activity - including antiviral, antiproliferative and immuno modulatory activities -- in the species of animal from which the substances are derived.
  • interferon production Although originally isolated from cells of avian origin (chick allantoic cells), interferon production has been observed in cells of all classses of vertebrates, including mammals, amphibians, reptiles, etc. Interferon production by vertebrate cells is seldom spontaneous but is often readily "induced” by treatment of cells (in vivo or in vitro) with a variety of substances including viruses, nucleic acids (including those of viral origin as well as synthetic polynucleotides), Hpopolysaccharides and various antigens and mitogens.
  • viruses including viruses, nucleic acids (including those of viral origin as well as synthetic polynucleotides), Hpopolysaccharides and various antigens and mitogens.
  • Interferon is generally named in terms of correlation to the species of an imal cells producing the substance (e.g., human, murine, bovine, etc.) as well as to the type of cell involved (e.g., leukocyte, lymphoblastoid, fibroblast) and, occassionally, the type of inducer material responsible for interferon production (e.g., virus, immune).
  • an imal cells producing the substance e.g., human, murine, bovine, etc.
  • type of cell involved e.g., leukocyte, lymphoblastoid, fibroblast
  • inducer material responsible for interferon production e.g., virus, immune
  • interferon is loosely classified by some researchers according to induction mode as either Type I or Type II, with the former classification comprehending viral and nucleic acid induced interferon and the latter class including the material produced as a lymphokine through induction by antigens and mitogens.
  • Various forms of interferon are distinguished by size, antigenic
  • interferon was employed exdu sively as an antiviral agent and the most successful clinical therapeutic applications to date have been in the treatment of viral or virus-related disease states. It became apparent, however, that exogenous interferon was sometimes capable of effecting regression or remission of various metastatic diseases.
  • a summary of clinical trials of interferon as an antiviral and antiproliferative therapeutic agent through late 1978 is contained in Dunnick, et al. supra.
  • Interferon is administered parenterally, i.e., intramuscularly and intradermally, with some successul topical usages having been reported. It is seldom administered intravenously owing to substantial adverse effects attributable to "contaminants" in crude and even highly purified isolates. Parenthetically, while providing interferon dosages in the range of 1 to 5 x 10 6 IU, interferon isolates employed in clinical studies actually contain less than about 0.1 percent interferon glycoprotein -- the balance of the preparations comprising extraneous materials such as cellular debris, viral fragments and the like. To date, there have been no reports of therapeutically successful oral administration of interferon.
  • glycoprotein will not withstand exposure to a digestive environment, such as found in mammalian therapy candidates. It is simply not expected that the biological activity of the glycoprotein could be retained after the molecules are subjected to the degradative effects of carbohydrases (e.g., amylase in saliva), or simple esterases, or the proteolytic hydrolytic enzymes in gastrointestinal secretions (e.g., trypsin, pepsin, chymotrypsin, carboxy peptidases A and B) and in cells of the intestinal mucosa (e.g. the aminopeptidases).
  • carbohydrases e.g., amylase in saliva
  • simple esterases e.g., the proteolytic hydrolytic enzymes in gastrointestinal secretions (e.g., trypsin, pepsin, chymotrypsin, carboxy peptidases A and B) and in cells of the intestinal mucosa (e.g. the aminopeptidases).
  • interferon In addition to use in antiviral and antitumor therapy, interferon has rather recently been noted to possess immunomodulatory effects, both immunopotentiating and immunosuppressive in nature. See, e.g., Sonnenfeld, et al., "A Regulatory Role For Interferon In Immunity", Annals, N.Y. Acad. Sci., Vol. 322, pp. 345-355 (1979). While no human clinical or in vivo animal work specifically directed to evaluation of immunological effects of interferon has been reported, it is proposed by some that the antitumor effects of interferon are at least in part related to immune stimulation or activation of so-called “natural killer cells," macrophages and T-lymphocytes. See, e.g., Kershner, "New Directions in Cancer Chemotherapy” A.S.M.News, Vol. 46, No. 3, pp. 102 et sec. (1980).
  • Carter has exhaustively reviewed the art teachings with respect to in vitro activities of interferon in protecting cells of heterologous species from infection by virus and proposes an integrative model wherein the ability of interferon glycoprotein to cross or not cross species lines lies in the carbohydrate moiety and the cross-species biological activity is the function of the polypeptide portion. See also, Braude, et al., "Differential Inactivation and Separation of Homologous and Heterologous Antiviral Activity of Human Leukocyte Interferon By A Proteolytic Enzyme", Biochem. Biophys. Res.
  • interferon glycoprotein is presently recog-nized in the art as possessing enormous therapeutic potentiaL Interferon is as yet incompletely characterized as to biologically active components and precise mode of action. Species specificity characteristics impose severe limits on the range of its therapeutic utilities and concurrently severely restrict availability of interferon for clinical application.
  • mammals including humans, are treated with therapuetically effective amounts of interferon glycoprotein isolated from cells of heterologous mammalian species origin. More specifically, antiviral, antiproliferative and/or immunomodulatory effects heretofore ordinarily obtained only upon parenteral administration of isolates of homologous species interferon are obtainable through administration of more readily available isolates of interferon glycoprotein having heterologous mammalian species origins.
  • Heterologous species interferon preparations are first subjected to a digestive environment wherein non-species-specific biologically active fractions thereof are substantially freed from extraneous polypeptides and/or carbohydrates with which the biologically active fractions are ordinarily associated.
  • the active components are administered to the circulatory system of the recipient animal, preferably through digestive tract tissue.
  • heterologous species interferon is administered to the alimentary canal of the recipient mammal, whereby the digestive materials in the canal operate on the isolate.
  • extraneous carbohydrate and/or polypeptide materials which are not essential to the activity of biologically active fractions of interferon (but which are normally associated therewith when isolated) are degraded without detectable inactivation of the biologically active fractions.
  • active fractions are thereafter absorbed through digestive tract tissues and enter the circulatory system of the recipient.
  • the heterologous species interferon isolate may be treated in vitro under conditions substantially duplicating the digestive environment of the recipient mammal and thereafter administered to the mammal, either orally or, after suitable isolative procedures, parenterally.
  • Mammals treatable according to the invention and suitable as cell sources for interferon production include those of the human, feline, bovine, equine, laprine and porcine species.
  • the preferred types of interferon for use in the invention include fibroblast interferon as well as immune type interferon.
  • Presently preferred practices of the invention include oral administration of bovine fibroblast and/or immune type interferon to human patients suffering from neoplatsic and/or viral diseases, including, e.g., malignant melanomas and benign papillomas of probable viral origin.
  • interferon and interferon glycoprotein shall be synonymous and shall have the meaning ordinarily attributed thereto in the art, including, but not limited to the meaning ascribed thereto in U.S. Patent No. 3,699,222.
  • isolated from cells of heterologous mammalian species origin shall designate derivation not only from in vitro mammalian cell growth media and in vivo mammalian cellular exudates or secretions, but also from other suitable cellular sources.
  • the term is intended to designate interferon such as may be obtained as an in vitro isolate from media supporting growth of non-mammalian cells which have been the object of genetic transformation involving mammalian DNA.
  • isolatedate shall comprehend preparationsresulting from attempted purification of interferon present in cell growth media, cell exudates and cell secretions, with no specific limitation as to precise concentration of interferon.
  • “Digestive environment” shall mean and include conditions substantially duplicating those commonly present within the digestive tract of a recipient mammal, including, but not limited to, pH and temperature conditions and the presence of one or more hydrolytic, phosphorylytic, oxidation-reduction, transferring, decarboxylating, hydrating or isomerizing enzymes.
  • alimentary canal and “digestive tract” shall be essentially synonymous and shall mean and include that anatomical portion of a mammal, e.g., the mouth, pharynx, stomach, duodenum, jejunum, ileum and large intestine in humans, wherein digestive processes occur.
  • Parenteral administration shall mean and include administration to a mammal by means other than introduction into the alimentary canal.
  • Circulatory system shall mean and include the hematic and/or lymphatic system of a mammal.
  • Bovine fibroblast interferon was prepared as follows:
  • BFK Primary bovine fetal kidney
  • BT bovine testicular
  • the supernatant fluids were dialyzed for 24 hours in a K Cl-HCl buffer (pH 2.0) and 24 hours in a phosphate buffered saline (pH 7.4) before ultracentrifugation at 100,000 X g for 60 minutes.
  • the interferon activity (expressed as "units” as opposed to IU) was assayed by a plaque reduction method using vesicular stomatitis virus (VSV) as a challenge virus on BFK cells [Rosenquist and Loan, "Interferon Production With Strain SF-4 of Parainfluenza-3 Virus" Am. J. Vet. Res., 28, pp. 619-628 (1967)] .
  • VSV vesicular stomatitis virus
  • Bovine nasal secretion interferon was prepared as f ollows:
  • Example 3 This example illustrates therapeutic effectiveness of orally administered heterologous species interferon in treatment of benign papillomas of probable viral origin in human patients.
  • Example 2 Approximately 12 weeks after commencement of treatment, a single oral dose of 5250 units of interferon of Example 2 was given, followed one week later with 21,000 units of Example 1 interferon, orally administered in ten, twice-daily doses. Within three weeks thereafter, the plantar warts were somewhat painful upon application of pressure and "drier" as well as further reduced in size. No more interferon was given and no further improvements in the warts were noted.
  • the xanthalasma which had been unchanged for two years, flattened and was reduced in size within a week after the first dose of interferon.
  • the xanthalasma reappeared but partially regressed again after the second dose of interferon.
  • the xanthalasma reappeared and has remained essentially unchanged since administration of the third dose.
  • C A male patient with a plantar wart was given a single, 8600 units, oral dose of Example 2 interferon. Within three weeks, there appeared to be a n increase in blood supply to the wart and a size reduction of about one-half. No further treatments were given nor were further improvements noted.
  • This Example relates to the therapeutic effectiveness of orally administered heterologous species interferon in treatment of malignant melanoma in human patients.
  • Example 5 This Example relates to oral administration of bovine interferon to a human patient terminally ill with metastatic breast cancer. A total of 8400 units of interferon of Example 1 was administered in 21 equal doses BID. The patient suffering from metastases to the brain and bone, expired two weeks after treatment was commenced.
  • This example relates to the therapeutic effectiveness of orally administerd heterologous species interferon in the treatment of feline leukemia.
  • a kitten showing clinical signs of chronic oral ulcers, non-regenerative anemia, enlarged lymph nodes, lymphocytosis, and a positive feline leukemia virus test (Leukassay from Pitman-Moore) was treated with 1.7 X 10 6 units of bovine fibroblast interferon (per Example 1) orally.
  • the oral ulcers have healed, the anemia has resolved, the lymph nodes appear normal, and the amount of feline leukemia viral antigen in the blood had declined (as measured by performing the Leukassay on serial dilutions of blood).
  • the lymphocytosis has, however, continued.
  • a third cat with a leukocytosis, and anemia, severe depression, and positive for feline leukemia virus (Leukassay) was treated for five days with a total of 5 x 10 5 units of bovine interferon of Example 1. Prednisolone was also administered. Within ten days after treatment the cat appeared clinically normal, the white blood cell count returned to normal and the hematocrit improved from 12 to 18.
  • Example 7 Three hamsters, four guinea pigs, and eight mice have been treated orally with varying amounts of bovine interferon of Example 1. No clinical illness occurred during treatment, no weight loss was noted, and no signs of toxicity attributable to interferon were seen histopatho logiclily after one week's therapy. Total dosages have ranged up to 400,000 units of interferon per kg of body weight.
  • bovine interferon While the foregoing illustrative examples describe use of bovine interferon, and while bovine interferon is preferred on grounds of its easy availability in relatively large quantity, it will be recognized that mammals may be effectively treated with heterologous species interferon of procine, equine, laprine, feline and human sources. Cross species in vitro antiviral activity of varying degree is described for the bovine, porcine, equine, laprine, feline and human species. [See Tovey et al., J. Gen. Virol. 36, pp. 341-344 (1977); Carter, Life Sciences 25, pp. 717-728 (1979); Babiuk and House, Intervirology, 8, pp.
  • phosphate buffered saline or Eagles' Minimal Essential Medium was used as a carrier for interferon in the above Examples, other pharmaceutically acceptable diluents adjuvants and carriers such as are commonly employed in oral and parenteral therapy may be employed.
  • Dosage required for therapeutic effect are expected to vary widely depending on the mammal patient and condition treated, with from about 10 to about 1,000 units per kg in unit dosage form is believed operative.
  • a specific heterologous species interferon isolate may be efficaciously pretreated under digestive conditions and administered to the recipient animal's circulatory system.
  • Such practice involves "pre-digesting" the isolate in vitro in a suitable digestive environment comprising, e.g., a strongly acidic solution of pepsin and/or solutions or suspensions of the various enzymatic substances operative in digestive processes. If the digestive environment substantially duplicates that of a proposed recipient animal, the entire combination of reagents, reactants, and products may be administered to the alimentary canal of the recipient to effect delivery of the biologically active component of the isolate to the circulatory system.
  • the resultant "digested" isolate containing the active fracion may be reclaimed, i.e., separated as smaller molecular weight components from the digestive environment (e.g. by dialysis, centrifuga tion and chromatography), and administered orally or parenterally.
  • the active component will be suitably rapidly incorporated into the recipient animal's circulatory system in a manner essentially eliminating the risks of adverse reaction which ordinarily accompany the administration of "foreign, " undergraded polypeptides.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Toxicology (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Immunology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Des substances isolees de glycoproteines d'interferons d'origine d'especes heterologues sont soumises a un traitement dans un milieu digestif et leurs fractions biologiquement actives de non specificite d'especes sont administrees, de preference par les tissus de la voie digestive, vers le systeme circulatoire des mammiferes, y compris des etres humains, pour produire des effets anti-viraux, d'anti-proliferation, (p.ex. antineoplastiques) et immunomodulateurs (p.ex. d'immuno potentialisation) communement associes uniquement avec l'administration parenterale d'interferons d'especes homologues.
EP81902402A 1980-08-22 1981-08-18 Administration de composants biologiquement actifs d'isolats d'interferons d'especes heterologues Withdrawn EP0058192A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US18046480A 1980-08-22 1980-08-22
US180464 1980-08-22

Publications (1)

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EP0058192A1 true EP0058192A1 (fr) 1982-08-25

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EP (1) EP0058192A1 (fr)
JP (1) JPS57501236A (fr)
KR (1) KR830005872A (fr)
WO (1) WO1982000588A1 (fr)

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5827694A (en) * 1982-03-08 1998-10-27 Genentech, Inc. DNA encoding non-human animal interferons, vectors and hosts therefor, and recombinant production of IFN polypeptides
US5831023A (en) * 1982-11-01 1998-11-03 Genentech, Inc. Recombinant animal interferon polypeptides
US4820515A (en) * 1982-12-13 1989-04-11 Texas A&M University System Method of using interferon in low dosage to regulate appetite and efficiency of food utilization
US4497795A (en) * 1982-12-13 1985-02-05 The Texas A&M University System Method of regulating appetite and efficiency of food utilization employing interferon
US4820514A (en) * 1985-12-30 1989-04-11 Texas A&M University System Low dosage of interferon to enhance vaccine efficiency
CA1320905C (fr) * 1986-11-06 1993-08-03 Joseph M. Cummins Traitement d'affections immuno-resistantes
ZA878295B (en) * 1986-11-06 1988-05-03 Amarillo Cell Culture Co. Inc. Treatment of immuno-resistant disease
US5017371A (en) * 1988-01-06 1991-05-21 Amarillo Cell Culture Company, Incorporated Method for reducing side effects of cancer therapy
WO1990007618A1 (fr) * 1988-12-28 1990-07-12 Toshiro Suzuki Materiau de construction en beton
AUPN976596A0 (en) * 1996-05-09 1996-05-30 Pharma Pacific Pty Ltd Stimulation of host defence mechanisms
US6207145B1 (en) 1997-05-09 2001-03-27 Pharma Pacific Pty Ltd. Therapeutic applications of high dose interferon
CN1151840C (zh) * 1996-05-09 2004-06-02 太平洋制药控股公司 干扰素在制备用于治疗哺乳动物肿瘤病的药剂中的应用
AU724689B2 (en) 1996-05-09 2000-09-28 Pharma Pacific Pty Ltd Method of treatment
US6660258B1 (en) 1997-05-09 2003-12-09 Pharma Pacific Pty Ltd Oromucosal cytokine compositions and uses thereof

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK485977A (da) * 1977-11-01 1979-05-02 Ess Foodeksport Fremgangsmaade til udvinding af et biologisk aktivt materiale fra svineblodfraktioner
JPS5562024A (en) * 1978-10-31 1980-05-10 Hayashibara Takeshi Preventive and remedy for interferon-sensitive disease
ZA796175B (en) * 1978-11-24 1980-11-26 Hoffmann La Roche Purified proteins and process therefor

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8200588A1 *

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Publication number Publication date
WO1982000588A1 (fr) 1982-03-04
KR830005872A (ko) 1983-09-14
JPS57501236A (fr) 1982-07-15

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